This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Roach, M. Articles by Rubagotti, A. Search for Related Content PubMed PubMed Citation Articles by Roach, M., III Articles by Rubagotti, A. Social Bookmarking                            What's this?

Is the Use of Anti-Androgen Monotherapy Appropriate in Patients With Advanced Prostate Cancer?

University of California, San Francisco San Francisco, CA

To the Editor:We wish to comment on the recent study by Boccardo et al entitled "Bicalutamide Monotherapy Versus Flutamide Plus Goserelin in Prostate Cancer Patients: Results of an Italian Prostate Cancer Project Study."¹ The principal finding of this study, namely that antiandrogen monotherapy with bicalutamide is therapeutically equivalent to standard androgen deprivation, has important implications for the treatment of advanced prostate cancer. However, a number of flaws in the design and execution of this study make the results unreliable. Several of the key criticisms are shown in Table 1.

The study also treated patients with both clinical stage C and D disease. These patients have marked differences in prognosis and should not be analyzed in the aggregate. The median follow-up time of 38 months is also too short to allow appropriate survival comparisons, particularly in patients with stage C disease, where one would expect the large majority of patients to survive prostate cancer at that time point. Competing causes of death and the small sample sizes further compound this matter.^3,4

There seem to have been imbalances in treatment arms in terms of extent of disease and disease-related symptoms. More patients with stage D disease were treated on the goserelin plus flutamide (maximal androgen blockade [MAB]) arm. In addition, the median prostate specific antigen level in the MAB arm was 80.3 ng/mL, compared with 56.7 ng/mL in the monotherapy arm. Notably, a higher percentage of patients receiving MAB had high-grade tumors, which may be associated with a worse prognosis.

Finally, there are several issues regarding the quality-of-life (QoL) analysis that require comment. It does not seem that the appropriate methods were used for analysis of paired data for changes in hemoglobin or QoL. When calculating mean differences, only patients with data available at both time points should be included; however, the data in Fig 5B do not seem to be limited to those with paired data. In addition, the differences presented do not seem to be significant, because all 95% confidence intervals overlap. Thus, conclusions about QoL seem to be based on one third of the patients enrolled onto an underpowered study.

In summary, the methodologic flaws, potential imbalances in treatment arms, and short follow-up of this trial suggest that its conclusion that monotherapy is therapeutically equivalent to MAB cannot be justified. Standard androgen deprivation should remain the standard of care for patients with advanced prostate cancer, unless more definitive data are available, or in those cases in which the patient refuses medical or surgical castration and is well informed about the potential inferiority of monotherapy.

REFERENCES

1. Boccardo F, Rubagotti A, Barichello M, et al: Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: Results of an Italian Prostate Cancer Project Study. J Clin Oncol 17:2027-2038, 1999[Abstract/Free Full Text]

2. Tyrrell CJ, Kaisary AV, Iversen P, et al: A randomised comparison of ‘Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 33:447-456, 1998[Medline]

3. Crawford ED, Blumenstein BA, Goodman PJ, et al: Leuprolide with and without flutamide in advanced prostate cancer. Cancer 66:1039-1044, 1990[Medline]

4. Roach M III, Lu J, Pilepich MV, et al: Long-term survival after radiotherapy alone: Radiation Therapy Oncology Group prostate cancer trials. J Urol 161:864-868, 1999[Medline]

Response

On behalf of the Italian Prostate Cancer Project University and National Cancer Institute Genoa, Italy

In Reply:While we share the caution expressed by Roach et al, we disagree with most of the points raised by them.

First, we never used the term equivalent to define the results achieved by bicalutamide monotherapy in our trial. This is a misinterpretation of our conclusions. We just limited to recognize that the results achieved by bicalutamide were comparable to those achieved by maximum androgen deprivation.

Roach et al are correct in saying that trial amendment (which was required for ethical reasons) did further weaken the power of the trial. However, they are probably wrong in stating that "trial design was altered" and that amendment "led to potential biases in interpretation." In fact, as it is clearly stated in the article,¹ different lists of randomization were available by disease stage. Moreover, only 11 patients with stage C disease were entered since the date of amendment.

