What is the treatment for Rhabdomyosarcoma (RMS)?

Rhabdomyosarcoma (RMS): Treatment Overview

Rhabdomyosarcoma treatment is guided by international clinical trial protocols (such as FaR-RMS) and requires multimodal therapy combining chemotherapy, surgery, and radiotherapy, with treatment intensity stratified by risk factors including stage, group, histology, and patient age. 1

Core Treatment Principles

Multimodal Therapy Framework

• All RMS patients require combination chemotherapy as the backbone of treatment, with dactinomycin FDA-approved at 15 mcg/kg intravenously once daily for 5 days every 3 to 9 weeks for up to 112 weeks as part of multi-agent regimens. 2
• Surgery plays a critical role in determining risk stratification and achieving local control, with complete resection including negative microscopic margins (Group I) significantly improving survival outcomes. 3, 4
• Radiotherapy is incorporated in approximately 62.5% of cases to achieve adequate local control, particularly when complete surgical resection is not feasible. 5

Risk Stratification Determines Treatment Intensity

• The hierarchy of prognostic factors includes T stage (most significant), M stage, clinical grouping, primary tumor site, patient age, and histologic subtype. 3
• High-risk RMS features include incompletely resected embryonal RMS at unfavorable sites, age ≥10 years, tumor size >5 cm, embryonal RMS with nodal involvement, and alveolar RMS with or without nodal involvement. 1
• Alveolar RMS (ARMS) with T2 tumors requires more aggressive staging evaluation including immunohistochemistry and cytogenetics, given 13% lung metastasis rate and 23% bone marrow involvement rate. 3

High-Dose Chemotherapy Considerations

Evidence Against HDT/ASCT in RMS

• There is no proven survival benefit of high-dose chemotherapy with autologous stem cell transplant (HDT/ASCT) in RMS for primary localized, metastatic, or relapsed disease. 1
• Multiple prospective non-randomized studies (MMT4-89 and MMT4-91) demonstrated that HDT/ASCT consolidation after complete remission did not significantly improve event-free survival or overall survival compared to conventional chemotherapy. 1
• One retrospective study showed patients receiving HDT/ASCT had lower overall survival compared to oral maintenance regimens (OS 0.27 vs 0.52, p = 0.03). 1

Clinical Implication

• Standard multiagent chemotherapy regimens remain the treatment of choice rather than dose-intensification strategies with HDT/ASCT. 1
• Prospective randomized trials are still required to definitively determine any potential utility of HDT/ASCT in RMS. 1

Treatment by Disease Status

Localized Disease (>80% 5-Year Survival)

• Contemporary multiagent systemic therapy combined with adequate local control (surgery and/or radiotherapy) achieves >80% survival in localized disease. 1
• Complete surgical resection with negative margins (Group I) provides the best outcomes and should be pursued when anatomically feasible without significant functional compromise. 3, 4
• Minimal staging evaluation can be tailored for embryonal RMS with T1 tumors, omitting bone marrow aspirate/biopsy and bone scan due to 0% rate of bone/bone marrow involvement. 3

Metastatic Disease (<30% 5-Year Survival)

• Outcomes in primary metastatic RMS remain poor with 5-year overall survival below 30% despite aggressive multimodal therapy. 1
• Standard multiagent chemotherapy protocols are used, but survival benefits from HDT/ASCT have not been confirmed. 1

Relapsed Disease

• Nearly one-third of patients with localized RMS and over two-thirds with metastatic RMS will experience disease recurrence, generally within three years. 6
• Patients with favorable relapse features (botryoid RMS or stage 1/group I embryonal RMS with no prior cyclophosphamide) have the highest chance of long-term cure with multiagent chemotherapy at relapse. 6
• The majority of relapsed patients have poor outcomes with standard regimens, and strong consideration should be given for clinical trial enrollment. 6
• For relapsed RMS, there is no proven survival benefit of HDT/ASCT. 1

Critical Management Caveats

Multidisciplinary Team Requirement

• RMS management requires specialized sarcoma multidisciplinary teams including radiologists, surgeons, medical and clinical oncologists, pathologists, and specialist nurses. 1
• Close collaboration between children's cancer MDTs and sarcoma MDTs is essential, particularly for adolescent and young adult patients. 1

Histologic Subtype Considerations

• Embryonal RMS (ERMS) and alveolar RMS (ARMS) typically occur in children and young adults, while pleomorphic subtype occurs in older adults. 1
• FOXO1-PAX3/7 gene fusion confers poorer prognosis, is found in 80-90% of ARMS, and distinguishes ARMS from ERMS. 1
• Receptor tyrosine kinase/RAS/PIK3CA pathway aberrations are found in 93% of RMS cases, suggesting critical roles in tumor development. 7

Long-Term Sequelae

• Survivors face therapy-related complications including bone growth abnormalities, endocrinopathies, and infertility. 8
• Current clinical trials are exploring lower doses of chemotherapy or radiotherapy to decrease side effects without compromising survival. 8

Age-Related Outcomes

• Adult RMS patients have significantly poorer outcomes compared to pediatric patients, largely due to lack of standardized treatment protocols and increased prevalence of advanced presentations. 8
• The pleomorphic variant, more common in adults, represents <1% of all solid tumor malignancies in adults but has worse prognosis. 8