Systemic therapy

Knowledge of the histologic spectrum of retroperitoneal sarcomas, in addition to appreciation of their significantly disparate biologies, is critical to optimal management. Well-differentiated liposarcomas have the most favourable prognosis, and are disposed almost exclusively to local recurrence, with negligible incidence of distant metastasis. They are also of low histological grade with no known responses to cytotoxic chemotherapy. These factors thus suggest no rationale for adjuvant systemic therapy with cytotoxic agents in primary or recurrent well-differentiated liposarcoma. Both dedifferentiated liposarcoma and leiomyosarcoma are high grade tumours with equally poor prognosis relative to well-differentiated liposarcoma. Crucially, this similar eventual survival is mediated by diametrically disparate patterns of recurrence while dedifferentiated liposarcoma, akin to well differentiated liposarcoma, is chiefly prone to local recurrence, leiomyosarcoma manifests primarily distant relapses.22This disparity in the pattern of treatment failure necessitates a tailored, histology-specific approach in thinking about primary and adjuvant therapy. For instance, of these diagnoses, it may be argued that leiomyosarcomas could benefit most from effective adjuvant systemic therapy.

Perhaps because of the predominance of well differentiated/dedifferentiated liposarcoma in the retroperitoneum and its relative chemotherapy resistance, scant prospective data are available regarding the use of adjuvant chemotherapy specifically in resected localised primary retroperitoneal sarcoma. Fewer than 10% of major adjuvant chemotherapy trials in sarcoma conducted thus far were comprised of patients with retroperitoneal disease.23,24A retrospective analysis of neoadjuvant therapy in high grade retroperitoneal sarcomas revealed no improvement insurvival relative to that predicted by the appropriate nomogram, although histopathologic response to neoadjuvant therapy predicted for improved outcomes compared with non-responders.25 There are is no prospective data assessing the value of perioperative systemic therapy in the setting of locally recurrent disease. At this time, we do not recommend adjuvant chemotherapy as a routine standard of care in resected retroperitoneal soft tissue sarcoma except in rare chemotherapy sensitive subtypes more common in children, e.g. Ewing sarcoma.

While the objective of chemotherapy in the setting of unresectable or metastatic disease is palliative, a consideration especially relevant to retroperitoneal sarcomas is the significant morbidity of bulky abdomino-peritoneal disease, thus amplifying the value of achieving substantive clinicoradiologic responses with systemic therapy. A large French study evaluating almost 600 patients with locally advanced or metastatic retroperitoneal sarcoma demonstrated an objective response rate of 16% and a progression-free survival of nearly six months with palliative chemotherapy.26 Although histological subtype did not feature as a significant prognostic factor for chemotherapy response or overall outcome in this particular study, it remains the most important factor in choosing systemic agents for treatment. Well-differentiated and dedifferentiated liposarcomas respond poorly to cytotoxic chemotherapy, associated with objective response rates of 1012% with anthracycline-based treatment.27,28A defining molecular pathway amplification of the anti-apoptotic proteins HDM2, which inhibits the tumour suppressor p53, and CDK4, which suppresses the tumour suppressor retinoblastoma protein is present in over 90% of well and dedifferentiated liposarcomas.29These aberrations have become molecular signatures used for definitive diagnosis of liposarcoma, and present unique therapeutic opportunities through pharmacological antagonism of HDM2 and CDK4 in tumours with functional p53 and Rb protein, respectively. Early phase clinical studies of both HDM2 and CDK4 inhibitors have revealed so far modest activity so far.30,31In the case of leiomyosarcomas, there is moderate sensitivity, above and beyond anthracycline-based chemotherapy, to one of several agents given either singly or in combination, including gemcitabine in combination with docetaxel ,32, single agent trabectedin (approved outside of U.S.),33, dacarbazine or temozolomide, and gemcitabine in combination with dacarbazine.34Other histologies that make up a small proportion of retroperitoneal disease include undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumours, and solitary fibrous tumour. While the former two diagnoses are high grade tumours often treated with anthracycline-based combination chemotherapy, solitary fibrous tumour has a more varied biology, and a less predictable response to cytotoxic agents. It has, however, been shown to derive benefit from therapy directed against vascular endothelial growth factor, either singly or in combination with chemotherapy.35,36Pazopanib, a multi-targeted tyrosine kinase inhibitor directed against vascular endothelial growth factor, platelet derived growth factor, fibroblast growth factor receptor and KIT, remains an option for any non-liposarcoma soft tissue sarcoma failing other chemotherapy in the recurrent or metastatic setting, having demonstrated significant benefit in progression-free survival in a landmark randomised phase 3 trial.37