Tri-weekly Cisplatin Based Chemoradiation in Locally Advanced Cervical Cancer

Study Overview
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Brief Summary
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Current standard treatment for locally advanced cervical cancer is cisplatin-based concurrent chemoradiation (CRT). Although recently reported meta-analysis studies also demonstrated improved local control rates and survival with cisplatin-based chemotherapy concurrent to radiation therapy (RT), the optimal cisplatin dose and dosing schedule are still undetermined. In light of the results of the previous clinical trial, weekly cisplatin 40 mg/m2 considered to be a standard regiment in cisplatin doses and dosing schedules. However, our randomized phase II trial showed that tri-weekly cisplatin 75mg/m2 has lower toxicities and a better outcome in locally advanced cervical cancer. In this randomized phase III trial, the investigators investigate that there may be a survival difference between weekly cisplatin 40 mg/m2 and tri-weekly cisplatin 75 mg/m2 administration concurrent to RT in cervical cancer.

Detailed Description
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Cervical carcinoma is one of the most common gynecologic cancers worldwide. The prognosis of cervical cancer is favorable, with around 80-90% 5-year survival rate in early stage disease. However, advanced disease carries a poor prognosis. Current standard treatment for locally advanced cervical cancer, which is not eligible for surgical treatment, is cisplatin-based concurrent chemoradiation (CRT). Based on the results of five randomized clinical trials, which consistently showed improved survival in patients treated with cisplatin-based CRT, the National Cancer Institute (NCI) of the United States announced that 'Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with RT in women who require radiation therapy for treatment of cervical cancer' in 1999. Although recently reported meta-analysis studies also demonstrated improved local control rates and survival with cisplatin-based chemotherapy concurrent to radiation therapy (RT), the optimal cisplatin dose and dosing schedule are still undetermined. Among the previous five randomized clinical trials, two trials performed by the Gynecologic Oncology Group (GOG) used weekly cisplatin 40 mg/m2 while the other three trials used tri-weekly cisplatin at a dosage range of 50 mg/m2 to 75 mg/m2 combined with 5-fluorouracil (5-FU). Despite the diversity in cisplatin dose and dosing schedules, weekly cisplatin at a dose of 40 mg/m2 concurrent to RT is widely accepted as the standard regimen of CRT because of its convenience, equal effectiveness, and favorable toxicity in comparison to other 5-FU combined regimens. However, as a result of the GOG 165 study, which was closed prematurely because an interim analysis found that patients in the 5-FU treatment group were not likely to achieve a better outcome, the role of 5-FU (previously popularly included in clinical trials) as a radiosensitizer became subject to debate. Furthermore, a clinical trial performed by the NCI in Canada comparing pelvic RT alone with weekly cisplatin 40 mg/m2 concurrent to RT failed to show improvement of progression free and 5-year survival. While the authors suggested several possible reasons for why their study failed to demonstrate a survival benefit with concurrent weekly cisplatin 40 mg/m2 chemotherapy, other investigators have tried to find another optimal dose and dosing schedule for cisplatin administration. In light of the results of the previous clinical trial that indicated 5-FU may not be an active radiosensitizer, weekly cisplatin 40 mg/m2 and tri-weekly cisplatin 75 mg/m2 remain the most popular cisplatin doses and dosing schedules. However, despite the possible advantages of tri-weekly cisplatin 75 mg/m2, which offer an increased peak concentration of cisplatin and cisplatin administration during brachytherapy, no clinical trials thus far have directly compared weekly and tri-weekly cisplatin-based chemotherapy concurrent to RT. Recently the investigators reported a randomized phase II trial to compare the compliance to and toxicity of weekly cisplatin 40 mg/m2 and tri-weekly cisplatin 75 mg/m2 administration concurrent to RT. The study showed that tri-weekly cisplatin 75 mg/m2 concurrent to RT is feasible and increase 5-year survival rate significantly compared to weekly cisplatin 40 mg/m2 in patients with locally advanced cervical cancer (66.5% in the weekly arm, 88.7% in the tri-weekly arm; HR=0.375, 95% CI: 0.154-0.914, p= .03). Therefore, in this randomized phase III trial, The investigators intend to confirm the survival difference between weekly cisplatin 40 mg/m2 and tri-weekly cisplatin 75 mg/m2 administration concurrent to RT in this patient population.

