Maintenance Chemo Fails to Improve Localized Osteosarcoma Outcomes

The use of a metronomic chemotherapy approach did not improve over standard chemotherapy in patients with high-grade, non-metastatic, operable osteosarcoma of the extremities, according to a new randomized study.

“Long-term survival for patients with localized osteosarcomas of the extremities has improved to approximately 70% because of the introduction of multiagent neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy,” wrote study authors led by Andreza A. Senerchia, MD, of Federal University of Sao Paulo in Brazil. High-dose methotrexate, doxorubicin (Adriamycin), and cisplatin (Platinol; MAP) is the standard regimen, but efforts to further improve chemotherapy have failed in recent decades.

Metronomic chemotherapy involves administration of lower doses on a daily or weekly basis without long breaks, in order to achieve antitumoral effects through anti-angiogenesis or through immune stimulation. In the new study, 296 patients with non-metastatic osteosarcomas were randomized to MAP alone for 31 weeks (157 patients) or to MAP followed by 73 weeks of metronomic chemotherapy (MC) with oral cyclophosphamide and methotrexate. All patients began with 10 weeks of MAP therapy followed by surgery. The results were published online ahead of print in Cancer.

Of the 139 patients in the MC group, 35% did not start MC due to osteosarcoma progression, toxicity, death, or several other reasons.

The mean event-free survival time was 51.58 months for the MC group, and 58.81 months for the MAP-alone group. The use of MC was not significantly prognostic for event-free survival, with a hazard ratio (HR) of 1.211 (P = .406). Surgery type, necrosis grade, and tumor size were all significant predictors of event-free survival. At 5 years 61% of MC patients and 64% of MAP-alone patients were event free (P = .395).

The same was true of overall survival. The mean overall survival was 65.82 months with MC, and 66.16 months without it, and the HR for overall survival was 0.985 (P = .957). At 5 years, 76% of MC patients and 73% of MAP-alone patients remained alive (P = .539).

“This result must be considered cautiously because 35% of the patients randomized to maintenance therapy did not start it, and another 10% stopped the treatment for reasons other than tumor progression, toxicity, or death,” the authors wrote. However, an analysis to take non-compliance into account did not change the results.

They also noted that though these results do not support the use of metronomic approaches to maintenance therapy in osteosarcoma patients, maintenance therapy in general still deserves further attention based on other research, in particular some preclinical work suggesting the approach may be more effective in metastatic disease.