Spinal Oncology - Moffitt Cancer Center

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Ac C PI OU O N R su ce U IO r v ss ey o N N @ ur TS M re of ad ! fit e t.o rs rg hi /c p cj MOFFITT.org/ccj

Vol. 21, No. 2, April 2014

H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE, AN NCI COMPREHENSIVE CANCER CENTER

Primary Spine Tumors: Diagnosis and Treatment

Michelle J. Clarke, MD, Ehud Mendel, MD, and Frank D. Vrionis, MD, PhD

Spinal Tumor Surgery: Management and the Avoidance of Complications Michelle J. Clarke, MD, and Frank D. Vrionis, MD, PhD

Surgical Management of Primary and Metastatic Spinal Tumors Paul E. Kaloostian, MD, Patricia L. Zadnik, BA, Arnold B. Etame, MD, PhD, et al.

Palliative Strategies for the Management of Primary and Metastatic Spinal Tumors Paul E. Kaloostian, MD, Alp Yurter, BS, Arnold Etame, MD, PhD, et al.

Spinal Neoplastic Instability: Biomechanics and Current Management Options Andreas K. Filis, MD, Kamran V. Aghayev, MD, James J. Doulgeris, MSME, et al.

Controversial Issues in Kyphoplasty and Vertebroplasty in Malignant Vertebral Fractures Ioannis D. Papanastassiou, MD, Andreas K. Filis, MD, Maria A. Gerochristou, MD, et al.

Management of Locally Advanced Pancoast (Superior Sulcus) Tumors With Spine Involvement

Matthias Setzer, MD, Larry E. Robinson, MD, and Frank D. Vrionis, MD, PhD

Separation Surgery for Spinal Metastases: Effect of Spinal Radiosurgery on Surgical Treatment Goals Nelson Moussazadeh, MD, Ilya Laufer, MD, Yoshiya Yamada, MD, and Mark H. Bilsky, MD

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SAVE THE DATE June 13–15, 2014 Cheeca Lodge & Spa | Islamorada, Florida MOFFITT.org/MOC2014 COURSE DIRECTORS G. Douglas Letson, MD

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COURSE DESCRIPTION This course is designed to show the correlation between clinical, radiographic, and pathologic data. The course will present the medical and surgical management of musculoskeletal disease and will feature didactic sessions and interactive case presentations. The topics will include clinical staging, clinicoradiological interpretation, pathology, and treatment. A concentrated focus will be placed on various types of tumors, such as bone, osseous, cartilaginous, lipomatous, muscular, and neurogenic.

TARGET AUDIENCE The intended audience includes orthopaedic residents, orthopaedic surgeons, pathologists, radiologists, physician assistants, and nurse practitioners, who may diagnose and treat musculoskeletal abnormalities and tumors.

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Editorial Board Members Editor: Lodovico Balducci, MD Senior Member Program Leader, Senior Adult Oncology Program Moffitt Cancer Center

Deputy Editor: Julio M. Pow-Sang, MD Senior Member Chair, Department of Genitourinary Oncology Director of Moffitt Robotics Program Moffitt Cancer Center

Editor Emeritus: John Horton, MB, ChB Professor Emeritus of Medicine & Oncology

Moffitt Cancer Center Journal Advisory Committee: Aliyah Baluch, MD Assistant Member Infectious Diseases Matthew C. Biagioli, MD Assistant Member Radiation Oncology Dung-Tsa Chen, PhD Associate Member Biostatistics

Bela Kis, MD, PhD Assistant Member Diagnostic Radiology Rami Komrokji, MD Associate Member Malignant Hematology Conor C. Lynch, PhD Assistant Member Tumor Biology Amit Mahipal, MD, MPH Assistant Member Clinical Research Unit Gastrointestinal Oncology Kristen J. Otto, MD Assistant Member Head & Neck Oncology Michael A. Poch, MD Assistant Member Genitourinary Oncology Jeffery S. Russell, MD, PhD Assistant Member Endocrine Tumor Oncology Elizabeth M. Sagatys, MD Assistant Member Pathology - Clinical Jose E. Sarria, MD Assistant Member Anesthesiology Saïd M. Sebti, PhD Senior Member Drug Discovery

Hey Sook Chon, MD Assistant Member Gynecological Oncology

Bijal D. Shah, MD Assistant Member Malignant Hematology

Jasreman Dhillon, MD Assistant Member Pathology - Anatomic

Lubomir Sokol, MD, PhD Associate Member Hematology/Oncology

Jennifer S. Drukteinis, MD Associate Member Diagnostic Radiology

Hatem H. Soliman, MD Assistant Member Breast Oncology

Timothy J. George, PharmD Pharmacy Residency Director Clinical Pharmacist - Malignant Hematology

Jonathan R. Strosberg, MD Assistant Member Gastrointestinal Oncology

Clement K. Gwede, PhD Associate Member Health Outcomes & Behavior

Sarah W. Thirlwell, RN Nurse Director Supportive Care Medicine Program

Sarah E. Hoffe, MD Associate Member Radiation Oncology

Eric M. Toloza, MD, PhD Assistant Member Thoracic Oncology

John V. Kiluk, MD Associate Member Breast Oncology

Nam D. Tran, MD Assistant Member Neuro-Oncology

Richard D. Kim, MD Assistant Member Gastrointestinal Oncology

Jonathan S. Zager, MD Associate Member Sarcoma and Cutaneous Oncology

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CANCER CONTROL: JOURNAL OF THE MOFFITT CANCER CENTER (ISSN 1073-2748) is published by H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Telephone: 813-745-1348. Fax: 813-449-8680. E-mail: [email protected]. Internet address: MOFFITT.org/ccj. Cancer Control is included in Index Medicus ®/MEDLINE ® and EMBASE ®/ Excerpta Medica, Thomson Reuters Science Citation Index Expanded (SciSearch®) and Journal Citation Reports/Science Edition. Send subscription requests to the publisher. Single copy: $10 US, $15 Canada and foreign. Subscription rates: nonqualified individuals $60 per year US, $75 per year outside US, institutions/libraries $120 per year US ($135 per year foreign). Send change of address to the publisher with old address label and new address. Publisher is not responsible for undelivered copies. Copyright 2014 by H. Lee Moffitt Cancer Center & Research Institute. All rights reserved. Printed on acid-free paper. Cancer Control: Journal of the Moffitt Cancer Center is a peer-reviewed journal that is published to enhance the knowledge needed by professionals in oncology to help them minimize the impact of human malignancy. Each issue emphasizes a specific theme relating to the detection or management of cancer. The objectives of Cancer Control are to define the current state of cancer care, to integrate recently generated information with historical practice patterns, and to enlighten readers through critical reviews, commentaries, and analyses of recent research studies. DISCLAIMER: All articles published in this journal, including editorials and letters, represent the opinions of the author(s) and do not necessarily reflect the opinions of the editorial board, the H. Lee Moffitt Cancer Center & Research Institute, Inc, or the institutions with which the authors are affiliated unless clearly specified. The reader is advised to independently verify the effectiveness of all methods of treatment and the accuracy of all drug names, dosages, and schedules. Dosages and methods of administration of pharmaceutical products may not be those listed in the package insert and solely reflect the experience of the author(s) and/or clinical investigator(s).

April 2014, Vol. 21, No. 2

Cancer Control 107

Table of Contents Editorial Spinal Oncology: An Innovative Field of Its Own?

110

Frank D. Vrionis, MD, PhD

Articles Primary Spine Tumors: Diagnosis and Treatment

114

Michelle J. Clarke, MD, Ehud Mendel, MD, and Frank D. Vrionis, MD, PhD

Spinal Tumor Surgery: Management and the Avoidance of Complications

124

Michelle J. Clarke, MD, and Frank D. Vrionis, MD, PhD

Surgical Management of Primary and Metastatic Spinal Tumors

133

Paul E. Kaloostian, MD, Patricia L. Zadnik, BA, Arnold B. Etame, MD, PhD, Frank D. Vrionis MD, PhD, Ziya L. Gokaslan, MD, and Daniel M. Sciubba, MD

Palliative Strategies for the Management of Primary and Metastatic Spinal Tumors

140

Paul E. Kaloostian, MD, Alp Yurter, BS, Arnold Etame, MD, PhD, Frank D. Vrionis, MD, PhD, Daniel M. Sciubba, MD, and Ziya L. Gokaslan, MD

Spinal Neoplastic Instability: Biomechanics and Current Management Options

144

Andreas K. Filis, MD, Kamran V. Aghayev, MD, James J. Doulgeris, MSME, Sabrina A. Gonzalez-Blohm, MSBE, and Frank D. Vrionis, MD, PhD

108 Cancer Control

April 2014, Vol. 21, No. 2

Table of Contents Controversial Issues in Kyphoplasty and Vertebroplasty in Malignant Vertebral Fractures

151

Ioannis D. Papanastassiou, MD, Andreas K. Filis, MD, Maria A. Gerochristou, MD, and Frank D. Vrionis, MD, PhD

Management of Locally Advanced Pancoast (Superior Sulcus) Tumors With Spine Involvement

158

Matthias Setzer, MD, Larry E. Robinson, MD, and Frank D. Vrionis, MD, PhD

Separation Surgery for Spinal Metastases: Effect of Spinal Radiosurgery on Surgical Treatment Goals

168

Nelson Moussazadeh, MD, Ilya Laufer, MD, Yoshiya Yamada, MD, and Mark H. Bilsky, MD

Department Ten Best Readings Relating to Spinal Oncology

175

Perspective Controversy Surrounding Mammography Screening? Not in Our Opinion.

176

Jennifer S. Drukteinis, MD, and John V. Kiluk, MD

About the art in this issue: Born 1962 in England to American parents, Burnell Shively began her career in Como, Italy, as a textile designer and continued freelance for 20 years around the globe. During her travels to 43 countries and 5 continents, she has been a fashion stylist in Biot, France, and Bali, Indonesia, an exhibiting fine artist and scenic artist in Hong Kong, an illustrator for World Wildlife magazine, lecturer for the Hong Kong Academy for Performing Arts, the founder of an American university–accredited summer art program in northern Italy, and the creator of a sister cityship between Feltre, Italy, and Golden, Colorado. Supported by the Slovenian government and UNESCO twice as the British representative, Burnell joined POOART for Peace in Slovenia. In New York’s Hudson Valley, she was Director of Membership for Olana, home and museum of painter Frederic Edwin Church. A full-time professional artist, Burnell’s work has been shown widely in the United States, Hong Kong, Slovenia, France, Poland, and Italy. She is always fascinated by life forms and their endless play of patterns. Her broad creative background has given her a particular talent to create a wide variety of site-specific pieces for private clients’ homes, offices, or hotels. Burnell also does voice-over work for television, radio, and various other productions. More of her work can be seen at www.burnellshively.com. Cover:

Big Beech, 2012. Oil on canvas, 6ʹ 5ʺ × 4ʹ 6ʺ.

Pages 108-109:

Red Onion, 2013. Oil on canvas, 31 ½ʺ × 31 ½ʺ. Blue Fish, 2013. Oil on canvas, 10ʺ × 10ʺ. Artichoke Heart, 2013. Oil on canvas, 31 ½ʺ × 31 ½ʺ. The Awakening (detail), 1998. Oil on canvas, 33ʺ × 40ʺ. Goddess Sprout, 2013. Oil on canvas, 36ʺ × 36ʺ. Fan Coral, 2013. Oil on canvas, 10ʺ × 10ʺ. Blue Crab Claws, 2013. Oil on canvas, 10ʺ × 10ʺ. Parrotfish, 2013. Oil on canvas, 10ʺ × 10ʺ.

April 2014, Vol. 21, No. 2

Cancer Control 109

Editorial

Spinal Oncology: An Innovative Field of Its Own? In the last 25 years, we have witnessed an improvement in the treatment of patients with spine tumors and the emergence of spinal oncology as a subspecialty of spine surgery. Although the overall rates of survival in patients with spine tumors remain dependent on the nature and extent of primary disease, we have also seen a steady improvement in the quality of life for these patients. Such an improvement has been possible through the development of better spinal instrumentation techniques, minimally invasive methods (vertebral augmentation, percutaneous stabilization, radiofrequency ablation), and the emergence of conformal spinal radiosurgery as a new treatment modality. Many of these treatment options are complementary and not mutually exclusive. Laminectomy followed by external beam radiotherapy used to be the standard technique in cases of spinal cord compression, but today the emphasis is on tumor resection through a variety of approaches (transpedicular vertebrectomy, thoracotomy) with concurrent spinal stabilization — if in fact it is needed. This issue of Cancer Control details the ways in which we have been more cognizant of the components of the problem and have recognized the importance of spinal instability, radiographic cord compression, neurological symptomatology, and the extent of disease in a multidisciplinary setting. The articles in this issue also reveal how we have minimized wound-healing complications in the postirradiation setting and addressed local control through en bloc resections for primary spine tumors. At the start of the issue, Dr Clarke and colleagues discuss that certain rare tumors are amenable to cure if excised in an oncological en bloc fashion. Because primary spine tumors can be benign or malignant, biopsy that allows future tract removal is important in the guidance of further treatment options. In the next article, Drs Clarke and Vrionis address surgical complications that decrease quality of life and delay adjuvant treatment in patients with spinal tumors. Avoiding complications begins with surgical planning because common complications (eg, wound infections, cerebrospinal fluid leaks) may be minimized by approach selection and muscle flaps. Late failures of instrumentation imply a lack of successful arthrodesis and will require morbid revisions. Dr Kaloostian and others focus on surgically managing primary and metastatic spinal tumors and review available treatment options for these tumors. 110 Cancer Control

They emphasize a tailored approach that correlates with the degree of aggressiveness for each tumor, noting that patients expected to live longer will require a more aggressive surgical approach. Incompletely resected or unresectable lesions require radiotherapy. In the next article, Dr Kaloostian and coauthors describe alternative options when traditional surgical treatment is not possible or is inappropriate. Understanding the nature of pain (whether it is nociceptive or neuropathic) and its intensity is important. Opioids, antidepressants, cannabinoids, bisphosphonates, and steroids are typical treatments when used in conjunction with radiotherapy and vertebral augmentation as part of palliative strategies. Dr Filis and colleagues then address spinal neoplastic instability, describing how it differs from the traditional definition of traumatic instability. Although the topic is controversial among experts, scoring systems like the Spinal Instability Neoplastic Score may help determine whether instability is present and when surgery may be indicated. In their article on kyphoplasty and vertebroplasty in patients with malignant vertebral fractures, Dr Papanastassiou and others explore the indications, contraindications, and supportive evidence for the use of vertebral augmentation in cancer-related fractures. Although these procedures are controversial in osteoporosis-related vertebral fractures, their role in cancer-related fractures is undisputed, as shown by results from the multicenter, randomized Cancer Patient Fracture Evaluation trial. Pancoast (superior sulcus) tumors are described in detail by Dr Setzer and coauthors. These tumors of the lung typically involve the inferior part of the brachial plexus. In the absence of distant metastases, these tumors can be cured with surgery and radiation in approximately 50% of cases. In the final article of this issue, Dr Moussazadeh and colleagues discuss the evolving paradigm of separation surgery for patients with radioresistant tumors. Spinal radiosurgery is effective against traditional “radioresistant” pathologies but requires a separation of several millimeters between the tumor and the spinal cord. Separation surgery accomplishes this and optimizes the safe delivery of subsequent tumoricidal radiosurgery. Taken together, these articles detail how the treatment of spine tumors must be multimodal, multidisciplinary, and individualized to each patient. We April 2014, Vol. 21, No. 2

now have many more treatment options than during the days of conventional external beam radiotherapy and laminectomy. However, the goals remain the same — at least for metastatic tumors: We must provide timely local tumor control that maximizes quality of life so that our patients can return to systemic therapy in order to prolong life. Frank D. Vrionis, MD, PhD Chief of Neurosurgery H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida Professor of Neurosurgery and Orthopedics University of South Florida Morsani College of Medicine Tampa, Florida [email protected]

April 2014, Vol. 21, No. 2

Cancer Control 111

Neuro-Oncology Program H. Lee Moffitt Cancer Center & Research Institute The Neuro-Oncology Program at Moffitt Cancer Center employs an interdisciplinary approach offering comprehensive therapy for patients with primary and metastatic tumors of the brain and spinal cord, as well as neurologic complications of cancer and its treatments. This interdisciplinary approach involves a team of physicians and other health care professionals to design a treatment plan specialized for each patient. Moffitt’s Neuro-Oncology Program is Florida’s only neuro-tumor treatment center that is a National Cancer Institute–funded member of the National Institutes of Health–sponsored New Approaches to Brain Tumor Therapy Consortium.

PROGRAM LEADER Peter A. Forsyth, MD Chair, Department of Neurosurgery

ENDOCRINOLOGY Howard S. Lilienfeld, MD MEDICAL ONCOLOGY Ronald C. DeConti, MD

NEUROSURGERY Frank D. Vrionis, MD, PhD, Chief Nam D. Tran, MD, PhD Arnold B. Etame, MD, PhD Kamran V. Aghayev, MD

NEUROLOGY Mohamod I. Saleh, MD, PhD

PATHOLOGY Faruk Aydin, MD

NEURO-ONCOLOGY Peter A. Forsyth, MD Solmaz Sahebjam, MD

PHARMACIST Jerry D. Yoder, PharmD RADIATION ONCOLOGY Prakash Chinnaiyan, MD Nikhl G. Rao, MD

ADMINISTRATIVE/CLINICAL SUPPORT Program Administrator Timothy D. Block, MPA/HSA Clinic Operations Manager Darcelle D. Welker, RN, BSN, OCN Physician Assistants Nurse Practitioners Registered Nurses Dietitians Clinical Trial Coordinator Patient Representatives

112 Cancer Control

COMMUNITY PROGRAMS Education/Awareness Advocacy and Support COMPREHENSIVE RESEARCH CENTER Clinical Trials Drug Discovery Experimental Therapeutics Proteomics Immunotherapy

RADIOLOGY John A. Arrington, MD F. Reed Murtagh, MD SCIENTIST Sabrina A. Gonzalez Blohm, MSBE James Doulgeris, MSME Kathleen M. Egan, ScD Rajappa Kenchappa, PhD Niveditha Krishma, MS William Lee, PhD Elphine Telles, MD Sasha Pisklavoka, MD Dapeng Wang, PhD

EDUCATION AND TRAINING Medical Students Residents Fellows International Scholars PATIENT & FAMILY SERVICES Social Workers Rosemary A. Demarco, MSW SUPPORTIVE CARE MEDICINE Margaret P. Booth-Jones, PhD

April 2014, Vol. 21, No. 2

Research The neuro-oncology team is exploring experimental treatments and clinical trials that promise greater efficacy with fewer adverse events. Our faculty provides access to the most up-to-date, “bench-to-bedside” research information available.

Clinical Trials Relating to the Brain and Nervous System MCC 15004 Southeastern Study of Cancer and the Environment MCC 16110 A Prospective, Multicenter Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in Patients With Newly Diagnosed Glioblastoma MCC 16527 Phase I/II Trial of Concurrent RAD001 (Everolimus) With Temozolomide/Radiation Followed by Adjuvant RAD001/Temozolomide in Newly Diagnosed Glioblastoma MCC 16653 Phase I Trial of Vorinostat Concurrent With Stereotactic Radiotherapy in Treatment of Brain Metastases From Non–Small-Cell Lung Cancer MCC 16983 Phase II Randomized Study of Rituximab, Methotrexate, Procarbazine, Vincristine, and Cytarabine With and Without Low-Dose Whole-Brain Radiotherapy for Primary Central Nervous System Lymphoma MCC 17017 Phase 1A/1B, Multicenter, Open Label, Dose-Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the Dual DNA-PK and TOR Kinase Inhibitor, CC-115, Administered Orally to Subjects With Advanced Solid Tumors and Hematologic Malignancies MCC 17164 Phase 1B, Multi-Center, Open Label, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors MCC 17380 Phase III, Multi-Center, Open Label, Randomized, Controlled Study of the Efficacy and Safety of Oral LDE225 Vs Temozolomide in Patients With Hh-Pathway Activated Relapsed Medulloblastoma MCC 17697 A Randomized Study of Nivolumab or Nivolumab Combined With Ipilimumab Vs Bevacizumab in Adult Subjects With Recurrent Glioblastoma (GBM) (CheckMate 143)

To schedule a patient appointment with a physician in the Neuro-Oncology Program, call the New Patient Appointment Center at 813-745-3980 or 1-888-860-2778 (during normal business hours). For information about clinical trials, call Cheryl Maker in the Clinical Research Department at 813-745-4106 or e-mail [email protected]. www.MOFFITT.org April 2014, Vol. 21, No. 2

Cancer Control 113

Primary tumors are rare and those localized to a single location offer the potential for cure.

Burnell Shively. Red Onion, 2013. Oil on canvas, 31 ½ʺ × 31 ½ʺ.

Primary Spine Tumors: Diagnosis and Treatment Michelle J. Clarke, MD, Ehud Mendel, MD, and Frank D. Vrionis, MD, PhD Background: Primary tumors are rare and those localized to a single location offer the potential for cure. To achieve this, early recognition of the primary tumor and proper workup and treatment are essential. Methods: The authors reviewed the literature and best practices to provide recommendations on primary spine tumor treatment. Appropriate workup of primary spine tumors and treatment algorithms are also discussed. Results: Patients suspected of a primary spine tumor should undergo fine-needle aspirate biopsy following consultation with the surgical team to ensure the biopsy tract is surgically resectable should the need arise. Once pathology is confirmed, metastatic workup should be performed to guide the level of treatment. If a localized lesion with poor radiation and chemotherapeutic response is diagnosed, then en bloc resection may be required for cure. If en bloc resection is not feasible or metastatic lesions are present, then radiation and medical oncology specialists must work in conjunction with the surgical team to determine the best treatment options. Conclusions: Patients with suspected primary tumors of the spine should be treated in a multidisciplinary fashion from the outset. With thoughtful management, these lesions offer the opportunity for surgical cure.

Introduction From the Department of Neurosurgery at the Mayo Clinic College of Medicine, Rochester, Minnesota (MJC), the Department of Neurosurgery and Orthopedics at The Ohio State University, Columbus, Ohio (EM), the Neuro-Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (FDV), and the Departments of Neurosurgery and Orthopedics at the University of South Florida Morsani College of Medicine, Tampa, Florida (FDV). Submitted September 26, 2013; accepted January 16, 2014. Address correspondence to Michelle J. Clarke, MD, Department of Neurosurgery, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905. E-mail: [email protected] Dr Vrionis receives grants/research support from Globus Medical, DePuy Synthes, and Spine360. He also is a consultant for Orthofix. No significant relationship exists between the remaining authors and the companies/organizations whose products or services may be referenced in this article. 114 Cancer Control

Primary vertebral tumors are rare, accounting for fewer than 5% of all neoplasms in the spinal column,1 making them 40 times less common than spinal metastases.2 These tumors are uncommon and infrequently encountered in practice. Nevertheless, because specific diagnostic and treatment modalities may impact outcome, these lesions must be included in the health care professional’s differential diagnosis. Unlike metastatic spine tumors, primary tumors localized to a single location offer the potential for true cure. However, this possibility may be eliminated by late recognition or improper workup. Becase many of these lesions poorly respond to chemotherapeutic April 2014, Vol. 21, No. 2

agents and radiation therapy, missteps can have a devastating effect on outcome. Thus, this paper focuses on a systematic approach to the diagnosis and treatment of primary spine tumors.

Workup

Clinical Presentation Most patients with primary spine tumors present incidentally or following a workup for nonspecific axial skeletal pain. As these tumors often originate in the vertebral body, symptoms are usually due to periosteal stretching with growth and localized bony destruction. Thus, unremitting pain that worsens at night or in the supine position is common.3 Mechanical pain due to instability may be reported. Radicular or myelopathic symptoms due to neurological element compression are rare. A new or progressive deformity, especially in younger patients, may be a presenting feature. If a tumor is suspected, or if a patient has persistent symptoms, then imaging studies should be pursued. Important clinical features and implications for treatment that distinguish primary from metastatic spine lesions are noted in Table 1.

In some cases, radiographic imaging can provide a definitive diagnosis. However, frequently imaging narrows the differential, supplying valuable information about the involvement and proximity of the tumor to neighboring structures. Although this may not be of definitive use from a diagnostic perspective, imaging suggests in many cases that a surgical approach will be required, and, prior to more invasive testing such as biopsy, it is reasonable to involve a surgeon in the patient’s care at this point. Depending on the differential diagnosis suggested by the imaging studies, it might be reasonable to begin the staging process, particularly in cases in which distant metastases are likely and may provide an easier biopsy target than with spinal imaging alone. In these cases, a technetium bone scan or positron emission tomography (PET) to look for metabolic activity in remote skeletal sites is a reasonable approach.

Biopsy Lesional biopsy is often the most important step toward diagnosis, as well as a stumbling block of the treatment paradigm. Technical mistakes resulting in tumor spread may preclude complete resection in a Diagnostic Imaging potentially curable patient, thus a multidisciplinary Imaging studies remain the most important diagnostic approach that combines an experienced interventionmodality in the face of a primary spinal column lealist in direct consultation with the surgeon responsion. In many cases, due to the nonspecific presentsible for potential resection is appropriate to avoid ing features, plain radiography is initially performed. errors at this stage. Consideration for biopsy must Although radiography is an excellent screening tool, be given to lesions that do not have a diagnostic apit should be noted that a negative radiograph is not pearance and harbor malignant characteristics such definitive. Computed tomography (CT) provides suas bony destruction. More benign appearing lesions, perior information on cortical bone and tumor calparticularly those in the posterior elements in younger cification, while magnetic resonance imaging is expatients, should be watched for signs of activity. Comcellent at delineating soft tissue, paraspinal lesions, mon primary tumor types are outlined in Table 2. neural encroachment, bone marrow infiltration, and There are 4 main biopsy techniques: fine needle epidural extension. aspirate biopsy (FNAB), core needle biopsy, incisional biopsy, and excisional biopsy. In patients in whom results from imaging Table 1. — Distinguishing Features of Primary and Metastatic Spine Tumors studies suggest a differential diagnosis that includes only benign lesions, excisional biPrimary Tumor Metastatic Tumor opsy may be appropriate for both diagnosis Percentage 5 95 and treatment. However, the likelihood of tumor disruption and local spread is high Presentation: for both incisional and excisional biopsies, Demographics Younger Older thus FNAB is recommended if the lesion Location Vertebral body/posterior elements Vertebral body is likely to harbor a malignant histology. Time to presentation Longer duration Shorter duration Core needle biopsy allows the health care Treatment: professional to obtain a column of tissue. Surgery En bloc Piecemeal It is a reasonable consideration if FNAB Radiation Proton beam Conventional is nondiagnostic, although a higher likeliChemotherapy Unlikely Common hood of tumor spillage may exist and tract resection should be considered. To reduce Treatment goal Cure Palliation the likelihood of tumor spread, sealing the Planned surgical Low High biopsy site with bone wax or using the comorbidity axial technique is recommended.4 April 2014, Vol. 21, No. 2

Cancer Control 115

Table 2. — Common Primary Spine Tumor Histologies, Imaging Features, and Treatment Paradigms Tumor Type

Radiographic Features

Treatment

Osteoid osteoma

Unique bony architecture (often diagnosed with CT or bone scan)

Intralesional curettage

Osteoblastoma

Diagnosed with plain radiography or bone scan but defined by CT

Intralesional curettage or marginal en bloc resection RT/chemotherapy may be used in recurrences/unresectable lesions

Osteochondroma

CT and MRI useful in defining lesion

Intralesional curettage or marginal en bloc

Giant cell tumor


En bloc resection recommended due to high local recurrence rate Documented sarcomatous degeneration with RT Chemotherapy may be warranted in recurrence

Aneurysmal bone cyst


Surgical resection with RT/embolization

Hemangioma


Most managed conservatively Bracing, vertebral augmentation, RT, embolization may be used Surgery reserved for cases of deformity or neurological deficit

Multiple myeloma Lymphoma Solitary plasmacytoma

Skeletal survey, blood work, plasma electrophoresis, bone marrow biopsy

RT and chemotherapy Surgery reserved for acute neurological deterioration, instability, or lack of diagnosis

Ewing sarcoma

CT/MRI, PET, or CT staging

RT and chemotherapy Surgery reserved for acute neurological deterioration or deformity or localized disease

Osteosarcoma


En bloc excision, postoperative RT Preoperative chemotherapy should be considered

Chordoma


En bloc resection, postoperative RT, including proton beam Chemotherapy may be considered for recurrent disease

Chondrosarcoma


En bloc resection, postoperative RT, including proton beam if positive margins

Benign

Malignant

CT = computed tomography, MRI = magnetic resonance imaging, PET = positron emission tomography, RT = radiotherapy.

Among the 4 techniques described above, CT-guided FNAB is the most common procedure, yielding a tissue diagnosis in 70% to 80% of procedures.5,6 The procedure also has a low complication rate and a lower likelihood of an extralesional spread of tumor cells.5,7,8 The importance of avoiding open biopsy cannot be overemphasized. In one series of patients with chordoma, 8% of the 25 patients undergoing FNAB followed by en bloc resection had a recurrence, yet 3 of the patients who underwent open biopsy (including 2 with subsequent en bloc resections) developed local tumor recurrence.9 Although the risk of tumor cell spillage is lessened by the FNAB approach, if possible, resection of the biopsy tract is still recommended. Thus, it is beneficial for the interventionalist and spine surgeon to discuss the likely surgical trajectory prior to biopsy. Along with selecting a trajectory easily incorporated into the planned surgical incision, marking the biopsy location is also helpful. Thus, in most cases, early referral to a tertiary center capable and with the appropriate 116 Cancer Control

surgical expertise is beneficial prior to biopsy despite diagnostic uncertainty. Pathological diagnosis must involve a thorough review. If necessary, FNAB can be repeated to ensure adequate tissue for diagnosis. Because the diagnosis impacts treatment planning and prognosis, a second opinion is often encouraged. Primary tumors are very rare, so sending specimens to a recognized expert to confirm the diagnosis can be useful. In cases of typical or atypical hemangiomas, it is not uncommon for the biopsy results to be interpreted as normal bone marrow. Metastatic Workup Pathological diagnosis, in combination with the results of a thorough metastatic workup in malignant disease, dictates the treatment plan. Metastatic lesions at presentation alter the extent and type of therapy; for example, solitary lesions may undergo local treatment, while metastatic lesions necessitate a systemic approach to therapy. Evidence of metastasis also affects April 2014, Vol. 21, No. 2

surgical decision-making. In patients without evidence of metastatic disease, aggressive en bloc resection of malignant lesions poorly responsive to adjuvant therapy may offer the opportunity of cure. Such a possibility is eliminated with evidence of metastatic lesions, changing the surgical plan from aggressive surgery with planned functional loss to a less aggressive debulking with preservation of function or completely forgoing resection. The type of metastatic workup may be dictated by pathological diagnosis because specific pathologies have specific metastatic predilections. In many cases, PET is an excellent option, although a modification may be needed as it may predominantly provide information on the chest, abdomen, and pelvis. For instance, PET can stage angiosarcoma, which is a highly aggressive lesion, provided that complete limb imaging is included. CT of the chest, abdomen, and pelvis as well as bone scans are also appropriate options. In cases of suspected plasmacytoma or multiple myeloma, a skeletal survey, bone marrow biopsy, and immunoelectrophoresis are useful.

cases, CT scanning is helpful in defining the lesion. Canal compromise caused by bony intrusion, such as that caused by a retropulsed pathological fracture, is unresponsive to radiation and must be mechanically decompressed. In the case of radiation-responsive tumors, the goals of surgery are to decompress the spinal canal and restore the stability and load-bearing capacity of the spine. This is accomplished by performing vertebral augmentation. Complete resection and reconstruction is occasionally completed; however, at a minimum, a reasonable margin between the tumor and spinal cord (“separation surgery”) should be developed to optimize subsequent radiation treatment.

Moderately Responsive Tumors

Chemotherapy/Radiation Responsivity Primary tumors fall into 2 basic categories, ie, those responsive to radiation and chemotherapeutic agents and those unresponsive to such treatment modalities. Primary tumors of the spine that respond well to adjuvant therapies include hematopoietic lesions and certain sarcomas.

Another group of tumors are those with an incomplete response to adjuvant therapy in which preoperative chemotherapy or radiation may be employed. Although it is preferable to preoperatively avoid cytotoxic therapies to reduce infection and optimize healing, a subset of patients exists in whom delaying surgical intervention might improve outcome. The most important of this tumor group is Ewing sarcoma, which is also the most common primary spinal column tumor in children.13 The lesion is so responsive to chemotherapeutic and radiation options that surgical treatment is reserved for issues of stability and neurological compromise. Surgical treatment has not been shown to improve local control.13,14 Although survival gains have been made, Ewing sarcoma is an aggressive lesion, with a 5-year survival rate of less than 50% in certain subsets of patients.15,16 Sarcomas may benefit from preoperative chemotherapeutics. Osteosarcoma and, in particular, angiosarcoma are aggressive lesions that benefit from upfront chemotherapy followed by en bloc resection and postoperative radiation. Despite such aggressive therapy, prognosis remains poor.

Hematopoietic Malignancies

Poorly Responsive Tumors

Lymphoma, multiple myeloma, and solitary plasmacytoma are the most common malignant neoplasms of the spine.2 Radiotherapy is the mainstay of treatment for these lesions, with excellent local control. Although these tumors are considered radiosensitive, recurrences following radiation may rarely occur and are especially seen in long-term survivors. Approximately 50% of patients with solitary plasmacytoma will develop multiple myeloma within 2 years.10-12 Thus, systemic chemotherapy may be useful in cases with widespread disease or in the setting of plasmacytoma conversion to multiple myeloma. Surgical intervention can be avoided in many cases. However, in the setting of neurological deficit due to spinal canal compromise or instability causing mobility-limiting pain, surgery may be considered. In these

Chordomas and chondrosarcomas are poorly sensitive to chemotherapeutic agents and radiation. The mainstay of their treatment is en bloc surgical resection. Protocols for upfront proton-beam radiation and neoadjuvant therapies are currently being studied,17 and they may be beneficial in cases where en bloc resection is impossible or technically challenging to reduce intraoperative tumor spillage. The importance of avoiding seeding the surrounding area must be underscored, because survival is frequently affected by local recurrence rather than metastatic disease progression.3,18,19

Treatment Once the diagnosis and the metastatic disease burden are established, attention should be turned to treatment. Patients with primary tumors require a multidisciplinary approach involving medical oncology, radiation oncology, and spine surgery specialties. Coordination of care is paramount to optimize the response for each treatment modality.

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General Surgical Strategies The preferred surgical approach to a lesion is dictated by tumor pathology, morphology, and metastatic status. The 2 main surgical goals involve resecting the Cancer Control 117

tumor and reconstructing the load-bearing capacity of the spine. A general approach is outlined in Fig 1. In general, a trade-off exists between surgical morbidity and the completeness of resection. Surgical options can range from intralesional curettage/ debulking to wide en bloc resection. Complex resections require larger operative corridors to appropriately visualize the tumor and neighboring structures Setup Adequate vascular access, appropriate operative positioning, electrophysiological monitoring

Ô Exposure Avoiding tumor disruption, expose the posterior spine, perform laminectomy above, below, and, at the level of interest, remove as much of the posterior elements as possible without transgressing the tumor

in order to achieve negative margins. Limb or nerve root sacrifice with associated permanent morbidity may be planned in these larger procedures to optimize tumor resection. En bloc resections involve the removal of the tumor in 1 nonviolated piece (Fig 2). En bloc resection conveys a survival advantage,1,18,20-23 but the procedure is far more technically demanding than removing a lesion piece by piece. In general, these cases are longer and more demanding than similar piecemeal intralesional resections. There may be a planned morbidity because adjacent structures may require sacrifice to remove the tumor in 1 piece. Nerve roots, major vessels, and dura are commonly resected along with the tumor mass to remove the lesion in en bloc fashion. In addition, planned tracheostomy, feeding tube placement, and ileostomy or colostomy may be necessary. The patient should be thoroughly counseled prior to surgery as to the expected perma-

Ô Free Neural Elements Sacrifice nerve roots if involved or, to provide access, gently create a plane between thecal sac and tumor capsule

Ô Place Instrumentation Once the spine is destabilized with full discectomy/osteotomy, ≥ 1 rod should be placed at all times to avoid sudden alignment changes

Ô Circumferentially Dissect the Tumor The thoracic spine will require bilateral removal of transverse processes and a portion of rib, sacrifice of the nerve root, and identification of the radicular arteries. Radicular vessels and parietal pleura can be pushed from the tumor to create a safe plane, allowing dissection between the spine and aorta.

A

Ô Transect the Spinal Column Perform via osteotomy or complete discectomy to free the specimen

Ô Remove the En Bloc Specimen

Ô Reconstruct the Spinal Column Perform complete arthrodesis

Ô Closure Fig 1. — A general algorithm for the en bloc primary tumor via costotransversectomy is shown. Although each step is important, operative location, approach, pathology, and adjacent structures will dictate the order of the intervention. The basic surgical principles may also be applied to en bloc resections in other locations. 118 Cancer Control

B Fig 2. — A 54-year-old man presented with a chordoma incidentally found using fine-needle aspirate biopsy. (A) He underwent high sacrectomy, including thecal sac ligation below the S1 nerve roots with anticipated loss of bowel and bladder continence. (B) The tumor was hemisected following resection and is compared with preoperative T2-weighted magnetic resonance imaging. April 2014, Vol. 21, No. 2

nent loss of function. Thus, the decision to continue with en bloc resection must be based on a tradeoff between expected increased survival and planned surgical morbidity rates. Biomechanical stability and spinal column reconstruction can be challenging. In complex cases, limbs, portions of the chest wall, and the pelvic ring may be resected along with the tumor. In general, the goal of reconstruction is to allow adequate load transfer while protecting the nearby spinal cord, remaining nerve roots, and other vital organs. It is worth noting that the patient may permanently rely on implanted instrumentation to maintain stability, as bony union in the face of massive reconstruction and cytotoxic adjuvant therapy is challenging to achieve. Despite the odds, long-term survivors are expected; therefore, fusion should be attempted. In the presence of radiation and other therapies, anterior load-bearing constructs are more likely to achieve fusion than posterior constructs, and it may be worth revising the surgical plan to encompass this type of reconstruction. In general, en bloc resection of large spinal tumors and their subsequent reconstruction are among the most challenging spinal procedures.

