Dose-finding study of weekly 24-h continuous infusion of 5-fluorouracil associated with alternating oxaliplatin or irinotecan in advanced colorectal cancer patients

L. Cals1,*, O. Rixe2, E. François3, R. Favre1, L. Merad1, G. Deplanque2, A. Laadem4, P. Juin1, J. M. Bereder1, D. Bernardini1 and P. Herait4

1 Fédération de Cancérologie des Etablissements Privés/Publics de la région PACA-Corse, Hôpital de la Timone, Marseille; 2 Clinique Claude Bernard, Metz; 3 Centre Antoine Lacassagne, Nice; 4 Cvitkovic et Associés Consultants, Le Kremlin-Bicêtre, France

*Correspondence to: Dr. L. Cals, Service d'Oncologie, Centre Hospitalier Fontpré, BP 1412, 83056 Toulon cedex, France. Tel: +33-4-94-61-60-52; Fax: +33-4-94-61-60-28; E-mail:Email: laurent.cals{at}ch-toulon.fr


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: To determine maximum tolerated dose, safety and efficacy of weekly 24 h infusional 5-fluorouracil (5-FU) combined alternately with oxaliplatin and irinotecan.

Patients and methods: Advanced colorectal carcinoma patients in first- or second-line chemotherapy received increasing doses of 5-FU (weekly 24 h continuous intravenous infusion without leucovorin) on days 1, 8, 15 and 22, irinotecan days 1 and 15; and oxaliplatin days 8 and 22, every 35 days.

Results: Thirty-four patients received 175 cycles. The median age was 64 years (range 47–78). Eighteen per cent of patients had the primary tumor in the rectum, with a median of one disease site (range one to three), and liver involvement in 88% and lung in 38%. Six (18%) patients had chemotherapy for prior advanced disease. The most frequent grade 3–4 toxicity was neutropenia (41% of patients), but the regimen was well tolerated clinically, with febrile neutropenia in two patients and grade 4 neutropenia lasting >7 days in one; grade 3–4 diarrhea, nausea and vomiting in 6% of patients; grade 3–4 peripheral neuropathy in 9% of patients. Seventeen patients had a partial response (50%; 95% confidence interval 33%–67%), 13 had stable disease and one had progressive disease. Five patients underwent metastatic surgical resection after tumor shrinkage. Median response duration was 14 months (range 4.7–29.2+) and median time to progression was 11.3 months (range 1.1+–30.7+).

Conclusions: This combination three-drug regimen is feasible and well tolerated without toxicity overlap. Preliminary antitumor activity compares well with standard double combinations, with an unusually long median time to progression. The recommended dose is 5-FU 3000 mg/m2, weekly for 4 weeks, irinotecan 100 mg/m2 days 1 and 15, oxaliplatin 80 mg/m2 days 8 and 22. Further assessment of antitumor activity and safety is warranted.

Key words: colorectal cancer, 5-fluorouracil, irinotecan, oxaliplatin


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
5-Fluorouracil (5-FU) has been the exclusive treatment for metastatic colorectal cancer (CRC) for 40 years [1Go], and is consequently a reference drug in this indication. Nonetheless, owing to its relatively modest response rate, over the past few decades research has focused on 5-FU optimization with different administration regimens and combination with two newly approved agents in CRC: irinotecan and oxaliplatin [2Go–5Go]. Continuous 5-FU infusion yielded higher response rates with similar survival and decreased toxicity, with the exception of hand–foot syndrome, than bolus administration [6Go]. No major differences are apparent between different infusional regimens [7Go–9Go]. Combination of irinotecan and fluorouracil has been shown to be superior to the same regimen of 5-FU alone (infusional [10Go] or bolus [11Go]) in terms of both response rate and survival. Likewise, combination of oxaliplatin and infusional 5-FU is superior to the same regimen of 5-FU alone [12Go, 13Go]. The response rate of these dual combination regimens is ~50% in first-line therapy. It is therefore worthwhile to assess the feasibility of the triple combination of these active drugs with non-cross-resistant mechanisms of action in CRC, in an attempt to further increase the response rate and/or magnitude of tumor shrinkage, increasing the possibility for patients to undergo secondary surgical resection of metastases.

