What is the standard treatment for rhabdomyosarcoma?

Treatment of Rhabdomyosarcoma

Standard treatment for rhabdomyosarcoma requires multimodal therapy consisting of multiagent chemotherapy (vincristine, dactinomycin, and cyclophosphamide or ifosfamide), surgical resection when feasible without major functional/cosmetic deficits, and radiotherapy based on surgical margins and clinical grouping. 1, 2, 3

Core Treatment Components

Chemotherapy Backbone

• All patients with rhabdomyosarcoma require systemic chemotherapy as the foundation of treatment, regardless of disease extent. 3, 4
• The standard regimen consists of vincristine and dactinomycin combined with either cyclophosphamide (VAC) or ifosfamide (IVA). 3, 5, 6
• Treatment is risk-adapted: patients with the most favorable disease characteristics may have the alkylating agent reduced or eliminated, while higher-risk patients receive intensified multiagent regimens. 3, 6

Surgical Management

• The surgical goal is complete excision with negative microscopic margins whenever possible without causing major functional or cosmetic deficits. 2, 3
• Wide excision is the preferred approach, though complete resection is often neither possible nor medically indicated due to the tumor's locally infiltrative growth pattern in certain anatomic sites. 3, 4
• Delayed primary resection after initial chemotherapy may increase the number of tumors that can be completely resected with acceptable morbidity in select primary sites. 6
• Re-operation is recommended following previous marginal or intralesional resection. 1

Radiotherapy Application

• Radiotherapy should be applied to the primary tumor site based on surgical margins and clinical grouping. 2, 3
• Incompletely resected tumors generally require radiotherapy for local control. 3, 4
• After wide excision of high-grade sarcomas, adjuvant radiation therapy is recommended. 1
• In radical surgery obtained by compartmental excision or amputation at large distance from the primary tumor, adjuvant radiation is not necessary. 1
• Newer delivery methods including intensity-modulated radiotherapy (IMRT), proton beam therapy, and brachytherapy may maintain efficacy while reducing long-term sequelae compared with conventional approaches. 1, 6

Treatment Sequencing

The standard sequence is neoadjuvant combination chemotherapy, followed by local treatment (surgery and/or radiotherapy), then postoperative adjuvant chemotherapy. 1, 3

• Neoadjuvant chemotherapy helps control the primary tumor and may facilitate subsequent surgical resection. 1, 3
• Some cooperative groups reduce radiation dose based on tumor response to chemotherapy and delayed primary resection, though this response-adjusted approach may reduce long-term effects but could increase recurrence risk. 3

Risk-Adapted Treatment Considerations

Localized Disease

• Contemporary trials report >80% survival in patients with localized disease using multimodal therapy. 1, 7
• Preoperative chemotherapy is not standard practice for operable patients but can be considered with radiotherapy in borderline resectable tumors. 1
• Adjuvant chemotherapy impact on overall survival remains debated, though it may improve distant and local control; it may be considered in younger patients with large, high-grade tumors. 1

High-Risk Features

• Adverse prognostic factors include: incompletely resected embryonal rhabdomyosarcoma at unfavorable sites, age ≥10 years, tumor size >5 cm, embryonal rhabdomyosarcoma with nodal involvement, and alveolar rhabdomyosarcoma with or without nodal involvement. 1, 7
• The FOXO1-PAX3/7 gene fusion confers poorer prognosis and is found in 80-90% of alveolar rhabdomyosarcoma. 1

Metastatic Disease

• Standard multiagent chemotherapy (typically doxorubicin-based regimens with or without ifosfamide) is the treatment of choice for metastatic disease. 1, 2
• Outcomes in primary metastatic rhabdomyosarcoma remain poor with 5-year overall survival below 30%. 1
• In completely resectable lung metastases, surgery should be considered. 1

Critical Treatment Pitfall to Avoid

High-dose chemotherapy with autologous stem cell transplant (HDT/ASCT) should NOT be used outside of clinical trials, as multiple prospective studies consistently demonstrate no survival benefit in primary localized, metastatic, or relapsed rhabdomyosarcoma despite theoretical rationale for dose intensification. 1, 7, 2

• This approach exposes patients to significantly higher toxicity and treatment-related mortality (0-4%) without improving outcomes. 1, 2
• The relative benefit of HDT/ASCT remains unproven and must be balanced against severe hematological and non-hematological toxicities. 1

Expected Toxicities

• Severe hematologic toxicities occur with standard chemotherapy, including 83% grade 3-4 neutropenia, 60% thrombocytopenia, and 45% anemia with intensive regimens. 2
• Acute toxicities include myelosuppression, febrile neutropenia, and hepatopathy. 3
• Long-term effects include infertility, second malignant neoplasms, bone growth arrest, muscle atrophy, bladder dysfunction, and radiation-induced malignancies. 3

Essential Management Framework

• All patients should be managed at specialized sarcoma reference centers with multidisciplinary teams including pathologists, radiologists, surgical oncologists, radiation oncologists, and medical oncologists. 2, 3
• Establishing correct pathologic diagnosis, histologic subtype, primary site, extent of disease (TNM stage), and extent of resection (clinical grouping) is essential before treatment planning. 8, 3, 6
• Specific types of small round cell tumors (extra-osseous Ewing's sarcoma, embryonal rhabdomyosarcoma) should be identified by immunohistochemistry and cytogenetics and treated accordingly. 1
• Enrollment in clinical trials is strongly recommended whenever possible, as rhabdomyosarcoma is relatively rare and requires highly specialized care with important management questions remaining. 1, 3