Therapy Insight: malignant primary cardiac tumors - Nature

REVIEW www.nature.com/clinicalpractice/cardio

Therapy Insight: malignant primary cardiac tumors Michael J Reardon*, Jon-Cecil Walkes and Robert Benjamin

INTRODUCTION

S U M M A RY Benign cardiac tumors are resected with a high degree of success with modern cardiac surgical techniques. Malignant cardiac tumors, however, continue to pose a therapeutic challenge to cardiac surgeons and oncologists because of the technical difficulty involved in extensive cardiac resections and the aggressive biological nature of the tumors. The majority of malignant cardiac tumors are sarcomas and can be categorized as right heart sarcoma, left heart sarcoma or pulmonary artery sarcoma. Right heart sarcomas are generally angiosarcomas, which infiltrate widely and metastasize early. A combination of chemotherapy and surgical resection is the preferred therapy. Left heart sarcomas, although large, are often less infiltrative and metastasize later than right heart sarcomas, but a similar approach to treatment is usually employed. Surgical resection is more-frequently necessary for left heart sarcomas because of intracardiac blood flow obstruction and congestive heart failure, although the anatomic position and relation of these tumors to cardiac structures can complicate surgery. We have developed and employed the technique of cardiac autotransplantation, which involves cardiac excision, ex vivo tumor resection with cardiac reconstruction, and cardiac reimplantation, to lessen these technical difficulties. Pulmonary artery sarcomas can be treated by radiotherapy, as well as by the other therapies, because the myocardium can be avoided by the radiation fields. Surgical resection of this sarcoma type often requires pneumonectomy and can require pulmonary root replacement. KEYWORDS cardiac autotransplantation, cardiac malignancy, sarcoma

REVIEW CRITERIA A complete PubMed search was carried out to identify all full-text, English-language articles published to date. The search terms used were “cardiac malignancy”, “cardiac tumor”, “cardiac sarcoma” and “cardiac mass”. The reference list of each selected paper was further searched for relevant publications.

MJ Reardon is a cardiovascular and thoracic surgeon in the Methodist DeBakey Heart Center, and Clinical Professor of Thoracic and Cardiovascular Surgery at the MD Anderson Cancer Center, J-C Walkes is a cardiovascular and thoracic surgeon in the Methodist DeBakey Heart Center, and R Benjamin is Professor of Sarcoma Medical Oncology at the MD Anderson Cancer Center, Houston, TX, USA. Correspondence *Department of Surgery, Methodist DeBakey Heart Center, 6560 Fannin Street, #1002, Houston, TX 77030, USA [email protected] Received 6 June 2005 Accepted 12 June 2006 www.nature.com/clinicalpractice doi:10.1038/ncpcardio0653

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Cardiac neoplasms are classified as primary tumors arising in the heart and secondary tumors that have metastasized to the heart. Primary cardiac neoplasm is rare, having an incidence of 0.0017–0.0028%, which roughly translates to about 1 case in every 500 cardiac surgeries.1,2 Secondary tumors are 20–40 times more common than primary tumors.3 Histologically, 75% of primary tumors are benign and an estimated 25% are malignant; of the primary malignant tumors, 75% are sarcomas.4 Modern surgical techniques allow successful treatment of benign tumors with low related mortality and morbidity and good long-term outcomes.5 Malignant cardiac tumors have remained a clinical challenge, however, with grave implications for the patient. In a combined series covering cases from two large institutions over a 25-year period, only 21 patients were surgically treated for cardiac sarcoma.4 Given this small number of surgical procedures, individual surgeons and even institutions are not able to develop substantial experience, and treatment options still have not been standardized. In this Review, we discuss primary cardiac sarcomas, their clinical manifestation and their therapeutic options. PRIMARY CARDIAC SARCOMAS

Primary cardiac sarcomas occur without an identified genetic linkage. Although these sarcomas can arise in patients of all ages, in our experience they occur most commonly in people aged 40–50 years (MJ Reardon et al., unpublished data). Symptoms depend on tumor histology, size and location. The most common symptoms at presentation are those of congestive heart failure, chest pain, malaise, and anorexia and weight loss.5 Pericardial effusion and tamponade are also common initial findings, especially in angiosarcoma,4 and arrhythmias and conduction disturbances can occur. Echocardiography remains the main diagnostic method,6 although chest CT scan or cardiac MRI are helpful to