Several combination schedules are possible (every 3 weeks, every other week, weekly with all drugs given together). Although the combination of irinotecan and oxaliplatin is feasible [14Go, 15Go], the benefit of these regimens not containing 5-FU has not yet been fully assessed in CRC, and the additive toxicity of these drugs given together leads to decreased dose intensity of each drug given alone. One interesting approach is to give alternating (or sequential) irinotecan and oxaliplatin combined with 5-FU. The potential benefit of this kind of combination regimen is the avoidance of toxicity overlap, while giving non-cross-resistant drugs in a short time period. The respective theoretical advantages of the alternating versus the sequential approaches have been discussed elsewhere [16Go]. However, this approach delivers relatively low planned dose intensity compared with all of the drugs being given together. We chose the 24 h infusion weekly regimen of 5-FU because it allows administration of irinotecan and oxaliplatin with a short interval without overlap of toxicity. The combinations of this 5-FU regimen with either irinotecan [10Go, 17Go] or oxaliplatin [18Go] have been studied, and the recommended doses (RD) established. In the original regimens, weekly administration was repeated for 6 consecutive weeks every 8 weeks [10Go, 17Go, 18Go]. However, to limit cumulative toxicity with the three drugs, we restricted the schedule to four consecutive infusions every 5 weeks. Furthermore, we deleted high dose (500 mg/m2) leucovorin, given that the benefit of leucovorin with infusional 5-FU schedules is a matter of debate. The pharmacological activity of leucovorin is to strengthen 5-FU, and it seems that the same effect can be achieved by merely increasing the dose of 5-FU [19Go]. Hence, it was expected that the starting dose of 5-FU 2600 mg/m2 without leucovorin would be suboptimal to avoid preventing dose escalation of the other drugs, and a dose of 3000 mg/m2 was planned. The principal objective of the present study was to determine the feasibility and the RD of this regimen. The secondary objective was to assess its antitumor activity (response rate and duration, rate of metastasis surgery rendered feasible, time to tumor progression and overall survival) in first- or second-line treatment of metastatic CRC.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Patients
Eligible patients had: histologically proven colorectal adenocarcinoma; at least one bidimensionally measurable lesion which had been measured by computed tomography (CT) scan <4 weeks before inclusion; prior adjuvant chemotherapy that had to have finished at least 6 months prior to study entry was allowed; no more than one prior line of chemotherapy for advanced disease; no radiotherapy in the 6 weeks prior to study entry or 4 weeks in the case of surgery; a World Health Organization (WHO) performance status (PS) ≤2; age between 18 and 75 years; a life expectancy ≥3 months; adequate hepatic, renal and bone marrow function [defined as hemoglobin >10 g/dl, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l, serum creatinine ≤1.25x the institutional upper limit of normal (ULN), bilirubin ≤1.25x ULN, transaminases ≤3x ULN; in case of liver metastases, bilirubin up to 1.5 x ULN and transaminases up to 5 x ULN were accepted].

Patients were excluded from the study if they: could undergo complete resection of metastases; were pregnant, breast-feeding or not using adequate contraceptive means; had symptomatic peritoneal carcinomatosis or intestinal obstruction not relieved by symptomatic treatment; had received prior treatment with a topoisomerase I inhibitor or oxaliplatin; had a history of chronic enteropathy or extensive gastrointestinal tract resection, severe uncontrolled infection, grade >1 neuropathy, prior history of coronary disease or other serious concomitant medical condition; or if they had participated in another clinical trial in the 4 weeks prior to study entry. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and the protocol was approved by the ethics committee at each participating investigational site. Signed informed consent was obtained from all patients,

Safety and efficacy assessment
Pretreatment evaluation included a complete medical history, physical examination, chest X-ray and abdominal CT scan of measurable target lesions. At baseline and before each infusion, a complete blood cell count and differential were conducted. Blood chemistry parameters were measured at the beginning of every cycle, and an ECG was performed. Tumor evaluation was carried every two cycles according to standard WHO criteria, with the appropriate clinical and the same radiological examinations, and responses were to be confirmed within 4 weeks and were not reviewed by an expert committee. All adverse events were graded using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 1.

