1 EHS Centre Pierre et Marie Curie, Algiers, Algeria; 2 Institue Salah Azaiz Bab Saadoun, Tunis, Tunisia; 3 Regionalne Centrum Oncologii, Bydgoszcz, Poland; 4 Pandy K Bekescountry County Hospital, Gyula, Hungary; 5 Oncology Center of Latvia, Riga, Latvia; 6 Clinicum of the University of Tartu, Tartu, Estonia; 7 National Cancer Institute, Cairo, Egypt; 8 Oncology Dispanser, Omsk, Russia; 9 Global Medical Affairs Oncology, Aventis Pharma, Antony, France
Received 18 October 2002; revised 13 February 2003; accepted 17 March 2003
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Abstract |
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Three different therapeutic regimens of irinotecan (CPT-11) in combination with 5-fluorouracil (5-FU) and folinic acid (FA) were evaluated for efficacy and safety in the first-line therapy of advanced colorectal cancer.
Patients and methods:
Patients were randomly assigned to receive intravenously either: CPT-11 125 mg/m2, FA 20 mg/m2 followed by 5-FU 500 mg/m2 bolus, weekly for 4 weeks (arm A, Saltz regimen); or CPT-11 180 mg/m2 day 1 then FA 200 mg/m2 over 2 h and 5-FU 400 mg/m2 bolus and 5-FU 600 mg/m2 22-h infusion on days 1 and 2, every 2 weeks (arm B, Douillard regimen); or CPT-11 350 mg/m2 (days 1 and 43) alternating with FA 20 mg/m2/day followed by 5-FU bolus 425 mg/m2/day during 5 days (days 2226) (arm C, Mayo Clinic regimen).
Results:
A total of 154 patients were included in the study (arm A, 51 patients; arm B, 53; arm C, 50). Overall response rates for the intention-to-treat populations were 33% [95% confidence interval (CI) 21% to 48%], 42% (95% CI 28% to 56%) and 30% (95% CI 18% to 45%) for arms A, B and C, respectively. Median times to progression were 6, 8 and 7 months for arms A, B and C, respectively. Median survival times were 15, 12 and 17 months for arms A, B and C, respectively. Overall response rates for the evaluable patient populations were 40% (95% CI 24% to 58%) in arm A, 44% (95% CI 29% to 60%) in arm B and 31% (95% CI 17% to 47%) in arm C. Neutropenia was the main serious adverse event in arms A (30% of patients) and C (22% of patients) but occurred in only 8% of patients in arm B. Delayed diarrhea was the main severe adverse event for the three regimens, from 15% to 22%.
Conclusion:
All three regimens were highly active. The biweekly combination of CPT-11 and 5-FU/FA (arm B) was notable for its low incidence of grade 3/4 neutropenia. The incidence of grade 3/4 delayed diarrhea was equivalent for the three treatment arms.
Key words: colorectal cancer, first-line, 5-fluorouracil/folinic acid, irinotecan
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Introduction |
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Irinotecan (CPT-11) (7-ethyl-10-[4(-1-piperidino)-1-piperidino] carbonyloxy camptothecin), a semisynthetic derivative of the natural alkaloid camptothecin, was introduced into the clinic in the late 1980s. CPT-11 belongs to a new class of antineoplastic agents, the topoisomerase I-interactive compounds, which interfere with DNA replication and cell division [4]. Clinical studies with CPT-11 have demonstrated tolerable side-effects and a broad spectrum of efficacy against solid tumors, including colorectal cancer [5]. As first-line chemotherapy in metastatic colorectal cancer, single-agent CPT-11 produced a combined response rate of 26% [95% confidence interval (CI) 20% to 32%)], a median time to progression (TTP) of 89 months and a median survival time of 12 months [69]. Thus, single-agent CPT-11 demonstrates an antitumor efficacy comparable to that achievable with standard FA-modulated 5-FU-based regimens. Furthermore, CPT-11 has demonstrated promising antitumor activity in patients with 5-FU-refractory colon cancer, producing response rates in the range of 1323% and median times to progression of 68 months [911]. In randomized phase III trials, second-line single-agent CPT-11 extended survival significantly compared with either best supportive care [12] or infusional 5-FU and FA [13]. The most frequent adverse events associated with CPT-11 include neutropenia, delayed diarrhea, acute cholinergic syndrome, alopecia, fatigue and nausea/vomiting [9].
