Playing Bad Cards Properly: Challenges to Improving Cure Rates in Rhabdomyosarcoma

“Success . . . comes not from having the right cards, but from playing bad ones properly.” —Joshua Dool. At least two thirds of children and adolescents with intermediateand higher-risk nonmetastatic rhabdomyosarcoma can be cured with multidisciplinary therapy. Although a reasonably good outcome, it clearly is not good enough. The total burden of therapy is high, with substantial acute and chronic toxicity. The best established therapy is a three-drug chemotherapy combination using vincristine, dactinomycin, and an alkylator (either cyclophosphamide or ifosfamide) and local control measures that cause substantial morbidity, particularly in our youngest patients. The therapy approach and anticipated outcome have not substantially changed in the last two decades. Oberlin et al report in Journal of Clinical Oncology the results of the MMT95 trial, a well-designed prospective, randomized study comparing intensified six-drug therapy versus standard three-drug chemotherapy in nonmetastatic rhabdomyosarcoma and other chemosensitive childhood soft tissue sarcomas. Intensification of chemotherapy provided no survival advantage, no reduction in the intensity of local therapy, and added toxicity—certainly not the answer for which these investigators had hoped. Why have we been unable to make any recent progress in treating rhabdomyosarcoma? Successful clinical trials must be well designed. Most advances in pediatric oncology have used prospective, randomized comparative study designs. However, good trial design certainly does not guarantee success. The two most recently completed intermediate-risk rhabdomyosarcoma studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group (IRS-IV comparing vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide; and vincristine, ifosfamide, and etoposide) and the Children’s Oncology Group (COG; D9803 comparing VAC v VAC plus topotecan and cyclophosphamide) were well designed and appropriately powered and evaluated agents with substantial clinical activity, yet they failed to show any improvement in the experimental arms. The MMT95 (Malignant Mesenchymal Tumor 1995) study prospectively randomly assigned patients to receive threeor six-drug therapy, with a switch to the six-drug combination in patients who had disease progression, less than 50% imaging response, or poor histologic response. This design decreased the number of patients who received either only threeor only six-drug therapy. In addition, a relatively high number of eligible patients were not randomly assigned (149 of 606; 25%). However, these flaws, while decreasing the statistical power of this study, are relatively minor and do not seem to have affected the final negative results. Selection of the right patient population is a key component of sound clinical trial design. The MMT95 study enrolled higher-risk patients with rhabdomyosarcoma with both embryonal and alveolar histologies. These two histologies are biologically distinct, yet all cooperative group trials in higher-risk rhabdomyosarcoma have included both histologies, with few data to suggest substantial differences in treatment response for the different histologic entities. In addition, the MMT95 study enrolled 72 patients with chemotherapy-sensitive nonrhabdomyosarcoma soft tissue sarcomas. Soft tissue primitive neuroectodermal tumors (27 patients enrolled onto MMT95) share morphologic, immunohistochemical, and genetic features with Ewing tumors arising in bone, are classified by WHO inclusively as Ewing sarcoma/primitive neuroectodermal tumor, and are currently treated in studies of the Ewing family of tumors. COG trials previously enrolled patients with undifferentiated sarcomas together with rhabdomyosarcomas, but these patients were recently treated on a study for other nonrhabdomyosarcoma soft tissue sarcomas (COG ARST0332: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas in patients under30yearsofage).Ratesofmetastasis inMMT95werehigher inthese patient subsets (P .03); the number of patients enrolled with these histologies was insufficient to provide insights into the impact of more intensive therapy. Cure rates have improved in some childhood cancers with the optimization of chemotherapy schedules and doses. Decades of empiric adjustments using a modest number of active chemotherapy