Clinical trial NCT01561586: Tri-weekly Cisplatin Based Chemoradiation in Locally Advanced Cervical Cancer
Official title: Randomized Phase III Clinical Trial of Weekly Versus Tri-weekly Cisplatin Based Chemoradiation in Locally Advanced Cervical Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Cervical Cancer
Keywords: Cervical cancer
Concurrent chemoradiation
Cisplatin
Lead sponsor: Korea Cancer Center Hospital
Sponsor class: OTHER
Collaborators: name: Seoul National University Hospital
name: Asan Medical Center
name: Gangnam Severance Hospital
First posted: 2012-03-23
Enrollment: 374
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall survival
timeFrame: From entry into the study to 5 year after treatment or death
Secondary outcomes:
measure: Progression Free Survival
timeFrame: 5 year after treatment
measure: Recurrence rate
timeFrame: 5 year after therapy
measure: Adverse events
timeFrame: 5 years after therapy
measure: Compliance to radiation protocol
timeFrame: 56~ 67 days after treatment start
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
city: Busan
country: Korea, Republic of
facility: Dongnam Inst.of Radiological/Medical Science
city: Cheonan
country: Korea, Republic of
facility: Soon Chun Hyang University Hospital
city: Daegu
country: Korea, Republic of
facility: Dongsan Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Mokdong Hospital
city: Seoul
country: Korea, Republic of
facility: Gachon University Gil Hospital
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital/Sinchon Severance Hospital
city: Bankok
country: Thailand
facility: Faculty of Medicine, Ramathibodi Hospital, Mahidol University
city: Ho Chi Minh
country: Vietnam
facility: Ho Chi Minh City Oncology Hospital
Study officials:
affiliation: STAFF
name: SANG YOUNG SY RYU, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Faculty of Medicine Ramathibodi Hospital, Mahidol University
name: SARIKAPAN WILAILAK, M.D.
role: PRINCIPAL_INVESTIGATOR
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