Toward a reduction in the burden of therapy in patients with rhabdomyosarcoma: How much is enough?

We read with interest the recent article by Mandeville et al. They evaluated a reduced-dose ifosfamide (IFO) combined with radiotherapy (RT) for standard-risk (SR), subgroup C nonalveolar rhabdomyosarcoma in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) rhabdomyosarcoma 2005 (RMS 2005) study (EudraCT no. 2005-000217-53) and reported that RT allows for a reduction of the cumulative dose of IFO from 54 to 30 g/m². This is a very important message because one of the most pertinent goals in the evolution of therapy concepts for children with malignancies is the precise risk-adaptation of known effective therapy modalities with the goal of achieving the best possible outcome with the least amount of therapy.

Similar results were achieved in the tze study conducted by the European Cooperative Soft Tissue Sarcoma (CWS)-2002P study.² The risk-stratification systems of the CWS-2002P and RMS 2005 studies were identical because they were based on joint analyses and agreements between the CWS, the Italian Pediatric Hematology and Oncology Association Soft Tissue Sarcoma Committee, and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor Group; therefore, the results are easily comparable. Forty-one percent of patients in the SR group in CWS-2002P received a reduced dose of IFO (24 g/m² instead of 54 g/m²; a cyclophosphamide-equivalent dose of approximately 6 g/m² instead of 13.5 g/m²) compared with 34% of patients in the current study, with almost identical results (CWS-2002P vs. RMS 2005: event-free survival [EFS], 79% vs. 77%; overall survival [OS], 88% vs. 93%), although only 46% of patients were irradiated compared with 65% in this article.

The question of how much alkylators contribute to local control and can replace or be replaced by RT was also the focus of the Children's Oncology Group (COG) studies.

Some patients treated in the SR arm, as defined by the CWS and EpSSG, are considered low-risk according to the COG stratification and were treated with a very low cumulative dose of cyclophosphamide according to COG protocol ARST0331 (4.8 g/m²; an IFO-equivalent dose of approximately 19.2g/m²) with results that were similar to those in the EpSSG and CWS studies (3-year EFS rate, 70%–89%; OS rate, 92%–98%, but local control in a subset was inferior to the previous Intergroup Rhabdomyosarcoma Study Group D9602 study (ClinicalTrials.gov identifier NCT00002995), which was attributed to the reduced cyclophosphamide dose.^{3, 4} Although the conclusion of Mandeville et al. regarding low-dose IFOS (LDI) is very important, some additional questions arise. The stratification of therapy after the three cycles of IFO, vincristine, and actinomycin D (IVA) allowed those patients with favorable age (younger than 10 years) and tumor size (<5 cm) who achieved complete remission and did not undergo delayed primary tumor excision (DPE) to receive either nine cycles of IVA (cumulative IFO dose, 54 g/m²) and no RT or five cycles of IVA (IFO dose, 30 g/m²) and four cycles of vincristine and actinomycin D plus RT. A similar reduced IFO dose was recommended for patients who had complete remission but unfavorable tumor size and age or patients who had partial remission and/or residual tumor mass after DPE. It would be interesting to see what the EFS and OS were in the strata defined by protocol (see Appendix S2 in Mandeville et al.). However, Mandeville and colleagues presented the results according to the therapy actually received: high-dose IFO (HDI) without RT, HDI with RT, low-dose IFO (LDI) without RT, and LDI agents with RT. In addition, it is difficult to assess the appropriateness of the therapy stratification when the results are presented only by the therapy received. Another point is that LDI with RT and HDI with RT produced similar EFS and OS rates, which the authors interpreted as RT allowing for LDI. What about the HDI with RT group? Do the authors have any evidence that this subgroup would not have the same outcome with those who receive a reduced dose of IFO?

Alkylating agents are associated with serious late effects, such as infertility in both sexes, secondary malignancies, and impaired renal and cardiac function. Many patients with rhabdomyosarcoma and low-risk features can be cured without alkylators, but further studies evaluating the optimal dose of alkylators in standard-risk and high-risk patients are warranted. Whether RT should be considered as a substitute for a higher alkylator dose is a matter of debate because the late effects of RT are no less detrimental to the chance of long-term survival and quality of life.

In this context, we found the finding by Mandeville et al. very important indicating that RT does not improve outcomes in patients who have resection with tumor free margins after DPE and can be omitted. We found similar results in our analysis of the latest CWS studies.⁵ Therefore, there is still a long way to go to achieve the optimal reduction of therapies associated with severe acute and late effects.

The authors disclosed no conflicts of interest.