Correspondence
Cetuximab for Colorectal Cancer
N Engl J Med 2008; 358:1195-1197March 13, 2008
- Article
To the Editor:
The study by Jonker et al. (Nov. 15 issue)1 showed that cetuximab improved survival among patients with colorectal cancer, but the authors give no details regarding sites of metastases in the cetuximab group. Were metastatic sites in patients receiving cetuximab correlated with survival? The authors do not mention thromboembolism, which may be associated with poor survival among patients with cancer.2 Was cetuximab associated with an increased risk of thromboembolism?
2 ReferencesFeng Yang, M.D.
Deliang Fu, M.D.
Quanxing Ni, M.D.
Huashan Hospital, Shanghai 200040, China
surgeonfu@yahoo.com. cn 1
Jonker DJ ,O'Callaghan CJ ,Karapetis CS , et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040-2048
Full Text | Web of Science | Medline2
Mandala M ,Moro C ,Labianca R ,Ferretti G . Erlotinib in pancreatic cancer patients: do we need more information from the NCIC CTG trial? J Clin Oncol 2007;25:4320-4321
CrossRef | Web of Science | Medline
To the Editor:
It would be useful to know whether Jonker et al. evaluated the pattern of immunoreactivity of epidermal growth factor receptor (EGFR) or the percentage of positive cells, and whether they tested primary cancers or metastatic sites for expression of EGFR.1 These considerations are important in light of their statement that “immunohistochemically detectable EGFR is no longer considered a clinically useful biomarker” and given that responses in patients with EGFR-negative tumors have been reported after cetuximab treatment.2
2 ReferencesFilippo Fraggetta, M.D.
Azienda Ospedaliera Cannizzaro, 95126 Catania, Italy
ffraggetta@yahoo.it Giuseppe Pelosi, M.D.
European Institute of Oncology, 20141 Milan, Italy1
Scartozzi M ,Bearzi I ,Berardi R ,Mandolesi A ,Fabris G ,Cascinu S . Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol 2004;22:4772-4778
CrossRef | Web of Science | Medline2
Chung KY ,Shia J ,Kemeny NE , et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005;23:1803-1810
CrossRef | Web of Science | Medline
To the Editor:
Although the trial reported by Jonker et al. was set up to detect an absolute increase of 9.6% in 1-year overall survival in patients treated with cetuximab as compared with those who received the best supportive care, it showed an increase of only 5% in 1-year overall survival (21% vs. 16%). The authors present an increase in the median survival of 1.5 months (6.1 months vs. 4.6 months) as the relevant result, but this is of minor clinical significance. The benefit in terms of quality of life is not interpretable, first because of the high number of patients who did not complete the quality-of-life questionnaire — especially in the supportive-care group — after only 8 weeks, and second because the trial was not blinded.
Fausto Roila, M.D.
Perugia Hospital, 06050 Perugia, ItalyMarina C. Garassino, M.D.
Cristina Mantica, M.D.
Ospedale Fatebenefratelli, 20121 Milan, ItalyTo the Editor:
In the report by Jonker et al., the Kaplan–Meier curves for disease progression show a difference between the groups in the pattern of events. The curve for cetuximab plus best supportive care has a stepwise decline in progression-free survival, suggesting adherence to the protocol schedule of radiographic evaluation every 8 weeks. The curve for best supportive care alone, however, is smooth, indicating tumor measurements between the scheduled evaluations. This difference in ascertaining tumor response is information bias owing to the lack of blinding of treatment allocation and may have led to an overestimation of the actual treatment effect. Moreover, a visual inspection of the Kaplan–Meier curve suggests a violation of the proportional-hazards assumption that underlies Cox regression analysis.
Ellen van der Spek, M.D.
University Medical Center Utrecht, 3584 CX Utrecht, the NetherlandsGabe S. Sonke, M.D., Ph.D.
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
g.sonke@nki. nl Author/Editor Response
In reply to Yang and colleagues, the sites of metastases did not affect survival. The incidence of thromboembolism during the study was low (3.5% in patients receiving cetuximab and 4.7% in patients receiving best supportive care), which makes correlation with response difficult.
With regard to the comments by Fraggetta and Pelosi, EGFR immunohistochemical analysis with the use of the Dako pharmDxTM kit was performed largely on the primary tumor and was graded from 0 to 3+; EGFR was considered detectable (positive) if any stained cells were identified. Earlier trials indicated no correlation of intensity with cetuximab activity, so this analysis was not undertaken.1,2
Roila et al. raise the issue of clinical benefit. The observed clinical benefit as measured by the reduction in the risk of death (23%) was close to that postulated (26%); we believe this is clinically relevant. The observed 1-year overall survival among patients receiving best supportive care was higher than estimated (16% vs. 14.1%), which led to a smaller difference.
Finally, with regard to the comments of van der Spek and Sonke, the determination of progression in a nonblinded setting may be biased, but similar hazard ratios for disease progression and for death provide support for the premise that bias in removing patients from the study did not affect the results. The data from all patients may not satisfy the proportional-hazards assumption, but the stratified log-rank test was the primary comparison between the treatment groups.
2 ReferencesDerek J. Jonker, M.D.
Chris J. O'Callaghan, Ph.D.
National Cancer Institute of Canada Clinical Trials Group, Kingston, ON K7L 3N6, Canada
djonker@ottawahospital.on. ca 1
Cunningham D ,Humblet Y ,Siena S , et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-345
Full Text | Web of Science | Medline2
Lenz HJ ,Van Cutsem E ,Khambata-Ford S , et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006;24:4914-4921
CrossRef | Web of Science | Medline
