6
Research Proposal
1 .Title of the project: Single Versus Combination 5-Fluoruracil Based Chemotherapy Regimens After Palliative Gastric Resection in Advanced Gastric Cancer
2. Research Objective :
We aim to study the efficacy of the single 5-FU chemotherapy regimen for treatment of gastric cancer in Maharaj Chiangmai Hospital. The goal is to assess this regimen comparing with other 5-Fluoruracil based combination regimen for benefit of the prolonging the overall survival in gastric cancer patients who underwent gastrectomy. And we will evaluate safety of these regimens by comparing the adverse side effect and toxicity.The cost of treatment and benefit in survival will be discussed.
3. Background:
Gastric carcinoma remains a relatively common gastrointestinal cancer and a major health problem worldwide despite the incidence declined over the past 60 year1. Adenocarcinoma of the stomach is a leading cause of cancer death. In Asian countries, gastric cancer remains a major cause of cancer-related death. In Maharaj Chiangmai Hospital the prevalence of gastric cancer are more than hundred cases per year and it is also be the one of common gastrointestinal tract cancer disease that present in our hospital.
Surgery is still the treatment of choice2, but most patients with gastric cancer are not curable by surgery alone because of late detection. Gastric carcinoma is often diagnosed at an advanced stage because screening for gastric carcinoma is not performed in most of the world (except in Japan, where early detection of gastric carcinoma is pursued on a limited basis). At diagnosis, approximately 50% of patients have gastric carcinoma that extends beyond the locoregional confines and 50% of patients with locoregional gastric carcinoma cannot underwent a curative resection (R0)3.
The 5-year survival rate of gastric carcinoma is less than 20 %. It has not changed significantly during the last 30 to 40 years 4. Some randomized trials demonstrated chemotherapy regimen in the way of adjuvant treatment that provided superior survival when comparing with the best supportive care alone in patients with advanced gastric cancer5-7.
Of these, almost patients with advanced disease required several regimens chemotherapy such as a Cisplatin-based, 5-FU based, Taxane-based, or Irinotecan-based combination8-10. However, these regimens have not been clearly verified of which regimen will improve survival rate and quality of life. And systemic chemotherapy is frequenly associated with related toxicity which particularly serves patients presenting with poor general condition. This even may decrease overall survival rate of the patients.
Unfortunately, no definite conclusion have been drawn from randomized clinical trials of which regimens that improve survival
, low side effects, and make patients in good quality of life.
4.Rationale
5-fluorouracil (5-FU) is the most widely used single chemotherapy agent in gastric cancer. Other regimens are the 5-FU in combination with other cytotoxic drugs. The use of continuous 5-FU infusion is promising and may lead to the development of even more effective treatment. This method could eventually alter the belief that gastric cancer is not a chemo sensitive neoplasm.
Recently, combined chemotherapy regimen achieved modest response rate, but it has significantly impacted on survival because of there toxicity. A combination of 5-FU, doxorubicin and mitomycin (FAM) is frequently cited as the standard regimen for treatment of advanced gastric carcinoma in Maharaj hospital. There was not shown a survival benefit for treatment, and it also associated with threatened toxicity such as myelosupression, cardio toxic, febrile neutropenia.
While some study showed single agent with proven activity in the first line setting are 5-FU, cisplatin, etoposide, doxorubicin, mitomicin c
, paclitaxel and irinotecan. With these agents, the respond rate range from 14 – 44 % have been reported11. 5-FU, cisplatin, paclitaxel and irinotecan have also been used as single agents and second line. The achieved response rate was about 12 – 26 %11. However, the benefit of FAM regimen over single agent chemotherapy patients has not been clearly verified in any randomized controlled study.
Some study showed that the therapeutic effectiveness of FAMe (5-FU, doxorubicin, and methyl lomustine), FAP (5-FU, doxorubicin and cisplatin) and FAMe alternating with triazinate (TZT) when compared with a standard therapy of 5-FU alone in patients with advanced gastric cancer did not showed a significant advantage over 5-FU alone to improve performance score, weight gain and patient survival. Each of the three combinations have more toxic than 5-FU alone.12-14
Many studies have demonstrated that combination regimen produced modest response rate than 5-FU alone but the combination regimen did not influence significant overall survival rate than 5-FU alone.14-16 They have claimed that It would seem standard to prove the value of any new treatment approach by a randomized comparison to single agent therapy with 5-FU alone.15
From these rationale, this study was designed to compare the
effectiveness and feasibility of single 5-FU regimen with another 5-FU base combinations regimen that used in Maharaj Hospital for patients with advanced gastric cancer.
5. Reserch Methodology
The medical records of all patients underwent curative resection of a pathologically confirmed gastric adenocarcinoma in Department of General Surgery, Chiangmai University, Maharaj Chiangmai Hospital,Thailand between 2000 and 2005 were reviewed. Some data was collected by directed interview or send questionnaires to the patient’s home. And we also collect data for recurrent, survival rate and toxicity as an prospective trials with intension to treat basis.