Study design
5-FU was to be given over a 24 h continuous infusion weekly for four consecutive weeks (on days 1, 8, 15 and 22) every 5 weeks (day 1=day 36). Irinotecan (CPT-11; 30 min infusion) was administered on days 1 and 15, and oxaliplatin (2 h infusion) on days 8 and 22 (Figure 1Go). Doses were escalated in successive patient cohorts as shown in Table 1Go. The starting doses of irinotecan and oxaliplatin were below those recommended when either drug alone is combined with this 5-FU schedule (i.e. 80 mg/m2 for irinotecan [10Go, 17Go] and 60 mg/m2 for oxaliplatin [18Go]).



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Figure 1 Treatment plan.

 

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Table 1 Number of patients and treatment cycles according to dose level

 
Routine antiemetic prophylaxis was administered. No systematic prophylaxis of irinotecan-induced cholinergic syndrome was planned. If this syndrome occurred, atropine (0.25 mg subcutaneous) was to be given curatively, then prophylactically before further irinotecan administrations. Standard guidelines were provided for the treatment of irinotecan-induced diarrhea: high dose oral loperamide (4 mg as soon as the first loose stool occurs, followed by 2 mg every 4 h for at least 12 h) was to be given for a maximum of 48 h. If diarrhea persisted, the patient was to be hospitalized for parenteral hydration, anti-diarrheal treatment adaptation and broad-spectrum oral antibiotherapy (e.g. fluoroquinolones). Such antibiotherapy was also to be given in the event of grade 4 diarrhea (regardless of duration), or diarrhea (regardless of grade) associated with grade 3–4 neutropenia or fever. In-patient hospitalization was also required in the event of diarrhea associated with nausea/vomiting precluding oral hydration and loperamide intake.

Each infusion could be administered only if neutrophils were ≥1 x 109/l, platelets ≥75 x 109/l and non hematological toxicity grade ≤1. If, at the time of any infusion, neutrophils were >0.5 x 109/l and <1 x 109/l or platelets >25 x 109/l and <75 x 109/l, or if diarrhea or mucositis grade 2 persisted, the infusion was to be postponed until recovery to accepted levels. Doses were to be adjusted (20% reduction) as follows: irinotecan in the event of neutrophils ≤0.5 x 109/l, febrile neutropenia, platelets ≤25 x 109/l, or grade 3 or 4 diarrhea (after an irinotecan-containing infusion); oxaliplatin in the event of grade 3 or 4 diarrhea (after an oxaliplatin-containing infusion); and 5-FU in the event of grade 3 or 4 mucositis. If severe functional impairment due to paresthesia/dysesthesia neurotoxicity lasting >7 days occurred, oxaliplatin was to be reduced by 20%, and if toxicity persisted between cycles, oxaliplatin treatment was to be stopped.

Treatment was administered until disease progression, unacceptable toxicity or toxicity leading to treatment delay >6 weeks after the start of the cycle or patient refusal. Dose-limiting toxicities (DLTs) were defined as any treatment related febrile grade 3 or 4 neutropenia, grade 4 neutropenia, thrombocytopenia or nausea/vomiting, any other grade 3–4 non-hematological toxicity, or grade 2 diarrhea lasting >7 days despite curative treatment, treatment delay of >1 week due to grade >1 toxicity, or more than one delay in any one cycle. Three to six patients were planned for each dose level. At least three patients had to be followed for one cycle (5 weeks) before permitting dose escalation. If at least three patients at a given dose level developed a DLT during the first cycle, it was considered to be the maximum tolerated dose (MTD). The dose level immediately below was considered to be the RD.


    Results
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 Patients and methods
 Results
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Between 15 February 1999 and 15 March 2002, 34 patients were entered in the study in four French centers. All patients were assessed for safety and 31 patients were assessed for response.

