Japanese Journal of Clinical Oncology Advance Access originally published online on June 16, 2005
Japanese Journal of Clinical Oncology 2005 35(6):332-337; doi:10.1093/jjco/hyi096
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© 2005 Foundation for Promotion of Cancer Research
Phase I Evaluation of Continuous 5-Fluorouracil Infusion Followed by Weekly Paclitaxel in Patients with Advanced or Recurrent Gastric Cancer
1 Department of Surgery, Nagoya National Hospital, Nagoya, 2 First Department of Surgery, Kochi Medical School, Nankoku, Kochi, 3 Aichi Prefectural Hospital, Okazaki, Aichi, 4 Asa Municipal Hospital, Hiroshima, 5 Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, 6 Second Department of Surgery, Nagoya University School of Medicine, Nagoya and 7 Department of Epidemiological and Clinical Research Information Management, Kyoto University Graduate School of Medicine, Kyoto, Japan
For reprints and all correspondence: Ken Kondo, Department of Surgery, Nagoya National Hospital, 1-1, San-nomaru 4-chome, Naka-ku, Nagoya 460-0001, Japan. E-mail: kkondnnh{at}ce.mbn.or.jp
Received January 16, 2005; accepted May 8, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: We conducted a phase I trial of escalating doses of weekly paclitaxel (Taxol) in combination with a fixed systemic administration of 5-fluorouracil (5-FU) in patients with advanced or metastatic gastric cancer.
Methods: Patients with advanced or recurrent gastric cancer were treated with escalating doses of weekly paclitaxel as a 60 min intravenous (i.v.) infusion, along with a fixed dose of continuous 5-FU infused over 5 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel.
Results: Eighteen patients received combination therapy at four dose levels of weekly Taxol, ranging from 60 to 90 mg/m2/week. Dose-limiting toxicities >grade 3 were observed at the 90 mg/m2/week dose level. Toxicities included anemia, neutropenia, thrombocytopenia, nausea and alopecia. Two episodes of grade 4 neutropenia occurred in two of the three patients receiving this dose. At each dose level, pharmacological studies documented the persistence of significant serum paclitaxel levels over 24 h after drug administration. The maximum tolerated dose (MTD) for this regimen was 90 mg/m2/week of paclitaxel for 3 weeks plus 600 mg/m2/day of continuous 5-FU for 5 days.
Conclusions: The combination of weekly paclitaxel and 5-FU demonstrated an acceptable toxicity profile and feasible pharmacokinetic results suggesting its practical applicability. Based on these findings, the recommended dose and schedule for phase II study of combination chemotherapy is paclitaxel 80 mg/m2/week x 3 over 4 weeks, and continuous 5-FU 600 mg/m2/day x 5 days every 4 weeks.
Key Words: 5-fluorouracil • weekly paclitaxel • gastric cancer
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INTRODUCTION |
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The most commonly used traditional standard regimens to date for advanced gastric cancer include EAP (etoposide/doxorubicin/cisplatin) (1), FAP [5-fluorouracil (5-FU)/doxorubicin/cisplatin] (2) and FP (5-FU/cisplatin) (3). Recently, the development of new anticancer drugs, such as CPT-11 (4), S1 (5) (a new fluorinated pyrimidine derivative) and taxanes (6) has succeeded in increasing the response rate and improving the median survival of patients with advanced gastric carcinoma. However, 5-FU still appears to be the key chemotherapeutic agent in many combination regimens for gastric cancer. Among various suggested schedules, continuous 5-FU infusion was found to be more effective than a conventional bolus schedule (7).
On the other hand, many of these patients are likely to develop a recurrence of refractory disease within a very short period of time, after a few cycles of the pre-existing treatment. Therefore, despite initial high response rates, the long-term benefits of these treatments are not as dramatic as expected. Furthermore, peritoneal dissemination occurs in nearly half of refractory gastric cancers, which often causes multiple bowel obstructions and severe ascites. Impaired quality of life in such patients remains one of the most serious and urgent problems in the treatment of gastric cancer.
Paclitaxel is one of the taxanes which exhibit clinically relevant activity against several tumors. However, the optimal dose and schedule of paclitaxel for patients with metastatic gastric cancer still remain to be defined. In a Japanese phase II trial (8) of paclitaxel administration by 3 h infusion every 3 weeks for patients with gastric cancer, objective responses were observed in 23% of cases. Considering the cellular mode of action of paclitaxel, which is predominantly cytotoxic for dividing cells, repeated doses should show added benefits. Weekly administration of paclitaxel has been demonstrated to be well tolerated and feasible in patients with ovarian (9) and breast cancers (10).
