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Originally published as JCO Early Release 10.1200/JCO.2005.11.909 on February 22 2005 © 2005 American Society of Clinical Oncology.
Rhabdomyosarcoma: Many Similarities, a Few Philosophical Differences1 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA
2 Department of Preventive and Societal Medicine, University of Nebraska Medical School, Omaha, NE In this issue of the Journal of Clinical Oncology, Stevens et al1 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) IRS-IV2 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 44% local recurrence.4 Patients who relapse may require very aggressive chemotherapy programs with drugs known to carry serious toxicity when administered in high-doses and for long durations. Much of the toxicity from such combination chemotherapy is not yet recognized, and may not be expressed for decades. Patients who relapse may require very aggressive local therapy (surgery plus radiation), which all too often carries unacceptable morbidity. We do not know if modern radiotherapy techniques using 3-dimensional conformal radiotherapy and intensity-modulated radiation therapy for select patients will significantly reduce the recognized toxicity of previously used high-dose, large-field radiation. Preliminary studies suggest that intensity-modulated radiation therapy is effective and likely to reduce toxicity.6 It is clear, that while differences in treatment between the MMT and IRSG studies are largely ones of philosophy, both groups desire the highest cure rate and the best quality of life for their patients. Understanding the total burden of therapy requires years of follow-up, which cooperative groups are finding increasingly difficult to provide. Until we have this answer, we must accept that for some patients it seems that treatment success may be compromised by a treatment approach that is conservative with respect to local therapy. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Stevens MCG, Rey A, Bouvet N, et al: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: Third study of the International Society of Paediatric Oncology—SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23:2618-2628, 2005
2. Crist WM, Anderson JR, Meza JL, et al: Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J Clin Oncol 19:3091-3102, 2001 3. Benk V, Rodary C, Flamant F, et al: Parameningeal rhabdomyosarcoma: Results of an international workshop. Int J Radiat Oncol Biol Phys 36:533-540, 1996[CrossRef][Medline]
4. Oberlin O, Rey A, Anderson J, et al: Treatment of orbital rhabdomyosarcoma: Survival and late effects of treatment—Results of an international workshop. J Clin Oncol 19:197-204, 2001 5. Anderson J, Raney RB, Carli M, et al: International study of characteristics and outcome of patients with primary rhabdomyosarcoma of the bladder/prostate. Med Pediatr Oncol 37:181, 2001 6. Wolden SL, Wexler L, Kraus D, et al: Intensity modulated radiation therapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 60:S246-S247, 2004[CrossRef]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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