Patient characteristics
A summary of patient characteristics is shown in Table 2Go. Median patient age was 64 years (range 47–78). Most patients were in good general condition, 94% having a PS of 0–1. Nevertheless, 13 patients (38%) had undergone a weight loss of at least 5% at study entry. The primary tumor was located in the colon in 82% of patients and in the rectum in 18%. The overall tumor burden was moderate, with a median of one involved organ (range one to three). Thirty patients (88%) had liver and 13 (38%) lung metastases. All but four patients had undergone prior surgery. Ten patients (29%) had received prior adjuvant chemotherapy, and only six (18%) had undergone chemotherapy for metastatic disease (four, one line; one, two lines; and one, three lines). None of these six patients had obtained an objective response on their last regimen. Twenty patients were chemotherapy-naïve.


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Table 2 Patient characteristics

 
Study treatment exposure
Six dose levels were examined (Table 1Go). A total of 175 treatment cycles were administered, with a median of five cycles administered per patient (range one to 11). In 18 cycles, at least one weekly infusion had to be omitted. The median dose intensities and cumulative doses of 5-FU, irinotecan and oxaliplatin per dose level are presented in Table 3Go. The median dose intensity increased regularly with dose increments and the relative dose intensity remained close to 1, showing the feasibility of the highest tested dose levels.


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Table 3 Median dose intensity (DI) and cumulative doses per dose level

 
Determination of the MTD
No DLTs were observed in the first three patients entered at dose level I during their first cycle (Table 4Go). At dose level II, one patient reported febrile grade 3 neutropenia and another had fatal septic shock (not associated with neutropenia), which was considered retrospectively to be treatment-related and hence a DLT. Two DLTs were reported at dose level III, one patient experiencing an episode of angina pectoris and another grade 4 diarrhea. No DLTs were reported in the four patients treated at dose level IV during their first cycle. Given the good tolerance of the regimen, a protocol amendment was made introducing two additional dose levels, giving a total of six dose levels. One of the eight patients treated at dose level V reported treatment delays >1 week of the first day of cycle 2 due to treatment-related hematological absence of recovery, and one had asymptomatic, short-lasting grade 4 neutropenia. At dose level VI, a 5-FU-related toxidermia occurred, leading to treatment discontinuation. In addition, although the protocol definitions of MTD and RD were based on DLTs occurring during the first cycle, note that three additional patients experienced grade 3–4 diarrhea or grade 2 diarrhea lasting >7 days at cycle 2. Thus, the MTD was reached at dose level VI, with doses of irinotecan and oxaliplatin superior to those recommended in either double combination with this 5-FU regimen. However, it would not be logical to recommend dose level V, given that the only difference from dose level VI was a lower oxaliplatin dose and the DLTs observed at dose level VI were 5-FU- or irinotecan-related. Thus, the doses of 5-FU 3000 mg/m2 and irinotecan 100 mg/m2, tested in 14 patients and 65 cycles (at dose levels V and VI), are recommended for further phase II trials in combination with 80 mg/m2 oxaliplatin.


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Table 4 Dose-limiting toxicities (DLTs) during the first cycle, by patient

 
Safety
Three deaths probably or possibly related to study treatment occurred during this study. One patient at dose level II experienced grade 2–3 diarrhea for 10 days (fifth cycle), which became grade 4 with functional renal failure during hospitalization. Her general condition worsened and she died. She had concomitant deep venous thrombosis of the lower limbs and progressive disease. Another patient at dose level II died in cycle 1 from septic shock not associated with a neutropenia. Her death was originally deemed to be unrelated to study treatment; however, a relationship cannot be ruled out, especially given that she had concomitant grade 1 diarrhea lasting >7 days. A third patient at dose level VI died during cycle 6 as a result of febrile pancytopenia, associated with grade 4 vomiting and grade 2 diarrhea. In addition, eight patients discontinued treatment as a result of toxicity probably or possibly related to study treatment (fever and chills, two patients; peripheral neuropathy, two patients; angina pectoris, toxidermia, myoclonus and asthenia, one patient each).

The most frequently observed grade 3–4 toxicities (Table 5Go) were hematological, neutropenia being reported in 41% of patients in a total of 18% of cycles. Only one episode of grade 4 neutropenia lasted >7 days, and only two episodes of febrile neutropenia occurred. Of note, grade 4 neutropenia occurred in six patients (during the first cycle in only one patient and in cycles 2, 4, 5, 6 and 8 in others).


