Japanese Journal of Clinical Oncology 31:610-615 (2001)
© 2001 Foundation for Promotion of Cancer Research
Phase II Study of a Weekly 8-Hour 5-Fluorouracil and Leucovorin Infusion for Patients with Advanced Colorectal Cancer: Dose Adjusted According to its Toxicity
1Division of Hematology–Oncology, Department of Internal Medicine and 2Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: 5-fluorouracil (5-FU) clearly behaves as two different drugs according to the schedules for its administration. A weekly, 8-h 5-FU continuous infusion (CI) regimen may produce a dual effect, because it elicits both a high plasma 5-FU level and also a durable exposure to 5-FU, which may have the advantage of inhibiting both DNA synthesis and RNA activities. The plasma 5-FU level, however, cannot be monitored in most hospitals, so we initiated a pragmatic clinical trial with this weekly 8-h 5-FU CI regimen and adjusted the drug’s dose according to the detected toxicity.
Methods: The initial dose of 5-FU was 1200 mg/m2 and this was escalated by 200 mg/m2 weekly, provided that no evidence of significant (grade 2 or greater) toxicity became apparent. Twenty-six patients entered the study from June 1998 to March 1999.
Results: The median dose of 5-FU delivered was 1600 mg/m2. The major symptoms precluding dose escalation were nausea and vomiting. Seven patients demonstrated a partial response (26.9%), 11 patients revealed stable disease (42.3%) and eight exhibited progressive disease (30.8%).
Conclusion: This weekly 8-h CI 5-FU protocol with the adjustment of dose according to toxicity was not able to achieve the same 5-FU dose and response rate as in previous studies with pharmacokinetic monitoring of 5-FU levels. However, with the concurrent administration of intensive anti-emetic premedication, it is still possible to achieve adequate plasma 5-FU levels by adjusting the 5-FU dose according to elicited toxicity.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Since its discovery 40 years ago, 5-fluorouracil (5-FU) remains the most useful drug for the treatment of patients with advanced colorectal cancer (1). Although intravenous administration of 5-FU is the most widely accepted method of administering the drug, the optimum schedule has not yet been settled and controversy prevails. It is clear that, by employing a continuous infusion (CI) schedule, a much higher dose of 5-FU can be administered (2–4). Moreover, the toxicity of 5-FU is determined by its plasma concentration and the duration of the drug’s administration, but not by the total dose of 5-FU administered (3,4). Myelosuppression has been shown to be the dose-limiting toxicity for intravenous bolus 5-FU schedules with a much higher plasma 5-FU concentration (5,6), while stomatitis and hand–foot syndrome are the dose-limiting toxicity of CI 5-FU schedules (6–8). In general, studies have reported that the CI of 5-FU may be considered a better regimen than bolus injection for advanced colorectal cancer owing to a superior response rate and its lower toxicity (9–12).
5-FU clearly behaves as two different drugs according to the schedules of administration. A plasma 5-FU level >1 µmol/l is adequate for inhibition of the enzyme thymidylate synthase (TS) for DNA synthesis and this threshold level can be achieved by both bolus and CI regimens (13). Given the tight S-phase dependence of TS inhibition, the duration of patient exposure to 5-FU is more influential. Conversely, the 5-FU peak concentration rather than its duration of exposure may be the key factor for the extent of incorporation into RNA activities (14). In this regard, the two different schedules for 5-FU administration could also be applied concomitantly, the approach intending to take the synergy between bolus and CI 5-FU administration regimes, as has recently been described for a series of in vitro experiments (15). From the literature, the ‘de Gramont regimen’ is composed of a hybrid of bolus and CI 5-FU administration and appears to be popular in northern Europe. Despite a lower dose intensity of 5-FU associated with such a regimen than other 48-h CI 5-FU regimens (2), better response rate and progression-free survival than the Mayo Clinic regimen were documented (16). The advantage of this regimen is the dual effects upon the inhibition of TS and the incorporation into RNA via CI and bolus 5-FU (17).
