The 7 Pillars of Nonsurgical Oncology Approaches to Primary Cardiac Sarcoma

Introduction

Primary cardiac tumors are extremely rare, with nearly 75% of them being benign tumors and 25% being malignant.^1–3 Primary cardiac sarcomas are the most common type of primary malignant cardiac tumors.^1–3 Angiosarcomas account for about 40% of primary cardiac sarcomas, while other histologies include leiomyosarcoma, undifferentiated pleomorphic sarcoma, rhabdomyosarcoma, intimal sarcoma, and synovial sarcoma.^4–9 Primary cardiac sarcomas are commonly seen in a younger population in their 40s. ⁵ They are highly aggressive tumors with a median survival of 7 months. ⁵ The 5-year survival is less than 10%. ⁵ There are no standardized guidelines for the management of primary cardiac sarcoma. However, surgery remains the primary treatment modality when feasible. ⁴ Systemic therapy, independently and in combination with surgery, has shown improved survival outcomes in patients.^5,7,10 In this review, we attempt to highlight the strategies that we consider to be the 7 pillars of nonsurgical oncology approaches to the management of primary cardiac sarcoma.

1. Multimodality Imaging and Confirmation of Histologic Diagnosis

Transthoracic echocardiography is often the first imaging approach to diagnosis followed by transesophageal echocardiography.^3,11,12 Cardiac magnetic resonance imaging (MRI) is the preferred modality to assess the tumor location, size, and infiltration into surrounding tissues.^11,12 MRI can also better define the composition of a mass and help with histopathological characterization of the tumor.^11,12 Echocardiography has a poor accuracy of about 50% in the histological diagnosis of primary cardiac sarcomas. ³ Whenever feasible, we recommended a biopsy to confirm the histopathological diagnosis, particularly if the tumors are on the right side. It enables choosing appropriate therapy regimens based on tumor histology. It also helps to avoid unnecessary surgery for histologies such as lymphoma that do not require resection.^4,13 In our experience, pericardiocentesis has limited utility in establishing histological diagnosis as the cytology is often negative. A negative cytology in a patient presenting with pericardial effusion and suspicion of a cardiac mass should not be regarded as inflammatory or infectious and further workup is necessary.

2. Multidisciplinary Approach

Most primary cardiac tumors are identified by a cardiologist, who then refers the patient to a cardiac surgeon for resection of the tumor. Only about 25% of patient tumors are resected with negative margins, which affords a significantly better survival outcome than margin-positive resections. ¹⁴ Hence, it is essential to increase the number of patients receiving margin-negative resections. We believe that a multidisciplinary approach is key to achieving this outcome. Our multidisciplinary cardiac tumor team includes cardio-oncologists, sarcoma oncologists, cardiac surgeons, pathologists, and radiation oncologists. The cases are discussed with the multidisciplinary team to plan the best treatment approach for each patient. The cases are also discussed at different stages in their treatment journey to make appropriate decisions based on the disease stage and quality of life goals for the patient.

3. Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy is recommended for all patients with resectable, nonmetastatic, primary cardiac sarcomas. The chemotherapy is continued until no further response is noted or no further tumor shrinkage can be achieved. Our group has previously shown that overall survival in patients who receive neoadjuvant chemotherapy is doubled compared with those who do not. ¹⁰ A margin-negative resection, which is a predictor of longer overall survival, was also achieved in a greater percentage of patients who received neoadjuvant chemotherapy. ¹⁰ In patients older than 65 years, the most preferred systemic therapy agents for neoadjuvant chemotherapy are a combination of adriamycin at a dose of 75 mg/m² and ifosfamide at a dose of 10 g/m². ¹⁰ If patients do not tolerate this combination or if optimal treatment response is not obtained, alternative regimens that can be considered are a combination of gemcitabine at a dose of 900 mg/m² and docetaxel at a dose of 75 mg/m² or single-agent paclitaxel at a dose of 80 mg/m². ¹⁰ We have previously proposed a management algorithm for neoadjuvant chemotherapy in order to optimize treatment response prior to resection, which can be found in our previous publication by Abu Saleh et al. ¹⁰

4. Adjuvant Chemotherapy

In our experience, primary cardiac sarcomas have a high rate of recurrence and metastases despite a margin negative resection. Hence, we recommend adjuvant chemotherapy for all surgically resected patients, even in the absence of radiologic evidence of tumor. A recent study has shown that postoperative therapy doubles the median survival for patients compared with surgery alone. ⁷ Our preferred regimens for adjuvant chemotherapy (after neoadjuvant adriamycin and ifosfamide) include a combination of gemcitabine at a dose of 900 mg/m² and docetaxel at a dose of 75 mg/m² or single-agent paclitaxel at a dose of 80 mg/m². The role of immunotherapy following chemotherapy requires further investigation, with preliminary data suggesting a benefit.