Oncological Staging By incorporating information about pathology, general morphology, and metastatic status of a lesion, generalizations about growth and behavior can be made in order to dictate the surgical approach. The Enneking classification24 originally designed to stage limb lesions has been ported to primary spine tumors and provides an excellent overview (Table 3).2,7,24-26 Benign tumors are divided into 3 categories. S1 tumors are latent, asymptomatic, have a prominent

capsule, and are often observed. An example of an S1 tumor is a schwannoma. S2 lesions are active with slow growth, mild symptoms, and a thin capsule or pseudocapsule of reactive tissue. Osteoid osteomas and smaller osteoblastomas fall into this category and can be treated with intralesional curettage unless marginal en bloc resection is achievable. S3 lesions are aggressive, demonstrate rapid growth, and often have a hypervascular pseudocapsule. Aggressive osteoblastomas are the hallmark of this type, and they may be treated with marginal en bloc resection. A “marginal margin” implies that the tumor pseudocapsule has not been violated; however, additional tissue is not included in the surgical specimen. This fact is important because spinal column tumors may reach the thecal sac, and a marginal margin can provide adequate treatment without neurological sacrifice (Fig 3). All malignant tumors require a wide en bloc resection. Although these lesions can be further categorized by location (whether confined to the vertebral body or within the paraspinal tissues) and whether islands of tumor are within the pseudocapsule or exist beyond the recognized pseudocapsule (low vs high grade), the pseudocapsule itself — unlike a benign tumor — cannot be considered a safe margin.22 Originally described by Roy-Camille27 for long-bone tumors, wide en bloc resection has been adapted to the spine. Due to the proximity of spinal cord and other vital structures to the axial spine, this procedure may not be feasible; however, limb amputation is recommended if necessary. Adjuvant therapy is generally recommended, particularly in cases of high-grade malignant lesions. Patients with metastasis on presentation are candidates for palliative surgery and subsequent adjuvant therapy. The main goal of en bloc resection is to avoid

Table 3. — Basic Surgical Staging Considerations Based on Modified Enneking Classification

Benign

Malignant

Staging

Description

Treatment

S1 (latent): No growth

Well-defined capsule

Nonoperative (unless decompression/stabilization required)

S2 (active): Slow growth

Thin capsule Reactive pseudocapsule

Intralesional curettage

S3 (aggressive): Rapid growth

Capsule incomplete Wide reactive pseudocapsule

Marginal en bloc resection

Low grade (I): IA (confined to vertebra) IB (paravertebral extension)

Wide pseudocapsule

Wide en bloc resection

High grade (II): IIA (confined to vertebra) IIB (paravertebral extension)

Pseudocapsule infiltrated by tumor

Wide en bloc resection with adjuvant therapy

High grade with metastasis (III)

Distant metastasis

Palliative surgery and adjuvant therapy

Data from references 2, 24, and 26.

April 2014, Vol. 21, No. 2

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local and distant seeding by violating the tumor. Thus, if a patient has metastases on presentation, en bloc resection is irrelevant, and the patient should be directed from a high morbidity procedure and instead toward adjuvant therapies, palliative debulking, and spinal stabilization. Consideration for en bloc resection can also be provided to patients without evidence of metastases but in whom the tumor capsule was violated (eg, cases of previous resection or open biopsy) or in the presence of local recurrence. Although not ideal, it may be possible that local seeding has occurred and en bloc resection will lessen the likelihood of distant metastases. Due to local seeding, adjuvant therapy is usually recommended.

Surgical Staging Once the preferred method of resection has been determined, patients must be surgically staged to determine the technical feasibility of the procedure. Invasiveness into nearby unresectable structures is the primary reason some tumors, particularly in the case

of sarcomas, are unresectable in en bloc fashion and may rely on debulking with adjuvant therapy. In all other cases, other systems have been proposed,18,25 but the determination must be whether a surgical corridor exists in order to deliver the tumor in 1 piece without disrupting vital structures. Oftentimes, the limiting factor for determining the tumor trajectory is the spinal cord, which is encircled by a bony wall composed of vertebral body, pedicles, and lamina. To remove a tumor specimen en bloc, the ring must be broken wide enough to pass around the spinal cord. Thus, if the tumor completely encircles the spinal cord, a marginal en bloc resection is not possible without violating the tumor. The break in the ring also determines the surgical corridor for tumor removal; it must be removed opposite the break in the ring. Thus, immobile vital structures beyond the spinal column may preclude removal. Nearby structures, such as the great vessels and heart, may limit the resectability of a tumor or increase the difficulty of the procedure. Generally, location on the spinal axis predicts the technical difficulty associated with en bloc resection

A

C

B

D

Fig 3. — (A) A 34-year-old woman developed sudden back and radicular leg pain. A giant cell tumor with a pathological fracture was diagnosed via fine-needle aspirate biopsy. (B-D) Because these tumors have a high propensity for recurrence following intralesional resection, posterior and subsequent anterior en bloc resections and reconstruction were undertaken. The tumor between the great vessels was removed. 120 Cancer Control

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and reconstruction; surgery is more challenging from the sacrum to clivus. Distal sacrectomies may be accomplished using a posterior-only approach. Mid to upper sacrectomies may involve the posterior-only or the anterior and posterior approach to aid dissection and utilize rectus vascularized flaps to aid in closure. Total sacrectomies, in which S1 is removed, require instrumented reconstruction. In the lumbar spine, the great vessels, renal arteries, ureters, and digestive structures must be considered, as well as nerves involved in lower extremity function. In the thoracic spine, mediastinal structures preclude certain surgical trajectories, and chest wall reconstruction may be indicated. The subaxial cervical spine may be challenging because upper extremity and diaphragmatic innervation, the vertebral arteries, trachea, and esophagus are in close proximity. However, high cervical spine and clival lesions are challenging because transoral and transmandibular approaches may be

required. In these cases, cranial nerves and vascular structures make resection difficult. Fig 4 outlines the overall surgical strategy.

Strategies for Capsular Violation Patients commonly present following partial resection or open biopsy, which is often a diagnostic procedure (Fig 5). Although capsular violation precludes true en bloc resection as the margins are already contaminated, using the en bloc techniques to eliminate tumor spillage is the preferred approach in these situations. If it is possible to widen the margin or include a portion of the surgical tract in the specimen, then there may be a reduced likelihood of local and distant recurrence; however, no data exist on this patient population, so the approach is inferred but commonly agreed upon. Another frequent scenario involves unintended capsular violation during the initial en bloc resection in a previously unviolated tumor. If possible,

Suspected Primary Spine Tumor

Biopsy

Diagnosis

Benign

Malignant

Staging

Treatment

Salvage

ILR

Sensitive

Insensitive

Metastatic Workup

Metastatic Workup

Chemotherapy/ Radiation

Positive

Negative

Restage

ILR/GTR

En Bloc

Residual

Unstable

OpenBx/ Contamination

Observe

GTR/En Bloc

Stabilize

Protons +

Protons +

Fig 4. — A diagnostic and treatment algorithm for primary tumors is illustrated, including a specific approach for malignant histologies. GTR = gross-total resection, ILR = intralesional resection, OpenBx = open biopsy. April 2014, Vol. 21, No. 2

Cancer Control 121

oversewing the tear in the tumor capsule can preserve the structural integrity of the tumor, because further manipulation is often necessary during removal. Regardless of whether or not the tear is reparable, the area can be coated in a fibrin sealant to prevent spillage. Oftentimes the soft internal structure of the tumor will extrude through the tear. In such a case, thoroughly removing the extruded compoA nent and inspecting the nearby area are both imperative. In some cases, tumor morphology may require modified en bloc resection in which tumor violation is planned to protect nearby neural and vascular structures (“planned transgression”). For instance, if the tumor wraps around the spinal cord and no window wide enough exists for the spinal cord to slip through when the mass is removed, either the spinal cord or the mass must be incised. Although such a scenario is neurologically devasB tating, planned paraplegia with en bloc resection and spinal cord sacrifice in the Fig 5. — (A) A 74-year-old farmer presented with leg weakness, mild incontinence, and a palsetting of aggressive sarcoma is arguably pable abdominal mass. Via fine-needle aspirate biopsy a 12 × 12 × 21 cm L2 to S1 chordoma was diagnosed, which had arisen from the L3 vertebral body. (B) The patient developed acute an option; commonly, however, it is the cauda equina syndrome due to the pathological fracture and was emergently decompressed tumor that is incised. In these cases, the posteriorly with gross violation of the tumor. He underwent posterior fusion in this setting. same techniques apply. Oftentimes it is Multidisciplinary discussion resulted in neoadjuvant proton-beam and intensity-modulated radiotherapy followed by laparotomy and pseudo en bloc tumor resection. The L3 vertebral possible to achieve a useful exposure win- body tumor was not resected. After 2 years of postoperative follow-up, the patient is alive dow by removing the posterior elements, with stable disease and no neurological deficits. violating the tumor as it extends through the pedicles. In such a scenario, carefully protecting Local control is achieved with radiation. Prisurrounding structures and promptly coating the remary tumors are often considered for proton beam maining pedicle with bone wax is the appropriate opradiotherapy (PBR) alone or in combination with tion. Because a patient in this case has contaminated intensity-modulated radiotherapy (IMRT). The adtumor margins, any instruments in contact with the vantage of PBR is the steep Bragg peak, allowing tumor must be considered contaminated and, thus, high-dose radiation delivery near critical structures. be permanently removed from the field. Although IMRT is conformal, it does not have the Clearly communicating tumor violation to radiasame steep drop in dose, thus it effectively delivers tion and medical oncologists is important. Depending a through-and-through dose of radiation. However, on tumor pathology, close imaging follow-up may PBR is geographically limited and expensive, so combe the standard therapy following en bloc resection; bination PRB/IMRT has been employed to achieve however, upfront adjuvant therapy may be desirable a similar effect.28 in cases of contaminated margins. Chemotherapeutics also play an important role, particularly in sarcomas and hematologic malignanPostoperative Adjuvant Therapy cies. In other cases, such as giant cell tumors, experiFollowing optimal surgical debulking, patients should mental chemotherapeutics have been attempted with be considered for adjuvant chemotherapy and radiareasonable effect in patients with inoperable tumors tion. If a patient has undergone successful en bloc or recurrences. resection (with marginal margins in a benign lesion or clean wide margins in a low-grade malignant leOngoing Monitoring sion), then the patient should be observed for signs Depending on pathology, patients should be folof distant metastases or local recurrence. Adjuvant lowed at variable intervals. Although many benign therapy should be timed to allow adequate wound tumors have a very low incidence of recurrence, healing and to decrease the risk of infection. certain lesions such as giant cell tumors have an 122 Cancer Control

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80% local recurrence rate with intralesional resection.25 Malignant lesions require ongoing periodic monitoring for local recurrence and periodic restaging for metastatic lesions. Due to the multispecialty team involved in patient care, the coordination of monitoring is valuable.

Recurrence/Late Metastasis If a patient has local recurrence or distant metastasis, then further treatment and possible restaging are both warranted. In the case of distant metastasis, the mainstay of treatment is adjuvant radiation and chemotherapy, although accessible solitary lesions may be amenable to resection. Local recurrence presents a different challenge. Provided no distant lesions are present during the metastatic workup, pursuing treatment as though it was a disrupted primary lesion might be appropriate. Although such a patient is likely to have a higher risk of repeat local recurrence than a patient undergoing first-time en bloc resection, initiating treatment may prevent late distant metastasis. However, it is worth noting that, in certain tumor types, survival may be related to local recurrence more than distant metastases. Due to the rarity of these lesions, little data exist on the efficacy of en bloc resection for recurrence.

Conclusions Although primary spine tumors are rare, they must remain high on the differential diagnosis, because early diagnostic and treatment decisions may have farreaching implications for additional treatment options and survival rates. However, appropriate diagnostic tests, thoughtful biopsy techniques, and challenging surgery may provide a cure.

12. Kleinman WB, Kiernan HA, Michelsen WJ. Metastatic cancer of the spinal column. Clin Orthop Relat Res. 1978;136:166-172. 13. Grubb MR, Currier BB, Prichard DJ, et al. Primary Ewing’s sarcoma of the spine. Spine (Phila Pa 1976). 1994;19(3):309-313. 14. Sailer SL, Harmon DC, Mankin HJ, et al. Ewing’s sarcoma: surgical resection as a prognostic factor. Int J Radiat Oncol Biol Phys. 1988;15(1):43-52. 15. Venkateswaran L, Rodriguez-Galindo C, Merchant TE, et al. Primary Ewing tumor of the vertebrae: clinical characturistics, prognostic factors, and outcome. Med Pediatr Oncol. 2001;37(1):30-35. 16. Smith MA, Seibel NL, Altekruse SF, et al. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol. 2010;28(15):2625-2634. 17. Delaney TF, Trofilmov AV, Engelsman M, et al. Advanced-technology radiation therapy in the management of bone and soft tissue sarcomas. Cancer Control. 2005;12(1):27-35. 18. Boriani S, Chevalley F, Weinstein JN, et al. Chordoma of the spine above the sacrum. Treatment and outcome in 21 cases. Spine (Phila Pa 1976). 1996;21(13):1569-1577. 19. Hug EB, Fitzek MM, Liebsch NJ, et al. Locally challenging osteo- and chondrogenic tumors of the axial skeleton: results of combined proton and photon radiation therapy using three-dimentional treatment planning. Int J Radiat Oncol Biol Phys. 1995;31(3):467-476. 20. Boriani S, De Iure F, Bandiera S, et al. Chondrosarcomas of the mobile spine: report on 22 cases. Spine (Phila Pa 1976). 2000;25(7):804-812. 21. Hsieh PC, Xu R, Sciubba DM, et al. Long-term clinical outcomes following en bloc resections for sacral chordomas and chondrosarcomas: a series of twenty consecutive patients. Spine (Phila Pa 1976). 2009;34(20): 2233-2239. 22. Talac R, Yaszemski MJ, Currier BL, et al. Relationship between surgical margins and local recurrence in sarcomas of the spine. Clin Orthop Relat Res. 2002;397:127-132. 23. Chi JH, Sciubba DM, Rhines LD, et al. Surgery for primary vertebral tumors: en bloc versus intralesional resection. Neurosurg Clin N Am. 2008;19(1):111-117. 24. Enneking W. Musculoskeletal Tumor Surgery. New York: Churchill Livingston; 1983. 25. Hart RA, Boriani S, Biagini R, et al. A system for surgical staging and management of spine tumors. A clinical outcome study of giant cell tumors of the spine. Spine (Phila Pa 1976). 1997;22(15):1773-1783. 26. Enneking W. A staging system for musculoskeletal neoplasms. Clin Orthop. 1986;204:9-24. 27. Roy-Camille R, Saillant G, Hernigou P. Resection en bloc of the scapulohumeral joint and the upper end of the humerous for tumor (author’s transl) [in French]. Rev Chir Orthop Reparatrice Appar Mot. 1982;68(3):211-214. 28. Torres MA, Chang EL, Mahajan A, et al. Optimal treatment planning for skull base chordoma: photons, prontons, or a combination of both? Int J Radiat Oncol Biol Phys. 2009;74(4):1033-1039.

References 1. Boriani S, Biagini R, De Iure FD, et al. Primary bone tumors of the spine: a survey of the evaluation and treatment at the Instituto Ortopedico Rizzoli. Orthopedics. 1995;18(10):993-1000. 2. Jacobs W, Fehlings M. Primary vertebral column tumors. In: Dickman C, Fehlings M, Gokaslan Z, eds. Spinal Cord and Spinal Column Tumors: Principles and Practice. New York: Thieme; 2006: 369-386. 3. Weinstein J, McLain R. Primary tumors of the spine. Spine (Phila Pa 1976). 1987;12(9):843-851. 4. Tehranzadeh J, Tao C, Browning CA. Percutaneous needle biopsy of the spine. Acta Radiol. 2007;48(8):860-868. 5. Phadke DD, Lucus DR, Madan S. Fine-needle aspiration biopsy of vertebral and intervertebral disc lesions: specimen adequacy, diagnostic utility, and pitfalls. Arch Pathol Lab Med. 2001;125(11):1463-1468. 6. Carson H, Castelli M, Reyes CV, et al. Fine-needle aspiration biopsy of vertebral body lesions: cytologic, pathologic, and clinical correlations of 57 cases. Diagn Cytopathol. 1994;11(4):348-351. 7. Boriani S, Weinstein J, Biagini R. Primary bone tumors of the spine. Terminology and surgical staging. Spine (Phila Pa 1976). 1997;22(9):1036-1044. 8. Saad R, Clary K, Liu Y, et al. Fine needle aspiration biopsy of vertebral lesions. Acta Cytol. 2004;48(1):39-46. 9. Clarke MJ, Dasenbrock H, Bydon A, et al. Posterior-only approach for en bloc sacrectomy: clinical outcomes in 36 consecutive patients. Neurosurgery. 2012;71(2):357-364. 10. Friedman M, Kim TH, Panahon AM. Spinal cord compression in malignant lymphoma. Treatment and results. Cancer. 1976;37(3):40-51. 11. Hall AJ, Mackay NN. The results of laminectomy for compression of the cord or cauda equina by extradural malignant tumour. J Bone Joint Surg Br. 1973;55(3):497-505. April 2014, Vol. 21, No. 2

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Surgical treatment of spinal tumors involves multidisciplinary preoperative planning, a high index of suspicion in the event of a problem, and prompt treatment.

Burnell Shively. Blue Fish, 2013. Oil on canvas, 10ʺ × 10ʺ.

Spinal Tumor Surgery: Management and the Avoidance of Complications Michelle J. Clarke, MD, and Frank D. Vrionis, MD, PhD Background: Complication avoidance is paramount to the success of any surgical procedure. In the case of spine tumor surgery, the risk of complications is increased because of the primary disease process and the radiotherapy and chemotherapeutics used to treat the disease. If complications do occur, then life-saving adjuvant treatment must be delayed or withheld until the issue is resolved, potentially impacting overall disease control. Methods: We reviewed the literature and our own best practices to provide recommendations on complication avoidance as well as the management of complications that may occur. Appropriate workup of suspected complications and treatment algorithms are also discussed. Results: Appropriate patient selection and a multidisciplinary workup are imperative in the setting of spinal tumors. Intraoperative complications may be avoided by employing proper surgical technique and an understanding of the pathological changes in anatomy. Major postoperative issues include wound complications and spinal reconstruction failure. Preoperative surgical planning must include postoperative reconstruction. Patients undergoing spinal tumor resection should be closely monitored for local tumor recurrence, recurrence along the biopsy tract, and for distant metastatic disease. Any suspected recurrence should be closely watched, biopsied if necessary, and promptly treated. Conclusions: Because patients with spinal tumors are normally treated with a multidisciplinary approach, emphasis should be placed on the recognition of surgical complications beyond the surgical setting.

From the Department of Neurosurgery at the Mayo Clinic College of Medicine, Rochester, Minnesota (MJC), the Neuro-Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (FDV), and the Departments of Neurosurgery and Orthopedics at the University of South Florida Morsani College of Medicine, Tampa, Florida (FDV). Submitted September 26, 2013; accepted November 15, 2013.

124 Cancer Control

Address correspondence to Michelle J. Clarke, MD, Department of Neurosurgery, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905. E-mail: [email protected]. Dr Vrionis receives grants/research support from Globus Medical, DePuy Synthes, and Spine360. He also is a consultant for Orthofix. Dr Clarke reports no significant relationship with the companies/ organizations whose products or services may be referenced in this article. April 2014, Vol. 21, No. 2

Introduction Successful surgical treatment of spinal column tumors entails avoiding and promptly treating surgical complications. Although the goals of surgery are different in cases of metastatic and primary tumors, many of the same principles of complication management may be applied. Surgical treatment is palliative in patients with metastatic disease. Skeletal metastases are a frequent issue because 10% of patients with cancer will develop symptomatic spinal metastases; of these, 50% will require treatment due to pain or neurological deficit.1-3 Mirroring the overall rate of prevalence, the most common solid primary tumors to metastasize to the spine are those in the breast, lung, prostate, and colon.4 Decompression of neurological elements and stabilization of the spinal column are primarily performed to preserve neurological function. Early and complete spinal cord decompression and spinal column stabilization have been shown to preserve or restore ambulation and continence,5 reduce pain,6 and maximize quality of life.7 However, surgery necessitates the temporary suspension of life-prolonging adjuvant cytotoxic therapies to allow healing at the surgical site. Surgical complications, especially those involving wound healing, may further delay the resumption of these therapies and ultimately shorten a patient’s life. Thus, optimizing outcomes in metastatic spine disease focuses on the preservation of function, early mobilization, and the prevention of complications that may delay adjuvant treatment. By contrast, primary tumors make up less than 5% of spinal column tumors,8 but these lesions offer spinal oncologists the opportunity to induce a surgical cure. Because many lesions metastasize late, it is possible to remove the tumor in its undisrupted entirety and completely eliminate the disease. However, such radical “en bloc” procedures are technically challenging and often highly morbid. To remove the tumor in en bloc fashion, surgeons may plan to sacrifice normal tissue and function with the goal of achieving a cure. Strategies to lessen the negative impact of the planned functional loss must be incorporated into the surgical and subsequent treatment plans. Because the goal in this case is cure, the surgeon must also focus on the long-term durability of the procedure. To avoid late failures, an emphasis on restoring biomechanical function with true bony fusion is necessary in patients with long life expectancies. This article will explore the preoperative, intraoperative, and postoperative management options of spinal tumors, emphasizing the prevention of complications. Appropriate workup of suspected complications and treatment algorithms will also be discussed. In general, issues involving primary and metastatic tumor surgery are similar; however, where appropriApril 2014, Vol. 21, No. 2

ate, unique features of en bloc resections of primary lesions will be specifically addressed.

Presurgical Planning Appropriate patient selection and thoughtful multidisciplinary workup are imperative for patients with spinal tumors. The overall rates of disease burden, medical comorbidities, and neurological status must be investigated to determine the expected surgical benefits and anticipated morbidity before committing a patient to an extensive procedure. An appropriate metastatic workup to assess disease burden is also necessary. Radical surgery for cure is possible in patients with disease localized to the primary site, and palliative surgery for functional gains is possible if the patient has a reasonable chance of maintaining or regaining quality of life. A medical evaluation should be performed to ensure that the patient can tolerate the expected physiological challenges of surgery and healing, and that he or she has an expected life span long enough to enjoy the benefits of the procedure. Reasonable expectations should be provided regarding useful neurological function or pain reduction postoperatively and at the convalescence stage. If these basic criteria are not met, then the patient may not achieve the surgical goals of potential cure or successful palliation. If the patient is a surgical candidate, then accurately assessing the feasibility of the procedure and anticipating challenges is the best way to avoid complications. Patient selection and surgical planning for both primary and metastatic tumor surgery are discussed in more detail by Dr Kaloostian and colleagues on page 133 of this issue. Biopsy and Diagnosis Special mention should be made of biopsying suspected primary tumors. If the surgeon desires to affect a cure, then the tumor must be removed in a single, nonviolated mass. Any tumor spillage can result in local recurrence or eventual metastatic spread. Thus, we recommend that the diagnosis be obtained through fine-needle aspirate biopsy with consideration for biopsy tract resection at the time of definitive surgery. To accomplish this, the interventional team should discuss the potential surgical trajectory to ensure tract resection is possible at a later time. Failure to heed this procedure may eliminate the possibility of cure. In many cases, primary tumor pathology is not expected and the patient will undergo open biopsy or partial resection. If the surgeon suspects primary tumor pathology during such a procedure, then he or she should promptly contain the tumor and reduce further spillage, stop the procedure, and complete the workup before proceeding any further. At this point, the surgical site is contaminated. Recommendations on dealing with intraoperative capsular violations are Cancer Control 125

discussed below, including postoperative monitoring and adjuvant therapy options. Hemorrhage Prevention Although intraoperative hemorrhage due to oncological factors is rare, it must be considered, particularly in cases of metastatic spine disease. The cause of hemorrhage in these patients is twofold, coagulation dysfunction due to the primary disease and the direct violation of a hemorrhagic lesion. The preoperative correction of coagulation abnormalities, presurgical and surgical strategies to minimize blood loss, and a plan for intraoperative resuscitation should be outlined prior to the procedure. Of note, intraoperative blood salvage is always avoided due to the risk of metastasizing tumor from the operative site. Frequently the coagulation pathway is disrupted in patients with cancer. Patients with hematological malignancies, those with liver lesions, and patients treated with agents that suppress bone marrow are at especially high risk for hemorrhagic complications. A preoperative assessment of the coagulation cascade and factor correction is mandatory. Blood, fluid, and body warming devices may reduce the likelihood of coagulopathy. Conversely, some patients with cancer are hypercoagulable and are at risk for disseminated intravascular coagulation, deep venous thrombosis, and pulmonary emboli. These later complications may be magnified by reduced mobility in the setting of neurological compromise or pain. Thus, sequential compression devices and early mobilization are mandatory. When feasible, postoperative anticoagulation, such as subcutaneous heparin, may be considered. Therefore, health care professionals should have a low threshold for workup and aggressive treatment of suspected deep venous thrombosis and pulmonary emboli due to these risks. Many highly vascular tumors bleed until they are completely resected and may be difficult to cauterize. In these cases, preoperative embolization may provide an opportunity to decrease overall blood loss9 and provide greater intraoperative visualization of the surgical field. Renal cell carcinoma, follicular thyroid carcinoma, neuroendocrine tumors, and those suspected of hypervascularity on preoperative imaging studies may be considered for preoperative embolization.10 Embolization has the added benefit of localizing important feeding vessels such as the artery of Adamkiewicz, which may be avoided to lessen the risk of spinal cord infarction. If embolization is not technically feasible and the risk of hemorrhage precludes an intralesional tumor resection, then en bloc resection may be considered. This allows the surgeon to avoid violating the hemorrhagic tumor and potentially lessening blood loss; however, the technique is more challenging than intralesional resection. 126 Cancer Control

Intraoperative Complications Intraoperative complications in spinal tumor surgery may be avoided by employing proper surgical technique and an understanding of the pathological changes in anatomy. Tenets such as gentle tissue handling, adequate exposure, ongoing hemostasis, and approaching from normal to abnormal are important. Systematically protecting vital structures and achieving good visualization of the surgical field will make surgery easier in the event of an unanticipated complication. Specific intraoperative complications and management strategies are discussed in the Table. Table. — Selected Intraoperative Complications and Management Strategies of Spinal Tumor Surgery Type

Prevention Strategies

Neurological

Preoperative: Steroids Positioning Intraoperative: Electrophysiological monitoring Elevation of blood pressure Postoperative: Steroids Control of blood pressure

Wound Complications

Preoperative: Appropriate antibiotics Intraoperative: Consider plastic surgery closure/flaps, drains to reduce dead space, and attention to CSF leak repair Consider colostomy if planned sacral root sacrifice and incontinence

CSF Leak

Intraoperative: Primary repair Attention to negative pressure drains/spaces (eg, pleural cavity)

Vascular Injury

Preoperative: Embolization Intraoperative: Vascular surgery or Interventional teams

Visceral Organ Injury

Intraoperative: Protect with adequate retraction General surgery repair

Instrumentation Failure

Intraoperative: Technically adequate reconstruction (eg, load-sharing) Consider vascularized fibulas Postoperative: Close follow-up to catch late failures

CSF = cerebrospinal fluid.

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Neurological Injury Worsening neurological injury through spinal cord or nerve root damage is one complication of spinal tumor surgery. The use of preoperative neuroprotectants, taking care with operative positioning, performing intraoperative electrophysiologic monitoring, and taking a standard approach to suspected injuries should be employed in all cases. In cases of new neurological deficit, high-dose steroids are often preoperatively employed to reduce traumatic edema and potential tumor compression.11 Dosing remains controversial, but often a high loading dose and subsequent maintenance doses as described by Patchell et al5 are used. Following surgery, dosing is tapered off or supplied at an oncologically appropriate dose. Patient positioning is important to protect the central and peripheral nervous systems. Most patients with operative metastatic spine disease also have metastatic epidural spinal cord compression, spinal column instability, or both, so care must be taken to avoid worsening spinal cord compression upon positioning. A documented preoperative neurological examination and prepositioning electrophysiological monitoring provide useful baseline data. Patients should be carefully positioned using the log-rolling or Jackson table sandwich technique. Postpositioning electrophysiological monitoring, radiographic studies of alignment, and wake-up tests may be required before proceeding. If a change occurs during the examination, then the positioning changes should be reversed, the patient awakened and reassessed, and a spinal cord injury protocol considered (as outlined below). In addition, patients may have been exposed to neurotoxic chemotherapeutic agents, thus increasing their risk of compressive peripheral neuropathies with positioning, which can be reduced with judicious attention to operative table padding and straps. Intraoperative electrophysiological monitoring may be helpful for continuously assessing the patient for signs of spinal cord or root dysfunction. Monitoring of somatosensory evoked potentials and motor evoked potentials in cases of spinal cord compression can be employed. In cases of root compression, free-running electromyography may be used. Preoperative baseline data are useful for determining changes. In some cases, spinal cord dysfunction may be so severe that monitoring is not possible. The surgical anesthesia and monitoring teams should quickly respond in the event of an electrophysiological monitoring change. The monitoring technicians should ensure that equipment is properly functioning and not providing erroneous readings. It is useful to monitor proximal to the surgical lesion, because a sudden loss in all signals would indicate an April 2014, Vol. 21, No. 2

equipment failure rather than a local issue at the surgical site. The anesthesia team should ascertain whether a change has occurred in the anesthetic agents used and whether the blood pressure is sufficient for cord perfusion. When a signal change occurs, perfusion pressure may be increased and a steroid infusion begun. The surgical team should assess the spinal cord for reversible compression, particularly if instrumentation placement or deformity correction preceded the change. Immediately relieving the compression, including reversing the deformity correction, should be performed. The blood pressure level may be artificially elevated postoperatively to continue spinal cord perfusion and steroids may be given to the patient, especially in the setting of a new deficit. In both primary and metastatic tumor surgery, nerve roots are often sacrificed to remove the tumor. Because the radicular arteries supplying the cord may also be sacrificed, spinal cord perfusion may be altered, thus putting the patient at risk for ischemic injury. Therefore, even without a neurological deficit, efforts should be taken to avoid hypotension during the perioperative period. Cerebral Spinal Fluid Leak Leakage of cerebral spinal fluid (CSF) may impair wound healing and cause intradural tumor seeding. In some cases, the thecal sac or nerve roots are tied off or a portion of the dura is removed if it has been invaded by the tumor or rhizotomy is performed to provide surgical access. Commonly these are planned events, so the surgeon can plan the repair. However, inadvertent durotomies may also occur and should be promptly addressed. In most cases, repair is accomplished using the standard techniques, such as primary repair, muscle pledget, and dural sealants. Patch grafting may be necessary if a portion of dual is missing. Consideration may be given to temporary lumbar drainage to decrease the level of hydrostatic pressure on the repair. CSF leaks into spaces of negative pressure, such as the thoracic cavity, deserve special mention because metastases most commonly occur in the thoracic spine. Of the two major thoracic approaches, the transthoracic approach has a higher likelihood of an ongoing CSF leak than costotransversectomy, although pleural violations are possible with the latter procedure. If a leak does occur, then close attention to the primary repair is mandatory, and an attempt should be made to separate the leak from the negative pressure chest cavity and tube. In multidisciplinary cases, excellent communication is needed between departmental figures because experts in nonspinal fields may be less attuned to drain management in the event of a CSF leak. Ongoing leakage may lead to CSF hypotension and intracranial subdural hematoCancer Control 127

mas. Any patient with changes in mental status and a known spinal fluid leak should have his or her drains removed from suction and computed tomography of the head should be performed. Spinal fluid leaks can also impair wound healing and promote infection. Although a stable pseudomeningocele (Fig 1) is not ideal, it is also acceptable; however, a multilayer, watertight closure is more durable. Any transcutaneous fistula must be promptly addressed. In these cases, reoperation, attempts at primary closure, and plastic surgery flap placement may be necessary. In addition, CSF diversion techniques, including subfascial drain placement, lumbar drainage, and various lumboperitoneal or ventriculoperitoneal shunts may be employed to promote wound healing. Adjacent Organ and Vascular Injury Surgery may be complicated by injury to an adjacent structure; this is because pathological and anatomical changes may draw normal structures into the operating field. Recognizing this complication preoperatively may allow the patient to undergo protective interventions such as endovascular vessel sacrifice or ureteral stent placement. Specific injuries may prompt emergent intervention by specialty-specific teams. The most life-threatening injury is major vascular transgression. If this occurs, the surgeon must simultaneously alert

A

B

C Fig 1. — A patient underwent a resection for metastatic renal cell carcinoma complicated by a dural tear, followed by local external beam radiotherapy. Three years later, adjacent segment degeneration necessitated revision fusion. At the time of surgery, the previously stable pseudomeningocele (A-B) was breached and the surrounding tissue was friable and devascularized. Despite plastic surgery closure (C), the patient had repeated fascial dehiscences that required multiple wound revisions, lumbar- and ventriculoperitoneal shunt placements, and the permanent use of a corset brace. The patient was hospitalized for 4 months due to wound complications. 128 Cancer Control

the anesthesia team to potential, rapid, high-volume blood loss and attempt to control bleeding. Vascular surgery and interventionalist teams may be required. Similarly, esophageal and bowel injuries often require the prompt attention of otolaryngology or general surgery teams to attempt repair. It should be noted that gastrointestinal tract transgressions greatly increase the risk of infection, and attention must be given to antibiotic management and infection parameters during the postoperative period. Expected Morbidity and Planned Sacrifice In some cases surgical treatment necessitates the sacrifice of adjacent structures, either due to their involvement with the tumor or in order to access the operative cavity. Oftentimes neural structures are sacrificed, the most of which are distal spinal roots in the setting of sacrectomies with a known loss of volitional bowel and bladder control. In these cases, attention to dural repair is necessary to avoid potential wound complications, particularly during possible adjuvant therapies. Chest wall and lung resections, major vascular reanastomoses, and diverting colostomies are common adjuvant procedures depending on the complexity of planned surgical resection. Many permanent long-term sequelae can be predicted based on the surgical plan.

