Japanese Journal of Clinical Oncology 32:9-13 (2002)
© 2002 Foundation for Promotion of Cancer Research
Effect of a 3-hour Interval Between Methotrexate and 5-Fluorouracil in the Treatment of Metastatic Colorectal Cancer
Division of Gastrointestinal Oncology, Department of Medicine, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Objective: This phase II study was designed to evaluate the efficacy and toxicity of 3-h interval sequential methotrexate (MTX) and 5-fluorouracil (5-FU) with leucovorin (LV) rescue in the treatment of patients with metastatic colorectal cancer.
Methods: Forty-two patients with histologically confirmed metastatic colorectal cancer and at least one two-dimensionally measurable lesion, aged 30–74 years old, with performance status 
2 and no or one prior chemotherapy were selected. Patients received sequential MTX 100 mg/m2 by bolus injection and 5-FU 600 mg/m2 at 3 h followed by LV rescue initiated after 24 h (15 mg per body every 6 h for six doses). The treatment was repeated every week or every 2 weeks until disease progression. All patients were treated as out-patients unless complications arose.
Results: All 42 patients entered in this study were assessable both for response and toxicity. Fifteen patients achieved objective responses (one complete and 14 partial), for an overall response rate of 36% (95% CI: 11–51%). Response rates in pretreated patients and patients with naive chemotherapy were 27 and 42%, respectively. Sixteen patients had stable disease and 11 progressed with therapy. The median survival for all patients was 378 days. The hematological toxicity was mild with no grade 3/4 leukopenia. The major non-hematological toxicity was diarrhea (one grade 4, four grade 3).
Conclusions: This 3-h interval sequential MTX and 5-FU with LV rescue is an active regimen in patients with metastatic colorectal cancer. The treatment showed mild toxicity and was administered on an out-patient basis. The present findings suggest that this regimen warrants further investigation in patients with metastatic colorectal cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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5-Fluorouracil (5-FU) is still the key drug in the field of gastrointestinal oncology including colorectal cancer. The response rates of 5-FU alone for colorectal cancer, however, have been shown to be less than 20% (1).
To enhance the therapeutic activity of 5-FU, several biochemical modulators to alter its metabolic pathway have been investigated. Among them, methotrexate (MTX) was shown to induce enhanced antitumor activity of 5-FU in terms of DNA synthesis inhibition (2) or RNA synthesis inhibition (3). In addition, clinical studies revealed that the modulation of 5-FU by MTX with leucovorin (LV) rescue (MFL) was a superior alternative to 5-FU alone in the treatment of patients with advanced colorectal cancer in terms of both the response rate and survival (4,5).
The administration of LV is well known to enhance the cytotoxicity of 5-FU by expanding intracellular pools of reduced folate and, therefore, potentiating ternary complex formation and stabilization (6). A meta-analysis of nine randomized trials comparing 5-FU alone with 5-FU + LV (FL) in patients with advanced colorectal cancer showed that the overall response rate with 5-FU + LV was more than twice that with 5-FU alone (23 vs 11%). FL, however, did not show a survival advantage in comparison with 5-FU alone (11 months for 5-FU alone vs 11.5 months for FL) (1).
These two combinations (MFL and FL), both based upon biochemical modulation of 5-FU, were compared in 202 symptomatic patients with advanced colorectal cancer in a randomized trial (7). In that study, there was no difference between the two arms in terms of response rate or survival. However, it was suggested that FL could be recommended as a first-line treatment before MFL because FL was easier to administer and carried less risk of serious toxicity. In the MFL regimen of the randomized study, both 3- and 23-h intervals between MTX and 5-FU were used because of the known heterogeneity of human tumors (7).
Several basic or clinical studies indicated that the time interval between sequential administration of MTX and 5-FU was important for determining the extent of synergy. Herrmann et al. reported that a >4-h interval was superior in response rate to a 1-h interval in the treatment of patients with advanced colorectal cancer (8). Marsh et al. conducted a randomized comparison of 1- vs 24-h interval of MTX and 5-FU in patients with advanced colorectal cancer (9). They concluded that the efficacy of MFL was increased in colon but not rectal cancer when the interval between MTX and 5-FU was long (24 h) rather than short (1 h). In a summary of the findings of several trials, a 7–24-h interval between MTX and 5-FU appeared to provide an advantage (10).
A >7-h interval between MTX and 5-FU, however, cannot be applied to patients on an out-patient basis. In reality, this long interval was one of the reasons why Glimelius and the Nordic Gastrointestinal Tumor Adjuvant Therapy Group recommended FL as a first-line treatment before MFL in patients with advanced symptomatic colorectal cancer when they conducted a randomized trial between MFL and FL (7). In Japan, a 3-h interval between MTX and 5-FU in the MFL regimen had been verified to be safe and effective in patients with advanced stomach cancer (11).