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establish tumor anatomy, particularly extracardiac extension. The role of PET scans is not yet fully elucidated and remains controversial, but we have incorporated this method into our diagnostic routine to help exclude extracardiac metastatic disease; if extracardiac metastatic disease is identified, surgical resection is reserved for palliative indications. We use coronary angiography for any patient with symptoms of potential coronary artery disease, possible coronary artery involvement by virtue of tumor location, or age older than 40 years, so that any coronary artery involvement can be dealt with at surgery. Right atrial masses are more frequently malignant than left atrial masses,7,8 and if malignancy is suspected because of location, size or wide involvement, a preliminary biopsy is useful in planning therapy. The prognosis for primary cardiac sarcomas is poor, with median survival reported as being 16.5 months and 9.6 months in two series of 24 cases and 17 cases, respectively.9,10 Histologic grade of malignancy has the greatest correlation with survival.9 We have employed a multidisciplinary approach to all cardiac sarcomas because we believe that even those that appear confined to the heart and have a complete resection will benefit from chemotherapy.11 We have found it clinically beneficial to group cardiac sarcomas by anatomic location rather than tissue type when making clinical decisions. Right heart sarcomas, left heart sarcomas and pulmonary artery sarcomas represent our clinical groups.

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Figure 1 An extensive right atrial sarcoma. (A) A CT scan showing the sarcoma and right pleural effusion. (B) The explanted sarcoma. A

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Right heart sarcomas

Most right heart sarcomas are angiosarcomas. This type of neoplasm is two to three times more common in men than it is in women, and more than 80% occur in the right atrium.12 Angiosarcomas tend to be bulky, to infiltrate the cardiac muscle, and to metastasize early, especially to the lungs. We have seen several patients whose initial tumor was diagnosed by thoracoscopic biopsy of pulmonary nodules, after which the cardiac primary site was confirmed by echocardiography. Transvenous endocardial biopsy can be performed for diagnosis in right heart lesions. Historically, without resection over 90% of patients with right heart sarcoma die within 1 year despite radiation therapy or chemotherapy.13 Because of these dismal results we have adopted a protocol beginning with chemotherapy to assess response and reduce the extent of the tumor if surgery is contemplated.

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Figure 2 Artist’s depiction of a right atrial sarcoma and the stages of resection and reconstruction. (A) The right atrial sarcoma. (B) Resection of the right atrium tricuspid valve and part of the right ventricular freewall. (C) Tricuspid valve replacement with tissue valve. (D) Reconstruction of the right atrium with bovine pericardium and right coronary artery using internal mammary artery free graft.

Surgical resection is useful in patients who have residual tumor tissue and no metastatic disease, or remaining bulky tumor affecting hemodynamics (Figure 1). Surgical resection for tumor tissue extending into the superior vena cava, the inferior vena cava or both might require deep hypothermia and circulatory arrest. Venous cannulation can be achieved by direct cannulation of the superior vena cava and the

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Figure 3 Echocardiograms of left atrial tumors. (A) A left atrial myxoma. (B) A left atrial sarcoma.

femoral vein to leave the entire right atrium free for resection. The entire right atrium can be removed and reconstructed with bovine pericardium (Figure 2). When the tricuspid valve has been extensively involved and replacement is necessary, we have chosen to use biological valves to avoid the use of Coumadin® (BristolMyers Squibb, Wilmington, DE), despite the general age of the patients being less than 65 years. These patients are likely to require additional surgical procedures, but the opportunity to reoperate in 10–12 years for structural deterioration of the replacement valve would be considered a victory in this aggressive disease. When the right coronary artery has been involved and resected, we have used a free graft of right internal mammary artery to replace the coronary artery (Figure 2). Resection of angiosarcoma (Figure 3) involving up to 30% of the right ventricular free wall and reconstruction with bovine pericardium has proven successful in our experience (MJ Reardon et al., unpublished data; Figure 4) The superior vena cava can also be resected and reconstructed with graft. The most difficult area to resect and reconstruct has proven to be the junction of the tricuspid valve and the aortic valve in the fibrous skeleton of the heart. The inter ventricular septum is easily entered but can be difficult to repair and we believe it should be avoided if possible. Chemotherapy after resection is always recommended, even when clear surgical margins are obtained, because of the high likelihood of missed microscopic disease and the typically aggressive nature of this disease. We have follow-up data for a series of 16 patients who underwent right heart resection for sarcoma, although these data are as yet unpublished. All 16 patients required extensive resection of the right atrium and reconstruction


