Japanese Journal of Clinical Oncology Advance Access published online on July 15, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn062
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© The Author (2008). Published by Oxford University Press. All rights reserved
A Phase I Study of Bolus 5-fluorouracil and Leucovorin Combined with Weekly Paclitaxel (FLTAX) as First-line Therapy for Advanced Gastric Cancer
Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Junichi Matsubara, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045, Japan. E-mail: junjun0808{at}hotmail.com
Received May 10, 2008; accepted June 20, 2008
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Abstract |
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Objective: To determine the dose-limiting toxicity (DLT) and the maximum-tolerated dose (MTD) of combination chemotherapy with leucovorin-modulated weekly bolus 5-fluorouracil (5-FU) and weekly paclitaxel in patients with advanced gastric cancer (GC).
Methods: Chemotherapy-naïve patients with histologically proven metastatic or recurrent GC were enrolled. Paclitaxel was administered as a 1-h intravenous (i.v.) infusion followed by 5-FU as a bolus i.v. infusion on Days 1, 8 and 15. A 2-h i.v. infusion of l-leucovorin was started at the same time as the paclitaxel infusion on Days 1, 8 and 15. Treatment cycles were repeated every 28 days until disease progression or unacceptable toxicity occurred. Patients were scheduled to receive 5-FU, l-leucovorin and paclitaxel at four dose levels (mg/m2/week): 500/250/60 (level 1), 500/250/80 (level 2), 600/250/80 (level 3) and 600/250/100 (level 4), respectively.
Results: Eighteen patients were enrolled. During the first cycle of the highest dose level (level 4), two of the six patients had DLT involving Grade 3 diarrhea and Grade 3 skin rash. Furthermore, three of the four patients who received the second consecutive cycle of treatment at dose level 4 had Grade 4 neutropenia. Dose level 3 was thus determined to be the MTD. Eleven (61%) of the 18 patients had partial responses, and the median progression-free survival time was 6.8 months.
Conclusions: The MTD and the recommended dose for phase II studies of this regimen were determined to be 5-FU 600 mg/m2/week, l-leucovorin 250 mg/m2/week and paclitaxel 80 mg/m2/week.
Key Words: gastric cancer • chemotherapy • weekly paclitaxel • bolus 5-fluorouracil • leucovorin
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgementsReferences |
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Globally, gastric cancer (GC) is the second most common cause of cancer death. Even though the incidence of GC is declining,
930 000 cases are newly diagnosed each year (1). Because of the vague and non-specific symptoms associated with GC, the disease is often advanced at the time of diagnosis. Despite the identification and development of several new classes of anticancer agents, GC remains an aggressive malignancy, with a median survival of 9–13 months in patients with metastatic or recurrent disease (2–5). Paclitaxel, a unique antimicrotubule agent derived from a type of Western yew, Taxus brevifolia, is effective against a variety of cancers, including breast cancer, ovarian cancer, lung cancer and GC (6–10). Recent studies have shown that a weekly regimen of paclitaxel is less toxic than paclitaxel given once every 3 weeks (11,12). Weekly regimens of paclitaxel have thus become popular in Japan, producing good results in patients with advanced GC (13,14).
5-Fluorouracil (5-FU) remains a key drug for the management of GC. In the last decade, oral fluoropyrimidines, such as S-1 and capecitabine, have been tested in many clinical trials as alternative treatments to intravenous (i.v.) 5-FU (3–5,15–17). However, patients with advanced GC often have gastrointestinal symptoms, negatively affecting their general condition and sometimes precluding the administration of oral drugs. Since patients who are in poor condition or who have peritoneal dissemination cannot tolerate aggressive hydration and are at increased risk for intestinal obstruction, treatment with cisplatin or irinotecan is not indicated. New regimens of infusional chemotherapy that are less toxic and more effective than conventional therapy are thus required for patients in poor condition or with poor oral intake, as well as those in good condition.
A sequence-dependent, synergistic cytotoxic effect of paclitaxel followed by 5-FU has been demonstrated in vitro (18,19), and these drugs are relatively free of overlapping toxic effects. Many clinical trials have thus evaluated combination chemotherapy with 5-FU and paclitaxel (20–22). To our knowledge, however, no study has previously examined the safety and efficacy of leucovorin-modulated weekly bolus 5-FU combined with weekly paclitaxel, a regimen that can be given on an outpatient basis.
In this phase I study, 5-FU and l-leucovorin were administered weekly as a bolus i.v. infusion of 5-FU and a 2-h i.v. infusion of l-leucovorin in combination with a 1-h i.v. infusion of paclitaxel (FLTAX regimen). The primary objectives were to define the dose-limiting toxicity (DLT) and the maximum-tolerated dose (MTD) of this regimen in patients with metastatic or recurrent GC. Secondary objectives were characterization of the safety profile and assessment of the antitumor activity of the FLTAX regimen.
