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

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For patients with bone sarcomas, chemotherapy has a proven role in the primary therapy of osteogenic sarcoma and Ewing sarcoma but no role for chondrosarcoma. Chemotherapy’s role is currently more limited for patients with soft-tissue sarcomas, as it is generally used to palliate metastatic disease in most subtypes of soft-tissue sarcoma and remains largely investigational in the treatment of operable disease. The chemotherapy regimens for musculoskeletal sarcomas often carry significant potential toxicities, so the efficacy of less intensive and less toxic regimens is a focus of ongoing research.



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 following3:

  • Azospermia (in 100% of patients who received a total ifosfamide dose > 75 g/m2)
  • 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

Patients with disease limited to the primary tumor and no more than one or two bone lesions fare best. The presence of multiple metastases is associated with the poorest prognosis, as few patients with this profile live past 2 years.10 In a review of 202 pediatric and adult patients with documented metastases at the time of osteosarcoma diagnosis, the presence of more than 5 metastatic lesions (which was reported in 91 patients) was associated with a 5-year overall survival rate of 19%.9

Chemotherapy for Ewing sarcoma

Perioperative chemotherapy in patients with localized Ewing sarcoma is believed to reduce the burden of micrometastasis that is thought to be present in most patients with early-stage disease. Five-year survival rates of 50% to 72% have been reported among patients with resectable Ewing sarcoma treated perioperatively with multiagent chemotherapy.11,12 Notably, randomized trials that studied intense multiagent chemotherapy regimens (consisting of doxorubicin, cyclophosphamide, vincristine, and dactinomycin alternating with etoposide and ifosfamide) reported the best outcomes despite significant but acceptable toxicity. In a large randomized trial involving 398 patients with resectable disease, a 5-year survival rate of 72% was achieved with the above regimen, compared with 61% in patients treated with a less intense regimen that did not contain ifosfamide and etoposide (p = .01).12

Compressing these standard regimens to an every-14-day instead of every-21-day schedule improved event-free survival at 3 years from 65% to 76% (p = .028) without any significant increase in toxicity in a randomized trial involving 568 patients.13 Data on overall survival from this trial are not yet published.

Metastatic disease. Metastatic Ewing sarcoma is found in 15% to 35% of patients with newly diagnosed disease and is treated with multiagent chemotherapy; resection of residual disease is considered in good responders.3 This approach produces objective responses to therapy, but long-term survival is rare.

Toxicity. Myelodysplastic syndrome and acute myeloid leukemia are the most dreaded long-term complications of intensive multiagent chemotherapy for Ewing sarcoma and develop in up to 8% of patients.14 Additionally, ifosfamide can lead to hematuria (~12% incidence), encephalopathy (mild somnolence and hallucinations to coma), chronic renal impairment (6% incidence), and hemorrhagic cystitis (though administration of mesna and generous intravenous hydration can minimize this latter complication).15 Recent efforts are therefore focused on testing less-intensive regimens in patients who have good prognostic features.

Chondrosarcoma: No role for chemotherapy

Chondrosarcoma, which represents approximately 20% of all bone sarcomas and has a peak incidence in older adults (ie, in the sixth decade of life), is insensitive to chemotherapy. Radiotherapy is also of limited value and is reserved for patients treated in the palliative setting.16 Definitive management of chondrosarcoma involves adequate surgical resection alone.

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