Annals of Oncology

Annals of Oncology Advance Access published online on February 13, 2008
Annals of Oncology, doi:10.1093/annonc/mdm607

This Article Abstract FREE Full Text (PDF) All Versions of this Article: 19/4/734    most recent mdm607v1 E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Tol, J. Articles by Punt, C. J. A. Search for Related Content PubMed PubMed Citation Articles by Tol, J. Articles by Punt, C. J. A. Social Bookmarking          What's this?

© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity

J. Tol¹, M. Koopman¹, C. J. Rodenburg², A. Cats³, G. J. Creemers⁵, J. G. Schrama⁶, F. L. G. Erdkamp⁷, A. H. Vos⁸, L. Mol⁹, N. F. Antonini⁴ and C. J. A. Punt^1,*

¹ Department of Medical Oncology, University Medical Centre St Radboud, Nijmegen
² Department of Internal Medicine, Meander Medical Centre, Amersfoort
³ Department of Gastroenterology, The Netherlands Cancer Institute, Amsterdam
⁴ Department of Biometrics
⁵ Catharina Hospital, Eindhoven
⁶ Department of Internal Medicine, Spaarne Hospital, Hoofddorp
⁷ Department of Internal Medicine, Maasland Hospital Sittard, Sittard
⁸ Department of Internal Medicine, Bernhoven Hospital, Oss
⁹ Comprehensive Cancer Centre East (IKO), Nijmegen, The Netherlands

^* Correspondence to: Prof. C. J. A. Punt, Department of Medical Oncology, University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31-24-3610353; Fax: +31-24-3540788; E-mail: c.punt{at}onco.umcn.nl

	Abstract

Top Abstract introduction patients and methods results discussion funding Acknowledgements References

 
Background: Targeting the vascular endothelial growth factor or the epidermal growth factor receptor (EGFR) has shown efficacy in advanced colorectal cancer (ACC), but no data are available on the combination of these strategies with chemotherapy in the first-line treatment. The CAIRO2 study evaluates the effect of adding cetuximab, a chimeric mAb against EGFR, to capecitabine, oxaliplatin and bevacizumab in the first-line treatment of ACC.

Patients and methods: In all, 755 patients were randomly assigned between treatment with capecitabine, oxaliplatin and bevacizumab with or without cetuximab. The primary end point is progression-free survival. We here present the toxicity results in the first 400 patients that entered the study.

Results: The incidence of overall grade 3–4 toxicity was significantly higher in arm B compared with arm A (81% versus 72%, P = 0.03). This difference is fully attributed to cetuximab-related skin toxicity. The addition of cetuximab did not result in an increase of gastrointestinal toxicity or treatment-related mortality.

Conclusions: The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab in the first-line treatment of ACC appears to be safe and feasible. No excessive or unexpected toxicity in the cetuximab-containing treatment arm was observed.

advanced colorectal cancer, bevacizumab, cetuximab, chemotherapy, interim analysis, safety

	introduction

Top Abstract introduction patients and methods results discussion funding Acknowledgements References

 
The standard chemotherapy for patients with advanced colorectal cancer (ACC) consists of fluoropyrimidines, irinotecan and oxaliplatin [1]. When these drugs are made available to patients during the course of their disease, a median overall survival of 17–20 months may be achieved. Our group, the Dutch Colorectal Cancer Group, recently showed in a prospective randomised study that first-line combination chemotherapy did not result in a survival benefit when compared with the sequential use of the same drugs [2]. These results may be relevant for the use of cytotoxic drugs when combined with targeted agents such as bevacizumab and cetuximab. These data, however, were not yet available when we initiated the CAIRO2 study in which the effect of adding cetuximab to capecitabine, oxaliplatin and bevacizumab in previously untreated patients with ACC is studied.

