Osteosarcoma: The Same Old Drugs or More?
Authors: Stefan S. Bielack, Neyssa Marina, Stefano Ferrari, Lee J. Helman, Sigbjørn Smeland, Jeremy S. Whelan, Gregory H. Reaman
Journal: Journal of Clinical Oncology (2008)

Evaluation of treatment strategies in osteosarcoma has historically been a controversial subject.In the early 1980s, many outstanding investigators argued both for and against the utility of adjuvant chemotherapy. 1-4This issue was eventually settled when prospective randomized trials demonstrated superior outcome for patients receiving adjuvant treatment.We are now faced with a similar controversy regarding the role of an adjunct to conventional chemotherapy.Meyers et al 5 and the Children's Oncology Group are to be congratulated on the largest ever completed randomized trial in osteosarcoma.After more than 20 years of stagnation with conventional chemotherapy, their report seems to suggest that liposomal muramyl tripeptide ethanolamine (MTP), an immune modulator, improves the overall survival for patients with this disease.In this trial, INT0133, 662 young patients with localized, resectable osteosarcoma were randomly assigned to high-dose methotrexate, cisplatin, and doxorubicin plus ifosfamide in a 2 ϫ 2 factorial design which also included a randomized evaluation of MTP. 5,6 Several osteosarcoma groups have obtained their best results using ifosfamide-containing regimens. 7In the schedule used by the authors, however, the addition of ifosfamide neither enhanced eventfree survival (EFS) nor overall survival. 5,6Before abandoning ifosfamide from osteosarcoma chemotherapy, however, it should be noted that cisplatin was omitted from preoperative chemotherapy in the ifosfamide-containing arm of INT0133, so that evaluation of the role of ifosfamide was hampered due to the lack of clarity as to its contribution as a substitute or adjunct.As for MTP, the first analysis reported by the authors concluded that there was a significant interaction with ifosfamide, and no significant impact on EFS. 6 In the current analysis, however, the authors report a trend for better EFS (P ϭ.08) and improved overall survival (P ϭ.03) for the MTP arm.The previously observed interaction was no longer apparent. 5Does this mean that MTP, provided it becomes commercially available, should now be considered an integral part of systemic first-line therapy for osteosarcoma?Must it be considered standard-of-care as an adjunct to any conventional chemotherapy for localized osteosarcoma?Like all other clinicians dedicated to the care of bone tumor patients, we would welcome additional effective agents as weapons in our armamentarium, but we believe that some words of caution are appropriate before universally adopting MTP as standard-of-care.First, even in rare diseases such as osteosarcoma, decisions with such wide-ranging implications should never be based on a single trial.Second, it is not evident that MTP improves EFS in osteosarcoma.INT0133 leaves ample room for discussion and speculation about the reasons behind any observed survival differences.Taking a closer look at the life-tables in the article, for instance, one cannot fail to observe that, despite the lack of a statistically proven interaction, the EFS for the three-drug arm was absolutely identical regardless of whether MTP was added or not.Such an observation argues against any substantial efficacy of MTP, at least in this combination.Furthermore, EFS and overall survival are extremely closely linked in osteosarcoma. 7The reasons why this should not be the case when MTP is used as part of treatment are obscure.The authors try to convince us that the differences in postrecurrence treatment were in no way responsible.Their claim, however, that there is no suggestion that the use of chemotherapy at the time of recurrence has an impact on subsequent survival is not substantiated by all of the references they use to support it-quite to the contrary: the use of chemotherapy in recurrent osteosarcoma correlates with prolonged survival in unresectable disease 8,9 and has been found to correlate with improved EFS in resectable recurrences in the largest reported series. 9 What happens after recurrence that would make prior treatment with MTP seem advantageous?Might different rates of surgical remissions or different approaches to second-line chemotherapy have influenced the results, rather than MTP? Could other factors have been responsible?Is MTP only beneficial when given in conjunction with ifosfamide?Is it or the combination truly efficacious in prolonging survival without any difference in intervening recurrences?In summary, the updated results of INT0133 strongly suggest that MTP is an agent that warrants additional investigation given the substantial uncertainties that remain regarding its true role in the treatment of osteosarcoma.The data reported here mandate a randomized comparative evaluation to substantiate its utility.Undoubtedly, confirmatory trials would be required before the agent can be considered for routine use.