with bovine pericardium. Three patients required tricuspid valve replacement because of extensive tumor involvement. Three patients had right coronary artery involvement and required resection and replacement with right internal mammary artery free graft. The superior vena cava was removed because of tumor involvement in one case, requiring Dacron® (Invista, Wilmington, DE) graft insertion. One patient with profound hypothermia and circulatory arrest required femoral venous cannulation because the extent of tumor precluded venous cannulation within the chest (Figure 1). Severe right heart failure despite chemotherapy prompted surgical resection in this patient. Pathology of the removed tumor revealed necrosis in 95% of the specimen; the patient regained normal cardiac function allowing resumption of chemotherapy. A further two patients in the series required permanent pacemaker implantation. Two patients died during surgery: one from right heart failure and one, who had undergone previous extensive mediastinal radiation therapy, from hemorrhage. Six patients died of distant metastatic disease 10–58 months after surgery. Eight patients are alive 1–69 months after surgery. Left heart sarcomas

Left heart sarcomas, in our experience, are most frequently malignant fibrous histiocytomas. They usually occur in the left atrium and on echocardiograms are often initially thought to be myxomas. It can be very difficult to distinguish between a sarcoma and a large myxoma (Figure 3).9 Large tumors should always be considered potentially malignant when planning a surgical approach. All our patients with left atrial sarcoma were referred after incomplete resection of a presumed myxoma that turned out to be sarcoma. Disease progression was seen in all patients within a short period of time, despite chemotherapy and required repeat resection. We have seen one intracavitary left ventricular osteosarcoma that was referred without a previous attempt at resection. The patient had mantle radiation at age 9 years for Hodgkin’s disease and developed mitral regurgitation and an enlarging left ventricular outflow mass viewed on echocardiogram. We have found left heart sarcomas to be less infiltrative and to metastasize later than right heart sarcomas. The anatomic location often leads to life-threatening congestive heart failure because of obstruction of the mitral valve orifice. The severity of the obstruction

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Figure 4 Artist’s representation of cardiac explantation, resection, reconstruction and reimplantation to treat a left atrial sarcoma. (A) Cardiac explantation showing left atrial sarcoma attached to mitral valve anterior left atrial wall. (B) Cardiac reconstruction with mitral valve replacement and left atrial reconstruction using bovine pericardium. (C) Cardiac reimplantation showing interposition graft between right atrium and inferior vena cava.

means that the patients we have seen and those reported in the literature have often needed resection urgently because radiation therapy and chemotherapy achieve poor results in quickly relieving the congestive heart failure. Surgical resection of left atrial sarcomas might be complicated by poor anatomic visualization of the left atrium, leading to incomplete resection and local progression in 4–10 months.14,15 Reports of repeated local resection due to multiple local recurrences15,16 led us to believe that incomplete resection was a major determinant of poor patient outcome. To overcome these anatomic obstacles and allow complete visualization of the left atrium, we applied cardiac excision, ex vivo tumor resection and reconstruction, and reimplantation—a procedure we term ‘cardiac autotransplantation’—to left atrial sarcomas. Complete removal of the heart allows excellent visualization from any angle of the tumor and surrounding cardiac structures. We have achieved extensive resection and accurate reconstruction by this approach. We have previously described our surgical technique for autotransplantation,17 but several points warrant being noted here. Firstly, excision of the heart must be done with care, since vital cardiac structures are at risk of being irreparably injured during excision, and this must be avoided. Secondly, reimplantation of the heart after reconstruction can prove more difficult than orthotopic cardiac transplantation, since extra tissue for tailoring cannot be left with the recipient or taken with the donor organ. Finally, the vena cava anastomoses have proven


