Docetaxel-based Chemoradiotherapy Plus Periradiation Chemotherapy Compared With INT 0116 Adjuvant Arm in Gastric Cancer

Study Overview
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Brief Summary
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Although the intergroup 0116 trial was the first to demonstrate that adjuvant chemoradiotherapy offers a significant survival benefit in completely resected gastric cancer,it is more toxic and less effective. It is reasonable to optimize this regimen.

Detailed Description
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The intergroup 0116 trial was the first to demonstrate that adjuvant chemoradiotherapy offers a significant survival benefit. In this study, 556 patients with R0 resected gastric cancer were randomly assigned to surgery plus postoperative chemoradiotherapy or to surgery alone. The adjuvant treatment consisted of 425 mg per square meter of bolus fluorouracil per day, 20 mg per square meter of leucovorin , per day, for 5 days, followed by 45 Gy of radiation with current fluorouracil ( 400mg per square meter ) and leucovorin (20mg per square meter) as an intravenous bolus on each of of the first four days and the last three days of irradiation. One month after the completion of radiotherapy, two 5-day cycles of fluorouracil and leucovorin chemotherapy were given one month apart. Patients in the adjuvant arm achieved a significant 3-year overall and relapse-free survival benefit of 9% and 17%, respectively. Despite the improvement in outcome, up to 120 of 281 patients in the chemoradiotherapy arm relapsed in local regional or/and distant sites within 3 years of potentially curative resection. Notably, the patients receiving chemoradiotherapy had a higher rate of distant metastasis compared with the control arm (40/281 vs 32/275), indicating that bolus 5-FU/LV was not suboptimal to control the development of distant metastases. Furthermore, the toxicity in INT 0116 trial was substantial, with grade 3 or higher overall toxicities observed in 73% of the cases. As a result, only 64% of the patients were able to complete protocol therapy. Obviously, it is reasonable to optimize the Intergroup 0116 chemoradiotherapy regimen. Docetaxel, as a monotherapy, is active in both first- and second-line treatment of advanced stage gastric cancer. In addition, in vitro and in vivo studies have demonstrated that docetaxel is a potent radiosensitizer in human cancer cell lines, making it an attractive agent combined with radiation. A phase I study has identified the phase II recommended dose of docetaxel as 20mg/m2 weekly for six weeks when administered with concurrent chest radiation of 60 Gy. Furthermore, docetaxel when added to standard cisplatin and infused fluorouracil (DCF regimen) demonstrated an advantage in survival, time to progression, and response rate (RR) over cisplatin and fluorouracil (CF) in a randomized phase Ⅲ trial, but the toxicity profile associated with the DCF regimen was significant. In addition, a favorable RR and median overall survival for DCF over epirubicin, cisplatin, protracted venous infusion fluorouracil (ECF) has been seen in a randomized phase Ⅱ trial. Two large phase III trials has demonstrated that the addition of perioperative chemotherapy (ECF) or adjuvant chemotherapy (S1) to radical surgery could significantly improve surgical outcomes in localized gastric cancer as compared with surgery alone in terms of progression-free and overall survival. These results suggest that adjuvant and neoadjuvant chemotherapy may have excellent effects on both the primary tumor and micrometasatsis. Based on these important findings, we designed a phase 3 trial to compared our novel docetaxel-based chemoradiotherapy regimen with the Intergroup 0116 adjuvant arm in patients with curatively resected gastric cancer

Official Title
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Docetaxel-based Chemoradiotherapy Plus Periradiation Chemotherapy in R0 Gastric Cancer

Conditions
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Gastric Cancer

Intervention / Treatment
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* Radiation: docetaxel-based chemoradiotherapy
* Radiation: FU-based chemoradiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with microscopically confirmed stages IB through IIIB adenocarcinoma of the stomach or gastroesophageal junction, who underwent a potentially curative resection (ie, R0 resection); Zubrod performance status 0 to 1; No prior chemotherapy or prior radiation therapy to the treatment field; Age 20-75; Absolute granulocyte count (AGC) ≥2 × 109 cells/L, platelets ≥ 100× 109 cells/L, hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable) Adequate renal and hepatic function (serum creatinine ≤1.5 × upper limit of normal [ULN], bilirubin and AST ≤1.5 × ULN). Exclusion Criteria: A history of prior upper abdominal radiotherapy or chemotherapy; Evidence of metastatic disease to distant organs, peritoneal carcinoma by computed tomography or positive cytology of peritoneal effusion; Prior malignancies (except cured cervical carcinoma in situ, non-melanoma skin cancer, or other curatively treated cancer with no evidence of disease for ≥5 years); active inflammatory bowel disease; Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; uncontrolled hypertension; Chronic Obstructive Pulmonary Disease(COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 60 days before registration; Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; Patients with Acquired Immune Deficiency Syndrome were excluded from the study because the treatments involved in this protocol may be significantly immunosuppressive. Hypersensitivity reaction to docetaxel; Uncontrolled neuropathy grade 2 or greater regardless of cause; Conditions precluding medical follow-up and protocol compliance; Pregnant or lactating women are excluded from study entry due to the embryotoxic effects of the protocol treatment.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FU-based chemoradiotherapy<br>patients will be treated with the INT0116 regimen. | Radiation: FU-based chemoradiotherapy<br>* The adjuvant treatment consisted of 425mg/m2 of bolus fluorouracil(5-FU) per day, 20 mg/m2 of leucovorin (LV), per day, for 5 days, followed by 45Gy of radiation with current 5-FU ( 400mg/m2 ) and LV (20mg/m2) as an intravenous bolus on each of of the first four days and the last three days of irradiation. One month after the completion of radiotherapy, two 5-day cycles of 5-FU and FV chemotherapy were given one month apart.<br>* Other names: the INT 0116 adjuvant arm;|
| Experimental: docetaxel-based chemoradiotherapy<br>patients will be treated with modified DCF chemotherapy in combination with docetaxel-based chemoradiotherapy. | Radiation: docetaxel-based chemoradiotherapy<br>* experimental:Patients with Zubrod performance status (PS) of 0-2 received up to 2 21-day cycles of pre- and post-radiation chemotherapy (docetaxel 37.5 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and a continuous infusion of fluorouracil (FU) 750 mg/m2 on days 1-5), respectively. CCRT between pre- and post-radiation chemotherapy was initiated on day 43 and consisted of 3-dimensional conformal intensity-modulated radiation therapy (45 Gy) plus concurrent docetaxel 20 mg/m2 weekly for 6 weeks;<br>* Other names: a docetaxel arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival rate | survival time was measured from the date of study enrollment to the date of death or last follow-up | 3-year (36-month) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival rate | progression free survival was measured from the date of study entry to the first event (ie,local-regional relapse or progression, distant recurrence, or death of any cause) | 3-year (36-month) |