Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy

This study will treat participants with newly diagnosed, low, intermediate and high risk rhabdomyosarcoma (RMS) using multi-modality risk-adapted therapy with standard or intensified dose chemotherapy, radiation and surgical resection. Intermediate and high risk participants will receive an additional 12 weeks (4 cycles) of maintenance therapy with anti-angiogenic chemotherapy. PRIMARY OBJECTIVE: * Estimate event-free survival for intermediate risk participants treated with vincristine, dactinomycin and cyclophosphamide with the addition of maintenance anti-angiogenic therapy. SECONDARY OBJECTIVES: * Estimate the false negative rate and incidence of additional positive lymph nodes in participants undergoing sentinel lymph node biopsy followed by limited nodal dissection. * Maintain a high local control rate in participants treated with surgery and/or limited volume proton and photon radiation without dose escalation. * Define the incidence and type of failure in participants who receive risk-adapted local therapy relative to the primary tumor volume. * Establish the feasibility of delivering 4 cycles of maintenance anti-angiogenic chemotherapy in intermediate and high risk patients following standard chemotherapy. * Estimate the event free survival for high risk patients receiving interval dose compressed therapy and maintenance anti-angiogenic therapy. * Define the incidence of CTC grade 3 and higher toxicities (and specific grade 1-2 toxicities) related to proton beam therapy.

Participants will be stratified based on both a pretreatment staging system and a post-surgery surgico/pathologic clinical grouping system. Treatment for low-risk (subset 1) participants will consist of chemotherapy and radiation. Low-risk (subset 2) and intermediate-risk participants will receive chemotherapy and radiation and/or undergo surgery to destroy/remove the tumor. Intermediate-risk participants will also receive 16 weeks of maintenance chemotherapy. High-risk participants will receive chemotherapy and radiation therapy. High-risk participants will also receive additional maintenance therapy with anti-angiogenic chemotherapy.

Inclusion Criteria: * Newly diagnosed participants with localized rhabdomyosarcoma (RMS). * Must have either low-, intermediate-, or high-risk disease, defined as: * Low-risk: Embryonal, botryoid, spindle cell tumors only (Subset 1: Stage 1, Group I; Stage 1 Group I; Stage 1 Group III orbital only; Stage 2 Group I; Stage 2 Group II) (Subset 2: Stage 1 Group III non orbit; Stage 3 Group I, II) * Intermediate-risk: Embryonal, botryoid, or spindle cell RMS Stage 2 or 3 and Group III; Alveolar, undifferentiated, or anaplastic RMS: Stage 1-3, group I-I; I) * High-risk: Embryonal, botryoid, spindle cell, alveolar, undifferentiated, or anaplastic RMS with metastatic disease at diagnosis (stage 4). * Participants treated on this protocol in the low or intermediate risk arm who experience disease progression prior to week 13 will transfer to the high risk arm and proceed with high risk chemotherapy starting at week 1 of the protocol. * Age \< 22 years (eligible until 22nd birthday) * Performance level corresponding to ECOG score of 0, 1, or 2. The Lansky performance score should be used for participants \< 16 years * Participant has received no prior radiotherapy or chemotherapy for rhabdomyosarcoma (excluding steroids) unless an emergency situation requires local tumor treatment. Prior biopsy, surgical resection and lymph node sampling is allowed. * Initiation of chemotherapy is planned within 6 weeks (42 days) of the definitive biopsy or surgical resection. * Adequate bone marrow function defined as: * Peripheral absolute neutrophil count (ANC) ≥ 750/μL * Platelet count ≥ 75,000/μL (transfusion independent) * Adequate liver function defined as total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. Participants with biliary or hepatic primaries with bilirubin values greater than 1.5 x ULN may be enrolled on study if all other eligibility criteria are met. * Adequate renal function defined as: * Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.732 or * Serum creatinine based on age and gender * Participants with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract. * Patients requiring emergency radiation therapy are eligible for enrollment on this study. * Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants ≥ 10 years of age or post-menarchal must have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment. Female participants who are breast feeding must agree to stop breast feeding. * Sexually active patients of childbearing potential must be willing to use effective contraception during therapy and for at least 1 month after treatment is completed. * No evidence of active, uncontrolled infection. * All participants and/or their parents or legal guardians must sign a written informed consent. Exclusion Criteria: * Participants who fail to meet one or more of the inclusion criteria will be excluded. Inclusion Criteria for Contrast-Enhanced Ultrasound (CEUS) Sub-Study: * Newly diagnosis or suspected diagnosis of previously untreated participants with rhabdomyosarcoma (RMS). NOTE: Patients with suspected diagnosis of RMS may enroll on screening part of study but must have histologic diagnosis to enroll on treatment part of study. * Must have either intermediate-risk or high risk disease. * 0-21 years of age. Exclusion Criterial for CEUS Sub-Study: * Undergoing upfront surgical resection of the primary tumor. * History of allergy to Optison(TM) contrast agent or blood products.