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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 thatmight explain aspirins effect. COX-2 is an isoenzyme

induced by mitogens, cytokines, and growth factors

that are associated with inflammation, ovulation,

and carcinogenesis.13 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 casecontrol 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 groups 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

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 soletreatment 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

Cyclooxygenase-2 inhibitors and prostate cancer

designed prospective randomised trials are needed

and are currently underway. Future meta-analyses willalso be useful, however, to confirm independently the

magnitude of benefit derived from these randomised

trials of new treatments.

Werner ScheithauerDepartment of Internal Medicine I and Cancer Center, Medical

University Vienna, Waehringer Guertel, Vienna, Austria

werner.scheithauer@meduniwien.ac.at

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 Golfinopoulo s V, Salanti G, Pavlidis N, Ioanidis JPA. Survival anddisease-progression benefits with treatment regimens foradvanced colorectal cancer: a meta-analysis. Lancet Oncol 2007;8: 898911.

2 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 single-agent therapy is used first line. J Clin Oncol 2005; 23: 944142.

3 Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results ofOPTIMOX2, a large randomized phase II study of maintenancetherapy or chemotherapy-free intervals (CFI) after FOLFOX inpatients with metastatic colorectal cancer (MCRC): a GERCORstudy. Proc Am Soc Clin Oncol 2007; 25 (suppl 166): (abstr) 4013.

4 Hurwitz H, Fehrenbacher L, Nowotny W, et al. Bevacizumab plus irinotecan,fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med2004; 351: 33745.

5 Saltz L, Clarke S, Diaz-Rubio E, et al. Bevacizumab (Bev) incombination with XELOX or FOLFOX4: Updated effi cacy results fromXELOX-1/N0 16966, a randomized phase III trial in first-line metastaticcolorectal cancer. Proc Am Soc Clin Oncol 2007;25 (suppl 170): (abstr)4028.

6 Grothey A, Sugrue M, Hedrick E, et al. Association between exposure tobevacizumab (BV) beyond first progression (BBP) and overall survival (OS)

in patients (pts) with metastatic colorectal cancer (mCRC): results from alarge observational study (BriTE). Proc Am Soc Clin Oncol 2007;25 (suppl 172): (abstr) 4036.

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outcomes and COX-2 expression in the Radiation

Therapy Oncology Group (RTOG) 92-02 trial thatstudied 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 includingaspirin, 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 effecton 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 Effi cacy (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 cardiovascularadverse 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 supportsfurther studies of drugs targeting the protein.

Nicholas Jamesn.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: 30714.

2 Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II).J Natl Cancer Inst 1998; 90: 160920.

3 Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part I).J Natl Cancer Inst 1998; 90: 152936.

4 Nelson JE, Harris RE. Inverse association of prostate cancer and

non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-controlstudy. Oncol Rep 2000; 7: 16970.

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: 21925.

6 Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic andantitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000;60: 130611.

7 Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectaladenomatous polyps. N Engl J Med 2006; 355: 88595.

8 Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for theprevention of sporadic colorectal adenomas. N Engl J Med 2006;355: 87384.

9 Kerr DJ, Dunn JA, Langman MJ, et al. Rofecoxib and cardiovascular adverseevents in adjuvant treatment of colorectal cancer. N Engl J Med 2007;357: 36069.

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 Oncol2007; 8: 91220.

11 Solomon SD, Pfeffer MA, McMurray JJ, et al. Effect of celecoxib oncardiovascular events and blood pressure in two trials for theprevention of colorectal adenomas. Circulation 2006;114: 102835.

Chemoradiotherapy alone for rectal cancer: a word of caution

In a recent issue of The Lancet Oncology, ONeill

and colleagues1 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-