|Year : 2009 | Volume
| Issue : 4 | Page : 272-276
Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer
Hind Mrabti1, Christelle De la Fouchardiere2, Francoise Desseigne2, Sophie Dussart3, Sylvie Negrier2, Hassan Errihani4
1 Department of Medical Oncology, Centre Leon Berard, Lyon France; Department of Medical Oncology, Institut National d'Oncologie Sidi Mohamed Ben Abdellah, Rabat, Morocco
2 Department of Medical Oncology, Centre Leon Berard, Lyon France
3 Biostatistics Unit, Centre Leon Berard, Lyon France
4 Department of Medical Oncology, Institut National d'Oncologie Sidi Mohamed Ben Abdellah, Rabat, Morocco
|Date of Web Publication||11-Feb-2010|
14 Rue Moulay Yaacoub, Av Ain Khalwiya, Souissi, Rabat, Morocco
Source of Support: None, Conflict of Interest: None
Aim : The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (MCRC).
Methods : We reviewed the clinical records of 50 patients with MCRC who began treatment with cetuximab from February 2004 to January 2007. Two different treatment schedules were used. In the first group (N = 32), cetuximab was given at an initial dose of 400 mg/m 2 , followed by weekly infusions of 250 mg/m 2 . In the second group (N = 18), cetuximab was administered every 2 weeks at a dose of 500 mg/m 2 . The two groups were compared for tumor response, time to progression (TTP), overall survival (OS), and toxicity.
Results : All patients had received irinotecan and 5-fluorouracil; a majority had previously received oxaliplatin. Disease control (partial response + stable disease) was achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% in the other group
(P = 0.21). The median follow-up for all patients was 34.2 months. TTP (Group 1: 28% vs. Group 2: 18%, P = 0.9356) and OS (Group 1: 75% vs. Group 2: 72%, P = 0.6748) rates at 7 months were similar in the two groups. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction.
Conclusion : There is no major difference of efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan.
Keywords: Cetuximab given every 2 weeks, metastatic colorectal cancer, weekly cetuximab
|How to cite this article:|
Mrabti H, la Fouchardiere C, Desseigne F, Dussart S, Negrier S, Errihani H. Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer. J Can Res Ther 2009;5:272-6
|How to cite this URL:|
Mrabti H, la Fouchardiere C, Desseigne F, Dussart S, Negrier S, Errihani H. Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer. J Can Res Ther [serial online] 2009 [cited 2019 Jan 19];5:272-6. Available from: http://www.cancerjournal.net/text.asp?2009/5/4/272/59907
| > Introduction|| |
The management of advanced colorectal cancer (CRC) has largely evolved over the past decades.
Several phase III trials investigating combination regimens with fluorouracil--leucovorin plus irinotecan or oxaliplatin as first-line therapy have achieved an improvement in disease-free survival (DFS) and overall survival (OS). ,,, The median duration of survival has increased from 12 months to about 18-21 months. 
In colorectal cancer, the epidermal growth factor receptor (EGFR) gene is expressed or upregulated in 60-80% of cases. The EGFR signaling pathway regulates cell differentiation, proliferation, migration, angiogenesis, and apoptosis, all of which become deregulated in cancer cells.  Cetuximab is a chimeric IgG1 monoclonal antibody that binds to the extra-cellular domain of EGFR, thus blocking ligand-induced phosphorylation of EGFR and the EGFR signaling pathway.
In 2004, two phase II studies using cetuximab assessed its safety and efficacy in metastatic CRC. In the first study, Saltz et al. evaluated the antitumor activity of cetuximab given as a single agent in 57 irinotecan-refractory metastatic CRC: the response rate was 9% and 35% of the patients had disease stabilization. 
Cunningham and co-workers published the results of the randomized phase II BOND study comparing cetuximab alone versus cetuximab plus irinotecan in patients with irinotecan-refractory CRC.  The response rate was 22.9% in the combination therapy group and 10.8% for patients receiving cetuximab alone. The median time to progression was 4.1 months and the median survival 8.6 months. Cetuximab was then approved for use in combination with irinotecan for the treatment of metastatic irinotecan-refractory CRC. The recommended dosing regimen, as used in all the trials, was an initial dose of 400mg/m 2 followed by 250 mg/m 2 weekly.
