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The Oncologist, Vol. 12, No. 9, 1134-1142, September 2007; doi:10.1634/theoncologist.12-9-1134
© 2007 AlphaMed Press

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Sarcomas

Primary Malignant Sarcomas of the Heart and Great Vessels in Adult Patients — A Single-Center Experience

Frank Mayera, Hermann Aebertb,g, Maximilian Rudertc,g, Alfred Königsrainerd, Marius Horgere,g, Lothar Kanza, Michael Bambergf, Gerhard Ziemerb, Jörg Thomas Hartmanna,g

Departments of aMedical Oncology/Hematology/Immunology/Rheumatology/Pulmonology, bThoracic, Cardiac and Vascular Surgery, cOrthopedic Surgery, dGeneral, Visceral Surgery and Transplantation, eDiagnostic Radiology, and fRadiooncology, gInterdisciplinary Sarcoma Center, South West German Cancer Center; Eberhard-Karls-University, Medical Center, Tuebingen, Germany

Key Words. Sarcomas of the heart/great vessels • Surgery • Radiotherapy • Chemotherapy • Neoadjuvant • Palliative

Correspondence: J.T. Hartmann, M.D., Department of Medical Oncology/Hematology/Immunology/Rheumatology/Pulmonology, UKT-Medical Center, South West German Cancer Center, Eberhard-Karls-University Tuebingen, Otfried-Mueller-Str. 10, 72076 Tuebingen, Germany. Telephone: 49-7071-29-82127; Fax: 49-7071-29-5689; e-mail: joerg.hartmann{at}med.uni-tuebingen.de

Received March 2, 2007; accepted for publication July 9, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
Background. Sarcomas arising in the heart or the great vessels are rare entities. The prognosis of the patients is dismal.

Methods. Between January 1993 and September 2006, of 1,429 patients registered to the Sarcoma Center, 14 had a primary sarcoma of the heart or large vessels.

Results. Tumors were located in the left ventricle (n = 3), left/right atrium (n = 2/3), pulmonary artery (n = 2), and ventricular septum, aorta, pericardium, and inferior vena cava (n = 1 each). The most frequently encountered histologic subtypes were leiomyosarcoma and angiosarcoma. Six patients presented with distant metastases to the lungs (n = 5), lymph nodes (n = 2), and liver (n = 1). Eight patients had localized disease. Six of them underwent resection with curative intent. Of those, two developed local recurrence within 2 and 10 months from surgery.

Eleven patients received palliative chemotherapy, seven of those as initial treatment. Eight patients attained a response to treatment, two had disease stabilization for 6 and 12 months. After a median follow-up of 14.5 months (range, 2–156), three patients were alive with no evidence of disease 11, 52, and 156 months after diagnosis. Two patients were alive with disease and nine patients had died.

Conclusions. Patients with primary sarcomas of the heart and the large vessels were of a young age, and more than half of them presented with advanced disease. Given the promising response to chemotherapy, an optimized treatment approach including neoadjuvant chemo-/radiotherapy in patients with locally advanced disease should be pursued.


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
Neoplasms arising in the heart or the large vessels are rare. Secondary cardiac tumors resulting from direct invasion or metastatic spread outnumber the primary tumors 20–40 times [1]. Over 75% of primary cardiac neoplasms are benign [2, 3]. For the broad range of benign tumors, including myxomas and rhabdomyomas, complete resection is the sole treatment of choice.

Sarcomas represent by far the most common primary malignancies arising in the heart. The few remaining cases are in large part lymphomas. Rhabdomyosarcomas are exceedingly rare, similar to the counterparts occurring at other sites, and they are more frequent in young patients. Rhabdomyosarcomas of the heart are almost exclusively of the embryonal subtype. They typically involve the cardiac valves and invade the pericardium [4]. In adults, the most common subtypes are undifferentiated pleomorphic sarcomas including the historically defined malignant fibrous histiocytoma. The latter are predominantly located in the left atrium. About one third of malignant cardiac sarcomas are angiosarcomas, which are frequently diagnosed in middle-aged patients. Angiosarcomas are typically located in the right atrium, leading to right-sided heart failure or cardiac tamponade [4–6]. Regarding sarcomas arising in large vessels, the sites most frequently involved are the pulmonary arteries and the aorta, followed by venous sarcomas, especially of the inferior vena cava. The most common histologic subtype in the vessels is leiomyosarcoma, which tends to grow to a large size without metastasizing [7–10].

