Irinotecan combined with bolus 5-fluorouracil and folinic acid Nordic schedule as first-line therapy in advanced colorectal cancer

B. Glimelius1,2,+, R. Ristamäki3, M. Kjaer4, P. Pfeiffer5, T. Skovsgaard6, K. M. Tveit7, T. Linné8, J. E. Frödin2, B. Boussard9, D. Oulid-Aïssa9 and S. Pyrhönen3

1 Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Uppsala; 2 Radiumhemmet, Karolinska Hospital, Stockholm, Sweden; 3 Turku University Central Hospital, Turku, Finland; 4 Department of Oncology, Aalborg Hospital, Aalborg; 5 Odense University Hospital, Onkologisk Afdeling R, Odense; 6 Department of Oncology, KAS Herlev, Herlev, Denmark; 7 Ullevaal University Hospital, Oslo, Norway; 8 Department of Oncology, Central Hospital, Sweden; 9 Global Medical Affairs Oncology, Aventis Pharma, Aron, Antony cedex, France

Received 27 May 2002; accepted 17 June 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

This multicentre phase II study evaluated the efficacy and safety of irinotecan combined with the Nordic schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line therapy in patients with advanced colorectal cancer.

Patients and methods:

Seventy-four patients with measurable disease and a WHO performance status of 2 or less were treated with irinotecan 210 mg/m2 as a 30–90 min intravenous infusion on day 1, followed by 5-FU 500 mg/m2 and FA 60 mg/m2 bolus on days 1 and 2, every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was the objective response rate.

Results:

Twenty-nine out of 68 evaluable patients achieved a complete (n = 7) or partial (n = 22) response, leading to an overall response rate of 43% [95% confidence interval (CI) 31% to 55%]. The median duration of response was 10 months. The estimated median time to progression and survival were 6.4 months (95% CI 5.4–9.0) and 15.6 months (95% CI 13.3–19.0), respectively, in the intention-to-treat population. A total of 860 cycles were administered to 74 patients. Neutropenia was the main adverse event with grade 3–4 toxicity in 66% of patients and 17.5% of cycles. Grade 3–4 non-haematological toxicities were infrequent and included diarrhoea in 16% of patients and 2% of cycles and nausea/vomiting in 10% of patients and 1% of cycles.

Conclusions:

Irinotecan combined with the bolus Nordic schedule of 5-FU/FA is active in advanced colorectal cancer with an easily managed safety profile which ensures good schedule compliance. The low incidence of grade 3–4 non-haematological toxicity justifies the further evaluation of this combination in the context of randomised clinical trials.

Key words: chemotherapy, colorectal cancer, irinotecan, Nordic schedule


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Colorectal cancer is one the commonest malignant tumours, affecting approximately one person in 20 in North America and most other developed countries. Although 50–60% of the patients may be cured with surgery, even after apparently curative surgical resections many will go on to develop metastatic disease. For the patients with metastatic disease, the standard therapy was, until recently, treatment with 5-fluorouracil (5-FU) usually modulated by folinic acid (FA), which typically yielded a median survival time of 10–12 months [1, 2].

Irinotecan (CPT-11) is an S-phase-specific derivative of camptothecin which interferes with DNA replication and cell division by inhibiting topoisomerase I [3]. Irinotecan has demonstrated anti-tumour activity against metastatic colorectal cancer when used either alone as first-line treatment or as second-line treatment after the failure of 5-FU, with overall response rates ranging from 13% to 32% [4]. In randomised trials, irinotecan administered as second-line treatment extended survival significantly when compared with supportive care alone or infusional 5-FU plus FA [5, 6]. The most frequent adverse events associated with irinotecan therapy included neutropenia, delayed onset diarrhoea, acute cholinergic syndrome, alopecia, fatigue and nausea and vomiting.