Capsular Violation in En Bloc Resection As noted above, tumor capsule violation may be a planned event in some cases; however, in most cases this is an unplanned occurrence during surgery. Due to the complexity of the cases, the tumor is exposed to trauma and is subjected to manipulation; therefore, both sharp and blunt violations may occur. At the time the violation occurs, the surgeon must quickly react to reduce and contain tumor spillage. Once the tumor and surrounding tissue has been appropriately addressed, any sterile item that may have contacted the tumor must be permanently removed from the sterile field, and all health care professionals present should regown and reglove prior to proceeding to lessen the likelihood of further contamination. The most easily treated violations are those in bone. Because most primary lesions originate in the vertebral body, the most commonly encountered site of bony invasion is tumor that has grown through the pedicles and into the posterior elements. If the bone has been skeletonized prior to encountering tumor, then the visible tumor is coated in bone wax to prevent further egress. If there is surrounding tissue that becomes contaminated, then it is removed and the skeletonized bone cauterized and waxed. The simplest area for planned tumor violation is the pedicles, in which case they are skeletonized, the surrounding area covered in surgical patties to minimize April 2014, Vol. 21, No. 2

contamination, and the posterior elements removed and immediately taken from the surgical field. The remaining pedicle stubs are promptly waxed, the area examined for evidence of contamination, and the surgical patties discarded from the field. By contrast, soft-tissue capsular violations are more difficult. The tumor is often soft and surrounded by a fibrous capsule. If the capsule is disrupted, then the tumor can extrude through the rent due to the pressure of manipulation; therefore, it is important to occlude the rent and reinforce the capsule to prevent further extrusion with ongoing manipulation. Internally debulking a portion of the tumor through the tear may also be necessary to reduce the likelihood of extrusion under pressure. If the surgeon is able, he or she should oversew the capsular tear to regain a degree of structural integrity. If it is possible to occlude the rent in a watertight fashion, then further tumor extrusion may be avoided. Following reapproximation of the rent, a fibrin sealant may be applied to further protect against spillage. In cases in which a large piece of the tumor breaks away and the capsule cannot be approximated, cautery and fibrin sealant are used. Care should be taken to manipulate this area as little as possible to prevent further contamination. In all cases, the surrounding area should be inspected, cauterized, and, if possible, resected once the tumor has been sealed to minimize local recurrence.

a previously irradiated field. Radiation may result in devitalized tissue in the operative bed, increasing the likelihood of healing and infection issues. Radiation treatment that includes issue sparing should be considered even if surgery is not planned at the time of treatment.14 Image-guided radiotherapy may allow tumor bed treatment without irradiating the skin and fascial closure, thus promoting wound healing. In addition, the surgeon should have a low threshold for plastic surgery intervention and well-vascularized soft-tissue flap closure.14

A

Postoperative Complications Major postoperative issues include wound complications and spinal reconstruction failure. Both incisional closure and spinal reconstructions are challenging, but adjuvant radiation and chemotherapy compound the healing process. Preoperative surgical planning must include postoperative reconstruction. Patients must be followed for appropriate signs of healing, and early intervention should be employed if wound or construct failures are noted. Wound Healing Wound dehiscence and infection are challenging issues that have considerable morbidity and can delay adjuvant therapies (Fig 2). Patients with cancer have a higher risk of surgical site infection than other patients undergoing spinal surgery.12-14 Immunosuppressing adjuvant therapies, local radiation, and systemic factors such as anemia and decreased nutritional status predispose patients with metastatic tumors to issues of wound healing and infection. In the setting of primary tumors, a patient’s risk increases with surgical site issues, such as previous radiation, long surgical duration, CSF leakage, and previous local radiation.14 In some cases, radiation is employed to promote local tumor control prior to surgery; however, in other cases, surgery is an unplanned necessity in April 2014, Vol. 21, No. 2

B

C Fig 2A-C. — A patient 65 years of age with a sacral aggressive hemangioma who had received 3 operations and radiation therapy twice underwent a fourth debulking for pain relief and to preserve continence. The patient’s incision became infected and required a 6-month inpatient course of multiple plastic surgery revisions to stabilize. This included (A) debridement, (B) a DermaClose (Wound Care Technologies, Chanhassen, Minnesota) tensioning device to slowly close the wound, and (C) use of a vacuumassisted closure device before definitive closure with a vascularized latissimus dorsi flap. Cancer Control 129

The morphology of the surgical site places the patient at risk for wound complications. Oncological spine approaches, particularly en bloc resections, require wide operative corridors to allow the surgeon to control the tumor and surrounding structures. Incisions may be difficult to approximate due to their size, location, or unusual features, such as those J-shaped in size to provide access. In addition, large voids in which the tumor or surrounding resected tissue was removed may create a large dead space that must be addressed. In many cases, plastic surgery may be useful at the time of original reconstruction to ensure closure of the dead space and coverage of the surgical site. In most cases in which a posterior approach is employed, paraspinal muscle flaps are the simplest and most effective way to provide soft-tissue coverage. Repeat wound infection or dehiscence also warrants plastic surgery intervention. In many cases, specific surgical site issues are present that make healing difficult. For example, protruding bone or hardware with inadequate soft-tissue coverage promotes wound breakdown. Likewise, ongoing spinal fluid leakage from open dural openings, ongoing chyle leak, or bowel injury may result in fluid collections, tissue tension, and local infection that preclude adequate healing. The surgeon should explore wounds and rule out or repair auxiliary issues before attempting plastic surgery closure. Three areas of the spine are challenging, including the upper cervical spine, the thoracic spine and chest wall, and the lower lumbar and sacral spine. Transoral or extended transoral/transmandibular split approaches may be necessary in the upper cervical spine. In these cases, reconstruction is likely required and may include titanium cages, cadaver bone, or, on occasion, vascularized autograft. A single layer of pharyngeal tissue may cover this graft, and the patient may be subjected to local adjuvant radiation depending on the surgical situation. Local rotational flaps used can include the trapezius, sternocleidomastoid, and the pectoralis major. Due to the extensive vascular supply in the head and neck, vascularized free flaps are also commonly employed. Otolaryngological and anesthesia support are required to compete these procedures, and delayed extubation, postoperative feeding tubes, and close attention to diet and swallowing functions are mandatory. Any sign of wound dehiscence must be treated with reclosure and intravenous antibiotics. It may not be possible to remove the instrumention due to the nature to reconstruction following high cervical en bloc resections. In the thoracic spine, wound closure may involve reconstruction of the chest wall to re-create respiratory biomechanics. In these cases, mesh and methylmethacrylate may be used to provide the scaffolding upon which the chest, shoulder, and back muscles 130 Cancer Control

will sit. It should be noted that lung expansion is not limited to the original chest volume. In some cases of circumferential decompression of the thoracic spinal cord, reinflation of the lungs resulted in decreased intraoperative spinal monitoring signals, and it was noted that the lungs themselves were compressing the spinal cord.15 Thus, re-creating the spinal canal may also be important. Local vascularized flaps may be rotated to provide soft-tissue coverage, with local paraspinal musculature, trapezius, and intercostal flaps most commonly employed. The sacral spine is challenging to reconstruct. A paucity of soft tissue covers the reconstruction cavity in this region, and nearby tissues have little flexibility. Most centers employ an anterior–posterior approach to large sacral resections, allowing the vascularized abdominis rectus flap to be harvested, which can then be passed through the surgical defect to close the skin under tension and fill the large dead space following tumor resection.16-18 A posterior-only approach has been advocated to reduce operative time and the additional morbidity of the anterior approach without an increase in wound issues.19,20 In this case, superior gluteal vascularized muscle flaps and paraspinal muscle advancement may be employed. Beyond the technical aspects of closure, planned incontinence increases the likelihood of wound infection in sacral tumor resections.21 In many cases, involved pelvic structures, including bowel or sacral roots, are resected along with the surgical specimen, leaving the patient with little to no voluntary bowel and bladder control in the setting of reduced mobility during the postoperative period. Combined with the proximity of the sacral wound, infection is common.22 Surgical techniques have been employed in an attempt to reduce infection, including preoperative povidone/ iodine enemas, tight closures with a layer of surgical glue, and watertight dressings. Diverting colostomies may assist patients in coping with incontinence while also simultaneously protecting the wound.16,23-28 Any sign of infection or wound dehiscence should be promptly treated. Imaging studies to assess the extent of the issue, baseline serologic inflammatory markers, cultures, and antibiotics under the supervision of infectious disease services should be employed. Oftentimes infections, especially those in the pharyngeal and sacral areas, may be caused by organisms not commonly seen in a neurosurgical or orthopedic setting. Patients may not present in a standard fashion, but instead with an insidious infection without a large systemic response, and they will not improve on standard skin-flora-specific antibiotics. In cases of suspected infection, there should be a low threshold for intraoperative culture and washout. Antibiotics can then be tailored to the causative agents. April 2014, Vol. 21, No. 2

Spinal Reconstruction Failure In most cases of spinal tumor resection, the biomechanical capacity of the spinal column must be reconstructed. However, the situation is unusual because multisegment gaps are common when all spinal elements have been removed. These gaps must be filled to restore the load-bearing capacity of the spine. This procedure is usually performed with titanium cages or bone grafts. In addition, the spine must be stabilized so that the weight is supported despite dynamic stresses, thus a posterior tension band involving screws and rods is usually employed. In certain areas such as the occipitocervical and spinopelvic regions, the transfer of forces is more complex. In the upper cervical region, the main load is transferred through the occipital condyles and lateral masses of C1 and C2, not the vertebral bodies, so multiple constructs have been employed. In the spinopelvic region, forces are transferred from the spine to the pelvic ring and onto the lower limbs. To restore function, this must be reapproximated despite very high biomechanical loads. Spinal reconstructions can fail in 3 major ways. Early failures occur before expected bony healing can occur. Examples of these failures include screw pullout and cage subsidence. Although early failures may involve technically poor surgery, the bone quality of patients with cancer exacerbates this issue due to bony tumor involvement, poor bone metabolism, and osteodestructive medications such as steroids. Many of the same techniques used to manage osteoporotic bone are useful in tumor reconstruction. Increasing the load sharing by lengthening constructs, undertapping, or not tapping screw holes may increase the purchase, and buttressing instrumentation with methylmethacrylate are useful adjuncts. Late failures involve a failure of bony healing. These cases manifest in pseudarthroses and rod breakage. Because the main goal of primary tumor surgery is to obtain a cure and many patients with metastatic tumors lead long lives, attention to successful arthrodesis is important. Bone healing is impaired by cancer-induced metabolic changes and adjuvant therapies, particularly local radiation. In some cases, reconstruction may include vascularized bone grafts, such as from the fibula or rib, to optimize healing.29,30 Bone morphogenic protein should not be used due to uncertainties regarding its effects on tumor growth. Late failures occur in the setting of successful fixation (Fig 3). In this case, junctional issues may occur above or below the construct in the same fashion as late adjacent segment disease manifests in spinal fusions for other conditions. Attention to basic spine surgical principals to optimize durability should be employed at the time of surgery. It may be possible to use cement augmentation to salvage junctional fracApril 2014, Vol. 21, No. 2

tures above or below the construct without resorting to instrumention revision, potentially allowing the patient to continue adjuvant treatments while avoiding a major surgical intervention. Despite the best surgical plans, instrumentation and construct failure may occur and may be catastrophic. As challenging as the reconstruction is at the index procedure, scarring, radiation changes, and broken bone or instrumentation may leave the surgeon with fewer options. However, any construct failure that risks further injury must be addressed. Further surgery may be warranted in cases of increased dis-

A

B

C

D Fig 3. — A patient with renal cell carcinoma underwent debulking and stabilization (A-B). Three years later he developed severe back pain and a compression fracture was found at the level adjacent to the fusion (C), necessitating revision surgery (D). Cancer Control 131

ease burden or in cases in which ongoing instability creates mobility-limiting pain.

Recurrent Tumor All patients undergoing spinal tumor resection should be closely monitored for local tumor recurrence, recurrence along the biopsy tract, and for distant metastatic disease. Any suspected recurrence should be closely watched, biopsied if necessary, and promptly treated. In most cases, primary tumors locally recur. Local recurrence is more closely linked to overall survival than with distant metastatic disease. If local recurrence is noted, then the patient should be restaged to determine if metastatic disease is present. If metastatic disease is located, treatment should be palliative, with adjuvant therapy and potential resection determined on a case-by-case basis. If the local recurrence is the only region of disease, then en bloc resection may be warranted. A paucity of evidence exists to determine the survival advantage to en bloc resection in these cases, but if the patient has not developed metastases, local control may still be possible. These cases are considered to have contaminated margins and postoperative local adjuvant therapy is warranted to maximize response. Although local tumor recurrence is frequent in metastatic disease, distant metastases and overall disease burden may dictate future treatment options. It is reasonable to restage patients to determine their overall fitness and to pursue further surgical options if new or recurrent spinal metastases are noted.

Conclusions Surgical resection of spinal tumors is one of the most rewarding areas of surgical oncology. However, these technically complex cases also have a unique set of potential complications. Meticulous multidisciplinary preoperative planning, a high index of suspicion in the event of a problem, and prompt, aggressive treatment are mandatory. References 1. Arrigo RT, Kalanithi P, Cheng I, et al. Predictors of survival after surgical treatment of spinal metastasis. Neurosurgery. 2011;68(3):674-681. 2. Harel R, Angelov L. Spine metastases: current treatments and future directions. Eur J Cancer. 2010;46(15):2696-2707. 3. Sciubba DM, Petteys RJ, Dekutoski MB, et al. Diagnosis and management of metastatic spine disease. A review. J Neurosurg Spine. 2010; 13(1):94-108. 4. Gokaslan ZL, York JE, Walsh GL, et al. Transthoracic vertebrectomy for metastatic spinal tumors. J Neurosurg. 1998;89(4):599-609. 5. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643-648. 6. Wang JC, Boland P, Mitra N, et al. Single-stage posterolateral transpedicular approach for resection of epidural metastatic spine tumors involving the vertebral body with circumferential reconstruction: results in 140 patients. Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2004. J Neurosurg Spine. 2004;1(3):287-298. 7. Laufer I, Sciubba DM, Madera M, et al. Surgical management of metastatic spinal tumors. Cancer Control. 2012;19(2):122-128. 8. Boriani S, Biagini R, De Iure F, et al. Primary bone tumors of the 132 Cancer Control

spine: a survey of the evaluation and treatment at the Istituto Ortopedico Rizzoli. Orthopedics. 1995;18(10):993-1000. 9. Guzman R, Dubach-Schwizer S, Heini P, et al. Preoperative transarterial embolization of vertebral metastases. Eur Spine J. 2005;14(3):263-268. 10. Bilsky MH, Fraser JF. Complication avoidance in vertebral column spine tumors. Neurosurg Clin North Am. 2006;17(3):317-329, vii. 11. Loblaw DA, Mitera G, Ford M, et al. A 2011 updated systematic review and clinical practice guideline for the management of malignant extradural spinal cord compression. Int J Radiat Oncol Biol Phys. 2012;84(2):312-317. 12. Xu R, Garcés-Ambrossi GL, McGirt MJ, et al. Thoracic vertebrectomy and spinal reconstruction via anterior, posterior, or combined approaches: clinical outcomes in 91 consecutive patients with metastatic spinal tumors. J Neurosurg Spine. 2009;11(3):272-284. 13. Omeis IA, Dhir M, Sciubba DM, et al. Postoperative surgical site infections in patients undergoing spinal tumor surgery: incidence and risk factors. Spine (Phila Pa 1976). 2011;36(17):1410-1419. 14. Dunning EC, Butler JS, Morris S. Complications in the management of metastatic spinal disease. World J Orthop. 2012;3(8):114-121. 15. Sciubba DM, Gokaslan ZL, Black JH III, et al. 5-Level spondylectomy for en bloc resection of thoracic chordoma: case report. Neurosurgery. 2011;69(2 suppl Operative):onsE248-256. 16. Miles WK, Chang DW, Kroll SS, et al. Reconstruction of large sacral defects following total sacrectomy. Plast Reconstr Surg. 2000;105(7):2387-2394. 17. Gallia GL, Haque R, Garonzik I, et al. Spinal pelvic reconstruction after total sacrectomy for en bloc resection of a giant sacral chordoma. J Neurosurg Spine. 2005;3(6):501-506. 18. Loessin SJ, Meland NB, Devine RM, et al. Management of sacral and perineal defects following abdominoperineal resection and radiation with transpelvic muscle flaps. Dis Colon Rectum. 1995;38(9):940-945. 19. McLoughlin GS, Sciubba DM, Suk I, et al. En bloc total sacrectomy performed in a single stage through a posterior approach. Neurosurgery. 2008;63(1 suppl 1):ONS115-ONS120. 20. Clarke MJ, Dasenbrock H, Bydon A, et al. Posterior-only approach for en bloc sacrectomy: clinical outcomes in 36 consecutive patients. Neurosurgery. 2012;71(2):357-364. 21. Sciubba DM, Nelson C, Gok B, et al. Evaluation of factors associated with postoperative infection following sacral tumor resection. J Neurosurg Spine. 2008;9(6):593-599. 22. Guo Y, Palmer JL, Shen L, et al. Bowel and bladder continence, wound healing, and functional outcomes in patients who underwent sacrectomy. J Neurosurg Spine. 2005;3(2):106-110. 23. Junge K, Krones CJ, Rosch R, et al. Mesh reconstruction preventing sacral herniation. Hernia. 2003;7(4):224-226. 24. Radice E, Nelson H, Mercill S, et al. Primary myocutaneous flap closure following resection of locally advanced pelvic malignancies. Br J Surg. 1999;86(3):349-354. 25. Diaz J, MacDonald W, Armstrong M, et al. Reconstruction after extirpation of sacral malignancies. Ann Plastic Surg. 2003;51(2):126-129. 26. Dasenbrock HH, Clarke MJ, Bydon A, et al. Reconstruction of extensive defects from posterior en bloc resection of sacral tumors with human acellular dermal matrix and gluteus maximus myocutaneous flaps. Neurosurgery. 2011;69(6):1240-1247. 27. Koh PK, Tan BK, Hong SW, et al. The gluteus maximus muscle flap for reconstruction of sacral chordoma defects. Ann Plast Surg. 2004;53(1): 44-49. 28. Di Mauro D, D’Hoore A, Penninckx F, et al. V-Y bilateral gluteus maximus myocutaneous advancement flap in the reconstruction of large perineal defects after resection of pelvic malignancies. Colorectal Dis. 2009;11(5): 508-512. 29. Ackerman DB, Rose PS, Moran SL, et al. The results of vascularizedfree fibular grafts in complex spinal reconstruction. J Spinal Disord Tech. 2011;24(3):170-176. 30. Eastlack RK, Dekutoski MB, Bishop AT, et al. Vascularized pedicled rib graft: a technique for posterior placement in spinal reconstruction. J Spinal Disord Tech. 2007;20(8):610-615.

April 2014, Vol. 21, No. 2

Management of primary and metastatic spinal tumors is complex and requires a multidisciplinary approach.

Burnell Shively. Artichoke Heart, 2013. Oil on canvas, 31 ½ʺ × 31 ½ʺ.

Surgical Management of Primary and Metastatic Spinal Tumors Paul E. Kaloostian, MD, Patricia L. Zadnik, BA, Arnold B. Etame, MD, PhD, Frank D. Vrionis, MD, PhD, Ziya L. Gokaslan, MD, and Daniel M. Sciubba, MD Background: The axial skeleton is a common site for primary tumors and metastatic disease, with metastatic disease being much more common. Primary and metastatic spinal tumors have a diverse range of aggressiveness, ranging from benign lesions to highly infiltrative malignant tumors. Methods: The authors reviewed the results of articles describing the treatment and outcomes of patients with metastatic disease or primary tumors of the spinal column. Results: En bloc resection is the mainstay of treatment for malignant primary tumors of the spinal column. Intralesional resection is generally appropriate for benign primary tumors. Low-quality evidence supports the use of chemotherapy in select primary tumors; however, radiation therapy is often used for incompletely resected or unresectable lesions. Surgical considerations for the treatment of metastatic disease are more nuanced and require that the health care professional consider patient performance status and the pathology of the primary tumor. Conclusions: The treatment of metastatic and primary tumors of the spinal column requires a multidisciplinary approach in order to offer patients the best opportunity for long-term survival.

Introduction The axial skeleton is a common site for primary tumors and metastatic disease, with metastatic disease being much more common. Both primary and meta-

From the Department of Neurosurgery at Johns Hopkins Hospital, Baltimore, Maryland (PEK, PLZ, ZLG, DMS), the Neuro-Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (ABE, FDV), and the Departments of Neurosurgery and Orthopedics at the University of South Florida Morsani College of Medicine, Tampa, Florida (ABE, FDV). Submitted October 1, 2013; accepted November 13, 2013. Address correspondence to Daniel M. Sciubba, MD, Johns Hopkins Hospital, 600 N. Wolfe Street, Meyer 5-185, Baltimore, MD 21287. E-mail: [email protected] April 2014, Vol. 21, No. 2

static spinal tumors have a diverse range of aggressiveness, ranging from benign lesions to highly infiltrative malignant tumors. This article will review a variety of primary and metastatic bony tumors of the spine,

Dr Vrionis receives grants/research support from Globus Medical, DePuy Synthes, and Spine360. He also is a consultant for Orthofix. Dr Gokaslan receives research grants from AO North America, the Neurosurgery Research and Education Foundation, Medtronic, Integra Life Sciences, Depuy Spine, and K2M. He receives honoraria from the AO Foundation and is a stock shareholder of US Spine and Spinal Kinetics. No significant relationship exists between the remaining authors and the companies/organizations whose products or services may be referenced in this article. Cancer Control 133

each of which display unique pathophysiological and histological properties that help determine current diagnostic and treatment modalities. We will also discuss a wide variety of surgical techniques, including advances in en bloc vertebrectomy, as well as recent advances in medical and stereotactic radiotherapy for the treatment of tumors within the vertebral column. Surgical treatments discussed include conventional debulking vs en bloc resection, conventional radiotherapy and radiosurgical techniques, and minimally invasive approaches. The differential diagnosis for primary cancer in metastatic spinal tumors is wide and includes lung, breast, prostate, renal cell, and gastrointestinal neoplasms. Although rare, tumors from other areas of the body may also spread to the spine. The differential diagnosis of primary bony tumors of the spine may include chordoma, giant cell tumor, hemangioma, osteosarcoma, chondrosarcomas, synovial sarcoma, aneurysmal bone cyst, hemangioma, eosinophilic granuloma, osteoid osteoma, and osteoblastoma pathologies. Other lesions that may mimic primary spinal tumors include infection, metastatic disease, and, possibly, spontaneous or traumatic hematoma.

Diagnosis of Spinal Tumors Patients who have spinal tumors commonly present with chronic and progressively worsening focal back pain.1-3 Depending on the morphological characteristics of the spinal tumor, tumor size, and infiltration to the surrounding neural and vascular structures, patients may have intractable radiculopathy, myelopathy, or cauda equina syndrome. Paraspinal pain is due to infiltration of the tumor into surrounding muscle and subcutaneous tissues, while radiculopathy is due to tumor extension into the neural foramen, compressing exiting nerve roots. Tumor burden extending within the spinal canal in the epidural space may cause compression of the spinal cord and neurological compromise. On physical examination, patients with cervical spinal cord compression have signs of myelopathy, such as a positive Hoffman sign, spastic weakness as well as hyperreflexia in the upper and lower extremities, upgoing Babinski signs bilaterally, and gait instability. With further tumor extension, vascular supply to the spinal cord becomes compromised and the neural structures become compressed. Patients with severe spinal cord compression may present with quadriplegia with a sensory or motor level. Patients with lumbosacral tumors with canal compromise may have weakness and/or numbness in one or both extremities, and evidence of perineal numbness and saddle anesthesia. Patients with lumbosacral tumors with severe canal and foraminal involvement may present with low back pain and cauda equina syndrome with 134 Cancer Control

perineal numbness, bowel and bladder dysfunction, and/or lower extremity weakness. Diagnostic modalities for tumors of the spine include computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) scans, and CT of the chest, abdomen, and pelvis.4 CT scans can help determine the extent of the tumor erosion within the vertebral anatomy as well as the extent of destruction from the anterior to the posterior columns of the spine. MRI scans (with and without contrast) are critical for observing tumors of the spinal column. Compared with CT, MRI can more clearly delineate the anatomy of the tumor and the extent of its enhancement. MRI will further identify regions of the tumor that may be cystic or necrotic without enhancement, as well as the extension of the tumor burden into surrounding tissues. In addition, MRI is important when identifying tumor burden within the epidural space and the extent of neural element compression or injury, either centrally or foraminally. PET scans are helpful in determining other areas of abnormal radioactive uptake of glucose throughout the body, signifying possible metastatic disease or tumor elsewhere. CT of the chest, abdomen, and pelvis (with and without contrast) is often obtained to rule out other areas of tumor burden to then rule out metastatic disease. Standard laboratory tests, including white and red blood cell counts, coagulation numbers, and electrolyte levels should be obtained to rule out infectious process and prepare the patient for possible surgical intervention. If no other lesions are noted elsewhere based on CT, MRI, and PET scans, then core biopsy should be performed of an isolated spinal column lesion without acute deterioration to obtain a definitive diagnosis. The interventional radiology team can percutaneously perform this procedure using fluoroscopic guidance. For malignant lesions, the biopsy tract should be carefully marked and excised upon definitive surgical management.5 Open biopsy for malignant lesions should be avoided to reduce the risk of metastatic seeding. Once this is done and a diagnosis is obtained, the multidisciplinary treatment plan can be arranged. Determining whether the spinal column mass is a primary spinal tumor vs metastatic disease or infection is crucial before beginning surgical treatment. Metastatic disease is classically treated with intralesional resection due to tumor burden elsewhere, while en bloc resection for primary spinal tumors has improved patient outcome and survival rates over the last decade.

Primary Tumors Primary spinal column tumors include malignant pathologies such as chondrosarcoma, osteosarcoma, Ewing sarcoma, and chordoma. For these pathologies, en bloc resection with adjuvant radiotherapy proApril 2014, Vol. 21, No. 2

vides the best chance of cure.6-15 By contrast, benign primary tumors, such as aneurysmal bone cyst, giant cell tumor, and osteoblastoma, may be safely treated with intralesional resection, radiotherapy, or both to reduce the risk of surgical morbidity.16,17 This section will review the indications for en bloc resection and the advances in adjuvant therapy for primary tumors. En Bloc Resection of Primary Spinal Tumors Many studies validate the role of en bloc resection as the standard of care for primary spinal column tumors.7,18-23 The goal of en bloc tumor resection is to provide local oncological control and prevent the seeding of tumor cells into surrounding tissues. This strategy avoids dissemination of the tumor and ultimately leads to decreased local recurrence as well as prolonged disease-free and overall survival rates.11,18-22,24 However, anatomical considerations often limit the feasibility of this approach. En bloc resection of cervical lesions is complex and is not without significant morbidity and mortality risks. For this reason, a preoperative understanding of patient pathology, involvement of neural and vascular structures, and intracranial vascular anatomy is important in determining patient outcomes. One such risk factor is injury to vertebral arteries. Depending on primary spinal tumor morphology and extension, the vertebral arteries may be encased with tumor on presentation, adding to the danger of surgical resection. Cranial anastomotic anatomy to the posterior circulation is critical in cases of bilateral or dominant vertebral artery injury or intraoperative and postoperative vasospasm. During vertebral artery manipulation, any neurological decline in neuromonitoring during temporary clipping necessitates artery preservation. Although some studies have recommended a clear avoidance of en bloc vertebrectomy in the cervical spine due to the risk posed to the vertebral arteries and cervical nerve roots, others have published data demonstrating its safety and feasibility. Hoshino et al25 published a study of 15 patients undergoing unilateral vertebral artery ligation during en bloc resection of cervical spinal tumors and noted no adverse events affecting the brain stem, spinal cord, or cerebellum. In a meta-analysis by Cloyd et al,26 8 of the 18 patients undergoing en bloc resection of primary cervical spinal tumors had unilateral vertebral artery ligation without complication. Other possible risk factors involved in en bloc resection of primary cervical spinal tumors include infection, significant bleeding, dysphagia, aspiration, spinal instability, seeding of tumor cells into surrounding tissues and into the cerebrospinal fluid if a dural tear is encountered, and spinal cord, nerve root, and large vessel injuries, including the internal carotid arteries, vertebral arteries, and internal jugular veins.26 April 2014, Vol. 21, No. 2

Careful preoperative planning may reduce complication rates for tumor resection at all levels of the spinal column. Tomita et al27 described the use of preoperative embolization of vessels supplying spinal tumors. A significant decrease was reported in intraoperative bleeding with preoperative embolization, meticulous blunt dissection, and tumor resection, as well as with the use of fibrin glue in the epidural venous plexus. In addition, use of a T-saw for pediculectomy or anterior column osteotomy was seen in a separate study.28 The researchers reported a decrease in tumor spread following the use of the T-saw. Postoperative considerations, such as reconstruction, are another cause for concern in patients undergoing en bloc resection. Specifically, for patients undergoing en bloc resection of the large mobile spine chordoma, generating a custom cage or construct may be necessary to facilitate adequate reconstruction. Similarly, in the sacral spine, resection of more than one-half of the sacroiliac joint requires reconstruction of the spinopelvic junction with bone grafts and instrumentation.21,29 However, with advances in surgical technique, the benefit of en bloc resection has been independently demonstrated for various pathologies of primary vertebral tumor. In a landmark study by Boriani et al,30 recurrence rates following surgical resection in a group of 22 patients with spinal chondrosarcoma were 21.4% for patients with en bloc resection compared with 100% for patients undergoing repeat curettage. Strike and McCarthy8 reported a cohort of 16 patients with predominantly low-grade chondrosarcoma with total resection. This study reported that, despite 14 of 16 patients receiving total resection, the mean interval to death was 3.6 years, and 43.8% of patients died from pulmonary metastases. Furthermore, 100% of patients with subtotal resection developed metastases.8 Talac et al31 studied patients with primary sarcomas of the spine undergoing en bloc resection with negative margins, piecemeal resection with negative margins, and all resections with positive margins, reporting recurrence rates of 11%, 33%, and up to 70% in these groups, respectively. En bloc resection in chordoma has also been studied. Patient outcomes are classically reported using the cervical, mobile spine, and sacral levels of disease. One group reported five cases of en bloc chordoma excision in the cervical spine with a mean disease-free survival rate of 84.2 months.18 Cloyd et al26 performed a meta-analysis of the existing literature on cervical primary spinal tumors with en bloc resection. The analysis involved 10 articles comprising 18 cases. The authors identified a combined recurrence rate of 22% in all published studies for primary cervical spine tumors, with a mean follow-up time of 47.4 months. The group then calculated disease-free survival rates of approximately 88% and 76% at 1 and 5 years, reCancer Control 135

spectively. No factors were identified as predictive of recurrence in this meta-analysis. During a 5-year follow-up period, Carpentier et al32 noted recurrence and mortality rates of 40% and 33%, respectively, in their study of 16 patients with occipitocervical chordoma undergoing intralesional resection. In addition, Barrenechea et al33 studied 7 patients with intralesional piecemeal resections of cervical chordomas and noted a recurrence rate of approximately 30% over a median of 2 years of follow-up. In the mobile spine and sacrum, en bloc resection of chordoma may prolong survival. In the largest study to date of patients with mobile spine chordoma, Boriani et al34 reported superior outcomes in patients with en bloc resection and adjuvant therapy; 4 patients remained free of disease for a mean of 77 months. Furthermore, multiple studies of sacral chordoma have confirmed improved survival and decreased recurrence rates for patients undergoing en bloc resection.7,21,35-39 Surgical treatment of Ewing and osteogenic sarcomas of the spine has noted recent advances in the previous decade. Sciubba et al14 published data with strong recommendations and moderate quality evidence of neoadjuvant chemotherapy, but with a weak recommendation with low evidence for en bloc surgical resection for Ewing sarcoma of the spine. They also reported that en bloc surgical resection provided improved local control but did not improve overall survival rates. By contrast, for benign but aggressive lesions in the spine, intralesional resection is generally recommended.17,40-42 In one study, Harrop et al17 reviewed the quality of evidence supporting surgical resection for an aneurysmal bone cyst, giant cell tumor, and osteoblastoma and concluded that gross resection is an appropriate therapy for these lesions. However, recurrence rates for these benign lesions are not negligible. Junming et al41 analyzed 21 patients undergoing piecemeal resection of cervical giant cell tumors and noted a recurrence rate of 33% over a mean follow-up of 68 months. Further, Boriani et al42 reported a case series of 51 patients with spinal osteoblastoma and found that en bloc resection was more effective for stage 3 lesions compared with those with stage 2 lesions. Adjuvant Therapy for Primary Tumors The role of adjuvant treatment along with chemotherapy and radiation is still unclear in the treatment of primary spinal tumors and varies by pathology. Chordomas are classically resistant to conventional radiation treatments at doses favorable to surrounding tissues at below 60 Gy.43 By contrast, proton beam radiotherapy (PBRT) utilizes ionizing radiation with reduced scatter in surrounding tissues and has demonstrable benefit in unresected or partially resected chordoma of the 136 Cancer Control

cervical spine, mobile spine, and sacrum.43-46 Further, in a cohort of 44 consecutive patients with chordoma and chondrosarcoma of the skull base, PBRT in combination with conventional photon radiotherapy resulted in 3-year local control rates of 83.1% for chordoma and 90% for chondrosarcoma.47 The use of radiotherapy to treat benign primary tumors, such as giant cell tumor, has been debated. In a retrospective review of 239 treated lesions, Leggon et al48 reported that recurrence rates were not low for patients who had surgery and radiation versus a solitary modality. Another retrospective review of 25 patients with giant cell tumors in the axial and appendicular skeleton reported a 5-year overall survival rate of 91%.49 The study authors concluded that conventional radiotherapy was appropriate for unresectable giant cell tumors or as adjuvant therapy. However, complications associated with radiotherapy are not insignificant. Such complications include wound breakdown and infection (particularly if performed at least 2 weeks before surgical treatment), neurological decline from radiation necrosis, and radiation-induced malignancy. Neoadjuvant chemotherapy for Ewing sarcomas and osteogenic sarcomas has shown to have benefits, along with radiotherapy for Ewing sarcoma. Expert consensus supports the use of radiation therapy alone or as adjuvant treatment for local control, although the evidence cited was very low.14 For patients with osteogenic sarcoma, the consensus supported a strong recommendation with moderate quality evidence favoring neoadjuvant chemotherapy. The consensus also strongly recommended (but with very low evidence) en bloc resection in order to provide improved local control and potentially improved overall survival rates. Chemotherapy with imatinib mesylate was shown in one study to benefit patients with spinal chordomas, although further studies are required.50,51

Metastatic Tumors Spinal metastatic disease with cord compression occurs in 5% to 14% of patients with cancer and results in significant morbidity rates.52-58 The most common tumors to metastasize to the spinal column are lung, breast, prostate, renal cell, and gastrointestinal tumors. A rare subset of spinal tumors has no known primary site identified.59-62 In addition, the histological diagnosis and grade of metastatic tumor pathology is critical in diagnosis and management. Indications for Surgery Historically, surgical intervention for patients with spinal metastatic disease has been controversial due to poor prognosis. Limited palliative intervention with radiation was previously utilized to minimize pain for patients with a terminal illness and at the end of life. However, Patchell et al63 published a nonrandomized April 2014, Vol. 21, No. 2

control clinical trial in 2005 of laminectomy plus radiation compared with radiation alone for the treatment of metastatic spine disease. The study was terminated early due to the overwhelming superiority of surgery with radiation versus radiation alone. Patients in the surgery plus radiation group were more likely to walk after treatment (odds ratio: 6.2) and retained the ability to walk for longer than their counterparts in the radiation-only group (122 vs 13 days). Further, the use of opiate and steroidal medications was reduced in the surgical cohort. Since the Patchell et al study, multiple studies have confirmed that surgery for spinal metastases improves patient quality of life.64,65 The outcome of surgical intervention for metastatic spinal cord compression is related to the preoperative clinical status of the patient. Patients who are severely disabled upon presentation may improve, but this likelihood decreases if their deficits are severe and have been present for a prolonged period of time prior to surgical intervention.66 Further, overall survival rates vary by pathology.67-70 Of note, the presence of visceral metastases does not appear to influence patient outcome68,71; thus, surgical decision-making varies depending on patient presentation, tumor type, and performance status. To guide surgical decision-making, a variety of scoring systems have emerged such as the Spinal Instability Neoplastic Score (SINS), Tokuhashi system, and the Tomita system.72-74 The 6-point SINS system considers instability based on the extent of vertebral body collapse, quality of pain, location of metastasis, alignment, radiographic appearance, and posterior element involvement.72 Tokuhashi et al74 devised a 15-point scale and later revised this system, taking into consideration Karnofsky performance score, extent of vertebral metastases, extent of extraspinal bone metastases, extent of visceral metastases, tumor histology, and neurological status. Based on the results of these studies, patients with a life expectancy based on the revised scoring scale of fewer than 6 months were recommended to undergo conservative treatment, while those with a life expectancy of 1 year or more were recommended to undergo excisional surgery. Those expected to survive 6 months or more were recommended to undergo limited palliative surgery. Tomita et al73 devised a 10-point scale taking tumor histology and extent of visceral and bony metastases into account in determining goals for surgery and prognosis. The use of these scoring systems was critically evaluated in the literature.75,76 In their evaluation of the SINS system, Fourney et al76 studied 30 patients with spinal tumors and classified these patients into one of 3 categories (stable, potentially unstable, or unstable) and according to the SINS system (≥ 6 weeks apart on 2 occasions). The authors identified that the interobserver and intraobserver reliability rates April 2014, Vol. 21, No. 2

were near perfect when determining the 3 levels of preoperative stability. Sensitivity and specificity rates of 96% and 80%, respectively, were reported for the potentially unstable and unstable cohorts.76 In a review of the Tomita and Tokuhashi scoring systems, the prognostic Tokuhashi score was found to be more useful than the Tomita score in predicting survival time and overall survival rate following an initial diagnosis among a prospective cohort study of 52 consecutive patients.75 Surgical Approaches Surgical approaches include direct posterior decompression alone, posterior decompression with posterolateral fusion, posterolateral costotransversectomy with corpectomy and placement of cage graft with posterolateral fusion, thoracotomy with corpectomy and cage graft placement, retroperitoneal approaches for corpectomy and cage placement with or without posterolateral instrumentation and fusion, vertebroplasty/kyphoplasty alone or in combination with posterolateral fusion, and radiosurgery alone or as an adjunct to surgical treatment. Minimally invasive approaches to the spine for metastatic spinal disease have been performed with varying success.77 The goals of surgery must be discussed with the patient and the family so that everyone has an understanding of treatment and desired outcomes. Goals of surgery include deformity correction and stabilization, restoration of neurological function, pain control, and oncological control.54 Surgical decompression ranges from intratumoral curettage to wide margin en bloc vertebrectomy. Patients with metastatic disease to the anterior thoracic spinal column with epidural extension and spinal cord compromise with associated kyphotic deformity may be offered surgical decompression with circumferential instrumentation and fusion. These patients are likely to undergo corpectomy and tumor resection via a posterolateral or anterolateral approach with placement of a cage constructed of titanium mesh or polyetherketone, usually filled with allograft, along with posterolateral instrumentation and fusion for added stabilization. Thoracic tumors from T3 to T12 may be accessed via a posterolateral costotransversectomy approach for corpectomy with the ability to sacrifice the nerve roots from T3 to T12 without any significant neurological compromise. In some cases, sacrifice of the T12 nerve root may produce a pseudohernia that may or may not require surgical treatment.78,79 Tumors along the cervical or cranial–cervical junction may benefit from a transnasal, transcervical, transoral, or endoscopic stereotactic transcervical approach toward accessing the anterior cervical region. Ventral access to the upper thoracic spine is complicated by the presence of the great vessels and Cancer Control 137

is generally deferred unless the tumor growth cannot be accessed any other way.78 If it is necessary, manubriotomy, sternotomy, or a trap-door approach may be performed to access the upper thoracic region. T5 to L1 can generally be accessed via a lateral/thoracotomy approach, while L2 to L5 may be accessed via a lateral retroperitoneal approach.78 These approaches may be performed by experienced neurosurgeons; the use of vascular surgeons for exposure may also be utilized. Although true en bloc procedures are not possible for metastatic disease, vertebrectomy for “en bloc” resection of a solitary bony metastatic lesion has been reported. This approach is effective for patients with hormonally active tumors. For example, a patient with metastatic pheochromocytoma to the thoracic spine underwent treatment as well as a patient with a metastatic tumor to the spine that caused severe hormonally induced osteomalacia.80 En bloc vertebrectomy led to the resolution of osteomalacia and a decline in fibroblast growth factor-23 levels.81 Complication rates vary by approach, but patient characteristics also influence postoperative complications. Over a period of 11 years, Jansson and Bauer82 studied 282 consecutive patients at a single institution with metastatic thoracolumbar disease undergoing surgical treatment. The primary surgical indication was neurological deficit as opposed to pain. A total of 13% of patients had a single metastasis, 64% had multiple skeletal metastases, and 23% had nonskeletal metastases. Preoperatively, 64% were Frankel A to C (nonwalkers), 30% were Frankel D, and 8% were Frankel E (normal motor function). A total of 212 patients had posterior decompression and stabilization, 47 had laminectomy alone, and 23 had anterior decompression and stabilization. The authors noted a complication rate of 20%, with 70% of patients showing an improvement of at least one Frankel grade. In more than 80% of patients, the ability to walk was retained.82 Lau et al83 studied 106 patients with a variety of metastatic spinal pathologies. The authors identified that patients above the age of 65 years had the greatest likelihood of complication (40.9%; P = .034). Patients with diabetes mellitus were isolated as having a higher risk of complications than those without diabetes (42.9% and 18.5%, respectively; P = .039). In this study, the authors noted an overall complication rate of 21.7%, with wound infections and deep venous thromboses being the most common.83 Furthermore, patients requiring more extensive surgery (> 7 instrumented levels) were more likely to have increased complications.67