to be technically challenging, especially for the inferior vena cava, which seems to dramatically shrink in length after division. We have data for a series of 12 autotransplants.17 These cases have all been technically very complex, with three patients requiring mitral valve replacement, two requiring pneumonectomy, one interventricular septum resection, one inferior vena cava resection, one superior vena cava resection, and all cases—except the left ventricular sarcoma mentioned—requiring extensive left atrial resection and reconstruction. There were no in-hospital or 30-day deaths, and all patients were discharged home. Four patients developed early distant metastatic disease, leading to deaths at 2, 3, 9 and 15 months. The longest survival we have seen following cardiac autotransplanation is 5 years and 6 months, and the median survival is 36 months. We recommend postoperative chemotherapy for all patients with left heart sarcomas; two patients in this series refused this treatment and represent the deaths at 2 and 3 months. Only one patient had a local recurrence, and this was the patient who died of distant metastatic disease at 15 months. We have achieved excellent local control and low operative mortality with the approach of cardiac autotransplantation.6 Additional work on adjuvant therapy for biologic control of disease is imperative. Pulmonary artery sarcomas

Most of the pulmonary artery sarcomas we have seen have been classified as angiosarcomas when a specific diagnosis has been possible, but



who has survived 42 months following pulmonary artery sarcoma resection, with no known disease. We always recommend chemotherapy after resection, even if clear surgical margins are obtained. CHEMOTHERAPY AND RADIATION THERAPY

Figure 5 CT scan of pulmonary artery sarcoma showing almost complete obstruction of the main pulmonary arteries by an angiosarcoma.

in some cases these sarcomas cannot be further classified. Patients frequently present with shortness of breath and peripheral swelling consistent with right heart failure. Unlike sarcomas of the heart muscle itself, for which echocardiography has proven the most common diagnostic method, chest CT or MRI is most beneficial in the diagnosis of pulmonary artery sarcoma (Figure 5). Chemotherapy and radiotherapy have proven poorly effective in the rapid relief of pulmonary artery obstruction and right heart failure in our patients, and surgical resection has proven necessary in the larger sarcomas to allow adequate hemodynamic status for chemotherapy to begin or be completed. Smaller tumors are seen less frequently, since they are usually clinically silent unless they are discovered in the process of a pulmonary artery endarterectomy for what is thought to be chronic pulmonary emboli. Resection often requires replacement of at least some of the pulmonary root with pulmonary allograft, and pneumonectomy is also often required.16,18 Occasionally, we can completely resect the angiosarcoma in the main pulmonary artery and salvage the lung. We have used pulmonary allograft for reconstruction of the main pulmonary artery, but also for replacement of an involved superior vena cava. We have data for five cases of pulmonary artery sarcoma resection, of which three required concomitant pneumonectomy. There were no in-hospital or 30-day deaths, and all patients were discharged home (MJ Reardon et al., unpublished data). Our greatest success so far has been in a patient


Radiation therapy has been useful in some patients with pulmonary artery sarcomas, but we rarely use it in primary cardiac sarcomas. The heart is usually more sensitive to radiation than the tumor, meaning that more of the normal heart muscle might be damaged than tumor, therefore precluding normal-dose radiotherapy; however, the use of lower doses has not been well studied. Chemotherapy for soft-tissue sarcomas is evolving, and many cardiac tumors can improve with chemotherapy, although long-term control remains uncommon. The high probability of metastatic disease, especially to the lungs, makes chemotherapy important even in patients without demonstrable metastases. The most common regimen, used for many sarcomas, is combined doxorubicin and ifosfamide. The best results are obtained with dose-intensive chemotherapy, and attention to supportive care for the potential complications of chemotherapy is critical.19 The activity of gemcitabine in soft-tissue sarcomas has been noted,20 and docetaxel and gemcitabine in a schedule-dependent combination provided promising results in patients with leiomyosarcoma21 and other sarcomas.22 Although the Sarcoma Alliance for Research through Collaboration is currently carrying out a randomized study to investigate the benefit of adding docetaxel to gencitabine for most softtissue sarcomas, this regimen is particularly attractive for patients with angiosarcomas. A complete response was seen with gemcitabine in our phase II trial in a patient with angiosarcoma, and angiosarcomas are the only sarcomas that are intrinsically sensitive to the taxanes.23 CONCLUSIONS

Primary cardiac sarcomas have a dismal prognosis if left untreated. Despite numerous advances in the oncologic treatment of thoracic malignancy, primary cardiac sarcoma continues to have a poor outlook with medical therapy alone. Surgical resection generally relieves symptoms well, but might require radical techniques and complex resections and reconstructions to

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achieve complete tumor removal. The use of multimodality oncologic treatment and aggressive surgical resection can improve patients’ survival. Clearly, the future treatment of these aggressive tumors lies in a more successful biologic approach to the disease.