The mechanism of action and single-agent efficacy of irinotecan, combined with the apparent absence of any cross-resistance with 5-FU provided the rationale for combining irinotecan with 5-FU and FA as first-line therapy for the treatment of colorectal cancer. A US randomised phase III clinical trial showed irinotecan combined with a bolus 5-FU/FA regimen to have superior efficacy to the Mayo Clinic bolus 5-FU/FA regimen in terms of response rate (39% versus 21%, P <0.001), median time to disease progression (TTP) (7 versus 4.3 months, P = 0.004) and overall survival (14.8 versus 12.6 months, P = 0.04) [7]. In another, European, randomised phase III study, the addition of irinotecan to a weekly (Arbeitsgemeinschaft Internische Onkologie, AIO) or bi-monthly (de Gramont) infusional 5-FU/FA regimen also resulted in superior efficacy, over the corresponding 5-FU/FA infusional regimens alone, in terms of response rate (35% versus 22%, P <0.005), TTP (median 6.7 versus 4.4 months, P <0.001) and survival (median 17.4 versus 14.1 months, P = 0.03) [8]. As a result the addition of irinotecan to weekly and bi-monthly 5-FU/FA infusional regimens has been recommended as the reference regimen for the first-line treatment of both advanced and metastatic colorectal cancer [8]. In fact, irinotecan in combination with either a bolus or infusional 5-FU/FA regimen has been approved by the US Food and Drug Administration for the first-line treatment of metastatic colorectal cancer.

In the Nordic countries, the Nordic bolus 5-FU regimen is considered to be the reference first-line treatment for advanced colorectal cancer [9]. Thus, following on from the US and European phase III studies of irinotecan in combination with different 5-FU/FA regimens, we have conducted a multicentre phase II study designed to evaluate the efficacy and safety of irinotecan in combination with the Nordic 5-FU/FA regimen as first-line therapy for patients with advanced colorectal cancer, using a dose that had been determined in a prior phase I study [10].


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient eligibility
Patients with a histologically confirmed diagnosis of adenocarcinoma of the colon or rectum, at least one measurable lesion and no potentially resectable metastases were recruited into the study. Other inclusion criteria were: age 18–75 years, a WHO performance status of 0–2, a life expectancy of more than 3 months, adequate haematological function (haemoglobin >=10 g/dl, neutrophils >=2 x 109/l and platelets >=150 x 109/l), satisfactory renal [creatinine <1.25 x upper normal limit (UNL)] and hepatic function [total bilirubin <1.25 x UNL, aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) <3 x UNL]; or in the case of liver metastasis: total bilirubin <1.5 x UNL, ASAT and ALAT <5 x UNL, no prior chemotherapy or only (neo) adjuvant chemotherapy which had been completed more than 6 months before study entry and no radiotherapy within the 4 weeks before study entry. Specific exclusion criteria included evidence of central nervous system metastasis, current infection, unresolved bowel obstruction or sub-obstruction, uncontrolled Crohn’s disease or ulcerative colitis and current history of chronic diarrhoea.

Pretreatment evaluations included a complete medical history and physical examination, complete blood cell count and blood chemistry, ECG, complete tumour imaging (X-ray, computerised tomography, ultrasound) and tumour markers. The study was approved by the local Ethical Committees and was conducted in accordance with the declaration of Helsinki. All patients provided written informed consent.

Treatment
All treatments had to be administered within 8 days of registration on the trial. Patients were treated with irinotecan (Campto®) at a dose of 210 mg/m2 administered as a 60–90-min intravenous (i.v.) infusion on day 1, followed immediately by 5-FU at 500 mg/m2 administered as an i.v. bolus, followed 30–40 min later by FA 60 mg/m2 i.v. bolus. The 5-FU/FA administrations were repeated again on day 2. This treatment combination was repeated every 2 weeks until disease progression or the occurrence of unacceptable toxicity. Dose adjustments were planned in the case of severe haematological and/or non-haematological toxicities. A 20% reduction in the dose of irinotecan and 5-FU was made in the case of grade 3–4 haematological and non-haematological toxicities.

