Correspondence
Chemotherapy and Immunotherapy in Metastatic Colorectal Cancer
N Engl J Med 2009; 360:2134-2136May 14, 2009
- Article
To the Editor:
Tol et al. (Feb. 5 issue)1 report that the addition of cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab reduced progression-free survival among patients with metastatic colorectal cancer, regardless of the KRAS status of the tumor. Similar results with panitumumab have been reported by Hecht et al.2
These results could be related to a reduced concentration of the main cytotoxic drug, oxaliplatin, caused by an artificially high level of plasma protein due to enormous doses of not one but two monoclonal antibodies.
In the blood, 6 hours after administration, 80 to 90% of oxaliplatin will become irreversibly bound primarily to albumin and immunoglobulin3,4 and also to hemoglobin inside erythrocytes.3
The unbound oxaliplatin is thought to be responsible for its antitumor activity. When oxaliplatin binds to human serum albumin, it causes a conformational change of the protein,5 but there are no corresponding data regarding the effect of oxaliplatin binding on immunoglobulin antigen-binding activity.
Did unbound oxaliplatin, bevacizumab, cetuximab, or total protein levels after infusion, along with anemia, correlate with the results? Should we monitor drug levels?
Paula R. Pohlmann, M.D., Ph.D.
Ray L. Mernaugh, Ph.D.
Laura W. Goff, M.D.
Vanderbilt University, Nashville, TN 37232
paula.pohlmann@vanderbilt. edu Dr. Goff reports receiving grant support from Sanofi-Aventis, ImClone, and Bristol-Myers Squibb. No other potential conflict of interest relevant to this letter was reported.
5 References1
Tol J ,Koopman M ,Cats A , et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563-572
Full Text | Web of Science | Medline2
Hecht JR, Mitchell E, Chidiac T, et al. An updated analysis of safety and efficacy of oxaliplatin (Ox)/bevacizumab (bev) +/− panitumumab (pmab) for first-line treatment (tx) of metastatic colorectal cancer (mCRC) from a randomized, controlled trial (PACCE). Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 25–27, 2008.
3
Allain P ,Heudi O ,Cailleux A , et al. Early biotransformations of oxaliplatin after its intravenous administration to cancer patients. Drug Metab Dispos 2000;28:1379-1384
Web of Science | Medline4
Pendyala L ,Creaven PJ . In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res 1993;53:5970-5976
Web of Science | Medline5
Yue Y ,Chen X ,Qin J ,Yao X . Spectroscopic investigation on the binding of antineoplastic drug oxaliplatin to human serum albumin and molecular modeling. Colloids Surf B Biointerfaces 2009;69:51-57
CrossRef | Web of Science | Medline
To the Editor:
In the study by Tol et al., only 15% of the patients had received previous adjuvant chemotherapy. Is this because of limited use of adjuvant chemotherapy for colorectal cancer, or is it a consequence of the exclusion of patients who had neurologic toxic effects? After tumor progression, second-line treatment was given to 47% of the patients; again, this seems to be a very limited use of active drugs in this patient population.
Concerning the expression of epidermal growth factor receptor (EGFR), the authors state that 64% of the tumors were positive and that positive tumors fared worse when cetuximab was added. Is EGFR staining a requirement for cetuximab use in the Netherlands? What was the effect of cetuximab in patients with tumors that were negative for EGFR?
Luigi Frati, M.D.
Giovanni Codacci-Pisanelli, M.D.
University La Sapienza, 00161 Rome, Italy
giovanni.codacci-pisanelli@uniroma1. it To the Editor:
In the study by Tol et al., the baseline characteristics of the patients in each treatment group were well matched except for a sex imbalance between the two groups. There were more men and fewer women in the combined-antibody group that received cetuximab in addition to capecitabine, oxaliplatin, and bevacizumab (P=0.04). Also, information on the type of previous adjuvant chemotherapy (fluorouracil–leucovorin, capecitabine, or FOLFOX [folinic acid, fluorouracil, and oxaliplatin]), radiation therapy, or both in each treatment group was not described. Sex steroid hormone receptors and EGFRs are widely expressed in colorectal tissue, with important functional linkages and bidirectional signaling between them.1,2 Sex-related, treatment-specific differences in patients with metastatic colorectal cancer have been shown.3,4 Germ-line polymorphisms of the EGFR gene can be associated with sex-related differences in overall survival.5 It would be interesting to know the effect of functional EGFR polymorphisms among patients with metastatic colorectal cancer in this study population — both in patients treated with anti-EGFR antibodies and in untreated patients — especially because of the sex imbalance between the treatment groups.
5 ReferencesMehmet S. Copur, M.D.
Max Norvell, Pharm.D.
Angela Obermiller, Pharm.D.
