Primary cardiac tumors represent a very rare disease entity and their frequency has been estimated to be 0.02%, based on the results of autopsy series. A quarter of these tumors are malignant, of which sarcomas are the most common. Primary cardiac sarcomas constitute approximately 1% of all soft tissue sarcomas and the median age at presentation is 39–44 years. Treatment of these tumors poses great challenges in diagnosis, biopsy, surgery and administration of chemotherapy and radiotherapy, especially since sarcomas are mostly high-grade and progress swiftly. Surgery with negative margins is associated with increased survival and is the mainstay of therapy but complete resection is possible in less than half of patients.
Chemotherapy has a role in neoadjuvant, adjuvant and metastatic settings, but its exact role needs to be defined. The high probability of developing distant metastases in completely resected patients prompts the use of adjuvant systemic therapy Citation[3,4,7]. Ifosfamide–epirubicin (or doxorubicin) and cyclophosphamide, vincristine, doxorubicin and dacarbazine (CyVADIC) are the main regimens used. Radiation therapy is not usually used in primary cardiac sarcomas (except pulmonary artery sarcomas) because of the risk of toxicity to the myocardium. Improvements in long-term prognosis in most patients will only be seen following the introduction of novel therapeutic agents.
There is little information regarding the etiology of primary cardiac tumors. However, cases occurring as a result of radiation (e.g., mantle field radiation for Hodgkin’s disease) have been described Citation[4]. These patients constitute a subgroup in which these tumors can be prevented by avoiding unnecessary radiation. Hopefully, advances in chemotherapy will help obviate the necessity of radiation, which results in the development of risk of radiation-induced sarcoma. Radiation-induced sarcomas are usually high-grade and associated with high mortality. The risk involves all the structures in the radiation field and increases at a rate of 1% per year after receiving radiation for a period of 10 years Citation[5].
Angiosarcomas, rhabdomyosarcomas, leiomyosarcomas, malignant fibrous histiocytomas myxoid sarcomas and undifferentiated sarcomas are the tumors most commonly described in adults Citation[2–4]. Rhabdomyosarcomas, of the embryonal type, are the most common tumors in children Citation[6]. The occurrence of primitive neuroectodermal tumors, synovial sarcomas and osteosarcomas has also been described Citation[2–4,6,7].
Angiosarcomas are typically located in the right atrium and, because of their location, are often diagnosed at an advanced stage Citation[8]. They may be either intracavitary and polypoid, or diffuse and infiltrative with pericardial involvement. Patients usually present with right-sided heart failure and cardiac tamponade. Rare cases of visceral Kaposi sarcoma involve the heart, typically in epicardial or myocardial locations Citation[9]. Rhabdomyosarcomas and fibrosarcomas have no specific chamber predilections and can present with ventricular involvement Citation[10,11]. They usually occur diffusely, although polypoid extension has been described occasionally. Malignant fibrous histiocytomas, leiomyosarcomas, myxoid sarcomas, osteosarcomas and undifferentiated sarcomas usually occur in the left atrium Citation[12,13].
In a major study, improved survival was documented in patients with left-sided tumors, no necrosis, low mitotic count and no metastases. Chemotherapy and radiotherapy improved survival. Age, gender, presence of differentiation and histologic type did not affect prognosis. On multivariate analysis, a low level of mitotic activity and any therapy significantly influenced survival rates Citation[3]. In a recent study, 14.8% of resected tumors were low-grade and all patients were alive at the final follow-up – a fact that illustrates the importance of tumor grade in defining survival Citation[14].
Sarcomas are mostly high-grade and progress swiftly. Widespread myocardial infiltration, outflow obstruction and distant metastasis result in death, occurring within a few weeks to 2 years of onset of symptoms; median survival ranges from 6 to 12 months. Metastatic rate at presentation ranges from 26 to 42.8% and is 75% at time of death Citation[2–4,6–14].
Delay in diagnosis is common; median time from onset of symptoms to diagnosis has varied from 4 months Citation[4] to 16 months Citation[15] in various studies. Hopefully, the practice of early echocardiography in patients with symptoms of cardiac disease, as is routinely done these days, will help shorten the time to diagnosis. Early detection might result in the diagnosis of a larger number of patients with operable tumors.
Echocardiography is the main diagnostic tool. Broad-based atrial masses in nonseptal locations and extension into the pulmonary vein are some of the features suggestive of malignancy Citation[16]. PET scanning could potentially aid the detection of metastases and possibly have a role in differentiating clots from tumors in the given clinical setting.