Based on the promising single-agent activity of CPT-11 in the treatment of colorectal cancer, it has been investigated in combination with different 5-FU-based regimens. Interesting results in terms of both efficacy and safety have been reported for CPT-11 in combination with either standard bolus or an alternating bolus 5-FU/FA schedule, or with a continuous infusional high-dose 5-FU/FA schedule as first-line therapy [1418]. Two international (North American and European) randomized phase III trials have confirmed the efficacy of CPT-11 combined with the most frequently used 5-FU/FA bolus and infusional regimens compared with the corresponding 5-FU/FA alone [19, 20]. The combination arms of both trials demonstrated a significant superiority in terms of efficacy (response rate, median TTP and median survival time), compared with 5-FU/FA alone [19, 20]. As a result, CPT-11 in combination with either bolus 5-FU/FA or an infusional 5-FU/FA regimen has been approved for the first-line treatment of patients with advanced or metastatic colorectal cancer in both the United States and Europe. Several studies are now ongoing in the United States and Europe to assess the efficacy and safety of the different CPT-11/5-FU/FA combinations.
The present phase II randomized study of CPT-11 combined with either an infusional or bolus 5-FU/FA or alternating bolus 5-FU/FA regimen, was designed to assess the response rates of three different, but established, therapeutic CPT-11/5-FU/FA regimens in the same trial. The safety profile, median TTP and survival data were also evaluated.
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Patients and methods |
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Treatment
CPT-11 (Campto") was supplied by Aventis Pharma (Antony, France) as a sterile solution of 20 mg/ml in 5 ml vials. Patients were randomly assigned to receive one of three regimens: arm A, consisting of CPT-11 125 mg/m2 administered i.v. over 3090 min, FA 20 mg/m2 administered i.v. over 15 min immediately after completion of the CPT-11 infusion and 5-FU 500 mg/m2 administered as an i.v. bolus immediately following FA, weekly for 4 weeks on days 1, 8, 15 and 22, every 6 weeks (Saltz regimen); arm B, consisting of CPT-11 180 mg/m2 administered i.v. over 3090 min on day 1, followed immediately by FA 200 mg/m2 administered i.v. over 2 h followed immediately by 5-FU 400 mg/m2 administered as an i.v. bolus and 5-FU 600 mg/m2 as a 22-h i.v. infusion on days 1 and 2, every 2 weeks (Douillard regimen); or arm C, consisting of CPT-11 350 mg/m2 administered i.v. over 3090 min on day 1 and day 43 (6 weeks) alternating with FA 20 mg/m2/day followed by 5-FU 425 mg/m2/day administered as an i.v. bolus daily for 5 days (days 2226) (Mayo Clinic regimen).
One cycle corresponded to 6 weeks for each treatment arm. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of patient consent. A cycle was considered to be delayed if the cycle duration was >6 weeks. If this duration was >8 weeks the patient was taken off study. A 20% reduction in the dose of CPT-11 and 5-FU was made in the case of grade 3/4 hematological and non-hematological toxicities, for the three arms. Concomitant medication included subcutaneous atropine (0.25 mg) as a curative treatment for severe cholinergic symptoms, including early diarrhea, which could be continued in subsequent cycles with prophylactic intent, and oral loperamide, 2 mg every 2 h, for at least 12 h as soon as the first liquid stool occurred and up to 12 h after the last liquid stool without exceeding a total treatment duration of 48 h, and oral rehydration for the curative treatment of delayed diarrhea. If diarrhea persisted for >48 h despite loperamide treatment, or in the case of severe diarrhea or diarrhea associated with vomiting, fever or severe neutropenia, prophylactic broad-spectrum oral antibiotics, with fluoroquinolone or cotrimoxazole, had to be administered for 7 days and the patient had to be hospitalized for rehydration. Patients with febrile neutropenia had to be hospitalized to receive i.v. antibiotics. No prophylactic antiemetics were allowed on day 1 of treatment, but could be used at the discretion of the investigator in subsequent cycles. Growth factor support was administered at the discretion of the investigator.
Response and toxicity evaluation
Tumor response was radiologically assessed every 12 weeks (or two cycles of treatment) according to WHO criteria [complete response (CR), partial response (PR), minor response, stable disease (SD) and progressive disease (PD)]. The overall response rate determined by the investigators was defined as the percentage of patients with a CR or PR. The period for CR lasted from the date the CR was achieved to the date thereafter on which PD was first noted. The period of overall response lasted from the first day of treatment to the date of first observation of PD. The duration of SD was taken from the date that SD was first recorded until the date thereafter when PD was first recorded. TTP was the time measured from the day of randomization to the first progression or death due to malignant disease. Toxicity, graded according to National Cancer Institute (NCI) Common Toxicity Criteria, was assessed before each infusion by clinical and biological examinations (before each infusion for hematology and every 6 weeks for biochemistry).