The prognosis of patients with soft tissue sarcoma (STS) of the heart and the great vessels is dismal, because many patients present with locally advanced or metastatic disease at the time of initial diagnosis. In the absence of data from clinical trials in this particular setting, treatment planning has to rely on data from sarcomas at other locations, case reports, and personal experience [11]. We report the experience on 14 patients suffering from sarcomas of the heart and great vessels who were treated at the Interdisciplinary Sarcoma Center of the Eberhard-Karls-University at Tuebingen. Despite the limited number of patients, it is one of the largest series of malignant tumors in these special locations to be reported.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Acknowledgments
 References
 
Between January 1993 and September 2006 the Interdisciplinary Sarcoma Center of Tuebingen University registered a total of 1,429 first contacts with patients suffering from sarcoma. Fourteen patients (1.0%) with a primary sarcoma of the heart or the great vessels were identified (Fig. 1). The medical records of these patients were reviewed. Detailed information on patient characteristics, such as location and histology of the primary sarcoma, extent of disease, diagnostic methods, treatment, response to treatment, and follow-up period, were acquired. Durations of follow-up and survival in this analysis were calculated based on the date of the first day of treatment until the date of last contact, if the patient was still alive, or the date of death. For all living patients the status as of January 2007 was verified. Tumor response was classified according to Response Evaluation Criteria in Solid Tumors [12]. The overall survival calculation used death for any reason as the endpoint. A descriptive retrospective analysis of the patient characteristics, their treatment sequences, and outcome and survival was performed.


Figure 1
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  		Figure 1. Overview of clinical course of the patients.

Abbreviations: AWD, alive with disease; CR, complete remission; DOD, dead of disease; NA, not available; NC, no change; NED, no evidence of disease; PR, partial remission.

 

   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Acknowledgments
 References
 
Patient Characteristics
The median age of these patients at the time of primary diagnosis was 42 years (range, 20–61 years). Eight patients (57%) were women. Only four patients were referred to the Sarcoma Center immediately for primary diagnostic workup and initial therapy. In the remaining 10 cases (71%), treatment had been initiated at outside hospitals.

The tumors originated from all parts of the heart and large vessels. The most frequent sarcoma subtypes found were angiosarcoma and leiomyosarcoma. Details on the locations of primary tumors, histologic subtypes, and grading according to Fédération Nationale des Centres de Lutte Contre le Cancer definitions are shown in Table 1Go.


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  		Table 1. Patient characteristics

 


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  		Table 1. (Continued)

 
All patients were symptomatic at the time of diagnosis; no tumor was detected incidentally. The following symptoms were reported at diagnosis: shortness of breath (64%), constitutional symptoms (weight loss, drenching night sweats, fever) (43%), pain (43%), fatigue (29%), tachycardia (21%), cough (21%), and neurological symptoms (14%).

Treatment Modalities

Local Approaches
At diagnosis, eight patients (57%) presented with localized disease. Six of them (43%) underwent resection with curative intent. The remaining patients were deemed unresectable because of local extension.

