Rhabdomyosarcoma: Many Similarities, a Few Philosophical Differences

In this issue of theJournal of Clinical Oncology, Stevens et al 1 present the 5-year results of the International Society of Pediatric Oncology Malignant Mesenchymal Tumor study (MMT 89), an important and well-analyzed clinical trial. The discerning reader will immediately discover many similarities with, yet some philosophical differences from, the Children’s Oncology Group approach to this heterogeneous disease. The differences in the treatment approaches and outcome data between the MMT 89 study and the Intergroup Rhabdomyosarcoma Study Group (IRSG) IRSIV 2 identify important issues plaguing oncologists managing this complex malignant disease. Both the MMT 89 and IRS-IV studies utilized similar eligibility criteria, recommended common pretreatment staging examinations, and differentiated the alveolar subtype from the more common embryonal subtype. Both studies used the TNM staging system and reported results in patients with nonmetastatic disease. Both studies built on data from previously published group studies. Both groups value each other’s work and have collaborated effectively in workshops pooling data to better understand the unique problems arising in particularly difficult sites: parameningeal, 3 orbit, 4 and bladder/prostate. 5 Investigators from both groups recognize the importance of analysis of the total treatment administered, and of the early and late effects of the disease and its treatment. The differences between the MMT and IRSG studies are largely those of management and treatment philosophy. An MMT 89 study objective was to reduce use of local therapy, with initial front-line chemotherapy followed by alternate second-line chemotherapy in the event of a poor response to initial chemotherapy, before local therapy was administered. Surgical resection was the preferred local therapy, with radiation therapy only after incomplete surgical resection, documented nodal involvement, and poor clinical response to combination chemotherapy. The study was designed to avoid “radical” surgery and radiation. Overall survival was the primary end point, accepting the possibility of poorer event-free survival (EFS) and the necessity of salvage therapy for those who relapsed. The primary IRS-IV study objective was early local therapy after induction chemotherapy, using radiation therapy for those with nonresected disease, with a goal to preserve form and organ function. EFS was the valued end point, to avoid relapse and the requisite salvage therapy. Thus, the IRSG study used radiation for all patients with an incompletely resected tumor, and for all with the alveolar subtype. IRS-IV also used radiation as the preferred method of local therapy for all patients with parameningeal disease, not just those age 3 years or older. As IRS-IV 5-year data are now available for comparison with the MMT 89 data, we have summarized the characteristics, eligibility criteria, and outcome results in Tables 1 and 2. The IRS-IV histologic data are restricted to those with embryonal and alveolar histologic subtypes. The update reveals that IRS-IV therapy produced superior EFS and somewhat better overall survival than the MMT 89 therapy. In some subsets of patients defined by primary site, the survival differences are striking (limbs, nonparameningeal head and neck); in others, the results are largely similar (genitourinary). Nevertheless, the overall impression is that survival for most patient subsets seems better with the use of initial local therapy, including irradiation, a philosophy of the IRSG studies. Total burden of therapy is important to all investigators. In the MMT 89 study, less than half the patients were cured without significant local therapy. Salvage therapy often requires more toxic treatment than initial therapy, is accompanied by more morbidity, and is not always successful. The philosophical difference in the initial approach to therapy is particularly pronounced in the case of primary orbital tumors, in which chemotherapy alone resulted in