Randomized Trial of Radiation Therapy With or Without Chemotherapy for Endometrial Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cisplatin, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving chemotherapy together with radiation therapy is more effective than giving radiation therapy alone in treating endometrial cancer. PURPOSE: This randomized phase III trial is studying chemotherapy and radiation therapy to see how well they work compared with radiation therapy alone in treating patients with high-risk, stage I, stage II, or stage III endometrial cancer.

Detailed Description
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OBJECTIVES: Primary Compare the overall survival and failure-free survival of patients with high-risk stage IB-III endometrial carcinoma treated with concurrent chemoradiotherapy followed by adjuvant chemotherapy vs pelvic radiotherapy alone. Secondary Compare the rates of pelvic and distant recurrence, severe (grades 3 and 4) treatment-related toxicity, and quality of life of patients treated with these regimens. OUTLINE: This is a multicenter, prospective, open-label, randomized, controlled study. Patients are stratified according to participating group (DGOG vs UK NCRI vs NCIC CTG vs MaNGO vs Unicancer), type of surgery (total abdominal hysterectomy and bilateral salpingo-oophorectomy [TAH-BSO] vs TAH-BSO plus lymphadenectomy vs laparoscopic hysterectomy [TLH-BSO] vs TLH-BSO plus lymphadenectomy), stage (IA vs IB vs II vs III), and histological type (endometrioid carcinoma vs serous or clear cell carcinoma). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive external-beam pelvic radiotherapy 5 days a week for up to 6 weeks, combined with cisplatin IV days 1 and 22. Patients with cervical involvement undergo vaginal brachytherapy boost. At least 3 weeks after completion of chemoradiotherapy, patients undergo adjuvant chemotherapy comprising paclitaxel IV and carboplatin IV on day 1. Adjuvant chemotherapy repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients undergo external-beam pelvic radiotherapy (and vaginal brachytherapy alone in case of cervical involvement) as in arm I. Quality of life is assessed at baseline, completion of radiotherapy, completion of chemotherapy, at 6 months, and then once a year for 5 years. After completion of study therapy, patients are followed periodically for up to 10 years. PROJECTED ACCRUAL: A total of 670 patients will be accrued for this study.

Official Title
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Randomized Phase III Trial Comparing Concurrent Chemoradiation and Adjuvant Chemotherapy With Pelvic Radiation Alone in High Risk and Advanced Stage Endometrial Carcinoma: PORTEC-3

Conditions
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Endometrial Cancer

Intervention / Treatment
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* Radiation: Radiation Therapy
* Drug: cisplatin
* Drug: carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed endometrial carcinoma, with one of the following postoperative FIGO 2009 stages and grade: stage IA with invasion, grade 3 with documented LVSI stage IB grade 3 stage II stage IIIA or IIIC; or IIIB if parametrial invasion only stage IA (with invasion), IB, II, or III with serous or clear cell histology WHO-performance status 0-2 WBC ≥ 3.0 x 109/L. Platelets ≥ 100 x 109/L. Bilirubin ≤ 1.5 x UNL ASAT/ALAT ≤ 2.5 x UNL Written informed consent Exclusion criteria: Uterine sarcoma (including carcinosarcoma) Previous malignancy (except for non-melanomatous skin cancer) < 10 yrs Previous pelvic radiotherapy Hormonal therapy or chemotherapy for this tumor Macroscopic stage II for which Wertheim type hysterectomy (eligible if stage II grade 3 or stage III at pathology) Prior diagnosis of Crohn's disease or ulcerative colitis Residual macroscopic tumor after surgery Creatinine clearance ≤ 60 ml/min (Cockroft) or ≤ 50 ml/min (EDTA clearance, or measured creatinine clearance) Impaired cardiac function, prohibiting the infusion of large amounts of fluid during cisplatin therapy Peripheral Neuropathy > or = grade 2 Hearing impairment > or = grade 3, or born deaf

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Radiation Therapy<br>Pelvic Radiotherapy alone | Radiation: Radiation Therapy<br>* External beam pelvic radiotherapy (48.6 Gy in 1.8 Gy fractions) Vaginal brachytherapy boost in case of cervical involvement<br>* Other names: brachytherapy;|
| Experimental: Radiation Therapy and Chemotherapy<br>Pelvic Radiation plus 2 concurrent cycles cisplatin followed by 4 adjuvant cycles carboplatin and paclitaxel | Radiation: Radiation Therapy<br>* External beam pelvic radiotherapy (48.6 Gy in 1.8 Gy fractions) Vaginal brachytherapy boost in case of cervical involvement<br>* Other names: brachytherapy;Drug: cisplatin<br>* cisplatin 50 mg/m2 i.v., 2 cycles during radiotherapy, 3 wks interval<br>* Other names: Cisplatine;Drug: carboplatin<br>* carboplatin AUC 5, 4 cycles after completion of radiotherapy, 3 wks interval<br>* Other names: Carbotaxol;Drug: Paclitaxel<br>* paclitaxel 175 mg/m2, 4 cycles after completion of radiotherapy, 3 wks interval<br>* Other names: Taxolcarbo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | co-primary endpoint | 5 years | 
| Failure-free survival | co-primary endpoint | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life by QLQ-C30 v3.0 | Health-related overall quality of life and patient-reported symptom measures | 5 years | 
| Severe treatment-related morbidity | Acute serious events and SAE and late grade 3-4 complications | 5 years | 
| Vaginal or pelvic relapse | Both vaginal or pelvic relapse as first failure and total vaginal or pelvic relapse | 5 years | 
| Distant metastases | Both distant relapse as first failure and total distant relapse | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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endometrial clear cell carcinoma, stage II endometrial carcinoma, stage IA grade 3 endometrial carcinoma, stage IB endometrial carcinoma, stage IIIA endometrial carcinoma, stage IIIB endometrial carcinoma, stage IIIC endometrial carcinoma