The addition of bevacizumab (Avastin®, Genentech), a humanised mAb against the vascular endothelial growth factor, results in a significant survival benefit when added to fluoropyrimidine-containing chemotherapy [3] and is currently considered as part of the standard first-line therapy. Cetuximab (Erbitux®, Merck and ImClone Systems) is a chimeric immunoglobulin (Ig) G1 mAb against the epidermal growth factor receptor (EGFR). In patients with ACC, cetuximab improves the median progression-free survival (PFS) of patients resistant to irinotecan monotherapy in combination with irinotecan [4]. Cetuximab monotherapy improves the median overall survival in ACC patients in whom all available standard treatments have failed [5]. In the first-line treatment of ACC, cetuximab improves the PFS in combination with bolus 5-fluorourail (5-FU) plus folinic acid plus irinotecan (FOLFIRI) compared with FOLFIRI alone, although the absolute increase in median PFS is modest (8.9 versus 8.0 months) [6].

So far, limited data are available on the efficacy and safety of the combination of bevacizumab and anti-EGFR targeted agents in ACC. A randomised phase II study comparing bevacizumab, cetuximab and irinotecan with bevacizumab and cetuximab in irinotecan-resistant patients with ACC (BOND-2) showed an acceptable toxicity profile in both arms and a median time to progression of 7.9 versus 5.6 months, respectively [7]. Recently, a study of chemotherapy and bevacizumab with or without panitumumab, a human IgG2 mAb against EGFR, was discontinued because of excessive toxicity and decreased efficacy in the panitumumab-containing treatment arm. We here present the results of an interim analysis of toxicity of the CAIRO2 study.

	patients and methods

Top Abstract introduction patients and methods results discussion funding Acknowledgements References

 
patients
The main eligibility criteria included histological proof of colon or rectal carcinoma, advanced disease not amenable for curative surgery, measurable disease parameters and no previous systemic chemotherapy for advanced disease. Adjuvant chemotherapy was allowed provided that the last administration was at least 6 months before randomisation, age 18 years, World Health Organisation performance status of zero or one, written informed consent, adequate bone marrow function (haemoglobin 6 mmol/l, white blood cells 3.0 x 10⁹/l and platelets 100 x 10⁹/l), adequate liver function [total bilirubin level 2 x upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase 3 x ULN, in case of liver metastases 5 x ULN], adequate renal function (serum creatinine clearance 1.5 ULN) and urinary excretion of protein 0.5 g/24 h. The main exclusion criteria were serious concomitant disease preventing the safe administration of study medication, previous EGFR targeted therapy, sensory neuropathy more than grade 1, symptomatic central nervous system metastases, bleeding diatheses, coagulation disorders or the use of therapeutic-dose anticoagulation, major surgery 28 days before the start of therapy, serious non-healing wound or ulcer, significant cardiovascular disease, any condition interfering with the absorption of oral drugs, serious active infections or other malignancies within the past 5 years except for adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix. Previous radiotherapy was allowed if completed 4 weeks before randomisation and provided that at least one measurable lesion is located outside the irradiated field. Ineligible patients or patients withdrawing the informed consent were excluded from all analyses. The study was conducted in accordance with the standards of good clinical practice and in agreement with the declaration of Helsinki and was approved by the Committee on Research Involving Human Subjects Arnhem–Nijmegen. A total of 755 patients were accrued in 79 Dutch hospitals from June 2005 to December 2006. The first 400 patients were included in this interim analysis. These patients entered the study from June 2005 to April 2006.

study design
The CAIRO2 study is a multicentre, randomised phase III trial. The primary end point is PFS. Secondary end points are overall survival, tumour response, duration of response, quality of life, safety and translational research on factors that predict the response to treatment. Data collection was carried out by the regional Comprehensive Cancer Centres (Nederlandse Integrale Kanker Centra). Patients were centrally randomly assigned to one of the treatment arms through adaptive minimisation. Central data management was carried out at the Comprehensive Cancer Centre East (IKO). Data analysis was carried out at the Department of Biostatistics of The Netherlands Cancer Institute. Patients were stratified according to serum lactate dehydrogenase (normal versus abnormal), prior adjuvant chemotherapy (yes versus no), number of affected organs (one versus more than one) and per institution. Treatment was to be started within 14 days after randomisation. An independent data monitoring committee continuously evaluated all serious toxicity. Central review was carried out of the charts of all patients who died within 30 days after the last administration of study drugs and whose death was accompanied by any other event than disease progression, irrespective of the causality reported for this event.

