What is the management of rhabdomyosarcoma in children?

Management of Rhabdomyosarcoma in Children

Multidisciplinary Team Requirement

All children with rhabdomyosarcoma must be managed by a specialized sarcoma multidisciplinary team at reference centers with high patient volumes, including pathologists, radiologists, surgeons, radiation oncologists, and medical oncologists. 1 Enrollment in clinical trials should be pursued whenever possible, as this represents optimal management for this relatively rare tumor requiring highly specialized care. 2

Diagnostic Workup

Tissue Diagnosis

• Establish histologic diagnosis through incisional biopsy or complete tumor resection when feasible without major functional or cosmetic deficits 1, 3
• Perform immunohistochemistry and molecular testing for PAX-FOXO1 fusion genes to distinguish embryonal from alveolar subtypes, as this impacts prognosis and risk stratification 4, 3
• PAX7-FOXO1 fusion carries more favorable prognosis than PAX3-FOXO1 in metastatic disease 3

Staging and Risk Stratification

• Apply dual classification using pretreatment TNM staging and postoperative clinical grouping (IRSG system) to determine risk-adapted treatment 1, 2
• Evaluate regional lymph nodes surgically as part of staging, since rhabdomyosarcoma frequently involves nodes unlike other pediatric sarcomas 5

Treatment by Disease Stage

Localized Disease

The treatment approach combines surgery, chemotherapy, and radiotherapy in a coordinated multimodality plan. 1

Surgical Management

• Perform wide excision with negative microscopic margins whenever possible without causing major functional or cosmetic deficits, including the cutaneous scar and biopsy tract 1, 2
• Complete resection is often neither possible nor medically indicated due to locally infiltrative growth patterns 2
• Consider delayed primary resection after initial chemotherapy to increase the number of tumors that can be completely resected with acceptable morbidity in certain primary sites 6
• Limit surgical intervention to initial biopsy, wide local excision when clear margins are feasible, and resection of residual disease 5

Chemotherapy

• Administer multiagent chemotherapy as the primary treatment modality for all patients 1, 5
• Use vincristine and dactinomycin with either cyclophosphamide (VAC) or ifosfamide (IVA) as the backbone regimen 2, 6
• Reduce or eliminate the alkylating agent for patients with the most favorable disease characteristics (embryonal histology, completely resected tumors) 2
• Expect severe hematologic toxicities including 83% grade 3-4 neutropenia, 60% thrombocytopenia, and 45% anemia 1, 3
• Treatment-related mortality ranges from 0-4%, primarily from sepsis and anthracycline-related cardiotoxicity 1, 3

Radiotherapy

• Apply radiotherapy to the primary tumor site based on surgical margins and clinical grouping 3
• Reserve radiation for patients with incompletely resected tumors, persistent disease, or recurrent disease 2, 5
• Consider dose reductions following delayed primary resection and response to chemotherapy, though this may increase recurrence risk 2
• Deliver by external beam, intensity-modulated radiotherapy (IMRT), proton beam, or brachytherapy to reduce long-term sequelae such as bone growth arrest, muscle atrophy, and second malignancies 2, 6

Metastatic Disease

Standard multiagent chemotherapy using doxorubicin-based regimens with or without ifosfamide is the treatment of choice for metastatic disease. 1, 3

Critical Pitfall to Avoid

High-dose chemotherapy with autologous stem cell transplant (HDT/ASCT) should NOT be used outside of clinical trials, as there is no proven survival benefit in primary metastatic rhabdomyosarcoma despite theoretical rationale for dose intensification. 1, 3 Multiple prospective studies consistently demonstrate no survival benefit and expose patients to significantly higher toxicity and treatment-related mortality. 3

Relapsed/Refractory Disease

• Relapse rates are 30-40% in initially localized disease and 60-80% in metastatic disease 3
• HDT/ASCT shows no proven survival benefit in relapsed rhabdomyosarcoma and should not be used outside clinical trials 3
• Consider novel chemotherapy administration schedules including interval compressed dosing or maintenance therapy 6
• Molecularly targeted agents are under investigation in combination with chemotherapy for recurrent disease 6

Histologic Subtype-Specific Management

Embryonal and Alveolar Rhabdomyosarcoma

• Manage using the same principles that apply to children, even when occurring in adults (which is exceedingly rare) 4, 1
• Embryonal/botryoid/spindle cell types are considered favorable histology 6
• Alveolar form is considered unfavorable histology and requires more intensive therapy 6

Pleomorphic Rhabdomyosarcoma

• Treat as a high-grade adult-type soft tissue sarcoma rather than using pediatric protocols 4, 1

Response Evaluation

• Perform response evaluation after 2-3 cycles of chemotherapy using the same radiological examinations that were positive before treatment 1

Expected Outcomes

• Current 5-year survival rate exceeds 70% for patients with localized rhabdomyosarcoma 2
• Outcome for patients presenting with metastatic disease remains poor despite multimodal therapy 2
• Survival has improved dramatically from 25% in 1970 to greater than 70% today with multimodal therapy 7

Key Clinical Considerations

• The tumor arises in a wide variety of primary sites (genitourinary tract, trunk/extremities, head/neck, retroperitoneum), each with specific patterns of local invasion and regional lymph node spread requiring site-specific treatment details 2
• Long-term effects of therapy include bone growth arrest, muscle atrophy, bladder dysfunction, infertility, and second malignant neoplasms 2
• Contemporary surgical procedures are less exenterative or mutilating than those employed historically, with emphasis on decreased morbidity 7