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PATIENTS AND METHODS |
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Patient Eligibility
Patients registered in this trial were treated at National Cancer Center Hospital, Tokyo, Japan. To be eligible, patients had to meet the following criteria: histologically proven metastatic or recurrent GC, an age of 20–75 years, a performance status of two or less according to the Eastern Clinical Oncology Group (ECOG) scale, an estimated life expectancy of >8 weeks after study entry, no prior chemotherapy for metastatic disease, adequate hematological function (a white blood cell count between 3000 and 12 000/mm3, a platelet count of
100 000/mm3), adequate hepatic function (a serum total bilirubin level of 
2.0 mg/dl, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of 100 IU/l), adequate renal function (a serum creatinine level of 1.5 mg/dl), a serum C-reactive protein level of 10 mg/dl and written informed consent. Patients also had to have radiographically measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (23). The exclusion criteria were watery diarrhea, marked pleural effusion or ascites, active infection, severe comorbidity such as heart disease or renal disease, metastasis to the central nervous system, mental disorder, a history of alcoholic hypersensitivity, active concomitant malignancy, pregnant or nursing women and women of childbearing age unless they were practicing effective contraception. This phase I study was approved by the Institutional Review Board of the National Cancer Center and conducted in accordance with the Declaration of Helsinki.
DLT and MTD
DLT was defined as follows: Grade 4, neutropenia lasting for 4 days; Grade 3–4, thrombocytopenia; Grade 3–4, febrile neutropenia; Grade 3–4, diarrhea despite adequate antidiarrheal medication; any Grade 3–4, non-hematological toxicity (excluding anorexia, nausea, vomiting, electrolyte abnormalities and alopecia), treatment interruption for 2 weeks and a delay of the start of the second cycle by 8 days because of toxicity.
The MTD was evaluated on the basis of toxic effects during the first cycle. If three or more patients had DLT at a given dose level, then the previous dose level was defined to be the MTD. However, if two or less patients had DLT during the first cycle at the maximum dose level (dose level 4), the MTD was evaluated on the basis of toxic effects during the second treatment cycle. The recommended dose (RD) for phase II studies was defined as the MTD.
Treatment Schedule and Dose Escalation Schedule
Paclitaxel (Taxol; Bristol-Myers K.K., Tokyo, Japan) was administered as a 1-h i.v. infusion followed by 5-FU (Kyowa Hakko Kogyo Co., Ltd, Tokyo, Japan) as a bolus i.v. infusion on Days 1, 8 and 15 of a 28-day cycle. A 2-h i.v. infusion of l-leucovorin (Isovorin; Wyeth K.K., Tokyo, Japan) was started at the same time as the paclitaxel infusion in the same days. This treatment was repeated until disease progression or unacceptable toxicity occurred. Short-term premedication was given to prevent paclitaxel-associated hypersensitivity reactions as follows: dexamethasone, 8 mg; ranitidine, 50 mg and chlorpheniramine, 10 mg administered 30 min before the infusion of paclitaxel. The initially administered dose of paclitaxel was 60 mg/m2 (dose level 1) and escalated to 100 mg/m2 (dose level 4) in increments of 20 mg/m2 (Table 1). The dose of 5-FU was 500 mg/m2 (dose levels 1 and 2) or 600 mg/m2 (dose levels 3 and 4, Table 1). l-Leucovorin was given at a fixed dose of 250 mg/m2 in 250 ml of normal saline solution.
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If patients had leukopenia of <2500/mm3, thrombocytopenia of <100 000/mm3, total bilirubin of >2.0 mg/dl, AST and ALT of >100 IU/l or serum creatinine of >1.5 mg/dl, both 5-FU/leucovorin and paclitaxel were withheld until recovery. To receive a subsequent cycle of chemotherapy, patients had to have a leukocyte count of
3000/mm3 and the recovery of any treatment-related non-hematological toxicity to grade 1 (except alopecia and neuropathy). If patients had DLT, the dose was reduced by one level for the subsequent cycle of treatment (Table 1). If DLT recurred at the reduced dose level, the patient was withdrawn from the study. At least three patients received each dose level. If one or two of the three patients assigned to a given dose had any DLT, three additional patients were assigned to receive the same dose. If one or two of the resulting six patients had DLT, the dose could be increased to the next level. Since the toxicity profiles of both weekly bolus 5-FU and weekly paclitaxel are well known and easy to manage, we used the criterion of three of six DLT for halting dose escalation rather than the standard criterion of two of six DLT.
Toxicity and Response Evaluation
Treatment-related toxic effects were assessed according to the Common Terminology Criteria for Adverse Events, version 3.0. During treatment, patients’ histories were obtained, and physical examinations, complete blood counts with differential counts, serum chemical analyses and urinalyses were carried out at least once a week. Tumor response was evaluated according to the RECIST guideline (23) every 8 weeks until tumor progression.