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Table 5 Grade 3–4 treatment-related toxicities, by patient and dose level

 
Diarrhea occurred in 53% of patients, including 32% with grade 2 and 6% with grade 4. Fifty per cent of patients experienced nausea, including 6% with grade 3–4. Vomiting was reported in 21% of patients, including 6% with grade 3–4. Peripheral sensory neuropathy was reported by 59% of patients, including 15% with grade 2. Grade 3–4 sensory neuropathy occurred in three patients (9%) at cycle 1, 6 and 9. One patient at dose level I experienced an episode of angina pectoris. One patient at dose level II experienced possibly oxaliplatin-related intravascular hemolysis at cycle 8.

Efficacy
Among the 34 treated patients (Table 6Go), 17 partial responses (PRs) (50%; 95% CI 33% to 67%) were reported. Responses were observed at all dose levels. Eleven of them (32.4%; 95% CI 16% to 48%) were confirmed by at least one second tumor assessment. Among the six non-confirmed PRs, two patients underwent surgical resection of their metastases before confirmation, obtaining a clinical benefit, two patients withdrew due to toxicity before confirmation and two had PRs lasting <2 months. Four of the 17 responses occurred in patients previously given chemotherapy for metastatic disease. These four patients were exposed to 5-FU and leucovorin alone. Of note, in seven patients, objective responses were not observed before cycle 4 or 6 (second or third tumor assessments). Thirteen patients had stable disease, three were not evaluable and one had progressive disease as best response. Five patients (15%; at all dose levels) underwent secondary surgical resection of their metastases, rendered possible by tumor shrinkage (Table 6Go). The median duration of PR was 14 months (range 4.7–29.2+). Median time to progression was 11.3 months (range 1.1–30.7+; Figure 2Go) and median overall survival was 26.1 months (range 1.1–32.1).


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Table 6 Responses

 


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Figure 2 Time to tumor progression (Kaplan–Meier estimate). Line, survival function; +, censored.

 

    Discussion
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 Abstract
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 Patients and methods
 Results
 Discussion
 References
 
This study reports for the first time this weekly alternated three-drug regimen in metastatic CRC, and shows that this schedule is feasible at the tested doses. The relative dose intensity reached was close to 1 for all three drugs. The absolute dose intensity of irinotecan and oxaliplatin at the RD (39 and 33 mg/m2/week, respectively) is clearly significantly lower than that given in double-combination regimens with the same 5-FU schedule (about 65 [10Go, 17Go] and 50 [18Go] mg/m2/week, respectively) or with the LV5FU2 regimen (90 [10Go] and 85 [13Go] mg/m2, respectively). Of note, the dose intensity of both irinotecan and oxaliplatin could have been increased if the starting dose of 5-FU had been lower.

This lower dose intensity is supposed to be compensated by the addition of a third active and non-cross-resistant drug. The preliminary substantial antitumor activity observed at all dose levels in the context of a phase I study with some patients in second-line therapy is compatible with this hypothesis. This activity is indeed similar to, or even higher than, that observed with double combination regimens (response rate about 50%, compared with 59% [12Go], 50% [11Go, 13Go] and 49% [10Go]; median response duration of 14 months, compared with 9.3 [10Go], 9 [11Go], 10.4 [13Go] months; and median time to progression of 11 months, compared with 7.2 [10Go], 7 [11Go], 8.7 [12Go] and 9 [13Go] months).

The safety profile is acceptable, with a particularly low incidence of hematological toxicity. Notably, febrile neutropenia and long-lasting grade 4 neutropenia seldom occurred. Febrile neutropenia/infection occurred in 6% of patients, compared with 11% [10Go] and 8% [11Go] with the irinotecan-based two-drug regimens. Nevertheless, there may be a cumulative effect, as severe neutropenia occurred beyond the first cycle in all but one episode. Diarrhea was the most frequent non-hematological toxicity, but the low incidence of grade >2 (6%) is of note when compared with 44% [10Go], 43% [12Go], 23% [11Go] or 12% [13Go] observed with the double combination regimens. This decreased incidence of severe diarrhea is related to the low dose intensity of both irinotecan and oxaliplatin in the alternating regimen. No clear dose–response relationship was observed. Nevertheless, the incidence of death possibly related to study treatment (three out of 34; 9%) is surprisingly high given the low incidence of severe toxicity. The incidence (59% of patients) and severity (9% grade 3 or 4) of peripheral neuropathy also seems to be decreased with this regimen as compared with the non-chronomodulated oxaliplatin-based double combination (18.2% grade 3) [13Go], due to the low dose intensity of oxaliplatin and the delay of high cumulative dose.

