Proton-Spatially Fractionated Radiotherapy and Standard Radiation Therapy for the Treatment of Newly Diagnosed Retroperitoneal Soft Tissue Sarcoma

Inclusion Criteria: * Patients must have newly diagnosed, histologically or cytologically confirmed, untreated retroperitoneal soft tissue sarcoma * The soft-tissue sarcoma tumor must be at least 3 cm in diameter * Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. * Patients must be age ≥ 18 years on day of signing any informed consent documents * Patients must exhibit a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale or \>70% on the Karnofsky Scale * Leukocytes (white blood cells \[WBC\]) ≥ 3,000/mcL * Absolute neutrophil count (ANC) ≥ 1,500/mcL * Note: growth factor/transfusion is not permitted prior to these measurements being taken * Hemoglobin (Hgb) ≥ 9 g/d * Platelets (PLT) ≥ 100,000/mcL * Total bilirubin \< 1.5 x upper limit of normal (ULN) (or direct bilirubin \< ULN) * Aspartate Transferase (AST) ( serum glutamic-oxaloacetic transaminase \[SGOT\]) ≤ 2.5 x institutional ULN * Alanine transaminase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) ≤ 2.5 x institutional ULN * Creatinine ≤ 1.5 x upper limit of normal (ULN) * Creatinine clearance ≥ 50mL/min * International normalized ratio (INR) (or prothrombin time \[PT\] or partial thromboplastin time \[PTT\]; one will be used) \< 1.5 x ULN (unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants \[within 10 days of treatment initiation\]) * Activated partial thromboplastin time (aPTT) \< 1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants \[within 10 days of treatment initiation\]) * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Patients of child-bearing potential (POCBP) must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) from time of informed consent and for the duration of study participation. Patients who can impregnate their partners must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) from time of informed consent and for the duration of study participation. Should a patient become pregnant or suspect they are pregnant while they or their partner is participating in this study, they should inform their treating physician immediately. * Note: At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) * Note: A POCBP is any person with an egg-producing reproductive tract (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) * POCBP must have a negative urine pregnancy test within 72 hours prior to undergoing CT simulation for P-SFRT. If a urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required * POCBP must be willing and able to use an adequate method of contraception * Patients with sperm-producing reproductive capacity (PWSPRC) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent, for the duration of study participation, and for 120 days following completion of therapy. PWSPRC treated or enrolled on this protocol must also agree to refrain from donating sperm from time of informed consent for the duration of study participation and for 120 days following completion of therapy * Patients must have the ability to understand and the willingness to sign a written informed consent document * Patients must be medically fit to undergo surgery * Patients must have plans to undergo neoadjuvant radiation therapy and surgery with curative intent Exclusion Criteria: * Patients who have had one of the following soft tissue sarcoma subtypes where neoadjuvant chemotherapy is established as standard-of-care: * Extra-skeletal Ewing sarcoma * Embryonal rhabdomyosarcoma * Alveolar rhabdomyosarcoma * Desmoplastic small round cell tumor * Patients who have had any prior radiation therapy to the affected area * Patients who have had chemotherapy, radiotherapy, or other antineoplastic agents ≤ 28 days (6 weeks for nitrosureas or mitomycin C) prior to planned treatment start date * Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia * Patients who have taken steroid therapy or any other immunosuppressive therapy within 7 days of first dose prior to trial treatment * Patients with a known history of active tuberculosis (TB) (Bacillus tuberculosis) * Patients with a known history of active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected) infection * Patients with current or a history of any distant metastatic disease (including brain). Note: an isolated or oligo-metastatic regional occurrence may be allowed if all other criteria have been met and curative attempt is being pursued * Patients with a known history of (non-infectious) pneumonitis that required steroids or had evidence of current pneumonitis * Patients who have received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally killed virus vaccines, and as such, patients who have received these vaccines are not excluded; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed * Patients who have had an allogenic tissue/solid organ transplant * Patients with a history of inflammatory bowel disorders (i.e., ulcerative colitis, Crohn's disease) or rheumatologic disorders (i.e., Sjogren's, scleroderma, rheumatoid arthritis) that serve as a contraindication to retroperitoneal radiation therapy * Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible: * Hypertension that is not controlled on medication * Ongoing or active infection requiring systemic treatment * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Major surgery within 30 days of registration * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient¡¦s safety or study endpoints * Patients with psychiatric illness/social situations that would limit compliance with study requirements * Patients who are pregnant (positive urine pregnancy test within 72 hours prior to enrollment) or nursing. If a urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required * Patients who are expecting to become pregnant or impregnate their partner within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment * Patients who are currently participating in or have participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention * Other study specific or disease criteria for exclusion (e.g., certain disease sub-types that are not eligible, patients who are unable to swallow oral medication if the study involves oral agents, etc.)