Correspondence

Treatment of Prostate Cancer with Goserelin and Radiotherapy

N Engl J Med 1997; 337:1693-1694December 4, 1997

Article

To the Editor:

The article by Bolla et al. (July 31 issue)1 has deficiencies, and the authors missed a golden opportunity to make a major scientific contribution. First, the study did not include a group of patients meeting the entry criteria who were treated only with goserelin for three years. Therefore, no valid conclusions can be reached about the preferred treatment for this group of patients. Comparisons with previous studies are of only limited value as compared with contemporaneous trials by the same investigators using the same standards.

Second, the patient group was heterogeneous, and the results were not stratified. Entry criteria allowed the enrollment of patients with T1 or T2 disease (grade 3) or T3 or T4 disease (any grade). Without stratification of the results, conclusions about so diverse a group are suspect.

Sheldon S. Schoen, M.D.
349 East Northfield Rd., Livingston, NJ 07039

1 References

1. 1

   Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295-300
   Full Text | Web of Science | Medline

To the Editor:

Bolla et al. provide few objective data supporting their conclusion that adjuvant treatment with goserelin, when started simultaneously with external-beam irradiation, improves local control and survival in patients with locally advanced prostate cancer. Their study suffers from several methodologic flaws, any one of which could substantially alter the outcome and result in an erroneous conclusion. The patients enrolled in their study were not randomized on the basis of the two most critical prognostic factors identified in the treatment of prostate cancer: the pretreatment prostate-specific antigen (PSA) value and the Gleason score. Despite an apparent balance of these factors between the two treatment groups (no statistical information was given, however), the Gleason score was unknown in more than one third of the patients, and all PSA values higher than 10 were lumped together rather than evaluated in more meaningful categories (e.g., >10 to 20 and >20). The authors also relied on clinical staging to randomize patients; their approach has been found to be inaccurate and is infrequently used alone to stratify patients in clinical trials.

The end points chosen to assess treatment efficacy are also questionable. Clinical evaluation of local control after external-beam irradiation has all but been abandoned by all academic centers because of inaccuracies as compared with post-treatment PSA values or biopsy results.1 Also, evaluating clinical progression actuarially at 5 years makes little sense when one considers that 55 percent of the patients in the combined-treatment group received 3 or more years of adjuvant therapy, the median follow-up was only 3.9 years, and the intervals were calculated from the date of randomization (not from the completion of treatment). The prolonged suppressive effect of androgen ablation on most of the end points studied requires that treatment efficacy be analyzed after a much longer period before any meaningful conclusions can be reached.

Despite these substantive problems, studies such as this one need to be performed when one considers the suboptimal results obtained with conventional, unimodal therapy. However, as we have recently pointed out, standardized methods of staging (e.g., on the basis of the PSA value and the Gleason score) and a consistent technique to evaluate the outcome (a PSA test or a biopsy) must be adopted before any conclusions can be reached about the efficacy of a particular therapy and patients can be advised about the most appropriate management of their cancer.2

Frank A. Vicini, M.D.
Vijay R. Kini, M.D.
Alvaro A. Martinez, M.D.
William Beaumont Hospital, Royal Oak, MI 48073-6769

2 References

1. 1

   Horwitz EM, Vicini FA, Ziaja EL, et al. Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control. Int J Radiat Oncol Biol Phys 1996;36:565-571
   CrossRef | Web of Science | Medline

2. 2

   Vicini FA, Horwitz EM, Gonzalez J, Martinez AA. Treatment options for localized prostate cancer based on pretreatment serum prostate specific antigen levels. J Urol 1997;158:319-325
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Vicini et al. and Schoen have raised methodologic questions about our study. Clinical staging of locally advanced prostate cancer on the basis of the endorectal examination, histologic score, and PSA value remains reliable; the World Health Organization histologic score was mandatory, but the Gleason score was not. There was no significant imbalance of the clinical characteristics in the two groups, according to Kruskal–Wallis and chi-square tests. If the radiotherapy group (163 patients) and the combined-treatment group (200 patients) are compared with the use of different PSA intervals (less than the upper limit of normal and 1 to 2, >2 to 5, >5 to 10, >10 to 20, and >20 times the upper limit of normal), there are no significant differences (P = 0.92). The analysis was not stratified according to the combination of tumor classification and histologic grade (T1–T2 and grade 3 or T3–T4 and any grade) because the randomization was stratified according to these criteria, which ensured a proper balance between the groups.

With a median follow-up of 3.9 years, an actuarial estimate at 3 years would have been based on more meaningful information, but our 5-year estimates were given together with confidence intervals, which show the precision of the estimates. The intervals were computed from the date of randomization to avoid any selection bias for the time of enrollment, and according to the intention-to-treat principle, all randomized patients were included in the analysis. If we had calculated the time from the date of the completion of treatment, we would have had to exclude patients who did not start treatment or had an early failure. A five-year estimate of clinical local control is insufficient, which is why we used the time to the first treatment failure after a biologic response, which is a stricter end point.

The trial was designed to detect a difference in the overall sample; the small number of patients with T1–T2, grade 3, disease was too small (17 in each group) to allow a separate analysis. For patients with stage T3–T4 disease, of whom there were 181 in the radiotherapy group and 186 in the combined-treatment group, the estimates of efficacy at five years are similar to those reported, with a significant difference in overall survival (P<0.001), disease-free interval (P<0.001), and local control (P<0.001). Hormonal treatment is another approach,1 but in 1986 it was not the aim of the Radiotherapy Cooperative Group of the European Organization for Research and Treatment of Cancer to launch a three-group randomized trial. Other trials are addressing this issue.

Michel Bolla, M.D.
University Hospital, 38043 Grenoble CEDEX 9, France

Laurence Collette, M.Sc.
European Organization for Research and Treatment of Cancer Data Center, 1200 Brussels, Belgium

1 References

1. 1

   Bolla M, Bartelink H, Gibbons R, et al. Treatment of regional disease. In: Murphy G, Denis L, Chatelain C, Griffiths K, Khoury S, Cockett AT, eds. Proceedings of the First International Consultation on Prostate Cancer, Monaco, June 20–22, 1996. Scientific Communication International, 1997:259-66.