Four tumors of the left or right atrium were resected with curative intent. In one patient, the tumor of the right atrium infiltrated the right coronary artery (RCA). The tumor was excised together with part of the RCA. The atrial defect was closed with a bovine pericardial patch. The patient received a coronary artery bypass graft with a saphenous vein; resection margins contained microscopically detectable tumor cells. The patient developed local relapse 10 months later. The second patient had a primitive neuroectodermal tumor (PNET) that also arose in the right atrium. The patient was treated with multiagent neoadjuvant chemotherapy. The residual tumor of the right atrium was resected together with the recurrent nerve, the free wall of the right atrium, the interventricular sulcus, and part of the RCA (Fig. 2). The atrium was closed with a GORE-TEX® (W. L. Gore & Associates, Elkton, MD) membrane. This patient also received a coronary artery bypass graft. Figure 3A illustrates the initial size of the tumor and Figure 3B illustrates the postsurgery status. The third patient presented with a tumor growing from the free wall of the right atrium. The tumor infiltrated the pericardium; two regional metastases of approximately 1–2 cm diameter were further detected, one between the ascending aorta and the pulmonary trunk and the other next to the aorta in the dorsal mediastinum. The primary tumor was resected together with the complete free wall of the right atrium. The defect was closed with a patch of autologous pericardium taken from the left part of the pericardium. The two metastases were resected. In the fourth patient, with a primary tumor located in the left atrium, the atrium could be closed directly after resection.


Figure 2
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  		Figure 2. A 23-year-old patient with a primitive neuroectodermal tumor of the right atrium and atrioventricular groove. (A): After resection of the right coronary artery (note bypass graft), right atrium, and part of the anulus of the tricuspid valve. (B): Surgical specimen with resected sarcoma.

 


Figure 3
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  		Figure 3. A 23-year-old patient with a primitive neuroectodermal tumor of the right atrium and atrioventricular groove. (A): At primary diagnosis. (B): After neoadjuvant chemotherapy, with six courses of vincristine, ifosfamide, doxorubicin, and etoposide, and residual tumor resection.

 
The fifth patient resected with curative intent was suffering from a tumor arising in the aorta, and no malignancy was suspected prior to surgery. The patient presented with shortness of breath, and the diagnostic workup revealed an aortic aneurysm extending from the distal aortic arch to the proximal descending aorta with a diameter of 4.0 cm x 3.2 cm. Coronary artery disease affecting the RCA and the left anterior descending artery was further diagnosed preoperatively. The patient received a two-vessel coronary artery bypass graft; the distal aortic arch and the proximal aorta were resected and replaced with an intervascular prosthesis. Free resection margins were not obtained, and the patient developed local relapse within 2 months of surgery and died.

The final patient treated with surgery with curative intent had a leiomyosarcoma of the inferior vena cava, which was resected following neoadjuvant chemotherapy. A 20-mm GORE-TEX® prosthesis was interposed.

Six patients presented with distant metastases. Three had metastases to the lungs only, one had lung and soft tissue metastases, one had lung and liver metastases, and one had bone metastases and lymph node involvement. Three of these patients were allocated to palliative resection of the primary tumor for hemodynamic reasons. One patient with a pleomorphic sarcoma (not otherwise specified) of the left ventricle had a debulking of intracardial tumor masses. The second patient, suffering from a sarcoma of the pulmonary artery, presented with multiple lung metastases. The primary tumor was resected with part of the right ventricular outflow tract, the pulmonary trunk, and the central parts of both pulmonary arteries. Reconstruction was performed using a homograft of the pulmonary artery and a composite prosthesis. The third patient, with a tumor of the left atrium, had the tumor excised and the defect in the atrium closed with an autologous pericardial patch.

One patient had a solitary brain metastasis that was resected in the late course of the disease.

Palliative radiation was applied to control the primary in one patient. Five patients who developed brain metastases received irradiation of the brain metastases.

Systemic Treatment
Neoadjuvant anthracycline plus ifosfamide–based chemotherapy was applied in the patient with the PNET and in the patient with leiomyosarcoma. The patient with the PNET received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) chemotherapy preoperatively within the European Ewing Tumour Working Initiative of National Groups (EURO-EWING) 99 protocol. Computed tomography scans prior to neoadjuvant chemotherapy and following resection are shown in Figure 3. In addition to the patient suffering from the PNET, one patient received neoadjuvant and one patient received adjuvant doxorubicin and ifosfamide–based chemotherapy.

