A MORE INTENSIVE REGIMEN FAILED IN RHABDOMYOSARCOMA 

July 13, 2012 — For high-risk nonmetastatic rhabdomyosarcoma and other soft tissue sarcomas in children, an intensified 6-drug chemotherapy regimen does not increase survival or reduce the intensity of local therapy. In addition, it is much more toxic than the standard 3-drug regimen.

The negative long-term results from the International Society of Pediatric Oncology MMT95 study, by Odile Oberlin, MD, Institut Gustave-Roussy in Villejuif, France, and colleagues, were published in the July 10 issue of the Journal of Clinical Oncology.

The study was "well designed" and the results are "certainly not" what the study team had hoped for, writes William H. Meyer, from the University of Oklahoma Health Sciences Center in Oklahoma City, in anaccompanying editorial.

Reasonably Good Outcome

At least two thirds of children and adolescents with intermediate- and higher-risk nonmetastatic rhabdomyosarcoma can be cured with multidisciplinary therapy, Dr. Meyer explains. "Although a reasonably good outcome, it clearly is not good enough. The total burden of therapy is high, with substantial acute and chronic toxicity," he notes.

The best established therapy is a 3-drug combination of vincristine, dactinomycin, plus an alkylator (either cyclophosphamide or ifosfamide), and local control measures, he writes. However, the treatment causes "substantial morbidity, particularly in the youngest patients," and this therapeutic approach and "anticipated outcome have not substantially changed in the past 2 decades," Dr. Meyer notes.

This MMT95 study shows that a more intense chemotherapy regimen does not mean better results. The researchers enrolled 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma, undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except the paratesticular region, vagina, and uterus, or untreated patients with alveolar rhabdomyosarcoma.

Patients were randomly assigned to receive either a 3-drug combination (ifosfamide, vincristine, plus dactinomycin [IVA]) or a 6-drug combination (IVA plus carboplatin, epirubicin, and etoposide), both delivered over 27 weeks. Patients who responded poorly to 3 courses of the 3-drug regimen were switched to the 6-drug regimen. Decisions on radiotherapy were made on the basis of site and/or response to chemotherapy with or without surgery.

According to Dr. Oberlin and colleagues, at 3 years, the overall survival rate for all patients was 81% (95% confidence interval [CI], 77% to 84%). There was no significant difference in 3-year overall survival between the 3-drug regimen (82%; 95% CI, 76% to 86%) and the 6-drug regimen (80%; 95% CI, 74% to 85%). Event-free survival rates also did not differ between the 2 groups.

Moreover, toxicity was significantly greater with the 6-drug regimen. Anemia, leukopenia, neutropenia, thrombocytopenia, and stomatitis (P < .001 for all) were more common with the 6-drug regimen, as were infection and fever (P < .01 for both). In addition, the 6-drug regimen did not reduce the overall burden of local therapy.

Available Drugs Not Ideal

"Despite broadening chemotherapy exposure with a 6-drug combination, this study did not find a difference in outcome compared with patients treated with IVA alone, and there was a statistically significant increase in toxicity," Dr. Oberlin and colleagues report.

They explain that the choice of agents to supplement IVA was based on evidence of their effectiveness in patients with rhabdomyosarcoma.

Unfortunately, currently available agents for rhabdomyosarcoma are "not ideal," Dr. Meyer states in his editorial.

"We all hope," he writes, "that gene profiling will identify molecular targets in rhabdomyosarcoma that can be exploited by new pharmaceutical and/or biologic agents. The challenges in accomplishing this goal are manifold, but evaluation of new agents should clearly continue."

However, "with only approximately 350 new cases of rhabdomyosarcoma occurring each year in the United States, identification of a targeted therapeutic agent in this rare and heterogeneous childhood tumor will be daunting," Dr. Meyer acknowledges.

"Perhaps the agents now available to treat rhabdomyosarcoma, although not ideal, are not so bad, and we just need to learn better ways to play them," he concludes.

Dr. Oberlin's team adds that the MMT95 study confirms that IVA is the "backbone" of ongoing studies of rhabdomyosarcoma. Still, it remains to be seen whether adding any agents to standard front-line therapy (IVA or vincristine, dactinomycin, plus cyclophosphamide) can improve outcomes for patients with nonmetastatic disease, they say.

There is, however, "considerable evidence" for the potential efficacy of doxorubicin in rhabdomyosarcoma, they note. The European Pediatric Soft Tissue Sarcoma Group is now evaluating doxorubicin, given in a dose-intensive manner, combined with IVA in front-line therapy.

The study was supported by Association Enfants et Sante, Institut Gustave-Roussy, Societe Francaise de Lutte Contre les Cancers et les Leucemies de l'Enfant et de l'Adolescent, and Cancer Research UK. Dr. Oberlin and colleagues and Dr. Meyer have disclosed no relevant financial relationships.

J Clin Oncol. 2012;30: 2431-2433, 2457-2465. Editorial, Abstract