- Email: [email protected]
Cyclooxygenase-2 inhibitors and prostate cancer
Reflection and Reaction
designed prospective randomised trials are needed and are currently underway. Future meta-analyses will also be useful, however, to confirm independently the magnitude of benefit derived from these randomised trials of new treatments.
2
Werner Scheithauer
4
Department of Internal Medicine I and Cancer Center, Medical University Vienna, Waehringer Guertel, Vienna, Austria [email protected] The author has been on advisory boards for Baxter, Amgen, and Ebecue, and has received speaker honoraria from Amgen, Pfizer, Merck, Roche, Ebecue, and Sanofi-Aventis. 1
Golfinopoulos V, Salanti G, Pavlidis N, Ioanidis JPA. Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis. Lancet Oncol 2007; 8: 898–911.
3
5
6
Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin, regardless of whether doublet or singleagent therapy is used first line. J Clin Oncol 2005; 23: 9441–42. Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MCRC): a GERCOR study. Proc Am Soc Clin Oncol 2007; 25 (suppl 166): (abstr) 4013. Hurwitz H, Fehrenbacher L, Nowotny W, et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 351: 337–45. Saltz L, Clarke S, Diaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: Updated efficacy results from XELOX-1/N0 16966, a randomized phase III trial in first-line metastatic colorectal cancer. Proc Am Soc Clin Oncol 2007; 25 (suppl 170): (abstr) 4028. Grothey A, Sugrue M, Hedrick E, et al. Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): results from a large observational study (BriTE). Proc Am Soc Clin Oncol 2007; 25 (suppl 172): (abstr) 4036.
Cyclooxygenase-2 inhibitors and prostate cancer Interest in the use of anti-inflammatory drugs in the treatment of cancer dates back to cardiovascular studies done in the 1970s that showed aspirin decreased the incidence of cancer. Subsequent research established cyclooxygenase-2 (COX-2) as a candidate protein that might explain aspirin’s effect. COX-2 is an isoenzyme induced by mitogens, cytokines, and growth factors that are associated with inflammation, ovulation, and carcinogenesis.1–3 Growing evidence suggests that inhibition of COX-2 might have an important role in the prevention of cancer and the delay of progression in established cancer. Several case–control studies have shown that the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk of prostate cancer, and one of this drug group’s mode of action is inhibition of COX-2.4 Pathological studies show that COX-2 is upregulated in patients with prostate carcinoma, and one study suggested that use of NSAIDs might delay progression from subclinical to clinical prostate cancer.5 Some data suggest that inhibition of COX-2 leads to anti-cancer effects in vitro, consistent with the suggestion that the association between COX-2 inhibition and cancer is causative and not incidental.6 Similar findings have been reported in clinical trials in patients with other cancers. Trials with celecoxib in patients with familial adenomatous polyps have shown a significant decrease in risk of recurrence7,8 http://oncology.thelancet.com Vol 8 October 2007
leading to the licensing of celecoxib for this indication. Several trials have used COX-2 inhibitors as adjuvant treatment or as an addition to standard treatment rather than as primary treatment; although ongoing trials are assessing, for example, celecoxib as sole treatment in patients with prostate cancer who have had biochemical relapse after primary treatment for localised disease. However, enthusiasm for these trials was dampened considerably by the cardiovascular adverse events noted (somewhat surprisingly given the cardioprotective effect of aspirin) in the VIOXX In Colorectal Cancer Therapy: definition of Optimal Regime (VICTOR) trial that compared rofecoxib with placebo in patients with colorectal cancer.9 Subsequent reviews by regulatory authorities worldwide confirmed these cardiovascular adverse events to be a class effect, affecting selective and non-selective COX-2 inhibitors; these reviews also noted that the magnitude of effect varied with the drug and seems to be lower for NSAIDs and certain selective COX-2 inhibitors, such as celecoxib, than for rofecoxib, which has been withdrawn. So should COX-2 inhibitors continue to be investigated in cancer trials? The study by Khor and colleagues10 in this issue of The Lancet Oncology lends support to the study of the COX-2 pathway in clinical trials. In keeping with previously published studies, their report notes an association between cancer
See Articles page 912
859
Reflection and Reaction
outcomes and COX-2 expression in the Radiation Therapy Oncology Group (RTOG) 92-02 trial that studied radiotherapy plus either short-term or longterm androgen deprivation in patients with locally advanced prostate cancer (T2c-T4) who had prostatespecific 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-workers10 shows that COX-2 remains a potentially important therapeutic target in prostate cancer and supports further studies of drugs targeting the protein. Nicholas James [email protected] 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 2 3 4
5
6
7 8
9
10
11
Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II). J Natl Cancer Inst 1998; 90: 1609–20. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J Natl Cancer Inst 1998; 90: 1529–36. 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. Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber MM, Jacobsen SJ. A population-based study of daily nonsteroidal antiinflammatory drug use and prostate cancer. Mayo Clinic Proc 2002; 77: 219–25. Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306–11. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885–95. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355: 873–84. 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. 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. 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 colleagues1 presented rationale for omission of surgery in patients with rectal cancer who have achieved clinical complete response after neoadjuvant 860
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 Habrhttp://oncology.thelancet.com Vol 8 October 2007
designed prospective randomised trials are needed and are currently underway. Future meta-analyses will also be useful, however, to confirm independently the magnitude of benefit derived from these randomised trials of new treatments.
