Study With Intensity Modulated Radiation Therapy With Cisplatin to Treat Stage I-IVA Cervical Cancer

Study Overview
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Brief Summary
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The purpose of this study is to find out whether patients with cervical cancer treated with IMRT have less side effects with equal cancer control compared to standard radiation techniques. With standard radiation techniques, normal pelvic organs near the tumor receive radiation dose, which leads to side effects. IMRT is a new radiation technique that can reduce radiation dose to these organs and may reduce side effects. Compared to conventional RT techniques, the hypothesis is that IMRT will reduce acute hematologic and gastrointestinal toxicity for cervical cancer patients treated with concurrent cisplatin.

Detailed Description
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Multiple randomized controlled trials have established concurrent cisplatin-based chemoradiotherapy as the standard of care for locally advanced cervical cancer [3-8]. The addition of concurrent cisplatin to radiotherapy (RT) increases pelvic control, disease-free survival (DFS) and overall survival; however, 5-year DFS and overall survival are still only approximately 60% and 5-year pelvic failure is approximately 30%. Moreover, acute gastrointestinal (GI) and hematologic toxicity are increased. Approximately 30% of patients will experience acute grade ≥ 3 toxicity, predominantly GI and hematologic. Methods to reduce toxicity during chemoradiotherapy, particularly gastrointestinal and hematologic, could mitigate this toxicity and take advantage of the therapeutic benefits of intensive concurrent chemotherapy. Intensity modulated radiation therapy (IMRT) is a modern RT technique that differs from conventional techniques in many ways. First, patients undergo computed tomography (CT) simulation so that customized target volumes can be defined 3-dimensionally. IMRT treatment planning involves multiple beam angles and uses computerized inverse treatment planning optimization algorithms to identify dose distributions and intensity patterns that conform dose to the target, reducing radiation dose to surrounding tissues. IMRT delivery is typically accomplished with the use of multileaf collimators, which involve small motorized leaflets (collimators) that move in and out of the beam path, modulating the dose intensity.

Official Title
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Phase II/III Clinical Trial of Intensity Modulated Radiation Therapy With Concurrent Cisplatin for Stage I-IVA Cervical Carcinoma

Conditions
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Cervical Cancer

Intervention / Treatment
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* Radiation: Intensity Modulated Radiation Therapy (IMRT)
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-proven, invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix Biopsy result positive for carcinoma within 60 days prior to registration FIGO clinical stage I-IVA disease, based on standard diagnostic workup, including:History/physical examination and/or Examination under anesthesia (if indicated) If the patient is status post hysterectomy, one or more of the following conditions must be present: positive lymph nodes, positive margins, parametrial invasion, or non-radical surgery (i.e., simple hysterectomy). If the patient is inoperable, one or more of the following conditions must be present: clinical stage IB2-IVA, positive lymph nodes on nodal sampling or frozen section, and/or parametrial invasion Within 42 days prior to registration, the patient must have any of the following, if clinically indicated: examination under anesthesia, cystoscopy, sigmoidoscopy, rigid proctoscopy, or colonoscopy. X-ray (PA and lateral), CT scan, or PET/CT scan of the chest within 42 days prior to registration; CT scan, MRI, or PET/CT of the pelvis within 42 days prior to registration; Karnofsky Performance Status 60-100 Absolute neutrophil count (ANC) ≥ 1500 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable); Creatinine clearance ≥ 50 mg/dl; Bilirubin < 1.5 mg/dl; WBC ≥ 3,000/μl; ALT/AST < 3 x ULN; INR ≤ 1.5 Negative serum pregnancy test for women of child-bearing potential Exclusion Criteria: Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a minimum of 3 years; Prior systemic chemotherapy within the past three years Prior radiotherapy to the pelvis or abdomen that would result in overlap of radiation therapy fields; Para-aortic, inguinal, or gross (unresected) pelvic nodal metastasis. Gross pelvic nodal metastasis is defined as either: Radiographic evidence of nodal metastasis on CT or MRI (node having short axis diameter > 1 cm)OR Radiographic evidence of nodal metastasis on diagnostic FDG-PET or PET/CT scan (abnormally increased FDG uptake as determined and documented by the radiologist)OR Biopsy-proven metastasis (e.g. needle biopsy) in undissected node Distant metastasis Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects Uncontrolled diabetes, defined as diabetes mellitus, which in the opinion of any of the patient's physicians requires an immediate change in management; Uncompensated heart disease or uncontrolled high blood pressure Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition

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: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase II<br>All patients receive IMRT with concurrent cisplatin 40 mg/m2 | Radiation: Intensity Modulated Radiation Therapy (IMRT)<br>* 45.0 Gy (intact) or 50.4 Gy (postoperative high-risk) in 1.8 Gy daily fractions over 5-5.5 weeks<br>Drug: Cisplatin<br>* Weekly infusion of 40 mg/m2 (80 mg max) x 5 weeks<br>|
| Active Comparator: Phase III - A<br>Patients in Phase III, Arm A receive 4-field box RT with concurrent cisplatin 40 mg/m2 | Drug: Cisplatin<br>* Weekly infusion of 40 mg/m2 (80 mg max) x 5 weeks<br>|
| Experimental: Phase III - B<br>Patients in Phase III, Arm B receive IMRT with concurrent cisplatin 40 mg/m2 | Radiation: Intensity Modulated Radiation Therapy (IMRT)<br>* 45.0 Gy (intact) or 50.4 Gy (postoperative high-risk) in 1.8 Gy daily fractions over 5-5.5 weeks<br>Drug: Cisplatin<br>* Weekly infusion of 40 mg/m2 (80 mg max) x 5 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Adverse Events as a Measure of Safety and Tolerability | To test whether IMRT will reduce the rate of acute grade ≥ 3 hematologic or clinically significant grade ≥ 2 gastrointestinal toxicity compared to conventional RT techniques for cervical cancer patients treated with concurrent cisplatin | Up to 10 weeks while on Treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Acute and Late Adverse Events as a Measure of Safety and Tolerability | To estimate and compare the probability of acute and late adverse events | Up to 36 months post treatment | 
| Number of Patients with Locoregional Failure as a Measure of Recurrence | To estimate and compare efficacy of cisplatin/IMRT in terms of locoregional failure, disease-specific survival, disease-free survival, and overall survival. | Up to 36 Months post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical, Carcinoma, Cisplatin, IMRT, Radiation, INTERTECC, International, External Beam, Brachytherapy, LDR, HDR, IGRT, CBCT