CORRESPONDENCE

Re: All-Cause Mortality in Randomized Trials of Cancer Screening

Chris Parker, David Dearnaley

Affiliation of authors: C. Parker, D. Dearnaley, Academic Radiotherapy Department, Royal Marsden Hospital, Surrey, U.K.

Correspondence to: Chris Parker, M.D., Academic Radiotherapy Department, Royal Marsden Hospital, Downs Rd., Sutton, Surrey, U.K. SM2 5PT (e-mail: cparker{at}icr.ac.uk).

We agree with Juffs and Tannock that "Screening trials are even more difficult than we thought they were" (1). We would add that the problem of slippery-linkage bias is not unique to screening trials and that adjuvant therapy trials may also be more difficult than we thought they were.

Consider, for example, the question of the optimum duration of adjuvant androgen deprivation in the treatment of prostate cancer. The Radiation Therapy Oncology Group (RTOG) 99–10 trial is comparing a treatment of 16 weeks with a treatment of 36 weeks for total androgen suppression in men with prostate cancer who are receiving radical radiotherapy. The main end point is disease-specific survival, and the trial is powered to detect a 33% reduction in the hazard rate for death from prostate cancer, with target accrual of 1540 patients. However, there is a real possibility that, in comparison with short-term therapy, long-term androgen deprivation may be associated with an excess mortality from causes other than prostate cancer. This possibility is analogous to the slippery-linkage bias described by Juffs and Tannock and would suggest that overall survival, and not disease-specific survival, should be the main end point of this trial.

Perhaps the best data to support this possibility come from subgroup analysis of the RTOG 92–02 trial (2). This trial recruited over 1500 men with locally advanced prostate cancer who received total androgen suppression for 2 months before and 2 months during radiotherapy to the prostate and pelvis. They were randomly assigned to receive an additional 24 months of the luteinizing hormone-releasing hormone agonist goserelin or to receive no further adjuvant therapy. The initial results show a trend toward an improved 5-year disease-specific survival with adjuvant treatment (92% versus 87%, P = .07), with no difference in the 5-year overall survival (78% versus 79%) (2). The subgroup of patients who had a Gleason score of 8–10 (22% of all participants) showed a statistically significant benefit for adjuvant goserelin in terms of disease-specific survival (90% versus 78%, P = .007) and of overall survival (80% versus 69%, P = .02). The outcome of the remaining 78% of patients with a Gleason score of 7 or less was not presented. However, this outcome may be estimated, because the percent survival for all patients is 0.78 (percent survival for patients with a Gleason score of 7 or less) plus 0.22 (percent survival for patients with a Gleason score of 8–10).

If we take into account the possibility of rounding errors, then the 5-year disease-specific survival shows an absolute difference of 1.7%–4.3% in favor of adjuvant goserelin (91.9%–93.2% versus 88.9%–90.2%), but the overall survival shows an absolute detriment of 3.1%–5.6% (76.8%–78.1% versus 81.2%–82.4%). Thus, a 2-year treatment with adjuvant goserelin was associated with an absolute increased risk of 4.8%–9.9% for nonprostate cancer death. The statistical significance of this increased risk cannot be calculated from the available data, but its magnitude is too large to be explained merely by the increased number of patients at risk.

The cause of any excess mortality associated with goserelin therapy is not known, but there is some evidence to suggest an effect on cardiovascular mortality. Low testosterone levels have been associated with a range of risk factors for cardiovascular disease (3), and luteinizing hormone-releasing hormone agonist therapy leads to both increased insulin resistance and arterial stiffness (4).

A 2-year treatment with adjuvant goserelin improves overall survival for men with locally advanced prostate cancer and a Gleason score of 8–10 who undergo radical radiotherapy (2). Trials are warranted in lower risk populations comparing different durations and different methods (e.g., antiandrogen versus androgen deprivation) of adjuvant hormonal therapy. Given the possibility of an adverse effect of androgen deprivation on nonprostate cancer mortality, it is important that the main end point of such trials be overall, and not disease-specific, survival. If the RTOG 99–10 trial were designed with 90% power and a statistical significance level of .05 to detect a 10% reduction in the hazard rate for overall mortality, a total of 7400 patients would be required. Adjuvant therapy trials may be even more difficult than we thought they were.

REFERENCES

1 Juffs HG, Tannock IF. Screening trials are even more difficult than we thought they were. J Natl Cancer Inst 2002;94:156–7.[Free Full Text]

2 Hanks G, Lu J, Machtay M, Venkatesan V, Pinover W, Byhardt R, et al. Proc of Am Soc Ther Rad Oncol (ASTRO), RTOG Protocol 92–02: a phase III trial of the use of long term total androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate [abstract 4]. Int J Radiat Oncol Biol Phys 2000;48:112.

3 Simon D, Charles MA, Nahoul K, Orssaud G, Kremski J, Hully V, et al. Association between plasma total testosterone and cardiovascular risk factors in healthy adult men: The Telecom Study. J Clin Endocrinol Metab 1997;82:682–5.[Abstract/Free Full Text]

4 Smith JC, Bennett S, Evans LM, Kynaston HG, Parmar M, Mason MD, et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab 2001;86:4261–7.[Abstract/Free Full Text]



             
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