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Journal of Clinical Oncology, Vol 22, No 4 (February 15), 2004: pp. 658-663 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.042 Phase II Trial of Biweekly Infusional Fluorouracil, Folinic Acid, and Oxaliplatin in Patients With Advanced Gastric CancerFrom the Krankenhaus Nordwest and Johann-Wolfgang-Goethe Universitätsklinik, Frankfurt; Universitätsklinikum Hamburg-Eppendorf, Hamburg; Onkologische Praxis, Jena; Onkologische Praxis, Bad Soden; Klinikum Darmstadt, Darmstadt; Internistisch-Onkologische Praxis, Eltville, Germany; Universitätsspital Zürich, Zürich, Switzerland Address reprint requests to E. Jaeger, MD, Krankenhaus Nordwest, 60488 Frankfurt am Main, Germany; e-mail: EJ200161{at}aol.com
PURPOSE: To evaluate the toxicity and activity of infusional fluorouracil (FU), folinic acid (FA), and oxaliplatin, administered every 2 weeks in patients with metastatic gastric cancer. PATIENTS AND METHODS: Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m2 (24-hour continuous infusion), FA 500 mg/m2 (2-hour intravenous infusion), and oxaliplatin 85 mg/m2 (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed. RESULTS: All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths. CONCLUSION: Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.
Gastric cancer is often diagnosed in locally advanced or metastatic stages and, therefore, of poor prognosis. Only 10% of patients with advanced gastric cancer treated with chemotherapy survive 2 years [1]. Systemic chemotherapy is widely accepted as palliative treatment, leading to objective responses, improvement of the quality of life, and prolonged survival [2-4]. Based on response results of several combination chemotherapy regimens, advanced gastric cancer is considered to be a chemotherapy-sensitive disease. However, results of survival have been unsatisfactory so far, with a median survival time ranging between 6 and 8 months [5,6]. In prospectively randomized studies, combination chemotherapy with epirubicin, cisplatin, and continuous infusion of fluorouracil (ECF) has led to significant response rates and survival benefit for patients with advanced gastric cancer [7,8]. The results of ECF were superior to those achieved with the former standard regimen consisting of fluorouracil (FU), doxorubicin, and high-dose methotrexate (FAMTX). However, significant treatment related toxicities and discomfort were reported from ECF which prevented this protocol from becoming the standard treatment regimen. Infusional high-dose FU proved to be an effective and well-tolerated treatment for patients with gastric cancer [9-11], providing a favorable basis for combination chemotherapy protocols [6]. Several nonrandomized studies demonstrated that superior response rates up to 70% were achieved by combining cisplatin with FU in various schedules [12-16] with only moderately increased toxicity [12]. Therefore, cisplatin combined with FU is now widely used for the treatment of patients with advanced gastric cancer, even though a randomized European Organization for the Research and Treatment of Cancer trial showed that the response rates and survival results of 5-day infusional FU plus cisplatin (CF) are not superior to those of FAMTX [17]. Most recently, superior efficacy results with respect to response rates and time to progression (TTP) could be achieved with docetaxel plus CF (DCF) compared with CF alone (response rate [RR], 38.7% v 23.2% and TTP 5.2 v 3.7 months, respectively) in patients with locally advanced and metastatic gastric cancer [18]. However, DCF caused significant hematologic toxicity including WHO grade 3/4 neutropenia in 84% and WHO grade 3/4 febrile neutropenia in 16% of patients. Thus, there is presently no chemotherapy regimen considered to be the standard of care for patients with advanced gastric cancer. New protocols are warranted to achieve superior treatment results, leading to an increased rate of effective disease control with more favorable toxicity profiles. Oxaliplatin is an alkylating agent inhibiting DNA replication by forming adducts between two adjacent guanines or guanine and adenine molecules. However, the adducts of oxaliplatin appear to be more effective than cisplatin adducts with regard to the inhibition of DNA synthesis [19-21]. In contrast to cisplatin, oxaliplatin has demonstrated efficacy alone and in combination with FU in advanced colorectal cancer. Many studies are ongoing to test the combination in noncolorectal gastrointestinal tumors and other malignancies [22]. Oxaliplatin has a more favorable toxicity profile compared to cisplatin. The dose-limiting toxicity is a cumulative sensory peripheral neuropathy [23]. Because of the limited response duration, TTP, and overall survival (OS) in patients with gastric cancer, safety and tolerability are prominent objectives for the assessment of new protocols. To minimize toxicity, we chose a biweekly protocol containing FU (24-hour continuous infusion) 2.6 g/m2 and folinic acid (FA) 500 mg/m2 combined with oxaliplatin 85 mg/m2, administered every 2 weeks to evaluate the activity and tolerability in patients with advanced gastric cancer.