Statistical analysis
According to the single-stage Fleming design, 45 patients needed to be recruited into each arm and the sample size was not calculated for comparative analysis. The analyses were performed with SAS" Software version 8.0 for Windows and S-plus V 4.5. The primary end point of the study was to evaluate the response rate of each combination, calculated with the 95% CI. The secondary efficacy criteria were the duration of response and of stabilization, TTP and survival. The times to event were estimated by the KaplanMeier method. Efficacy analyses were performed for both the intention-to-treat (ITT) and evaluable populations (eligible patients having received at least one complete cycle of treatment, except for patients whose disease had progressed before the end of the cycle, and same method of radiological assessment during the study). The survival was evaluated for the ITT populations only. Safety analyses were performed for all patients who had received one complete cycle of CPT-11/5-FU/FA.
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Results |
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Hematological toxicity. Hematological toxicity (worst grade) by patient is reported in Table 4. Neutropenia was the main severe adverse event in arm A (weekly CPT-11 plus bolus 5-FU/FA regimen) and arm C (alternating regimen). Grade 3/4 toxicity occurred in 30% of patients for arm A and in 22% of patients for arm C. The incidence of neutropenia was lower in arm B patients (biweekly CPT-11 plus bolus and infusional 5-FU/FA regimen) with the occurrence of grade 3/4 toxicity in 8% of patients. Febrile neutropenia only occurred in arm A patients (6% of patients). Grade 3/4 anemia occurred in 8% of patients in arm A, 2% of patients in arm B and 4% of patients in arm C. Grade 4 thrombocytopenia was rare, and was only reported in 2% of patients in arms A and C (and for no patients in arm B).
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Non-hematological toxicities. The most common non-hematological adverse events (all grades) that were possibly or probably related to the treatment were delayed diarrhea (6678% of patients), alopecia (5360% of patients), nausea (5762% of patients), vomiting (4558% of patients), anorexia (3039% of patients), stomatitis (2034% of patients) and cholinergic syndrome (2032% of patients). Grade 3/4 NCI adverse events per patient (Table 5) were delayed diarrhea (18% versus 15% versus 22% of patients in arms A, B and C, respectively), grade 3/4 nausea/vomiting (equivalent in the three arms at 78%), grade 3/4 stomatitis (6% in arms A and C), grade 3/4 infection (low incidence of 6% in arm A, 2% in arm B, none in arm C), and low incidence of grade 3/4 cholinergic syndrome in the three arms. Grade 2 alopecia occurred in 30% versus 40% versus 54% of patients in arms A, B and C, respectively. Hepatic and renal tolerance was good.
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Patient withdrawal and deaths. Patients were withdrawn from the study due mainly to disease progression (47% versus 60% versus 62% of patients in arms A, B and C, respectively), and withdrawal of patient consent (20% versus 13% versus 14% of patients in arms A, B and C, respectively). At the time of analysis, 58 patients were alive. The majority of deaths were due to malignant disease, but three deaths were related to the study treatment. There were two patients in arm A, one 70-year-old patient who died of septic shock 6 days after the last infusion of the first cycle and one 42-year-old patient who died of hypokalemia plus hyponatremia 3 days after the last infusion of the first cycle. The third treatment-related death, in arm C, was a 42-year-old patient who died 16 days after the last infusion of the fifth cycle of therapy from a cardiac arrest following grade 4 fever with infection. There were six deaths (4%) across all three treatment arms within the first 60 days of therapy. Four early deaths were reported for arm A. Two of these were considered to be treatment related as described above, and two unrelated to treatment due to malignant disease. Two early deaths (cerebral stroke, malignant disease) were also reported for arm B but both were unrelated to treatment (Table 6).
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Discussion |
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The biweekly Douillard regimen combination of CPT-11 180 mg/m2 (5-FU/FA fixed dose: 200 mg/m2 FA, 5-FU bolus 400 mg/m2 and 5-FU 600 mg/m2 over 22 h, on days 1 and 2) evaluated in arm B was previously shown to be safe in pretreated patients without overlapping toxicity in the phase I study reported by Ducreux et al. [18]. These results were confirmed by Douillard et al. [20] in a pivotal European phase III trial which evaluated CPT-11 in combination with either the biweekly de Gramont (LV5FU2) or the weekly German Arbeitsgemeinschaft Internische Onkologie 5-FU/FA infusional regimens (n = 387). The overall confirmed response rates were 35% and 22% (ITT analysis), respectively, for the CPT-11 combination arm and the 5-FU/FA control arm. Again, the median durations of response were approximately 9 months for both the CPT-11/5-FU/FA and 5-FU/FA arms [20]. The median TTPs were 6.7 and 4.2 months, and median survival times 17.4 and 14.1 months for the CPT-11/5-FU/FA and 5-FU/FA arms, respectively [20].
