Intensity-Modulated Radiation Therapy to the Pelvis With or Without Chemotherapy in Treating Patients With Endometrial Cancer or Cervical Cancer That Has Been Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Specialized radiation therapy (RT), such as intensity-modulated radiation therapy (IMRT), that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving intensity-modulated radiation therapy to the pelvis with or without chemotherapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well intensity-modulated radiation therapy to the pelvis with or without chemotherapy works in treating patients with endometrial cancer or cervical cancer that has been removed by surgery.

Detailed Description
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OBJECTIVES: Determine the transportability of intensity modulated radiotherapy (IMRT) to a multi-institutional setting in patients with resected endometrial or cervical cancer. Compare the efficacy, in terms of reducing short-term bowel injury, of IMRT versus standard treatments. Assess adverse events related to this regimen. Estimate the rates of local-regional control, distant metastasis, and disease-free and overall survival. Evaluate chemotherapy compliance with this regimen for patients with cervical carcinoma. OUTLINE: This is a multicenter study. Patients are stratified according to diagnosis (cervical vs endometrial cancer). All patients undergo intensity modulated radiotherapy (IMRT) once a day, 5 days a week, for 5.5 weeks. Patients with cervical cancer also receive cisplatin IV over 30-60 minutes on day 1 or 2. Treatment with cisplatin repeats every 7 days for 5 courses (during radiotherapy) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 6 weeks post-IMRT and then every 3 months for 2 years, every 6 months for years 3-5, and then annually for at least 3 years. PROJECTED ACCRUAL: A total of 92 patients will be accrued for this study.

Official Title
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A Phase II Study of Intensity Modulated Radiation Therapy (IMRT) to the Pelvis ± Chemotherapy for Post-Operative Patients With Either Endometrial or Cervical Carcinoma

Conditions
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Cervical Cancer, Endometrial Cancer

Intervention / Treatment
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* Drug: cisplatin
* Radiation: intensity-modulated radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Must have undergone a hysterectomy (total abdominal, vaginal, radical, or laparoscopic-assisted vaginal) within 7 weeks prior to study entry Patients with endometrial cancer must have also undergone a bilateral salpingo-oophorectomy Histologically confirmed diagnosis of 1 of the following: Endometrial cancer meeting 1 of the following criteria: Stage IB grade 3, IC grade 1-3, IIA, or IIB disease requiring postoperative pelvic radiotherapy Unstaged (no lymph node dissection or sampling) stage IB grade 2 disease Stage IIIC with all of the following: Pelvic lymph node positive only Para-aortic nodes sampled negative Not receiving chemotherapy Cervical cancer meeting 1 of the following criteria: Post-radical hysterectomy and requires postoperative pelvic radiotherapy due to any of the following: Positive pelvic nodes (negative para-aortic nodes) Microscopic parametrial involvement and negative margins Disease qualified by Sedlis criteria must have 2 of the following risk factors: 1/3 or more stromal invasion Lymph-vascular space invasion Large clinical tumor diameter (≥ 4 cm) Post-simple hysterectomy with negative margins and negative nodes by CT scan, MRI, or positron emission tomography-CT scan No requirement for extended-field radiotherapy beyond the pelvis No histologically confirmed papillary serous, clear cell, or neuroendocrine (either large or small cell) disease, endometrial stromal sarcoma, leiomyosarcoma, or malignant müllerian mixed tumor No evidence of metastatic disease outside of the pelvis No microscopic involvement of the resection margin (< 3 mm) PATIENT CHARACTERISTICS: Zubrod performance status 0-2 WBC (white blood cell count) ≥ 4,000/mm³ (cervical cancer patients only) Absolute neutrophil count ≥ 1,800/mm³ (cervical cancer patients only) Platelet count ≥ 100,000/mm³ (cervical cancer patients only) Hemoglobin ≥ 8.0 g/dL (transfusion allowed) Serum creatinine ≤ 2.0 mg/dL (cervical cancer patients only) Creatinine clearance ≥ 50 mL/min (cervical cancer patients only) AST (aspartate aminotransferase) ≤ 2 times upper limit of normal Bilirubin ≤ 2 times upper limit of normal Patients must not exceed the weight and size limits of the treatment table or CT scanner No mental status changes or bladder control problems that would preclude study compliance with bladder-filling instructions No active inflammatory bowel disease No severe, active, concurrent illness, defined as any of the following: Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months Transmural myocardial infarction within the past 6 months Acute bacterial or fungal infection requiring IV antibiotics Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects AIDS No history of allergy to cisplatin (cervical cancer patients) No prior invasive malignancy (except nonmelanoma skin cancer) unless disease-free for ≥ 3 years PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior radiotherapy to the pelvis that would result in overlap of radiotherapy fields No prior platinum-based chemotherapy (cervical cancer patients) No concurrent prophylactic growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or pegfilgrastim) No concurrent prophylactic thrombopoietic agents No concurrent amifostine or other protective agents