Saint Francis Cancer Center, Grand Island, NE 68802-9804
mcopur@sfmc-gi.org 1
Catalano MG ,Pfeffer U ,Raineri M , et al. Altered expression of androgen-receptor isoforms in human colon-cancer tissues. Int J Cancer 2000;86:325-330
CrossRef | Web of Science | Medline2
Levin ER . Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol 2003;17:309-317
CrossRef | Web of Science | Medline3
Levi F ,Gorlia T ,Tubiana N , et al. Gender as a predictor for optimal dynamic scheduling of oxaliplatin, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer: results from EORTC randomized phase II trial 05963. J Clin Oncol 2005;23:Suppl:267s-267s
CrossRef | Web of Science4
Elsaleh H ,Joseph D ,Grieu F ,Zeps N ,Spry N ,Iacopetta B . Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000;355:1745-1750
CrossRef | Web of Science | Medline5
Press OA ,Zhang W ,Gordon MA , et al. Gender-related survival differences associated with EGFR polymorphisms in metastatic colorectal cancer. Cancer Res 2008;68:3037-3042
CrossRef | Web of Science | Medline
To the Editor:
Tol and colleagues found that the addition of cetuximab to capecitabine plus oxaliplatin and bevacizumab decreased progression-free survival in patients with colorectal cancer. Moreover, the study suggested that a mutated KRAS gene in the tumor was associated with an inferior response to cetuximab.1 With regard to the 314 patients classified as having wild-type tumors, it is possible that up to 25% of them carried a B-type Raf kinase (BRAF) V600E oncogene (which may confer resistance to anti-EGFR treatment2) or other KRAS-activating mutations.3
We suggest that analysis of BRAF and other KRAS mutations will be beneficial in estimating the potential benefit associated with the combination of anti–vascular endothelial growth factor and anti-EGFR antibodies.
3 ReferencesFotios Loupakis, M.D.
Azienda Ospedaliero–Universitaria Pisana, 56126 Pisa, Italy
fotiosloupakis@gmail.com Massimo Di Maio, M.D.
National Cancer Institute, 80131 Naples, ItalyAlfredo Falcone, M.D.
University of Pisa, 56126 Pisa, Italy1
Bokemeyer C ,Bondarenko I ,Makhson A , et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27:663-671
CrossRef | Web of Science | Medline2
Di Nicolantonio F ,Martini M ,Molinari F , et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705-5712
CrossRef | Web of Science | Medline3
Edkins S ,O'Meara S ,Parker A , et al. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther 2006;5:928-932
CrossRef | Web of Science | Medline
Author/Editor Response
Pohlmann et al. postulate that the higher plasma protein concentration caused by the addition of a second antibody may have reduced the availability of oxaliplatin and thus may explain the negative outcome of our trial involving patients receiving chemotherapy plus bevacizumab and cetuximab. Although we did not measure drug concentrations, the similar incidence of neurotoxicity, a common side effect of oxaliplatin, between the two treatment groups does not support this hypothesis. However, it may be worthwhile to further investigate this idea.
Frati and Codacci-Pisanelli comment on the percentages of patients who received second-line treatment and patients who had received previous adjuvant treatment. First, these two factors are unlikely to have had any effect on the primary outcome of our study. Second, possible explanations are that patients with persistent neurotoxic effects after previous oxaliplatin-based adjuvant treatment were excluded from our study, and that the national Dutch guidelines on colorectal cancer do not routinely advocate adjuvant treatment in patients with stage III rectal cancer. Finally, the number of patients receiving second-line treatment may appear low because the definition of second-line treatment in our trial, unlike that used in many other trials, did not include the reintroduction of first-line treatment after a drug holiday; this narrower definition was also used in our previous trial.1 Even so, the percentages of patients who had received previous adjuvant treatment and patients who received second-line treatment in our trial do not differ substantially from the percentages in many other trials with similar patient populations.
EGFR expression was not an inclusion variable in our study, since EGFR expression detected by immunohistochemical analysis was previously shown not to correlate with response to cetuximab treatment.2 Our trial was not designed to detect survival differences in relation to EGFR expression.
Copur et al. address the effects of sex and EGFR polymorphisms. Few data are available on the effect of sex on treatment with targeted agents in colorectal cancer. In a study of cetuximab monotherapy as compared with best supportive care, no such effect was observed.3 We are currently investigating the role of several germ-line polymorphisms and of BRAF mutation status, as suggested by Loupakis et al.
3 ReferencesCornelis J.A. Punt, M.D., Ph.D.
Jolien Tol, M.D.
Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, the Netherlands
c.punt@onco. umcn. nl 1
Koopman M ,Antonini NF ,Douma J , et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007;370:135-142
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 | Medline3
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 | Medline
- Citing Articles (2)
Citing Articles
1
Harold J. Wanebo, David Berz. (2010) The neoadjuvant therapy of colorectal hepatic metastases and the role of biologic sensitizing and resistance factors. Journal of Surgical Oncology 102:8, 891-897
CrossRef2
Jolien Tol, Cornelis J.A. Punt. (2010) Monoclonal antibodies in the treatment of metastatic colorectal cancer: A review. Clinical Therapeutics 32:3, 437-453
CrossRef
