The treatment of bone sarcomas in adults is guided as much by experience as it is by medical evidence, say sarcoma experts who should know.
“[L]arge prospective clinical trials in adults with bone sarcomas are lacking. Although translation of findings in pediatric studies to adults is possible, it is not clear if findings from pediatric studies truly apply to adults,” Dr. Michael J. Wagner and his colleagues from the University of Texas MD Anderson Cancer Center in Houston said.
In a review article in the Journal of Oncology Practice, the investigators outline how they have melded lessons learned from pediatric clinical trials with clinical experience treating adults with bone sarcomas.
Although the peak incidence of osteosarcoma occurs in adolescents and young adults, some studies of various chemotherapy regimens have included middle-aged adults and even some patients in their 90s, although many have excluded patients older than 30, the authors noted.
In adults, and in children and adolescents and young adults, chemotherapy and definitive surgical resection are the mainstays of treatment, with the exception of osteosarcomas of the jaw, which are generally treated with resection alone. For the past three decades, adults with high-grade osteosarcomas have been treated with chemotherapy containing doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide.
“However, important differences to consider in the treatment of older patients include, but are not limited to, the increased incidence of histologic variants of osteosarcoma (including secondary osteosarcomas) and medical comorbidities that may limit tolerance of older adults to dose-intense chemotherapy,” wrote Dr. Wagner and his colleagues (J Oncol Pract. 2016 Mar. doi: 10.1200/JOP.2015.009944).
High-grade localized osteosarcoma is treated with neoadjuvant chemotherapy, followed by limb-sparing surgery and adjuvant chemotherapy.
A poor response to neoadjuvant chemotherapy, defined as tumor necrosis of less than 90% at resection, is a marker for poor prognosis.
The authors previously reported that for patients with a poor response following a regimen of doxorubicin intravenous infusion at 90 mg/m2 over 96 hours plus cisplatin infused intra-arterially at 120-160 mg/m2 over 2 to 24 hours, the addition of high-dose methotrexate and ifosfamide resulted in significant improvement in continuous relapse-free survival.
At MD Anderson, adults with osteosarcoma receive preoperative chemotherapy with doxorubicin and cisplatin for three to four cycles and then undergo surgical resection. Those who have a good response go on to receive adjuvant chemotherapy with doxorubicin 75 mg/m2 and ifosfamide 10g/m2 for four cycles. Patients who have a poor response to neoadjuvant chemotherapy receive alternating courses of ifosfamide 14 g/m2, high-dose methotrexate 10 to 12 g/m2, and doxorubicin 75 mg/m2 and ifosfamide 10 g/m2 for up to 12 cycles or until intolerable adverse events.
Patients with metastatic relapsed/refractory osteosarcoma have 5-year overall survival rates ranging from 15% to 20%, the authors noted, adding that chemotherapy has “limited efficacy” in this setting.
Targeted agents, including the tyrosine kinase inhibitor sorafenib (Nexavar) and the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) have been evaluated in phase II trials.
Evidence from clinical trials of chemotherapy regimens in Ewing sarcoma show that patients 18 and older tend to have less favorable outcomes than younger patients when treated with dose-dense regimens, the authors noted.
Their practice is to treat adults with Ewing sarcoma with upfront vincristine 2 mg on day 1, doxorubicin 75 to 90 mg/m2 in a continuous 72-hour infusion, and ifosfamide 2.5 g/m2 given over 3 hours daily for four doses, followed by surgery, and adjuvant chemotherapy with an ifosfamide-based regimen.
Giant cell tumors of bone
These rare osteolytic tumors are treated with surgery as the primary therapy if they are resectable. Patients with metastases (which paradoxically, are usually histologically benign) as well as those who have tumors in areas where surgery may cause unacceptable morbidities may be treated with serial embolization, denosumab (Xgeva), interferon, or pegylated interferon.
The so-called “conventional” sub-type of chondrosarcomas are not generally responsive to cytotoxic chemotherapy and best managed with surgery alone, the authors say. However, patients with mesenchymal chondrosarcoma are treated similarly to patients with Ewing sarcoma, and those with the dedifferentiated subtype are treated with an osteosarcoma regimens.
The authors noted that point mutations in IDH1 and IDH2 have recently been discovered in chondrosarcomas, making them potential targets for an experimental IDH-1 inhibitor.
Dr. Wagner and coauthor Dr. J. Andrew Livingston reported no relevant disclosures. Coauthors Dr. Shreyaskumar R. Patel and Dr. Robert S. Benjamin reported consulting, advisory roles, research funding, or ownership interests in various pharmaceutical companies.