The large molecular weight and bulky chemical structure of paclitaxel delay peritoneal clearance, increase exposure in the peritoneal cavity, and can thus be exploited in the treatment of gastric cancers (11). Furthermore, paclitaxel exerts its cytotoxic effects through a mechanism different from that of 5-FU, and thus shows no cross-resistance with 5-FU. In tumor cell lines, the combination of paclitaxel and 5-FU has demonstrated additive cytotoxicity, especially with sequential exposure (12).
Based on these clinical and laboratory data, we performed a phase I trial of paclitaxel in association with a fixed dose of 5-FU. The goals of this study were: (i) to determine the maximum tolerated dose (MTD) of weekly paclitaxel in association with a fixed dose of 5-FU; (ii) to describe and quantitate the toxicities of this drug combination; and (iii) to study the pharmacokinetics and pharmacodynamics of weekly paclitaxel.
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PATIENTS AND METHODS |
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ELIGIBILITY
Patients in this study had histologically proven metastatic gastric cancer with/without measurable lesions. Other inclusion criteria were: age 20–75 years, Eastern Cooperative Oncology Group (ECOG) performance status <2, life expectancy >2 months, adequate bone marrow function (white cell count >4000/mm3, platelet count >100000/mm3 and hemoglobin level >9.0 g/dl), adequate renal function (creatinine clearance >50 ml/min), adequate hepatic function (bilirubin level <1.5 mg/dl, and GOT and GPT less than twice the upper limit of normal), >1 month interval since prior chemotherapy, and no active cancer in other organs. All patients gave written informed consent conforming to institutional guidelines indicating that they were aware of the investigational nature of the study. This protocol was approved by the ethical committee of all participating institutions.
TREATMENT
Chemotherapy consisted of repeated doses of 5-FU and paclitaxel given at 4-week intervals. The 5-FU dose was 600 mg/m2/day administered by continuous infusion for 5 days on days 1–5. Paclitaxel was given as a 1 h infusion on days 8, 15 and 22, together representing one treatment cycle. Pre-medication consisted of intravenous (i.v.) dexamethasone (16 mg/body) and cimetidine (50 mg i.v.) given 30 min before every paclitaxel administration. The paclitaxel dose was escalated in successive patient cohorts to determine its MTD in association with the fixed dose of continuous 5-FU infusion.
The following doses of paclitaxel were chosen: dose level 1 (starting dose), 60 mg/m2; dose level 2, 70 mg/m2; dose level 3, 80 mg/m2; and dose level 4, 90 mg/m2. Subsequent dose levels were not started until safety and tolerance had been assessed at the previous dose level for all three patients for one complete cycle.
Determination of the MTD for paclitaxel was performed by evaluating individual cohorts of 3–6 patients at each dose level. If none of the first three patients had dose-limiting toxicities (DLTs) at a given dose, then the dose was escalated to the next level in a subsequent cohort. If a DLT occurred in one of three patients, an additional three patients were evaluated at the same dose level, and only if none or one of these additional three patients experienced DLT was the paclitaxel dose escalated. If two or more out of a cohort of three, or three or more out of a cohort of six patients displayed DLT, then accrual at that level was stopped, and the level was declared the MTD. No intrapatient dose escalation was allowed.
PATIENT EVALUATION AND FOLLOW-UP
At study entry, all patients had complete medical history and physical examinations, in addition to laboratory studies (complete blood cell count, urinalysis, electrolytes, and renal and liver function tests), chest X-ray and electrocardiogram. Computed tomography (CT), magnetic resonance imaging scans, plain radiograms or other appropriate imaging tests were performed to clarify and document the location, size and extent of disease, when measurable. Response to treatment was assessed after two cycles according to standard World Health Organization (WHO) criteria. A complete blood cell count, urinalysis, electrolytes, and renal and liver function tests were evaluated at least once weekly and before subsequent cycles, and at the conclusion of the study.
TOXICITY
During treatment, patients had weekly full hematological blood cell counts, determination of liver and renal function, and assessment of non-hematological toxicities. Toxicity was recorded every week according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) (13). Dose-limiting hematological and non-hematological toxicities were defined separately. Dose-limiting hematological toxicities were defined as NCI grade 4 leukopenia or grade 4 neutropenia lasting for >4 days, grade 4 leukopenia or grade 4 neutropenia accompanied by high fever (>38°C), and grade 3 thrombocytopenia (<20000/mm3). Dose-limiting non-hematological toxicities were defined as NCI grade 3 and 4 toxicity, with specific exclusion of grade 3 nausea, vomiting or alopecia.
PHARMACOKINETICS STUDIES
Blood samples for pharmacokinetic studies were collected from a subset of patients. To measure paclitaxel concentrations, blood samples were collected whenever possible during the initial treatment course. Samples were collected at 0, 0.5, 1.5, 6, 12 and 24 h after completion of drug instillation. Samples were collected in heparinized tubes, centrifuged, and the supernatant was stored at –20°C until assayed. Paclitaxel concentrations were measured in plasma using a reverse-phase high-performance liquid chromatographic assay.