In addition, certain studies have reported high individual variability in 5-FU pharmacokinetics when identical doses of the drug, adjusted to body-surface area, were delivered to different subjects (18,19), such a phenomenon being possibly due to the genetic polymorphism of 5-FU metabolism by dihydropyrimidine dehydrogenase (DPD) (20,21). Accordingly, in 1998, Gamelin et al. developed a weekly 8-h 5-FU CI regimen with 5-FU stepwise dose escalation based upon the 5-FU pharmacokinetic monitoring technique in order to obtain an optimum therapeutic and non-toxic 5-FU plasma level (individually) for each patient (22) These authors defined an optimum therapeutic range for 5-FU plasma levels of 2000–3000 µg/l. From this study, a promising 56% response rate was reported to have been obtained amongst the 117 patients with measurable lesions with acceptable toxicity (22). Such a regimen clearly demonstrated a much higher sustained 5-FU plasma level than has been the case for other 24- or 48-h 5-FU CI regimens (23–27). According to the hypotheses of the dual effect of 5-FU, this regimen exhibited both high plasma 5-FU levels and durable exposure to 5-FU, which may have the advantage of inhibiting both TS and RNA. Since it is frequently the case that plasma 5-FU levels cannot be monitored in most hospitals owing to a lack of appropriate equipment, we decided to initiate a pragmatic clinical trial with this weekly 8-h 5-FU CI regimen and adjusted the dose of its administration according to the observed patient toxicity.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria
Patients were required to suffer from an unresectable metastasis or local recurrence of an adenocarcinoma of the colon or rectum. The eligibility criteria required histologically proven colorectal adenocarcinoma, a two-dimensional measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 2, a white blood cell count
3500/µl, a platelet count 100 000/µl, a serum bilirubin level of 
3.0 mg/dl, a serum creatinine concentration of 3 mg/dl and a normal electrolytes assay. Patients having received any prior chemotherapy for metastatic disease and demonstrating any active infection, concurrent major systemic disease or any history of any other malignancy (except basal cell carcinoma of the skin) were excluded from the study. Patients who had received prior adjuvant chemotherapy must have completed their adjuvant treatment at least 6 months prior to study enrollment. An earlier history of radiotherapy was allowed, provided that the indicator lesion was outside the radiation port and at least 1 month had elapsed since the completion of radiotherapy. Informed consent was obtained from all patients.
Treatment Plan And Dose-escalation Schedule
Prior to the initiation of 5-FU therapy, all patients were required to be fitted with a central vascular device through the subclavian vein. All treatments were administered in the outpatient oncology clinics via portable infusion pumps and through the subcutaneous port. The therapy consisted of 5-FU administration combined with a fixed dose of leucovorin (LV) 100 mg/m2 via a portable infusion pump, administered intravenously over an 8-h period. The initial dose of 5-FU was 1200 mg/m2, the dose being escalated by 200 mg/m2 weekly provided that there was no significant (grade 2 or greater) toxicity occurrence. In the event of a grade 2 toxicity developing, the 5-FU dosage was returned to the previous week’s dose level. In the case of a grade 3 or 4 toxicity developing, treatment was interrupted until resolution of the toxicity was achieved, 5-FU therapy then being restarted with a 200 mg/m2 decrease of the dose from the preceding treatment. The 5-FU–LV admixture was administered to the patients once per week for five consecutive weeks followed by a 1-week rest period. This 6-week period constituted one treatment course. Prophylactic anti-emetic treatment with prochlorperazine and dexamethasone was routinely provided before each chemotherapy infusion.
Treatment with the 5-FU–LV admixture was continued until one of the following criteria was met: disease progression, the development of unacceptable toxicity or the patients’ refusal to continue. Patients who were refractory to this 5-FU–LV regimen were allowed to receive salvage chemotherapy at the physician’s discretion.
Patient Evaluation
Prior to entry into this study, all patients provided a complete history and underwent physical examinations. Laboratory studies included a complete blood count, differential count, platelet count, biochemical liver function test, chest X-ray, carcinoembryonic antigen (CEA) assay and abdominal computed tomography (CT) examination. During treatment, patients were seen by a physician on a weekly basis for a brief history, physical examination and toxicity assessment. A complete blood count was conducted prior to each chemotherapy infusion and a CEA assay was conducted subsequent to every treatment course. Tumor reassessment by abdominal CT scan and/or chest X-ray were performed subsequent to the first and second courses of therapy and every other course thereafter. In instances where there arose some clinical suspicion of the progression of disease during therapy, the patient’s response to therapy was re-evaluated immediately. The determination of tumor response to chemotherapy followed standard WHO criteria, a complete response (CR) being defined as the disappearance of all measurable or assessable cancer based upon a CT scan. A partial response (PR) was defined as a decrease of >50% in the value of the sum of the products of the largest perpendicular diameters of all measurable lesions, with no progression in any existing lesion and no appearance of any new lesion during this period. All responses were confirmed by repeat evaluation at a time at least 4 weeks subsequently. Progressive disease (PD) was defined as an increase of >25% in the tumor area of one or more measurable lesions, and/or the appearance of new lesions. Stable disease (SD) was defined as either a decrease in lesions, which lasted for at least 4 weeks but did not reach the criteria for a PR or a <25% increase in lesions.
Toxicity was evaluated weekly with particular attention being paid to nausea, vomiting, diarrhea, mucositis, hand–foot syndrome, fatigue and leucopenia. These toxic events were noted prospectively and evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria graduation scale.