Conclusion Management of primary and metastatic tumors is quite complex and requires a multidisciplinary understanding of tumor type, location, extension, and overall 138 Cancer Control

preoperative and neurological conditions. Precise and timely diagnosis with a history, physical examination, imaging, and biopsy are critical first steps. Meticulous preoperative planning for en bloc surgical resection of spinal tumors is necessary for improved patient outcomes as well as to minimize any intraoperative and postoperative complications. References 1. Ropper AE, Cahill KS, Hanna JW, et al. Primary vertebral tumors: a review of epidemiologic, histological and imaging findings, part II: locally aggressive and malignant tumors. Neurosurgery. 2012;70(1):211-219. 2. Sciubba DM, Cheng JJ, Petteys RJ, et al. Chordoma of the sacrum and vertebral bodies. J Am Acad Orthop Surg. 2009;17(11):708-717. 3. Hsu W, Kosztowski TA, Zaidi HA, et al. Multidisciplinary management of primary tumors of the vertebral column. Curr Treat Options Oncol. 2009;10(1-2):107-125. 4. Thornton E, Krajewski KM, O’Regan KN, et al. Imaging features of primary and secondary malignant tumours of the sacrum. Br J Radiol. 2012;85(1011):279-286. 5. Schwartz HS, Spengler DM. Needle tract recurrences after closed biopsy for sarcoma: three cases and review of the literature. Ann Surg Oncol. 1997;4(3):228-236. 6. Sundaresan N, Rosen G, Boriani S. Primary malignant tumors of the spine. Orthop Clin North Am. 2009;40(1):21-36. 7. Walcott BP, Nahed BV, Mohyeldin A, et al. Chordoma: current concepts, management, and future directions. Lancet Oncol. 2012;13(2):e69e76. 8. Strike SA, McCarthy EF. Chondrosarcoma of the spine: a series of 16 cases and a review of the literature. Iowa Orthop J. 2011;31:154-159. 9. Ross JS. Chondrosarcoma. In: Ross JS, Brant-Zawadzki M, Moore MR, eds. Diagnostic Imaging: Spine. 1st ed. Salt Lake City, UT: Amirsys Publishing; 2004:IV 1-38-IV 1-41. 10. Noel G, Feuvret L, Ferrand R, et al. Radiotherapeutic factors in the management of cervical-basal chordomas and chondrosarcomas. Neurosurgery. 2004;55(6):1252-1262. 11. Hsieh PC, Xu R, Sciubba DM, et al. Long-term clinical outcomes following en bloc resections for sacral chordomas and chondrosarcomas: a series of twenty consecutive patients. Spine (Phila Pa 1976). 2009;34(20):22332239. 12. Fuchs B, Hoekzema N, Larson DR, et al. Osteosarcoma of the pelvis: outcome analysis of surgical treatment. Clin Orthop Relat Res. 2009;467(2):510-518. 13. Crim J. Osteosarcoma. In: Ross JS, Brant-Zawadzki M, Moore MR, eds. Diagnostic Imaging: Spine. 1st ed. Salt Lake City, UT: Amirsys Publishing; 2004:IV 1-42-1-45. 14. Sciubba DM, Okuno SH, Dekutoski MB, et al. Ewing and osteogenic sarcoma: evidence for multidisciplinary management. Spine (Phila Pa 1976). 2009;34(22 suppl):S58-S68. 15. Boriani S, Amendola L, Corghi A, et al. Ewing’s sarcoma of the mobile spine. Eur Rev Med Pharmacol Sci. 2011;15(7):831-839. 16. Mankin HJ, Hornicek FJ, Ortiz-Cruz E, et al. Aneurysmal bone cyst: a review of 150 patients. J Clin Oncol. 2005;23(27):6756-6762. 17. Harrop JS, Schmidt MH, Boriani S, et al. Aggressive “benign” primary spine neoplasms: osteoblastoma, aneurysmal bone cyst, and giant cell tumor. Spine (Phila Pa 1976). 2009;34(22 suppl):S39-S47. 18. Hsieh PC, Galia GL, Sciubba DM, et al. En-bloc excision of chordomas in the cervical spine: review of 5 consecutive cases with over 4-year follow-up. Spine (Phila Pa 1976). 2011;36(24):E1581-E1587. 19. Cloyd JM, Acosta FL, Jr, Polley MY, et al. En bloc resection for primary and metastatic tumors of the spine: a systematic review of the literature. Neurosurgery. 2010;67(2):435-445. 20. Chi JH, Sciubba DM, Rhines LD, et al. Surgery for primary vertebral tumors: en bloc versus intralesional resection. Neurosurg Clin North Am. 2008;19(1):111-117. 21. Fourney DR, Rhines LD, Hentschel SJ, et al. En bloc resection of primary sacral tumors: classification of surgical approaches and outcome. J Neurosurg Spine. 2005;3(2):111-122. 22. Boriani S, Biagini R, De Iure F, et al. En bloc resections of bone tumors of the thoracolumbar spine. A preliminary report on 29 patients. Spine (Phila Pa 1976). 1996;21(16):1927-1931. 23. Boriani S, Bandiera S, Biagini R, et al. Chordoma of the mobile spine: fifty years of experience. Spine (Phila Pa 1976). 2006;31(4):493-503. 24. Liljenqvist U, Lerner T, Halm H, et al. En bloc spondylectomy in malignant tumors of the spine. Eur Spine J. 2008;17(4):600-609. 25. Hoshino Y, Kurokawa T, Nakamura K, et al. A report on the safety of unilateral vertebral artery ligation during cervical spine surgery. Spine (Phila Pa 1976). 1996;21(12):1454-1457. 26. Cloyd JM, Chou D, Deviren V, et al. En bloc resection of primary tuApril 2014, Vol. 21, No. 2

mors of the cervical spine: report of two cases and systematic review of the literature. Spine J. 2009;9(11):928-935. 27. Tomita K, Kawahara N, Murakami H, et al. Total en bloc spondylectomy for spinal tumors: improvement of the technique and its associated basic background. J Orthop Sci. 2006;11(1):3-12. 28. Tomita K, Kawahara N. The threadwire saw: a new device for cutting bone. J Bone Joint Surg Am. 1996;78(12):1915-1917. 29. Fourney DR, Gokaslan ZL. Surgical approaches for the resection of sacral tumors. In: Dickman CM, Fehlings MG, Gokaslan ZL, eds. Spinal Cord and Spinal Column Tumors: Principals and Practice. New York, NY: Thieme Medical Publishers, Inc; 2006:632-648. 30. Boriani S, De Iure F, Bandiera S, et al. Chondrosarcoma of the mobile spine: report on 22 cases. Spine (Phila Pa 1976). 2000;25(7):804-812. 31. Talac R, Yaszemski MJ, Currier BL, et al. Relationship between surgical margins and local recurrence in sarcomas of the spine. Clin Orthop Relat Res. 2002;(397):127-132. 32. Carpentier A, Blanquet A, George B. Suboccipital and cervical chordomas: radical resection with vertebral artery control. Neurosurg Focus. 2001;10(3):E4. 33. Barrenechea IJ, Perin NI, Triana A, et al. Surgical management of chordomas of the cervical spine. J Neurosurg Spine. 2007;6(5):398-406. 34. Boriani S, Chevalley F, Weinstein JN, et al. Chordoma of the spine above the sacrum. Treatment and outcome in 21 cases. Spine (Phila Pa 1976). 1996;21(13):1569-1577. 35. Mukherjee D, Chaichana KL, Gokaslan ZL, et al. Survival of patients with malignant primary osseous spinal neoplasms: results from the surveillance, epidemiology, and end results (SEER) database from 1973 to 2003. J Neurosurg Spine. 2011;14(2):143-150. 36. Stacchiotti S, Casali PG, Lo Vullo S, et al. Chordoma of the mobile spine and sacrum: a retrospective analysis of a series of patients surgically treated at two referral centers. Ann Surg Oncol. 2010;17(1):211-219. 37. Schwab JH, Healey JH, Rose P, et al. The surgical management of sacral chordomas. Spine (Phila Pa 1976). 2009;34(24):2700-2704. 38. Bergh P, Kindblom LG, Gunterberg B, et al. Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients. Cancer. 2000;88(9):2122-2134. 39. Soo MY. Chordoma: review of clinicoradiological features and factors affecting survival. Australas Radiol. 2001;45(4):427-434. 40. Boriani S, De Iure F, Campanacci L, et al. Aneurysmal bone cyst of the mobile spine: report on 41 cases. Spine (Phila Pa 1976). 2001;26(1):27-35. 41. Junming M, Cheng Y, Dong C, et al. Giant cell tumor of the cervical spine: a series of 22 cases and outcomes. Spine (Phila Pa 1976). 2008;33(3):280-288. 42. Boriani S, Amendola L, Bandiera S, et al. Staging and treatment of osteoblastoma in the mobile spine: a review of 51 cases. Eur Spine J. 2012;21(10):2003-2010. 43. Catton C, O’Sullivan B, Bell R, et al. Chordoma: long-term follow-up after radical photon irradiation. Radiother Oncol. 1996;41(1):67-72. 44. Chen YL, Liebsch N, Kobayashi W, et al. Definitive high dose photon/proton radiotherapy for unresected mobile spine and sacral chordomas. Spine (Phila Pa 1976). 2013;38(15):E930-E936. 45. Igaki H, Tokuuye K, Okumura T, et al. Clinical results of proton beam therapy for skull base chordoma. Int J Radiat Oncol Biol Phys. 2004;60(4):1120-1126. 46. Park L, Delaney TF, Liebsch NJ, et al. Sacral chordomas: impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor. Int J Radiat Oncol Biol Phys. 2006;65(5):1514-1521. 47. Noel G, Habrand JL, Mammar H, et al. Combination of photon and proton radiation therapy for chordomas and chondrosarcomas of the skull base: the centre de protontherapie D’orsay experience. Int J Radiat Oncol Biol Phys. 2001;51(2):392-398. 48. Leggon RE, Zlotecki R, Reith J, et al. Giant cell tumor of the pelvis and sacrum: 17 cases and analysis of the literature. Clin Orthop Relat Res. 2004;(423):196-207. 49. Caudell JJ, Ballo MT, Zagars GK, et al. Radiotherapy in the management of giant cell tumor of bone. Int J Radiat Oncol Biol Phys. 2003;57(1): 158-165. 50. Casali PG, Messina A, Stacchiotti S, et al. Imatinib mesylate in chordoma. Cancer. 2004;101(9):2086-2097. 51. Stacchiotti S, Longhi A, Ferraresi V, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol. 2012;30(9):914-920. 52. Posner JB. Spinal metastases. In: Posner JB, ed. Neurologic Complications of Cancer. Philadelphia, PA: FA Davis Company; 1995:111-142. 53. Sciubba DM, Petteys RJ, Dekutoski MB, et al. Diagnosis and management of metastatic spine disease. J Neurosurg Spine. 2010;13(1):94-108. 54. Laufer I, Sciubba DM, Madera M, et al. Surgical management of metastatic spinal tumors. Cancer Control. 2012;19(2):122-128. 55. Quraishi NA, Esler C. Metastatic spinal cord compression. BMJ. 2011;342:d2402. 56. Eleraky M, Papanastassiou I, Vrionis FD. Management of metastatic spine disease. Curr Opin Support Palliat Care. 2010;4(3):182-188. 57. Meyer SA, Singh H, Jenkins AL. Surgical treatment of metastatic spiApril 2014, Vol. 21, No. 2

nal tumors. Mt Sinai J Med. 2010;77(1):124-129. 58. Cole JS, Patchell RA. Metastatic epidural spinal cord compression. Lancet Neurol. 2008;7(5):459-466. 59. Toma CD, Dominkus M, Nedelcu T, et al. Metastatic bone disease: a 36-year single centre trend-analysis of patients admitted to a tertiary orthopaedic surgical department. J Surg Oncol. 2007;96(5):404-410. 60. Black P. Spinal metastasis: current status and recommended guidelines for management. Neurosurgery. 1979;5(6):726-746. 61. Abrams H, Spiro R, Goldstein N. Metastasis in carcinoma: analysis of 1000 autopsied cases. Cancer. 1950;3:74-85. 62. Gilbert RW, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor: diagnosis and treatment. Ann Neurol. 1978;3(1):40-51. 63. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643-648. 64. Ibrahim A, Crockard A, Antonietti P, et al. Does spinal surgery improve the quality of life for those with extradural (spinal) osseous metastases? An international multicenter prospective observational study of 223 patients. Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2007. J Neurosurg Spine. 2008;8(3):271-278. 65. Sciubba DM, Gokaslan ZL. Are patients satisfied after surgery for metastatic spine disease? Spine J. 2010;10(1):63-65. 66. Levack P, Graham J, Collie D, et al. Don’t wait for a sensory level — listen to the symptoms: a prospective audit of the delays in diagnosis of malignant cord compression. Clin Oncol (R Coll Radiol). 2002;14(6):472-480. 67. Ju DG, Zadnik PL, Groves ML, et al. Factors associated with improved outcomes following decompressive surgery for prostate cancer metastatic to the spine. Neurosurgery. 2013;73(4):657-666. 68. Zadnik PL, Hwang L, Ju DG, et al. Prolonged survival following aggressive treatment for metastatic breast cancer in the spine. Clin Exp Metastasis. 2014;31(1):47-55. 69. Aizenberg MR, Fox BD, Suki D, et al. Surgical management of unknown primary tumors metastatic to the spine. J Neurosurg Spine. 2012; 16(1):86-92. 70. Chaichana KL, Pendleton C, Sciubba DM, et al. Outcome following decompressive surgery for different histological types of metastatic tumors causing epidural spinal cord compression. clinical article. J Neurosurg Spine. 2009;11(1):56-63. 71. Sciubba DM, Gokaslan ZL, Suk I, et al. Positive and negative prognostic variables for patients undergoing spine surgery for metastatic breast disease. Eur Spine J. 2007;16(10):1659-1667. 72. Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the spine oncology study group. Spine (Phila Pa 1976). 2010;35(22):E1221-E1229. 73. Tomita K, Kawahara N, Kobayashi T, et al. Surgical strategy for spinal metastases. Spine (Phila Pa 1976). 2001;26(3):298-306. 74. Tokuhashi Y, Matsuzaki H, Oda H, et al. A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis. Spine (Phila Pa 1976). 2005;30(19):2186-2191. 75. Papastefanou S, Alpantaki K, Akra G, et al. Predictive value of tokuhashi and tomita scores in patients with metastatic spine disease. Acta Orthop Traumatol Turc. 2012;46(1):50-56. 76. Fourney DR, Frangou EM, Ryken TC, et al. Spinal instability neoplastic score: an analysis of reliability and validity from the spine oncology study group. J Clin Oncol. 2011;29(22):3072-3077. 77. Molina CA, Gokaslan ZL, Sciubba DM. A systematic review of the current role of minimally invasive spine surgery in the management of metastatic spine disease. Int J Surg Oncol. 2011;2011:598148. 78. Gokaslan ZL, York JE, Walsh GL, et al. Transthoracic vertebrectomy for metastatic spinal tumors. J Neurosurg. 1998;89(4):599-609. 79. Sundaresan N, Steinberger AA, Moore F, et al. Indications and results of combined anterior-posterior approaches for spine tumor surgery. J Neurosurg. 1996;85(3):438-446. 80. Kaloostian PE, Zadnik PL, Awad AJ, et al. En bloc resection of a pheochromocytoma metastatic to the spine for local tumor control and for treatment of chronic catecholamine release and related hypertension. J Neurosurg Spine. 2013;18(6):611-616. 81. Sciubba DM, Petteys RJ, Shakur SF, et al. En bloc spondylectomy for treatment of tumor-induced osteomalacia. J Neurosurg Spine. 2009;11(5):600-604. 82. Jansson KA, Bauer HC. Survival, complications and outcome in 282 patients operated for neurological deficit due to thoracic or lumbar spinal metastases. Eur Spine J. 2006;15(2):196-202. 83. Lau D, Leach MR, Than KD, et al. Independent predictors of complication following surgery for spinal metastasis. Eur Spine J. 2013;22(6):1402-1407.

Cancer Control 139

Vertebroplasty and kyphoplasty studies for treatment of metastatic spinal tumors have made significant improvements in pain, mobility, and vertebral height restoration.

Burnell Shively. The Awakening (detail), 1998. Oil on canvas, 33ʺ × 40ʺ.

Palliative Strategies for the Management of Primary and Metastatic Spinal Tumors Paul E. Kaloostian, MD, Alp Yurter, BS, Arnold B. Etame, MD, PhD, Frank D. Vrionis, MD, PhD, Daniel M. Sciubba, MD, and Ziya L. Gokaslan, MD Background: Technological advances during the last few decades have improved the success rate of surgery for the treatment of malignant spinal tumors. Nonetheless, many patients present with widespread tumor burden and minimal life expectancy, which excludes them from being surgical candidates. For these patients, palliative management is recommended. Methods: The authors reviewed prospective and retrospective clinical studies as well as case series regarding palliative treatments for primary and metastatic spinal tumors. Results: Analgesics, ranging from nonopioids to strong opioids, may be used depending on the degree of pain. Steroids may also improve pain relief, although they are associated with a number of adverse events. Vertebroplasty and kyphoplasty are conservative treatments with high rates of pain relief and vertebral body stabilization. Radiotherapy is the gold standard for palliative management, with approximately 60% of patients experiencing a decrease in tumor-related spinal pain and up to 35% experiencing complete relief. Stereotactic radiosurgery delivers high doses of radiation to patients to provide pain relief while also sparing delicate anatomical structures. Conclusion: Palliative management of spinal tumors is diverse. Analgesics may be used in conjunction with radiotherapy and/or kyphoplasty or vertebroplasty to offer pain relief. From the Department of Neurosurgery at Johns Hopkins Hospital, Baltimore, Maryland (PEK, AY, DMS, ZLG), the Neuro-Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (ABE, FDV), and the Departments of Neurosurgery and Orthopedics at the University of South Florida Morsani College of Medicine, Tampa, Florida (ABE, FDV). Submitted September 30, 2013; accepted January 14, 2014. Address correspondence to Ziya L. Gokaslan, MD, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287. E-mail: zgokasl1@ jhmi.edu 140 Cancer Control

Dr Vrionis receives grants/research support from Globus Medical, DePuy Synthes, and Spine360. He also is a consultant for Orthofix. Dr Gokaslan receives research grants from AO North America, the Neurosurgery Research and Education Foundation, Medtronic, Integra Life Sciences, Depuy Spine, and K2M. He receives honoraria from the AO Foundation and is a stock shareholder of US Spine and Spinal Kinetics. No significant relationship exists between the remaining authors and the companies/organizations whose products or services may be referenced in this article. April 2014, Vol. 21, No. 2

Introduction The management of primary and metastatic spinal tumors is quite diverse. During the last few decades, improvements in surgical strategies and technology have had high success rates and have increased disease-free survival rates in patients with a wide variety of malignant tumors that were once thought to be inoperable. Despite these advances, many types of patients present with such widespread tumor burden and minimal life expectancy that surgical treatment cannot be medically or ethically recommended. In such patients, palliative management is recommended. Palliative strategies are rarely discussed in the literature but are viable management options for advanced spinal oncological disease. Such methods include medical management, pain management consultation, vertebroplasty, and radiotherapy.

Pain and Medical Management Strategies Pain is one of the most common symptoms in patients with cancer, occurring in 30% to 50% of patients in the early stages and more than 70% of patients with advanced disease.1 A variety of medical treatments are available to manage advanced spinal oncological pathology. These strategies are based on the updated World Health Organization (WHO) analgesic ladder scale published in 19972 and the updated European Association for Palliative Care recommendations.3 In these guidelines, cancer pain may be diminished by opioid administration alone or in conjunction with adjuvant analgesic agents. The authors describe a 3-step framework for treating cancer pain.2-4 Step 1 refers to the nonopioid analgesics for mild pain; step 2 recommends the use of weak opioids for moderate pain; and step 3 recommends the use of strong opioids for severe pain. Data have demonstrated that an understanding of the pain type (ie, nociceptive, neuropathic, or both) can help alleviate cancer pain, although not completely.2-4 It is thought that the WHO guidelines offer a pain relief rate ranging from 70% to 80%.5 In addition to medical strategies, a combination of treatments may be administered to modulate pain relief. For example, adjuvant analgesics, drugs aimed at reversing the adverse events of opioids, radiotherapy, local nerve blocks, or neurolytic blocks may be used in a variety of ways to alleviate pain.6 Neuropathic pain typically responds to antidepressants, anticonvulsants, and local anesthetic medications. For patients with severe neuropathic pain, opioids in combination with N-methyl-D-aspartate receptor antagonists such as ketamine should be used.7 Cannabinoids may also be used as an adjuvant therapy to improve the quality of life of those with chronic pain, as well as treating those with chronic neuropathic pain.5 The use of steroids is controversial in the setting of palliative management of spinal cancer pain. Studies April 2014, Vol. 21, No. 2

have demonstrated their efficacy in inhibiting prostaglandin synthesis and reducing vascular permeability.8 The exact mechanism of steroid reduction of cancer pain is unclear. Some researchers propose that steroids act on every step of the nociception pathway. The proinflammatory cytokines synthesized or released during tissue injury allow for peripheral sensitization; thus, steroids act to inhibit these cytokines, decreasing nociceptor activation.9 In addition, glucocorticoids inhibit the expression of collagenase and stimulate the synthesis of lipocortin, blocking the production of pain-producing eicosanoids.10 In addition, as in cases of spinal cord injury, steroids have an antiswelling property that aids in tumor shrinkage, thus reducing the compression of surrounding pain-producing structures.11 Dexamethasone is the most commonly prescribed of these corticosteroids and causes the least fluid retention due to its decreased mineralocorticoid activity.12 The adverse events of steroids are varied and are generally associated with long-term or high doses; these events may include immunosuppression, hyperglycemia, Cushing myopathy, osteoporosis, peptic ulceration, and psychological symptoms.13 Nauck et al14 studied 55 palliative units and noted that corticosteroids were used in 17.8% of patients upon admission and in 32.4% of inpatients. Gannon and McNamara13 discovered a high prevalence of steroid use in their patient population, with 51% of 178 patients receiving steroids until death. Bruera et al15 studied 40 patients who had advanced cancer and bone, visceral, or neuropathic pain. Oral methylprednisolone (16 mg twice daily) or placebo was given to patients for 5 days. The patients were crossed over to the alternate treatment after 3 days of a washout period. They were then given methylprednisolone for 20 days. Visual analog scale scores for pain and analgesic intake were lower with methylprednisolone treatment for all types of pain. Della Cuna et al16 performed a randomized, double-blind study of 43 patients with advanced cancer who were given either intravenous methylprednisolone (125 mg/day) or placebo for 8 weeks. Visual analog scale scores for pain improved in the group treated with steroids. Several case reports have proven the efficacy of steroids in the treatment of patients with bone pain. Arkel et al17 showed the utility of steroids in treating bone pain in patients with hairy cell leukemia, and Vyvey8 demonstrated pain relief in a patient with metastatic pancreatic carcinoid to the liver and bones.

Radiotherapy and Radiosurgery Radiotherapy is an enduring, established means of achieving analgesia for bone metastases that dates back to 1930.18 Patchell et al19 demonstrated a benefit of surgical decompression followed by radiation therapy for patients with severe epidural metastatic Cancer Control 141

disease. Study participants who received surgery in combination with radiotherapy retained the ability to walk for a longer duration postoperatively relative to the radiotherapy-alone group. Despite these results, patients with severe spinal metastatic disease with cord compression or multiple levels of spinal disease are not generally suited for surgical palliation because they usually have limited life expectancy and significant comorbidities. As a result, radiotherapy is the gold standard of palliative treatment for patients with metastatic spine disease and is often used in combination with adjuvant steroids.20 Recently, technological progresses in radiotherapy and radiosurgery, whether used alone or in conjunction with surgical and chemotherapeutic management, have enhanced management. Due to these advancements, a subsequent decline has been seen in surgery for metastatic disease. For example, in cases of radiation therapy, approximately 60% of patients have decreased tumor-related spinal pain, while 23% to 35% experience complete pain relief.21 In patients with severe metastatic disease, doses may vary from 5 daily fractions of 4 Gy to 23 daily fractions of 2 Gy, without one schedule having a statistically significant functional advantage over the other.22 Specific dosefractionation schedules for uncomplicated metastatic spinal disease can vary. The literature suggests that no significant difference exist in complete and partial pain response rates following single fraction (8 Gy) versus multifraction regimens.21 Nonetheless, the likelihood of re-treatment is 2.5-fold higher in patients receiving single fraction therapy compared with those undergoing multifraction therapy. In addition, those receiving single fraction therapy have a significantly higher risk for subsequent pathological fracture.23 Patients can tolerate re-treatment palliative radiotherapy and are not at risk for increased spinal cord toxicity.24 Studies of radiosurgical techniques for metastatic spine disease have also demonstrated effective results. In a study of 294 patients with spinal metastases, Gerszten et al45 noted that radiosurgery using CyberKnife (Accuray, Sunnyvale, California) yielded a rate of 88% for local control and an 86% rate in longterm pain reduction. Moreover, of the 32 patients with neurological deficit at the beginning of the study, 84% improved following radiosurgery. Wowra et al26 found higher tumor control rates in 102 study participants with metastatic spinal disease. Single-dose fractions of 15 to 24 Gy using fiducial-free spinal radiosurgery resulted in a local control rate of 98%. In a study of 49 patients, Ryu et al27 reported a local control rate of 96% and an improvement in pain in 85% of patients whose lesions were treated with single-dose radiosurgery. The 1-year survival rate was 74%, and a 5% rate of radiological progression at adjacent levels was observed. 142 Cancer Control

Vertebroplasty and Kyphoplasty Advances in vertebroplasty and kyphoplasty for the treatment of metastatic spinal tumors without epidural compression have allowed surgeons to improve the anterior column stability of the spine in conjunction with medical and radiation therapies. In particular, these conservative procedures are beneficial for elderly patients at high risk because minimal blood loss occurs in addition to less operating time under anesthesia compared with their younger counterparts. Cement injection may provide structural support to the vertebral body. Thus, pain relief is achieved via mechanical stabilization.28,29 The most common complication is cement extravasation into the spinal canal, venous plexus, or both, and hematogenous embolization.30,31 A randomized, multicenter, controlled trial demonstrated the merits of kyphoplasty for patients with oncological vertebral compression fractures.32,33 The authors concluded that kyphoplasty is a safe, effective procedure that reduces pain, improves neurological function, and may be used in conjunction with posterior stabilization in cases of malignancy. Vertebroplasty and kyphoplasty studies for the treatment of metastatic spinal tumors have demonstrated significant improvements in pain, mobility, and vertebral height restoration.33-44 Vertebroplasty studies specific to spinal metastases have demonstrated pain improvement among 73% to 100% of patients.35,41 Although few studies exist that have documented changes in mobility, McDonald et al38 observed an improvement in mobility among 70% of the 67 study participants. To our knowledge, Yang et al37 conducted the largest vertebroplasty study in patients with metastatic spinal disease. A total of 196 patients were treated during the study, and a 98.5% improvement in pain was seen, as well as statistically significant improvements in vertebral body height. Studies of kyphoplasty have demonstrated pain improvement in 81% to 100% of patients.33,44 To our knowledge, Berenson et al33 conducted the largest controlled, randomized multicenter study of kyphoplasty for spinal metastases. Of the 70 study participants, 65% had improved mobility and 81% had improved pain. The next most statistically powered study consisted of 50 patients, demonstrating a 96% rate of pain improvement.43 Newer combination treatment paradigms have also proven beneficial, as demonstrated by Gerszten et al.45 Twenty-six patients were successfully treated by kyphoplasty followed by CyberKnife spinal radiosurgery, and 92% saw an improvement in axial pain.

Conclusions Palliative management of spinal tumors is diverse. Analgesics, ranging from nonopioids to opioids, may be used with adjuvant drugs, such as steroids, to treat cancer-related pain. Standard radiotherapy may also April 2014, Vol. 21, No. 2

reduce radiation-sensitive tumors, while stereotactic radiosurgery can provide concentrated doses to treat conventionally radioresistant tumors.46 Furthermore, cement augmentation procedures such as vertebroplasty and kyphoplasty are minimally invasive procedures that can offer significant pain relief via mechanical stabilization for patients with vertebral compression fractures. References 1. Goudas LC, Bloch R, Gialeli-Goudas M, et al. The epidemiology of cancer pain. Cancer Invest. 2005;23(2):182-190. 2. World Health Organization. Traitement de la Douleur Cancéreuse [in French]. Geneva: World Health Organization; 1997. 3. Caraceni A, Hanks G, Kaasa S, et al; European Palliative Care Research Collaborative, European Association for Palliative Care. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012;13(2):e58-e68. 4. Caraceni A. The EPCRC project to revise the European Association for Palliative Care (EAPC) guidelines on the use of opioids for cancer pain. Palliat Med. 2011;25(5):389-390. 5. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience [in English, French]. Can Fam Physician. 2010;56(6):514-7, e202-e205. 6. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain management. Oncologist. 2004;9(5):571-591. 7. Leppert W. Pain management in patients with cancer: focus on opioid analgesics [published correction appears in Curr Pain Headache Rep. 2011;15(6):422]. Curr Pain Headache Rep. 2011;15(4):271-279. 8. Vyvey M. Steroids as pain relief adjuvants [in French, English]. Can Fam Physician. 2010;56(12):1295-1297, e415. 9. Watanabe S, Bruera E. Corticosteroids as adjuvant analgesics. J Pain Symptom Manage. 1994;9(7):442-445. 10. Mensah-Nyagan AG, Meyer L, Schaeffer V, et al. Evidence for a key role of steroids in the modulation of pain. Psychoneuroendocrinology. 2009;34(suppl 1):S169-S177. 11. Posner JB, Howieson J, Cvitkovic E. “Disappearing” spinal cord compression: oncolytic effect of glucocorticoids (and other chemotherapeutic agents) on epidural metastases. Ann Neurol. 1977;2(5):409-413. 12. Lundström SH, Fürst CJ. The use of corticosteroids in Swedish palliative care. Acta Oncol. 2006;45(4):430-437. 13. Gannon C, McNamara P. A retrospective observation of corticosteroid use at the end of life in a hospice. J Pain Symptom Manage. 2002;24(3): 328-334. 14. Nauck F, Ostgathe C, Klaschik E, et al; Working Group on the Core Documentation for Palliative Care Units in Germany. Drugs in palliative care: results from a representative survey in Germany. Palliat Med. 2004;18(2): 100-107. 15. Bruera E, Roca E, Cedaro L, et al. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep. 1985;69(7-8):751-754. 16. Della Cuna GR, Pellegrini A, Piazzi M; Methylprednisolone Preterminal Cancer Study Group. Effect of methylprednisolone sodium succinate on quality of life in preterminal cancer patients: a placebo-controlled, multicenter study. Eur J Cancer Clin Oncol. 1989;25(12):1817-1821. 17. Arkel YS, Lake-Lewin D, Savopoulos AA, et al. Bone lesions in hairy cell leukemia. A case report and response of bone pains to steroids. Cancer. 1984;53(11):2401-2403. 18. Leddy ET. The roentgen treatment of metastasis to the vertebrae and the bones of the pelvis from carcinoma of the breast. Am J Roentgenol. 1930;24:657-672. 19. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643-648. 20. Vecht CJ, Haaxma-Reiche H, van Putten WL, et al. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology. 1989;39(9):1255-1257. 21. Chow E, Zeng L, Salvo N, et al. Update on the systemic revision of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012;24(2):112-124 22. Agarawal JP, Swangsilpa T, van der Linden Y, et al. The role of external beam radiotherapy in the management of bone metastases. Clin Oncol (R Coll Radiol). 2006;18(10):747-760. 23. Wu JS, Wong R, Johnston M, et al; Cancer Care Ontario Practice Guidelines Initiative Supportive Care Group. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys. 2003;55(3):594-605. 24. Mithal NP, Needham PR, Hoskin PJ. Retreatment with radiotheraApril 2014, Vol. 21, No. 2

py for painful bone metastases. Int J Radiat Oncol Biol Phys. 1994;29(5): 1011-1014. 25. Gerszten PC, Burton SA, Ozhasoglu C, et al. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976). 2007;32(2):193-199. 26. Wowra B, Zausinger S, Drexler C, et al. CyberKnife radiosurgery for malignant spinal tumors: characterization of well-suited patients. Spine (Phila Pa 1976). 2008;33(26):2929-2934. 27. Ryu S, Rock J, Rosenblum M, et al. Patterns of failure after singledose radiosurgery for spinal metastasis. J Neurosurg. 2004;101(suppl 3): 402-405. 28. Anselmetti GC, Manca A, Kanika K, et al. Temperature measurement during polymerization of bone cement in percutaneous vertebroplasty: an in vivo study in humans. Cardiovasc Intervent Radiol. 2009;32(3):491-498. 29. Yimin Y, Zhiwei R, Wei M, et al. Current status of percutaneous vertebroplasty and percutaneous kyphoplasty--a review. Med Sci Monit. 2013; 19:826-836. 30. Laufer I, Sciubba DM, Madera M, et al. Surgical management of metastatic spinal tumors. Cancer Control. 2012;19(2):122-128. 31. Gangi A, Clark WA. Have recent vertebroplasty trials changed the indications for vertebroplasty? Cardiovasc Intervent Radiol. 2010;33(4): 677-680. 32. Rastogi R, Patel T, Swarm RA. Vertebral augmentation for compression fractures caused by malignant disease. J Natl Compr Canc Netw. 2010; 8(9):1095-1102. 33. Berenson J, Pflugmacher R, Jarzem P, et al; Cancer Patient Fracture Evaluation Investigators. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12(3):225-235. 34. Cotten A, Dewatre F, Cortet B, et al. Percutaneous vertebroplasty for osteolytic metastases and myeloma: effects of the percentage of lesion filling and the leakage of methyl methacrylate at clinical follow-up. Radiology. 1996;200(2):525-530. 35. Weill A, Chiras J, Simon JM, et al. Spinal metastases: indications for and results of percutaneous injection of acrylic surgical cement. Radiology. 1996;199(1):241-247. 36. Fourney DR, Schomer DF, Nader R, et al. Percutaneous vertebroplasty and kyphoplasty for painful vertebral body fractures in cancer patients. J Neurosurg. 2003;98(1 suppl):21-30. 37. Yang Z, Xu J, Sang C. Clinical studies on treatment of patients with malignant spinal tumors by percutaneous vertebroplasty under guidance of digital subtraction angiography [in Chinese]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2006;20(10):999-1003. 38. McDonald RJ, Trout AT, Gray LA, et al. Vertebroplasty in multiple myeloma: outcomes in a large patient series. AJNR Am J Neuroradiol. 2008; 29(4):642-648. 39. Tseng YY, Lo YL, Chen LH, et al. Percutaneous polymethylmethacrylate vertebroplasty in the treatment of pain induced by metastatic spine tumor. Surg Neurol. 2008;70(suppl 1):78-84. 40. Masala S, Anselmetti GC, Muto M, et al. Percutaneous vertebroplasty relieves pain in metastatic cervical fractures. Clin Orthop Relat Res. 2011;469(3):715-722. 41. Mikami Y, Numaguchi Y, Kobayashi N, et al. Therapeutic effects of percutaneous vertebroplasty for vertebral metastases. Jpn J Radiol. 2011;29(3):202-206. 42. Dudeney S, Lieberman IH, Reinhardt MK, et al. Kyphoplasty in the treatment of osteolytic vertebral compression fractures as a result of multiple myeloma. J Clin Oncol. 2002;20(9):2382-2387. 43. Vrionis FD, Hamm A, Stanton N, et al. Kyphoplasty for tumor-associated spinal fractures. Techniq Reg Anesth Pain Manage. 2005;9(1):35-39. 44. Dalbayrak S, Onen MR, Yilmaz M, et al. Clinical and radiographic results of balloon kyphoplasty for treatment of vertebral body metastases and multiple myelomas. J Clin Neurosci. 2010;17(2):219-224. 45. Gerszten PC, Germanwala A, Burton SA, et al. Combination kyphoplasty and spinal radiosurgery: a new treatment paradigm for pathological fractures. J Neurosurg Spine. 2005;3(4):296-301. 46. Yu HH, Hoffe SE. Beyond the conventional role of external-beam radiation therapy for skeletal metastases: new technologies and stereotactic directions. Cancer Control. 2012;19(2):129-136.

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Surgical techniques to manage instability have evolved in recent years. Using a multidisciplinary approach, increasing patient survival and improving quality of life are the ultimate goals of treatment.

Burnell Shively. Goddess Sprout, 2013. Oil on canvas, 36ʺ × 36ʺ.

Spinal Neoplastic Instability: Biomechanics and Current Management Options Andreas K. Filis, MD, Kamran V. Aghayev, MD, James J. Doulgeris, MSME, Sabrina A. Gonzalez-Blohm, MSBE, and Frank D. Vrionis, MD, PhD Background: Often the spine is afflicted from primary or metastatic neoplastic disease, which can lead to instability. Instability can cause deformity, pain, and spinal cord compression and is an indication for surgery. Although overt instability is uniformly agreed upon, it is sometimes difficult for specialists to agree on subtle degrees of instability due to lack of objective criteria. Methods: In this article, treatment options and the spine instability neoplastic system are discussed and the neoplastic instability literature is reviewed. Results: The Spinal Instability Neoplastic Score helps specialists determine whether instability is present and when surgery may be indicated. However, other parameters such as spinal cord compression and extent of disease dictate whether surgery is the most appropriate option. A wide range of fusion techniques exists, each one tailored to the location of the lesion and goals for surgery. Conclusions: To optimize results, expert knowledge on the techniques and patient selection is of importance. Furthermore, a multidisciplinary approach is required because treatment of neoplastic disease is multimodal.

Introduction From the Neuro-Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (AKF, KVA, FDV), the University of South Florida Morsani College of Medicine (AKF, KVA, FDV) and the College of Engineering (JJD, SAG-B) at the University of South Florida, Tampa, Florida. Submitted October 21, 2013; accepted January 6, 2014. Address correspondence to Frank D. Vrionis, MD, Neuro-Oncology Program, Moffitt Cancer Center, 12902 Magnolia Drive, WCB-NEURO PROG, Tampa, FL 33612. E-mail: Frank.Vrionis@ Moffitt.org. Dr Vrionis receives grants/research support from Globus Medical, Inc, DePuy Synthes, and Spine360. He also is a consultant for Orthofix. No significant relationship exists between the remaining authors and the companies/organizations whose products or services may be referenced in this article. 144 Cancer Control

Neoplastic disease of the spine comprises a wide range of pathology. From a location standpoint, extradural and intradural lesions may exist, with the latter being further subdivided into intramedullary and extramedullary lesions. Intradural pathology rarely leads to instability. Spinal metastasis is the most common type of neoplasm, where autopsy investigations have shown that up to 70% of patients with cancer have spinal metastases.1 The thoracic (70%) and lumbar spine are most commonly affected, and the vertebral body is afflicted in most cases.1 In North America, April 2014, Vol. 21, No. 2

approximately 18,000 new cases of metastatic spine disease, with epidural involvement, are diagnosed each year.2 Cases are increasing as the population ages and cancer therapies evolve that allow patients to survive long enough for neoplastic disease of the spine to become symptomatic. The management of spinal neoplastic disease has significantly changed during the last few decades. Advancements include the improvement of adjuvant therapy, namely radiotherapy and chemotherapy, and research has improved our understanding of the biomechanics of the tumor-afflicted spine. Advancements in adjuvant therapy may have decreased the need of surgery, but neoplastic instability remains an important surgical indication. The evolution of stabilization techniques, the development of anterior and posterior instrumentation, and the development of innovative materials allow surgeons more flexibility; alternatively, this technology also dictates the necessity of expertise and careful patient selection for an optimal result.