Based on the background described above, we conducted a phase II trial to evaluate the efficacy and toxicity of MFL treatment with a 3-h interval between MTX and 5-FU.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Eligibility
Patients were eligible if they fulfilled the following criteria: (1) histologically confirmed colorectal cancer with measurable lesion; (2) age
75 years; (3) proper kidney function (serum creatinine 1.5 mg/dl and Ccr 
50 ml/min); (4) proper liver function (total bilirubin level <2.5 times the upper limit of normal or 3 times the upper limit of normal if patients had liver metastasis); (5) proper bone marrow function (WBC count 4000 cells/µl, platelet count 100 000 cells/µl); (6) normal cardiac function (no unstable angina, no history of myocardial infarction and no sign of congestive heart failure); (7) no sign of brain metastasis; (8) no severe infection; (9) no sign of gastrointestinal bleeding; (10) no other active malignancy; (11) performance status (PS) 0–2 on the Eastern Cooperative Oncology Group (ECOG) scale; (12) life expectancy >8 weeks; (13) written informed consent given; (14) no prior chemotherapy or prior treatment with <2 regimens including adjuvant chemotherapy; and (15) neither chemotherapy nor radiotherapy within 4 weeks before entry.
Treatment
A 100 mg/m2 dose of MTX was infused by i.v. bolus followed by hydration with 500 ml of saline for 3 h. At the end of the hydration, 600 mg/m2 of 5-FU were administered by i.v. bolus. Patients received LV orally, 15 mg, six times every 6 h, beginning 24 h after MTX injection.
The treatments were repeated every week or every 2 weeks until the appearance of disease progression. Almost all patients were treated on an out-patient basis except the first treatment. This study was approved by the Institutional Review Board at the National Cancer Center Hospital, Tokyo.
Evaluation of Response and Toxicity
Response to therapy was assessed every month or every 2 months according to World Health Organization (WHO) criteria. A complete response (CR) was defined as the disappearance of all measurable lesions for at least 4 weeks. A reduction of >50% in the sum of the products of the largest perpendicular diameters of all measurable lesions for at least 4 weeks without the development of new lesions, was defined as a partial response (PR). A <50% decrease or <25% increase in tumor burden was considered as stable disease (SD). Progressive disease (PD) was defined as a 25% increase in the sum of the perpendicular diameters of all measurable tumors or the appearance of new lesions. Time to progression was determined by the interval between the initiation of therapy to the first date that disease progression was objectively documented or treatment was discontinued. Toxicity was graded according to the Japan Clinical Oncology Group (JCOG) toxicity criteria.
Sample Size
Sample size was based on the response rate. According to Simon’s two-stage minimax design, with a minimum expected response rate of 10% and an average expected response rate of 25%, a sample of 27 patients was required in the first step. If a minimum of three responses were observed, it was planned to accrue a total of 40 patients. At the end of the study (40 patients), this study had to be stopped if six responses or fewer were observed (12).
Statistical Analysis
Survival was calculated on the basis of the period from the initiation of therapy to death from any cause. The survival curve was calculated using the method of Kaplan and Meier (13).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patients’ Characteristics
Between October 1997 and July 1998, 42 patients meeting the eligibility criteria were registered. All patients registered were eligible for the analysis of response, toxicity and survival. Table 1 shows the patients’ characteristics. Their ages ranged from 30 to 74 years, with a median of 58 years. The median performance status was ECOG1.
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Eighteen patients had previously been treated with fluoropyrimidine-based regimens but not with CPT-11. Ten patients (56%) had failed after adjuvant chemotherapy and eight patients (44%) had progressed after receiving first-line chemotherapy. The remaining 24 patients were chemotherapy-naive. Most patients had liver metastasis (48%) and lung metastasis (69%) and 18 patients had only one metastatic site.
Objective Tumor Response and Survival
Among the 42 patients treated, we observed one CR and 14 PR for an overall activity of 36% (95% CI: 11–51%). The duration of responses ranged between 55 and 700 days, with a median of 315 days.
SD was observed in 16 patients (38%) and PD was seen in 11 patients (26%) (Table 2). Among 15 patients with CR or PR, 10 (42%) were chemo-naive and five (27%) were pre-treated, although of these five patients, three were treated as an adjuvant setting and two were pretreated with UFT only for <1 month. The median time to PR was 50 days (range 18–99 days) (Table 3). The median time to progression was 174 days and the median survival was 378 days from the start of therapy. The Kaplan–Meier estimated probability of 1-year survival for the group as a whole was 50% (Fig. 1).