Official Title
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Randomized Phase III Clinical Trial of Weekly Versus Tri-weekly Cisplatin Based Chemoradiation in Locally Advanced Cervical Cancer

Conditions
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Cervical Cancer

Intervention / Treatment
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* Drug: Weekly cisplatin with RT
* Drug: Tri-weekly cisplatin with RT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible patients will have pathologically proven primary locally advanced cervical cancer with squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma histology suitable for primary treatment with chemoradiation with curative intent FIGO 2008 stage 1B2, 2B, 3B, 4A Age 18 years or older Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Patients must have adequate Hematologic function(ANC ≥ 1,500/mcl and platelets ≥ 100,000/mcl), Renal function(serum creatinine ≤ ULN or calculated creatinine clearance ≥ 60 mL/min), Hepatic function(serum bilirubin ≤ 1.5 x ULN and AST ≤ 2.5 x ULN and ALT≤ 2.5 x ULN) Patients must have signed an approved informed consent Exclusion Criteria: Patients with cervix cancer who have received any previous radiation or chemotherapy Patients assessed at presentation as requiring interstitial brachytherapy treatment FIGO stage 3A disease Para-aortic nodal involvement above the level of the common iliac nodes or L3/L4 (if biopsy proven, PET positive or > 15mm short axis diameter on CT) Patients with bilateral hydronephrosis unless at least one side has been stented and renal function fulfils the required inclusion criteria Previous chemotherapy for this tumor Evidence of distant metastases Prior diagnosis of Crohn's disease or ulcerative colitis Patients who are pregnant or lactating History of other invasive malignancies, with the exception of non-melanoma skin cancer and in situ melanoma, who had (or have) any evidence of the other cancer present within the last 5 years Serious illness or medical condition that precludes the safe administration of the trial treatment including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: A: Weekly cisplatin with RT<br>Weekly cisplatin 40mg/m2 six cycles concurrent to radiation therapy | Drug: Weekly cisplatin with RT<br>* Cisplatin 40mg/m2 IV Weekly For 6 Cycles.(The 6th cycle of cisplatin may be omitted if external beam radiation therapy has been completed) Cisplatin may be diluted and administered per established institutional guidelines. For general suggestion, 40 mg/ m2 of cisplatin may be diluted in 250 ml 0.9% sodium chloride and administered over one or two hours. Cisplatin will be given on the first day of external RT (Day 1), preferably, and must be given prior to radiation treatment on that day External beam RT will be followed by intracavitary brachytherapy. The total elapsed time for completion of external beam to the whole pelvis, intracavitary BT, and parametrial / nodal RT shall not exceed eight weeks (56 days)<br>* Other names: Cisplatin;|
| Experimental: B: Tri-weekly cisplatin with RT<br>Tri-weekly cisplatin 75mg/m2 three cycles concurrent to radiation therapy | Drug: Tri-weekly cisplatin with RT<br>* Tri-weekly cisplatin 75mg/m2 three cycles concurrent to radiation therapy Cisplatin may be diluted and administered per established institutional guidelines. For general suggestion, 75 mg/m2 of cisplatin may be diluted in 500 ml 0.9% sodium chloride and administered over one or two hours (rate of 1 mg of cisplatin per minute). Cisplatin will be given on the first day of external RT (Day 1), preferably, and must be given prior to radiation treatment on that day. External beam RT will be followed by intracavitary brachytherapy. The total elapsed time for completion of external beam to the whole pelvis, intracavitary BT, and parametrial / nodal RT shall not exceed eight weeks (56 days)<br>* Other names: Cisplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Observed length of life 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. | From entry into the study to 5 year after treatment or death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | The time from randomization to the time of disease progression as determined by the investigator (by clinical, radiological or pathological means) or death from any cause | 5 year after treatment | 
| Recurrence rate | Clinical, radiological or histological reoccurrence of disease since study entry. Site of First Recurrence (e.g. para-aortic or supraclavicular lymph nodes, lung, liver, bone, etc.) will also be documented. | 5 year after therapy | 
| Adverse events | Adverse event is any untoward medical occurrence in a patient or clinical investigational subject administered a study treatment and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An adverse event is any adverse change (developing or worsening) from the patient's pre-treatment condition, including intercurrent illness. | 5 years after therapy | 
| Compliance to radiation protocol | Variation acceptable: Total treatment completed within 56 days (+20% = 67 days) Total dose received to Point A inclusive of EBRT and BT = 80 - 86.4 Gy +/- 5% Deviation unacceptable: Total treatment greater than 67 days Total dose received at Point A less than 76 Gy or greater than 90.7 Gy | 56  67 days after treatment start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical cancer, Concurrent chemoradiation, Cisplatin