Clinical Biomechanics, Traumatic Instability, and Various Classification Systems Several authors have attempted to define and classify spinal instability. Denis3 divided the spine into 3 columns: the anterior consists of the anterior longitudinal ligament and the anterior half of the vertebral body; the middle column includes the posterior half of the vertebral body and the posterior longitudinal ligament; and the further posterior elements (pedicles, facet joints, and intraspinous ligaments) comprise the posterior column. Denis’ 3-column theory for traumatic instability proposed that damaging 2 or more of these columns would render the spine unstable; however, this theory is based on radiological, not biomechanical, studies. White and Panjabi4 described clinical instability as “the decrease of the spine’s ability, under normal physiological loads, to maintain a consistent displacement pattern so that there is no initial or additional deficit, no major deformity and no incapacitating pain.” In 1992, Panjabi5 introduced a model consisting of an osteoligamentous (passive), muscle, and neural control subsystem to explain spinal stability. He then defined the neutral zone as the range of physiological intervertebral motion, where motion is produced with the minimal internal resistance, and suggested that it has a higher correlation with instability than range of motion.6 Another classification system for traumatic instability is the subaxial cervical spine injury score described by Vaccaro et al,7 which focuses on injury morphology, disc–ligament integrity, and neurological status. Kostuik and Weinstein8 divided the vertebral column into 6 segments for assessing instability. According to their classification, instability was defined as 3 or more invaded segments. April 2014, Vol. 21, No. 2

Benzel9 divides instability into acute (overt and limited) and chronic (glacial and dysfunctional). He also divided the vertebral body into 27 cubes (a system of interlocking blocks) and emphasized that removing these cubes in certain parts of the vertebral body had a different effect on overall stability. Other factors, such as bone mineral density, may also play a role. Overall, the anterior column of the spine (vertebral bodies and discs) carries 75% to 97% of the compression loads, while the posterior elements serve as a tension band and carry 3% to 25% of the loads.10 Removal of the posterior elements (facets, lamina) predisposes the spine to translational deformity secondary to shear forces. By contrast, compression fractures may depend on whether the forces act in line with the instantaneous rotational axis of the spine. Taneichi et al11 showed that removal of the costovertebral joint in the thoracic spine was the largest contributor to instability compared with the lumbar spine, wherein the vertebral body was most important. Tumors differ from traumatic conditions in the sense that ligaments and discs are rarely affected, the mechanism of injury is not as important, and the ability of the spine to heal is compromised. Consequently, classifications of spinal instability based on trauma classifications are not as valid for tumors. In addition, iatrogenic instability, particularly in cases of en bloc tumor resections, and impending instability, with the potential for collapse and further injury, are concepts that primarily involve neoplasia. Instability is often determined by factors derived from clinical scenarios and biomechanical data. Ranking several qualitative observations and comparing the score to a preset value generally determines clinical instability. The point system approach has become very popular in determining spinal instability, but it often includes several “shades of grey,” thus leaving the ranking systems as more of a “probability of instability,” rather than an absolute system. For example, the stable portion may be interpreted as low probability and unstable as high probability, whereas the “grey zone” represents more of a medium probability. Therefore, it may be advisable to interpret the scores as a proportion (score divided by maximum point value) to help determine the likelihood of instability. Regardless of the criteria used or interpretation, the clinical decision as to whether a particular surgery or tumor will lead to instability relies on the intuition and experience of the surgeon. Alternatively, biomechanical instability is experimentally determined, with respect to quantitative values, and extrapolated to help determine the ranks of the injury or trauma. Several biomechanical factors, such as neutral and elastic zone stiffness, have been used to explain stability. These factors are useful in a biomechanical environment, but extrapolating them to Cancer Control 145

an in vivo situation can be difficult because the body can react to trauma in different ways. For example, if an osteoligamentous injury decreases stability, then the stabilizing muscles may preserve stability by preventing excessive motions, and, although muscle contributions may maintain loading stability, over time the spine may creep until it is out of alignment. Anticipated instability is understood as iatrogenic sequelae of extended resection. In neoplastic disease, a major concern is the acute instability via infiltration of osseous structures. The degree of instability varies depending on the location and extent of osseous infiltration. For example, ligaments are crucial to stability in the craniovertebral junction, most likely equally or more significant than the osseous integrity. By contrast, the ribs and the sternum provide internal stabilization in the thoracic spine.

Scoring System for Neoplastic Instability and Indications for Surgery

is indicative of instability. Lytic tumors are unstable compared with blastic or mixed tumors. The presence of translational or kyphotic deformity and the degree of vertebral body involvement (≥ 50%) significantly contribute to the instability score. Finally, the added involvement (or lack thereof) of 1 or 2 bilateral facet joints points to the importance of the posterior elements of the spine. The SINS classification was designed to efficiently communicate among medical oncologists, radiation oncologists, and surgeons, as well as other health care professionals, and to guide decision making with regard to patient care. Beyond the mechanical aspect as reflected by the SINS, the neurological status of the patient, the epidural extension of tumor, oncological parameters (eg, sensitivity of disease to adjuvant therapy), and systemic considerations (eg, tumor burden, comorbidities) comprise the neurological, oncological, mechanical, and systemic factors algorithm for decision making between surgery or radiation in cases of neoplastic spine disease. The SINS has a range of 0 to 18 and the score separately applies to each spinal lesion; that is, values for many lesions should not be added. The sensitivity and specificity rates for SINS were found to be 95.7% and 79.5%, respectively.13 A score of 6 or below implies a stable segment (Fig 1), whereas a score of 13 or higher implies instability (Figs 2 and 3). Instability is ambiguous in the grey zone between 7 and 12 (Fig 4). Generally, surgical consultation is warranted for scores higher than 7. Moreover, in cases of an unstable spine, the neurological, oncological, mechanical, and systemic factors algorithm will dictate the need for surgery. For example, surgery is not advisable in a patient with multiple morbidities because the complication risk may be unacceptably

For several years, neoplastic instability was undefined, which meant that knowledge about degenerative or traumatic instability was applied to neoplastic cases. However, extrapolation is problematic because oftentimes bone mineral density and ligaments are abated and pathological fractures do not follow the usual patterns with respect to traumatic and osteoporotic cases. In 2010, the Spine Oncology Study Group published a novel classification system with 6 components referred to as the Spinal Instability Neoplastic Score (SINS).12 According to the SINS system, localization of the pathology plays an important role in terms of instability. Junction areas, such as the cervicothoracic and occipitocervical junction, contribute to more points in the overall SINS, whereas less mobile areas, such as the subaxial and lumbar spine, add fewer points. For example, a tumor at a junction of the spine (occipitocervical, cervicothoracic, thoracolumbar) may be more destabilizing than a similar tumor in a less mobile part of the spine such as the sacrum. The semi-rigid thoracic spine contributes 1 point, and the most rigid sacral spine does not add any points to the overall score. In summary, the remaining components of the SINS system include pain, type of bone lesion, radiographic spinal alignment, vertebral A B C bone collapse, and involvement Fig. 1A-C. — (A) Sagittal and (B) axial T1-gadolinium–enhanced magnetic resonance imaging of of posterolateral spine elements. a 71-year-old patient with a history of prostate cancer. Spinal metastatic tumor is present in the lumbar Pain present when a patient is in spine with consecutive stenosis leading to radiculopathy. Spinal Instability Neoplastic Score: 4. an upright position but is relieved No fusion required. Panel C shows postoperative computed tomography following decompression by recumbence (mechanical pain) and kyphoplasty. 146 Cancer Control

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Every case of acute, overt spinal instability in neuro-oncology should be evaluated as soon as possible for surgical intervention. Patients with spine neoplasm as well as saddle anesthesia, high-grade paresis, and urinary retention may need emergent decompression with or without fusion. In such cases, instability is indeed a phenomenon of increments; therefore, dynamic imaging may be considered as a means of increasing sensitivity as to which spines are unstable. However, limited patient cooperation, particularly in the oncological and elderly patient populations, poses significant difficulties to assess instability, thus underlining A B C the importance of clinical judgment Fig 2A-C. — (A) Sagittal T1 and (B) axial Ti-gadolinium–enhanced magnetic resonance imaging of a and personal experience in terms of 38-year-old patient with a history of lymphoma metastatic to the spine causing instability. The patient surgical indication. high. According to a panel of experts, the interobserver and intraobserver variability rates of the system were 0.846 and 0.886, respectively13; however, a large-scale validation of SINS in routine clinical practice has not yet been performed.

presented with gait disturbance and pain. Spinal Instability Neoplastic Score: 13. Panel C shows postoperative radiography following T9 vertebrectomy with anterior reconstruction and fusion of T8 to T10 followed by posterior instrumentation of T6 to T12.

A

B

C

Fig 3A-C. — (A) Sagittal T1 and (B) axial Ti-gadolinium–enhanced magnetic resonance imaging of a 42-year-old patient with a history of germ cell carcinoma and L2 to L3 tumor infiltration. He presented with pain and was bed bound. Spinal Instability Neoplastic Score: 15. Panel C shows postoperative radiography following L2 and L3 corpectomy, decompression, and fusion of L1 to L4.

A

B

C

Fig 4A-C. — (A) Sagittal and (B) axial T1-gadolinium–enhanced magnetic resonance imaging of a 78-year-old patient with metastasis of malignant melanoma in the lumbar spine. He presented with L1 radiculopathy and weakness. Spinal Instability Neoplastic Score: 8, potentially unstable. Panel C shows postoperative radiography following decompression and fusion of T11 to L3. April 2014, Vol. 21, No. 2

Craniovertebral Junction Stability is often an issue in cases of neoplastic disease of the craniovertebral junction because this section of the spine undergoes the most motion. In the SINS system, pathology in the craniovertebral junction contributes 3 points to the overall score. By contrast, if the pathology were localized in more rigid areas like S2 to S5, then no points would be added. Intracranial tumors (eg, meningioma, schwannoma) may extend to the foramen magnum and may cause instability during their removal. The most common extradural pathology is chordoma, while other entities, such as eosinophilic granuloma, plasmocytoma, and fibrous dysplasia, are possible although rare. Metastases in the vertebral bodies are also worth mentioning because resection of most of the vertebral body of C2, more than 70% of one or more than 50% of both of the occipital condyles, or C1 lateral masses may generate instability. Tumor growth or surgical resection can also lead to instability insomuch that the stabilizing ligamentous elements could be weakened during surgical access to the pathology.14 Various techniques common in occipitocervical stabilization, such as wiring, plate-rod systems, Cancer Control 147

in/out buttons, and occipital condyle screw fixation, are often compared in the medical literature. Compared with wiring, current studies suggest that platerod systems have an increased fusion rate and a decreased pseudarthrosis rate.15,16 Uribe et al17 reported that stabilization with condyle screws is biomechanically equivalent to the standard plate-rod system. For atlantoaxial stabilization, combining the lateral mass C1 screws with C2 pedicle or pars screws is an option.18 De Iure et al19 reported positive outcomes with the Harm technique (C1 articular mass to C2 pedicle screws), which spared wiring as used in the Magerl method of transarticular C1-C2 fusion. In some cases in which parameters preclude surgery, a halo-vest or sternal-occipital-mandibular immobilizer brace may be considered to provide satisfactory stability for the upper cervical spine.20,21 Pathology located ventral to the medulla in the craniovertebral junction can be resected via an anterior approach (eg, transoral odontoidectomy with or without maxillotomy), but stabilization must be dorsally performed, thus making a second surgery necessary. In patients with cancer who undergo further radiotherapy, transoral tumor resections are strongly discouraged because these resections are associated with major wound healing complications.

Subaxial Cervical Spine The subaxial cervical spine is composed of levels C3 to C7. It is considered less mobile than the craniovertebral junction; thus, it contributes 2 points to the overall SINS. Posterior stabilization with lateral mass screws and C7 pedicle screws and rods is common practice following multilevel laminectomy in the subaxial cervical spine. Theoretically, cervical laminoplasty could spare the need for stabilization, but it may not be an option in certain neoplastic diseases. If the anterior column is compromised during intervention, then anterior fusion of the vertebrae with a plate may be required. In cases in which the vertebral body must be removed, it is mandatory to fill the gap with an expandable cage, bone graft, or polymethylmethacrylate (PMMA). Thus, a variety of different systems have been developed for this purpose. Percutaneous vertebral augmentation via a posterolateral or anterolateral route, as well as the transoral route, for metastatic disease in C1 to C2 has been reported.22,23 Vertebroplasty and kyphoplasty have also been employed for pain control in vertebral metastases as well as in the subaxial cervical spine.24 The presence of vertebral arteries and the narrow space between cervical nerve roots make corpectomy and reconstruction technically difficult from a posterior approach. In the majority of cases, the location of pathology dictates the surgical approach. Generally, lateral mass screw rod stabilization is considered more stable than anterior plating. Therefore, for multilevel 148 Cancer Control

anterior corpectomies with subsequent reconstructions, 360-degree fixation may be an option to provide robust stabilization.

Cervicothoracic Junction and Thoracic Spine The cervicothoracic junction is one of the most difficult areas of the spine to assess because osseous, major vascular, and neural structures hinder anterior approaches. Similar to the craniovertebral junction, it contributes 3 points to the overall SINS. Cauchoix and Binet25 described a direct approach through sternotomy. Over time various less-invasive techniques have been reported, such as midclavicle resection without manubriotomy and a transthoracic approach through rib removal. The transthoracic approach can be either lateral extrapleural (retropleural), where the surgical route is between the parietal pleura and the endothoracic fascia, or lateral transpleural (intrapleural), which involves opening the parietal pleura. The cervicothoracic junction can also be assessed through the posterior route, either using a midline approach and a pedicle screw fixation or via costotransversectomy or a lateral extracavitary approach. The posterior transpedicular approach can offer direct access to ventral pathology and 3-column stabilization when necessary.26 In most cases, in the cervicothoracic junction following posterior decompression and tumor removal, the instrumentation should extend 2 levels above and below the decompression. In terms of biomechanics, it may be challenging to bridge the lordotic and mobile cervical spine with the rigid thoracic spine. Cement augmentation through fenestrated screws is an emerging method that has been reported to reduce the likelihood of loosening of instrumentation.27 Posterior techniques are also employed in surgery of the middle and lower thoracic spine. Generally, if part of the vertebral body is afflicted and must be removed, then expandable cages may be beneficial; other options include reconstruction with bone graft or PMMA. Rajpal et al28 reported that although metal implants are used in the majority of reconstruction cases, they also have the highest rate of overall complications. In another study, reconstruction with expandable cages packed with bone graft revealed better fusion rates than PMMA, whereas the latter is more cost effective and might be preferable in patients with limited life expectancies.29

Lumbar Spine The lumbar spine is considered mobile and, similar to the subaxial spine, contributes 2 points to the overall SINS. For patients with tumors, when comorbidity dictates the least invasive type of surgery, percutaneous fusion may be an option that can be performed April 2014, Vol. 21, No. 2

with pedicle screws augmented with cement. In cases in which the pathology is located anteriorly, laterally, or both, an anterior retroperitoneal approach may be indicated. Following vertebrectomy, reconstruction should be carried out with a cage or bone graft, as well as a plate-screw system for stabilization. For the lower thoracic, upper lumbar levels, a combined transthoracic–transabdominal approach may be considered. Vertebroplasty and balloon kyphoplasty are useful for the reconstruction of compressed vertebral bodies as well as pain reduction if tumor removal and decompression are not the primary goals. For patients with metastatic disease who have a limited life expectancy, epidural tumor resection and open vertebroplasty/kyphoplasty followed by radiotherapy may also be an appropriate option.

Surgery and Quality of Life

Orthoses

Conclusions

External stabilization with orthoses is employed in selected cases when surgery is not an option or has been scheduled for a later date. The goal is to restore alignment and prevent neurological deterioration. Many kinds of orthoses have been developed to provide the best possible biomechanical stability in different spinal levels. Most data derive from spine injury series. To our knowledge, no systematic reviews exist regarding the usage of orthoses in pathological fractures. With that in mind, the literature supports halo-vest immobilization as an effective method of reconstruction of the unstable upper cervical spine20 and should be considered in cases of nonunion surgery.30 The Philadelphia collar is considered to be sufficient in stabilizing the upper cervical spine, and it may be an alternative to the halo-vest.31 The sternal-occipital-mandibular immobilizer orthosis controls flexion more effectively than extension in the cervical spine. Other cervicothoracic orthoses include the Minerva and Yale types. Thoracolumbosacral and lumbosacral orthoses are also available and generally increase the intra-abdominal pressure, thus decreasing the strain on the spine and intervertebral discs.

Fusion systems have evolved and now offer a variety of treatment options for use by health care professionals. However, the patient with cancer often has limited reserves to compensate, so a major issue of therapy is complication avoidance. Therefore, careful patient selection and an overall multidisciplinary approach to master surgical techniques are both required. Increasing patient survival and improving quality of life are the ultimate goals of treatment. However, a need for palliative therapy still exists in the majority of cases of oncological surgery.

En Bloc Resection Theoretically, en bloc resection in spinal neoplasia is a curative treatment option. However, because the extent of the tumor is multilevel in most cases, the strategy is not feasible. En bloc spondylectomy, a technically demanding, often 2-stage procedure, has previously been described.32 The resection must be followed by anterior reconstruction of the vertebra and posterior instrumentation. Local malignancies such as chordomas, selected sarcomas and chondrosarcomas, Pancoast tumors, giant cell tumors, and osteoblastomas are types of tumors in which en bloc resection should be considered.33 April 2014, Vol. 21, No. 2

Many classification systems for spinal tumors and prognostic scores have been developed over time. Most patients referred to spine surgeons have advanced disease and often adjuvant therapy is not possible. If neurological deterioration is imminent through a pathological fracture or instability, then the need for fusion becomes obvious. However, nonemergency surgery is controversial when performed in cases in which a patient’s life expectancy is less than a few months. Evidence should corroborate that a fusion can improve quality of life, which should ultimately guide the surgical decision. Pain reduction and an appropriate amount of ambulation following surgery are important because patients are likely to be motivated to continue with adjuvant therapy.

References 1. Klimo P Jr, Schmidt MH. Surgical management of spinal metastases. Oncologist. 2004;9(2):188-196. 2. Kaloostian PE, Yurter A, Zadnik PL, et al. Current paradigms for metastatic spinal disease: an evidence-based review. Ann Surg Oncol. 2014;21(1):248-262. 3. Denis F. The three column spine and its significance in the classification of acute thoracolumbar spinal injuries. Spine (Phila Pa 1976). 1983;8(8):817-831. 4. White AA, Panjabi MM. Clinical Biomechanics of the Spine. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkens; 1990. 5. Panjabi MM. The stabilizing system of the spine. Part I. Function, dysfunction, adaptation, and enhancement. J Spinal Disord. 1992;5(4):383-389. 6. Panjabi MM. The stabilizing system of the spine. Part II. Neutral zone and instability hypothesis. J Spinal Disord. 1992;5(4):390-397. 7. Vaccaro AR, Hulbert RJ, Patel AA, et al. The subaxial cervical spine injury classification system: a novel approach to recognize the importance of morphology, neurology, and integrity of the disco-ligamentous complex. Spine (Phila Pa 1976). 2007;32(21):2365-2374. 8. Kostuik J, Weinstein JN. Differential diagnosis and surgical treatment of metastatic spine tumors. In: Frymoyer J, ed. The Adult Spine: Principles and Practice. New York, NY: Raven Press; 1991. 9. Benzel EC, ed. Biomechanics of Spine Stabilization. Rolling Meadows, IL: American Association of Neurological Surgeons; 2001. 10. Yang KH, King AI. Mechanism of facet load transmission as a hypothesis for low-back pain. Spine (Phila Pa 1976). 1984;9(6):557-565. 11. Taneichi H, Kaneda K, Takeda N, et al. Risk factors and probability of vertebral body collapse in metastases of the thoracic and lumbar spine. Spine (Phila Pa 1976). 1997;22(3):239-245. 12. Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine. 2010;35(22):E1221-E1229. 13. Fourney DR, Frangou EM, Ryken TC, et al. Spinal instability neoplastic score: an analysis of reliability and validity from the spine oncology study group. J Clin Oncol. 2011;29(22):3072-3077. 14. Menezes AH. The craniocervical junction and its abnormalities [Editorial]. Childs Nerv Syst. 2008;24(10):1089-1090. Cancer Control 149

15. Lu DC, Roeser AC, Mummaneni VP, et al. Nuances of occipitocervical fixation. Neurosurgery. 2010;66(3 suppl):141-146. 16. Grob D, Crisco JJ III, Panjabi MM, et al. Biomechanical evaluation of four different posterior atlantoaxial fixation techniques. Spine. 1992;17(5): 480-490. 17. Uribe JS, Ramos E, Youssef AS, et al. Craniocervical fixation with occipital condyle screws: biomechanical analysis of a novel technique. Spine. 2010;35(9):931-938. 18. Mummaneni PV, Haid RW. Atlantoaxial fixation: overview of all techniques. Neurology India. 2005;53(4):408-415. 19. De Iure F, Donthineni R, Boriani S. Outcomes of C1 and C2 posterior screw fixation for upper cervical spine fusion. Eur Spine J. 2009; 18(suppl 1):2-6. 20. Wang J, Jin D, Yao J, et al. Application of Halo-vest in stable reconstruction of unstable upper cervical spine [in Chinese]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2004;18(5):399-401. 21. Ogihara N, Takahashi J, Hirabayashi H, et al. Stable reconstruction using halo vest for unstable upper cervical spine and occipitocervical instability. Eur Spine J. 2012;21(2):295-303. 22. Cohen M, Zeitoun D, Blanpain S, et al. Percutaneous vertebroplasty of the C2 body and dens using the anterior oblique ascending transdiscal approach. J Neuroradiol. 2013;40(3):211-215. 23. Clarencon F, Cormier E, Pascal-Moussellard H, et al. Transoral approach for percutaneous vertebroplasty in the treatment of osteolytic tumor lesions of the lateral mass of the atlas: feasibility and initial experience in 2 patients. Spine. 2013;38(3):E193-E197. 24. Seo SS, Lee DH, Kim HJ, et al. Percutaneous vertebroplasty at C7 for the treatment of painful metastases: a case report. Korean J Anesthesiol. 2013;64(3):276-279. 25. Cauchoix J, Binet JP, Evrard J. Les voies dàbord inhabituelles dans làbord des corps vertebraux, cervicaux et dorsaux [in French]. Ann Chir. 1957;74:1463-1472. 26. Metcalfe S, Gbejuade H, Patel NR. The posterior transpedicular approach for circumferential decompression and instrumented stabilization with titanium cage vertebrectomy reconstruction for spinal tumors: consecutive case series of 50 patients. Spine. 2012;37(16):1375-1383. 27. Frankel BM, Jones T, Wang C. Segmental polymethylmethacrylateaugmented pedicle screw fixation in patients with bone softening caused by osteoporosis and metastatic tumor involvement: a clinical evaluation. Neurosurgery. 2007;61(3):531-538. 28. Rajpal S, Hwang R, Mroz T, et al. Comparing vertebral body reconstruction implants for the treatment of thoracic and lumbar metastatic spinal tumors: a consecutive case series of 37 patients. J Spinal Disord Tech. 2012;25(2):85-91. 29. Eleraky M, Papanastassiou I, Tran ND, et al. Comparison of polymethylmethacrylate versus expandable cage in anterior vertebral column reconstruction after posterior extracavitary corpectomy in lumbar and thoracolumbar metastatic spine tumors. Eur Spine J. 2011;20(8):1363-1370. 30. Longo UG, Denaro L, Campi S, et al. Upper cervical spine injuries: indications and limits of the conservative management in Halo vest. A systematic review of efficacy and safety. Injury. 2010;41(11):1127-1135. 31. Grady MS, Howard MA, Jane JA, et al. Use of the Philadelphia collar as an alternative to the halo vest in patients with C-2, C-3 fractures. Neurosurgery. 1986;18(2):151-156. 32. Tomita K, Toribatake Y, Kawahara N, et al. Total en bloc spondylectomy and circumspinal decompression for solitary spinal metastasis. Paraplegia. 1994;32(1):36-46. 33. Vrionis FD, Small J. Surgical management of metastatic spinal neoplasms. Neurosurg Focus. 2003;15(5):E12.

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Indications, contraindications, outcomes, and complications of vertebral augmentation procedures are discussed.

Burnell Shively. Fan Coral, 2013. Oil on canvas, 10ʺ × 10ʺ.

Controversial Issues in Kyphoplasty and Vertebroplasty in Malignant Vertebral Fractures Ioannis D. Papanastassiou, MD, Andreas K. Filis, MD, Maria A. Gerochristou, MD, and Frank D. Vrionis, MD, PhD Background: Kyphoplasty (KP) and vertebroplasty (VP) have been successfully employed in the treatment of pathological vertebral fractures. Methods: A critical review of the medical literature was performed and controversial issues were analyzed. Results: Evidence supports KP as the treatment of choice to control fracture pain and the possible restoration of sagittal balance, provided that no overt instability or myelopathy is present, the fracture is painful and other pain generators have been excluded, and positive radiological findings are present. Unilateral procedures yield similar results to bilateral ones and should be pursued whenever feasible. Biopsy should be routinely performed and 3 to 4 levels may be augmented in a single operation. Higher cement filling appears to yield better results. Radiotherapy is complementary with KP and VP but must be individualized. Conclusions: In cases of painful cancer fractures, if overt instability or myelopathy is not present, unilateral KP should be pursued, whenever feasible, followed by radiotherapy. The technological advances in hardware and biomaterials, as well as combining KP with other modalities, will help ensure a safe and more effective procedure.

From the Neuro-Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (IDP, AKF, FDV), and the Departments of Neurosurgery and Orthopedics at the University of South Florida Morsani College of Medicine, Tampa, Florida (IDP, AKF, FDV), the Department of Orthopedics at the General Oncological Hospital Kifisias Agioi Anargyroi, Athens, Greece (IDP), and the University of Athens Andreas Syngros Hospital, Athens, Greece (MAG). Submitted December 12, 2013; accepted January 30, 2014. April 2014, Vol. 21, No. 2

Address correspondence to Ioannis D. Papanastassiou, MD, Neuro-Oncology Program, Moffitt Cancer Center, 12902 Magnolia Drive, WCB-NEURO PROG, Tampa, FL 33612. E-mail: [email protected] Dr Vrionis receives grants/research support from Globus Medical, DePuy Synthes, and Spine360. He also is a consultant for Orthofix. No significant relationship exists between the remaining authors and the companies/organizations whose products or services may be referenced in this article. Cancer Control 151

In cases of epidural spinal cord compression or vertebral fractures that require stabilization and open surgery, the estimated survival rate plays a critical role in the decision-making process; patients expected to live fewer than 6 months are not generally considered open surgical candidates.25-27 Various scores have been developed for estimating rates of patient survivorship, with those proposed by Tomita et al26 and Tokuhashi et al27 being the most commonly used, although the judgment of the health care professional is often the most accurate predictor.28 However, in the case of VAPs, the expected survivorship rate does not dictate

152 Cancer Control

41 patients 62 KP

34 patients 18 VP vs 16 KP 1-year FU MM cohort

65 patients 99 KP 2-year FU

18 patients 55 KP 7-month FU (mean)

134 patients 65 KP vs 52 NSM 1-year FU Crossover after 1 month (38 patients)

73 patients 35 KP vs 18 RT vs 20 medical treatment 2-year FU MM cohort

Vrionis 200519

Köse 200615

Pflugmacher 200818,a

Dudeney 20028,a

Berenson 201124,b

Kasperk 201213

Baseline Characteristics

Indications

Study

VAS KP superior to RT or medical treatment

VAS Significant difference in favor of KP (1 month) sustained until 1 year

Pain substantially reduced in all patients

VAS Significant improvement ≤ 2 years

VP and KP showed pain reduction at 6 months in favor of KP

95% partial or substantial pain relief

Pain Relief

ODI Significant improvement only in KP

RMDQ/SF-36 Significant difference in favor of KP (1 month) sustained until 1 year

SF36 score significantly improved

ODI, SF36 scores significantly improved ≤ 2 years

Improved No further data

NR

Disability/QOL

Only KP group improved Height loss in RT and medical treatment groups

Significant difference in favor of KP for midthoracic and transition zone fractures

34% VH restoration

Significant improvement ≤ 1 year

NR

6-degree correction with minimal loss of height at 1 year

Kyphotic Angle/VH

30.6%

NR

4%

12.1%

None

13%

Cement Leakage

KP (2%) and RT (4.8%) superior to medical treatment (9.7%)

No difference (12 of 62 in KP vs 8 of 47 in NSM)

NR

8%

No adjacent fracture

NR

New No.

KP more effective than RT or medical treatment in pain relief, disability improvement and incidence of new fractures

For painful VCFs KP is an effective and safe treatment, rapidly reduces pain, improves function

KP efficacious in MM, leads to early pain and disability improvement and height restoration

KP safe, provides immediate, long-term pain and disability improvement

VP and BKP effective in improving QOL and pain

KP safe, beneficial in painful compression fractures

Conclusions

The skeletal system is the third most common site of metastases following the lung and liver, while breast, prostate, lung, bladder, and thyroid cancers show a predilection for bone involvement.1,2 Spine involvement leads to painful vertebral compression fractures (VCFs), epidural cord compression, or both.3-5 Vertebral augmentation procedures (VAPs) include kyphoplasty (KP) or vertebroplasty (VP), and have been employed in the treatment of those fractures in the setting of osteoporotic6 or neoplastic disease.7 Apart from nonrandomized trials, highlevel evidence exists from the multicenter, randomized Cancer Patient Fracture Evaluation (CAFE) study of patients with malignant fractures being treated with KP (Table 1).8-24 In this review, we aim to investigate the indications, contraindications, outcomes, and complications of VAPs, the relative superiority of KP compared with VP, technical issues, and the relation of VAPs with radiotherapy (RT) and other treatment modalities.

Table 1. — Selected Studies Comparing KP and VP for the Management of Malignant Vertebral Fractures

Introduction

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Cancer Control 153

79 patients 22 KP 37 VP 20 KP/VP hybrid MM cohort

407 patients 156 KP 262 VP 111 KP/VP hybrids

19 patients 46 KP MM cohort

56 patients 32 KP 65 VP

41 patients 48 KP 6-month FU MM cohort

11 patients 23 KP 1.4-year FU (mean) or death

201 patients 316 levels (KP/VP) 6-month FU (median)

69 patients 105 KP (51 bilateral vs 54 unilateral) ≥ 3-month FU MM cohort

Mendoza 201220

Burton 201121

Lane 200416,a

Fourney 200322

Erdem 201310

König 201214,a

Hirsch 201123

Papanastassiou In press17

VAS Significant improvement No difference between bilateral/unilateral

VAS Significant improvement No difference regarding sequencing RT or VAPs

VAS Improvement (4.5 points: statistics NR)

VAS Significant improvement ≤ 6 months

VAS Significant improvement ≤ 1 year Marked or complete pain relief in 84%

NR

BPI Significant improvement

BPI Significant improvement

VAS Significant improvement

NR

RMDQ Significant improvement

ECOG activity score Improvement (statistics NR)

Activity assessment Significant improvement ≤ 6 months

NR

ODI Significant improvement in majority of patients

ESAS Significant improvement in anxiety, fatigue, depression No significant improvement in insomnia, nausea

ESAS Other symptoms reduced (anxiety, fatigue, depression), except insomnia

ODI Significant improvement

Significant improvement No difference between bilateral/unilateral

NR

NR

NR

KP: VH restoration = 42% (± 21%)

Significant improvement in VH

NR

NR

NS

18%

NR

8.7%

2%

KP: None VP: 9.2%

26.3%

VP: 24% KP: 19% (NS)

NR

10%

NR

NR

4.3% (adjacent fracture)

NR

NR

NR

24% (new fracture) 18% (adjacent fracture)

NR

No adjacent fracture

KP provides significant pain relief, VH restoration No difference between bilateral/unilateral procedure

KP/VP provide excellent palliation in malignant VCFs Sequence of KP/VP vs RT does not influence results

Quick pain relief favors KP as effective and safe palliative tool

Radiofrequency KP has optimum safety and efficacy in the treatment of malignant VCFs

KP and VP are safe, effective for pain control (lasting effect) in cancer-related fractures

KP is safe in patients with MM Efficacy comparable with osteoporotic-related fractures

KP/VP have good efficacy and low complication rate in painful cancer-related fractures

Pain reduction after KP/VP was positively associated with reduction in other cancer-related symptoms

KP safe and efficient in upper T-spine

b

Prospective study. Randomized control trial. BKP = balloon kyphoplasty, BPI = Brief Pain Inventory, ECOG = Eastern Cooperative Oncology Group, ESAS = Edmonton Symptom Assessment Scale, FU = follow-up, KP = kyphoplasty, MM = multiple myeloma, NR = not reported, NS = not significant, NSM = nonsurgical management, ODI = Oswestry Disability Index, QOL = quality of life, RMDQ = Roland Morris Disability Questionnaire, RT = radiotherapy, SF36 = Short Form-36, VAP = vertebral augmentation procedure, VAS = visual analog scale, VCF = vertebral compression fracture, VH = vertebral height, VP = vertebroplasty.

a

14 patients 30 KP (upper T-spine) 16-month FU (≥ 1 year)

Eleraky 20119

treatment options. If overt instability does not exist (the Spinal Instability Neoplastic Score is used to determine spinal stability29), KP/VP may be performed for pain control. The most important criteria are7,12: • The intensity of pain must be at least a 4 out of 10 (on a 0 to 10 pain scale). • Clinical examination should correspond with imaging studies (ie, exclude other pain generators unrelated to the fracture).11 • Edema must be seen on the involved vertebrae on magnetic resonance imaging (MRI; short T1 inversion recovery images). If MRI cannot be performed, then the bone scan must be positive, indicating a recent neoplastic pro cess.9,10,12,16 However, as discussed further below, good results have been obtained in subacute or chronic fractures; therefore, in care fully selected cases, VAPs are still valuable regardless of status on MRI.30 Although kyphotic deformity may be partially restored with KP,8,9,12,13,17,18,24 this is not considered a primary indication per se, either in osteoporotic- or cancer-related fractures. Particularly in patients with cancer, kyphosis reduction is frequently without significant clinical implications, because a long-term survival rate is not anticipated, and pain reduction, early mobilization, and an improvement in quality of life are the goals of treatment.

Contraindications Table 2 summarizes absolute and relative contraindications.12 Overt instability and cord compression with neurological symptoms are the most established contraindications. In such cases, vertebral augmentation can be combined with laminectomy, with or without instrumentation.31 Radiographic cord compression is considered by many to be a relative contraindication (without myelopathy),9,32,33 and our approach is to perform VAPs under neuromonitoring or local anesthesia with an anterior delivery of cement. 9 The same is true for upper thoracic or cervical spine locations.9,34,35 Table 2. — Summary of Absolute and Relative Contraindications for Kyphoplasty/Vertebroplasty in Malignant Vertebral Fractures12 Overt instability Cord compression with clinical myelopathy Infection at the fracture site Bleeding disorder Low platelet count Contraindications to local/general anesthesia Allergy to contrast medium Data from reference 12

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Adverse Events Pain relief of approximately 4 to 5 points on a visual analog scale has been described in previous studies and should be anticipated in properly selected patients.6,10,14,17,24,36,37 The best results are seen with acute or hyperacute fractures6,24; however, satisfactory results have also been reported in patients with older fractures.24 The initial hypothesis for the possible mechanism of pain resolution was that polymethyl methacrylate (PMMA) polymerization causes an exothermic reaction, thus inducing ablation of intraosseous nerve endings and pain fibers or direct toxicity from the monomer.38-41 However, other studies refuted this notion because minimal osteonecrosis has been seen,42,43 no evidence exists of intraosseous neural tissue necrosis,43 and similar results have been replicated following an injection of calcium phosphate cement, which crystallizes at body temperature.44 It is more likely that the cement acts as a means of internal fixation, either in the form of a solid, hard ball (KP) or interdigitation in the bony trabeculae (VP).42 Mechanical stability may prevent pain fiber irritation in the periosteum, bone marrow, and the haversian system.44 Height restoration up to 34% to 38% of preoperative values and sagittal alignment improvement of 3 to 7.6 degrees have both been described.8,9,11-13,16-18,24 These changes have established beneficial effects, including reducing flexion moments of affected vertebrae, encouraging upright posture, and reducing subsequent fractures.45,46 Adjacent/subsequent fractures may occur,18,24 but the incidence is similar24 or reduced compared with conservative management.6,13,36,47 Leakage of cement into the disk space,48-50 osteoporosis, and the magnitude of corrected sagittal alignment predisposes the patient to adjacent fractures,47,49,50 which can be addressed by performing prophylactic VP/KP.51,52 Numerous complications have been noted in the literature, with fatal penetration of vital structures (eg, lungs, pericardium, aorta), and PMMA has been found throughout the human body, including in segmental arteries, the foot (dorsalis pedis artery), heart, and lungs.53-57 However, the rate of serious complications is low, with the most common complication being asymptomatic PMMA extravasation, which, in general, occurs less frequently in KP than VP.6,9,12,18

KP vs VP Controversy exists regarding the value of VP after Buchbinder et al58 and Kallmes et al59 showed no benefit of VP over a sham procedure, leading the American Academy of Orthopaedic Surgeons to advise against the use of VP.60 Within the setting of cancer, 1 small study by Köse et al15 revealed an advantage of KP over VP in pain control; overall, however, the authors considered both procedures successful. The April 2014, Vol. 21, No. 2

randomized CAFE trial strongly favored KP over nonsurgical management.24 Because no level 1 or 2 studies exist for VP, a safe profile has been proven with KP (ie, a low incidence of PMMA extravasation), and more potential exists for kyphosis restoration with KP, we favor KP over VP, particularly in cases of vertebra plana.7,15 However, VP may be performed in patients with nonindex fractures or nondeformed vertebrae; it may also be considered to reduce implant cost, particularly with ultra-high viscosity cements.61,62

Technical Considerations

Bilateral vs Unilateral Procedures Traditionally, KP and VP have been performed with bilateral pedicle cannulation63; however, surgeons now use extrapedicular approaches,34,64,65 allowing the procedure to be unilaterally performed. Growing evidence suggests that the unilateral and bilateral approaches are equivalent whenever the former is technically feasible in terms of pain control or kyphotic reduction.17,66-68 For patients with cancer-related fractures in whom pain relief is the main goal and multiple levels have been augmented, we recommend unilateral VAPs as the gold standard because they reduce operative time and radiation exposure. MRI may determine which levels are amenable for unilateral cannulation.17 A role still exists for bilateral VAPs, including when the unilateral approach appears hazardous from preoperative planning, when central placement of the balloon cannot be accomplished, or in cases of severely crushed vertebrae in which the lateral pillars of the vertebrae are better preserved than the middle portion.17 Technical Advances Ultra-high viscosity cements and special cement delivery instruments allow for slow and uniform PMMA filling, thus reducing the rate of cement extravasation.61,62 Curved curettes allow the procedures to be unilaterally performed.18,62 Novel devices utilized for cavity creation, rather than the traditional balloons, show promising results.18,61,62,69 Levels and Cement Three to 4 levels may be augmented without a significant increase in the operative time or morbidity rate.12,17 In addition to the index fracture, prophylactic augmentation may be performed in “sandwich” vertebrae (ie, when both adjacent vertebrae have been augmented), if PMMA extravasation occurs in the disk space, or in tumor-infiltrated, nondeformed vertebrae to prevent future fracture.7,51,52 The optimal amount of cement has not been established. Biomechanical and clinical studies suggest that smaller PMMA volumes may suffice to restore body stiffness and strength and achieve good clinical April 2014, Vol. 21, No. 2

results.70,71 However, other authors propose a larger amount of cement filling for better biomechanical behavior,72,73 and growing evidence suggests that larger cement volumes yield superior outcomes. For example, Roder et al74 found that the most important predictor for pain alleviation was cement volume following a dose-dependent pattern. Recent studies report that cement volume is of the utmost importance for correcting deformities and maintaining vertebral height.75,76 We share the same experience and try to achieve maximum filling in a safe manner, particularly when the anterior column is substantially compromised, if concomitant percutaneous screw fixation is performed,77 or VAPs are performed in combination with laminectomy (without instrumentation), leading to loss of the posterior tension band and further instability. Biopsy Biopsy should be routinely performed because it does not add to the morbidity or procedure length; moreover, biopsy can reveal information that can help dictate future treatment, such as confirming the presence of metastasis or revealing a new neoplasm.7,78 VAP vs RT VAP and RT modalities are complementary. RT destroys tumor cells but also has known detrimental effects on bone cell biology,79,80 leading to higher incidences of vertebral fractures (≤ 40% in radiosurgical cases).81,82 VAPs strengthen the vertebral body and ameliorate this effect of radiation while also exerting pain control.7,46 The therapeutic sequence has not been determined from previous studies and does not affect pain palliation23; therefore, its use should be determined on an individualized basis.7 Kasperk et al13 conducted the only retrospective study to date comparing RT with KP in a cohort of patients with multiple myeloma. They found that KP was superior to RT in terms of pain and disability improvement, new fractures, and vertebral height restoration.