treatment
Treatment consisted of capecitabine 1000 mg/m² orally twice daily on days 1–14, oxaliplatin 130 mg/m² i.v. on day 1 and bevacizumab 7.5 mg/kg i.v. on day 1(arm A) or the same schedule plus cetuximab 400 mg/m² i.v. in week 1 of the first treatment cycle and 250 mg/m² i.v. weekly thereafter (arm B). All cycles were administered every 3 weeks. To prevent serious peripheral sensory neurotoxicity, oxaliplatin was administered during a maximum of six cycles, after which the capecitabine dose was increased to 1250 mg/m² orally twice daily in both arms. Treatment was continued until disease progression, death, unacceptable toxicity or patient refusal, whichever came first. Clinical and laboratory toxicity were graded according to National Cancer Institute' Common Terminology Criteria for Adverse Events version 3.0. The causality between serious adverse events and study drugs was graded as not related, unlikely, possible, probable or definitely related. Dose reductions for grade 2–4 toxicity were carried out for capecitabine as previously described [8]. A 25% dose reduction was carried out for oxaliplatin in case of non-painful paresthaesia during >14 days or temporary (7–14 days) painful paresthaesia or functional impairment. In case of grade 2–3 toxicity, oxaliplatin administration was discontinued until recovery of the symptoms and then restarted at 50%. If despite 50% dose reduction neurotoxicity recurred, oxaliplatin was permanently discontinued. Dose reductions of bevacizumab were not carried out. The administration of bevacizumab was permanently discontinued in case of grade 4 thromboembolic events or grade 3–4 bleeding. In case of proteinuria >2 g/24 h bevacizumab treatment was withheld pending the results of 24-h total protein excretion. Cetuximab treatment was interrupted in case of grade 3 skin reactions and was only resumed when the reactions had resolved to grade 2. At the recurrence of severe skin reactions, a dose reduction to 200 mg/m² was carried out whereas at the second recurrence the dose was reduced to 150 mg/m². In case of a third recurrence, treatment with cetuximab was permanently discontinued. Cetuximab administration was also permanently discontinued in case of grade 3–4 allergic reactions. The following evaluations were carried out every 3 weeks: clinical examination, assessment of toxicity, symptoms of disease, performance status and assessment of bone marrow, liver and renal functions. Assessment of tumour response was carried out every three cycles (9 weeks).

statistical analysis
The main objectives of this interim analysis were to evaluate the safety of the study medication, especially with regard to cetuximab or interactions between cetuximab and bevacizumab, to compare the toxicity profile between the two treatment arms and to assess the probability of a causal relationship between toxicity and study drug.

All toxicity data collected until 1 September 2007 of the first 400 patients were taken into account. The median follow-up at the time of this analysis was 6.8 months.

All analyses were carried out according to the intention-to-treat principle. Ineligible patients or patients who did not receive any protocol treatment were excluded from the safety analysis. Comparisons of toxicity grades between the treatment arms were carried out using the chi-square test. Significance level was set at 0.05. All analyses were carried out in SAS 9.1.3.

	results

Top Abstract introduction patients and methods results discussion funding Acknowledgements References

