© 2005 Foundation for Promotion of Cancer Research
A Phase II Study of Epirubicin, Cisplatin and Uracil–Tegafur for Advanced Gastric Carcinoma
Department of Internal Medicine, College of Medicine, Catholic University, Seoul, Korea
For reprints and all correspondence: Dr Jin-Hyoung Kang, Department of Internal Medicine, Kangnam St Mary's Hospital, The Catholic University of Korea, Banpo-dong 505, Seocho-gu, Seoul 137-040, Korea. E-mail: insookwoo{at}catholic.ac.kr
Received August 6, 2004; accepted November 23, 2004
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Due to its greater convenience, a combination of uracil and tegafur (referred to as UFT) taken orally is an attractive alternative to continuous intravenous (i.v.) 5-fluorouracil (5-FU) infusion. This phase II study assessed the response rate and toxicity profile of the combination of epirubicin, cisplatin and UFT in patients with metastatic adenocarcinoma of the stomach.
Methods: Epirubicin (50 mg/m2) and cisplatin (60 mg/m2) were administered i.v. to 35 patients with metastatic gastric carcinoma on day 1, and subsequently UFT (300 mg/m2/day) was administered orally in divided doses for 21 days. The treatment was repeated every 3 weeks. The response rate, time to disease progression, survival and toxic effects were analyzed.
Results: Thirty-two of the 35 enrolled patients were assessed subsequently for response. The median number of cycles was four. Thirteen patients (40.6%) showed partial responses, while none showed a complete response. The median time to progression of carcinoma was 20.4 weeks, and the median survival was 37 weeks. Grade 3 and 4 neutropenia was observed in 25% of patients. Grade 3 nausea and vomiting was observed in 28% of patients. No treatment-related death was observed. All patients received doses as planned, except for one who required a 75% dose reduction due to nephrotoxicity. Six of 132 cycles were delayed >7 days after four cycles.
Conclusions: The combination of epirubicin, cisplatin and UFT showed anticancer activity against metastatic gastric adenocarcinoma, had a tolerable toxicity profile and showed excellent patient compliance.
Key Words: epirubicin • cisplatin • tegafur • gastric cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Gastric cancer is the most common malignancy and the second most common cause of cancer-related death in Korea (1). The majority of gastric cancers show distant metastasis at the time of diagnosis. Many patients with gastric cancer have a poor prognosis when presenting with inoperable or metastatic disease. Systemic chemotherapy improves survival and quality of life (QOL) in patients with advanced gastric cancer compared with the best supportive care alone (2,3). Although FAMTX [5-fluorouracil (5-FU), doxorubicin, mitomycin-C] (2,4), FAM (5-FU, doxorubicin, mitomycin C) (2,5) and FP (5-FU, cisplatin) (2,6) treatments have shown relatively high response rates for advanced or metastatic gastric cancer, median survival remains at 10 months.
5-FU and cisplatin act synergistically, and cytotoxicity is enhanced with epirubicin and anthracyclin, which have lower cardiotoxicity compared with doxorubicin (5–8). The ECF (epirubicin, cisplatin, 5-FU) regimen is a combination chemotherapy which attained high response rates: between 61–71% for unresectable or metastatic gastric cancer including locally advanced disease (9,10). A prospective randomized trial comparing ECF with 5-FU, doxorubicin and methotrexate (FAMTX) in advanced esophagogastric cancer patients found that the ECF regimen gave a superior response rate, failure-free rate and overall survival (11). Continuous intravenous (i.v.) infusion of 5-FU showed comparable or higher response rates with fewer adverse effects on the bone marrow compared with bolus i.v. administration. Patients receiving bolus 5-FU had frequent myelosuppression and high incidences of severe diarrhea, stomatitis and vomiting (12). Effective and well tolerated oral administration of 5-FU could replace continuous 5-FU i.v. infusion. An advantage of this oral approach would be to alleviate the inconvenience of using an infusion pump, which in turn would improve QOL. Oral UFT alone on a 28-day schedule showed blood concentrations comparable with low dose continuous i.v. infusion of 5-FU, and resulted in a response rate of 
20% (13). We conducted a phase II study of combination chemotherapy of epirubicin, cisplatin and oral UFT in patients with metastatic or recurrent gastric cancer to determine the response rate and toxicity profile of this combination in patients with metastatic gastric cancer.