Concomitant medication included subcutaneous atropine 0.25 mg as a curative treatment for severe cholinergic symptoms including early diarrhoea and then on a prophylactic basis for subsequent cycles, and oral loperamide, 2 mg every 2 h for at least 12 h, as a curative treatment for delayed diarrhoea, administered as soon as the first liquid stool occurred and for up to 12 h after the last liquid stool without exceeding a total treatment duration of 48 h. If the diarrhoea persisted for more than 48 h despite loperamide treatment, or in case of severe diarrhoea or diarrhoea associated with vomiting, fever or severe neutropenia, a prophylactic broad spectrum oral antibiotic with fluoroquinolone or cotrimoxazole was to be administered for 7 days and the patient had to be hospitalised for rehydration. Patients with febrile neutropenia had to be hospitalised to receive i.v. antibiotics.

Response and toxicity evaluation
Tumour response was assessed according to WHO criteria [complete response (CR), partial response (PR), minor response, stable disease and progressive disease (PD)] every 8 weeks (or four cycles of treatment). The overall response rate was defined as the percentage of patients with CR or PR. A minimum of 8 weeks of treatment was required for a patient to be included in the efficacy evaluation. The duration of response was calculated from the date of first infusion to the first date of documented progression. TTP was calculated from the date of treatment allocation to the first objective evidence of tumour progression or death due to progression. Toxicity, graded according to National Cancer Institute common toxicity criteria (NCI-CTC), was assessed by clinical examinations every cycle and biological examinations every four cycles (weekly for haematology).

Statistical analyses
According to the optimal two-stage Simon design, the total number of patients to be recruited was 48. The analyses were performed with SAS® Software version 8 and Stat X Tract, S plus. The primary end point was to evaluate the response rate, calculated with the 95% confidence interval. The secondary efficacy criteria were the duration of response, TTP and survival. The times to event were estimated by the Kaplan–Meier method. Efficacy analyses were performed for both the intention-to-treat (ITT) and evaluable (eligible patients having received a minimum of four cycles of treatment) patient populations. Safety analysis was performed on the ITT population only.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between May 1999 and February 2000, 74 patients were enrolled into the study in eight centres from four Nordic countries. Four patients (5%) were ineligible due to no measurable lesion (one patient), inadequate record of biological function (one patient missing creatinine data), prior history of uterine cancer (one), and first treatment not within 8 days of registration (one). The demographic and baseline disease characteristics are listed in Table 1.


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Table 1. Patients characteristics (n = 74)
 
Dose intensity
A total of 860 cycles of irinotecan combined with 5-FU/FA were administered to 74 patients with a median number of cycles per patient of 12 (range 1–26). The median relative dose intensity was 83.8% (range 51–114%) for irinotecan, 83.9% (range 51–114%) for 5-FU and 84.9% (range 46–117%) for FA. The median cumulative dose was 1916 mg/m2 for irinotecan (range 210–5460), 9922 mg/m2 for 5-FU (range 998–26 000) and 1293 mg/m2 for FA (range 120–3120). A total of 207 cycles (24%) had to be delayed (106 cycles for personal reasons or by the judgement of the investigator and 93 for haematological toxicity) and in 42 cycles (5%) the dose had to be adjusted due principally to haematological toxicity.

Efficacy results
Of the 70 eligible patients, two were not assessable for response (less than four cycles of treatment). Seven patients achieved a CR and 22 patients a PR leading to an overall response rate of 43% in evaluable patients and 39% in the ITT population (Table 2). The median duration of response (CR and PR) was 10 months and the median duration of stabilisation was 6 months; median survival time was 15.6 months in the ITT population (Table 2).