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Primary cardiac malignant tumors are rare and are generally sarcomas

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Primary cardiac malignant tumors usually require a multimodality approach, and sometimes complex surgical resections

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In our center, we classify cardiac sarcomas into right heart sarcomas, left heart sarcomas and pulmonary artery sarcomas because of the differences in surgical approaches for each type Use of aggressive forms of surgical resection and multimodality therapy can improve survival in some patients

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18 References 1 Straus R and Merliss R (1945) Primary tumors of the heart. Arch Pathol 39: 74–78 2 McAllister HA and Fenoglio JJ Jr (Eds; 1978) Tumors of the cardiovascular system. Atlas of Tumor Pathology, series 2. Washington, DC: Armed Forces Institute of Pathology 3 Bisel HF et al. (1953) Incidence and clinical manifestations of cardiac metastases. JAMA 153: 712–715 4 Murphy MC et al. (1990) Surgical treatment of cardiac tumors: a 25-year experience. Ann Thorac Surg 49: 612–617 5 Bakaeen FG et al. (2003) Surgical outcome in 85 patients with primary cardiac tumors. Am J Surg 186: 641–647 6 Putnam JB et al. (1991) Primary cardiac sarcomas. Ann Thorac Surg 51: 906–910 7 Perchinsky MJ et al. (1997) Primary cardiac tumors: forty years’ experience with 71 patients. Cancer 79: 1809–1815


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Meng Q et al. (2002) Echocardiographic and pathologic characteristics of primary cardiac tumors: a study of 149 cases. Int J Cardiol 84: 69–75 Basso C et al. (1997) Surgical pathology of primary cardiac and pericardial tumors. Eur J Cardiothorac Surg 12: 730–738 Donsbeck AV et al. (1999) Primary cardiac sarcomas: an immunohistochemical and grading study with long-term follow-up of 24 cases. Histopathology 34: 295–304 Bakaeen FG et al. (2003) Surgical outcome in 85 patients with primary cardiac tumors. Am J Surg 186: 641–647 Herrmann MA et al. (1992) Primary cardiac angiosarcoma: a clinicopathologic study of six cases. J Thorac Cardiovasc Surg 102: 655–664 Wiske PS et al. (1986) Intracardiac tumor regression documented by two-dimensional echocardiography. Am J Cardiol 58: 186–187 Dein JR et al. (1987) Primary cardiac neoplasms: early and late results of surgical treatment of 42 patients. J Thorac Cardiovasc Surg 93: 502–511 Okita Y et al. (1994) Recurrent malignant fibrous histiocytoma of the left atrium with extracardiac extension. Am Heart J 127: 1624–1628 Gabelman C et al. (1979) Surgical treatment of recurrent primary malignant tumor of the left atrium. J Thorac Cardiovasc Surg 77: 914–921 Reardon MJ et al. (2006) Cardiac autotransplantation for primary cardiac tumors. Ann Thorac Surg 82: 645–650 Reardon MJ et al. (1999) Cardiac autotransplant for surgical treatment of a malignant neoplasm. Ann Thorac Surg 67: 1793–1795 Patel SR et al. (1998) Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol 21: 317–321 Patel SR et al. (2001) Phase II clinical investigation of gemcitabine in advanced soft-tissue sarcomas and window evaluation of dose-rate on gemcitabine triphosphate accumulation. J Clin Oncol 19: 3483–3489 Hensley ML et al. (2002) Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 20: 2824–2831 Leu KM et al. (2004) Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 22: 1706–1712 Fata F et al. (1999) Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 86: 2034–2037

Competing interests The authors declared they have no competing interests.