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PATIENTS AND METHODS |
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PATIENT ELIGIBILITY
All patients had histologically proven metastatic gastric cancer measurable or assessable by clinical examination, X-ray and computed tomography (CT). There were no age limits on the patients enrolled in the study. Patients had an ECOG performance status (PS) of
2, the ability to take oral agents and no other prior chemotherapy history. Patients fulfilled the following criteria: white blood cell (WBC) count 4000 µl, hemoglobin 9.5 g/dl, platelets 100 000/µl, aspartate transaminase (AST) and alanine aminotransferase (ALT) within three times the upper limit, bilirubin 
2.0 mg/dl, serum blood urea nitrogen 25 mg/dl, serum creatinine 1.5 mg/dl, creatinine clearance 50 ml/min and a life expectancy of 3 months or longer. The exclusion criteria included other types of prior or concomitant malignant tumors, heart failure or any previous chemotherapy for advanced disease. Prior to the study, written informed consent was obtained from patients or their family members. The study protocol was approved by the Institutional Review Board.
TREATMENT PLAN
On day 1, epirubicin (50 mg/m2 i.v.) and cisplatin (60 mg/m2 i.v. infusion with standard hydration) were administered. UFT in the form of 100 mg capsules (100 mg of tegafur plus 224 mg of uracil) was given orally for at least 1 h before meals at 300 mg/m2/day in three divided doses for 21 days. The patients were asked at each follow-up visit whether they had taken the capsules as prescribed. The treatment was repeated every 3 weeks until disease progression, patient refusal or unacceptable adverse reactions. Anti-emetic prophylaxis was administered. Granulocyte colony-stimulating factor (G-CSF) was used when necessary.
DOSE MODIFICATION
Toxicity was graded according to the National Cancer Institute (NCI) common toxicity criteria 2.0. Treatment was continued without interruption or dose reduction if patients experienced grade 1 toxicities or other toxicities considered by the investigator unlikely to become serious or life threatening (e.g. alopecia). Dose reduction was not required after the first appearance of any grade 2 toxicity, although treatment was interrupted until the toxicity had resolved to grade 0–1, and symptomatic treatment was initiated where possible. Chemotherapy was interrupted and doses reduced by 25% in patients who experienced a second occurrence of grade 2 toxicity. If patients experienced a third occurrence of grade 2 toxicity, or a second occurrence of grade 3 toxicity, the dose was reduced by 50%. Chemotherapy was discontinued if toxicity occurred a fourth time at grade 2, a third time at grade 3 or a second time at grade 4 despite dose reduction. In patients showing grade 3 or 4 neutropenia, UFT administration was interrupted and G-CSF was given. Hand–foot syndrome was graded on the basis of appearance, distribution and symptoms, and was graded as follows: grade 1 = dysthesia/paresthesia, tingling in the hands and feet; grade 2 = discomfort in holding objects and upon walking, painless swelling or erythema; grade 3 = painful erythema and swelling of palms and soles, periungal erythema and swelling; and grade 4 = desquamation, ulceration, blistering and severe pain.
EVALUATION OF TREATMENT
Screening assessment, including medical history, physical examination, ECG, chest X-ray, bone scans and tumor measurements, was conducted within 2 weeks before the start of treatment. Further assessments conducted within 7 days before the start of treatment included vital sign examination, performance status and laboratory tests (hematology, blood chemistry and urinalysis). Patients were examined between day 7 and 10 of each cycle, at which time any subjective toxicities were noted, and blood counts, serum creatinine, sodium and potassium levels were determined. Laboratory measurements were made before each cycle. Responses were classified according to the World Health Organization (WHO) criteria (14), and the best overall response achieved was reported. Response rates were calculated as the proportion of assessable cases. Abdominal CT scan were repeated after two, four and six cycles and then at 12 week intervals until disease progression. Adverse events were recorded throughout the study and for 21 days after the last drug administration of the study.
STATISTICAL METHODS
According to the optimal Simon two-step design, if a minimum objective response rate >40% was observed in the first 15 patients, an additional 15 patients should be enrolled, and if >12 responses were observed in 30 patients (40%), the regimen was considered active to be submitted for further evaluation (15). Time to disease progression (TTP) was defined as the interval between initial treatment and the time of disease progression or death. Survival time was calculated from the date of treatment initiation until the date of the last follow-up evaluation or death. TTP and overall survival (OS) were analyzed according to the Kaplan–Meier method. Survivors were censored on the date they were last known to be alive. The confidence intervals (CIs) for response rates were calculated using methods for exact binominal confidence interval.
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RESULTS |
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PATIENT CHARACTERISTICS
Thirty-five patients with metastatic gastric carcinoma were enrolled in the study from March 2001 to October 2002. Of three patients not subsequently evaluated, one did not receive a full first cycle and two had received prior chemotherapy. Therefore, 32 patients were evaluable for response. Patient characteristics are listed in Table 1. Patients had a median age of 56 years (range, 34–70), and comprised 18 males and 14 females. Twenty-three patients (72%) had a performance status of 0 or 1. All tumors were adenocarcinoma, which included nine signet ring cell carcinomas. Eighteen patients (56%) had lymph node metastasis, while eight (25%) had liver metastases, and seven (21%) and three (9%) had peritoneum and bone metastatic sites, respectively (Table 1).
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RESPONSE TO THERAPY
Six of the first 15 patients showed partial response (response rate 40%). No patients showed complete remission in this study, while 13 showed partial responses, resulting in a response rate of 40.6% (13 of 32 patients). Ten patients had stable disease (31%). Disease stabilization was achieved in 71.6% of patients (Table 2). The median time to response was 6 weeks (range 3–12), and the median number of treatment courses was four (range 1–10). The median TTP was 20.4 weeks (95% CI, 4.5–36.3) (Fig. 1), and the median survival time of all patients was 37 weeks (95% CI 21.8–52.2) (Fig. 2).
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TOXICITY
The total number of treatment courses was 132 (median, four courses per patient; range, 2–10 courses). The most frequent adverse reaction was neutropenia, and grade 4 neutropenia was observed in 6% of patients. Eight of the 132 cycles of UFT administration were interrupted for >7 days due to grade 4 neutropenia. While one patient experienced febrile neutropenia, grade 4 neutropenia for others was resolved promptly with G-CSF support. Other hematological toxicities were mild. Although gastrointestinal toxicities including nausea and vomiting were major adverse effects, these toxicities were generally tolerable. Mucositis and diarrhea were mild. Three patients showed grade 1 or 2 hand–foot syndrome. One patient required a 75% reduction in cisplatin dosage due to increases in blood urea nitrogen (BUN) and creatinine levels, and decreases in creatinine clearance at the 4th and 5th cycle. There were no episodes of hepatic or cardiac toxicity, and no treatment-related death was observed (Tables 3 and 4).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Gastric cancer remains a major cause of cancer death worldwide, and the prognosis of patients with advanced gastric cancer is extremely poor. A standard chemotherapy regimen for gastric cancer has not yet been established, even though chemotherapy is more beneficial than the best supportive care alone in patients with advanced and recurrent gastric cancer (2,3). 5-FU is widely used as a major chemotherapeutic agent for gastric cancer. The oral form of 5-FU has been used as an alternative to protracted i.v. infusion of 5-FU, which is an effective method of delivery. Oral 5-FU can be used on an out-patient basis, eliminating the inconvenience associated with use of infusion pumps, and thus improves QOL for patients.
UFT, an oral anticancer chemotherapeutic with good absorption in the small intestine, is composed of tegafur (TGF, a pro-drug of 5-FU) and uracil (with a 5-FU degradation-inhibitory effect) in a 1:4 molar ratio. The anti-tumor activity of tegafur is enhanced by uracil, which inhibits 5-FU degradation by hepatic dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU catabolism (16). Oral UFT produces a higher maximal plasma level of fluorouracil compared with that achieved by a protracted i.v. injection of fluorouracil at a dose equimolar to the amount of tegafur in UFT (13). In addition, UFT and its metabolites have an inhibitory effect on tumor angiogenesis in mice (17). It is recommended that food should not be consumed for at least 1 h before and after an oral dose of UFT, because simultaneous administration of UFT with food may reduce the systemic exposure to 5-FU (18).
A previous phase I–II study was conducted on 30 patients with advanced upper gastrointestinal tract cancer (22 gastroesophageal, five biliary tract and three pancreas) to examine the effects of a combination chemotherapy of epirubicin, cisplatin and oral UFT, with UFT being administered at escalating doses ranging from 150 to 325 mg/m2/day (19). That study concluded that UFT should be used at 200 mg/m2/day, and found that two-thirds of patients on higher doses required dose reductions. However, UFT was used at doses ranging between 300 and 600 mg/day in phase II clinical trials (13). A phase II trial of oral UFT (480 mg/m2/day) and leucovorin (25 mg/m2/day for 21 days every 4 weeks) in 16 patients with advanced gastric carcinoma showed one complete and three partial responders, and an overall response rate of 28.5%, with tolerable toxicity (20). Several studies suggest 5-FU cytotoxicity can be modulated by use of leucovorin or other cytotoxic drugs (doxorubicin, cisplatin, etoposide and mitomycin C) (21–25). Even though leucovorin has been combined with 5-FU, the optimal dose and schedule of leucovorin administration have not yet been determined (19). In the present study, we conducted a 3-week based phase II study of the combination chemotherapy epirubicin (50 mg/m2/day on day 1), cisplatin (60 mg/m2/day on day 1) and UFT (300 mg/m2/day for 21 days) in patients with metastatic gastric cancer. Since 5-FU is a time-dependent rather than dose-dependent drug and a daily regimen of oral 5-FU is an effective way of maintaining its blood levels, we administered oral UFT without a 1 week break. Grade 4 leukopenia and grade 3 mucositis were observed in 6 and 3% of patients. Jeen et al. reported a 4-week based phase II trial using epirubicin (50 mg/m2/day on day 1), cisplatin (60 mg/m2/day on day 1), UFT and leucovorin (360 and 45 mg/m2/day, respectively, administered together for 21 consecutive days) in 47 patients with advanced gastric cancer, resulting in an overall response rate of 57.5%, including three complete responders, and 42% of patients showing grade 3 or 4 neutropenia (26). In the study using epirubicin, cisplatin and protracted venous infusion of 5-FU for esophagogastric carcinoma including locally advanced disease, the overall response rate of the patients with metastatic disease was 57% and median survival was 7.8 months (10). In the present study, the response rate was 40.6% and median survival was 9.25 months. In addition, patient compliance was very good and consecutive UFT administration was well tolerated by patients. All doses were administered as planned, except in one patient who required a cisplatin dose reduction due to renal toxicity. Only four patients required their schedule to be delayed more than 1 week. Our response rate was inferior to the response rate of ECF, but median survival time was longer and disease stabilization was achieved in 72% of patients (40.6% partial response and 31% stable disease), and toxicities were mild. In conclusion, the combination chemotherapy of epirubicin, cisplatin and UFT is one of the effective and convenient palliative regimens in patients with metastatic adenocarcinoma of the stomach.
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References |
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