Use of chemotherapy for patients with bone and soft-tissue sarcomas

SOFT-TISSUE SARCOMAS

Aside from recent advances in the treatment of gastrointestinal stromal tumors with the small-molecule tyrosine kinase inhibitors imatinib and sunitinib (which are beyond the scope of this article), an overall survival advantage with chemotherapy has not been demonstrated in adults with soft-tissue sarcoma.¹⁷

Resectable disease

The decision to use chemotherapy needs to be weighed against the magnitude of potential clinical benefit and the acute and chronic toxicities that can develop.

Toxicity. Chemotherapy regimens with activity against soft-tissue sarcomas often contain anthracyclines, alkylating agents, and taxanes. These agents can produce serious long-term toxicities, which is especially important in patients treated with curative intent. Doxorubicin and other anthracyclines, for example, may result in cardiomyopathy, the risk of which rises with increasing cumulative dose.¹⁸ In addition, acute myeloid leukemia may develop in 2% to 12% of patients treated with anthracyclines or alkylating agents such as ifosfamide and dacarbazine.^3,19 Renal failure and an elevated risk of bladder carcinoma are uncommonly reported in patients with a history of ifosfamide treatment.¹⁵ Sensory neuropathy associated with the use of taxanes (eg, paclitaxel and docetaxel) is dose dependent and reversible in more than half of patients. However, some patients treated with high doses of these agents can have persistent symptoms of paresthesias, burning, and decreased reflexes, which can be debilitating.²⁰

Efficacy of adjuvant chemotherapy. Because chemotherapy puts patients at risk of such serious chronic toxicities, its use can be justified only if it results in significant benefit, such as prolongation of survival. A 1997 meta-analysis of 14 clinical trials evaluating adjuvant chemotherapy in patients with resectable soft-tissue sarcomas found chemotherapy to have an absolute benefit of 10% in recurrence-free survival at 10 years (ie, from 45% survival to 55% survival), with a hazard ratio of 0.75 (95% confidence interval [CI], 0.64–0.87; p = .0001) for recurrence or death.²¹ However, when the analysis was limited to overall survival at 10 years, the survival difference between patients who received adjuvant chemotherapy and those who did not (54% vs 50%, respectively) was not statistically significant (hazard ratio = 0.89; 95% CI, 0.76–1.03, p = .12).²¹

The concept of adjuvant therapy has been revisited since the antisarcoma activity of ifosfamide was established. A large European trial randomized 351 patients with resected soft-tissue sarcoma either to placebo or to doxorubicin and ifosfamide given every 21 days.²² The preliminary results, reported in abstract form at the 2007 annual meeting of the American Society of Clinical Oncology, showed a higher 5-year survival rate in the placebo arm (69%) compared with the chemotherapy arm (64%).²² This and other trials using ifosfamide in various drug combinations showed no difference in survival, suggesting that adjuvant chemotherapy should not be considered to be standard practice outside of a clinical trial.

Efficacy of neoadjuvant chemotherapy. Neoadjuvant chemotherapy also has been studied in patients with soft-tissue sarcomas. A retrospective analysis found that the greatest benefit is derived in patients with primary tumors larger than 10 cm, in whom neoadjuvant chemotherapy increased 3-year disease-specific survival from 62% to 83%.²³ However, differing results came from a prospective multicenter trial that randomized patients with large primary and recurrent tumors to either surgery alone or surgery preceded by three cycles of neoadjuvant doxorubicin and ifosfamide (all patients could also receive adjuvant radiation therapy, depending on grade and adequacy of resection).²⁴ The trial suffered from slow accrual, and only 150 patients were enrolled. At 5 years, survival was similar between the groups with and without neoadjuvant chemotherapy.²⁴ Therefore, neoadjuvant chemotherapy is not yet recommended pending results of larger randomized trials.

No clear role for recurrent disease. Local recurrence of the primary tumor after resection occurs in 10% to 50% of cases of soft-tissue sarcoma, with the specific rate depending on the primary tumor location. The highest incidence of recurrence is found in patients with retroperitoneal and head and neck sarcoma (40% and 50%, respectively), mainly because of the difficulty of obtaining clear margins. Chemotherapy has not been well studied in this setting and is of uncertain value.³

Metastatic disease

Metastatic soft-tissue sarcomas may respond to chemotherapy, but there is a lack of evidence that chemotherapy improves overall survival. Pulmonary lesions are the most common site of distant recurrence, and resection of such metastases is sometimes undertaken in well-selected patients. However, there is no level 1 evidence supporting chemotherapy in this clinical setting despite its common preoperative use. There is a paucity of randomized phase 3 trials that compare established palliative chemotherapy regimens to best supportive care. It is believed that some groups of patients do benefit, however, including those who are young and have good performance status, low tumor grade, absence of liver metastasis or pulmonary metastasis only, and a long interval between treatment of the primary tumor and development of metastatic disease.³ Some histologies, such as uterine leiomyosarcomas and facial/scalp angiosarcomas, respond better to chemotherapy.¹⁷

Drugs found to have activity against metastatic sarcoma include doxorubicin, ifosfamide, platinum agents, gemcitabine, taxanes, and dacarbazine. Used either alone or in combinations, these drugs produce responses (ie, shrink metastatic tumors) in about 13% to 33% of patients.³ Use of chemotherapy is frequently curtailed by the acute toxicity of these agents, which includes pancytopenia, transfusion requirements, febrile neutropenia, nausea, alopecia, and significant fatigue, as well as renal failure with ifosfamide or cisplatin and peripheral neuropathy with platinum agents or taxanes. Appropriate patient selection for chemo­therapy and exclusion of those who should be managed solely with best supportive care is an important challenge that oncologists often face when managing patients with metastatic soft-tissue sarcoma.

Future directions

Trabectedin (ET-743) is a novel compound with promising activity against soft-tissue sarcomas that acts by inhibiting cell-cycle transition from the G₂ to M stages. The drug covalently binds to the minor grove of the DNA molecule, changing its three-dimensional structure and impairing transcription and possibly DNA repair.²⁵ Phase 2 studies showed durable responses to trabectedin in 3% to 8% of heavily pretreated patients^26–28 and in 17% of treatment-naïve patients with advanced soft-tissue sarcomas.²⁵ Time to progression of up to 20 months has been reported in patients who respond or develop stable disease.³

Toxic effects of trabec­tedin include myelosuppression, fever, edema, arthralgias, hepatotoxicity, and (rarely) rhabdomyolysis. To date, these toxicities have been self-limiting. Larger clinical trials and longer follow-up is needed to assess whether this agent has any significant long-term toxicities.

Trabectedin has already been approved in Europe for treatment of chemotherapy-refractory soft-tissue sarcoma when given as a 24-hour infusion every 21 days.

More broadly, an active effort is under way to better understand the molecular derangements in a variety of soft-tissue sarcoma subtypes. The hope is that this understanding will lead to improved therapies that target aberrant proliferation, angiogenesis, and other biologic processes that drive the growth and metastasis of soft-tissue and bone sarcomas.