Combining VAPs and Other Modalities VAPs can be combined with other treatment modalities. Conventional RT has been the cornerstone of therapy for alleviating pain and preventing local disease progression. With the advent of stereotactic radiosurgery, the spinal cord may be spared from unnecessary irradiation. CyberKnife (Accuray, Sunnyvale, California) is a safe and effective salvage therapy in patients who have received RT, with some authors suggesting that it may be combined with KP as a treatment paradigm.83,84 Radiofrequency ablation has been coupled with KP for the treatment of pathological spinal fractures. To reduce pain, radiofrequency destroys the tumor cells and the sensory nerve fibers in the periosteum. Cancer Control 155

By contrast, PMMA has a toxic effect on neoplastic cells due to the monomer toxicity and the exothermal reaction from the polymerization process. Studies have reported an improvement in visual analog scale and Oswestry Disability Index scores after combining KP with ablation over a single augmentation.85 Cryotherapy is a tumoricidal method that may be used in conjunction with VAPs if a probe-based cryosurgical system is available.86 In cases in which gross instability is present and KP or VP alone is deemed insufficient from a biomechanical standpoint, percutaneous screw fixation can offer further stability.77

Conclusions In cases of painful malignant fractures, unilateral kyphoplasty should be employed, whenever feasible, if overt instability or myelopathy does not exist. It is complementary with radiotherapy and may be combined with other modalities, such as ablation, cryosurgery, and percutaneous screws. The technological advances in hardware, delivery systems, and biomaterials, as well as combining kyphoplasty with other modalities, will help ensure a safe and more effective procedure. References 1. Buckwalter JA, Brandser EA. Metastatic disease of the skeleton. Am Fam Physician. 1997;55(5):1761-1768. 2. Jacofsky DJ, Frassica DA, Frassica FJ. Metastatic disease to bone. Hosp Physician. 2004;40(11):21-28, 39. 3. Papanastassiou ID, Aghayev K, Saleh E, et al. The actual management of tumor and vertebral compression fractures. J Neurosurg Sci. 2012;56(2):77-85. 4. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(8 suppl):1588-1594. 5. Eleraky M, Papanastassiou I, Vrionis FD. Management of metastatic spine disease. Curr Opin Support Palliat Care. 2010;4(3):182-188. 6. Papanastassiou ID, Phillips FM, Van Meirhaeghe J, et al. Comparing effects of kyphoplasty, vertebroplasty, and non-surgical management in a systematic review of randomized and non-randomized controlled studies. Eur Spine J. 2012;21(9):1826-1843. 7. Papanastassiou ID, Aghayev K, Berenson JR, et al. Is vertebral augmentation the right choice for cancer patients with painful vertebral compression fractures? J Natl Compr Canc Netw. 2012;10(6):715-719. 8. Dudeney S, Lieberman IH, Reinhardt MK, et al. Kyphoplasty in the treatment of osteolytic vertebral compression fractures as a result of multiple myeloma. J Clin Oncol. 2002;20(9):2382-2387. 9. Eleraky M, Papanastassiou I, Setzer M, et al. Balloon kyphoplasty in the treatment of metastatic tumors of the upper thoracic spine. J Neurosurg Spine. 2011;14(3):372-376. 10. Erdem E, Akdol S, Amole A, et al. Radiofrequency-targeted vertebral augmentation for the treatment of vertebral compression fractures as a result of multiple myeloma. Spine (Phila Pa 1976). 2013;38(15):1275-1281. 11. Gaitanis IN, Hadjipavlou AG, Katonis PG, et al. Balloon kyphoplasty for the treatment of pathological vertebral compressive fractures. Eur Spine J. 2005;14(3):250-260. 12. Hussein MA, Vrionis FD, Allison R, et al; International Myeloma Working Group. The role of vertebral augmentation in multiple myeloma: International Myeloma Working Group Consensus Statement. Leukemia. 2008;22(8):1479-1484. 13. Kasperk C, Haas A, Hillengass J, et al. Kyphoplasty in patients with multiple myeloma: a retrospective comparative pilot study. J Surg Oncol. 2012;105(7):679-686. 14. König MA, Jehan S, Balamurali G, et al. Kyphoplasty for lytic tumour lesions of the spine: prospective follow-up of 11 cases from procedure to death. Eur Spine J. 2012;21(9):1873-1879. 15. Köse KC, Cebesoy O, Akan B, et al. Functional results of vertebral augmentation techniques in pathological vertebral fractures of myelomatous patients. J Natl Med Assoc. 2006;98(10):1654-1658. 16. Lane JM, Hong R, Koob J, et al. Kyphoplasty enhances func156 Cancer Control

tion and structural alignment in multiple myeloma. Clin Orthop Relat Res. 2004;426:49-53. 17. Papanastassiou I, Eleraky M, Murtagh R, et al. Comparison of unilateral vs bilateral kyphoplasty in multiple myeloma patients and the importance of pre-operative planning. Asian Spine J. In press. 18. Pflugmacher R, Taylor R, Agarwal A, et al. Balloon kyphoplasty in the treatment of metastatic disease of the spine: a 2-year prospective evaluation. Eur Spine J. 2008;17(8):1042-1048. 19. Vrionis FD, Hamm A, Stanton N, et al. Kyphoplasty for tumor-associated spinal fractures. Tech Reg Anesth Pain Manag. 2005;9(1):35-39. 20. Mendoza TR, Koyyalagunta D, Burton AW, et al. Changes in pain and other symptoms in patients with painful multiple myeloma-related vertebral fracture treated with kyphoplasty or vertebroplasty. J Pain. 2012;13(6):564-570. 21. Burton AW, Mendoza T, Gebhardt R, et al. Vertebral compression fracture treatment with vertebroplasty and kyphoplasty: experience in 407 patients with 1,156 fractures in a tertiary cancer center. Pain Med. 2011; 12(12):1750-1757. 22. Fourney DR, Schomer DF, Nader R, et al. Percutaneous vertebroplasty and kyphoplasty for painful vertebral body fractures in cancer patients. J Neurosurg. 2003;98(1 suppl):21-30. 23. Hirsch AE, Jha RM, Yoo AJ, et al. The use of vertebral augmentation and external beam radiation therapy in the multimodal management of malignant vertebral compression fractures. Pain Physician. 2011;14(5):447-458. 24. Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12(3):225-235. 25. White BD, Stirling AJ, Paterson E, et al; Guideline Development Group. Diagnosis and management of patients at risk of or with metastatic spinal cord compression: summary of NICE guidance. BMJ. 2008;337:a2538. 26. Tomita K, Kawahara N, Kobayashi T, et al. Surgical strategy for spinal metastases. Spine (Phila Pa 1976). 2001;26(3):298-306. 27. Tokuhashi Y, Matsuzaki H, Oda H, et al. A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis. Spine (Phila Pa 1976). 2005;30(19):2186-2191. 28. Nathan SS, Healey JH, Mellano D, et al. Survival in patients operated on for pathologic fracture: implications for end-of-life orthopedic care. J Clin Oncol. 2005;23(25):6072-6082. 29. Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976). 2010;35(22):E1221-1229. 30. Voormolen MH, van Rooij WJ, van der Graaf Y, et al. Bone marrow edema in osteoporotic vertebral compression fractures after percutaneous vertebroplasty and relation with clinical outcome. AJNR Am J Neuroradiol. 2006;27(5):983-988. 31. Pan J, Qian ZL, Sun ZY, et al. Open kyphoplasty in the treatment of a painful vertebral lytic lesion with spinal cord compression caused by multiple myeloma: a case report. Oncol Lett. 2013;5(5):1621-1624. 32. Stoffel M, Wolf I, Ringel F, et al. Treatment of painful osteoporotic compression and burst fractures using kyphoplasty: a prospective observational design. J Neurosurg Spine. 2007;6(4):313-319. 33. Hentschel SJ, Burton AW, Fourney DR, et al. Percutaneous vertebroplasty and kyphoplasty performed at a cancer center: refuting proposed contraindications. J Neurosurg Spine. 2005;2(4):436-440. 34. Han KR, Kim C, Eun JS, et al. Extrapedicular approach of percutaneous vertebroplasty in the treatment of upper and mid-thoracic vertebral compression fracture. Acta Radiol. 2005;46(3):280-287. 35. Masala S, Anselmetti GC, Muto M, et al. Percutaneous vertebroplasty relieves pain in metastatic cervical fractures. Clin Orthop Relat Res. 2011;469(3):715-722. 36. Wardlaw D, Cummings SR, Van Meirhaeghe J, et al. Efficacy and safety of balloon kyphoplasty compared with non-surgical care for vertebral compression fracture (FREE): a randomised controlled trial. Lancet. 2009;373(9668):1016-1024. 37. Klazen CA, Lohle PN, de Vries J, et al. Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial. Lancet. 2010;376(9746):1085-1092. 38. Lai PL, Chen LH, Chen WJ, et al. Chemical and physical properties of bone cement for vertebroplasty. Biomed J. 2013;36(4):162-167. 39. Krishnan EC, Nelson C, Neff JR. Thermodynamic considerations of acrylic cement implant at the site of giant cell tumors of the bone. Med Phys. 1986;13(2):233-239. 40. Deramond H, Wright NT, Belkoff SM. Temperature elevation caused by bone cement polymerization during vertebroplasty. Bone. 1999;25(2 suppl):17S-21S. 41. Belkoff SM, Molloy S. Temperature measurement during polymerization of polymethylmethacrylate cement used for vertebroplasty. Spine (Phila Pa 1976). 2003;28(14):1555-1559. 42. Togawa D, Kovacic JJ, Bauer TW, et al. Radiographic and histologic findings of vertebral augmentation using polymethylmethacrylate in the primate spine: percutaneous vertebroplasty versus kyphoplasty. Spine (Phila Pa 1976). 2006;31(1):E4-E10. April 2014, Vol. 21, No. 2

43. Urrutia J, Bono CM, Mery P, et al. Early histologic changes following polymethylmethacrylate injection (vertebroplasty) in rabbit lumbar vertebrae. Spine (Phila Pa 1976). 2008;33(8):877-882. 44. Grafe IA, Baier M, Nöldge G, et al. Calcium-phosphate and polymethylmethacrylate cement in long-term outcome after kyphoplasty of painful osteoporotic vertebral fractures. Spine (Phila Pa 1976). 2008;33(11):1284-1290. 45. Glassman SD, Bridwell K, Dimar JR, et al. The impact of positive sagittal balance in adult spinal deformity. Spine (Phila Pa 1976). 2005;30(18):2024-2029. 46. Aghayev K, Papanastassiou ID, Vrionis F. Role of vertebral augmentation procedures in the management of vertebral compression fractures in cancer patients. Curr Opin Support Palliat Care. 2011;5(3):222-226. 47. Movrin I. Adjacent level fracture after osteoporotic vertebral compression fracture: a nonrandomized prospective study comparing balloon kyphoplasty with conservative therapy. Wien Klin Wochenschr. 2012;124 (9-10):304-311. 48. Lin EP, Ekholm S, Hiwatashi A, et al. Vertebroplasty: cement leakage into the disc increases the risk of new fracture of adjacent vertebral body. AJNR Am J Neuroradiol. 2004;25(2):175-180. 49. Ma X, Xing D, Ma J, et al. Risk factors for new vertebral compression fractures after percutaneous vertebroplasty: qualitative evidence synthesized from a systematic review. Spine (Phila Pa 1976). 2013. Epub ahead of print. 50. Rho YJ, Choe WJ, Chun YI. Risk factors predicting the new symptomatic vertebral compression fractures after percutaneous vertebroplasty or kyphoplasty. Eur Spine J. 2012;21(5):905-911. 51. Diel P, Freiburghaus L, Röder C, et al. Safety, effectiveness and predictors for early reoperation in therapeutic and prophylactic vertebroplasty: short-term results of a prospective case series of patients with osteoporotic vertebral fractures. Eur Spine J. 2012;21(suppl 6):S792-S799. 52. Mao H, Zou J, Geng D, et al. Osteoporotic vertebral fractures without compression: key factors of diagnosis and initial outcome of treatment with cement augmentation. Neuroradiology. 2012;54(10):1137-1143. 53. Gosev I, Nascimben L, Huang PH, et al. Right ventricular perforation and pulmonary embolism with polymethylmethacrylate cement after percutaneous kyphoplasty. Circulation. 2013;127(11):1251-1253. 54. Lee SH, Kim WH, Ko JK. Multiple pulmonary cement embolism after percutaneous vertebroplasty. QJM. 2013;106(9):877-878. 55. Liu FJ, Ren H, Shen Y, et al. Pulmonary embolism caused by cement leakage after percutaneous kyphoplasty: a case report. Orthop Surg. 2012;4(4):263-265. 56. Llanos RA, Viana-Tejedor A, Abella HR, et al. Pulmonary and intracardiac cement embolism after a percutaneous vertebroplasty. Clin Res Cardiol. 2013;102(5):395-397. 57. Sifuentes Giraldo WA, Lamúa Riazuelo JR, Gallego Rivera JI, et al. Cement pulmonary embolism after vertebroplasty [in English, Spanish]. Reumatol Clin. 2013;9(4):239-242. 58. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361(6):557-568. 59. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361(6):569-579. 60. Esses SI, McGuire R, Jenkins J, et al. The treatment of symptomatic osteoporotic spinal compression fractures. J Am Acad Orthop Surg. 2011;19(3):176-182. 61. Dalton BE, Kohm AC, Miller LE, et al. Radiofrequency-targeted vertebral augmentation versus traditional balloon kyphoplasty: radiographic and morphologic outcomes of an ex vivo biomechanical pilot study. Clin Interv Aging. 2012;7:525-531. 62. Georgy BA. Comparison between radiofrequency targeted vertebral augmentation and balloon kyphoplasty in the treatment of vertebral compression fractures: addressing factors that affect cement extravasation and distribution. Pain Physician. 2013;16(5):E513-E518. 63. Deramond H, Depriester C, Galibert P, et al. Percutaneous vertebroplasty with polymethylmethacrylate. Technique, indications, and results. Radiol Clin North Am. 1998;36(3):533-546. 64. Brugieres P, Gaston A, Heran F, et al. Percutaneous biopsies of the thoracic spine under CT guidance: transcostovertebral approach. J Comput Assist Tomogr. 1990;14(3):446-448. 65. Cho SM, Nam YS, Cho BM, et al. Unilateral extrapedicular vertebroplasty and kyphoplasty in lumbar compression fractures: technique, anatomy and preliminary results. J Korean Neurosurg Soc. 2011;49(5):273-277. 66. Chen L, Yang H, Tang T. Unilateral versus bilateral balloon kyphoplasty for multi-level osteoporotic vertebral compression fractures: a prospective study. Spine (Phila Pa 1976). 2011;36(7):534-540. 67. Song BK, Eun JP, Oh YM. Clinical and radiological comparison of unipedicular versus bipedicular balloon kyphoplasty for the treatment of vertebral compression fractures. Osteoporos Int. 2009;20(10):1717-1723. 68. Wang Z, Wang G, Yang H. Comparison of unilateral versus bilateral balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures. J Clin Neurosci. 2012;19(5):723-726. 69. Korovessis P, Vardakastanis K, Repantis T, et al. Balloon kyphoplasty versus KIVA vertebral augmentation--comparison of 2 techniques for osApril 2014, Vol. 21, No. 2

teoporotic vertebral body fractures: a prospective randomized study. Spine (Phila Pa 1976). 2013;38(4):292-299. 70. Liebschner MA, Rosenberg WS, Keaveny TM. Effects of bone cement volume and distribution on vertebral stiffness after vertebroplasty. Spine (Phila Pa 1976). 2001;26(14):1547-1554. 71. Rollinghoff M, Hagel A, Siewe J, et al. Is height restoration possible with a comparatively smaller amount of cement in radiofrequency kyphoplasty using a monopedicle approach? [In German]. Z Orthop Unfall. 2013;151(2):156-162. 72. Belkoff SM, Mathis JM, Jasper LE, et al. The biomechanics of vertebroplasty. The effect of cement volume on mechanical behavior. Spine (Phila Pa 1976). 2001;26(14):1537-1541. 73. Molloy S, Mathis JM, Belkoff SM. The effect of vertebral body percentage fill on mechanical behavior during percutaneous vertebroplasty. Spine (Phila Pa 1976). 2003;28(14):1549-1554. 74. Röder C, Boszczyk B, Perler G, et al. Cement volume is the most important modifiable predictor for pain relief in BKP: results from SWISSspine, a nationwide registry. Eur Spine J. 2013;22(10):2241-2248. 75. Krüger A, Baroud G, Noriega D, et al. Height restoration and maintenance after treating unstable osteoporotic vertebral compression fractures by cement augmentation is dependent on the cement volume used. Clin Biomech (Bristol, Avon). 2013;28(7):725-730. 76. Xu C, Liu HX, Xu HZ. Analysis of related factors on the deformity correction of balloon kyphoplasty. AJNR Am J Neuroradiol. 2014;35(1):202-206. 77. Kim CH, Chung CK, Sohn S, et al. Less invasive palliative surgery for spinal metastases. J Surg Oncol. 2013;108(7):499-503. 78. Muijs SP, Akkermans PA, van Erkel AR, et al. The value of routinely performing a bone biopsy during percutaneous vertebroplasty in treatment of osteoporotic vertebral compression fractures. Spine (Phila Pa 1976). 2009;34(22):2395-2399. 79. Pelker RR, Friedlaender GE, Panjabi MM, et al. Radiation-induced alterations of fracture healing biomechanics. J Orthop Res. 1984;2(1):90-96. 80. Triantafyllou N, Sotiropoulos E, Triantafyllou JN. The mechanical properties of the lyophylized and irradiated bone grafts. Acta Orthop Belg. 1975;41 suppl 1(1):35-44. 81. Rose PS, Laufer I, Boland PJ, et al. Risk of fracture after single fraction image-guided intensity-modulated radiation therapy to spinal metastases. J Clin Oncol. 2009;27(30):5075-5079. 82. Boehling NS, Grosshans DR, Allen PK, et al. Vertebral compression fracture risk after stereotactic body radiotherapy for spinal metastases. J Neurosurg Spine. 2012;16(4):379-386. 83. Gerszten PC, Germanwala A, Burton SA, et al. Combination kyphoplasty and spinal radiosurgery: a new treatment paradigm for pathological fractures. J Neurosurg Spine. 2005;3(4):296-301. 84. Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes? Spine (Phila Pa 1976). 2009;34(22 suppl):S78-S92. 85. Katonis P, Pasku D, Alpantaki K, et al. Treatment of pathologic spinal fractures with combined radiofrequency ablation and balloon kyphoplasty. World J Surg Oncol. 2009;7:90. 86. Lim CT, Tan LB, Nathan SS. Prospective evaluation of argon gas probe delivery for cryotherapy of bone tumours. Ann Acad Med Singapore. 2012;41(8):347-353.

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Triple modality therapy with complete resection of locally advanced T4 Pancoast tumors with involvement of the spine offers an advantage to other therapeutic modalities or therapies with incomplete resections.

Burnell Shively. Blue Crab Claws, 2013. Oil on canvas, 10ʺ × 10ʺ.

Management of Locally Advanced Pancoast (Superior Sulcus) Tumors With Spine Involvement Matthias Setzer, MD, Lary A. Robinson, MD, and Frank D. Vrionis, MD, PhD Background: The preferred treatment for locally aggressive lung cancers is triple modality therapy with concurrent and induction chemotherapy with radiation therapy followed by surgery. Patients with locally advanced T4 Pancoast tumors with spine involvement, without mediastinal N2 lymph node involvement and without distant metastases, are appropriate candidates for complete resection with subsequent spine reconstruction. This review addresses the questions of whether triple modality therapy with complete en bloc resection of locally advanced Pancoast tumors offers an advantage in terms of overall survival and complication rates compared with other therapeutic modalities or therapies with incomplete resection. Methods: A comprehensive literature search was conducted using common medical databases. Inclusion and exclusion criteria for the articles were prospectively defined. The articles were independently reviewed and a consensus decision was made about each article. Selected papers were graded by level of evidence. Results: A total of 1,001 abstracts and 93 articles fulfilled the criteria; from these studies, 14 were included in this systematic review. No level 1 study was found in this search. Four level 2 studies and 10 level 3 retrospective case series were found. The overall 5-year survival rate reported in these studies ranged from 37% to 59% and the mortality rate ranged from 0% to 6.9%. Conclusions: Evidence suggests that triple modality therapy with complete resection of locally advanced Pancoast tumors with involvement of the spine offers an advantage over other therapeutic modalities or therapies with incomplete resections.

From the Neuro-Oncology (MS, FDV) and Thoracic Oncology (LAR) Programs at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, the Department of Neurosurgery at the University Hospital Frankfurt at Goethe University, Frankfurt, Germany (MS), and the Departments of Neurosurgery (MS, FDV) and Orthopedics (FDV) at the University of South Florida Morsani College of Medicine, Tampa, Florida. Submitted January 31, 2014; accepted February 24, 2014. Address correspondence to Matthias Setzer, MD, Department of Neurosurgery, University Hospital Frankfurt, Goethe 158 Cancer Control

University, Schleusenweg 2-16, 60528 Frankfurt, Germany. E-mail: [email protected] Dr Vrionis receives grants/research support from Globus Medical, DePuy Synthes, and Spine360. He also is a consultant for Orthofix. No significant relationship exists between the remaining authors and the companies/organizations whose products or services may be referenced in this article.

April 2014, Vol. 21, No. 2

Introduction The estimated world incidence of lung cancer is 1.35 million new cases every year the estimated annual mortality rate is 1.18 million deaths—of these, the highest rates of death are found in North America and Europe.1-3 Pancoast tumors account for 3% to 5% of all non–small-cell lung carcinomas (NSCLCs), or approximately 7,000 cases per year in the United States.4 Pancoast tumors are primary lung carcinomas arising from the apex of the lung and are generally located in the superior pulmonary sulcus. In most cases, Pancoast tumors are NSCLCs, most commonly squamous cell (52%), followed by adenocarcinomas (23%) and large cell carcinomas (20%); only about 5% of Pancoast tumors are of small cell origin.5-7 Pancoast tumors may extend in 3 directions8: • Anteriorly by invading major blood vessels (eg, subclavian artery) • Superiorly by primarily invading the brachial plexus • Medially by invading the stellate ganglion, vertebral bodies, or mediastinal structures Pancoast tumors cause characteristic symptoms, such as arm, shoulder, or scapular pain, radicular pain and muscle weakness in the distributions of the C8, T1, and T2 nerve roots, and Horner’s syndrome (ptosis, miosis, and anhidrosis), when the sympathetic chain is involved.4,9 This symptom complex is also called Pancoast syndrome and includes ipsilateral anhidrosis, which is in contrast to lesions above the carotid bifurcation lacking this feature. In questionable cases, instilling cocaine drops in the affected eye will not cause pupillary dilation if Horner’s syndrome is present. Nerve root involvement must be differentiated from ulnar neuropathy, cervical radiculopathy (at C7–T1), intramedullary processes (syringomyelia, spinal cord tumors), and motor neuron disease, such as amyotrophic lateral sclerosis, which may occasionally start with atrophy of the intrinsic muscles of the hand. Pancoast tumors typically compress or invade the medial cord of the brachial plexus (C8, T1), giving rise to hand weakness and hypesthesia in the medial arm and forearm. Because it may be difficult to preoperatively differentiate between compression and invasion, patients with C8 symptoms should not be excluded from surgery based on clinical grounds alone. The absence of fasciculations and sensory findings excludes amyotrophic lateral sclerosis, while the absence of numbness in the medial arm and forearm excludes ulnar neuropathy. It is not uncommon to see patients with Pancoast tumors who previously underwent anterior cervical discectomies and fusions for tumor symptoms, and who thus then lacked improvement. Pancoast tumors invading the mediastinal pleura, chest wall, and spine were previously considered April 2014, Vol. 21, No. 2

generally unresectable and had an overall poor prognosis; radiotherapy alone or in combination with chemotherapy was the only available therapeutic option.10 However, newer therapies have improved the overall prognosis, leading to some cure and longterm survival rates. Researchers for a phase 2, nonrandomized, intergroup Pancoast tumor trial added chemotherapy to induction radiation therapy followed by resection.11,12 Based on better results with this course of therapy, this regimen was adopted as the current standard of care. However, due to significant limitations, including wound-healing issues, poor tolerance to concurrent chemoradiotherapy in debilitated patients with Pancoast tumors, and the low tolerance of postoperative chemotherapy, alternative treatment strategies were developed.4 Several major cancer centers favor a sequential triple modality therapy with induction chemotherapy or with a platinum doublet for 3 cycles (generally tumor pain lessens or resolves within 7–10 days after the start of chemotherapy), surgical resection 3 to 5 weeks after completing chemotherapy, followed by full-dose radiotherapy (6600 cGy) to the tumor bed, which is tumoricidal for close margins and any residual microscopic disease.4,13 The recent progress of spinal instrumentation — in addition to the development of reliable hardware and a wider acceptance of total “en bloc” spondylectomy — makes radical surgical modalities feasible.4,14 Because an incomplete resection is considered a poor prognostic factor, recent studies have focused on exploring the use of extended operations to achieve complete resection of Pancoast tumors invading the spine.15,16 The aim of the present article is to systematically review the literature and focus on the current multimodality treatment of locally advanced Pancoast tumors with spinal involvement.

Systematic Literature Review A systematic review was designed to answer these questions: 1. Does triple modality therapy with complete resection of locally advanced T4 Pancoast tumors offer an advantage in terms of overall survival compared with other therapeutic strategies? 2. Does triple modality therapy with complete resection of locally advanced T4 Pancoast tumors offer an advantage in terms of compli cation rate compared with other therapies? A comprehensive literature search was conducted using MEDLINE, EMBASE, Paper First, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews. The MEDLINE search terms included the terms “Pancoast tumors” and “superior pulmonary sulcus tumors.” Cancer Control 159

160 Cancer Control

35 Wright et al23

All studies carried level of evidence III according to Sackett criteria.17 aQuestion 1: Does triple modality therapy with complete resection of locally advanced T4 Pancoast tumors offer an advantage in terms of overall survival compared with other therapeutic strategies? bQuestion 2: Does triple modality therapy with complete resection of locally advanced T4 Pancoast tumors offer an advantage in terms of complication rate compared with other therapies? cFor patients with negative nodes. CT = chemotherapy, N = no, NA = not available, RT = radiation therapy, Y = yes.

N NA NA NA 48 RT: 49 RT + CT: 84 — RT: 16 RT + CT: 14

101 Rusch et al22

10

N Y NA 4 12 13 — T3: 46 T4: 5

139 Martinod et al21

62

N Y NA 7.2 NA 35 26 113

143 Komaki et al20

52

N Yc NA NA NA Complete: 55 Incomplete: 18 29 33

16 Koizumi et al19

76

N Y 31 0 NA Complete: 59 Incomplete: 0 5 11

105 Attar et al10

7

N Not applicable NA NA 20.8 26 12 55

Y 18 9 NA Complete: 45 Incomplete: 0 12

Incomplete Complete

55 6 67 Alifano et al18

64

N

2b 1a

Questions Complications (%) Postoperative Mortality Rate (%) Median Survival (mos) 5-Year Survival (%) No. of Resections

No. of Patients With Spinal Involvement Total No. of Patients Study

Table 1. — Selected Studies With Neoadjuvant Therapy Plus Trimodality Therapy

Inclusion criteria were as follows: articles published between 1980 and 2013, articles written in either English, French, German, Italian, Japanese, Portuguese, Russian, or Spanish; had an adult age group (≥ 18 years); case series; and review articles. Exclusion criteria included articles focusing on primary spine or intradural tumors, tumors in a pediatric population, case reports with mixed pathology (eg, tumor plus trauma plus degeneration in the same series), or studies with data insufficient to extract pertinent information about the tumor population. Articles reporting on treatments other than trimodality therapy (induction chemotherapy followed by radiation and surgery) were also excluded. Two independent reviewers screened the abstracts of all articles matching the search terms and inclusion/exclusion criteria. The screeners reviewed the full-text versions of suitable articles, which were then studied for information relevant to the research questions; their bibliographies were then searched for any additional references missed in the original literature search. Any disagreement on the selection of articles was resolved by discussion between the 2 reviewers. Selected papers were graded by level of evidence according to Sackett criteria.17 The results of the literature search are tabulated in Table 110,18-23 and Table 2.12,24-29 A total of 1,001 abstracts and 93 articles fulfilled the inclusion criteria. From these papers, 14 studies were included in the systematic review. No level 1 study was found in this search. Four level 2 studies were found, comprising 256 patients (76 patients with spinal involvement), as well as 10 level 3 studies (retrospective case series), including a total of 726 patients (299 patients with spinal involvement). However, some of the older studies found used various types of neoadjuvant therapy in addition to trimodality therapy. Three level 3 studies exclusively used trimodality protocols (120 patients, 22 with spinal involvement). The

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b

a

Y 13.6 Overall: 33 Complete: 94 II Rusch et al12

110

32

83

Overall: 44 Complete: 54

2.6

N 10.3 — 31 Marra et al

II

6

29

46

6.9

N 27 31.6 37 III Kwong et al28

29

5

37

—

2.7

Y 10.5 — 76 II Kunitoh et al

27

20

54


3.5

N 40.9 — 39 II Kappers et al26

18

100

37

0

Y 31 40 39 III Goldberg et al25

3

34

47.9

5

Y 54.5 — 44 III Fischer et al24

14

39


5

1

Question 1: Does triple modality therapy with complete resection of locally advanced T4 Pancoast tumors offer an advantage in terms of overall survival compared with other therapeutic strategies? Question 2: Does triple modality therapy with complete resection of locally advanced T4 Pancoast tumors offer an advantage in terms of complication rate compared with other therapies? Levels of evidence according to Sacket et al17: level II evidence, systematic review of cohort studies, cohort studies, and low-quality randomized control trials; level III evidence, retrospective case series. N = no, Y = yes.

N

N

N

N

N

N

N

2b Questions a

Complications (%) Mortality Rate (%) Median Survival (mos) 5-Year Survival (%) No. of Complete Resections No. of Patients With Spinal Involvement Study

Level of Evidence

Total No. of Patients

Table 2. — Selected Studies With Trimodality Therapy Alone

April 2014, Vol. 21, No. 2

reported overall 5-year survival rates in these studies ranged from 37% to 59% and the mortality rates ranged from 0% to 6.9% (Table 110,18-23 and Table 212,24-29). The introduction of combined concurrent chemotherapy with radiotherapy as induction therapy has significantly increased survival rates in patients with Pancoast tumors compared with radiotherapy alone.10,18-23 Although level 1 studies do not exist, newer studies that exclusively use neoadjuvant chemotherapy plus radiation therapy as part of trimodality protocols have confirmed the safety and feasibility of these treatment strategies and have shown improved survival rates in patients with complete resections. Furthermore, the treatment was well tolerated with acceptable rates of mortality and morbidity.12,24-28 Other studies suggest that trimodality therapies using induction chemotherapy and surgery followed by full-dose postoperative radiation therapy avoid the drawbacks of preoperative radiation therapy and are well tolerated, safe, and have good survival rates.13,20 However, which trimodality therapy is best for locally advanced Pancoast tumors is unclear. This is a question best addressed in large randomized trials, but, because of the rarity of the disease, it is unlikely such trials will be feasible.

Tumor-Node-Metastasis Classification System Pancoast tumors are classified according to the tumor-node-metastasis (TNM) system of the American Joint Committee on Cancer and the International Union Against Cancer.30-32 Due to the peripheral location and involvement of the chest wall in Pancoast tumors, most are classified as T3 tumors or higher, typically invading resectable areas of the chest wall or superficially extending into the mediastinum. Further invasion of the brachial plexus, mediastinal structures, or the vertebral bodies classifies them as T4 tumors, which are less readily resectable (Figure). Table 3 provides an overview of the seventh revision of the TNM descriptors for staging NSCLC developed by the International Association for the Study of Lung Cancer and adopted by the International Union Against Cancer.30-32 Based on this staging classification, Pancoast tumors are either stage IIb or IIIa (T3N0-1; T4N0-1) in the absence of mediastinal N2 node involvement or distant metastasis. Cancer Control 161

Surgical Classification Although the TNM staging system helps in general decision-making, it cannot be used to determine the extent of vertebral body resection, the operative approach, and whether or not instrumentation is needed. Therefore, spine surgeons have developed a classification of vertebral involvement to facilitate surgical planning.4,14,33 Type A Tumors Type A tumors involve the transverse process and extend to but not beyond the neural foramina. The tumor may be attached to the vertebral body, but the tumor has not infiltrated it. Type B Tumors Type B tumors extend beyond the neural foramina into the epidural space and may cause cord compression and involve at least 1 root. The vertebral body is infiltrated or destroyed, but no more than one-third of the vertebral body is affected. These tumors

require partial vertebral body resection and posterior instrumentation. Type C Tumors Type C tumors have vertebral body involvement of more than one-third in at least 1 level. In addition to vertebral body involvement, nerve root, cord compression, or both are also found.4 Anterior vertebral body reconstruction, together with posterior instrumentation, is typically performed.

Therapeutic Management The management of Pancoast tumors has changed over the last decades. Before the introduction of radiation treatment in 1954 and the first successful removal of a Pancoast tumor with postoperative adjuvant radiation, the lung cancer was uniformly fatal.10,34 In 1961, Shaw et al35 published the first clinical series that used preoperative neoadjuvant radiation, demonstrating improved tumor resectability and long-term survival rates,5,36 making neoadjuvant radiation and surgical resection the standard method for the management of Pancoast tumors. Five-year survival rates range from 27% to 46% for tumors up to stage IIB.22,23 Table 3. — TNM Staging of Non–Small-Cell Lung Cancer 6th ed. Descriptor

A

B

C

D Figure. — Patient with a T4N0 tumor. (A,B) Magnetic resonance imaging reveals a contrast-enhancing tumor extending into the vertebral bodies and the neural foramen with involvement of the right pedicle and transverse process. (C,D) Computed tomography and positron emission tomography/ computed tomography show the destruction of the transverse process on the right side. Because the tumor does not extend beyond the neural foramen into the spinal canal, it is classified as a type A tumor. 162 Cancer Control

7th ed. Revised Descriptor

N0

N1

N2

N3

T1 (≤ 2 cm)

T1a

IA

IIA

IIIA

IIIB

T1 (> 2–3 cm)

T1b

IA

IIA

IIIA

IIIB

T2 (≤ 5 cm)

T2a

IB

IIA

IIIA

IIIB

T2 (> 5–7 cm)

T2b

IIA

IIB

IIIA

IIIB

T2 (> 7 cm)

T3

IIB

IIIA

IIIA

IIIB

T3 invasion

T3

IIB

IIIA

IIIA

IIIB

T4 (same lobe nodules)

T3

IIB

IIIA

IIIA

IIIB

T4 (extension)

T4

IIIA

IIIA

IIIB

IIIB

M1 (ipsilateral lung)

T4

IIIA

IIIA

IIIB

IIIB

T4 (pleural effusion)

M1a

IV

IV

IV

IV

M1 (contralateral lung)

M1a

IV

IV

IV

IV

M1 (distant)

M1b

IV

IV

IV

IV

Cells in bold and red indicate a change from the sixth to the seventh edition of the TNM Classification of Malignant Tumors for a particular TNM category. TNM = tumor-node-malignancy. From Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2(8):706-714. Republished with permission from Wolters Kluwer Health. Copyright © 2007 by the International Association for the Study of Lung Cancer.

