The Library

Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer

Tools

Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) Trial Group (Including: Kerr, David J., Dunn, Janet A., Langman, Michael J., Smith, Justine L., Midgley, Rachel S. J., Stanley, Andrew, Stokes, Joanne C., Julier, Patrick, Iveson, Claire, Duvvuri, Ravi and McConkey, Christopher C.). (2007) Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. New England Journal Of Medicine , Vol.357 (No.4). pp. 360-369. ISSN 0028-4793

Preview

PDF
WRAP_Dunn_360.pdf - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (230Kb)

Official URL: http://dx.doi.org/10.1056/NEJMoa071841

Abstract

Background
Selective cyclooxygenase inhibitors may retard the progression of cancer, but they
have enhanced thrombotic potential. We report on cardiovascular adverse events in
patients receiving rofecoxib to reduce rates of recurrence of colorectal cancer.
Methods
All serious adverse events that were cardiovascular thrombotic events were reviewed
in 2434 patients with stage II or III colorectal cancer participating in a randomized,
placebo-controlled trial of rofecoxib, 25 mg daily, started after potentially curative
tumor resection and chemotherapy or radiotherapy as indicated. The trial was terminated
prematurely owing to worldwide withdrawal of rofecoxib. To examine possible
persistent risks, we examined cardiovascular thrombotic events reported up to 24
months after the trial was closed.
Results
The median duration of active treatment was 7.4 months. The 1167 patients receiving
rofecoxib and the 1160 patients receiving placebo were well matched, with a median
follow-up period of 33.0 months (interquartile range, 27.6 to 40.1) and 33.4 months
(27.7 to 40.4), respectively. Of the 23 confirmed cardiovascular thrombotic events,
16 occurred in the rofecoxib group during or within 14 days after the treatment
period, with an estimated relative risk of 2.66 (from the Cox proportional-hazards
model; 95% confidence interval [CI], 1.03 to 6.86; P = 0.04). Analysis of the Antiplatelet
Trialists’ Collaboration end point (the combined incidence of death from
cardiovascular, hemorrhagic, and unknown causes; of nonfatal myocardial infarction;
and of nonfatal ischemic and hemorrhagic stroke) gave an unadjusted relative
risk of 1.60 (95% CI, 0.57 to 4.51; P = 0.37). Fourteen more cardiovascular thrombotic
events, six in the rofecoxib group, were reported within the 2 years after trial
closure, with an overall unadjusted relative risk of 1.50 (95% CI, 0.76 to 2.94;
P = 0.24). Four patients in the rofecoxib group and two in the placebo group died
from thrombotic causes during or within 14 days after the treatment period, and
during the follow-up period, one patient in the rofecoxib group and five patients in
the placebo group died from cardiovascular causes.
Conclusions
Rofecoxib therapy was associated with an increased frequency of adverse cardiovascular
events among patients with a median study treatment of 7.4 months’ duration.
(Current Controlled Trials number, ISRCTN98278138.)

Item Type:

Journal Article

Subjects:

R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RS Pharmacy and materia medica

Divisions:

Faculty of Medicine > Warwick Medical School

Library of Congress Subject Headings (LCSH):

Clinical trials, Colon (Anatomy) -- Cancer, Rofecoxib

Journal or Publication Title:

New England Journal Of Medicine

Publisher:

Massachusetts Medical Society

ISSN:

0028-4793

Official Date:

26 July 2007

Dates:

Date	Event
26 July 2007	UNSPECIFIED

Volume:

Vol.357

Number:

No.4

Page Range:

pp. 360-369

Identification Number:

10.1056/NEJMoa071841

Status:

Peer Reviewed

Access rights to Published version:

Open Access

Description:

Final version (published as open access)

References:

Midgley, R.S. Kerr, D.J. (2007). ABC of colorectal cancer: adjuvant therapy. BMJ, 321, pp. 1208-1211.
QUASAR Collaborative Group. (2000). Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet, 355, pp. 1588-1596.
QUASAR Collaborative. (2007). QUASAR: a randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. Journal of Clinical Oncology, 22(14), pp. 3501a-3501a.
Sargent, D.J. Wieand, H.S. Haller, D.G. et al. (2005). Disease-free survival versus overall survival as a primary end point of adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomised trials. Journal of Clinical Oncology, 23(34), pp. 8664-8670.
Oshima, M. Murai, N, Kargman, S. et al. (2001). Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cycooxygenase-2 inhibitor. Cancer Research, 61, pp. 1733-1740.
Sheehan, K.M. Sheahan, K. O'Donoghue, D.P. et al. (1999). The relationship between cyclo-oxygenase-2 expression and colorectal cancer. JAMA, 282, pp.1254-1257.
Fenwick, S.W. Toogood, G.J. Lodge, P.A. Hull, M.A. (2003). The effect of the selective cyclo-oxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases. Gastroenterology,125, pp. 716-729.
Giovannucci, E. Rimm, E.G. Stampfer, M.J. Colditz, G.A. Ascherio, A. Willett, W.C. (1994). Aspirin use and the risk of colorectal cancer and adenoma in male health professionals. Ann Intern Med,121, pp.241-246.
Thun, M.J. Namboodiri, M.M. Calle, E.E. Flanders, D.W. Heath, C.W. Jr. (1993). Aspirin use and risk of fatal cancer. Cancer Res, 53, pp.1322-1327.
Langman, M.J.S. Cheng, K.K. Gilman, E.A. Lancashire, R.J. (2000). Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database. BMJ, 320, pp.1642-1646.
Langman, M.J. Jensen, D.M. Watson, D.J. et al. (1999). Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA, 282, pp.1929-1933.
Bresalier, R.S. Sandler, R.S. Quan, H. et al. (2005).Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med, 352, pp. 1092-1102.
Solomon, S.D. McMurray, J.J.V. Pfeffer, M.A. et al. (2005). Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med, 352, pp. 1071-1080.
Kearney, P.M. Baigent, C. Goodwin, J. Halla, H. Emberson, J.R. Patrono, C. (2006). Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ, 332, pp.1302-1305.
Antiplatelet Trialists' Collaboration. (1994). Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ, 308, pp.81-106.
Lagakos, S.W. (2006). Time-to-event analyses for long-term treatments -- the APPROVe trial. N Engl J Med, 355, pp.113-117.
Johnsen, S.P. Larsson, H. Tarone, R.E. et al. (2005). Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med, 165. pp.978-984.
Mamdani, M. Rochon, P. Juurlink, D.N. et al. (2003). Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med,163, pp. 481-486.
Andersohn, F. Suissa, S. Garbe, E. (2006). Use of first- and second-generation cyclooxygenase-2-selective drugs and risk of acute myocardial infarction. Circulation, 113, pp.1950-1957.
McGettigan, P. Henry, D. (2006). Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA, 296, pp.1633-1644.
Public CHMP assessment report for medicinal products containing non-selective non-steroidal anti-inflammatory drugs (NSAIDs). (2007). London: European Medicines Agency,
Moussa, O. Yordy, J.S. Abol-Enein, H. et al. (2005). Prognostic and functional significance of thromboxane synthase gene overexpression in invasive bladder cancer. Cancer Res, 65, pp.11581-11587.