Surgery with negative margins is associated with increased survival and is the mainstay of therapy Citation[2–4,6–15]. Surgery is technically demanding and the necessity of securing negative margins may entail further procedures such as coronary artery bypasses, valve replacements, reconstruction procedures, installation of pacemakers and pericardial repairs, resulting in an increased risk of postoperative complications. Complete resection is possible in fewer than half of patients Citation[15]. In one recent study, 65% of patients planned for surgery could undergo complete resection Citation[4]. The risk of positive margins and/or incomplete surgery is higher in patients with ventricular involvement, and tumors of the left atrium can be associated with difficulty in exposure Citation[17]. Surgery offers useful palliation, even when complete margins cannot be secured in conditions such as outflow tract obstruction Citation[4,7]. Patients who undergo complete resection have a median survival of 17–24 months, as compared with approximately 6–10 months for patients unable to undergo complete resection Citation[4,18]. Autotransplantation has facilitated the complete removal of tumors in technically difficult situations, especially tumors of the left atrium. Citation[16] The role of orthotopic cardiac transplantation in the management of locally advanced non-metastatic tumors appears to be limited, since it has been seen that two-thirds of patients so treated die of local recurrence or distant metastases within a year, despite 25% of patients (7/28) having a mean survival of 27 months without recurrent disease Citation[19].
Neo-adjuvant chemotherapy can make subsequent surgery easier, especially in inoperable tumors, potentially treat micrometastatic disease earlier and guide further chemotherapy based on the degree of tissue necrosis observed in the operative specimen or regression noted radiologically Citation[3,4,7].
Ifosfamide–epirubicin (or doxorubicin) and CyVADIC (cyclophosphamide, vincristine, doxorubicin and dacarbazine) are the two main regimens used in adult soft tissue sarcomas and have conferred a rather modest survival advantage Citation[20,21]. A meta-analysis revealed that chemotherapy conferred a 7% survival advantage that was confined to the group of extremity soft tissue sarcomas Citation[22]. A recent meta-analysis yielded similar results Citation[23].
The combination of ifosfamide and an anthracycline (epirubicin /doxorubicin) or single-agent chemotherapy with these agents has also been tested for efficacy against cardiac sarcomas in the setting of metastatic disease and exhibited significant palliative benefit Citation[7]. In fact, a cure has been described with this regimen in one such case.Citation[7]
It would be pertinent to consider the histology while deciding upon the treatment course. Rhabdomyosarcoma and primitive neuroectodermal tumors are extremely chemosensitive and benefit from multimodality therapy, including surgery, adjuvant (or neoadjuvant) chemotherapy and radiotherapy, with high rates of cure especially in pediatric populations. Typical regimens for these diseases include vincristine, doxorubicin and cyclophosphamide (dactinomycin, in particular, for rhabdomyosarcoma) and the combination of ifosfamide and etoposide.
Myxoid liposarcomas and synovial sarcomas are highly sensitive to ifofsamide–anthracycline combinations Citation[24,25]. Synovial sarcomas are uniquely sensitive to ifosfamide. Leiomyosarcomas and malignant fibrous histiocytomas are sensitive to gemcitabine–docetaxel combinations, which can be a good second-line regimen in these cases Citation[26]. Dacarbazine and doxorubicin show activity against leiomyosarcoma but ifosfamide has minimal activity Citation[27]. Weekly paclitaxel has shown activity in angiosarcomas Citation[28].
Radiotherapy should not ordinarily be used when surgical resection alone can be performed with appropriate confidence. Adjuvant radiotherapy is usually administered in cases of close or positive margins or large, high-grade tumors. Radiotherapy has been used in some patients with cardiac sarcomas but its efficacy has not been precisely determined Citation[3,7]. There is one case report of a patient with an unresectable high-grade cardiac sarcoma who was cured using hyperfractionated radiotherapy (7050 cGy) with 5-iododeoxyuridine as the radiosensitizer Citation[29]. In a study of soft tissue sarcomas (noncardiac), hyperfractionated photon beam radiation was combined with intravenous iododeoxyuridine as a radio sensitizer, and local control rates of 60% were achieved at a median follow-up of 4 years Citation[30].
The use of intraoperative radiotherapy and brachytherapy (in neoadjuvant, adjuvant and palliative settings) needs to be explored in order to provide the benefits of radiotherapy to these patients (especially those with locally advanced disease) while minimizing the toxicity. However, it seems that improvements in long-term prognosis for the majority of patients awaits the introduction of novel therapeutic agents.
Expert commentary & five-year view
Primary cardiac sarcomas are rare and lethal. Complete resection offers the best chance of cure (especially in low-grade tumors) and the best hope for prolonged survival in high-grade tumors. Chemotherapy and radiotherapy have the potential to prolong survival; since they are effective in pediatric tumors such as rhabdomyosarcoma. However, only radical advances in systemic therapy will potentially result in long-term cures for the majority of the patients. Improvements in long-term prognosis for the majority of patients awaits the introduction of novel therapeutic agents.
Financial & competing interests disclosure
Ajay Gupta is the recipient of the 2008 Brigid Leventhal ASCO Foundation Merit Award. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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