Statistical Analysis
The primary end-point of this study was the patient response rate to chemotherapy. The Simon optimum, two-stage, phase II clinical trial design was used. The sample size was estimated to detect at least a 60% response rate, with a 40% rate for a minimal hypothesis. In the first stage, the study would have been halted if less than 11 of the first 25 evaluable patients had responded. The time to progression was measured from the day of commencement of therapy to the day of progression. Response duration was defined as the interval from the onset of a response to the time that evidence of disease progression was identified. Progression-free survival and survival were calculated from the start of chemotherapy, using the Kaplan–Meier method (28).
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RESULTS |
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Patients’ Characteristics
Twenty-six patients entered the study from June 1998 to March 1999. There were 18 men and eight women. Their median age was 56 years (range, 29–79 years). A summary of baseline patient characteristics is given in Table 1. All 26 patients were found to be eligible for assessment of response and toxicity. The median ECOG performance status was 1. Sixteen patients were in a metastatic stage at the initial diagnosis and the remainder relapsed following radical surgery. The liver was the predominant metastatic site (61.5%) and 18 patients (69.2%) experienced multiple metastatic sites. Six patients had previously received 5-FU-based adjuvant chemotherapy.
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Treatment
All patients received at least one course of weekly 8-h 5-FU–LV treatment. Fourteen patients (53.8%) completed at least four courses (20 weekly infusion treatments) of chemotherapy. The median number of therapy courses was four. A total of 515 sessions (range, 5–30; median, 20) of weekly 8-h 5-FU–LV therapy were given in this trial. All patient withdrawals from therapy were due to disease progression.
The final dosage of 5-FU administered to each patient is given in Table 2. The median dose delivered was 1600 mg/m2 (range, 1200–2200 mg/m2). The major cause that precluded chemotherapy dose escalation was nausea and vomiting (42.3%). Fatigue, mucositis, hand–foot syndrome and diarrhea were other dose-limiting factors in that order (Table 3). The initial chemotherapy dose of 1200 mg/m2 was the optimum dosage for only five patients in this study, the remaining 21 patients needing an adapted dose. The level of the optimum dose was not correlated with the patient response despite most of the responders being found to be located at lower dose levels (Table 2).
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Response and Survival
No patients achieved a complete response and seven patients experienced a partial response that lasted from 4 to 11 months (median response duration, 7.9 months). This represents a 26.9% response rate [95% confidence interval (CI), 8.7–45.1%] amongst the 26 patients in this series. Eleven patients revealed stable disease (42.3%) and eight patients exhibited progressive disease (30.8%). Further, CEA levels normalized or decreased by >50% for eight of 22 patients (36.4%).
As of December 2000, 23 patients had died and three were still alive. The median survival for all 26 patients was 12.1 months (range, 1.5–28.3+ months). The median time to progression was 5.1 months. The overall survival rate was 53.8% after 1 year and 11.5% after 2 years.
Toxicity
Data corresponding to therapy toxicity for all 26 patients are shown in Table 4. The toxicities recorded represent the maximum-grade toxicity seen for any given patient for that patient’s entire course of therapy. Hematological toxicity was absent for all 26 patients and gastrointestinal toxicity with symptoms of nausea, vomiting, diarrhea and mucositis were the most frequent toxicities. These toxicities were the major dose-limiting factors restricting further dose escalation (65.4%). Because this is a weekly treatment regimen, most patients experienced difficulty in tolerating even mild nausea or vomiting for a period of several days from the time of administration of 5-FU. Hand–foot syndrome was observed for three patients (11.5%). This reversible syndrome has been previously reported to be uniquely associated with protracted infusion of 5-FU, the side-effect never being noted to be life-threatening, although, typically, very bothersome to patients. Fatigue or a sensation of asthenia was another common side-effect (57.7%), although most patients were able to continue their daily life activity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This study was terminated in the first stage because the anticipated response rate was not able to be achieved as expected (22). This poor result may be due to an inadequate dose in our protocol compared with the studies of Gamelin et al. (4,22). These authors’ studies showed the wide variability of 5-FU metabolism, virtually independently of the dose of 5-FU administered, the 5-FU resultant plasma level being significantly predictive of an objective response and better survival. It was further reported that the optimum therapeutic and non-toxic range of plasma 5-FU concentration was 2000–3000 µg/l (4,22). From our work, it would appear that the establishment of an ‘adequate’ plasma 5-FU concentration may be imperative in this weekly 8-h 5-FU CI regimen and that such a plasma level can only really be achieved by continuously monitoring the plasma 5-FU level and individually modifying the dose of 5-FU depending upon plasma 5-FU levels (22). Despite the fact that we did not monitor the plasma 5-FU level, a lower plasma 5-FU level was expected as the median dose of 5-FU was 200 mg/m2 lower than that in the study of Gamelin et al. This may explain the poorer result achieved in our study compared with that reported in the two studies by Gamelin et al.