There is no doubt that there are marked differences in the prognosis of patients with stage C and those with stage D. For this reason, separate analyses by stage were provided in the article (Fig 4 and Table 2) together with an analysis of all patients.¹ The imbalances in treatment arms recalled by Roach et al were not significant and were "corrected" through multivariate analysis. As it is clearly stated in the article, patient age, initial alkaline phosphatase level, and baseline hemoglobin level were included in the model in addition to baseline prostate-specific antigen level, disease stage, and tumor grade.¹ The analysis of paired data for changes in hemoglobin level relative to the patients for whom baseline, 3-month, and 6-month data were available are reported in Table 1.

Evaluation of QoL was not the primary end point of this study, and we already recognized that "the reliability of QoL analysis might be biased by the low compliance of patients." However, our results are enforced by those reported on in this regard in the previous trials comparing bicalutamide monotherapy with castration.^2,3 Moreover, data on sexual functioning were drawn after all patients were interviewed, and there is no doubt that fewer patients in the bicalutamide group complained of loss of libido and erectile dysfunction. This finding is common to the majority of previous trials reporting on pure antiandrogen monotherapy.^2-5

Loss of sexual potency has proved to be of special concern for younger men. An estimation of the perception of sexual dysfunction as an event negatively influencing QoL comes from the studies performed in men treated either with surgery or with radiotherapy for localized or locally advanced disease. Comparative trials have shown that the decline in sexual function was the most common cause of disease-specific stress among men with prostate cancer.⁶ Singer et al⁷ reported that of a sample of 50 men without known prostate cancer, 68% were willing to trade a 10% or greater advantage in 5-year survival in order to maintain sexual potency. A larger trial of 230 men in a general medicine clinic supported this finding, with 67% of men stating they would be willing to trade an increase of 14% in survival time in order to prevent impotence.⁸

If it is acceptable, at least in principle, that men who are virtually candidates for cure might trade an increase of 10% or more in expected survival in order to prevent impotence, why should we not accept that men who are no longer candidates to be cured of their disease, like those with locally advanced or metastatic disease, could be willing to trade a modest (42 days in the trials of bicalutamide v castration,²) deficit in expected survival to achieve the same goal? Of course, the balance of risk and benefit should be integral to the discussion between the patient and the physician. However, not informing patients about the possible alternatives to androgen deprivation could limit their ability to choose. It has been said that a distinguished Italian surgeon in the 1970s chose to die of his prostate cancer because he did not want to accept the consequences of androgen deprivation. Let’s believe that should this gentleman be born 20 years later, he would probably live longer (and maybe die of a competing cause!) and benefit from a more appropriate palliation of his disease thanks to antiandrogen monotherapy.

REFERENCES

1. Boccardo F, Rubagotti A, Barichello M, et al: Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: Results of an Italian Prostate Cancer Project study. J Clin Oncol 17:2027-2038, 1999

2. Tyrrell CJ, Kaisary AV, Iversen P, et al: A randomised comparison of ‘Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 33:447-456, 1998

3. Iversen P, Tyrrell CJ, Kaisary AV, et al: Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: Results from two multicenter randomized trials at a median follow-up of 4 years. Urology 51:389-396, 1998[Medline]

4. Kaisary AV: Antiandrogen monotherapy in the management of advanced prostate cancer. Eur Urol 31:14-19, 1997 (suppl 2)

5. Migliari R, Muscas G, Usai E: Effect of Casodex on sleep-related erections in patients with advanced prostate cancer. J Urol 148:338-341, 1992[Medline]

6. Helgason AR, Adolfsson J, Dickman P, et al: Sexual desire, erection, orgasm and ejaculatory functions and their importance to elderly Swedish men: A population-based study. Age Ageing 25:285-291, 1996[Abstract/Free Full Text]

7. Singer PA, Tasch ES, Stocking C, et al: Sex or survival: Trade-offs between quality and quantity of life. J Clin Oncol 9:328-334, 1991[Abstract]

8. Mazur DJ, Hickham DH: Patient preferences: Survival versus quality of life. J Gen Intern Med 8:374-377, 1993[Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Roach, M. Articles by Rubagotti, A. Search for Related Content PubMed PubMed Citation Articles by Roach, M., III Articles by Rubagotti, A. Social Bookmarking                            What's this?