 
Of the 400 patients included in this analysis, 10 patients were found to be ineligible, 4 patients in arm A and 6 patients in arm B. The reasons for ineligibility were second primary tumour (n = 2), withdrawal of informed consent before the start of first treatment cycle (n = 1), death before randomisation (n = 1), laboratory parameters above ULN (n = 1), obstructing primary tumour (n = 2), previous intolerability of fluoropyrimidines (n = 1), serious concomitant disease (n = 1) and concomitant use of therapeutic-dose anticoagulant drugs (n = 1). One patient in arm B never started treatment and therefore was not assessable for toxicity. Therefore, 389 patients were eligible and assessable for toxicity: 197 in arm A and 192 in arm B. Patient characteristics are shown in Table 1.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the assessable patients (n = 389)

 
toxicity
The most important toxic effects are listed in Table 2. The incidence of overall grade 3–4 toxicity was significantly higher in arm B compared with arm A (81% versus 72%, P = 0.03). All grade skin toxicity as well as grade 3 acneiform skin reactions were significantly more prevalent in patients treated with cetuximab (arm B). When skin toxicity with the exception of hand–foot syndrome was excluded from the overall grade 3–4 toxicity, the incidence of all grade 3–4 toxicity was 71% in arm B and 72% in arm A (P = 0.87). A small but not statistically significant increase in grade 3–4 allergic reactions was observed in arm B. The incidence of arterial and venous thromboembolic events was equally distributed between both treatment arms. Gastrointestinal side-effects also did not differ between the groups. Gastrointestinal perforations occurred in seven patients (1.8%) (three in arm A and four in arm B) and were lethal in four patients. Grade 2–3 hand–foot syndrome was observed in 33% and 43%, respectively (P = 0.06), of which 15% versus 27% was grade 2. Hypomagnesaemia was observed more frequently in arm B (15% versus 37%, P < 0.001). This, however, concerned predominantly grade 1 toxicity (serum magnesium <0.70 mmol/l and >0.50 mmol/l, in 13% versus 33% of the patients, respectively). Toxicity as the main reason for treatment discontinuation was reported similarly in both treatment arms, 33% in arm A and 32% in arm B. A total of 221 patients underwent a dose reduction of capecitabine, oxaliplatin or bevacizumab due to toxicity, 110 patients (56%) in arm A and 111 (58%) in arm B. Dose reduction for toxicity of cetuximab was carried out in 66 patients (34%).

View this table: [in this window] [in a new window]   Table 2. The incidence of toxic effects

 
mortality
By 1 September 2007, a total of 122 patients were known to have died. Nineteen patients died within 30 days after the last administration of study drugs (Table 3), of which progressive disease was the cause of death in five patients. After revision of individual patient charts, the cause of death was probably treatment related in five patients (four in arm A and one in arm B). Four patients in arm A and five patients in arm B died within 60 days after randomisation, resulting in a 60-day all-cause mortality of 2% versus 3%, respectively. Causes of death within 60 days in arm A were progressive disease (n = 1), cardiac arrhythmia (n = 1), pneumonia (n = 1) and gastrointestinal perforation (n = 1). Reasons of death in arm B were progressive disease (n = 1), sepsis (without neutropenia) (n = 2), gastrointestinal perforation (n = 1) and pulmonary embolism (n = 1).

View this table: [in this window] [in a new window]   Table 3. Causes of all deaths occurring within 30 days after the last study drug administration

 

	discussion

Top Abstract introduction patients and methods results discussion funding Acknowledgements References

