What is the role for systemic therapy in advanced soft-tissue sarcoma?
Soft-tissue sarcomas comprise over fifty histologically distinct subtypes, with corresponding differences in molecular aetiology and biological behaviour. The first presentation with advanced (metastatic or unresectable) disease raises the issue of the timing and types of therapeutic options.
There are three therapeutic options that may be considered. The first is watchful waiting, which may be suitable particularly for indolent and asymptomatic sarcoma subtypes, especially in an elderly or frail population. The second is consideration of local therapies, particularly radiotherapy, for symptomatic or rapidly progressive single or oligometastatic disease. Objective local control rates for radiotherapy approach 80%. Finally, consideration may be given to systemic therapy. Most (but not all) types of soft-tissue sarcoma tend to be relatively resistant to systemic therapies, with objective response rates ranging from 0-50%, depending on subtype. In no circumstance is systematic therapy for advanced or unresectable soft-tissue sarcoma considered curative, although a subset of patients may have substantial, long-term survival in this situation.
Systemic therapy for advanced soft tissue sarcoma may be divided into aggressive and gentle palliation. The therapeutic decision between these two approaches usually depends on the need for rapid disease control, the state of fitness of the patient, the type of sarcoma, and the therapeutic philosophy of the patient and treating clinician. The need for rapid disease control is determined by the symptoms of the patient, and the rate and sites of progression of the tumours. Recent data suggest little difference on overall survival between doxorubicin alone or when administered with ifosfamide, when administered in first line for advanced disease.
For the most common subtypes of soft-tissue sarcomas (pleomorphic high-grade undifferentiated sarcoma, leiomyosarcoma, well- or de-differentiated liposarcoma, pleomorphic liposarcoma and myxoid liposarcoma, and synovial cell sarcoma), the major therapeutic options with Australian regulatory approval for soft-tissue sarcoma are based on anthracycline and alkylating agents, gemcitabine with taxanes or dacarbazine, or dacarbazine alone. Gemcitabine and docetaxel may be superior to single agent doxorubicin for uterine leiomyosarcoma. It is notable that doxorubicin and alkylators appear to have significant dose-response relationships, which may influence the choice of agent depending on the need for disease control.
Newer agents are emerging with clinical activity in advanced soft-tissue sarcomas, such as trabectedin and pazopanib. Trabectedin is not approved by the Therapeutic Goods Administration for this indication. Pazopanib has recently been recommended for listing by the Pharmaceutical Benefits Advisory Committee onto the Pharmaceutical Benefits Scheme.
For a specific subset of sarcomas, including dermatofibrosarcoma protuberans, alveolar soft-part sarcoma, perivascular epithelioid cell tumor (PEComa), and to a lesser extent for angiosarcoma and desmoid tumours, evidence for the selective activity of various targeted and non-targeted therapies may be considered.
Given the difficulties in making clear pathologic diagnoses, the absence of level I or II evidence for most therapeutic recommendations, and the complexities of expert multidisciplinary care, patients with soft-tissue sarcoma should be referred to a multidisciplinary service with dedicated interests in the management of sarcomas.
Where there is no high level evidence for standard practice, then entering patients into clinical trials should be considered.
Specific soft-tissue sarcoma subtypes
The development of kinase inhibitor therapy (KIT) and other kinase-directed inhibitors for gastrointestinal stromal tumours (GIST) have sparked a strong effort to identify similar specific molecular drivers for other sarcoma subtypes. GISTs will not be discussed as part of these guidelines, but it is important to note that the differential diagnosis of GIST should be considered carefully in any patient with an intra-abdominal soft tissue sarcomas (STS) given the treatment implications.
Apart from GIST, there have been other noted examples of molecularly-targeted therapies that should be considered for selected subtypes. Dermatofibrosarcoma protuberans (DFSP) have a characteristic translocation (t17:22) that results in the creation of a fusion oncogene between COL1A1 and PDGFB, which results in constitutively activated PDGF. These tumours are highly sensitive to PDGF inhibition with imatinib, which is registered/reimbursed for inoperable DFSP in Australia.
Activity has also been noted in the following sarcoma subtypes with molecularly-targeted therapies. Malignant perivascular epithelioid cell tumors (PEComas) are often associated with the loss of tuberous sclerosis complex (TSC1/TSC2 tumour supressors), with clear activity noted with mammalian target of rapamycin (mTOR) inhibitors.
Inflammatory myofibroblastic tumours are associated with transolcations of anaplastic lymphoma kinase (ALK) in approximately 50% of cases; activity has been reported with the ALK inhibitor crizotinib.
