Rhabdomyosarcoma (RMS) affects ∼350 children per year in North America and represents 8% of all pediatric solid tumors. Of these, 15%–20% occur in genitourinary organs.¹ Through cooperative clinical trials and improved multimodal management, survival for genitourinary RMS has improved to over 80%.¹ This improvement in survival has led to an increased focus on reducing treatment morbidity. Here, we will discuss findings from multicenter clinical trials on risk stratification, local control and chemotherapy for genitourinary RMS.

The Children’s Oncology Group (COG) has traditionally taken both presurgical TNM staging and postsurgical clinical grouping into account when risk-stratifying patients into low, intermediate or high-risk groups (see table). This COG-modified TNM staging is based on tumor location and size, nodal involvement and presence of metastatic disease.¹ Clinical grouping is based on the presence and extent of residual (postoperative) tumor, nodal involvement and distant spread.¹ The European pediatric Soft Tissue Sarcoma Study Group (EpSSG) utilizes a similar system with the major difference being that any lymph node positivity is considered high risk by EpSSG.¹ A recent multivariate analysis of 9 studies identified 4 prognostic factors that have been incorporated in COG and EpSSG risk stratification: age <1 year or >10 years, unfavorable tumor location (including bladder and prostate), ≥3 metastatic sites, and bone marrow involvement.¹ Molecular markers, such as PAX3/7-FOXO1 translocations and mutations in MYOD1 and TP53, have also been identified as important adverse prognostic indicators and are now being incorporated into COG risk stratification.² Work on other similar biological prognostic indicators is an active field of inquiry.

Local control strategies have also shifted within the last few decades. Previously, local control for genitourinary RMS consisted of pelvic exenteration with adjuvant chemotherapy and radiation. Such aggressive initial treatment is no longer recommended as subsequent trials demonstrated that neoadjuvant chemotherapy and radiation result in similar survival rates with higher rates of bladder preservation.¹ Because complete excision is rarely feasible without removing multiple pelvic organs, the current preferred strategy for most pelvic/bladder/prostate RMS is biopsy, chemotherapy and radiation. Delayed primary excision (DPE), defined as surgery undertaken after initiation of chemotherapy, is only indicated if a complete (R0) excision is clearly achievable. DPE has not been shown to improve survival in genitourinary RMS. By contrast, Pretreatment ReExcision (PRE)–defined as wide local excision of RMS prior to initiation of chemotherapy–has been shown to improve survival and should be undertaken if feasible (for example, excision of RMS at the bladder dome).³ Importantly, paratesticular RMS in patients >10 years of age or with nodal involvement on preoperative imaging (N1) require an up-front ipsilateral retroperitoneal lymph node evaluation as their risk of relapse is greater.¹ The current challenge is identifying exactly which patients would benefit from less aggressive local control in order to balance the burden of both disease and treatment.

Recent trials reflect the difficulty of balancing long-term control and survival with the risks of long-term toxicity. The COG low-risk trial ARST0331 demonstrated higher-than-expected local failure rates in incompletely resected vaginal RMS after the elimination of radiotherapy. Of note, ARST0331 had lower alkylator dosing compared to prior studies, which may have contributed to the increased local recurrence rate.⁴ Another recent analysis of vaginal and uterine RMS found that while elimination of radiotherapy did not impact overall survival (89%), the event-free survival was diminished compared to those receiving radiotherapy (71% vs 81%).⁵ A recent intermediate-risk study, ARST0531, introduced early radiation with irinotecan but ultimately demonstrated inferior local control compared to the preceding COG intermediate-risk study, D9803. Although the exact cause is unclear, many suspect it may be due to suboptimal cyclophosphamide doses in ARST0531.⁶ A comparison of the specific effect of DPE on local control and survival between D9803 and ARST0531 found that DPE decreased the radiation dose in 81% of patients with equivalent outcomes compared to no DPE.⁷ The ongoing intermediate-risk ARST1431 (clinical trial NCT02567435) study is examining higher doses of radiation for bulkier (>5 cm) tumors and encouraging DPE (when R0 resection is feasible) as a local control option.

The standard of care for all RMS risk groups includes adjuvant chemotherapy as RMS cells are known to be present in blood or bone marrow in the majority of grossly localized RMS cases.¹ The standard treatment regimen consists of an alkylator with vincristine and actinomycin D. Cyclophosphamide (combination VAC) is used in North America and ifosfamide (combination IVA) is used in Europe with proven equivalency between the 2 regimens.¹ For intermediate-risk RMS, alternating VAC with vincristine and irinotecan has been shown to have comparable event-free survival with less risk of hematologic toxicity, hemorrhagic cystitis, infertility and secondary malignancy. ARST0331 (low-risk study) evaluated cyclophosphamide dose reduction and found excellent 3-year overall survival rates. However, for the subset of patients with stage 1 group III nonorbital or stage 3 group I/II tumors, the 3-year failure-free survival was only 70% overall and 57% for genitourinary tumors, which was significantly lower than anticipated.⁸ Similarly, ARST0531 (intermediate-risk study) reduced cyclophosphamide dosing was associated with inferior outcomes.⁶ Of note, ARST0531 was compared to D9803, which favored primary resection, although this difference was accounted for in the regression models.

Unfortunately, high-risk genitourinary RMS has not seen the same improvements as low and intermediate-risk RMS. The COG study ARST0431 examined an alternating schedule of vincristine, doxorubicin, and cyclophosphamide with ifosfamide and etoposide in high-risk RMS and found outcomes improved only in a tiny subset of all patients studied.⁹ Similarly, recurrent RMS has a very poor prognosis (5-year overall survival 17%) with few clinical trials to guide management.¹ Currently, a combination of cyclophosphamide, vinorelbine, and temsirolimus and/or an irinotecan-based therapy is recommended.¹ In part motivated by the dismal prognosis of high-risk and recurrent RMS, COG recently convened an interdisciplinary task force to prioritize classes of pharmacological agents for new clinical trials.¹⁰

While insights from clinical trials have resulted in much improved cure rates for genitourinary RMS, many challenges remain. Continued trials are needed to optimize multimodal treatment for low and intermediate-risk RMS, while there is a significant need for research into new approaches to improve outcomes in high-risk and recurrent RMS.