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RESULTS |
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PATIENT CHARACTERISTICS
Eighteen patients with metastatic gastric cancer entered this phase I trial between June 2001 and June 2002. The patient characteristics are summarized in Table 1. Twelve men and six women entered the study. The mean age was 59 years (range 22–72), and ECOG performance statuses were 0 (eight patients), 1 (eight patients) and 2 (two patients). Six out of a total of 18 patients had measurable disease. Seven patients underwent surgery and received fluorinated pyrimidine-based chemotherapy prior to entry into the study. Seven patients underwent only surgery, and four patients had not received any prior treatment before enrollment in the study. No patient had received prior paclitaxel chemotherapy. The histological features of the gastric cancers were 11 intestinal type and seven diffuse-type adenocarcinomas. Of 18 patients entered in the study, three (17%) did not complete the 8 weeks of planned combination therapy. The reasons for premature discontinuation of treatment were toxicity (two patients) and disease progression (one patient).
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TOXICITY AND DETERMINATION OF DLT AND MTD
All 18 patients were fully evaluated for toxicity. Table 2 summarizes the incidence of toxic events that occurred at each dose level. Dose-limiting hematological toxicity did not occur in any patient at dose levels 1–3. Ten out of 18 patients experienced grade 1 or 2 alopecia. At dose level 1 (paclitaxel 60 mg/m2), one of six patients had DLT. The patient developed grade 3 diarrhea, probably due to 5-FU, at the time of the first paclitaxel administration. Therefore, three more patients were added to this first cohort. No grade 3–4 toxicity was observed among these additional patients. At dose level 2 (paclitaxel 70 mg/m2), no DLT was noticed in any of the three patients. At dose level 3 (paclitaxel 80 mg/m2), one of the first three patients showed grade 3 stomatitis, which was considered to be a DLT. Among the three additional patients given dose level 3, one developed grade 3 diarrhea, which was also regarded as a DLT. At dose level 4 (paclitaxel 90 mg/m2), two of the three patients demonstrated DLTs. One showed grade 3 diarrhea, hyperbilirubinemia and hyponatremia, and the other patient developed grade 4 leukopenia, neutropenia, hyperbilirubinemia and liver dysfunction. The latter patient died before the completion of treatment due to a severe bronchopneumonia. The Efficacy and Safety Assesment Committee could not find a direct relationship between the treatment and the death. As a consequence of these collective results, the regimen consisting of continuous 600 mg/m2 5-FU for 5 days + 90 mg/m2 weekly paclitaxel for 3 weeks was declared the MTD. The DLTs observed in this portion of the study included myelosuppression as well as gastrointestinal symptoms and liver dysfunction.
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EFFICACY
Two-thirds of the patients could not be assessed for responses according to the WHO criteria, since many cases of advanced or refractory gastric cancer were not measurable by pre-existing imaging modalities. Thus, only six of the 18 patients had measurable disease and had received at least two cycles of chemotherapy. One patient without prior chemotherapy achieved a complete response in the liver metastasis, and the overall response rate was one out of six (17%) among patients evaluated in this study. Four patients showed stable disease (SD). In one of these four patients, an obvious relief from symptoms caused by severe ascites was demonstrated. Also, in two other patients with SD, reduction in tumor marker levels to the normal range (patient 7, CEA from 45.8 to 4.9; patient 10, CA19.9 from 57 to 12) was noted. A marked decrease in tumor marker levels was also observed in two of the nine patients with non-measurable disease (patient 5, CA19.9 from 57 to 39; patient 17, CA19.9 from 7882 to 161).
At the time of this report, the median follow-up time since study entry was 10 months (range 1–20 months). The observed median survival time was 335 days, with an estimated 1-year survival rate of 39% (Fig. 1).
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PHARMACOKINETIC ANALYSIS
Plasma specimens were collected from all 18 patients who received paclitaxel on week 1 of course 1. Steady-state paclitaxel levels were assessed at 0, 0.5, 1.5, 6, 12 and 24 h after the completion of the paclitaxel infusion. The area under the curve (AUC) was calculated in ng/h/ml. The mean (range) AUC (ng/h/ml) for each dose level was as follows: level 1 (60 mg/m2), 2573 ± 571; level 2 (70 mg/m2), 3742 ± 1234; level 3 (80 mg/m2), 4461 ± 2401; and level 4 (90 mg/m2), 6623 ± 3033. These values are depicted graphically in Fig. 2. There was a positive correlation between increasing paclitaxel dose and AUC. The agents in the systemic circulation achieved biologically relevant concentrations, which were maintained for a long duration, even when administered weekly and in combination with continuous 5-FU therapy.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Although gastric cancer has been decreasing in most developed countries, it still shows an exceptionally high rate of morbidity and mortality in Japan. Attempts to establish a standard treatment regimen for advanced gastric cancer have been the goal of many clinical investigators. The ECF (cisplatin/epirubicin/5-FU) regimen in Europe and the DCF (docetaxel/cisplatin/5-FU) regimen in the USA are actually regarded as standard first-line therapies (14). In Japan, in addition to these therapies, a newly developed oral fluorinated pyrimidine drug, TS-1, has been widely accepted as a first-line treatment for advanced gastric cancers. Considering these various modalities and the devastating consequences of this cancer, an effective therapy for gastric cancer has to be established and globally agreed upon.