5. Monitoring for and Management of Metastases

Primary cardiac sarcomas are aggressive tumors that metastasize rapidly. Studies have reported that 35% to 50% of patients have metastatic disease at the time of diagnosis.^4–6,15 The most common sites for metastases include lungs, bone, liver, and brain. ⁴ Imaging at the time of initial diagnosis must include a whole-body positron emission tomography/computed tomography (CT) or CT of the chest, abdomen, and pelvis and MRI of the brain to check for metastatic sites. At the sites where metastatic disease is identified, we recommend regular imaging with the same modalities to assess response to treatment. In patients with localized disease or postoperative patients with no evidence of disease, CT of the chest, abdomen, and pelvis should suffice for surveillance. MRI of the brain at baseline is particularly important in patients with primary cardiac angiosarcoma, as it is associated with an increased risk of brain metastases leading to terminal intracranial hemorrhage. ¹⁶ Treatment for metastatic disease is primarily with systemic therapy agents. The regimens used include a combination of adriamycin at a dose of 75 mg/m² and ifosfamide at a dose of 10 g/m², a combination of gemcitabine at a dose of 900 mg/m² and docetaxel at a dose of 75 mg/m², or single-agent paclitaxel at a dose of 80 mg/m². Alternative agents that can be considered in patients who cannot tolerate these regimens or if treatment response is not observed include targeted therapies such as pazopanib, sorafenib, and bevacizumab. We also advise radiation therapy for the definitive management of metastases wherever feasible.

6. Immunotherapy and Clinical Trials

The efficacy of immunotherapy with checkpoint inhibitors has been studied for various soft-tissue sarcomas. Clinical activity with immune-oncologic agents has been reported in selected histologies of sarcomas. In the SARC028 study of pembrolizumab for soft-tissue sarcomas, 4 of the 10 patients with undifferentiated pleomorphic sarcoma (UPS) had a response to treatment. ¹⁷ In the Alliance A091401 study of nivolumab with or without ipilimumab for soft-tissue sarcomas, responses were seen in patients with UPS and angiosarcoma. ¹⁸ Our group has also reported on the clinical activity of pembrolizumab in angiosarcoma in a cohort that included 3 patients with cardiac angiosarcoma. ¹⁹ The results from these studies suggest that checkpoint inhibition is an efficient treatment strategy in selected subtypes of sarcomas and must be considered in patients with these histologies of primary cardiac sarcoma. We also recommend that patients be regularly screened for enrollment into active clinical trials for sarcomas. There are a few ongoing clinical trials to assess the efficacy of adoptive cellular therapy and tumor-infiltrating lymphocyte therapy in the treatment of sarcomas, which could likely benefit patients with primary cardiac sarcoma. ²⁰

7. Genomic and Molecular Profiling

The association between targeted therapy and the genomic profile of primary cardiac sarcomas is poorly understood. Whenever feasible, we perform next-generation sequencing including whole-exome sequencing, RNA sequencing, and profiling of the tumor microenvironment, to better define the tumor biology of primary cardiac sarcomas. Genomic profiling can also help in establishing the histological subtype in some cases as well as identify actionable targets for therapy.

Conclusions

Confirmation of diagnosis is the cornerstone of effective oncologic management of primary cardiac sarcomas. Histologic subtype guides the use of systemic therapy regimens. A multidisciplinary approach from the outset is essential to optimize the benefit from systemic therapies. Regular imaging surveillance for metastases is required for early intervention. Systemic chemotherapy forms the backbone of management of metastatic disease. Immunotherapy and clinical trials can be a potential treatment strategy after completion of conventional therapy.