Statistical Analysis
Progression-free survival time was defined as the time from the date of starting treatment to the date of the first documentation of disease progression or death. Progression-free survival time in patients with protocol treatment cessation for toxicity was calculated as the time to the date of the first documentation of disease progression in subsequent therapies. Time-to-treatment failure was measured from the date of starting treatment to the date of treatment cessation for any reason. Progression-free survival time and time-to-treatment failure were calculated by the Kaplan–Meier method. If patients were receiving treatment according to the protocol at the time of analysis, data were censored at the time of the last evaluation.
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RESULTS |
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Patient Characteristics
Eighteen patients were enrolled in this study between June 2006 and April 2007 at National Cancer Center Hospital, Tokyo, Japan. All patients received at least two cycles of chemotherapy. Toxicity and response were assessable in all patients. The clinical characteristics of the patients are given in Table 2. The median age was 63 years (range: 40–75). A total of 107 cycles of chemotherapy were administered, with a median of 6.5 treatment cycles per patient (range: 2–13). As of November 2007, one patient was receiving the seventh cycle of the protocol treatment and another was receiving the eighth cycle. No patient was lost to follow-up. After a 1-week-observation period in the hospital, all patients could receive treatment on an outpatient basis.
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Toxicity
The number and the type of DLT that occurred during the first treatment cycle in the 18 patients are listed in Table 1. Major toxic effects occurring during the first cycle are summarized in Table 3 according to the dose level. There was no DLT at dose level 1 or 2 (Table 1). At dose level 2, one patient already had Grade 3 anemia at the start of the protocol treatment. At dose level 3, treatment had to be interrupted for longer than 2 weeks because of the prolonged Grade 2 leukopenia in one patient, and another patient had to be hospitalized because of Grade 3 infection (pneumonia) without neutropenia. Both of these reactions were DLT (Tables 1 and 3). Although the former patient subsequently continued to receive the protocol treatment at a reduced dose level, the latter patient, who had a history of mild emphysema, discontinued the protocol treatment and switched to another chemotherapy regimen because of recurrent pneumonia after the first episode. At dose level 4, one patient had Grade 3 diarrhea and another had Grade 3 skin rash during the first cycle (Tables 1 and 3). Both of these reactions were classified as DLT. Both patients subsequently continued to receive the protocol treatment at a reduced dose level. Although diarrhea (
Grade 1: 22%) and skin rash (Grade 1: 22%) developed in other patients at all dose levels, these reactions were mild and promptly resolved after appropriate medical treatment, such as antidiarrheal agents, antihistamines and steroids. As for hematological toxicity at dose level 4, Grade 3 neutropenia occurred in only one patient during the first cycle of treatment.
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The MTD could not be determined on the basis of the toxic effects described above. The MTD was therefore estimated on the basis of toxic effects during the second cycle, as stipulated by the protocol. During the second cycle, no DLT occurred at any dose level. There was no difference in non-hematological toxicity between the first and the second cycles at any dose level. As for hematological toxicity, Grade 4 neutropenia developed in three of the four patients who received the second consecutive cycle of treatment at dose level 4 (Table 4). Although febrile neutropenia did not develop in any of these patients, we decided that dose level 4 was beyond the limits of tolerance. Two patients who had DLT during the first cycle of dose level 4 received subsequent cycles of treatment safely at a reduced dose level. At dose levels 1–3, there were no differences in hematological toxic effects between the first and the second cycles. Thus, the MTD and the RD were defined as dose level 3.
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As for cumulative toxicity, four patients (22%) had Grade 2 sensory neuropathy after the second or subsequent cycles. In one of these patients, the protocol treatment was discontinued after the ninth cycle because of the prolonged Grade 2 sensory neuropathy. In another patient, the protocol treatment had to be withdrawn at the end of the second cycle because of Grade 3 sensory neuropathy. No other cumulative toxicity occurred at any dose level.
At dose levels 1–3, 85–90% of the initially planned doses of 5-FU, l-leucovorin and paclitaxel were administered (Table 5). At dose level 4, however, only 75% of the initially planned doses were administered, supporting our decision to designate dose level 3 as the RD.
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Efficacy
All patients were included in the evaluation of response. Objective tumor responses at each dose level are given in Table 5. Eleven patients (level 1, two; level 2, three; level 3, three and level 4, three) had partial responses, yielding an overall response rate of 61% (95% confidence interval, 36–83%). Although partial responses were obtained at all dose levels, no patient had a complete response.