Plasma 5-FU levels are predominantly dependent upon the activity of DPD, a key enzyme of the endogenous pyrimidine metabolism pathway, which is submitted to genetic polymorphism (20,21). Although the plasma 5-FU concentration also varied for different patients in the weekly 24- or 48-h 5-FU CI regimen, the plasma 5-FU concentration appeared to not be very important in such 5-FU-administration regimens (23–27). There would appear to be two possible explanations for this observation. First, the main target of those regimens is the enzyme TS, which may be inhibited by a lowered plasma 5-FU concentration. The duration of such TS inhibition is more influential than is the peak 5-FU level for such therapy regimens. Second, the plasma 5-FU concentration is also important for those regimens, but they did not monitor it. According to the regimen specified in the study of de Gramont et al. (26), the CI component of the 5-FU was only 600 mg/m2/day, that is, a very low dose intensity compared with reports of other 24- or 48-h CI 5-FU regimens (23–27). The last report using such a regimen suggests that the high activity is obtained at the cost of low toxicity (16). Therefore, of the two potential alternatives proffered above for the explanation of why the plasma 5-FU concentration appears to not be very important in such 24- or 48-h 5-FU administration regimens, we believe that the first option is more favored. By contrast, in a bolus 5-FU administration regimen, even a short prolongation of the administration time of a fixed dose of 5-FU (e.g. by 10–30 min) results in a lower 5-FU peak and area under the curve (AUC) (29). In a randomized trial, Larsson et al. (29) reported that the efficacy of 5-FU is less when the same dose of the drug is infused for ~15 min as compared with a rapid injection over 3 min. In this regard, the peak plasma 5-FU level is more influential than the duration of exposure since the peak plasma 5-FU concentration would appear to be the key factor for incorporation of the drug into RNA. In our weekly 8-h 5-FU CI regimen, both the inhibition of TS and the incorporation of the drug into RNA for patients may be equally important owing to the relatively short duration of infusion of the drug and the higher peak plasma 5-FU level resulting from such an 8-h infusion protocol as compared with other 24- or 48-h 5-FU CI regimens (23–27). Therefore, achieving an adequate plasma 5-FU concentration is more difficult in this weekly 8-h CI 5-FU regimen because incorporation into RNA is another important target in this drug regimen.
The major toxicity of Gamelin et al.’s report was diarrhea and hand–foot syndrome (22), whereas nausea and vomiting were the major dose-limiting toxicity in our series. The mean 5-FU dosage referred to in Gamelin et al.’s study was 1803 mg/m2, which is 200 mg/m2 greater than that in our series. Most of our patients were unwilling to proceed with continually escalating doses of 5-FU, even if the noted symptoms included only mild nausea or vomiting resulting from this weekly-adjusted dose schedule. The administration of a concurrent more aggressive anti-emetic premedication, such as a serotonin blocker plus steroids, may help to resolve this problem, although we did not try to include a serotonin blocker as part of the chemotherapeutic regimen here, because the use of such a drug was not covered by our hospital’s insurance policy if only 5-FU is administered. Indeed, we may have the opportunity here to achieve the same dose level and efficacy for 5-FU as that achieved in Gamelin et al.’s study if we can overcome the problem of gastrointestinal toxicity. It is possible to achieve adequate plasma 5-FU concentration by adjusting the 5-FU dose according to the drug’s resultant toxicity if our presumption is true.
During the last few years, two new active agents against colorectal cancer have emerged: irinotecan and oxaliplatin. Optimum use of these agents in combination with 5-FU will require an intricate understanding of the mechanism of action of 5-FU as a function of its dose, schedule and modulation. For example, the mechanism of action of irinotecan and oxaliplatin is DNA damage and it may therefore be worthwhile to add one or both of these drugs to a protocol incorporating LV-modulated 5-FU CI treatment. However, further investigations on different 5-FU–LV schedules in combination with these drugs are warranted.
In conclusion, achieving an adequate 5-FU plasma level is very important in this weekly 8-h 5-FU CI regimen. This weekly 8-h 5-FU CI protocol with adjustment of dose according to the drug-elicited toxicity cannot achieve the same 5-FU dose and response rate as reported in the studies of Gamelin et al.
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FOOTNOTES |
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+ For reprints and all correspondence: Tsai-Shen Yang, Division of Hematology–Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, 199 Tung-Hwa North Road, Taipei, Taiwan. E-mail: tsyangss@ms27.hinet.net
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Received May 9, 2001; accepted September 5, 2001.
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