1646 COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER OF PROSTATE

times, and recognize that the disease is progressing even though they are asymptomatic. My experience has been that these patients gladly accept a luteinizing hormone-releasing hormone agonist and antiandrogen, only to start expressing concern after approximately 6 to 9 months of therapy. They find the weight gain, hot flashes, cost and inconvenience of monthly injections challenging, and frequently stop the treatments.

This combination of finasteride and flutamide may address many of these concerns, while delivering effective androgen ablation. We have now treated 27 patients with increasing PSA levels after rad- ical prostatectomy or radiation therapy with a similar regimen, using 5 mg. finasteride plus 125 mg. flutamide twice daily. We have seen similar results with decreased PSA to undetectable levels in 25 of the 27 patients. I t should be emphasized that the regimen pro- posed by the authors or the one that we have used would likely be ineffective in cases of advanced prostate cancer. This study estab- lishes the necessity of a randomized trial with interval to progression and survival as an end point before we can conclude that this is an appropriate way to treat advanced prostate cancer. A number of other treatment options that do not use standard castration include single agent flutamide, bicalutamide and intermittent hormonal ab- lation. It is hoped that proper randomized trials will be conducted to address the effect on patient survival and quality of life.

E. David Crawford Dicrision of Urology Department of Urology Uniuersity of Colorado Health Sciences Center Denver, Colorado

1. Crawford, E. D.: Changing concepts in the management of ad- vanced prostate cancer. Urology, suppl., 44: 67, 1994.

2. Pummer, K., Crawford, E. D., Daneshgari, F., Andros, B., Pfister, S. and Miller, G. J.: Hormone pretreatment does not affect the final pathologic stage in locally advanced prostate cancer. Urology, suppl., 44: 38, 1994.

REPLY BY AUTHORS

While we welcome the comments of Walsh. we respectfully dis- aeree with some of his criticisms of our study. The reason for not

efficacy are demonstrated does i t then become appropriate to per- form a phase 3 study. In addition, the known inferiority of mono- therapy finasteride or flutamide coupled with our laboratory data (reference 7 in article), which revealed an additive effect of the drug combination, led us to conclude that it would be inappropriate to treat patients with sequential monotherapy. Furthermore, an in- crease in PSA secondary to temporary finasteride withdrawal in 1 patient treated with this regimen lends credence to the fact that there is to some degree an additive effect of this combination (un- published data). However, flutamide provides the major antiandro- genic effect.

Although we agree that mean nadir PSA values are minimally higher than with standard therapy, it is important to realize that 4 of the 15 evaluable patients had undetectable levels at 24 months. In addition, nadir levels are well within the range that predicts good response to androgen deprivation therapy.' Nevertheless, we believe that patients with long disease duration (patients with T3, node- positive and post-radical therapy recurrent disease) may be willing to sacrifice minimally less optimal therapy for improved overall quality of life. Surgical or medical castration can perhaps salvage these patients when disease progresses.

We agree with Walsh that there is no proof that early hormonal therapy prolongs survival but, to our knowledge, no adequately powered study addressing this issue has ever been performed. Fur- thermore, we concur with Crawford that many patients in whom radical treatment fails become obsessed with PSA levels and desire therapy. Therefore, these patients may be placed on total androgen blockade for long periods. However, there are concerns about long- term castrate levels of testosterone, including sexual dysfunction, muscle wasting, psychosocial disturbances, hot flashes and osteopo- rosis. Finasteride and flutamide in combination may provide the correct balance between effective therapy and improved quality of life. This therapy is also less expensive than luteinizing hormone- releasing hormone analogues plus flutamide. Clearly a randomized study with time to progression, survival and overall quality of life are needed to define better the appropriate, if any, uses of this novel drug combination.

1. Cooper, E. H., Armitage, T. G., Robinson, M. R., Newling, D. W., Richards, B. R., Smith, P. H., Denis, L. and Sylvester, R.:

commencing a controlled study is because of the need for phase l and 2 testing of any new drug or drug combination. Only after safety and

Prostate specific antigen and prediction of prognosis in meta- static prostatic cancer. Cancer, suppl., 66: 1025, 1990.