Accepted Manuscript Intensity Modulated Radiation Therapy for Squamous Cell Carcinoma of the Vulva: Treatment Technique and Outcomes Yuan James Rao, MD, Anupama Chundury, MD, Julie K. Schwarz, MD, PhD, Comron Hassanzadeh, BS, Todd DeWees, PhD, Daniel Mullen, DDS, MS, Matthew A. Powell, MD, David G. Mutch, MD, Perry W. Grigsby, MD PII:
S2452-1094(17)30037-4
DOI:
10.1016/j.adro.2017.02.006
Reference:
ADRO 79
To appear in:
Advances in Radiation Oncology
Received Date: 15 November 2016 Revised Date:
11 February 2017
Accepted Date: 21 February 2017
Please cite this article as: Rao YJ, Chundury A, Schwarz JK, Hassanzadeh C, DeWees T, Mullen D, Powell MA, Mutch DG, Grigsby PW, Intensity Modulated Radiation Therapy for Squamous Cell Carcinoma of the Vulva: Treatment Technique and Outcomes, Advances in Radiation Oncology (2017), doi: 10.1016/j.adro.2017.02.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Intensity Modulated Radiation Therapy for Squamous Cell Carcinoma of the Vulva:
Yuan James Rao, MD1 Anupama Chundury, MD1 Julie K. Schwarz, MD, PhD1
Todd DeWees, PhD1
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Comron Hassanzadeh, BS3
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Treatment Technique and Outcomes
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Daniel Mullen, DDS, MS1 Matthew A. Powell, MD2 David G. Mutch, MD2
Perry W. Grigsby, MD1
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Department of Radiation Oncology
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Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Alvin J. Siteman Cancer Center
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Washington University School of Medicine, St. Louis, MO 63110 University of Missouri - Kansas City School of Medicine, Kansas City, MO 64108
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Corresponding Author: Perry Grigsby MD Department of Radiation Oncology Washington University School of Medicine 4921 Parkview Place, Campus Box 8224 St. Louis, MO 63110 Tel: 314-747-7236 Fax: 314-362-8521 Email:
[email protected] Conflict of Interest Statement: The authors report no actual or potential conflicts of interest associated with this research.
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Summary
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We present the treatment technique and outcomes from a retrospective review of 39 patients with squamous cell carcinoma of the vulva treated with IMRT. The 3-year locoregional control was 89% in patients treated post-operatively, and 42% in patients treated definitively. Complete pathological response was observed in 44% of patients treated with definitive or neoadjuvant IMRT. There was limited acute and late toxicity.
ACCEPTED MANUSCRIPT Abstract
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Objective: The objective of this study was to present the treatment technique and evaluate clinical outcomes
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after intensity modulated radiotherapy (IMRT) for vulvar cancer.
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Methods: This retrospective study included 39 patients with squamous cell carcinoma of the vulva treated with
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IMRT from 2005 to 2015. There were 21 patients treated with post-operative IMRT, 13 with definitive IMRT,
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and 5 with pre-operative IMRT. Tumor staging was FIGO stage I in 6, stage II in 7, stage III in 19, and stage
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IV in 7. Concurrent chemotherapy was administered to 14 patients. Brachytherapy was delivered in 8 patients.
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Results: The median follow-up was 34 months (range, 3.3-71). Median IMRT dose to patients receiving pre-
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or post-operative IMRT was 5040 cGy (range, 5040-6080). Median combined IMRT and brachytherapy dose
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to gross tumor was 7000 cGy (range, 5040-7520) in those treated with definitive RT. The 3-year locoregional
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control (LRC) and overall survival (OS) for those receiving post-operative RT were 89% and 67%, respectively.
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The 3-year LRC and OS for those receiving definitive IMRT were 42% and 49%, respectively. In patients
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receiving definitive or neoadjuvant IMRT, 69% had complete clinical response and 44% had complete
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pathological response. The actuarial 3-year inguinal recurrence rate was 7%. There were no acute grade 3-4
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hematological, gastrointestinal (GI), or genitourinary (GU) toxicities. There were no late grade 3-4 GI or GU
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toxicities.
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Conclusions: IMRT for vulvar cancer is associated with high rates of locoregional control in the postoperative
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setting, and limited radiation related toxicity. Durable locoregional control of disease after definitive IMRT
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remains challenging, and several refinements to our treatment technique are suggested.
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INTRODUCTION Radiation therapy (RT) has played an important role in the treatment of vulvar cancer, in both the pre-
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and post-operative setting as well as the definitive setting.1,2 Radiation has traditionally been administered in
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the supine, frog-legged position using opposed AP-PA field setup in addition to supplemental dose to the vulva
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or inguinal nodes as needed. Beriwal et al.3 and Bloemers et al.4, have shown in dosimetric studies that
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intensity modulated radiation therapy (IMRT) may be advantageous in the treatment of vulvar cancer as it may
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reduce dose to small bowel, rectum, bladder, and femurs.
