Antitumour treatmentA role for maintenance therapy in managing sarcoma
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.
References (119)
- et al.
Chemotherapy-induced resistance by ATP-binding cassette transporter genes
Biochim Biophys Acta
(2007) - et al.
Results of randomised studies of the EORTC soft tissue and bone sarcoma group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients
Eur J Cancer
(2002) - et al.
Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas
Eur J Cancer
(2002) - et al.
Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group
Eur J Cancer
(2008) - et al.
Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a gynecologic oncology group phase II study
Gynecol Oncol
(2008) - et al.
Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study
Lancet Oncol
(2007) - et al.
Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT)
Ann Oncol
(2008) - et al.
Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide
Ann Oncol
(2003) - et al.
Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study
Lancet
(2009) - et al.
Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a southwest oncology group and gynecologic oncology group phase 3 trial
Gynecol Oncol
(2009)
Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial
The Lancet Oncol
Soft-tissue sarcomas in adults
N Engl J Med
Epidemiological evaluation of concordance between initial diagnosis, central pathology review in a comprehensive, prospective series of sarcoma patients in the Rhone–Alpes region
BMC Cancer
Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978–2001: an analysis of 26, 758 cases
Int J Cancer
Standards and novel therapeutic options in the treatment of patients with soft tissue sarcoma
Rev Recent Clin Trials
On behalf of the ECECPoe. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up
Ann Oncol
Long-term follow-up of patients with doxorubicin-induced cardiac toxicity after chemotherapy for osteosarcoma
Anticancer Drugs
Overview of resistance to systemic therapy in patients with breast cancer
Adv Exp Med Biol
Trends in survival for patients with metastatic soft-tissue sarcoma
Cancer
Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program
Cancer
Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973–2005
Cancer
Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database
J Bone Joint Surg Am
Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma
Cochrane Database Syst Rev
Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas
J Clin Oncol
Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European organization for research and treatment of cancer soft tissue and bone sarcoma group
J Clin Oncol
Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte–macrophage colony-stimulating factor in advanced soft tissue sarcomas: a trial of the European organization for research and treatment of cancer/soft tissue and bone sarcoma group
J Clin Oncol
Phase III trial of standard versus dose-intensified doxorubicin, ifosfamide and dacarbazine (MAID) in the first-line treatment of metastatic and locally advanced soft tissue sarcoma
Invest New Drugs
High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas
J Clin Oncol
Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules
J Clin Oncol
Phase II study of ET-743 in advanced soft tissue sarcomas: a European organisation for the research and treatment of cancer (EORTC) soft tissue and bone sarcoma group trial
J Clin Oncol
Phase II trial of paclitaxel in patients with soft-tissue sarcoma
Cancer Invest
Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study
J Clin Oncol
Phase II study of docetaxel in advanced soft tissue sarcomas
Am J Clin Oncol
Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the european organization for research and treatment of cancer soft tissue and bone sarcoma group
J Clin Oncol
Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial
J Clin Oncol
Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis
Int J Cancer
Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]
J Clin Oncol
Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target exploration consortium study B2225
J Clin Oncol
Denosumab for the treatment of giant cell tumor (GCT) of bone: final results from a proof-of-concept, phase II study
J Clin Oncol
Activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in alveolar soft part sarcoma
J Clin Oncol
Phase II study of sorafenib in patients with metastatic or recurrent sarcomas
J Clin Oncol
An open-label multicenter phase II study of bevacizumab for the treatment of angiosarcomas
J Clin Oncol
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