Radiation Therapy With or Without Chemotherapy in Patients With Stage I-IIA Cervical Cancer Who Previously Underwent Surgery

Study Overview
=================
Brief Summary
-----------------
This randomized phase III trial studies radiation therapy with chemotherapy to see how well they work compared to radiation therapy alone in treating patients with stage I-IIA cervical cancer who previously underwent surgery. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving radiation therapy together with chemotherapy is more effective than radiation therapy alone in treating patients with cervical cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To determine if post-operative adjuvant chemo-radiation therapy (CRT) can significantly improve recurrence-free survival (RFS) when compared to radiation therapy (RT) alone in stage I-IIA cervical cancer patients with intermediate-risk factors after treatment with radical hysterectomy. SECONDARY OBJECTIVES: I. To determine whether post-operative adjuvant CRT can improve overall survival (OS) when compared to RT alone in stage I-IIA cervical cancer patients with intermediate risk factors after treatment with radical hysterectomy. II. To assess differences (across treatment arms) in incidence and severity of therapy attributed adverse events utilizing the active version of Common Terminology Criteria for Adverse Events (CTCAE). III. To provide assessment of patient risk version (vs) benefit (positive study only). QUALITY OF LIFE OBJECTIVE: I. To determine whether post-operative adjuvant CRT improves the health-related quality-of-life (QOL) (compared to RT alone) as measured by Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) Trial Outcome Index (TOI) and produce favorable toxicity profiles (with particular focus on treatment related genitourinary, gastrointestinal, neurological, pain and sexual adverse events). TRANSLATIONAL RESEARCH OBJECTIVES: I. To bank archival tumor tissue for research studies, including studies that evaluate the association between biomarkers, RFS, OS, and clinical-surgical-pathologic characteristics in patients randomized to post-operative adjuvant CRT compared to RT alone. II. To bank deoxyribonucleic acid (DNA) from whole blood for research studies, including studies that evaluate associations between single nucleotide polymorphisms (SNPs), and measures of clinical outcome, including RFS, OS, and adverse events in patients randomized to post-operative adjuvant CRT compared to RT alone. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients undergo pelvic external-beam radiation therapy (EBRT) or intensity-modulated radiation therapy (IMRT) 5 days a week for 5.5 weeks. ARM II: Patients receive cisplatin IV over 1-2 hours on day 1 and undergo radiotherapy as in Arm I. Treatment with cisplatin repeats every 7 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
-----------------
Randomized Phase III Clinical Trial of Adjuvant Radiation Versus Chemoradiation in Intermediate Risk, Stage I/IIA Cervical Cancer Treated With Initial Radical Hysterectomy and Pelvic Lymphadenectomy (NCT #01101451)

Conditions
-----------------
Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Cervical Squamous Cell Carcinoma, Not Otherwise Specified, Stage I Cervical Cancer AJCC v6 and v7, Stage IA Cervical Cancer AJCC v6 and v7, Stage IB Cervical Cancer AJCC v6 and v7, Stage IIA Cervical Cancer AJCC v7

Intervention / Treatment
-----------------
* Drug: Cisplatin
* Radiation: External Beam Radiation Therapy
* Radiation: Intensity-Modulated Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically proven primary cervical cancer I-IIA with squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma initially treated with a standard radical hysterectomy with pelvic lymphadenectomy Patients with the following characteristics (depth of stromal invasion and lymphovascular space involvement to be pathologically confirmed): Positive capillary-lymphovascular space involvement and one of the following: Deep third penetration Middle third penetration, clinical tumor >= 2 cm Superficial third penetration, clinical tumor >= 5 cm Negative capillary-lymphatic space involvement Middle or deep third penetration, clinical tumor >= 4 cm Absolute neutrophil count (ANC) >= 1,500/mcl Platelets >= 100,000/mcl Creatinine =< upper limit of normal (ULN) or calculated creatinine clearance >= 60 mL/min Bilirubin =< 1.5 x normal Alkaline phosphate =< 3 x normal Serum glutamic oxaloacetic transaminase (SGOT) =< 3 x normal Gynecologic Oncology Group (GOG) performance status 0, 1, 2 Patients should not be randomized less than 3 weeks post-surgery but will not be acceptable for randomization more than 8 weeks post-surgery Patients who have met the pre-entry requirements Patients must have signed an approved informed consent and authorization permitting release of personal health information Exclusion Criteria: Patients with tumor in the parametria, pelvic lymph nodes or any other extra uterine site or with positive surgical margins Patients with septicemia or severe infection Patients with intestinal obstruction or gastrointestinal bleeding Patients with postoperative fistula Patients with cervix cancer who have received any previous radiation or chemotherapy Patients whose circumstances do not permit completion of the study or the required follow-up Patients with renal abnormalities requiring modification of radiation field (pelvic kidney, renal transplant, etc.) Patients with GOG performance status of 3 or 4 Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: Arm I (EBRT, IMRT)<br>Patients undergo pelvic EBRT or IMRT once daily, 5 days a week, for 5.5 weeks. | Radiation: External Beam Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation, External Beam;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm II (cisplatin, EBRT, IMRT)<br>Patients receive cisplatin IV over 1-2 hours on day 1 and undergo radiotherapy as in Arm I. Treatment with cisplatin repeats every 7 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: External Beam Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation, External Beam;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival (RFS) | Product-limit estimates according to the method of Kaplan and Meier and the one sided log-rank test (alpha=0.05) will be used to compare RFS between treatment arms. | From protocol registration to date of first documented recurrence, death or date of last contact, assessed up to 11 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Product-limit estimates according to the method of Kaplan and Meier and the one sided log-rank test (alpha=0.05) will be used to compare OS between treatment arms. | From entry into the study to death; or for living patients, the date of last contact regardless of whether or not this contact is on a subsequent protocol, assessed up to 11 years | 
| Local control | Assessed with Exact Logistic Regression adjusted known prognostic factors. | Up to 11 years | 
| Site(s) of recurrence | The site(s) of first disease recurrence will be classified as: pelvic-only, extra-pelvic-only or pelvic-and-extra-pelvic and tabulated by treatment group. The test of the hypothesis that the probability of local failure is independent of randomized treatment will be assessed with exact logistic regression adjusted know prognostic factors. | Up to 11 years | 
| Incidence of adverse events | Graded according to the active version of Common Terminology Criteria for Adverse Events (CTCAE). In addition to displaying frequency of adverse events for each grade category, significance of observed differences between treatment arms within each category will be analyzed using Fishers' exact test. | Up to 5 years | 
| Patient risk-benefit |  | Up to 11 years | 
| Treatment compliance | Assessed by the number of cycles and amount of chemoradiotherapy administered, treatment span, incidence and duration of treatment delays, reason for delays, and reason why off study therapy. | Up to 11 years | 
| Quality of life | Assessed using the Functional Assessment of Cancer Therapy (FACT)-Cervix, FACT-Gynecologic Oncology Group (GOG)/neurotoxicity 4 subscale, and the Brief Pain Inventory (BPI). | Up to 9 months following the first day of treatment |