 
This is the first study to present safety data on the combination of bevacizumab and cetuximab with chemotherapy in the first-line treatment of ACC. Our results show that the addition of cetuximab to capecitabine, oxaliplatin and bevacizumab is feasible and does not result in excessive or unexpected toxicity. The increase of overall grade 3–4 toxicity in the cetuximab-containing treatment arm can be fully attributed to cetuximab-related skin toxicity. Cetuximab did not increase the incidence of other toxic effects. The incidence of all grade skin reactions in arm B is comparable with the incidences found in other studies on cetuximab [4], whereas the incidence of grade 3 skin reactions is somewhat higher (26%) than that reported by others (9%–19%) [4, 5, 7]. The higher incidence of grade 2 hand–foot syndrome (although not statistically significant) may be the result of clinical overlap with cetuximab-related skin toxicity. Cetuximab did not increase the incidence of grade 3–4 diarrhoea. In general, the incidence of diarrhoea in patients treated with capecitabine is higher than in patients treated with infusional 5-FU [9], although other studies do not confirm this finding [10, 11]. The incidence of gastrointestinal perforations is in accordance with published data [12]. In both arms an incidence of 3% arterial thromboembolic events (myocardial ischaemia and cerebrovascular ischaemia) was observed, which is in accordance with a pooled analysis of patients treated with chemotherapy plus bevacizumab [13]. The incidence of grade 3–4 venous thromboembolic events (deep vein thrombosis and pulmonary embolisms) was comparable between the arms and in accordance with the published data [13–15]. Severe hypomagnesaemia was a rare event in our study. Hypomagnesaemia is a known side-effect of cetuximab treatment, caused by excessive renal excretion of magnesium [16]. The occurrence and severity of hypomagnesaemia is related to the duration of treatment with cetuximab [17]. Treatment-related mortality was slightly higher in arm A (four patients) compared with arm B (one patient), which difference is not statistically significant.

Our results are of particular interest given the preliminary results of the Panitumumab Advanced Colorectal Cancer Evaluation study (PACCE) trial, a phase III study in which the addition of panitumumab, a human monoclonal anti-EGFR antibody, to chemotherapy [bolus 5-FU plus folinic acid plus oxaliplatin (FOLFOX) or FOLFIRI] and bevacizumab was investigated in a comparable patient population. The PACCE study was prematurely discontinued due to an excess of grade 3–4 diarrhoea (21% versus 11%), dehydration (14% versus 4%) and infection (15% versus 7%) in the panitumumab-containing treatment arm, which was accompanied by a significantly inferior PFS (9.0 versus 10.5 months) [18]. The incidence of grade 3–4 diarrhoea in both arms of our study is comparable to the experimental arm of the PACCE trial, but apparently did not result in serious complications such as dehydration and infection in our series. Currently, there is no obvious explanation between the different outcome of the PACCE and CAIRO2 studies, and further analysis of both studies has to be awaited. Data from the Cancer and Leukaemia Group B/Southwest Oncology Group 80405 study, which randomises between FOLFOX or FOLFIRI with either cetuximab or bevacizumab or cetuximab plus bevacizumab, are not yet available.

In conclusion, our data show that cetuximab may be safely added to a regimen of capecitabine, oxaliplatin and bevacizumab as first-line treatment of ACC.

	funding

Top Abstract introduction patients and methods results discussion funding Acknowledgements References

 
Commissie Klinisch Toegepast Onderzoek of the Dutch Cancer Foundation (KWF); Merck-Serono, Roche; Sanofi-Aventis.

	Acknowledgements

Top Abstract introduction patients and methods results discussion funding Acknowledgements References

 
We thank the members of the independent data monitoring committee: G. Stoter, D. Sleijfer and P. De Mulder (passed away) for monitoring the safety of the CAIRO2 study. These results have been presented at the European Cancer Conference (ECCO14) in Barcelona, 25 September 2007.

Received for publication December 18, 2007. Accepted for publication December 19, 2007.

	References

Top Abstract introduction patients and methods results discussion funding Acknowledgements References

 
1. Punt CJ. New options and old dilemmas in the treatment of patients with advanced colorectal cancer. Ann Oncol (2004) 15(10):1453–1459.[Abstract/Free Full Text]

2. 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(9582):135–142.[CrossRef][Web of Science][Medline]

3. Tol J, Punt CJA. Targeted therapy in advanced colorectal cancer, an update. Targeted Oncology (2007) 2(3):165–172.[CrossRef]

4. 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(4):337–345.[Abstract/Free Full Text]

5. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med (2007) 357(20):2040–2048.[Abstract/Free Full Text]

6. van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5FU/LV with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL study. Proc Am Soc Clin Oncol (2007;) 25:164S [Abstr 4000].