2
Werner Scheithauer
4
Department of Internal Medicine I and Cancer Center, Medical University Vienna, Waehringer Guertel, Vienna, Austria [email protected] The author has been on advisory boards for Baxter, Amgen, and Ebecue, and has received speaker honoraria from Amgen, Pfizer, Merck, Roche, Ebecue, and Sanofi-Aventis. 1
Golfinopoulos V, Salanti G, Pavlidis N, Ioanidis JPA. Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis. Lancet Oncol 2007; 8: 898–911.
3
5
6
Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin, regardless of whether doublet or singleagent therapy is used first line. J Clin Oncol 2005; 23: 9441–42. Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MCRC): a GERCOR study. Proc Am Soc Clin Oncol 2007; 25 (suppl 166): (abstr) 4013. Hurwitz H, Fehrenbacher L, Nowotny W, et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 351: 337–45. Saltz L, Clarke S, Diaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: Updated efficacy results from XELOX-1/N0 16966, a randomized phase III trial in first-line metastatic colorectal cancer. Proc Am Soc Clin Oncol 2007; 25 (suppl 170): (abstr) 4028. Grothey A, Sugrue M, Hedrick E, et al. Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): results from a large observational study (BriTE). Proc Am Soc Clin Oncol 2007; 25 (suppl 172): (abstr) 4036.
Cyclooxygenase-2 inhibitors and prostate cancer Interest in the use of anti-inflammatory drugs in the treatment of cancer dates back to cardiovascular studies done in the 1970s that showed aspirin decreased the incidence of cancer. Subsequent research established cyclooxygenase-2 (COX-2) as a candidate protein that might explain aspirin’s effect. COX-2 is an isoenzyme induced by mitogens, cytokines, and growth factors that are associated with inflammation, ovulation, and carcinogenesis.1–3 Growing evidence suggests that inhibition of COX-2 might have an important role in the prevention of cancer and the delay of progression in established cancer. Several case–control studies have shown that the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk of prostate cancer, and one of this drug group’s mode of action is inhibition of COX-2.4 Pathological studies show that COX-2 is upregulated in patients with prostate carcinoma, and one study suggested that use of NSAIDs might delay progression from subclinical to clinical prostate cancer.5 Some data suggest that inhibition of COX-2 leads to anti-cancer effects in vitro, consistent with the suggestion that the association between COX-2 inhibition and cancer is causative and not incidental.6 Similar findings have been reported in clinical trials in patients with other cancers. Trials with celecoxib in patients with familial adenomatous polyps have shown a significant decrease in risk of recurrence7,8 http://oncology.thelancet.com Vol 8 October 2007
leading to the licensing of celecoxib for this indication. Several trials have used COX-2 inhibitors as adjuvant treatment or as an addition to standard treatment rather than as primary treatment; although ongoing trials are assessing, for example, celecoxib as sole treatment in patients with prostate cancer who have had biochemical relapse after primary treatment for localised disease. However, enthusiasm for these trials was dampened considerably by the cardiovascular adverse events noted (somewhat surprisingly given the cardioprotective effect of aspirin) in the VIOXX In Colorectal Cancer Therapy: definition of Optimal Regime (VICTOR) trial that compared rofecoxib with placebo in patients with colorectal cancer.9 Subsequent reviews by regulatory authorities worldwide confirmed these cardiovascular adverse events to be a class effect, affecting selective and non-selective COX-2 inhibitors; these reviews also noted that the magnitude of effect varied with the drug and seems to be lower for NSAIDs and certain selective COX-2 inhibitors, such as celecoxib, than for rofecoxib, which has been withdrawn. So should COX-2 inhibitors continue to be investigated in cancer trials? The study by Khor and colleagues10 in this issue of The Lancet Oncology lends support to the study of the COX-2 pathway in clinical trials. In keeping with previously published studies, their report notes an association between cancer
See Articles page 912
859
Reflection and Reaction
outcomes and COX-2 expression in the Radiation Therapy Oncology Group (RTOG) 92-02 trial that studied radiotherapy plus either short-term or longterm androgen deprivation in patients with locally advanced prostate cancer (T2c-T4) who had prostatespecific 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-workers10 shows that COX-2 remains a potentially important therapeutic target in prostate cancer and supports further studies of drugs targeting the protein. Nicholas James [email protected] 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 2 3 4
5
6
7 8
9
10
11
Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 307–14. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II). J Natl Cancer Inst 1998; 90: 1609–20. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J Natl Cancer Inst 1998; 90: 1529–36. 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. Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber MM, Jacobsen SJ. A population-based study of daily nonsteroidal antiinflammatory drug use and prostate cancer. Mayo Clinic Proc 2002; 77: 219–25. Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306–11. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885–95. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355: 873–84. 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. 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. 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 colleagues1 presented rationale for omission of surgery in patients with rectal cancer who have achieved clinical complete response after neoadjuvant 860
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 Habrhttp://oncology.thelancet.com Vol 8 October 2007