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Drug Administration and Toxic Effects
Drugs were administered a total of 598 times, with a median of 11 (range 3–47) times per patient. Almost all treatments were repeated every 2 weeks. The toxicity profiles are shown in Table 4. Diarrhea was the dominant toxic effect. Three patients with grade 3 or 4 diarrhea were hospitalized. Only one patient experienced grade 3 nausea and vomiting. Stomatitis was mild and hepatotoxicity was also mild with only four patients experiencing grade 1. Hematological toxicity was mild with only two patients developing grade 3 anemia. There was no treatment-related death or life-threatening toxicity in this study.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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5-FU has been the most widely used anticancer agent for patients with gastrointestinal cancers including colorectal cancer, although the response rates to single-agent 5-FU have not been satisfactory (14). A biomodulation of 5-FU with leucovorin enhanced the response rates over 5-FU alone but showed only minor effects on survival according to a meta-analysis (1). MTX is another biomodulating agent of 5-FU. A meta-analysis of 5-FU plus MTX versus 5-FU alone revealed a significant improvement in response rates (19 vs 10%) and a small but definite advantage for overall survival (10.7 vs 9.1 months). In addition, there was a larger number of patients still alive at 2, 3 and 4 years in the MFL group than the 5-FU alone group (5). From these meta-analyses, the significant survival benefit of MFL is in contrast to the lack of benefit of FL. However, this apparently discrepant result should not be overestimated in view of the magnitude of the benefit. A similarly small benefit might easily have been missed in the FL meta-analysis as a result of chance. In fact, a direct comparison of FL and MFL showed no difference both in terms of response rate and survival (7). Moreover, the authors of that study recommended FL as a first-line therapy before MFL because FL is easier to administer than MFL. One of the reasons for difficulties in terms of the administration of MFL was that there was a 23-h interval between MTX and 5-FU in that study, which could not be applied to out-patients. Experimental evidence appears to indicate the favorable advantage of a 24-h interval between MTX and 5-FU (15,16). Clinically, a direct comparison between two schedules of administration of 5-FU and MTX was conducted in a randomized trial for patients with advanced colorectal cancer (9). Patients received MTX 200 mg/m2 followed by 5-FU 600 mg/m2 either 1 or 24 h after MTX. The 24-h interval appeared to be better than the 1-h interval in terms of the response rate (29 vs 14%) and the median survival (15.3 vs 11.4 months).
From the background described above, the present study utilizing a 3-h interval between MTX and 5-FU is important in clarifying the value of MFL.
In our phase II trial, the objective response rate was 36% for all assessable patients. The median time to progression for the whole group was 5.8 months. For patients who achieved a CR or PR, the median time to progression was 11.6 months. Among patients who responded to this therapy, five were pretreated with the fluoropyrimidine-based regimen but three of those five patients were treated as an adjuvant setting and two were pretreated with UFT alone for <1 month. This means these five patients are difficult to term 5-FU refractory. Therefore, it may be difficult to say that this regimen is still effective for patients who are 5-FU refractory. In general, the present results were suggested to be equal or superior to those obtained with a >7-h interval between two drugs.
In view of the palliative aim of treatment for metastatic colorectal cancer, the chemotherapy should be mild. The major toxicity was grade 3/4 diarrhea, which occurred in 12% of the treatment cycles. Among them, only three patients had to be hospitalized to improve their dehydration state. However, they did not show a serious condition after treatment with loperamide and adequate hydration. This is consistent with the incidence rate of grade 3/4 diarrhea reported in previous MFL or FL studies (7). Overall, this regimen was well tolerated in most patients. Only one grade 3 and no grade 4 nausea and vomiting were observed in the present study and stomatitis was minimal. Non-gastrointestinal toxicities were rare, with three cases of grade 3 anemia.
During the last decade, a variety of new active agents against colorectal cancer have appeared. Among them, irinotecan (CPT-11), a topoisomerase I inhibitor, and oxaliplatin, a novel platinum derivative, have received special attention. A recent phase III trial of CPT-11 in combination with 5-FU and LV as the first-line therapy for patients with metastatic colorectal cancer resulted in a significant increase in remission and also time to treatment failure (17). However, the most common toxicities associated with CPT-11 were delayed diarrhea despite loperamide therapy, occurring in as many as 22% of patients, and grade 4 neutropenia in 23% of patients (17).
Oxaliplatin in combination with 5-FU and LV showed an increased tumor response (34%) and with chronomodulated 5-FU/LV, a further increase to a 53% response rate and a survival of 19 months were demonstrated with relatively strong toxicities (18). Grade 3/4 toxicities most common with oxaliplatin (130 mg/m2) are nausea and vomiting (72%) and acute neurotoxicity (17%) (19).
In conclusion, the present phase II study of the 3-h interval sequential MTX and 5-FU with LV rescue provides evidence that this method is an active regimen in previously untreated patients with metastatic colorectal cancer. Of the treatments currently available or those under investigation for first-line chemotherapy of metastatic colorectal cancer, this 3-h interval MFL therapy would offer patients a favorable response rate and survival and a tolerable safety profile as well as good quality of life. We are currently considering 3-h interval MFL therapy as a candidate for a phase III study in the first-line treatment of metastatic colorectal cancer.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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We thank Miss H. Orita for secretarial assistance. This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare.
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FOOTNOTES |
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+ For reprints and all correspondence: Yasuhiro Matsumura, Division of Gastrointestinal Oncology, Department of Medicine, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: yhmatsum@ncc.go.jp
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received August 10, 2001; accepted October 12, 2001.
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