Clinical trial NCT02640898: Docetaxel-based Chemoradiotherapy Plus Periradiation Chemotherapy Compared With INT 0116 Adjuvant Arm in Gastric Cancer
Official title: Docetaxel-based Chemoradiotherapy Plus Periradiation Chemotherapy in R0 Gastric Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Gastric Cancer
Lead sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
First posted: 2015-12-29
Enrollment: 500
Sex: ALL
Minimum age (years): 20
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: 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.

Primary outcomes:
measure: overall survival rate
timeFrame: 3-year (36-month)
Secondary outcomes:
measure: progression free survival rate
timeFrame: 3-year (36-month)
Other outcomes:
Locations:
city: Shanghai
country: China
facility: the Ethic Committee of Shanghai General Hospital
state: Shanghai
Study officials:
affiliation: the ethic committee of shanghai genernal hospital
name: tingfeng chen, MD
role: PRINCIPAL_INVESTIGATOR
References:
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