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Prognostic factors that predict a poor prognosis have been identified and include direct extension of the tumor into the vertebral bodies, great vessels, brachial plexus, and neck base, involvement of mediastinal (N2, N3) lymph nodes, and incomplete resection with positive margins.37-43 However, survival is associated with complete resection, which is a fact that has triggered the search for new treatment modalities.38 With the introduction of modern spine reconstruction techniques, some recently published series have stressed the benefit of en bloc resection of locally advanced tumors with vertebral and subsequent spine reconstruction. Two major strategies exist in the treatment of tumors invading the spine, including intralesional tumor resection with subsequent spine reconstruction, and en bloc resection of the tumor and subsequent spine reconstruction. Although the first strategy is palliative, the second strategy is intended to be curative. Specifically, it is necessary to resect the tumor as 1 piece, without violating the tumor borders, in particular, to strive for the histological proof of tumor-free margins.22,44 In certain cases in which the tumor is in the epidural space, true en bloc resection is impossible. In such cases, the resection is termed “en bloc with planned transgression” and may include the involved dura.45,46 The following criteria are considered when deciding for or against Pancoast tumor resection with spine involvement4,44,47: • Histological diagnosis • Whether the tumor is attached to the vertebral column (demonstrated by radiographic findings) • Presence or absence of mediastinal nodal in volvement • Presence or absence of distant metastasis Generally, patients with locally advanced NSCLC of the superior sulcus, without mediastinal N2 to N3 lymph node involvement and without distant metastases, are considered appropriate candidates for surgical therapy. If the decision to proceed with surgery is made, then the appropriate approach must be selected. Such a selection is usually made on the basis of magnetic resonance imaging (MRI) and computed tomography (CT) studies of the chest. MRI is important to reveal or rule out tumor growth through the neural foramina into the spinal canal with resulting spinal cord compression. Using MRI and CT scans, it should be possible to assign the tumor to 1 of 3 spine tumor types to make the appropriate decision concerning the need for vertebral body resection and, if necessary, how much of the vertebral body must be resected (partial vs complete vertebrectomy). If spinal stabilization is necessary, then it must be decided which approach is most appropriate and whether the procedure should be staged.4 The iniApril 2014, Vol. 21, No. 2

tial evaluation should include a thorough physical examination, including a detailed neurological examination, contrast-enhanced CT scans of the chest with 3-dimensional reconstructions, MRI with contrast of the thorax (including the brachial plexus and thoracic inlet), fusion positron emission tomography (PET)/CT scan, MRI of the brain, pulmonary function tests, standard laboratory tests, and possibly a stress test, depending on cardiac risk factors. The use of standard CT scanning with intravenous contrast material to evaluate the mediastinum for lymph node metastases is limited by substantial false-positive and false-negative results, with pooled estimates of sensitivity and specificity rates of 51% and 85%, respectively.48 Newer-generation fusion PET/CT scans have improved the accuracy of mediastinum staging, with sensitivity and specificity rates of 74% and 85%, respectively.48 With equivocal lymph node enlargement (1.5-cm diameter nodes on the short axis), surgeons generally recommend an invasive assessment of the mediastinum with sampling of suspicious lymph nodes prior to attempting a curative surgical approach.49,50 Current techniques for mediastinal lymph node sampling include endobronchial ultrasonography–guided needle biopsy, transesophageal endoscopic ultrasonography–guided needle biopsy, or mediastinoscopy.51-55 If mediastinal N2 or N3 nodes are proven to be invaded by tumor, then patients should be medically treated with chemotherapy and radiation therapy. However, hilar N1 lymph node involvement alone does not preclude surgery, and patients with T3N1 or T4N1 tumors are eligible for the trimodality approach with curative intent. Because the presence of distant metastases is important when selecting patients with Pancoast tumors, a thorough search for distant metastatic spread begins with an analysis of the patient’s history, findings on physical examination, and the results of blood tests. PET/CT plays a critical role in searching for common sites of extracranial metastatic disease. Due to the elevated incidence of brain metastases in locally advanced lung cancer, contrast-enhanced MRI of the brain is recommended to complete the metastatic workup.8,56 CT scans of the chest generally provide information concerning the extent of the Pancoast tumor, including the extent of parenchymal disease along with chest wall and mediastinal lymph node involvement. 6,57 However, MRI scans are superior to CT scans in terms of imaging tumor extension to the brachial plexus, subclavian vessels, vertebral bodies, and the spinal canal.58-61 With the current accuracy of contrast-enhanced CT and MRI scans, in questionable cases venous or arterial angiography is rarely needed to determine whether subclavian vessels are invaded by tumor. Cancer Control 163

Cytologic analysis of expectorated sputum generally yields a malignant diagnosis in 11% to 20% of cases when the tumor is centrally located, but the yield is much lower with more peripheral tumors.37,62,63 Fiberoptic bronchoscopy with transbronchial biopsy and lavage with cytologic analysis may increase the diagnostic accuracy to 30% or 40%, even in peripheral tumors.37,63 However, in the usual peripheral Pancoast tumor, transthoracic CT–guided needle biopsy may be needed to histologically confirm the diagnosis of cancer prior to beginning induction therapy.

Preoperative Radiation Therapy and Chemotherapy The potential benefits of preoperative radiation therapy were first promoted by Shaw et al35 and include a decrease in tumor size, improved resectability, and a reduction in viable cells, theoretically preventing the dissemination of the tumor during surgery.64 In addition, by examining the specimen the pathologist may determine whether the irradiation significantly affected the tumor. The disadvantages of induction radiation therapy include difficulty in determining “true” margins during surgery, because postradiation scarring limits useful, tactile, surgical feedback and visual cues with regard to the limit of the tumor. In addition, complications, such as infection, cerebrospinal fluid (CSF) leakage, pseudarthrosis, and hardware failure, increase with preoperative irradiation. Other disadvantages of preoperative radiation therapy include the symptomatic debilitation of patients before undergoing a major surgical procedure and potential wound-healing problems in which the surgical incision (superior–posterior extent) is located in the radiation field. The addition of concurrent chemotherapy to preoperative radiation therapy is motivated by the rationale of improving resection rates and preventing or treating occult systemic disease.23,28,43,64,65 This approach has proved beneficial as preoperative neoadjuvant therapy in the treatment of high-grade sarcomas; however, the optimum neoadjuvant regimen for Pancoast tumors remains to be determined. The only major multi-institutional phase 2 trial of combined preoperative concurrent and induction chemotherapy with radiation therapy in Pancoast tumors showed a complete resection rate of 92% and a significantly improved survival rate compared with historical control trials of preoperative radiation therapy alone followed by surgery.11,12 However, this preoperative regimen is difficult to tolerate because patients with Pancoast tumor often are debilitated, as indicated by the 75% rate of patients in the trial being strong enough to undergo subsequent surgical resection following initial treatment.11 Another treatment approach includes high-dose 3-dimensional radiation therapy (dose range, 164 Cancer Control

50–70 Gy) integrated into trimodality therapy by Kwong et al.28 These investigators recommend performing restaging mediastinoscopy following induction therapy with chemotherapy and radiation therapy, and, if nodes are positive, surgical options should be reassessed in terms of palliation of local symptoms rather than curative surgery. Despite the widespread use of preoperative chemotherapy and radiation therapy for Pancoast tumors, no randomized trials support this treatment, and the paucity of cases with this presentation will likely limit completion of subsequent randomized studies. Despite the popularity of induction and concurrent chemotherapy with radiation therapy, the recommended dose of induction radiation therapy is 45 Gy, which is minimally cytotoxic for lung cancer. If positive margins are present after subsequent surgical resection, then adding 20 Gy of postoperative radiation therapy (split-course radiation) will have little additional effect. An empirical approach favored by some major cancer centers is induction doublet chemotherapy alone followed 3 to 5 weeks later by resection, and then full-dose postoperative radiation therapy (65–70 Gy), which is a more cytotoxic dose likely to cover close or positive margins. With this approach, we have found no impaired resectability, and patients have a better clinical status prior to surgery and after chemotherapy alone compared with concurrent chemotherapy with radiation therapy. Although this approach has not yet been validated in clinical trials, we estimate that local recurrence rates will be lower than the reported local recurrence rates of 25% to 27.7% for induction and concurrent chemotherapy with radiation therapy.28

Surgical Approaches Various surgical approaches have been described for invasive Pancoast tumors with spine involvement requiring vertebral body resection.15,16,66,67 Recent studies of surgical case series have shown that the use of extended operations to achieve complete resection of locally advanced T4 Pancoast tumors invading the subclavian vessels or spinal column is feasible.15,16,33,44 The surgical goal is resection of the upper lobe with the involved ribs, transverse processes, and all involved structures (eg, lower trunk of the brachial plexus [T1 nerve root], stellate ganglion, spinal elements) in an en bloc fashion to obtain negative margins.44,68 More advanced T4 tumors are generally resected in 2 stages because instrumentation and spinal stabilization are required. In some studies, a single lateral approach is used for resection and instrumentation placement; however, performing dorsal spinal fixation is technically demanding while maintaining proper alignment with the patient in a lateral position. In the event that instrumentation is not necessary (no verteApril 2014, Vol. 21, No. 2

bral body involvement, only chest wall involvement), single-stage surgery through posterolateral thoracotomy (classic Shaw-Paulson approach35) may suffice.68,69 One alternative approach occasionally favored is the anterior transcervical approach popularized by Dartevelle et al.70-72 This method allows better exposure of the extreme anterior apex of the lung and cervically based structures (brachial plexus and subclavian vessels). The incision parallels the lower border of the sternocleidomastoid muscle and courses across the manubrium, laterally turning below the ipsilateral clavicle. Grunenwald and Spaggiari73 developed a transmanubrial technique involving a manubrial L-shaped transection and first costal cartilage resection. Dartevelle,74 Fadel et al,75 and Grunenwald et al68 developed a combination transcervical or transmanubrial technique and a posterior midline approach. The trapdoor approach described by Nazzaro et al76 is often used for an anteriorly located tumor or a tumor mass with kyphotic angulation and/or involvement of the esophagus or the subclavian artery. Although the anterior weight–bearing spinal column can be reconstructed with polymethyl methacrylate, bone graft, or mesh following vertebra removal, the placement of adequate anterior instrumentation is difficult to achieve using such an approach. Whenever possible, lobectomy is favored for pulmonary resection (with lower recurrence rates than apical segmentectomy)35,77; however, in these anterior apical approaches, apical segmentectomy may be substituted, especially for small tumors, with an anticipated good outcome.35,77 Most described surgical methods for locally advanced T4 lesions involve at least 2 stages (tumor types B and C). Typically, spinal stabilization is performed through a posterior approach (first stage) followed by posterolateral or trapdoor thoracotomy for definitive resection (second stage). Our group showed that a single-stage posterior approach is feasible in selected patients and can lead to a good outcome in patients with Pancoast tumors who require spinal stabilization and en bloc resection.14 Such an approach offers 1-stage definitive resection, spinal stabilization (anterior, posterior, or both), and simultaneous chest wall and lobectomy resection. The surgery is well tolerated when performed in experienced centers, and it eliminates the need for patients to undergo a secondstage operation. However, the thoracic surgeon must perform upper lobectomy through the chest wall defect after the tumor is disconnected from the chest wall and spine, a technique that may be challenging depending on tumor size. The choice of approach depends on several factors, including the medical and neurological status of the patient; the nature, location, and extent of the tumor; the need for spinal stabilization; and the April 2014, Vol. 21, No. 2

experience of the surgeons and anesthesiologists. In general, 3 types of spine tumor involvement have been identified.4,14 To select the appropriate approach, Pancoast tumors with spine involvement are classified according to the extent of vertebral involvement.14 In type A tumors, the chest wall, including the ribs and transverse processes, are involved and instrumentation is not required; therefore, these tumors can be approached and resected by single-stage posterolateral thoracotomy. Scoliosis (nondebilitating) may develop following surgery. In cases of type B tumors, part of the vertebral body has been infiltrated but is confined to a single side. In such cases, osteotomy is required through the medial wall of the involved pedicle obliquely, followed by an incision through the vertebral body (partial vertebrectomy), combined with posterior instrumentation and fusion. Anterior reconstruction is not necessary because at least 50% of the vertebral body will remain intact. This procedure can be achieved by an initial posterior midline approach with posterior instrumentation, followed later by a definitive resection during second-stage posterolateral thoracotomy. Type C tumors cross over the midline, involving more than 50% of the vertebral body, thus necessitating anterior reconstruction with a cage, allograft, or polymethyl methacrylate and additional posterior instrumentation in a second-stage procedure through a ventral approach. In such cases, bilateral nerve root clipping is carried out, and osteotomy is performed from the opposite side (total vertebrectomy). This technique can also be carried out as a 2-stage surgical approach, namely, as posterolateral thoracotomy and a posterior midline approach. As mentioned previously, it is possible to achieve en bloc resection in selected cases with circumferential stabilization in a single-stage, posterior midline approach.14 An anterior trapdoor approach may be employed when the tumor invades the subclavian artery, esophagus, sternum, and anterior mediastinum. This surgical technique provides exposure in selected cases.4

Surgical Results Several surgical series on locally advanced Pancoast tumors suggest that en bloc resection with tumor-free margins results in prolonged rates of survival and an increased median time to recurrence. The rates of complete tumor resections ranged from 56% to 79% compared with rates of 21% to 44% for incomplete resections.15,16,33,78 Some investigators found a significant difference in rates of median survival times between complete and incomplete resection groups.78 With complete resection, 2-year survival rates ranged from 47% to 54%, and 5-year survival rates ranged from 14% to 27%.15,33 Recurrence rates were 41% to 59%.15,33 Cancer Control 165

Complications

Conclusions

Pancoast tumor surgery involves complications and adverse events related to the need for en bloc resection and the frequent sacrifice of the T1 nerve root and stellate ganglion. Although T1 is not the dominant root innervating the intrinsic muscles of the hand (C8), its sacrifice may lead to hand weakness. However, patients can typically continue to use their hands for daily activities but not for heavy labor. Generally, Horner’s syndrome presents as an aesthetic-related issue rather than a functional one. Some atrophy of the muscles in the back, along with prominence of the posterior hardware, can be expected. Ipsilateral shoulder misuse due to pain issues can occur, and early physical therapy is instrumental in recovery. Pulmonary complications (atelectasis and pneumonia) can arise and should be treated with aggressive pulmonary hygiene, careful pain management, and other appropriate interventions. Patients with type A tumors undergoing chest wall resection may develop compensatory scoliosis over time, but this is typically not disabling. As with any surgical procedure, appropriate planning may prevent most complications. Preoperatively, the number of vertebrae involved must be assessed, as well as the extent of osteotomies and the relationship of the tumor to the subclavian vessels. If the subclavian vessel appears to be involved by tumor, then a vascular surgeon must be involved early on in the planning and execution of the surgical procedure. The extent and type of instrumentation must also be determined. Hardware failure can occur, including junctional kyphosis/scoliosis, rod breakage (typically at transition points), and pulling out of screws or hooks. Late failures are typically the result of pseudarthrosis and require fusion revision. Among reported series on surgical treatment of locally advanced Pancoast tumors, mortality rates ranged from 0% to 5%, and complication rates ranged from 28% to 52%.15,16,19,33 The most frequent complications in these series were the result of pulmonary issues such as prolonged intubation for respiratory failure, pneumonia, and atelectasis. Other complications may include deep venous thrombosis, pulmonary embolism, chylothorax, excessive blood loss, wound dehiscence or infection (particularly in combination with postoperative radiation), nerve root injury, spinal cord injury, injury of the dura with neurological deficits, and CSF leakage. If there is a CSF leak within the thoracic cavity, then treatment may be difficult due to negative intrathoracic pressure. In our experience, this complication typically requires surgical repair with a multilayered patch and a vascularized graft (intercostal muscle or trapezius muscle flap).4

Although no level 1 studies exist on the treatment of Pancoast tumors, the present review provides evidence that triple modality therapy along with complete resection of locally advanced T4 Pancoast tumors with involvement of the spine offers an advantage to other therapeutic modalities or therapies with incomplete resections. Evidence from the literature is insufficient to support the hypothesis that triple modality therapy is superior to other therapeutic modalities in terms of complication rates.

166 Cancer Control

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Ann Thorac Surg. 1994;58(2):290-295. 44. Mazel C, Grunenwald D, Laudrin P, et al. Radical excision in the management of thoracic and cervicothoracic tumors involving the spine: results in a series of 36 cases. Spine (Phila Pa 1976). 2003;28(8):782-92. 45. Boriani S, Bandiera S, Donthineni R, et al. Morbidity of en bloc resections in the spine. Eur Spine J. 2010;19(2):231-241. 46. Li H, Gasbarrini A, Cappuccio M, et al. Outcome of excisional surgeries for the patients with spinal metastases. Eur Spine J. 2009;18(10):1423-1430. 47. Mazel C, Balabaud L, Bennis S, et al. Cervical and thoracic spine tumor management: surgical indications, techniques, and outcomes. Orthop Clin North Am. 2009;40(1):75-92, vi-vii. 48. Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd ed). Chest. 2007;132(3 suppl):178S-201S. 49. Stanford W, Barnes RP, Tucker AR. Influence of staging in superior sulcus (Pancoast) tumors of the lung. Ann Thorac Surg. 1980;29(5):406-409. 50. Wright CD, Moncure AC, Shepard JA, et al. Superior sulcus lung tumors. Results of combined treatment (irradiation and radical resection). J Thorac Cardiovasc Surg. 1987;94(1):69-74. 51. Eckardt J, Petersen HO, Hakami-Kermani A, et al. Endobronchial ultrasound-guided transbronchial needle aspiration of undiagnosed intrathoApril 2014, Vol. 21, No. 2

racic lesions. Interact Cardiovasc Thorac Surg. 2009;9(2):232-235. 52. Ernst A, Eberhardt R, Krasnik M, et al. Efficacy of endobronchial ultrasound-guided transbronchial needle aspiration of hilar lymph nodes for diagnosing and staging cancer. J Thorac Oncol. 2009;4(8):947-950. 53. Rintoul RC, Tournoy KG, El Daly H, et al. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international multicentre experience. J Thorac Oncol. 2009;4(1):44-48. 54. Tournoy KG, De Ryck F, Vanwalleghem LR, et al. Endoscopic ultrasound reduces surgical mediastinal staging in lung cancer: a randomized trial. Am J Respir Crit Care Med. 2008;177(5):531-535. 55. Tournoy KG, Rintoul RC, van Meerbeeck JP, et al. EBUS-TBNA for the diagnosis of central parenchymal lung lesions not visible at routine bronchoscopy. Lung Cancer. 2009;63(1):45-49. 56. Rusch VW. Management of Pancoast tumors. Lancet Oncol. 2006; 7(12):997-1005. 57. Webb WR, Jeffrey RB, Godwin JD. Thoracic computed tomography in superior sulcus tumors. J Comput Assist Tomogr. 1981;5(3):361-365. 58. Gefter WB. Magnetic resonance imaging in the evaluation of lung cancer. Semin Roentgenol. 1990;25(1):73-84. 59. Takasugi JE, Rapoport S, Shaw C. Superior sulcus tumors: the role of imaging. J Thorac Imaging. 1989;4(1):41-48. 60. Webb WR, Gatsonis C, Zerhouni EA, et al. CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology. 1991;178(3):705-713. 61. Webb WR, Sostman HD. MR imaging of thoracic disease: clinical uses. Radiology. 1992;182(3):621-630. 62. Walls WJ, Thornbury JR, Naylor B. Pulmonary needle aspiration biopsy in the diagnosis of Pancoast tumors. Radiology. 1974;111(1):99-102. 63. Maxfield RA, Aranda CP. The role of fiberoptic bronchoscopy and transbronchial biopsy in the diagnosis of Pancoast’s tumor. N Y State J Med. 1987;87(6):326-329. 64. Paulson DL, Shaw RR, Kee JL, et al. Combined preoperative irradiation and resection for bronchogenic carcinoma. J Thorac Cardiovasc Surg. 1962;44:281-294. 65. Barnes JB, Johnson SB, Dahiya RS, et al. Concomitant weekly cisplatin and thoracic radiotherapy for Pancoast tumors of the lung: pilot experience of the San Antonio Cancer Institute. Am J Clin Oncol. 2002;25(1):90-92. 66. Grunenwald D, Mazel C, Girard P, et al. Total vertebrectomy for en bloc resection of lung cancer invading the spine. Ann Thorac Surg. 1996;61(2): 723-726. 67. Grunenwald D, Mazel C, Baldeyrou P, Girard P. En bloc resection of lung cancer invading the spine. Ann Thorac Surg. 1996;61(6):1878-1879. 68. Grunenwald DH, Mazel C, Girard P, et al. Radical en bloc resection for lung cancer invading the spine. J Thorac Cardiovasc Surg. 2002;123(2): 271-279. 69. Shaw RR. New approaches to treatment of bronchogenic carcinoma. Med Bull (Ann Arbor). 1961;27:231-238. 70. Dartevelle P, Levasseur P, Rojas-Miranda A, et al Combined cervical and thoracic approach to the removal of tumours responsible for the Pancoast and Tobias syndrome (author’s transl) [in French] Nouv Presse Med. 1981;10(13):1051-1054. 71. Dartevelle P, Levasseur P, Rojas-Miranda A, et al. Value of the combined cervical and thoracic approach in the surgery of Pancoast and Tobias’s syndrome of tumoral origin [in French]. Chirurgie. 1983;109(5):399-403. 72. Dartevelle PG, Chapelier AR, Macchiarini P, et al. Anterior transcervical-thoracic approach for radical resection of lung tumors invading the thoracic inlet. J Thorac Cardiovasc Surg. 1993;105(6):1025-1034. 73. Grunenwald D, Spaggiari L. Transmanubrial osteomuscular sparing approach for apical chest tumors. Ann Thorac Surg. 1997;63(2):563-566. 74. Dartevelle PG. Extended operations for the treatment of lung cancer. Ann Thorac Surg. 1997;63(1):12-19. 75. Fadel E, Missenard G, Chapelier A, et al. En bloc resection of nonsmall cell lung cancer invading the thoracic inlet and intervertebral foramina. J Thorac Cardiovasc Surg. 2002;123(4):676-685. 76. Nazzaro JM, Arbit E, Burt M. “Trap door” exposure of the cervicothoracic junction. Technical note. J Neurosurg. 1994;80(2):338-341. 77. Jones DR, Detterbeck FC. Pancoast tumors of the lung. Curr Opin Pulm Med. 1998;4(4):191-197. 78. Bilsky MH, Vitaz TW, Boland PJ, et al. Surgical treatment of superior sulcus tumors with spinal and brachial plexus involvement. J Neurosurg. 2002;97(3 suppl):301-309.

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Focused resection of epidural disease followed by adjuvant spinal stereotactic radiosurgery is an effective palliative approach.

Burnell Shively. Parrotfish, 2013. Oil on canvas, 10ʺ × 10ʺ.

Separation Surgery for Spinal Metastases: Effect of Spinal Radiosurgery on Surgical Treatment Goals Nelson Moussazadeh, MD, Ilya Laufer, MD, Yoshiya Yamada, MD, and Mark H. Bilsky, MD Background: The treatment of epidural spinal cord compression due to metastatic cancer represents an important clinical challenge. The NOMS (neurologic, oncologic, mechanical, and systemic) framework facilitates the determination of the optimal combination of systemic, radiation, and surgical therapies for individual patients. Spinal stereotactic radiosurgery (SRS) is an effective and safe modality for achieving durable control of local disease. Integrating SRS into the postoperative treatment plan allows surgical goals to be modified, thus decreasing the extent of tumor resection required. Methods: Separation surgery is indicated for patients with spinal cord compression secondary to solid tumor metastases. During separation surgery, the spinal column is stabilized and the epidural tumor is resected without requiring significant vertebral body resection. Results: Tumor separation from the spinal cord allows patients to undergo postoperative SRS. Conclusions: The combination of separation surgery and high-dose hypofractionated or single-fraction SRS results in high local tumor control at 1 year and is an effective palliative paradigm for this patient population.

Multimodal Treatment for Metastatic Epidural Spinal Cord Compression From the Departments of Neurological Surgery (NM, IL, MHB) and Radiation Oncology (YY) at the Memorial Sloan-Kettering Cancer Center, New York, New York, and the Department of Neurological Surgery at the New York Presbyterian Hospital-Weill Cornell Medical, Center, New York, New York (NM, IL, MHB). Submitted January 22, 2014; accepted February 5, 2014 Address correspondence to Mark H. Bilsky, MD, Department of Neurological Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York NY 10065. E-mail: [email protected] No significant relationship exists between the authors and the companies/organizations whose products or services may be referenced in this article. 168 Cancer Control

Spinal metastases occur in 30% to 40% of all patients with cancer.1,2 Certain cancers, such as prostate, breast, and melanoma, display osseous tropism, with more than one-half of patients with these cancers developing spinal metastases over the course of their illness.3 Metastatic disease in the spine leads to spinal instability, neurological deficits, and pain. Metastatic epidural spinal cord compression (ESCC) affects 5% to 10% of all patients with cancer and up to 40% of those with other bony metastases.4-6 Approximately 20,000 Americans present each year with spinal cord compression April 2014, Vol. 21, No. 2

at the time of cancer diagnosis,7,8 with the Nationwide Inpatient Sample database reporting more than 8,000 annual admissions for malignant spinal cord compression.9 Symptom palliation represents the main treatment goal in these patients and is used to preserve or restore spinal stability and neurological function. As such, all local treatments must be planned to allow for the shortest interruption of systemic therapy. Multimodal therapy is critical for the management of metastatic ESCC. In addition to medical treatment for the systemic burden of disease, numerous surgical and radiotherapeutic models have been employed. Historically, surgical approaches have included laminectomy without instrumented fusion, an approach largely abandoned due to the inability to resect ventral epidural and vertebral body disease, as well as the potential destabilization of the biomechanically vulnerable cancer spine with resultant pain and risk of neurological deterioration. With the improvement and popularization of spinal instrumentation, circumferential decompression requiring instrumented stabilization is frequently used. In a review of retrospective studies from 1964 to 2005, Witham et al10 demonstrated that adding laminectomy to radiation, as well as adding posterior stabilization to laminectomy and radiation, improved neurological function, with stable perioperative mortality rates among surgical series (36% vs 42% vs 64% mean improvements in neurological function). Although anterior decompression is associated with increased mean neurological improvement (75%), it is also associated with increased perioperative mortality (10% vs 5%–6% in the posterolateral series).10 In a randomized controlled study of surgical decompression with conventional radiotherapy (30 Gy in 10 fractions) compared with radiotherapy alone for metastatic ESCC secondary to solid malignancies, Patchell et al11 demonstrated superiority of a combined surgical and radiotherapeutic approach for the maintenance and recovery of ambulation, duration of ambulation, functional ability, maintenance of continence, and survival. While surgery provides spinal stabilization and neural element decompression, radiation therapy provides local tumor control. Conventional external beam radiation therapy (cEBRT) has been the mainstay of spinal radiation for decades.12 Histology-specific sensitivity to cEBRT traditionally serves as the basis for the classification of tumors (radiosensitive vs radioresistant). cEBRT confers durable local control in radiosensitive metastatic pathologies, including hematological malignancies (lymphoma, plasmacytoma, multiple myeloma), small cell cancers, germ cell tumors, and breast and prostate carcinomas, with 2-year local control rates of 80% to 98%.13-16 However, most solid tumor metastases exhibit a spectrum of April 2014, Vol. 21, No. 2

resistance to cEBRT, including tumors of renal, thyroid, hepatocellular, and colorectal origins, in addition to sarcoma and melanoma and, to a lesser extent, non–small-cell lung cancer. cEBRT conveyed 2-year control rates as low as 30% in gastrointestinal metastases, with a brief duration of motor improvement for bladder, lung, and kidney metastases, demonstrating durable improvements of 1 month, 4 months, and 5 months, respectively.17-20 Therefore, these tumor histologies were classified as radioresistant due to the unsatisfactory local control generally conferred by cEBRT. However, because spinal stereotactic radiosurgery (SRS) generally overcomes the resistance of these tumors to cEBRT — thus providing durable local control — the term “radioresistant” describes the relative resistance to cEBRT, rather than the overall outcome of radiation treatment. High-dose hypofractionated radiotherapy using image-guided stereotactic techniques has largely overcome the radioresistance of spinal metastases that poorly respond to cEBRT. SRS delivers radiation to contoured target volumes with improved collateral tissue sparing, which is achieved via a steep dose gradient between target volumes and adjacent organs at risk. This technology is attractive for the treatment of spinal disease given the morbidity associated with local failure and the risk of toxicity associated with overdosing tissues in tumor proximity, including the spinal cord and esophagus. When treating spinal metastases without epidural extension, single-fractionated and multifractionated SRS each demonstrated 70% to 90% rates of durable local disease control, progression-free survival (PFS), and palliation as firstline therapy, re-treatment therapy, or both following failed cEBRT21-23; in the series by Gerszten et al,23 500 lesions were treated. One prospective report of radiosurgery for ESCC due to nonradiosensitive tumors (with eligible participants having a minimum of 4/5 lower extremity strength) describes a 65% mean reduction in epidural tumor volume at 2 months and an 81% rate of improvement in neurological function at 11.5 months of follow-up.24 However, of the 35 patients neurologically intact at presentation, the neurologic deterioration of 2 patients raised concerns about the safety and efficacy of SRS alone in patients with spinal cord compression.24 Two prospective studies demonstrated the safety and effectiveness of spinal SRS as first-line therapy for spinal metastasis in the absence of significant spinal cord compression.25,26 Furthermore, the conformal nature of radiation delivery decreases the radiation dose given to tissues surrounding the spine, allowing the delivery of SRS to previously radiated spinal regions.27-31 A meta-analysis of spinal reirradiation series yielded a median local control rate of 80% at 1 year (range: 66%–93%).32 Spinal toxicity, including myelopathy, paraparesis, Cancer Control 169

or both, is rare with post–cEBRT SRS salvage, with 1 prospective report describing a case of grade 3 lumbar plexopathy characterized as foot drop in addition to radicular pain and paresthesia.29 Sixty-three lesions were treated with either 30 Gy in 5 fractions or 27 Gy in 3 fractions and were followed-up for 17.6 months.29 Other series indicate that standard regimens impose no significant neurological toxicity: these series included 37 cases treated with a median dose of 24 Gy in 3 fractions, two-thirds of which were followed for at least 6 months27; 79 cases treated with doses of 27 to 30 Gy in 3 fractions, with 15.9 months of follow-up33; and 81 cases treated with 24 Gy in 3 fractions or 30 Gy in 5 to 6 fractions, with an overall survival rate of 11 months.31 One case-control study–based model suggested the safety of SRS reirradiation regimens, administered at least 5 months following cEBRT, delivering a maximal thecal sac normalized, biologically effective dose (Pmax nBED) of 20 to 25 Gy (2/2) if the total Pmax nBED did not exceed 70 Gy (2/2) and the thecal sac SRS Pmax nBED was 50% or less of the total nBED.34 The durable and reliable local control rates provided by cEBRTin spinal metastases sensitive to conventional fractionation and by SRS in cEBRT-resistant tumors have largely obviated the need for cytoreductive surgery in spinal metastases. Data indicate that the rate of local control following SRS is independent of tumor volume.35 Although cEBRT can be delivered, regardless of the degree of epidural tumor extension in radiosensitive tumors, SRS requires a separation of several millimeters between the tumor and the spinal cord to deliver tumoricidal radiation doses without risking radiation toxicity to the spinal cord. Therefore, the integration of radiation therapy into surgical planning has shifted the goal from maximal tumor resection surgery to separation surgery to provide a separation of the tumor from the spinal cord and to optimize the conditions for the safe and effective delivery of SRS.

Patient Evaluation The ESCC scale provides a common vocabulary to describe and stratify patients on the basis of the degree of epidural tumor extension.36 Tumors confined to bone (stage 0) and tumors with minor epidural extension without abutment or compression of the spinal cord (stages Ia and Ib) have the requisite separation from the spinal cord to be safely treated with SRS. These tumors are classified as low-grade ESCC. By contrast, tumors displacing or compressing the spinal cord (stages II and III, respectively) are classified as high-grade ESCC and require resection of the epidural component to separate the tumor from the spinal cord prior to SRS (Fig 1). The ESCC scale has goodto-excellent intra- and inter-rater reliability scores. The ESCC scale represents 1 of the 4 considerations in the NOMS (neurological, oncological, mechanical, and systemic) algorithm (Fig 2). The NOMS framework allows the determination of the optimal combination and type of surgical, radiation and pharmacologic modalities for each patient by integrating neurological (N), oncological (O), mechanical (M), and systemic (S) considerations.37 The neurological consideration includes the degree of radiographic ESCC and a clinical determination of neurological symptomatology attributable to spinal cord or nerve root compression, while the oncological consideration relies on tumor histology to classify tumors into either radioresistant and radiosensitive pathology. Patients with radiosensitive tumors are generally treated with cEBRT regardless of ESCC, achieving good local control. By contrast, radioresistant tumors benefit from SRS for local control. Although patients with lowgrade ESCC may undergo SRS without surgery, those with high-grade ESCC secondary to radioresistant tumors require separation surgery prior to SRS. The mechanical consideration serves as an independent surgical indication. Patients with mechanical instability often require stabilization. The spinal

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Fig 1. — ESCC scale. (A) Stage 0 describes disease confined to bone; 1a involves the epidural space without causing dural deformity; stage 1b refers to epidural disease compressing the thecal sac without abutting the spinal cord; stage 1c describes spinal cord abutment. (B) Stage 2 disease deforms the spinal cord without circumferentially obliterating the CSF space. (C) Stage 3 ESCC describes spinal cord compression with complete obliteration of the CSF space at the affected level. CSF = cerebrospinal fluid, ESCC = epidural spinal cord compression. From Bilsky MH, Laufer I, Fourney DR, et al. Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine. 2010;13(3):324-328. Reproduced with permission from Journal of Neurosurgery: Spine. 170 Cancer Control

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Oncological

Neurological

column may be stabilized using open or percutaneously placed instrumentation in addition to cement augmentation. The Spinal Instability Neoplastic Score is a validated decision-making tool that facilitates the diagnosis of instability.38,39 Factors reflecting and governing stability — including tumor-level biomechanics (with increased instability with junctional or mobile spine disease over semirigid thoracic or rigid sacral involvement), the presence of pain, bony lysis, vertebral body collapse, posterolateral element involvement, or frank misalignment — are tallied and weighted to provide a score classified into stable, unstable, or indeterminate categories. For patients with an indeterminate or unstable score, surgical referral is indicated. Mechanical radiculopathy and the severe exacerbation of pain with recumbence or neck movement provide reliable symptoms of spinal instability.40 The comprehensive evaluation described in the NOMS algorithm also accounts for systemic tumor burden and any additional medical comorbidity affecting the expected survival of the patient and his or her tolerance for surgery.

Separation Surgery The goals of separation surgery include epidural decompression and spinal stabilization without gross total or en bloc tumor resection.41 Generally, instrumented stabilization is performed prior to decompression in order to avoid the manipulation of hardware across an open spinal canal. Typically, pedicle or lateral mass screw-rod fixation is performed at a minimum of 2 levels superior and inferior to the level of decompression. Longer constructs or cement reinforcement of screw purchase may be required in patients with poor bone quality. Laminectomy is performed at the level of epidural tumor extension and at least partially above and below the levels of the tumor. Most of the bone removal is carried out using a 3-mm matchstick bur on a high-speed drill rather than a Kerrison punch to avoid iatrogenic injury. Tumor and ligamentous resections are performed using sharp dissection with a No. 15 blade and tenotomy scissors. The ligament resection is initiated at a tumor-free level so normal dural planes can be identified and the epidural tumor can be safely dissected.

Low-Grade ESCC No Myelopathy

Radiation

High-Grade ESCC ± Myelopathy

cEBRT

Radiosensitive

SRS

Radioresistant/ Previously Radiated

Systemic

Mechanical

Separation Surgery Stable

Unstable

Stabilization

Able to Tolerate Surgery Unable to Tolerate Surgery

Fig 2. — The NOMS (neurological, oncological, mechanical, and systemic) algorithm for the treatment of spinal metastases. Radiosensitive malignancies are referred to conventional radiotherapy regardless of degree of cord compression. Radioresistant disease requires IMRT either upfront (in the absence of high-grade cord compression) or following decompressive separation surgery. Generally, IMRT is the chosen modality of adjuvant radiation for previously radiated tumors. Mechanical instability provides an independent surgical indication. cEBRT = conventional external-beam radiation, ESCC = epidural spinal cord compression, IMRT = intensity-modulated radiation therapy, SRS = stereotactic radiosurgery. Republished with permission of AlphaMed Press, from Laufer I, Rubin DG, Lis E, et al. The NOMS framework: approach to the treatment of spinal metastatic tumors. Oncologist. 2013;18(6):744-751; permission conveyed through Copyright Clearance Center, Inc. April 2014, Vol. 21, No. 2

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To access the ventral epidural space, unilateral or bilateral facetectomy is performed followed by pedicle resection with a high-speed drill. This transpedicular approach allows the posterior longitudinal ligament and the ventral epidural tumor to be exposed without manipulation of the spinal cord. Following coagulation of the ventral epidural plexus, the posterior longitudinal ligament is resected to ensure complete dural decompression and to ventrally clear the dural margin. When dissecting the lateral dura, it is important to identify the exiting nerve roots, which are typically preserved during the dissection. When necessary for tumor resection, thoracic nerve roots below T1 are sacrificed. Two vascular clips are placed proximal to the dorsal root ganglion, which are then bipolar cauterized and ligated with tenotomy scissors. Partial corpectomy may be performed to facilitate decompression without aggressive attempts for gross total tumor or vertebral body resection. As a result, anterior constructs are rarely required. In cases with severe vertebral body destruction, anterior reconstruction may be carried out using polymethylmethacrylate with Steinmann pins; alternatively, polyether ether ketone or titanium cage placement can also be used with this posterolateral approach.41

Stereotactic Radiosurgery Postoperative myelography is performed to delineate spinal cord and dural margins, as well as to avoid any radiographic artifact encountered on magnetic resonance imaging in the setting of proximate spinal instrumentation. The myelography and simulation are often performed prior to patient discharge from perioperative hospitalization. Single-fraction (24 Gy) or hypofractionated SRS (typically 18–36 Gy in 3–6 fractions)

A

B

C

D

E

is administered.21,42 Individual fractionation regimens are prescribed on the basis of previous radiation, histological radiosensitivity, ESCC stage, paraspinal extension, and the number of spinal treatment levels. Typically, larger tumors (> 2 spine segments), epidural disease in excess of stage Ib ESCC, and cases of previous radiation are treated with high-dose hypofractionated regimens. High-dose single-fraction therapy is typically prescribed otherwise. For example, a 1- or 2-level tumor with stage Ia ESCC and no significant paraspinal tumor volume would likely be treated with a single fraction of 24 Gy. Alternatively, a 3-level tumor with stage Ib ESCC and esophageal abutment would likely be treated with a hypofractionated dose. Treatment plans may be affected by the use of intraoperative or percutaneous high-dose-rate brachytherapy, which allows conformal doses to the target lesion and improved critical-tissue sparing. Single-fraction SRS dose constraints in cases with no prior history of radiation are composed of a maximal spinal cord dose (as defined on myelography) of 14 Gy, an esophageal dose of 14.5 Gy, and a cauda equina dose of 16 Gy. Gross tumor volume treatment contours are delineated on the basis of preoperative magnetic resonance imaging and include intraosseous, epidural, and paraspinal disease, with radiation prescribed to the presurgical tumor extent, thus accounting for the decompressed postoperative dural margin demonstrated via myelography. Clinical tumor volumes are defined as extensions of the gross tumor volume to account for the presumed microscopic disease extension into adjacent marrow spaces (eg, the entire vertebral body when only a proportion of the body is radiographically involved).43 The planning treatment volume is a 2- to 3-mm expansion of the clinical tumor volume to

F

Fig 3. — Representative case of epidural spinal cord compression amenable to separation surgery plus radiosurgery. This 70-year-old man with metastatic renal cell carcinoma presented with severe neck pain and left upper extremity weakness. Panel A shows MRI (sagittal T1–gadolinium-enhanced). Panel B (axial) demonstrates C6 metastasis with a burst fracture and extension into the posterior elements with circumferential epidural disease and high-grade cord compression. Posterolateral instrumented fusion was performed with bilateral lateral mass screws at C3, C4, and C5, and with pedicle screws at T1 and T2. Laminectomy was performed at C5 to C7 and facetectomy at C6–7 bilaterally. The epidural tumor was circumferentially removed, including from the left-sided C6 and C7 nerve roots, as demonstrated on (C) postoperative myelogram and (D) MRI. Lateral radiographs demonstrate the hardware position (E). Adjuvant SRS (27 Gy in 3 fractions) was administered beginning on postoperative day 18. Hand strength was improved at the latest follow-up. Panel F shows the dose distribution of image-guided radiation therapy. Planning target volume is depicted by the inner magenta line; the 95% isodose line is navy; and the 50% isodose-exposed region is cyan. MRI = magnetic resonance imaging, SRS = stereotactic radiosurgery. 172 Cancer Control

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compensate for the small margin of error expected in the planning and delivery of radiation treatment. We generally administer postoperative SRS within 10 to 20 days of surgery, frequently prior to staple removal. A representative case is presented in Fig 3.