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Endometrial Cancer: IMRT<br>Endometrial Cancer patients receive Intensity Modulated Radiation Therapy (IMRT) 28 fractions over 5.5 weeks. | Radiation: intensity-modulated radiation therapy<br> <br> |
| Other: Cervical Cancer: IMRT + Chemotherapy (cisplatin)<br>Cervical patients receive Intensity Modulated Radiation Therapy (IMRT) 28 fractions over 5.5 weeks and concurrent weekly cisplatin 40 mg/m^2 for five weeks. | Drug: cisplatin<br> <br> Radiation: intensity-modulated radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reproducibility of Radiation Technique (Number of Unacceptable Deviations in Central IMRT Quality Assurance Review) | Central quality assurance review of the IMRT planning and dosing categorized unacceptable deviations (UD) from protocol compliance with the delineation of planning target volume for the vagina and pelvic lymph nodes. Each arm of this study is considered independently, they are not compared to each other. The study was designed such that, for each arm, 5 or more of 42 subjects scored as unacceptable would determine the respective treatment technique as not reproducible. For each arm this design provides 90% power with a 0.05 type I error to reject the null hypothesis that the true probability of concluding the given technique to be reproducible is <= 80%. The alternative hypothesis is that the true probability is >= 95%. For [vagina / pelvic lymph nodes]: UD is defined as: The 90% isodose surface covers < 95% of [internal target volume (ITV)/ planned target volume (PTV)] 50.4 or > 5% of the [ITV/PTV] 50.4 receives over 115%. | IMRT planning and dosing data is centrally reviewed for quality assurance after treatment delivery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Grade 2+ Bowel Adverse Events | Bowel adverse events are defined as any of the following adverse events: diarrhea; enteritis; fistula; ileus:gastrointestinal (GI); incontinence:anal; necrosis:GI; obstruction:GI; perforation:GI; proctitis; stricture/stenosis (including anastomotic):GI. Adverse events are graded using Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to adverse event. | From the start of treatment to 90 days. | 
| Percentage of Patients With Any Grade 3+ Treatment-related Adverse Events | Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. | From start of treatment to the end of follow-up. Maximum follow-up at time of analysis was 10.2 years for endometrium cancer patients and 9.5 years for cervical cancer patients. | 
| Percentage of Patients With Any Late Grade 3+ Treatment-related Adverse Events | Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each adverse events (AE) based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Late is defined as more than 90 days after the start of radiation therapy. | From 91 days after start of study treatment to the end of follow-up. Maximum follow-up at time of analysis was 10.2 years for endometrium cancer patients and 9.5 years for cervical cancer patients. | 
| Percentage of Cervical Carcinoma Patients That Were Chemotherapy Compliant | Chemotherapy treatment was centrally reviewed for quality assurance and compliance once complete chemotherapy treatment data was received from sites. | From start to end of chemotherapy, approximately five weeks from registration. | 
| Rate of Local-regional Failure at Five Years | Local-regional failure time is defined as time from registration to date of local-regional failure (any failure in the treatment field, which will be the pelvis only), death without local-regional failure (competing risk), or last known follow-up (censored). Local-regional failure rates are estimated by the cumulative incidence method. | From registration to five years. | 
| Rate of Distant Metastases at Five Years | Distant Metastases failure time is defined as time from registration to date of distant disease, death without distant metastases (competing risk), or last known follow-up (censored) and is estimated by the cumulative incidence method. Para-aortic nodal disease is considered to be distant disease for a cervical primary, but not for an endometrial primary. | From registration to five years | 
| Rate of Disease-free Survival at Five Years | Disease-free survival time is defined as time from registration to date of failure (any tumor recurrence, development of distant metastases or death from any cause) and is estimated by the Kaplan-Meier method. Patients last known to be alive without failure are censored at the date of last contact. | From registration five years | 
| Rate of Overall Survival at Five Years | Overall survival time is defined as time from randomization to the date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. | From randomization to five years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I endometrial carcinoma, stage II endometrial carcinoma, stage III endometrial carcinoma, endometrial adenoacanthoma, endometrial adenocarcinoma, endometrial adenosquamous cell carcinoma, stage IB cervical cancer, stage IIA cervical cancer, stage IIB cervical cancer, cervical adenocarcinoma, cervical adenosquamous cell carcinoma, cervical squamous cell carcinoma