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Table 2. Response rate in intention-to-treat (ITT) and evaluable patients
 
Safety results
Haematological toxicity
Haematological toxicity is reported in Table 3 both by patient and by cycle. Neutropenia was the main adverse event with NCI-CTC grade 3–4 toxicity occurring in 66% of patients and 17.5% of cycles. The median time to nadir was 7 days (range 5–22 days). The median durations of grade 3 and grade 4 neutropenia were 3 days (range 1–31 days) and 1 day (range 1–11 days), respectively. Two patients (3%) experienced febrile neutropenia and six patients (8%) had grade 3 and grade 4 infection with grade 3–4 neutropenia. No patient experienced severe anaemia or thrombocytopenia.


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Table 3. Haematological toxicity related to irinotecan and 5-fluorouracil/folinic acid treatment by patient and by cycle
 
Non-haematological toxicities
The most common non-haematological adverse events possibly or probably related to the treatment were alopecia (77% of patients), fatigue (72%), nausea (68%), diarrhoea (63%), cholinergic syndrome (57%), stomatitis (49%), vomiting (43%), anorexia (34%), constipation (26%) and hand and foot syndrome (12%). NCI-CTC grade 3–4 treatment-related adverse events by patient and by cycle are summarised in Table 4. Overall, grade 3–4 adverse events were uncommon and included diarrhoea (16% of patients and 1.7% of cycles), nausea (11% of patients and 1.2% of cycles), vomiting (9% of patients and 0.9% of cycles), pain, anorexia or constipation (3% of patients and 0.3% of cycles), stomatitis or fatigue (3% of patients and 0.2% of cycles). Hepatic tolerance was excellent. Grade 3 toxicity was observed for bilirubin increase in two patients (3%). Twenty-seven patients (36%) experienced grade 2 alopecia.


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Table 4. Grade 3–4 non-haematological toxicity related to irinotecan and 5-fluorouracil/folinic acid treatment by patient and by cycle (74 patients, 860 cycles)
 
Patients were withdrawn from the study due to disease progression (46 patients), completion of treatment after 1 year (four patients), CR (four patients), toxicity from study drug (four patients), withdrawal of consent (three patients), deviation from the protocol (three patients), death (one patient) and other reasons (nine patients: one laparotomy, one no change after 12 cycles of therapy, three patients possibly requiring surgery, four patients personal preference). At the time of analysis, 24 patients were alive.

The majority of deaths were due to PD, although one death, due to intestinal haemorrhage, was related to the study treatment. The patient concerned had grade 2 diarrhoea after his first course of treatment. Due to cancer-related pain during the second course, diclofenac (100 mg x 3) was prescribed. During the third course of treatment, the patient had an episode of grade 4 diarrhoea and grade 3 anorexia for which he was hospitalised 5 days after the last infusion. The diarrhoea was resolved upon treatment with loperamide. Having been hesitant to receive palliative chemotherapy before entry into the study, and with no immediate relief of his tumour-related symptoms, the patient opted for no further chemotherapy, and was sent to his local palliative home-care team. On day 18 after the last infusion, he had a large intestinal bleed and died on day 24. The autopsy showed mucosal damage in the intestine and liver metastases.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The primary objective of this multicentre, open, phase II study was to evaluate the efficacy of irinotecan combined with 5-FU plus FA, administered according to the Nordic schedule (bolus injection for 2 days, every 2 weeks) that is commonly used in Northern Europe in patients with advanced colorectal cancer. Irinotecan was administered at a dose of 210 mg/m2, which was recommended as a result of a phase I study [10]. The present study showed this combination regimen to be highly active, for patients with advanced colorectal cancer, with an objective response rate of 39% in the ITT patient population and 43% in the evaluable patient population. The ITT study population was representative of the candidates for first-line chemotherapy in clinical practice, and the results recorded are comparable with those obtained for irinotecan combined with either the bi-monthly de Gramont or the weekly German AIO infusion regimens in the European phase III clinical trial [8] or with the bolus Saltz regimen in the North American phase III trial [7]. The overall response rates in these trials ranged from 33% to 39%, and were significantly higher than the response rates reported for the corresponding control 5-FU/FA regimens, which had response rates of between 21% and 25% [7, 8]. The median durations of response for both these phase III studies were approximately 9 months. The median TTP (6.5–7.2 months) and median survival (14.8–17.4 months) were comparable with those observed in the present phase II study (6.4 and 15.6 months, respectively). Maiello et al. [11] have also shown in a randomised phase II study that the addition of irinotecan to a hybrid LV5FU2 regimen provides an overall response rate of 40%, which was superior to the response rate obtained with 5-FU/FA alone (18%) as first-line therapy.