Palliative chemotherapy was applied in 11 patients (79%), for seven of them as initial treatment; for the remaining four, after relapse. In order to achieve a rapid response for symptomatic disease, a combination of doxorubicin and ifosfamide was chosen in 10 cases. One patient was treated with ifosfamide alone following adjuvant anthracycline-based therapy. Eight (73%) of the 11 patients treated with palliative chemotherapy attained a response to treatment (two complete remissions, six partial remissions); two (18%) had disease stabilization for 10 and 12 months. Responses were seen in all histologic subtypes. Five patients were offered second-line chemotherapy. Two patients achieved short-lasting disease stabilization.

Details on local and systemic treatment procedures as well as individual outcome are given in Table 1Go.

Outcome and Survival
After a median follow-up of 15 months (range, 2–156), three patients were alive with no evidence of disease 11, 52, and 156 months after diagnosis. The median survival duration was 17 months (Fig. 4). This includes one patient with a sarcoma of the inferior vena cava after neoadjuvant chemotherapy and resection as well as a single patient with histologically proven subcutaneous metastases, who attained complete remission after palliative chemotherapy with doxorubicin and ifosfamide lasting >10 years. Also, the patient with the PNET was still alive without relapse after completion of pre- and postoperative chemotherapy. Two patients were alive with disease 13 and 26 months after diagnosis. Nine patients had died as a result of tumor progression.


Figure 4
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  		Figure 4. Overall survival in 14 patients with sarcoma of the heart or the great vessels (Kaplan–Meier plot).

 

   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Acknowledgments
 References
 
STS of the heart or the large vessels is a rare entity, accounting for only 1% of all sarcomas. Thus, clinical trials of sufficient size to define standard treatment approaches are hardly realistic. Apart from data from autopsy-based series [13], information on sarcomas of the heart or large vessels is restricted to case reports and small retrospective series frequently consisting predominantly of benign neoplasms. Accordingly, clinical decisions have to fall back on studies of STS in other locations. The current series, despite the limited number of patients, is one of the largest series of sarcomas arising in the heart or the large vessels. In our registry, 1.0% of all STS patients identified between January 1993 and September 2006 had sarcoma of the heart or great vessels.

Among the multitude of histologic subtypes of STS, it is important to identify small cell sarcomas of the pediatric type, which are far more responsive to systemic treatment and derive a clear benefit from an interdisciplinary approach. The typical cardiac rhabdomyosarcomas of the embryonal type and extraosseous Ewing's sarcoma/PNETs are aggressive tumors requiring neoadjuvant and/or adjuvant multiagent chemotherapy. In our series, one patient with a PNET fell into this group. The patient was treated with neoadjuvant and adjuvant chemotherapy (VIDE regimen according to the EURO-EWING 99 protocol). The patient was alive with no evidence of disease 38 months after completion of treatment.

For the remaining cases of STS of the heart or the large vessels, the treatment of choice is complete resection, whenever feasible. However, many patients present with unresectable disease. In our series, six of all 14 patients were considered resectable. Following resection, four developed a relapse, either at the primary site or with distant metastases. This high probability of relapse underlines the need for effective neo-/adjuvant strategies in high-grade sarcomas. Again, only small retrospective series have been reported in cardiac STS [14–16]. In general, the role of adjuvant chemotherapy in adult-type sarcomas is still unclear. A large meta-analysis based on individual patient data from patients with sarcomas who received doxorubicin-containing chemotherapy showed significantly lower risks for local relapse (p = .016) and distant relapse (p = .0003) and a longer disease-free survival time (p = .0001). However, only a trend for a longer overall survival duration (p = .12) was found, translating into a 4% higher survival rate after 10 years [17]. A small, prospective, randomized trial using a chemotherapy regimen with higher dose intensity in selected high-risk patients showed a proof-of-principle benefit in the recurrence-free interval and relapse-free survival and overall survival times. That trial, conducted by the Italian Sarcoma Group, was closed early for ethical reasons [18]. The update of the study presented in 2003 showed a difference in the median time to progression (31.2 months), median survival time (not reached versus 48.6 months), and survival rate at 4 years (69.8% versus 52.2%) [19].