Alveolar soft-part sarcoma (ASPS) are highly vascular tumours that typically affect adolescents and young adults.Clear activity has been noted in patients treated with VEGF-directed tyrosine kinase inhibitors including sunitinib and cediranib. Of note, in a recent large phase II trial with cediranib, 15 of 43 patients achieved a partial response (35%) with a disease control rate at 24 weeks of 84%.
Desmoid tumours (also known as aggressive fibromatosis or desmoid type fibromatosis) have a highly variable natural history, with some patients having prolonged stable disease or even spontaneous regressions. Although they are not at risk of metastasising, local invasion into vital structures can cause significant morbidity and may be fatal. Intra-abdominal desmoids tumours in particular, are invariably infiltrative into surrounding mesenteric structures, making R0 surgery very difficult to achieve. The clinical algorithm for patient management is therefore complex, and should be individualised after taking into account the above factors. As a general principle, a watchful waiting approach is preferred. Systemic therapies should be reserved for patients with clear disease progression on serial assessments, or in patients with clear symptoms from their disease and for whom localised measures such as radiotherapy or surgery have also been considered. Systemic therapy options include cytotoxic and non-cytotoxic agents, with a general approach to consider a stepwise progression from less toxic non-cytotoxic agents to cytotoxics.
Angiosarcomas, although not characterised molecularly, need to be considered as a distinctive soft tissue subtype, and treated accordingly.
Evidence summary and recommendations
Systemic approaches to common soft-tissue sarcomas
| Doxorubicin, alone or in combination with ifosfamide is standard first-line treatment.
Although the response rate to doxorubicin as a single agent is lower than to the combination, the toxicity of the combination is greater and there is to date no evidence of a difference in overall survival for patients treated with the combination.
|I, II, IV||, , , , |
|For patients in whom doxorubicin is considered inappropriate (for example, for patients who have received doxorubicin as part of adjuvant or neoadjuvant therapy, or for patients who have cardiac dysfunction, or who have glucose-6-phosphate dehydrogenase deficiency), ifosfamide as a single agent has the second highest objective response rate.||II, IV||, |
|For patients with uterine leiomyosarcoma, the combination of docetaxel and gemcitabine may be considered in first-line.||III-1, IV||, , |
|There is no evidence to support combination chemotherapy regimens over sequential single agent regimens in the first-line treatment of advanced soft-tissue sarcomas.||B|
Second-line and third-line
|For patients who have not received ifosfamide as first-line, single agent ifosfamide may be considered.||I, II||, |
|For patients with myxoid liposarcoma or leiomyosarcoma, consideration may be given to trabectedin.*||II, III-2, IV||, , , |
|For patients who have been exposed to both doxorubicin and ifosfamide, dacarbazine is considered the next most active approved agent. If aggressive combination therapy is indicated, the combination of dacarbazine and gemcitabine has demonstrated a survival benefit compared to dacarbazine alone.||II|||
|The antiangiogenic agent, pazopanib, was superior to placebo in progression-free but not overall survival, in patients with advanced soft tissue sarcomas (excluding GIST and adipocytic tumours) who have received prior chemotherapy.||II|||
*Trabectedin is not approved in Australia for soft-tissue sarcoma.
|Single agent ifosfamide can be considered as second-line treatment for patients who have not received ifosfamide as first-line.||B|
|Dacarbazine with or without gemcitabine is reasonable third-line therapy after exposure to doxorubicin and ifosfamide in advanced soft tissue sarcoma.||B|
Systemic approaches to other selected soft-tissue sarcomas
| Hormonal agents (anti-oestrogens such as tamoxifen), alone or in combination with nonsteroidal anti-inflammatory drugs (sulindac) have shown some activity in treating Desmoid tumours.
Molecularly-targeted agents including imatinib* and sorafenib* have been assessed in single-arm, non-randomised phase II trials, with some level of activity.
If other options have failed or are there is a need for a more aggressive approach, cytotoxic options include those that are less toxic (combination of methotrexate and vinblastine or vinorelbine) or more toxic (doxorubicin by prolonged intravenous infusion, or ideally delivered in its liposomal formulation) have shown some levels of activity. However, all of these results must be taken in context, given the highly variable natural history of disease and lack of control arm comparisons with any of these studies
|III-2, IV||, , , , , , |
|Paclitaxel (administered weekly) and liposomal doxorubicin both have activity in angiosarcomas. Although primary angiosarcomas, which often arise in the head and neck, are more chemo-sensitive than those that are radiation-associated, systemic therapy should be considered in all of these patients given the palliation that can be offered by these agents.||IV|||
*Imatinib and sorafenib are not approved or reimbursed for this indication in Australia.
|Systemic therapy with paclitaxel is reasonable in all patients with angiosarcoma, given the palliation that can be offered by these agents.||D|
Clinical trial participation should be considered for patients with soft tissue sarcomas.
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