Surgical resection is the mainstay of treatment for musculoskeletal sarcomas, as detailed earlier in this supplement, but chemotherapy also has a proven role in the primary therapy of most bone sarcomas and a potential role for some patients with soft-tissue sarcomas. This article provides an overview of the roles of chemotherapy for patients with bone and soft-tissue sarcomas and addresses key considerations surrounding chemotherapy in the context of overall patient management.
Because most bone sarcomas occur in pediatric patients and young adults, studies of chemotherapy in this disease have often enrolled predominantly young subjects. As a result, very limited data are available in older adults. Single-institution experiences indicate that adults with bone sarcomas have inferior outcomes compared with their pediatric and adolescent counterparts, 1 but the literature on these tumors in adults is scant. Therefore, the following discussion on chemotherapy for bone sarcomas incorporates data from trials conducted predominantly in children and young adults (ie, generally younger than 30 years and with a very large majority younger than 20 years).
Chemotherapy for osteosarcoma
At present, neoadjuvant (preoperative) chemotherapy followed by definitive resection with subsequent adjuvant (postoperative) chemotherapy is the well-established approach to treatment of localized osteosarcomas. Chemotherapy can eradicate the micrometastatic disease that is believed to be present in the majority of patients with clinically resectable cancer. 2
Efficacy. Historically, prior to the institution of effective chemotherapy, metastatic disease developed in 80% to 90% of patients who underwent curative resection with or without radiation therapy, which resulted in a long-term survival rate of less than 20%. 3 In the 1980s, clinical trials that randomized patients with resectable osteosarcoma to surgery alone or to surgery plus chemotherapy found that the addition of perioperative chemotherapy led to significant improvements in recurrence rates and survival. 4,5 More recent randomized trials have shown that treatment of such patients with modern multiagent chemotherapy regimens results in a 5-year survival rate of approximately 70%. 6 Additionally, response to neoadjuvant (preoperative) treatment has become the most important predictor of outcome, as the median survival of osteosarcoma patients who have greater than 90% necrosis in the resected specimen following neoadjuvant chemotherapy is about 90% at 5 years. 7,8
Toxicity. Current chemotherapy regimens are based on high doses of methotrexate and leucovorin in combination with doxorubicin, ifosfamide, and platinum. Long-term effects of such regimens include the following 3:
- Azospermia (in 100% of patients who received a total ifosfamide dose > 75 g/m 2)
- Subclinical renal impairment (in 48% of patients treated with high doses of ifosfamide)
- Hearing impairment (in 40% of patients treated with cisplatin)
- Second malignancies (in 2.1%)
- Cardiomyopathy (in 1.7%). 3
In light of this, the development of equally effective but less intensive regimens for patients whose disease carries a better prognosis is highly desirable. Ongoing clinical trials are investigating this strategy.
Metastatic disease. Metastatic osteosarcoma is found in approximately 20% of patients at the time of diagnosis. Sarcoma mainly spreads hematogenously, and the lungs are the most common initial site of metastases, being affected in more than 60% of patients who develop metastatic disease. 9 Patients with metachronous lung lesions are initially considered for aggressive treatment with neoadjuvant chemotherapy and subsequent resection of clinically apparent disease, which results in event-free survival rates of 20% to 30%. 3