Cetuximab is frequently given in combination with chemotherapy (irinotecan) administered every 2. A phase I study by Tabernero et al. has shown that cetuximab monotherapy every 2 weeks provides pharmacokinetic results similar to those obtained with the standard weekly cetuximab dosing regimen.  The conclusion of this trial is that cetuximab can be safely administered every 2 weeks at doses of 400 and 500 mg/m 2 . Further information will be available after the evaluation of the combination therapy with irinotecan.
After this trial, we simplified in our center the way of administration of cetuximab to an every 2-week schedule because it allows patients to not come to the hospital every week, so it certainly improves their quality of life.
The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (CCR).
| > Material and Methods|| |
We reviewed the clinical records of all patients with metastatic CRC who began treatment with cetuximab from February 2004 to January 2007.
Patients included were those with histologically confirmed stage IV colorectal adenocarcinoma. All must have progressed under irinotecan before initiating treatment with cetuximab and irinotecan (progression of disease during or within 3 months after treatment).
The identification of the EGFR status was made by immunohistochemical analysis of a paraffin-embedded tumor specimen. The test was not performed systematically.
Two different treatment schedules were used. In the first group, cetuximab was given at an initial dose of 400 mg/m 2 , followed by weekly infusions of 250 mg/m 2 . In the second group, cetuximab was administered every 2 weeks at a dose of 500 mg/m 2 . In both groups, the first dose was preceded by a 20-mg test dose to check for signs of allergic reaction. All patients received premedication with a histamine-receptor inhibitor.
Irino tecan was given every 2 weeks at a dose of 180 mg/m 2 .
All patients were treated until disease progression or occurrence of unacceptable toxicity. Only patients who received at least 2 or 3 months of treatment and had an evaluation were eligible for the study.
Evaluation of tumor response was performed every 2 months from the beginning to the end of treatment using response evaluation criteria in solid tumors (RECIST). Tumor measurement techniques included physical examination and CT scan. Median time to progression (TTP) was measured from the initiation of treatment until disease progression. Survival was also measured from the initiation of treatment. Toxicity was evaluated in accordance with the National Cancer Institute Common Toxicity Criteria (NCI-CTC).
Quantitative variables were compared between the two groups using Student's test when the data were normally distributed or using the nonparametric Wilcoxon's rank-sum test otherwise. Differences in qualitative variables between the two groups were evaluated by means of a two-sided Fisher's exact test. A P value of less than 0.05 was considered to indicate statistical significance.
TTP and OS were estimated using the Kaplan-Meier method with a 95% confidence interval, and compared between the two groups using the log-rank test.
All analyses were performed using SAS software (version 8.2).
| > Results|| |
Patients' characteristics [Table 1]
Between February 2004 and January 2007, 50 patients with irinotecan-refractory CRC were identified: 32 received the weekly dosing regimen of cetuximab (Group 1) and 18 received cetuximab every 2 weeks (Group 2). Median age was 53.2 years (range: 28-85) in the first group and 54.4 years (33-80) in the second group. Twelve patients were females and 20 were males in the first group, whereas 13 were females and 5 were males in the second group. The primary site was the colon in almost all cases (Group 1: 84.4%; Group 2: 66.7%). Most patients had undergone primary tumor resection (Group 1: 87.5%; Group 2: 88.9%). Metastatic sites were the liver, lung, lymph nodes, and peritoneum. In the first group, 50% of patients had one metastatic site whereas in the second group, 50% had two metastatic sites. All patients had received irinotecan and 5-fluorouracil, and a majority had previously received oxaliplatin: 75% in the first group and 94.4% in the second group. Cetuximab and irinotecan were administered as second, third, or fourth line of treatment. The median duration of treatment was 3.5 months (seven cycles in both groups).
The EGFR status was assessed in 60% of patients: 62.5% EGFR-positive tumors were identified in the first group and 55.5% in the second group.
In the first group, 28.1% of patients obtained a partial response and 28.1% (9 patients) had disease stabilization or minor response, versus 11.1% and 66.7% (12 patients) respectively in the second group. Disease control (partial response + stable disease) was thus achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% of patients receiving cetuximab every 2 weeks, with no statistical difference between groups (P = 0.21).
There was no complete response. Fourteen patients (43.8%) had progressive disease after 3 months of treatment in Group 1 versus four patients (22.2%) in Group 2 [Table 2].