Separation Surgery Plus Adjuvant Stereotactic Radiosurgery

In our experience, complications associated with separation surgery combined with adjuvant SRS are minimal. In our recent series, radiotherapy was not associated with any neurological morbidity, and 4 patients required repeat surgery for hardware failure (1 of whom had local progression).45 These data are in line with our previous findings of grade 1 skin reactions in 3 of 21 patients, 1 case of transient acute neuritic pain, 3 cases of grade 2 esophagitis, and 1 case of grade 4 esophagitis that required surgical repair of a fistula.44 Furthermore, in the most recent analysis of our 7-year experience, the overall rate of symptomatic hardware failure requiring reoperation following separation surgery in patients who did not have anterior reconstruction was 9 out of 318 patients (2.8%).46 Risk factors for failure included chest wall resection and initial construct length of 6 levels or more.46 SRS puts the treated vertebral bodies at risk for fracture when used as a stand-alone treatment.47-49 Postoperative vertebral body compression fractures within or adjacent to instrumented construct may be stabilized using percutaneous cement augmentation.50

Cumulative Incidence

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0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

We recently described our experience with 186 patients (from 2002 to 2011) treated with decompressive separation surgery followed by adjuvant hypofractionated or high-dose single-fraction SRS.44,45 Among these patients, 136 exhibited high-grade cord compression (stage II or III ESCC) at presentation. Patients were treated with 1 to 8 levels of spinal decompression (median of 2 levels) followed by either low-dose per fraction (18–36 Gy in 5 or 6 fractions) hypofractionated SRS (58.6% of patients), high-dose per fraction (24–30 Gy in 3 fractions) hypofractionated SRS (19.9%), or 24 Gy single-fraction SRS (21.5%), with completion within a median of 1.6 months following surgery. Postoperative SRS provided durable local control rates regardless of tumor histology.45 Overall, 18.3% of patients demonstrated local progression at a meConclusions dian of 4.8 months, 55.6% died without local progresFor patients with metastatic epidural spinal cord comsion at a median of 5.6 months, and the remaining pression and high-grade spinal cord compression, 26.3% of patients were alive and without progression separation surgery is a safe and effective treatment at the last follow-up (median of 7.1 months), with a option. Although most spinal metastases can be succumulative local progression incidence of 16.4% at cessfully treated with conventional external-beam ra1 year (95% confidence interval: 10.7–22.2; Fig 4).45 diation or stereotactic radiosurgery depending on their Univariate competing-risks analysis revealed the superiority of postoperative high-dose over low-dose hypofractionated SRS in PFS rates (95.9% vs 77.4%, Single-fraction SRS respectively; hazard ratio High-dose hypofractionated SRS [HR]: 0.12; P = .04) and a Low-dose hypofractionated SRS trend toward superiority of single-fraction versus low-dose hypofractionated SRS (1-year PFS: 91.0%; HR: 0.45; P = .09).45 The analysis failed to demonstrate an association between previous radiation or tumor histology with local control. These data provide evidence 0 6 12 18 24 30 36 42 48 54 60 66 that high-dose per fraction Months from Completion of SRS SRS delivered either as single-fraction or hypofracFig 4. — Long-term local control of spinal metastases with separation surgery plus adjuvant IMRT by fractionated treatments provide tionation regimen. These data demonstrate superiority of high- vs low-dose hypofractionated SRS, in addition durable local control rates to a trend toward superiority of high-dose single-fraction SRS vs low-dose hypofractionated SRS. regardless of prior radiation IMRT = intensity-modulated radiation therapy, SRS = stereotactic radiosurgery. From Laufer I, Iorgulescu JB, Chapman T, et al. Local disease control for spinal metastases following “separation surgery” and adjuvant or histology-intrinsic resis- hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine. 2013;18(3):207-214. Reproduced with permission from Journal of Neurosurgery: Spine. tance to cEBRT. Cancer Control 173

radiosensitivity, surgery remains indicated in cases of high-grade spinal cord compression in radioresistant or unknown malignancies. In this setting, focused resection of the epidural tumor via the posterolateral approach followed by adjuvant stereotactic radiosurgery provides durable, long-term local disease control regardless of prior radiation or tumor histology. Thus, integrating stereotactic radiosurgery into the treatment framework for spinal metastases may reduce the extent of tumor resection. Prospective studies of adjuvant radiotherapy timing and dosing are directed at outcome optimization with a minimization of late toxicity. References 1. Wong DA, Fornasier VL, MacNab I. Spinal metastases: the obvious, the occult, and the impostors. Spine (Phila Pa 1976). Jan;15(1):1-4. 2. Ortiz Gómez JA. The incidence of vertebral body metastases. Int Orthop. 1995;19(5):309-311. 3. Sutcliffe P, Connock M, Shyangdan D, et al. A systematic review of evidence on malignant spinal metastases: natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression. Health Technol Assess. 2013;17(42):1-274. 4. Gilbert RW, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor: diagnosis and treatment. Ann Neurol. 1978;3(1):40-51. 5. Gerszten PC, Welch WC. Current surgical management of metastatic spinal disease. Oncology (Williston Park). 2000;14(7):1013-1024, 1029-1030. 6. Sciubba DM, Petteys RJ, Dekutoski MB, et al. Diagnosis and management of metastatic spine disease. A review. J Neurosurg Spine. 2010;13(1):94-108. 7. Schiff D. Spinal cord compression. Neurol Clin. 2003;21(1):67-86. 8. Ecker RD, Endo T, Wetjen NM, et al. Diagnosis and treatment of vertebral column metastases. Mayo Clin Proc. 2005;80(9):1177-1186. 9. Mak KS, Lee LK, Mak RH, et al. Incidence and treatment patterns in hospitalizations for malignant spinal cord compression in the United States, 1998-2006. Int J Radiat Oncol Biol Phys. 2011;80(3):824-831. 10. Witham TF, Khavkin YA, Gallia GL, et al. Surgery insight: current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol. 2006;2(2):87-94. 11. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643-648. 12. Bilsky MH, Lis E, Raizer J, et al. The diagnosis and treatment of metastatic spinal tumor. Oncologist. 1999;4(6):459-469. 13. Rades D, Veninga T, Stalpers LJ, et al. Outcome after radiotherapy alone for metastatic spinal cord compression in patients with oligometastases. J Clin Oncol. 2007;25(1):50-56. 14. Rades D, Karstens JH, Hoskin PJ, et al. Escalation of radiation dose beyond 30 Gy in 10 fractions for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys. 2007;67(2):525-531. 15. Mizumoto M, Harada H, Asakura H, et al. Radiotherapy for patients with metastases to the spinal column: a review of 603 patients at Shizuoka Cancer Center Hospital. Int J Radiat Oncol Biol Phys. 2011;79(1):208-213. 16. Rades D, Fehlauer F, Schulte R, et al. Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression. J Clin Oncol. 2006;24(21):3388-3393. 17. Brown PD, Stafford SL, Schild SE, et al. Metastatic spinal cord compression in patients with colorectal cancer. J Neurooncol. 1999;44(2):175-180. 18. Sze WM, Shelley M, Held I, et al. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev. 2004;(2):CD004721. 19. Rades D, Freundt K, Meyners T, et al. Dose escalation for metastatic spinal cord compression in patients with relatively radioresistant tumors. Int J Radiat Oncol Biol Phys. 2011;80(5):1492-1497. 20. Rades D, Huttenlocher S, Bajrovic A, et al. Surgery followed by radiotherapy versus radiotherapy alone for metastatic spinal cord compression from unfavorable tumors. Int J Radiat Oncol Biol Phys. 2011;81(5):e861-868. 21. Yamada Y, Bilsky MH, Lovelock DM, et al. High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys. 2008;71(2):484-490. 22. Gibbs IC, Kamnerdsupaphon P, Ryu MR, et al. Image-guided robotic radiosurgery for spinal metastases. Radiother Oncol. 2007;82(2):185-190. 23. Gerszten PC, Burton SA, Ozhasoglu C, et al. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976). 2007;32(2):193-199. 24. Ryu S, Rock J, Jain R, et al. Radiosurgical decompression of metastatic epidural compression. Cancer. 2010;116(9):2250-2257. 174 Cancer Control

25. Garg AK, Shiu AS, Yang J, et al. Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer. 2012;118(20):5069-5077. 26. Ryu S, Pugh SL, Gerszten P, et al. RTOG 0631 phase II/III study of image-guided stereotactic radiosurgery for localized (1-3) spine metastases: phase II results. Int J Radiat Oncol Biol Phys. 2011;81(2):S131-S132. 27. Sahgal A, Ames C, Chou D, et al. Stereotactic body radiotherapy is effective salvage therapy for patients with prior radiation of spinal metastases. Int J Radiat Oncol Biol Phys. 2009;74(3):723-731. 28. Damast S, Wright J, Bilsky M, et al. Impact of dose on local failure rates after image-guided reirradiation of recurrent paraspinal metastases. Int J Radiat Oncol Biol Phys. 2011;81(3):819-826. 29. Garg AK, Wang XS, Shiu AS, et al. Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy: the University of Texas MD Anderson Cancer Center experience. Cancer. 2011;117(15):3509-3516. 30. Choi CY, Adler JR, Gibbs IC, et al. Stereotactic radiosurgery for treatment of spinal metastases recurring in close proximity to previously irradiated spinal cord. Int J Radiat Oncol Biol Phys. 2010;78(2):499-506. 31. Mahadevan A, Floyd S, Wong E, et al. Stereotactic body radiotherapy reirradiation for recurrent epidural spinal metastases. Int J Radiat Oncol Biol Phys. 2011;81(5):1500-1505. 32. Masucci GL, Yu E, Ma L, et al. Stereotactic body radiotherapy is an effective treatment in reirradiating spinal metastases: current status and practical considerations for safe practice. Expert Rev Anticancer Ther. 2011;11(12):1923-1933. 33. Wang XS, Rhines LD, Shiu AS, et al. Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial. Lancet Oncol. 2012;13(4):395-402. 34. Sahgal A, Ma L, Weinberg V, et al. Reirradiation human spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2012;82(1):107-116. 35. Ahmed KA, Stauder MC, Miller RC, et al. Stereotactic body radiation therapy in spinal metastases. Int J Radiat Oncol Biol Phys. 2012;82(5):e803e809. 36. Bilsky MH, Laufer I, Fourney DR, et al. Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine. 2010;13(3):324-328. 37. Laufer I, Rubin DG, Lis E, et al. The NOMS framework: approach to the treatment of spinal metastatic tumors. Oncologist. 2013;18(6):744-751. 38. Fourney DR, Frangou EM, Ryken TC, et al. Spinal instability neoplastic score: an analysis of reliability and validity from the spine oncology study group. J Clin Oncol. 2011;29(22):3072-3077. 39. Campos M, Urrutia J, Zamora T, et al. The Spine Instability Neoplastic Score: an independent reliability and reproducibility analysis. Spine J. 2013;pii:S1529-9430(13)01492-7. 40. Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976). 2010;35(22):E1221-E1229. 41. Wang JC, Boland P, Mitra N, et al. Single-stage posterolateral transpedicular approach for resection of epidural metastatic spine tumors involving the vertebral body with circumferential reconstruction: results in 140 patients. J Neurosurg Spine. 2004;1(3):287-298. 42. Yamada Y, Lovelock DM, Yenice KM, et al. Multifractionated imageguided and stereotactic intensity-modulated radiotherapy of paraspinal tumors: a preliminary report. Int J Radiat Oncol Biol Phys. 2005;62(1):53-61. 43. Cox BW, Spratt DE, Lovelock M, et al. International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012;1;83(5):e597-e605. 44. Moulding HD, Elder JB, Lis E, et al. Local disease control after decompressive surgery and adjuvant high-dose single-fraction radiosurgery for spine metastases. J Neurosurg Spine. 2010;13(1):87-93. 45. Laufer I, Iorgulescu JB, Chapman T, et al. Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine. 2013;18(3):207-214. 46. Amankulor NM, Xu R, Iorgulescu JB, et al. The incidence and patterns of hardware failure after separation surgery in patients with spinal metastatic tumors. Spine J. 2013;pii:S1529-9430(13):1623-1629. 47. Rose PS, Laufer I, Boland PJ, et al. Risk of fracture after single fraction image-guided intensity-modulated radiation therapy to spinal metastases. J Clin Oncol. 2009;27(30):5075-5079. 48. Boehling NS, Grosshans DR, Allen PK, et al. Vertebral compression fracture risk after stereotactic body radiotherapy for spinal metastases. J Neurosurg Spine. 2012;16(4):379-386. 49. Cunha MV, Al-Omair A, Atenafu EG, et al. Vertebral compression fracture (VCF) after spine stereotactic body radiation therapy (SBRT): analysis of predictive factors. Int J Radiat Oncol Biol Phys. 2012;84(3):e343-e349. 50. Laufer I, Sciubba DM, Madera M, et al. Surgical management of metastatic spinal tumors. Cancer Control. 2012;19(2):122-128.

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Ten Best Readings Relating to Spinal Oncology Laufer I, Iorgulescu JB, Chapman T, et al. Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine. 2013;18(3):207-214. Postoperative adjuvant stereotactic radiosurgery following epidural spinal cord decompression and instrumentation is a safe and effective strategy for establishing durable local tumor control regardless of tumor histology–specific radiosensitivity. Kunitoh H, Kato H, Tsuboi M, et al. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non–small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol. 2008; 26(4):644-649. This trimodality approach is safe and effective for the treatment of patients with superior sulcus tumors. Gomez DR, Cox JD, Roth JA, et al. A prospective phase 2 study of surgery followed by chemotherapy and radiation for superior sulcus tumors. Cancer. 2012;118(2):444-451. Surgery followed by postoperative chemoradiation is safe and effective for the treatment of marginally resectable superior sulcus tumors. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643-648. Direct decompressive surgery plus postoperative radiotherapy is superior to treatment with radiotherapy alone for patients with spinal cord compression caused by metastatic cancer. Omeis IA, Dhir M, Sciubba DM, et al. Postoperative surgical site infections in patients undergoing spinal tumor surgery: incidence and risk factors. Spine (Phila Pa 1976). 2011;36(17):1410-1419. Surgery for spine tumors appears to be associated with a higher incidence of surgical site infections (SSIs) than nontumor spine surgery. Identification of perioperative risk factors will help delineate this subset of patients with high risk for developing SSIs, thus potentially allowing perioperative modification for such factors, which may lead to an overall better clinical outcome and patient satisfaction. Chow E, Zeng L, Salvo N, et al. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012;24(2):112-124. Overall and complete response rates were similar in both intention-to-treat and assessable patients. Single and April 2014, Vol. 21, No. 2

multiple fraction regimens provided equal pain relief; however, significantly higher retreatment rates occurred in those receiving single fractions. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician. 2010;56(6):514-517, e202-e205. This proposed modification of the World Health Organization analgesic ladder is not intended to negate or advise against the use of the original ladder. On the contrary, after 24 years of use the analgesic ladder has demonstrated its effectiveness and widespread usefulness; however, modifications are necessary to ensure its continued use for knowledge transfer in pain management. Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976). 2010;35(22):E1221-E1229. The Spine Instability Neoplastic Score is a comprehensive classification system with content validity that can guide clinicians in identifying when patients with neoplastic disease of the spine may benefit from surgical consultation. It can also aid surgeons in assessing the key components of spinal instability due to neoplasia and may become a prognostic tool for surgical decision-making when put in context with other key elements such as neurologic symptoms, extent of disease, prognosis, patient health factors, oncologic subtype, and radiosensitivity of the tumor. Boriani S, De Iure F, Bandiera S, et al. Chondrosarcoma of the mobile spine: report on 22 cases. Spine (Phila Pa 1976). 2000;25(7):804-812. En bloc excision, with wide or marginal histologic margins, is the suggested management for chondrosarcomas of the spine. Early diagnosis and careful surgical staging and planning are necessary for conducting adequate management. However, tumor contamination of the specimen margins, even in a small area, or spreading of the tumor myxoid content can worsen the prognosis. Berenson J, Pflugmacher R, Jarzem P, et al; Cancer Patient Fracture Evaluation (CAFE) Investigators. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12(3):225-235. For painful vertebral compression fractures in patients with cancer, kyphoplasty is an effective and safe treatment that rapidly reduces pain and improves function.

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Perspective

Controversy Surrounding Mammography Screening? Not in Our Opinion. Mammography has been the subject of many passionate and intense debates; nonetheless, mammography remains the gold standard in breast cancer screening and the only breast cancer screening test proven to reduce breast cancer–related mortality in large population-based studies.1 The most recent results from the Canadian National Breast Screening Study (CNBSS) published by Miller et al2 in the February 11, 2014, issue of the British Medical Journal once again bring the mammography controversy to a head. The authors of that article conclude that mammography screening does not reduce breast cancer mortality. This conclusion is in opposition to a vast body of literature as well as results from the largest and longest running breast cancer screening trials, all of which conclude that mammography screening reduces breast cancer–related mortality by approximately one-third.3,4 Mammography can help detect small and more treatable tumors, thus reducing breast cancer–related mortality and improving quality of life for women who can then undergo less invasive surgery and cancer treatment. Health care professionals who care for women with breast cancer have witnessed many cancers caught too late. These providers know that the earlier breast cancer is caught, the greater chance a woman has for survival. Smaller tumors have a better prognosis than larger ones and are also less likely to spread to the lymph nodes or to more distant sites.5 Population-based breast cancer screening with mammography became widely available in the United States in the mid 1980s; since that time, a reduction of more than 30% was seen in annual rates of breast cancer–related mortality.6 Beginning in the early 1970s — the early years of mammography —approximately 40% of cancers were detected by screening alone.7 However, the CNBSS, which began in the mid 1980s, showed that screening alone detected 32% of cancers.2 This low number is consistent with reports indicating that the equipment used for mammography screening was of poor quality and was not state-of-the-art at the time,8 a fact that may account for the low percentage of cancers detected by screening. The mammography technologists and radiologists also received no special training in — what was at the time — such a relatively new technique.2 Using high-quality digital mammography, 176 Cancer Control

more than 60% of breast cancers may be found by screening alone.9 In addition, the size of the cancers found in the screening arm of the CNBSS were approximately the same size as those in the control arm (1.9 and 2.1 cm, respectively).2 This supports the idea that the study employed poor-quality mammography. The mean tumor size of a cancer detected on mammography is between 1.0 and 1.5 cm, which is nearly one-half of the size of the tumors found by mammography in the CNBSS.10 Furthermore, for a randomized control trial to be valid, the study must ensure that women are randomly assigned to screening and control groups. No details about the participants that could potentially bias the results should be known until they are assigned to one of these groups. The CNBSS researchers did not adhere to these rules.2,11 Patients enrolled in the CNBSS first underwent a physical examination prior to entering the trial and were then randomized to the screened or nonscreened group. This action most likely resulted in the statistically significant excess of women with advanced breast cancers to the screening arm, as women with palpable masses or lymphadenopathy could be “randomized” to the screening arm.12 Of the 252 women with breast cancer assigned to the screening arm, 52 patients (28.9%) died during the first year compared with 26 patient deaths (15.2%) in the 170 women with breast cancer assigned to the control arm.2 The difference in percentage of breast cancer deaths between the 2 groups during the first year of the study provides further evidence for our concern that the CNBSS was an invalid randomized trial. In conclusion, the CNBSS has 2 fundamental flaws — poor quality mammography and flawed randomization — that have led us to question the validity of its results. We believe these flaws should be strongly considered prior to making any conclusions based on results from the CNBSS. The mammographic equipment utilized was not digital and was not state-of-the-art for the 1980s; thus, the methods used are different from the high-quality digital mammography currently utilized in the United States. Prerandomizing female participants to undergo a physical examination is a flaw in the randomization process that likely resulted in a statistically significant excess of women with advanced breast cancers to be April 2014, Vol. 21, No. 2

“randomized” to the screening arm. A multiplicity of facts supports the CNBSS as being flawed, some of which we outlined above, thus limiting any merit given to the conclusions of that study. Jennifer S. Drukteinis, MD Assistant Member Department of Diagnostic Radiology H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida

John V. Kiluk, MD Associate Member Comprehensive Breast Program Department of Women’s Oncology H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida

References 1. Duffy SW, Tabar L, Vitak B, Warwick J. Tumor size and breast cancer detection: what might be the effect of a less sensitive screening tool than mammography? Breast J. 2006;12(suppl 1):S91-S95. 2. Miller AB, Wall C, Baines CJ, et al. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ. 2014;348:g366. 3. Tabár L, Vitak B, Chen TH, et al. Swedish two-county trial: impact of mammographic screening on breast cancer mortality during 3 decades. Radiology. 2011;260(3):658-663. 4. Hellquist BN, Duffy SW, Abdsaleh S, et al. Effectiveness of population-based service screening with mammography for women ages 40 to 49 years: evaluation of the Swedish Mammography Screening in Young Women (SCRY) cohort. Cancer. 2011;117(4):714-722. 5. Koscielny S, Tubiana M, Lê MG, et al. Breast cancer: relationship between the size of the primary tumour and the probability of metastatic dissemination. Br J Cancer. 1984;49(6):709-715. 6. American Cancer Society. Breast Cancer Facts & Figures 2013-2014. Atlanta: American Cancer Society, Inc. 2013. 7. Baker LH. Breast Cancer Detection Demonstration Project: five-year summary report. CA Cancer J Clin. 1982;32(4):194-225. 8. Yaffe MJ. Correction: Canada study [letter]. J Natl Cancer Inst. 1993;85:94. 9. Mathis KL, Hoskin TL, Boughey JC, et al. Palpable presentation of breast cancer persists in the era of screening mammography. J Am Coll Surg. 2010;210(3):314-318. 10. Güth U, Huang DJ, Huber M, et al. Tumor size and detection in breast cancer: Self-examination and clinical breast examination are at their limit. Cancer Detect Prev. 2008;32(3):224-228. 11. American College of Radiology. BMJ article on breast cancer screening effectiveness incredibly flawed and misleading. www.acr.org/ News-Publications/News/News-Articles/2014/ACR/BMJ-Article-on-Breast -Cancer-Screening-Effectiveness-Incredibly-Flawed-and-Misleading. Accessed February 27, 2014. 12. Tarone RE. The excess of patients with advanced breast cancer in young women screened with mammography in the Canadian National Breast Screening Study. Cancer. 1995;75(4):997-1003.

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FACULTY POSITION: HOSPITALIST Moffitt Cancer Center’s Department of Internal Medicine is seeking a candidate at the level of Assistant/Associate Member to join the Internal and Hospital Medicine Program. The successful candidate will enjoy a balanced position, involving inpatient attending and consultation duties, resident education, and ambulatory care services that include both scheduled and urgent patients. Moffitt serves an appreciative and diverse patient population with a wide range of malignant and nonmalignant diseases. The H. Lee Moffitt Cancer Center & Research Institute, the only Florida-based NCI-designated comprehensive cancer center, is a rapidly growing center affiliated with the University of South Florida and is committed to education through a wide range of residency and fellowship programs. The Cancer Center is composed of a large ambulatory care facility and a 206-bed hospital, with a 36-bed blood and marrow transplant program, 15 state-of-the-art operating suites, a 30-bed intensive care unit, a high-volume screening program, and a basic science research facility. The Moffitt Research Institute is composed of approximately 150 principal investigators, 58 laboratories, and 306,000 square feet of research space. Faculty of Moffitt Cancer Center are eligible for primary and secondary academic appointments at the University of South Florida College of Medicine. Academic rank is commensurate with qualifications and experience. The successful candidate must hold an MD or DO and be board certified or eligible in internal medicine. Experience in a multidisciplinary academic setting is preferred. Florida medical license or eligibility is required. For inquiries about the position, contact Bryan Bognar, MD, Chair, Department of Internal Medicine, at 813-745-3134 or [email protected]. To apply, visit our Web page at MOFFITT.org/careers and refer to requisition number 11304. Moffitt Cancer Center provides a tobacco-free work environment. It is an equal opportunity, affirmative action employer and a drug-free workplace.

FACULTY POSITION: ACADEMIC NOCTURNIST Moffitt Cancer Center’s Department of Internal Medicine is seeking a candidate at the level of Assistant/Associate Member to join the Internal and Hospital Medicine Program for the Direct Referral Center, Moffitt’s urgent care outpatient onsite facility. This full-time position would involve three to four 12-hour shifts each week and include didactic resident teaching responsibilities. No on-call duties are required. Moffitt Cancer Center is affiliated with the University of South Florida. Primary and secondary university appointments are available, as applicable. Academic rank is commensurate with qualifications and experience. Moffitt serves an appreciative and diverse patient population with a wide range of malignant and nonmalignant disease. An outstanding compensation package with competitive benefits and a relocation allowance is provided. The H. Lee Moffitt Cancer Center & Research Institute, the only Florida-based NCI-designated comprehensive cancer center, is a rapidly growing center affiliated with the University of South Florida and is committed to education through a wide range of residency and fellowship programs. The Cancer Center is composed of a large ambulatory care facility and a 206-bed hospital, with a 36-bed blood and marrow transplant program, 15 state-of-the-art operating suites, a 30-bed intensive care unit, a high-volume screening program, and a basic science research facility. The Moffitt Research Institute is composed of approximately 150 principal investigators, 58 laboratories, and 306,000 square feet of research space. Successful candidates must hold an MD or DO and be board certified or eligible in internal medicine. Experience in a multidisciplinary academic setting is preferred. Florida medical license or eligibility is required. For inquiries about the position, contact Bryan Bognar, MD, Chair, Department of Internal Medicine, at 813-745-3134 or [email protected]. To apply, visit our Web page at MOFFITT.org/careers and refer to requisition number 11014. Moffitt Cancer Center provides a tobacco-free work environment. It is an equal opportunity, affirmative action employer and a drug-free workplace.

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FACULTY POSITION: CLINICAL GENETICIST The H. Lee Moffitt Cancer Center & Research Institute is seeking a candidate at the level of Assistant/Associate Member to join its section of medical genetics. The primary role of the successful candidate will be to provide outpatient services to clinical cancer genetics patients at Moffitt Cancer Center Screening & Prevention. Phone triage, night call, and weekend inpatient coverage is shared among section members. In addition, opportunities to pursue research are available in a number of areas such as inherited genetic alterations that predispose to cancer genetic conditions as well as molecular mechanisms of inherited cancers and other genetic diseases. Moffitt Cancer Center, a Florida-based NCI-designated comprehensive cancer center, is a rapidly growing institute affiliated with the University of South Florida. The Cancer Center is composed of a large ambulatory care facility and a 206-bed hospital, with a 36-bed blood and marrow transplant program, 15 state-of-the-art operating suites, a 30-bed intensive care unit, a high-volume screening program, and a basic science research facility. The Moffitt Research Institute is composed of approximately 150 principal investigators, 58 laboratories, and 306,000 square feet of research space. Candidates must hold an MD or DO and be board certified or eligible by the American Board of Medical Genetics in clinical genetics. Experience in provision of services in adult genetic and cancer genetic conditions is preferred. Moffitt Cancer Center is affiliated with the University of South Florida and courtesy university appointments are available, as applicable. Academic rank is commensurate with qualifications and experience. Florida medical licensure or eligibility is required. For inquiries about the position, contact Bryan Bognar, MD, Chair, Department of Internal Medicine, at 813-745-3134 or [email protected]. To apply, visit our Web page at MOFFITT.org/careers and refer to requisition number 11376. Moffitt Cancer Center provides a tobacco-free work environment. It is an equal opportunity, affirmative action employer and a drug-free workplace.

FACULTY POSITION: INTERNAL AND HOSPITAL MEDICINE PROGRAM LEADER The H. Lee Moffitt Cancer Center & Research Institute, a Florida-based NCI-designated comprehensive cancer center, is seeking a Program Leader for the Internal and Hospital Medicine (IHM) Program, which is part of the Department of Internal Medicine. The IHM Program participates in a broad range of activities that bridge the gap between highly specialized cancer care and general medicine. Clinical services provided by the program include 2 hospitalist ward teams, inpatient and outpatient consultations, high-risk preoperative assessment, as well as staffing the center’s 8-bed urgent care area, the Direct Referral Center. The Program Leader is responsible for strategic planning, clinical operations, and oversight of faculty academic and creative scholarly activities. Moffitt Cancer Center includes a 206-bed hospital, 3 ambulatory care facilities, a 36-bed inpatient blood and marrow transplant program, a high-volume screening program, and state-of-the-art clinical, translational, and basic science research space. The successful candidate must hold an MD or DO and be board certified in internal medicine. Leadership qualities, including strategic vision, are essential. Candidates must have an established track record. Experience in a multidisciplinary clinical setting is preferred. Florida medical license or eligibility is required. Moffitt Cancer Center is affiliated with the University of South Florida. Primary and secondary university appointments are available, as applicable. Academic rank is commensurate with qualifications and experience. An outstanding compensation package with competitive benefits and a relocation allowance is provided. For inquiries about the position, contact Bryan Bognar, MD, Chair, Department of Internal Medicine, at [email protected] or 813-745-3134. To apply, visit our Web page at MOFFITT.org/careers and refer to requisition number 9208. Moffitt Cancer Center provides a tobacco-free work environment. It is an equal opportunity, affirmative action employer and a drug-free workplace.

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FACULTY POSITION: MEDICAL ONCOLOGIST Moffitt Cancer Center’s Department of Gastrointestinal Oncology is seeking a candidate at the level of Junior Member. The successful candidate will have an interest in clinical duties and research activities focused on neuroendocrine oncology and will place and refer patients for clinical trials. Moffitt Cancer Center has one of the largest neuroendocrine tumor clinics in the country. The H. Lee Moffitt Cancer Center & Research Institute, a Florida-based NCI-designated comprehensive cancer center, is a rapidly growing institute affiliated with the University of South Florida and is committed to education through a wide range of residency and fellowship programs. The Cancer Center is composed of a large ambulatory care facility and a 206-bed hospital, with a 36-bed blood and marrow transplant program, 15 state-of-the-art operating suites, a 30-bed intensive care unit, a high-volume screening program, and a basic science research facility. The Moffitt Research Institute is composed of approximately 150 principal investigators, 58 laboratories, and 306,000 square feet of research space. Faculty members of Moffitt Cancer Center are eligible for primary and secondary appointments at the University of South Florida. Academic rank is commensurate with qualifications and experience. The successful candidate must hold an MD or DO, be board certified/eligible by the American Board of Internal Medicine, and fellowship trained in medical oncology. Experience in a clinical multidisciplinary academic setting is preferred. Florida medical license or eligibility is required. For inquiries about the position, contact Jonathan Strosberg, MD, Department of Gastrointestinal Oncology, at [email protected] or 813-745-3636. To apply, visit our Web page at MOFFITT.org/careers and refer to requisition number 11756. Moffitt Cancer Center provides a tobacco-free work environment. It is an equal opportunity, affirmative action employer and a drug-free workplace.

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INVITATION TO OUR READERS: If you would like to receive intermittent updates from Moffitt Cancer Center concerning topics such as clinical trials, clinical pathways, personalized medicine, and treatment advances, please submit your e-mail address to [email protected].

H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE, AN NCI COMPREHENSIVE CANCER CENTER | TAMPA, FL 1-888-MOFFITT | MOFFITT.org

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Contact and General Information

To Access The Journal Online: Most issues and supplements of Cancer Control are available at MOFFITT.org/ccj.

To Change Your Mailing Address: Please provide your old address and your new address: Veronica Nemeth, Editorial Coordinator Cancer Control Journal Moffitt Cancer Center MBC-JRNL 12902 Magnolia Drive Tampa, FL 33612 e-mail: [email protected] fax: (813) 449-8680 phone: (813) 745-1348

To Cancel A Subscription: Please send your cancellation request, including your name and address, to the Editorial Coordinator, as listed above.

To Order An Individual, Institutional Or International Subscription:

To Request Permission To Reprint Copyrighted Materials: To request permission to reprint tables, figures, or materials copyrighted by Cancer Control, please contact the Editorial Coordinator.

To Inquire About Reprints: For information on obtaining reprints and pricing information, please contact the Editorial Coordinator.

To Submit An Article For Publication: The editor welcomes submission of manuscripts pertaining to all phases of oncology care for possible publication in Cancer Control. Articles are subject to editorial evaluation and peer review. Author guidelines are available online at MOFFITT.org/ccj.

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YOUR OPINION COUNTS! Access our readership survey @Moffitt.org/ccj

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About Cancer Control: Journal of the Moffitt Cancer Center

Cancer Control: Journal of the Moffitt Cancer Center is published by H. Lee Moffitt Cancer Center & Research Institute and is included in Index Medicus®/MEDLINE® and EMBASE®/Excerpta Medica, Thomson Reuters Science Citation Index Expanded (SciSearch®) and Journal Citation Reports/Science Edition. Cancer Control currently has an impact factor of approximately 3.6. This peer-reviewed journal contains articles on the spectrum of actions and approaches needed to reduce the impact of human malignancy. Cancer Control is sent at no charge to approximately 15,000* medical professionals, including oncologists in all subspecialties; selected primary care physicians; medical researchers who specialize in oncology; and others who have a professional interest in cancer control. * This includes approximately 1,000 international oncologists of all varieties from about 85 countries.

Circulation Breakdown Circulation to all physicians in the specialties of oncology, hematology, radiation oncology, surgical oncology, gynecologic oncology, infectious disease in office-based practice, hospital-based practice (including resident physicians, fellows and full-time staff physicians), medical teaching physicians and oncology researchers.

Sources That Link to and/or Highlight Select Articles from Cancer Control Include: • Index Medicus®/MEDLINE® and EMBASE®/ Excerpta Medica • PubMed (US National Library of Medicine) • Thomson Reuters Science Citation Index Expanded (SciSearch®) • Thomson Reuters Journal Citation Reports/Science Edition • Medscape

Thomson Reuters Journal Citation Reports ® Impact Factor as of January 2014: • Impact factor: 3.593 • Impact factor without self cites: 3.556

Medscape Statistics: • Total number of views since 1997 to present: 8,769,485 • Total number of articles featured on Medscape since 1999: 365 of 764

PubMed Statistic: • Link use since 2004 indexing: 432,468

Celebrating Over 20 Years of Publishing April 2014, Vol. 21, No. 2

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THE ONLY NCI COMPREHENSIVE CANCER CENTER BASED IN FLORIDA MOFFITT CANCER CENTER OFFERS A LEVEL OF CARE THAT STANDS ABOVE THE REST. FOR OUR DOCTORS AND SCIENTISTS, THIS MEANS MORE RESEARCH, MORE CLINICAL TRIALS AND MORE PEOPLE TREATED THAN ANY OTHER HOSPITAL IN THE STATE. FOR YOUR PATIENTS, THIS MEANS THE BEST CHANCE FOR BEATING CANCER. REQUEST AN APPOINTMENT AT MOFFITT.ORG/REFER

MOFFITT CANCER CENTER 12902 MAGNOLIA DRIVE, TAMPA, FL MOFFITT CANCER CENTER AT INTERNATIONAL PLAZA 4101 JIM WALTER BOULEVARD, TAMPA, FL


H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE AN NCI COMPREHENSIVE CANCER CENTER | TAMPA, FL | 1-888-MOFFITT

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Save the Date!

presents

Advances in the Management of Multiple Myeloma March 6–7, 2015 San Juan, Puerto Rico Course Directors: Melissa Alsina, MD, Rachid Baz, MD, and Kenneth H. Shain, MD, PhD Moffitt Cancer Center, Tampa, Florida Conference Overview: Advances in the Management of Multiple Myeloma conference is designed to foster the exchange of the most recent advances in the biology and treatment of multiple myeloma. National and international leading experts in the field will present in a format promoting discussion and interaction with participants. Target Audience: This education program is directed toward hematologists, medical and surgical oncologists, and BMT physicians who diagnose, treat, and manage patients with multiple myeloma. Oncology fellows, nurses, and physician assistants who are interested in the diagnosis, care, and treatment of multiple myeloma are also invited to attend.

TO BE ADDED TO THE CONFERENCE MAILING LIST, CONTACT: MOFFITT CANCER CENTER I CHRYSTYNA POSPOLYTA, MPH I 813-745-4918 I [email protected]

May 16–17, 2014 Grand Hyatt Tampa Bay Tampa. Florida

CONFERENCE CONTACT:

[email protected]

MOFFITT.org/PersonalizedMedicine

S P O N S O R E D BY