The UPPROACH (Upfront Intensity Modulated Proton Beam Therapy) Approach

Study Overview
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Brief Summary
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A phase 2 study with the primary objective of testing treatment compliance of Upfront Intensity Modulated Proton Beam Therapy (IMPT) and Concurrent Chemotherapy (UPPROACH) for Post-operative Treatment in Loco-regionally Advanced Endometrial Cancer is non-inferior to the historic compliance rate of the chemoradiation arm of GOG 258 study

Detailed Description
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While there is a consensus that both adjuvant ChT and RT benefit patients with respect to locoregional and distant control, the sequencing of these therapies varies between institutions. Common approaches include sequential treatment, with 4-6 cycles of ChT followed by RT, sandwich therapy with RT sandwiched between 3 cycles of ChT, or concurrent CRT. Small retrospective studies have shown a benefit with respect to PFS and OS in the sandwich approach, however this has not been replicated in larger studies. In more recent years, proton beam therapy (PBT) has become an increasingly common modality for the treatment of uterine malignancies and is capable of even more precise dose distributions than photon-based RT due to intrinsic properties of these much heavier particles. Dosimetric/planning studies from other institutions confirm the significant reduction of dose to critical normal tissues like bladder, bowel, rectum, and bone marrow. Preliminary data from the University of Maryland Medical Center has suggested that IMPT using pencil beam scanning is feasible in patients with endometrial cancer, with only 10% of patients developing grade 2 GI toxicity and no patients developing ≥ grade 3 GI or GU toxicities (abstract under review). The investigators would like to test the hypothesis that in the postoperative setting, patients with advanced endometrial cancer will be able to complete a course of full dose ChT - carboplatin and paclitaxel - concurrent with upfront pelvic IMPT.

Official Title
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The Upproach Approach: A Phase 2 Study Of Upfront Intensity Modulated Proton Beam Therapy (Impt) And Concurrent Chemotherapy For Post-Operative Treatment In Loco-Regionally Advanced Endometrial Cancer

Conditions
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Endometrial Cancer

Intervention / Treatment
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* Drug: carboplatin and paclitaxel
* Radiation: pelvic IMPT (Intensity Modulated Proton Therapy)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Surgery must have included a hysterectomy. Bilateral salpingo-oophorectomy, pelvic lymph node sampling, para-aortic lymph node sampling, and omentectomy are optional Patients will be staged according to FIGO 2009 staging system. Eligibility is defined based on clinical-pathologic features. Patients with endometrioid endometrial cancer with the following: Stage IA grade 3 with extensive LVSI Stage IB grade 3 Stage II Stage III (A, B, and C) Stage IVA who are recommended adjuvant whole pelvic RT (+/- lower para-aortic up to renal hilum) and systemic chemotherapy. Patients with clear cell, serous papillary carcinoma, or carcinosarcoma with stages IA-III who are recommended adjuvant whole pelvic RT (+/- lower para-aortic up to renal hilum) and systemic chemotherapy. Patients with a GOG Performance Status of 0, 1, or 2 Patients with adequate organ function, reflected by the following parameters: WBC ≥ 3000/mcl Absolute neutrophil count (ANC) ≥ 1000/mcl Platelet count ≥ 100,000/mcl SGOT, SGPT, and alkaline phosphatase ≤ 2.5 X upper limit of normal (ULN) Bilirubin ≤ 1.5 X ULN Creatinine ≤ institutional ULN (if serum creatinine > ULN, estimated GFR ≥ 45 ml/min) Patients who have signed an approved informed consent and authorization permitting release of personal health information Patients must be 18 years of age or older Exclusion Criteria: Patients with leiomyosarcoma Patients with clinically significant pelvic or para-aortic nodal disease, on post-surgery CT scan, that was not dissected and would require higher boost dose Patients with recurrent endometrial cancer with gross nodal or vaginal disease requiring high dose radiotherapy, or history of prior chemotherapy Patients with a history of prior pelvic/abdominal RT or with history of prior cancer treatment that contraindicates this protocol therapy including history of prior chemotherapy for any other malignancy. Patients with a history of serious co-morbid illness or uncontrolled illnesses that would preclude protocol therapy Patients with an estimated survival of less than three months Patients with FIGO 2009 Stage IVB endometrial cancer Patients with a history of myocardial infarction, unstable angina, or uncontrolled arrhythmia within 3 months from enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Concurrent chemoradiation<br>Concurrent carboplatin and paclitaxel and IMPT (Intensity Modulated Proton Therapy) | Drug: carboplatin and paclitaxel<br>* carboplatin and paclitaxel 5-6 cycles (dosage per standard of care according to treating oncologist)<br>Radiation: pelvic IMPT (Intensity Modulated Proton Therapy)<br>* whole pelvis will receive a total dose of 4500 cGy in 25 fractions to 5040 cGy in 28 fractions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance rates | This will be measured as proportion of patients completing full 6 cycles of chemotherapy concurrently with IMPT | End of study, approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute GI and urinary toxicity | Measured by CTCAE (Common Terminology Criteria for Adverse Events) | once a week during radiation treatment (5-6 weeks) | 
| Acute GI and urinary toxicity | Measured by PRO-CTCAE (Patient reported outcomes Common Terminology Criteria for Adverse Events) | once a week during radiation treatment (5-6 weeks) | 
| Acute GI and urinary toxicity | Measured by EPIC (Expanded Prostate Cancer Index Composite ) bowel and urinary domain | once a week during radiation treatment (5-6 weeks) | 
| Acute hematologic toxicity | Measured by CTCAE (Common Terminology Criteria for Adverse Events) | Prior to each cycle of chemotherapy (once every 21 days for 106 days) | 
| Late GI and urinary toxicity | Measured by CTCAE (Common Terminology Criteria for Adverse Events) | 6-month following radiation therapy | 
| Late GI and urinary toxicity | Measured by PRO-CTCAE (Patient reported outcomes Common Terminology Criteria for Adverse Events) | 6-month following radiation therapy | 
| Late GI and urinary toxicity | Measured by EPIC (Expanded Prostate Cancer Index Composite ) bowel and urinary domain | 6-month following radiation therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endometrial cancer, Gynecologic cancers, Radiotherapy, Proton Therapy, Chemotherapy, Chemoradiation