7. Saltz LB, Lenz HJ, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol (2007) 25(29):4557–4561.[Abstract/Free Full Text]

8. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol (2001) 19(21):4097–4106.[Abstract/Free Full Text]

9. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX 4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol GI Cancer Symp (2007) [Abstr 238].

10. Diaz-Rubio E, Tabernero J, Gomez-Espana A, et al. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol (2007) 25(27):4224–4230.[Abstract/Free Full Text]

11. Porschen R, Arkenau HT, Kubicka S, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol (2007) 25(27):4217–4223.[Abstract/Free Full Text]

12. Saif MW, Elfiky A, Salem RR. Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol (2007) 14(6):1860–1869.[CrossRef][Web of Science][Medline]

13. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst (2007) 99(16):1232–1239.[Abstract/Free Full Text]

14. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med (2004) 350(23):2335–2342.[Abstract/Free Full Text]

15. Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol (2005) 23(16):3706–3712.[Abstract/Free Full Text]

16. Schrag D, Chung KY, Flombaum C, Saltz L. Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst (2005) 97(16):1221–1224.[Abstract/Free Full Text]

17. Tejpar S, Piessevaux H, Claes K, et al. Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol (2007) 8(5):387–394.[CrossRef][Web of Science][Medline]

18. Hecht JR, Chidiac T, Mitchell E. An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab (Bev) for metastatic colorectal cancer (mCRC). Proceedings of the 9th World Congress on Gastrointestinal Cancer. Ann Oncol (2007) 18:vii21. (Abstr 0-0033).

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				J. Tol, M. Koopman, M. C. Miller, A. Tibbe, A. Cats, G. J. M. Creemers, A. H. Vos, I. D. Nagtegaal, L. W. M. M. Terstappen, and C. J. A. Punt Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents Ann. Onc., October 27, 2009; (2009) mdp463v1. [Abstract] [Full Text] [PDF]

				L. Mol, M. Koopman, P. B. Ottevanger, and C. J. A. Punt A prospective monitoring of fatal serious adverse events (SAEs) in a Dutch Colorectal Cancer Group (DCCG) phase III trial (CAIRO) in patients with advanced colorectal cancer Ann. Onc., July 24, 2009; (2009) mdp330v1. [Abstract] [Full Text] [PDF]

				S. S. Shord, L. R. Bressler, L. A. Tierney, S. Cuellar, and A. George Understanding and managing the possible adverse effects associated with bevacizumab Am. J. Health Syst. Pharm., June 1, 2009; 66(11): 999 - 1013. [Abstract] [Full Text] [PDF]

				J. Tol, M. Koopman, A. Cats, C. J. Rodenburg, G. J.M. Creemers, J. G. Schrama, F. L.G. Erdkamp, A. H. Vos, C. J. van Groeningen, H. A.M. Sinnige, et al. Chemotherapy, Bevacizumab, and Cetuximab in Metastatic Colorectal Cancer N. Engl. J. Med., February 5, 2009; 360(6): 563 - 572. [Abstract] [Full Text] [PDF]

				K. Kolinsky, B.-Q. Shen, Y.-E Zhang, J. Kohles, U. Dugan, T. F. Zioncheck, D. Heimbrook, K. Packman, and B. Higgins In vivo activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models Mol. Cancer Ther., January 1, 2009; 8(1): 75 - 82. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) All Versions of this Article: 19/4/734    most recent mdm607v1 E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Tol, J. Articles by Punt, C. J. A. Search for Related Content PubMed PubMed Citation Articles by Tol, J. Articles by Punt, C. J. A. Social Bookmarking          What's this?

Online ISSN 1569-8041 - Print ISSN 0923-7534

Copyright © 2009 European Society for Medical Oncology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics