Elsevier

Cancer Treatment Reviews

Volume 38, Issue 5, August 2012, Pages 368-378
Cancer Treatment Reviews

Antitumour treatment
A role for maintenance therapy in managing sarcoma

https://doi.org/10.1016/j.ctrv.2011.07.003Get rights and content

Summary

Despite the use of recommended chemotherapy regimens, patients with metastatic sarcomas have a poor prognosis. To date, the median overall survival for metastatic disease remains less than 18 months. First-line treatment of most metastatic sarcomas consists of chemotherapy with or without surgical excision of residual disease, followed by “watchful waiting” until disease progression or recurrence. According to the current treatment paradigm, recommended by United States and European clinical guidelines, chemotherapy is administered for a fixed number of cycles, and then a watchful waiting approach is taken once a best response is achieved. Single-agent doxorubicin remains the standard for treatment of most soft-tissue sarcomas (STS), as combination and dose-intense regimens have largely failed to improve survival. Combination chemotherapy is the standard treatment approach for osteosarcoma and Ewing’s sarcoma, but outcomes are poor for patients with recurrent disease. In order to improve outcomes (in particular, progression-free survival [PFS] and overall survival [OS]), strategies shown to be effective in other solid malignancies, such as maintenance therapy and long-term treatment with targeted therapy, are being investigated in patients with advanced sarcomas. One potential promising approach is the use of mammalian target of rapamycin (mTOR) inhibitors for maintenance therapy. One such mTOR inhibitor, ridaforolimus (AP23573, MK-8669), is currently being evaluated in patients with advanced bone and STS in the ongoing Sarcoma mUlti-Center Clinical Evaluation of the Efficacy of riDaforolimus (SUCCEED) trial.

Introduction

Sarcomas—a heterogeneous group of rare solid tumors of mesenchymal origin—are broadly categorized as soft-tissue, visceral, or bone sarcomas.1 Soft-tissue or visceral sarcomas can arise in muscle, fat, nerves, blood vessels, and fibrous and connective tissue at any site in the body, but the majority occur within the abdominal cavity (mostly gastrointestinal stromal tumors [GISTs]), or in a limb or limb girdle.2 Several large case-series studies show that the most common soft-tissue sarcoma (STS) subtypes are GIST, liposarcomas, leiomyosarcomas, dermatofibrosarcomas, and rhabdomyosarcomas, as well as sarcomas not otherwise specified.[3], [4], [5] In comparison, bone sarcomas are approximately 4 times less common than STS; the most common subtypes are osteosarcoma, chondrosarcoma, and Ewing’s sarcoma, which account for approximately 35%, 30%, and 16% of all primary bone cancers, respectively.6 Together, soft-tissue and bone sarcomas represent 1% of all malignancies in adults, but 15–20% of pediatric cancers.[7], [8]

Subtypes of sarcoma have distinct clinical and pathological features, with many having aggressive characteristics that predispose to metastatic spread of disease, typically to the lungs.[1], [6], [9], [10] Chemotherapy is initially used to treat most metastatic sarcomas, with surgery or other local interventions (e.g., radiotherapy, radiofrequency ablation, cryo surgery) used to address residual disease whenever feasible. According to the current treatment paradigm, chemotherapy is administered for a fixed number of cycles depending on the sarcoma type, and then a “watchful waiting” approach is taken once a best response is achieved—a strategy supported in treatment recommendations from the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN).[1], [9], [10]

Surgery remains the cornerstone of treatment and the only curative locoregional approach of localized resectable STS; first-line treatment usually consists of wide margin surgery plus radiotherapy.1 An optimal initial resection is one of the most reproducible and reliable prognostic factors for survival in resectable STS. Nevertheless, despite improved local control rates, more than half of the patients still develop and die from unresectable, locally advanced, and/or metastatic disease. Second-line therapy is subsequently offered upon evidence of disease progression or recurrence.6 When a watchful waiting strategy is not employed, chemotherapy may be continued until disease progression, or until intolerance or toxicity limitation. For example, the cumulative dose of doxorubicin, a key agent used in treatment of many sarcomas, is limited to 550 mg/m2 by dose-related cardiotoxicity.11 Moreover, the benefit-risk ratio of chemotherapy declines over time, not only due to increasing cumulative toxicity but likely also due to decreasing efficacy as tumor cells adapt to the chemotherapeutic insult.[12], [13]

Despite the use of recommended chemotherapy regimens, patients with metastatic sarcomas have a poor prognosis. Median overall survival (OS) is only 15–21 months, although patients with less aggressive subtypes (e.g., well-differentiated liposarcomas) survive for longer periods of time.14 Similarly, outcomes in metastatic bone sarcomas depend on the subtype, but long-term survival is still less than or equal to 30%.[15], [16], [17] The poor outcomes associated with the current treatment paradigm, combined with a lack of evidence to support longer-term use of chemotherapy, illustrate the need for better treatment options in sarcoma. This paper reviews current treatment approaches for metastatic soft-tissue and bone sarcomas and their respective effects on clinical outcomes, then discusses a maintenance therapy approach utilized in other solid cancer models and the rationale for its use in sarcomas.

Section snippets

First-line treatment

Single-agent or combination chemotherapy are options for first-line treatment of advanced STS.[1], [9] Doxorubicin, an anthracycline antibiotic, is generally considered to be the most active single agent, producing objective responses in 15–35% of patients. Median OS is only 8–12 months.18 In many early trials with single-agent doxorubicin, progression-free survival (PFS) was not measured, but typically is only several months. In the last 30 years, various cooperative groups have investigated

Current treatment of advanced bone sarcomas

Combination chemotherapy is indicated in first-line treatment of primary metastatic osteosarcoma and Ewing’s sarcoma, with surgical removal of residual metastatic disease whenever possible.[6], [10], [49] Further chemotherapy after local treatment is then adapted based on the evaluated histological response. However, outcomes are poor, with 5-year survival rates of up to 30%. In contrast, chemotherapy does not play a role in the treatment of conventional chondrosarcomas. Radiation therapy is

A role for mammalian target of rapamycin inhibitors for advanced sarcomas

The mammalian target of rapamycin (mTOR) may be another attractive therapeutic target for patients with advanced sarcomas. The first-to-market mTOR inhibitor sirolimus (rapamycin) provided initial clinical evidence that blocking mTOR may be beneficial, based on a study in patients with angiomyolipomas.66 Ridaforolimus (AP23573, MK-8669), another mTOR inhibitor, showed promising activity in advanced sarcoma patients in a phase 1 trial,67 and was subsequently evaluated in a phase 2 trial

Lessons from other solid malignancies: emergence of a maintenance paradigm

The poor long-term outcomes with current treatment approaches for metastatic soft-tissue and bone sarcomas underscore the need for a new treatment strategy. Advances made in the treatment of other solid malignancies, particularly advanced non-small cell lung cancer (NSCLC), ovarian carcinoma, and GISTs, offer insight into a new treatment paradigm—maintenance therapy—that has the potential to improve PFS and OS, as well as quality of life. Maintenance therapy is defined as the continued

Moving towards a maintenance paradigm in metastatic sarcomas

Thus far, strategies evaluated to try and increase responses to chemotherapy (such as high-dose chemotherapy and combination chemotherapy) have not been successful. The extended use of standard cytotoxic agents has been generally disappointing, and no strategy applied in the first remission setting has prolonged OS. As therapeutic options move beyond classic chemotherapy to novel drugs including hormones, immune interventions, and biologic agents, the consolidation treatment strategy is

Conclusions

The outcome of patients with metastatic sarcomas remains poor, despite the current chemotherapy-watchful waiting treatment paradigm. Efforts to improve outcomes by using combination chemotherapy regimens in STS or dose-intense regimens in both soft-tissue and bone sarcomas have been largely disappointing. Administration of chemotherapy for prolonged periods is limited by a decreasing benefit–risk ratio over time, as well as by increasing cumulative toxicities. These factors underscore the need

Conflict of interest

Dr. Ray-Coquard has received funding for research in sarcoma from INCA, patient advocacy group DAM’S and ligue départementale de lutte contre le cancer de l’AIN. Dr. Le Cesne has no conflicts of interest related to this manuscript.

Acknowledgments

The authors would like to thank Brigitte Teissedre, PhD, and Kakuri M. Omari, PhD, of Medicus International New York, for editorial assistance, which was funded by Merck & Co., Inc. The authors were responsible for all content and editorial decisions and received no compensation for the development of the manuscript.

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