Other triple therapy approaches have been tested. The LV5FU2 schedule was alternately combined with irinotecan 180 mg/m2 or oxaliplatin 85 mg/m2 every 2 weeks and randomly assigned versus the two-drug combination of irinotecan 200 mg/m2 and oxaliplatin 85 mg/m2 every 2 weeks [20Go] in patients with 5-FU-resistant CRC. The efficacy of the alternated three-drug regimen was disappointing (6% response rate versus 23% with irinotecan plus oxaliplatin), and attributed to the low dose intensity of the two active drugs without the benefit of adding 5-FU in this context of 5-FU failure. This fact underlines the necessity to assess the activity of three-drug regimens in first-line therapy of metastatic disease. Of note, the planned dose intensity of irinotecan (45 mg/m2/week) was higher, and that of oxaliplatin (21.25 mg/m2) lower, than in the present study. Another study [21Go] tested the triple association of irinotecan 200 mg/m2 and oxaliplatin 85 mg/m2 with increasing 5-FU doses, given as a continuous intravenous infusion over 96 h in a phase I study. The recommended 5-FU dose was 2000 mg/m2 and the DLTs were diarrhea and febrile neutropenia. No responses were observed in the seven heavily pretreated CRC patients. A third study assessed the combination of a full-dose LV5FU2 regimen every 2 weeks with increasing doses of irinotecan and oxaliplatin, with simultaneous administration of the three drugs [22Go]. The RDs were oxaliplatin 85 mg/m2 and irinotecan 180 mg/m2 with a simplified LV5FU2 regimen with only one-day bolus 5-FU, which is less myelotoxic. Of note, the irinotecan and oxaliplatin doses recommended with this regimen were the same as those given with the double combination regimens of either irinotecan [10Go] or oxaliplatin [13Go] with LV5FU2 or of oxaliplatin plus irinotecan every 2 weeks [15Go]. The planned dose intensity achieved with this regimen is therefore significantly higher than that in the present study. However, although the actual dose intensity is not provided, 78% of patients had delayed cycles and 51% had dose reductions. Furthermore, granulocyte colony-stimulating factor (G-CSF) was required in 51% of patients (29% at the RD and 5-FU schedule) to treat neutropenia or to maintain dose intensity. This regimen was less well tolerated than the alternating regimen used in the present study. Grade 3–4 neutropenia was observed in 78% of patients and febrile neutropenia in 22%. Grade 3–4 diarrhea was reported in 27%, grade 3–4 nausea/vomiting in 24% and grade 3–4 neuropathy in 20% of patients. Antitumor activity was observed, including two of six pancreatic and two of three biliary duct carcinomas. Higher dose intensities were therefore achieved with the three drugs given together at the expense of much higher incidence of severe toxicity and G-CSF use. These two different approaches should be evaluated in terms of overall patient benefit in randomized studies.

In conclusion, alternating administration of irinotecan or oxaliplatin with a weekly 24-h infusion of 5-FU is an active and safe regimen in advanced CRC that warrants comparison, in randomized phase II or III studies, with standard double-combination regimens and/or other triple-combination approaches. Indeed, the preliminary results suggest that this regimen may be at least as active and significantly less toxic than 5-FU double-combination regimens with either irinotecan or oxaliplatin, or non-alternating triple-combination regimens. Of note, therapeutic alternatives after failure of these three-drug regimens are currently only investigational, and the global benefit of this strategy should be assessed in terms of overall survival.


    Acknowledgements
 
We thank Aude Soccorsi for statistical analysis and Sarah Mackenzie for help in editing the manuscript. This work was supported by a grant from Aventis Pharma.

Received for publication November 4, 2003. Revision received February 18, 2004. Accepted for publication February 20, 2004.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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