A number of new agents have been introduced recently, either alone or in combination, for the treatment of solid tumors. Paclitaxel is one newly developed anticancer drug which has appeared promising for the treatment of gastric cancer, especially for patients with advanced and refractory peritoneal dissemination. Chang and associates (15) found that paclitaxel was effective in inhibiting the growth of gastric carcinoma cell lines, and suggested that the drug has great potential for the treatment of gastric cancer. Although a number of clinical trials have examined the effects of paclitaxel alone, response rates were 
25% and no survival advantages were shown in most of these reports (16). Therefore, some groups have started clinical trials to examine several new combination regimens of paclitaxel with other chemotherapeutic agents. Cascinu et al. (17) reported a phase I study of weekly 5-FU plus paclitaxel every 3 weeks in patients with advanced gastric cancer that was refractory to the PELF regimen (5-FU, leucovorin, cisplatin, epidoxorubicin). Bokemeyer et al. (18) performed a phase II study of weekly 5-FU/leucovorin plus paclitaxel every 3 weeks and showed a 32% response rate for advanced gastric cancer. Despite the promising evidence provided by previous studies, there remains a need for more phase I studies to investigate other combinations of chemotherapeutic agents with weekly paclitaxel.
The present phase I study was designed to obtain robust evidence concerning the combination of paclitaxel and 5-FU chemotherapy. In this study, the safety profile of continuous 600 mg/m2 5-FU for 5 days plus weekly paclitaxel given for three out of every 4 weeks was examined. Continuous 5-FU infusion was reported by the Meta-analysis Group for Cancer (MAGIC) (19), and its efficacy and safety have been widely accepted for patients with advanced gastrointestinal cancers. Continuous 600 mg/m2 5-FU infusion for 5 days was selected as the ideal combination agent with paclitaxel based on a study by the Japan Clinical Oncology Group (20). We chose weekly paclitaxel based on our clinical experience indicating that the duration and dose of paclitaxel infusion are strongly correlated with its toxicity and efficacy (21). Compared with a treatment schedule of three-weekly 24 h infusions, 1 h infusions given weekly appear to be less myelotoxic (22). Furthermore, weekly administration of paclitaxel was shown to be dose-intense (23) and to have a favorable safety profile. Based on these considerations, this phase I trial was initiated to evaluate the MTD of a weekly paclitaxel schedule after continuous 5-FU infusion. To our knowledge, this is the first report on the combination therapy with continuous 5-FU and weekly paclitaxel for advanced gastric cancer.
The pharmacological data demonstrated that weekly paclitaxel doses between 60 and 90 mg/m2 produce plasma paclitaxel levels that remain above 0.01 µmol/l for at least 24 h after the administration over 1 h, and an AUC of 90 mg/m2 is similar to that observed with a dose of 105 mg/m2 delivered over 3 h (24). Prolonged exposure to a low concentration of paclitaxel, of the order of 0.01 µmol/l, has been shown to induce apoptosis in several different cell lines (15).
The results of this study demonstrate that paclitaxel doses can be safely escalated to 90 mg/m2/week, with a fixed dose of 5 days continuous 5-FU infusion, with hematological and liver toxicity limiting further dose escalation. Overall, this regimen was adequately tolerated for up to 8 weeks and was associated with moderate toxic effects. Although the MTD of paclitaxel combined with 5-FU on this schedule was 90 mg/m2 weekly for three out of every 4 weeks, the recommended dose for a future phase II trial was one level lower.
In conclusion, this study demonstrates the tolerability of combination therapy with weekly paclitaxel and continuous 5-FU in patients with advanced gastric cancer. On the basis of the analysis of delivered dose intensity, the recommended dose of paclitaxel (80 mg/m2/week) for additional investigation of this regimen was one dose level below the achieved MTD. A further phase II study, which has just started, will more precisely define the effects and safety of this combination chemotherapy for advanced gastric cancers.
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Acknowledgments |
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This work is supported, in part, by the non-profit organization Epidemiological & Clinical Research Information Network (ECRIN), and by the Osaka Cancer Research Foundation.
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References |
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