Metastatic Rhabdomyosarcoma: Still Room for Improvement
Authors: Leonard H. Wexler
Journal: Journal of Clinical Oncology (2015)

Of the approximately 400 children and adolescents diagnosed each year in the United States with rhabdomyosarcoma, between one in five and one in six will be considered high-risk patients by virtue of the presence of one or more sites of distant metastatic disease, most commonly involving lymph nodes, bones, bone marrow, and the lungs. These patients tend to be disproportionately older, of male sex, and have alveolar histology, and most present with bulky tumors (. 5 cm). Typically, though, even in patients with widespread disease, these bulky tumors respond promptly and dramatically to any number of chemotherapy regimens. It is not unusual for patients who present with extensive disease to achieve complete, or near-complete, radiographic responses within 3 to 6 months from the start of systemic therapy. Indeed, in the First Intergroup Rhabdomyosarcoma Study that opened in 1972, fully three quarters of patients with metastatic rhabdomyosarcoma achieved either a complete (50%) or partial (25%) response within 15 weeks of therapy that would, by modern standards, be considered mild. 1 The challenge for this population, generally, is not eradicating macroscopic disease visible at the time of diagnosis but, rather, preventing the recurrence of occult disease that is invariably still present at the completion of therapy. Curative front-line therapy is administered to no more than one third of newly diagnosed patients with high-risk rhabdomyosarcoma, with most patients experiencing relapses within 24 months of diagnosis, and with few patients surviving more than 3 years after experiencing relapse. Unfortunately, over the past four decades, intensification of therapy through five generations of United States-led cooperative group clinical trials under the auspices of the Intergroup Rhabdomyosarcoma Study Group and its successor, the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG), has produced no meaningful improvement in outcome for the vast majority of patients with metastatic rhabdomyosarcoma. 2-6 In the article accompanying this editorial, Weigel et al 7 report the final results of the most recently completed COG clinical trial, ARST-0431, for patients with high-risk rhabdomyosarcoma. This 54-week treatment regimen builds on the striking activity and relatively favorable toxicity profile of the combination of vincristine and irinotecan in preclinical 8 and phase IIwindow testing 6 in newly diagnosed patients with metastatic rhabdomyosarcoma. In addition, the regimen uses filgrastim in an attempt to maximize alkylator dose intensity by administering standard doses of the other agents at reduced intervals of 2 weeks. ARST-0431 enrolled 109 patients with stage IV (metastatic) rhabdomyosarcoma during a 23-month period. Of those patients enrolled, 80% received irinotecan once per day for 5 days. Radiation of the primary site was generally delayed until after approximately 6 months of treatment, and selective irradiation of sites of metastatic disease was encouraged. Surgical resection of the primary site was generally not recommended unless it would significantly reduce the radiation field (or for palliation). The primary objective was to improve 3-year event-free survival (EFS) to 55%, representing a 60% reduction in the risk of treatment failure compared with standard multiagenttherapy. As expected, more than halfofpatients were older than 10 years and had large, predominantly alveolar tumors, and more than half also had regional nodal involvement in addition to distant metastatic disease. Fewer than 20% of patients were younger than 10 years with embryonal rhabdomyosarcoma. Furthermore, it was determined, using a prognostic risk-classification schema developed from a pooled international analysis of patient outcomes for metastatic rhabdomyosarcoma, 9 that approximately 60% of patients had two or more risk factors— ag roup for whom long-term outcome has been particularly grim. Unfortunately, the results of this trial proved to be as disappointing as previous results. With a median follow-up time ofmorethan3.5yearsforsurviving patients (minimum, 7.7 months), patients experienced a 3-year EFS of 38% and an overall survival of 56%. For patients with alveolar rhabdomyosarcoma (the majority of the patients enrolled onto the study), 5-year EFS was 16% (range, 8% to 28%), and 5-year EFS was essentially identical, at 19%, for patients with an Oberlin risk score of $ 2. The best outcome was seen in the relatively small proportion of children younger than 10 with embryonal rhabdomyosarcoma (, 20% of the total patient population) whose 3-year EFS of 60% is comparable to the outcome of patients with nonmetastatic, intermediate-risk rhabdomyosarcoma. 10 Thoughnot unanticipated, toxicity was substantial: with the exception of the first 6 weeks of vincristine and irinotecan window therapy, febrile neutropenia, with or without documented infection, occurred in well over half of patients; treatment delays, rare in the beginning weeks of therapy, became common during the middle portion of therapy concurrent with the administration of radiation therapy. What, then, can we learn from this study? The good news, though limited, is that outcome for the relatively small number of younger children with embryonal rhabdomyosarcoma and limited metastatic