A resection of hepatic metastases was possible in two patients in each arm. The median follow-up for all patients was 34.2 months.
In the weekly regimen group, the progression-free survival rate at 7 months was 28% (95% confidence interval [CI], 0.13-0.44) versus 18% (95% CI, 0.00-0.40) in patients receiving cetuximab every 2 weeks. There was no statistically significant difference between groups (P = 0.9356 by the log-rank test) [Figure 1].
The overall survival rate at 7 months was 75% in the weekly regimen group (95% CI, 0.60-0.90) versus 72% in the other group (95% CI, 0.49-0.96). Again, no statistically significant difference between groups was observed (P = 0.6748 by the log-rank test) [Figure 2].
Treatment toxicity [Table 3]
No patient experienced an allergic reaction to cetuximab. There was no treatment-related death. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction. Standard treatments were given-drying agents, topical emollients, and oral antibiotics-with an improvement in cutaneous lesions. Other cutaneomucosal reactions were associated with the acne-like rash: paronychial cracking, hypertrichosis, trigomegaly of the eyelashes, conjunctivitis.
Grade 1-2 diarrhea and nausea-vomiting were the most frequent gastrointestinal adverse events reported in both groups. Few patients experienced hematological toxicity (Group 1: 21.8%; Group 2: 16.6%). Grade 3-4 nonhematological toxicity was rare in both groups (grade 3-4 skin toxicity: 3.1 and 5.5%, gastrointestinal toxicity: 3.1 and 5.5%, respectively).
| > Discussion|| |
Cetuximab in association with irinotecan has shown consistent activity when used as third-line treatment in oxaliplatin- and irinotecan-pretreated colorectal cancer patients.
It is currently recommended that cetuximab be administered weekly at a dose of 250 mg/m 2 . Inspired by a study of Tabernero et al. demonstrating similar pharmacokinetic results between weekly and cetuximab every 2 weeks,  the administration schedule was simplified in our institution to a double dose every 2 weeks. This way of administration is more convenient for patients; it allows them to have a more prolonged stay at home, especially as irinotecan is also given every 2 weeks.
Pfeiffer et al. performed a similar study and concluded that simplified cetuximab every second week, in association with irinotecan, is a convenient, effective, and well-tolerated regimen in irinotecan-refractory CRC. ,
In previous trials, the side effects of cetuximab used in association with irinotecan were fairly mild. In the BOND study,  grade 3 or 4 acne-like rash occurred in only 9.4% of patients in the combination therapy group, and grade 3-4 gastrointestinal toxicity in 28.3%. The present study shows that cetuximab can be safely administered every 2 weeks at doses of 500 mg/m 2 , without increasing skin or nonskin toxicity compared with a weekly schedule. The duration of treatment, disease control, progression-free survival, and overall survival rates at 7 months were similar in the two groups. Our results are in essence comparable with previously published data. 
| > Conclusion|| |
In conclusion, this retrospective study is in accordance with results of the phase I trial conducted by Tabernero showing that there is no major difference in efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan.
Prospective randomized trials should be designed to confirm these results.
Cetuximab given every 2 weeks may be an alternative and convenient schedule of administration, mainly when used in association with irinotecan that is also administered every 2 weeks.
| > References|| |
|1.||De Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-47. |
|2.||Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-7. |
|3.||Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136-47. |
|4.||Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30. |
|5.||Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209-14. |
|6.||Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183-232. |
|7.||Saltz LB, Meropol NJ, Loehrer Sr PJ, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201-8. |
|8.||Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45. |
|9.||Tabernero J, Cervantes A, Martinelli E, Rojo F, Perez-Fidalgo A, Casado E, et al. Optimal dose of cetuximab given every two weeks (q2w): a phase I pharmacokinetic and pharmacodynamic study of weekly (q1w) and q2w schedules in patients with metastatic colorectal cancer. J Clin Oncol 2006;24:142s. |
|10.||Pfeiffer P, Bjerregaard JK, Qvortrup C, Jensen BV, Yilmaz M, Nielsen D. Simplification of cetuximab administration: double dose every second week as a 60 minute infusion. J Clin Oncol 2007;25:4133. |
|11.||Tabernero J, Pfeiffer P, Cervantes A. Administration of cetuximab every 2 weeks in the treatment of metastatic colorectal cancer: an effective, more convenient alternative to weekly administration? Oncologist 2008;13:113-9. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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