The benefit of IMRT in reducing toxicity in pelvic malignancies has been demonstrated in multiple
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prospective phase II trials.5,6 Additionally, phase III randomized trials comparing post-operative 3D-conformal
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radiotherapy versus IMRT have been performed for cervical cancer in India7 and for cervical or endometrial
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cancer in a multinational setting.8 Preliminary data from these studies also suggest reduced acute or late
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toxicity with IMRT. IMRT may reduce dose to pelvic bones which could in turn reduce hematologic toxicity
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for patients receiving concurrent chemotherapy.6 Beriwal et al. have published extensively on the use of
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preoperative IMRT with concurrent chemotherapy for vulvar cancer, and which resulted in a complete
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pathological response rate of 48.5% and limited treated-related toxicity.3,9,10 There is additional interest in the
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use of IMRT for vulva cancer after the publication of consensus contouring guidelines11 and National
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Comprehensive Cancer Network12 clinical guidelines allowing IMRT as a therapeutic option. The
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Gynecological Oncology Group (GOG) has opened a clinical trial (protocol 279) that prospectively investigates
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combined weekly gemcitabine and cisplatin chemotherapy with IMRT to 6400 cGy in patients with locally
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advanced vulvar cancer.13 The purpose of our study was to present our institutional experience of IMRT in the
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treatment of vulvar cancer with an emphasis on treatment technique, patient outcomes, and toxicity.
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METHODS AND MATERIALS
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Study Population: The records of thirty-nine patients with squamous cell carcinoma of the vulva treated with
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curative intent IMRT at XXXXXX School of Medicine from January of 2005 to January of 2015 were
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reviewed. All patients underwent a complete staging workup according to the International Federation of
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clinical staging criteria, including a full history and physical examination, routine laboratory evaluation, and
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metastatic evaluation. Patients underwent imaging with 18-fluoro-deoxyglucose positron emission tomography
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(FDG-PET) (33 of 39), magnetic resonance imaging (MRI) (10 of 39), and/or computed tomography (CT) (39
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of 39). The data source for this study was the XXXXXX Radiation Oncology Department’s IRB-approved,
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retrospective registry of treatment data (IRB Approval # 20131149). The data was de-identified by an “honest
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broker” before research use.
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Surgical Resection: Surgical resection was performed in 26 patients, while 13 had a biopsy alone. A radical
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vulvectomy was performed on 16 patients, and 10 had a modified radical vulvectomy, hemi-vulvectomy, or
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wide local excision. Bilateral inguinal lymph node dissection was performed on 19 patients. Sentinel lymph
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node sampling was performed on 2 patients.
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Radiotherapy: All patients received IMRT with or without high dose rate brachytherapy. Adjuvant post-
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operative IMRT was administered to patients with high risk features such as surgical margins < 8-10 mm,
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extracapsular extension, > 1 positive lymph node, or lymphovascular space invasion.14 Definitive or
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neoadjuvant IMRT was performed for unresectable tumors, medically inoperable patients, or for patients where
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surgical resection had a high likelihood of unacceptable GI or GU toxicity. All patients underwent a treatment
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planning CT simulation for IMRT. Patients receiving definitive or neoadjuvant IMRT underwent FDG-PET/CT
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simulation. Diagnostic FDG-PET scans were fused with the planning CT to aid in treatment planning. Patients
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were routinely simulated in the supine position with the legs straight and were fitted with a customized
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immobilization device (Alpha Cradle®, Smithers Medical Products, Inc., North Canton, OH) to minimize daily
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setup variability. Bolus on the vulva was not routinely used in the post-operative setting, but bolus was used
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over the vulvar tumor and superficial or bulky lymph nodes in the definitive or preoperative setting. Treatment
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positioning was confirmed via daily 2-D imaging as well as weekly cone beam CT.
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Intensity Modulated Radiation Therapy: The gross tumor volume (GTV) as defined by FDG-PET, and the
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clinical target volume (CTV), and organs at risk (OAR) were contoured for treatment planning. The entire
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ACCEPTED MANUSCRIPT vulva was included in the vulvar CTV (CTVvulvar). The low pelvic vessels were contoured from 1 cm above the
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bifurcation of the common iliac artery and extended inferiorly to include the internal and external iliac vessels,
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the obturator space, and the inguinal region along the femoral vessels until the deep femoral artery branches and
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goes deep into the thigh. An isotropic 7 mm expansion was performed on the vessel contour, excluding the
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pelvic bones, to create the nodal CTV (CTVnodal). Of note, more recent consensus guidelines recommend
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contouring the CTVnodal in the inguinal region as a compartment rather than a 7 mm isotropic expansion on the
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inguinal vessels, and this will be discussed in detail later in the study. The CTVnodal was edited to include FDG-
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avid or involved lymph nodes. The CTVvulvar and CTVnodal were combined to form the final CTV (CTVfinal) as
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seen in Figure 1. The planning target volume (PTV) was defined as a 5 mm isotropic expansion on the
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CTVfinal.
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The IMRT prescription doses to the CTVfinal ranged from 5040 cGy to 5120 cGy in 160-180 cGy per fraction. The GTV was typically treated to a total dose of 6000 cGy to 7000 cGy via an integrated boost in
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200cGy per fraction. Some patients received a lower dose of 5040 cGy to the vulva GTV by IMRT, and
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additional dose was given later by brachytherapy to achieve a total dose of >6000 cGy. FDG avid nodal disease
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typically received an integrated boost to 6000 to 6600 cGy in 180-200 cGy per fraction. The median doses and
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ranges for adjuvant, and neoadjuvant IMRT were 5040 cGy (range 4960–6080 cGy), and 5040 cGy (range
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5040-6000 cGy) respectively. In patients treated definitively, the median external beam dose to the vulva (not
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including dose from brachytherapy) was 6000 cGy (range 5040-7000 cGy), the median total definitive dose to
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the vulva including brachytherapy (8 patients with IMRT and brachytherapy, and 5 patients with IMRT alone)
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was 7000 cGy (range 5040-7520 cGy). The median IMRT dose to the involved FDG-avid lymph nodes was
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6000 cGy (range 5040-7000 cGy). Plans were created to limit the rectum V40 Gy to < 60%, bladder V45 Gy to
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