Patients
Inclusion criteria
Patients in this study will require to fulfill the following eligibility criteria
1. They had undergone curative resection of a pathologically confirmed gastric adenocarcinoma
2. They will enroll in this study if they have had lymph node or serosal involvement or both Surgical resection was either total or partial gastrectomy according to the site of the tumor
3. Age 18 - 75 years
4. Patients also will require to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or better
5. No prior history other than surgery
6. Adequet marrow ( WBC count ≥4,000/μL, hemoglobin ≥ 9.5
g/dL, platelets ≥ 100,000/μL), liver (AST and ALT within three times the upper limit, bilirubin ≤ 2.0 mg/dL), renal (creatinine clearance ≥ 50 mL/min), and cardiac function (normal EKG)
7. Life expectancy of 12 weeks or longer
Exclusion criteria
1. Patients with serious complications, active carcinoma at other sites, or large amounts of ascites were excluded.
2. Unresectable case
Chemotherapy
After surgery, patients were randomly assigned, with equal probability,to receive either single chemotherapy or combination chemotherapeutic treatment. The randomization was administered. Chemotherapy was started within 28 days after surgery and
was administered according to the following schedule
· 5-Fluorouracil (5-FU) alone (500 mg/m2 days 1-5)17
Leucovorine 20 mg/m2
cycle 28 days
· FAM 5FU 600 mg/m2
Adriamycin 30 mg/m2
Mitomicin C 10 mg/m2
Cycle 56 days
Study Design
1. Evaluate patient’s Characteristic : Mean age (year) ,Sex (male/female) ,Location of tumor,Type of gastrectomy, Lymph node involvement, staging
2.Evaluate toxic side effect
3. The primary end point of this study was overall survival. The initially planned sample size of this study was calculated on the basis of our historical survival data.The overall survival data was evaluated by The Kaplan-Meier curves.
6.Usefullness of the study
- To use chemotherapy regimen that have safety and efficacy for patients
- To decrease the cost of adjuvant chemotherapy treatment for patients with Advanced gastric cancer
7. รายละเอียดหัวหน้าโครงการ
อัตตประวัติ ( Curriculum vitae )
ชื่อและตำแหน่ง
แพทย์หญิง ปาริชาติ ฤทธิ์ฉิ้ม
คุณวุฒิการศึกษา
แพทยศาสตร์บัณฑิต มหาวิทยาลัยเชียงใหม่
ส่วนที่จะรับผิดชอบในโครงการวิจัย
วางแผนงานการดำเนินงานวิจัย
ดำเนินงานวิจัย
ร่วมวิเคราะห์และแปรผลงานวิจัย
สรุปการดำเนินงาน
8. รายละเอียดผู้วิจัยร่วม ( Co-Investigator )
อัตตประวัติ ( Curriculum vitae )
ชื่อ
อาจารย์แพทย์หญิงสิริกาญจน์ ยามาดะ
ตำแหน่ง
Lecturer and staff in General Surgery division A ,Department of Surgery
,Faculty of Medicine ,Chiangmai University ,Chiangmai , Thailand
( ดังเอกสารแนบ )
9. ผลงานวิจัยนี้ หากนำไปตีพิมพ์เผยแพร่ในวารสารวิชาการ โปรดระบุผู้นิพนธ์เรียงลำดับ และภาระงานโดยประมาณ
ชื่อ แพทย์หญิง ปาริชาติ ฤทธิ์ฉิ้ม ภาระที่รับผิดชอบร้อยละ 60
ชื่อ ผู้ช่วยศาสตราจารย์ แพทย์หญิงสิริกาญจน์ ยามาดะ ภาระที่รับผิดชอบร้อยละ 40
10. ข้าพเจ้าขอรับรองว่า ข้อความทั้งหมดข้างต้นนี้เป็นความจริงทุกประการ และข้าพเจ้าจะตั้งใจทำวิจัย และรับผิดชอบในการใช้จ่ายเงินทุนที่ได้รับมาให้ตรงต่อวัตถุประสงค์ของโครงการวิจัยเท่านั้น จะส่งผลรายงานวิจัยพร้อมทั้งใช้จ่ายทุนวิจัยตามกำหนด จะตีพิมพ์งานวิจัยดังกล่าวในวารสารทันทีที่เสร็จโครงการ และยินดีจะเผยแพร่ผลงานวิจัยโดยเสนอผลงานวิธีอื่นๆ ตามความเหมาะสมด้วย และข้าพเจ้าจะเขียนขอบคุณในวารสารหรือการเสนอผลงานวิจัยนี้ได้รับการสนับสนุนจาก กองทุนพัฒนาคณะแพทย์ศาสตร์(supported by the Faculty of Medicine Endowment Fund, Faculty of Medicine, Chiang Mai University)
ลงนาม______
( แพทย์หญิง ปาริชาติ ฤทธิ์ฉิ้ม )
หัวหน้าโครงการ
ลงนาม______(ผู้ช่วยศาสตราจารย์ แพทย์หญิงสิริกาญจน์ ยามาดะ)
ผู้วิจัยร่วม