The reasons for cessation of the protocol treatment were progressive disease in 12 patients (67%), sensory neuropathy in two (11%), skin rash in one (6%) and infectious pneumonia in one (6%). The median progression-free survival time and time-to-treatment failure were 6.8 and 6.3 months, respectively. At the time of analysis, six patients had died of tumor progression and two patients continued to receive the protocol treatment (the seventh and eighth cycle, respectively). The median survival time was not yet reached, and the median follow-up time was 9.6 months.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgementsReferences |
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Recently, several randomized-controlled trials have suggested that the triple-drug combinations (2,4) or oral fluoropyrimidine-based regimens (3,5) are suitable as standard chemotherapy for advanced GC. However, such regimens are very toxic and can be tolerated only by the patients with adequate organ functions, making them unsuitable for many patients with advanced GC because of the poor performance status at initial diagnosis. Thus, further investigations of effective and less toxic regimens are warranted in patients with GC.
The toxicity profile of the FLTAX regimen, a combination of leucovorin-modulated weekly bolus 5-FU and weekly paclitaxel, was acceptable. Grade 3–4 toxicities were infrequent and the only Grade 4 toxicity during the first two cycles was neutropenia at dose level 4 (Tables 3 and 4). As expected, the addition of weekly paclitaxel (13,14) to a leucovorin-modulated weekly bolus 5-FU regimen (24) was associated with a modest increase in adverse events. The toxicity profile of the FLTAX regimen was similar to those in previous studies using different administration schedules for 5-FU/leucovorin and paclitaxel (22,25,26). The good toxicity profile of the FLTAX regimen might make it a viable alternative treatment for patients who cannot receive intensive triple-drug combination regimens. In patients who cannot tolerate more toxic regimens, the good toxicity profile of the FLTAX regimen might also permit the concurrent use of new targeted agents.
We combined a leucovorin-modulated weekly bolus 5-FU regimen with a weekly paclitaxel regimen for several reasons. First, to our knowledge, clinical trials of this combination regimen have not been reported, although it can be used on an outpatient basis. Because metastatic and recurrent GC is incurable, maintenance of an acceptable quality of life and avoiding repeated hospitalization to receive chemotherapy are very important issues. Second, a weekly regimen of paclitaxel is less toxic and has a higher dose-intensity than paclitaxel given once in every 3 weeks (12,27,28). Furthermore, a weekly paclitaxel schedule makes it possible to take advantage of the sequence-dependent synergistic cytotoxic effect of paclitaxel followed by 5-FU (18,19). Third, the leucovorin-modulated weekly bolus 5-FU incorporated in the FLTAX regimen is effective, and 5-FU-associated toxicity can be easily managed (29,30). Although protracted 5-FU infusion might be associated with less toxicity (31), protracted weekly or monthly 5-FU infusions require indwelling venous access devices and ambulatory pumps to permit treatment on an outpatient basis. Such lower toxicity should be balanced against the disadvantages presented by the use of these devices. Our study showed that the FLTAX regimen, which does not need such devices for outpatient treatment, was well tolerated with minimal toxicity. Fourth, although oral fluoropyrimidines, such as S-1 and capecitabine, have been evaluated in many clinical trials to determine whether these newer drugs can replace i.v. 5-FU (3,15–17), they cannot be used in some patients with advanced GC. For examples, tumors associated with obstruction of the pylorus or the cardia or with peritoneal invasion cause dysphagia, nausea, vomiting, often precluding the administration of oral anticancer drugs as prescribed. Furthermore, diffuse peritoneal spread of disease frequently causes intestinal obstruction at other sites, a common characteristic of advanced GC.
In the present study, five patients (28%) experienced Grade 2 sensory neuropathy and two of them (11%) had to discontinue protocol treatment due to neurotoxicity: one was typical Grade 2 cumulative toxicity after the ninth cycle and another was atypical Grade 3 sensory neuropathy in the second cycle. The incidence of Grade 3 neuropathy (6%) was identical with previous reports (22,28). In general, cumulative neurotoxicity of paclitaxel can be managed by dose reduction or postponement strategy as is successfully applied to the remaining three patients with Grade 2 sensory neuropathy in our study.
In conclusion, our study suggested that the FLTAX regimen would be well tolerated when used for the first-line treatment in patients with metastatic or recurrent GC. The MTD and the RD for phase II studies was dose level 3 (i.e., weekly bolus 5-FU, 600 mg/m2; l-leucovorin, 250 mg/m2 and weekly paclitaxel, 80 mg/m2). Eleven of the 18 patients in this study had partial responses, suggesting that the FLTAX regimen is a promising treatment for advanced GC. A multicenter phase II study of the FLTAX regimen is now underway in patients with metastatic or recurrent GC, and a feasibility study of this regimen in patients with diffuse peritoneal spread of GC is being planned.
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Acknowledgements |
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We thank Ms. Hiromi Orita, Ms. Maiko Muroya, Ms. Michiyo Tada and Mr. Yushi Nagai for their help in collecting and organizing the clinical data.
Conflict of interest statement None declared.
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References |
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