Even though there is no proof for a benefit of adjuvant chemotherapy in terms of overall survival for patients suffering from STS of the trunk [17], it seems justified to pursue a neoadjuvant approach when local extension does not allow complete resection up front. In these cases, a biopsy for histological analysis should be performed as in sarcomas at other locations. In our series, two patients received neoadjuvant treatment. The patient with the PNET was alive and free of disease at the time of writing of this paper, as discussed above. In the second case, resection of the primary tumor achieved clear margins following neoadjuvant chemotherapy with doxorubicin and ifosfamide; however, the follow-up of 11 months is rather short.

The use of radiotherapy in the setting of STS of the heart or great vessels is only reported in single patients or small collectives [14, 15]. Radiation was applied to achieve local control of the tumor in only one case. The patient had disease progression shortly thereafter and received palliative chemotherapy.

When complete tumor resection with curative intent cannot be achieved, surgery might still be necessary for hemodynamic reasons [20]. In this analysis, more than half of the patients presented in an incurable situation with locally advanced or metastatic disease at primary diagnosis. Palliative resection for hemodynamic reasons was performed in three cases. All patients had a clear symptomatic benefit from the operation. The patients survived 12, 17, and 29 months. However, as illustrated by the patient with subtotal obstruction of the right ventricular outflow tract at initial presentation (Fig. 5), even in patients with impaired hemodynamics, chemotherapy can be successfully applied. With this approach, the patient suffering from metastatic disease can be spared a cumbersome surgery and the associated inevitable time loss before systemic treatment can be started. Thus, surgery can also be a valid option within a palliative concept. The expected morbidity of the surgery and the associated lead time to possible start of systemic treatment has to be balanced against the expected hemodynamic benefit.


Figure 5
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  		Figure 5. A 29-year-old patient with angiosarcoma of the ventricular septum, right and left chamber, and pericardium, and subtotal obstruction of the right ventricular outflow tract. (A, B): At primary diagnosis. (C, D): After application of two cycles of doxorubicin and ifosfamide, showing partial regression of the mass at the right ventricular outflow, in the apex of both ventricles, and of the pericardial effusion. (Transverse contrast-enhanced computed tomography scan at the level of the right ventricular outflow tract and left ventricular apex.)

 
Palliative chemotherapy was applied in 11 of our patients. Seven of these 11 patients attained a response to first-line treatment (two complete remissions, five partial remissions), and two had disease stabilization for 10 and 12 months. Of note, the patient achieving the complete response was alive and free from disease >12 years after the completion of treatment. This patient obviously belongs to the small group of patients with advanced disease being cured by systemic chemotherapy [21]. The response rate in this series following palliative chemotherapy was good and underlines the potential benefit of this approach. As most patients are symptomatic at the time of initiation of chemotherapy, it seems justified to use a combination chemotherapy up front to achieve rapid relief of symptoms, even though there are no data from randomized trials to support the approach.

In summary, the treatment outcome for patients suffering from STS of the heart and the large vessels remains poor. It is important to filter out patients with rare entities like Ewing's sarcoma/PNET or potential embryonal rhabdomyosarcoma, because these patients can be cured by multimodality approaches. For the remaining patients, aggressive surgery remains the only curative option. The patients should preferentially be referred to specialized cancer centers immediately after diagnosis without preceding treatment attempts. Although the majority of patients cannot be treated with curative intent, an optimized treatment approach, including neoadjuvant chemotherapy and probably additional radiotherapy, might enhance the rate of complete resections depending on the histologic subtype and response to treatment.


   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
References
 
Presented in part at the 40th annual meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5–8, 2004.


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 

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