In the present study, the combination of irinotecan plus 5-FU/FA according to the Nordic schedule was well tolerated and the toxic effects were reversible, non-cumulative, and manageable. The compliance for this treatment regimen was excellent, with relative dose intensities of at least 84% for each compound. As expected, on the basis of previous studies, neutropenia and delayed onset diarrhoea were the most common toxic effects. Neutropenia was the main adverse event with grade 3–4 neutropenia reported in 66% of patients and 17.5% of cycles. However, the duration of these episodes was short and recovery rapid. Febrile neutropenia occurred in 3% of patients and 0.2% of cycles. Severe non-haematological toxicities were infrequent and included diarrhoea in 16% of patients (3% grade 4) and 1.7% of cycles and vomiting in 9% of patients and 1.2% of cycles. Irinotecan-induced delayed-onset diarrhoea was well managed by following the anti-diarrhoeal guidelines that included the intensive and early use of loperamide which had been determined in phase II studies of irinotecan as a single agent [4]. Cholinergic syndrome was also well controlled with the appropriate medication. One death, due to intestinal haemorrhage, was considered to be related to study treatment. If we include the patients treated during the preceding phase I study [10], one (1%) toxic death occurred among 91 patients, which represents an acceptable figure for patients with metastatic disease [12]. All deaths which occurred in patients while on treatment were independently reviewed, prompted by the alarm from the US adjuvant and palliative trials using the Saltz regimen [13].

The Nordic 5-FU and FA acid regimen was developed to be an active, but at the same time a highly tolerable and practical palliative bolus regimen. In several large multicentre trials, it has yielded independently reviewed objective response rates of around 25% and overall survivals of about 12 months, coupled with very low toxicity, in patients generally having symptoms of their disease and a deteriorating performance status [9, 14, 15]. The Nordic schedule has never been compared in a randomised trial with either the Mayo Clinic regimen [16] or any of the infusional regimens [1719]. Thus, any conclusions about efficacy and tolerability in relation to other regimens must be interpreted with caution. However, the safety profile of the Nordic schedule with irinotecan appears to compare favourably with the safety profiles observed in both the phase III trials using irinotecan in combination with different bolus or infusional 5-FU/FA regimens [7, 8]. The dose of irinotecan used in the present study in combination with the bimonthly Nordic 5-FU/FA schedule was higher (210 mg/m2) than with the bi-monthly de Gramont schedule (180 mg/m2) [8].

In conclusion, the results of this phase II study add support to the notion that a combination of irinotecan plus 5-FU and FA should be considered as a reference first-line treatment for advanced colorectal cancer. Irinotecan combined with the bolus Nordic schedule of 5-FU/FA is highly active with an easily managed safety profile which ensures good schedule compliance. The low incidence of grade 3–4 non-haematological toxicity justifies the further evaluation of this therapy combination in formal clinical trials. Presently, the Nordic group is comparing this regimen with the de Gramont irinotecan regimen [8] in a randomised phase III trial.


    Acknowledgements
 
We thank the International Drug Development Institute and Barbara Raoult for statistical analysis, Maryse Berlion for support in the writing of the manuscript, and all Monitor’s Aventis affiliates for attentive site management. This study was sponsored by Aventis Pharma, France, and the Swedish Cancer Society.


    Footnotes
 
+ Correspondence to: Dr B. Glimelius, Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, S-75185 Uppsala, Sweden. Tel: +46-18-611-3000; Fax: +46-18-611-5528; E-mail: bengt.glimelius{at}onkologi.uu.se Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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