On the current management of osteosarcoma. A critical evaluation and a proposal for a modified treatment strategy.

The current management of osteosarcoma (OS) is critically reviewed and a modified treatment strategy is put forward for discussion. The overall treatment results in high-grade OS are less impressive than widely assumed. Whereas in 'classical OS' survival has indeed increased during the past decades from approximately 20% to at least 60%, in other subgroups, comprising more than 40% of the entire OS population, the prognosis has been only modestly improved. Today still more than half of an unselected OS population eventually succumbs to the disease despite the current multimodal primary treatments as well as second-line chemotherapy and surgical metastasectomy(ies). Analysis of the reported results indicates that a survival plateau of approximately 60% can be achieved by several different drug combinations. The inclusion of additional drugs and treatment with complex combinations to all patients has not yielded a convincing survival benefit. These expensive regimens overtreat a large number of patients, namely those who could have been cured by the previous less drastic regimens, and it increases the acute and delayed side-effect. Toxic deaths occur and life-threatening side-effects are not infrequent, necessitating interruption of the treatment or reduction in the dose intensity. A possible marginal early survival benefit may well be offset by late side-effects. For the above reasons, we propose an alternative, risk-adapted, treatment strategy, to retain the present results at a lower price in terms of acute toxicity and late morbidity. It is suggested that all patients with classical OS should be treated pre-operatively with optimal doses of only the two most active agents, methotrexate and doxorubicin. This presumably is sufficient in the majority of these patients. The most toxic treatment involving additional anticancer agents should be reserved for high-risk and relapsing patients, i.e. for situations where drastic measures are necessary and warranted. An important consideration is that relapsing patients are likely to benefit in particular from drugs to which they have not been previously exposed.