The alternating schedule of CPT-11 (350 mg/m2) day 1 with FA (20 mg/m2/day) followed by 5 days bolus of 5-FU (425 mg/m2/day) (Mayo Clinic regimen) evaluated in arm C was previously reported by Van Cutsem et al. [16] in a phase II trial, and was shown to have a good tolerability profile, without any cumulative or overlapping toxicity.
The present study showed that all three of the CPT-11/5-FU/FA combination regimens were highly active and comparable in terms of overall response rates (from 31% to 44% in the evaluable populations, and 30% to 42% in the ITT populations), median duration of response (8.512 months) and median TTP (68 months) for the evaluable population, and median survival times [1217 months (ITT)]. The study populations were representative of the candidates for first-line chemotherapy seen in clinical practice in both western Europe and the Unites States and the efficacy data were consistent with the efficacy data from the USA and European pivotal phase III trials [19, 20]. In previous phase II trials of the alternating schedules of bolus 5-FU/FA (Mayo Clinic regimen) and CPT-11 given either on a weekly-times-four schedule at 100 mg/m2 [15] or every 6 weeks at 350 mg/m2 [16] similar efficacy was shown with overall response rates of approximately 30% and median survival times of between 16 and 18 months.
The three combinations of CPT-11 plus 5-FU and FA were well-tolerated and the toxic effects reversible, non-cumulative and manageable. Consistent with the observations made in previous studies, neutropenia and delayed diarrhea were the most common toxic effects. Neutropenia was the main severe adverse event occurring in the weekly CPT-11 plus bolus 5-FU/FA regimen and in the alternating regimen, as already observed in previous trials. Saltz et al. [19] reported grade 3/4 neutropenia in 54% of patients using the weekly regimen (n = 225). This was higher than our experience in the present study (30% of patients with grade 3/4 neutropenia). Similarly, Van Cutsem et al. [16], using the alternating schedule, reported 64% of patients with grade 3/4 neutropenia (n = 33), which was higher than that reported in the present trial (22% of grade 3/4 neutropenia). However, the frequency of severe neutropenia was higher (46% of grade 3/4 toxicity) in the European randomized phase III study than in the present study (8% grade 3/4 toxicity) [20]. The incidence of grade 3/4 delayed diarrhea was approximately 20% in arms A and C (18% for the weekly schedule and 22% for the alternating regimen), which was comparable to the previously reported data [16, 19]. Delayed diarrhea also occurred in the biweekly schedule combining CPT-11 with bolus and infusional 5-FU/FA, with 15% of patients exhibiting grade 3/4 toxicity. This incidence of severe diarrhea was similar to that observed in the European randomized phase III study, and was well managed by following the antidiarrheal guidelines with intensive and early use of loperamide. However, this regimen was distinguishable from the other two regimens by virtue of the very low incidence of grade 3/4 neutropenia (8% of patients and 2% of cycles).
The other severe non-hematological toxicities occurred at a low incidence in all treatment arms and included mainly alopecia, and nausea/vomiting. No case of severe stomatitis was noted in the biweekly regimen, while 6% of patients experienced grade 3/4 toxicity in both the weekly regimen and the alternating regimen. The occurrence of cholinergic syndrome was low in all three arms.
In conclusion, the three different therapeutic regimens combining CPT-11 with concomitant (weekly or biweekly) or alternated bolus and/or infusional 5-FU/FA were highly active in patients with advanced colorectal cancer, and were associated with an easily managed safety profile, which ensured good schedule compliance. The low incidence of grade 3/4 neutropenia observed with the biweekly combination of CPT-11 and 5-FU/FA (arm B), means that this regimen has the best tolerability profile of the three regimens tested.
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Acknowledgements |
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Additional principal participating investigators of the Irinotecan Study Group were: P. P. Bapsy (India), S. Ben Ahmed (Tunisia), T. Salek (Slovakia), S. Donea (Romania), D. A. Gerges (Lebanon), D. C. Doval (India), E. Buyukunal (Turkey), I. N. Chernozemsky (Bulgaria), V. I. Tzekova (Bulgaria), H. A. El-Azim (Egypt), H. Errihani (Morocco), R. Samlali (Morocco), J. S. Godz (Poland), N. Ghilezan (Romania), B. A. Berdov (Russia), G. N. Tchaikovsky (Russia), M. Wagnerova (Slovakia), N. F. Aykan (Turkey), J. Zidan (Israel) and G. Chachine (Lebanon).
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Footnotes |
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Additional members of the Irinotecan Study Group are listed in the Acknowledgements.
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References |
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