Reflection and Reaction 860 http://oncology.thelancet.com Vol 8 October 2007 outcomes and COX-2 expression in the Radiation Therapy Oncology Group (RTOG) 92-02 trial that studied radiotherapy plus either short-term or long- term androgen deprivation in patients with locally advanced prostate cancer (T2c-T4) who had prostate- specific antigen concentrations less than 150 ng/mL. In particular, COX-2 overexpression was associated with an increased risk of important clinical outcomes, such as development of metastasis, clinical failure, and biochemical failure of primary treatment. Assuming that COX-2 is a suitable therapeutic target, the question arises of how to inhibit this protein. Several drugs are known to inhibit the pathway including aspirin, NSAIDs, and selective COX-2 inhibitors, for example, celecoxib and rofecoxib. The only drug that does not seem to have the adverse cardiovascular effects is aspirin. However, long-term aspirin use can cause gastrointestinal side-effects. Therefore, use of a COX-2 inhibitor in a clinical trial is, as with any drugs, a matter of balancing risks with benefits. Generally, NSAIDs and selective COX-2 inhibitors have good safety profiles. The cardiovascular effects are now well-known and the risks can be factored into trial design. Some evidence exists of a schedule effect on cardiovascular toxicity; cardiovascular toxicity only becomes evident after 1 year of taking celecoxib. 11 We started the multi-arm Systemic Therapy in Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial to assess a range of treatments, including celecoxib, as adjuncts to standard hormone treatment for patients with high-risk prostate cancer. The trial, which opened in 2005, was delayed while rofecoxib data were assessed by regulatory agencies worldwide and the original trial design was then amended to restrict celecoxib treatment to 1 year and to exclude patients with known cardiovascular disease. In parallel, we modelled the probable occurrences of cardiovascular adverse events by use of data from published studies. We were then able to show that we would need only a small anti-cancer effect (given the high-risk population under study) to counterbalance the likely cardiovascular adverse events. The decision to continue with the drug in the STAMPEDE trial was supported by the two patient representatives on the Trial Management Group. All of the above information was put before the relevant ethical and regulatory review boards in the UK and the amended trial was allowed to proceed. The above procedures show the additional steps that are necessary to undertake trials with these drugs after the withdrawal of rofecoxib. In conclusion, the paper by Khor and co-workers 10 shows that COX-2 remains a potentially important therapeutic target in prostate cancer and supports further studies of drugs targeting the protein. Nicholas James n.d.james@bham.ac.uk The author has received a research grant from Pfizer for the part-funding of the STAMPEDE trial. The main funding body of the STAMPEDE trial is Cancer Research UK. 1 Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. 2 Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II). J Natl Cancer Inst 1998; 90: 1609–20. 3 Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J Natl Cancer Inst 1998; 90: 1529–36. 4 Nelson JE, Harris RE. Inverse association of prostate cancer and non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-control study. Oncol Rep 2000; 7: 169–70. 5 Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber MM, Jacobsen SJ. A population-based study of daily nonsteroidal anti- inflammatory drug use and prostate cancer. Mayo Clinic Proc 2002; 77: 219–25. 6 Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306–11. 7 Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885–95. 8 Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355: 873–84. 9 Kerr DJ, Dunn JA, Langman MJ, et al. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 2007; 357: 360–69. 10 Khor LY, Bae K, Pollack A, et al. COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial. Lancet Oncol 2007; 8: 912–20. 11 Solomon SD, Pfeffer MA, McMurray JJ, et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 2006; 114: 1028–35. Chemoradiotherapy alone for rectal cancer: a word of caution In a recent issue of The Lancet Oncology, O’Neill and colleagues 1 presented rationale for omission of surgery in patients with rectal cancer who have achieved clinical complete response after neoadjuvant chemoradiotherapy. Here, we discuss additional data from published studies to shed more light on this issue. The concept of surgery omission after chemoradiation is based on the trial reported by Habr-