Patient Eligibility Patients were eligible with histologically confirmed inoperable or metastatic adenocarcinoma of the stomach; at least one measurable lesion, no prior chemotherapy, Eastern Cooperative Oncology Group performance status  2, age > 18 years, life expectancy  3 months, no concurrent uncontrolled medical illness, no other malignancies (with the exception of squamous cell carcinoma of the skin treated by surgery), creatinine clearance 50 mL/min, and sufficient hepatic and bone marrow function. Patients were excluded from the study if they had peripheral neuropathy of National Cancer Institute common toxicity criteria grade 2, or were pregnant or breast-feeding. Women of child-bearing potential were advised to take adequate precautions to prevent pregnancy. Participants gave written informed consent before they entered the study, which was approved by the local Ethic Committees of participating centers.
Chemotherapy
Toxicity Assessment
Assessment of Response The number of patients required for the study was calculated according to a Simon optimal design. An interim analysis was carried out after the first 18 assessable patients had completed treatment. Since more than two responses were observed, 23 additional patients were recruited. The regimen was considered active if the response rate exceeded 30%.
Between November 1999 and September 2002, 41 patients were enrolled onto the study at six German oncology centers. All patients were assessable for the safety analysis and 37 patients were assessable for response. Four patients were excluded from the response analysis because they did not complete three cycles of chemotherapy and did not show early progression; one patient refused continuation of treatment because of personal aspects after the second cycle. One patient received a treatment that was incompatible with the protocol (weekly FU schedule instead of biweekly) and was excluded from the study. Two patients went off study early, both after the first cycle, because of adverse events not related to the treatment (loss of memory and confusion in one patient and severe tachyarrhythmia in one patient). Patient characteristics are listed in Table 1.
Response The overall objective response rates are listed in Table 2. One CR of 37 assessable patients (2.7%) and 15 (40.5%) partial responses (PRs) were observed, adding to an overall response rate of 43.2% (95% CI, 27.1% to 60.5%). Twelve patients (32%; 95% CI, 10.0% to 49.8%) had stable disease and nine patients (24.3%) had progressive disease. No difference in response rates was observed with respect to the extent of disease dissemination (patients with one organ v more than one organ involvement). However, liver involvement seemed to be associated with lower response rates (Table 2). Of 16 responses, 14 (87.5%) were observed after three cycles and two (12.5%) after six cycles of chemotherapy. One patient with locally advanced disease and PR underwent successful curative surgery after 12 cycles. Four months later, the patient progressed with a distant relapse.
Survival Forty patients were included in the survival analysis on an intent-to-treat basis. One patient was excluded because he was lost to follow-up. The median follow-up time was 11.2 months (range, 5.2 to 27.3 months). The median TTP was 5.6 months (range, 1.3 to 22.3 months). The median TTP was 4.8 months in the patient group with newly diagnosed disease and 8.3 months in the patient group with recurrent disease after surgery (hazard ratio, 0.53; Peto-Wilcoxon test, P = .026). The median OS was 9.6 months (range, 1.7 to 27.3+ months). TTP and OS were assessed by Kaplan-Meier-Analysis shown in Figure 1. Sixteen patients were followed for longer than 12 months. For these patients the 1-year survival rate was 25%.
Safety Forty-one patients received a total of 311 treatment cycles. The median number of cycles administered was seven (range, one to 17 cycles). Seventy-six percent of patients received at least six cycles and 41% of patients received at least nine cycles. The median cumulative doses were 595 mg/m2 (range, 85 to 1,445 mg/m2) for oxaliplatin, 18,200 mg/m2 (range, 2,600 to 44,200 mg/m2) for FU, and 3,500 mg/m2 (range 500 to 8,500 mg/m2) for FA. No reduction of treatment doses was required. Five patients discontinued treatment because of treatment related adverse events; one for cardiac toxicity (recurrent anginal chest pain during and 24 hours after FU without myocardial infarction), one for renal toxicity (acute renal failure after 17 cycles), one for neurotoxicity other than peripheral neuropathy, and two patients for gastrointestinal toxicity (diarrhea). No treatment interruptions or discontinuation for peripheral neuropathy were reported and there were no treatment-related deaths. Toxicities observed during the treatment are listed in Table 3. WHO grade 1 and 2 nausea, vomiting, and diarrhea were reported in 73.1%, 41.5%, and 36.6% of the study population, respectively. WHO grade 3 and 4 nausea, vomiting, and diarrhea were reported in 0%, 4.9%, and 7.3%, respectively. Severe hematologic toxicities were uncommon. WHO grade 3 and 4 leucopenia, neutropenia, thrombocytopenia, and anemia were observed in 0%, 4.9%, 2.4%, and 7.3%, respectively. Mild and moderate peripheral neuropathy was observed in 48.8% (grade 1 in 29.3% and grade 2 in 19.50%) of the patients, while severe (grade 3) peripheral neuropathy was not reported. Renal failure requiring transient hemodialysis was observed in one patient after 17 cycles of chemotherapy, which was possibly related to oxaliplatin. Severe cardiac toxicity, related to FU, was reported in one patient. An episode of amnesia and anxiety was observed in one patient, which was possibly related to oxaliplatin.
The prognosis of advanced gastric cancer has remained poor despite the development of new palliative treatment modalities. Response rates achieved with different combination chemotherapy regimens range between 30% and 70%, but OS rarely exceeds 9 months [13-14,25-29]. Therefore, effective treatment approaches with moderate toxicity profiles are needed. Weekly and biweekly FU/FA/oxaliplatin regimens have been mainly explored so far in colorectal cancer with an encouraging efficacy profile [30,31]. This combination has also been evaluated in a number of phase II studies in the first- [32] and second- [33,34] line treatment setting of advanced gastric cancer. Response rates were higher than those achieved in studies using FAMTX, etoposide, leucovorin, and fluorouracil (ELF) and etoposide, doxorubicin, and cisplatin, and equivalent to those achieved with ECF or other anthracyclin-containing regimens. However, FOLFOX6 caused significant toxicity, including myelosuppression and peripheral neuropathy. Based on these results, we conducted a phase II study to explore the safety and efficacy of a biweekly reduced-dose combination therapy with FU/FA/oxaliplatin (FLO) without FU bolus in patients with advanced gastric cancer. Compared to FOLFOX6, our protocol consisted of significantly reduced doses of oxaliplatin (85 mg/m2 v 100 mg/m2) and FU (2.6 g/m2 without bolus over 24 hours v 2.4 to 3.0 g/m2 over 48 hours plus FU bolus 400 mg/m2) administered every 2 weeks. As a result of the modified treatment schedule in this study, the toxicity profile was moderate with grade 1 and 2 peripheral neuropathy representing the leading toxicity observed in 49% of patients. The absence of grade 3 neuropathy is probably related to the low median cumulative dose of oxaliplatin (595 mg/m2) administered in this study. As a result, no neuropathy-related discontinuation of treatment was reported. In contrast to our results, high rates of oxaliplatin-related neuropathy occurred in recent reports on the toxicity and efficacy of FOLFOX6 in patients with locally advanced and metastatic gastric cancer [32] and FOLFOX4 [35] in patients with advanced colorectal cancer (21% and 18% grade 3 neurotoxicity, after median cumulative doses of up to 900 mg/m2). The second most common toxicities observed in our study were nausea (73%) and vomiting (46%), followed by a low rate of hematologic toxicity (4.9%; WHO grade 3/4 neutropenia and 0% WHO grade 3/4 leucopenia). In contrast to our results, significantly higher rates of neutropenia and leucopenia were reported during ECF and FOLFOX6 (38% and 29%; WHO grade 3/4 neutropenia and 19% and 10% WHO grade 3/4 leucopenia, respectively). One female patient in our study experienced acute renal failure after 17 treatment cycles requiring transient hemodialysis. The patient had normal renal function parameters before the treatment. She had neither vomiting nor diarrhea, was not dehydrated, and did not receive concomitant medication with renal toxicity. She developed a PR that was confirmed by a CT scan 4 weeks after the event. Therefore, the investigator considered the adverse event as possibly related to oxaliplatin. The median TTP of 40 patients analyzed in this study was 5.6 months, and the median OS was 9.6 months. These results are comparable to those reported from standard combination regimens such as ECF, ELF, CF, and FAMTX (overall survival 8.7, 7.2, 7.2, and 6.7 months, respectively, in randomized studies) [7,17], which are known to cause substantial toxicity. The overall response rate analyzed in 37 assessable patients treated with FLO was 43.2%, including one CR (2.7%) and 15 PRs (40.5%), and is comparable to the results reported from studies using FAMTX, ECF, ELF, and FOLFOX6 [7,17,32], and the recent randomized study with DCF versus FU and CF in patients with locally advanced and metastatic gastric carcinoma [18]. In this study, the RR and TTP of DCF were superior to those of CF (RR, 38.7% v 23.2% and TTP 5.2 v 3.7 months, respectively), while the difference in OS (10.2 v 8.5 months, respectively) could not reach statistical significance. However, the hematologic toxicity in the DCF arm was significant, with WHO grade 3/4 neutropenia of 84% and WHO grade 3/4 febrile neutropenia of 16%. As a result of the low toxicity profile, FLO represents an active and well-tolerated treatment modality for patients with locally advanced and metastatic gastric cancer. The results reported here may be improved within integrated treatment approaches, including surgery following preoperative FLO, within sequential strategies for systemic treatment or by the addition of a third active drug. The favorable safety profile of FLO leads us to recommend this protocol for the palliative treatment of patients with previously untreated advanced and metastatic gastric cancer, and to consider further evaluation of the phase II data in randomized multicenter and multimodality trials.
The authors indicated no potential conflicts of interest.
We thank Antje Neumann and Cornelia Frisch for their help in the documentation of the study data and the study coordination. We thank Dr Axel Hinke (Wissenschaftlicher Service Pharma GmbH, Langenfeld, Germany) for the statistical analysis.
Submitted July 7, 2003; accepted December 10, 2003. Presented in part at the 2003 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
