Akakura K; Bruchovsky N; Goldenberg SL; Rennie PS; and others
Effects of intermittent androgen suppression on androgen-dependent tumors. Apoptosis and serum prostate-specific antigen.
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver Clinic, Canada.
Cancer 1993 May 1;71(9):2782-90
Unique Identifier: MEDLINE 93223135

Abstract:

BACKGROUND. Since postcastration progression of tumors to an androgen-independent state appears to be linked to the cessation of androgen-induced differentiation of tumorigenic stem cells, the authors hypothesized that the replacement of androgens at the end of a period of apoptotic regression might result in the regeneration of differentiated tumor cells with further apoptotic potential.

METHODS AND RESULTS. To determine the effect of intermittent exposure of androgens on the androgen-dependent Shionogi carcinoma, the tumor was transplanted into a succession of male mice, each of which was castrated when the estimated tumor weight became about 3 g. After the tumor had regressed to 30% of the original weight, it was transplanted into the next noncastrated male. This cycle of transplantation and castration-induced apoptosis was repeated successfully four times before growth became androgen-independent during the fifth cycle.

In four of Stage C and three of Stage D patients with prostate cancer, androgen withdrawal was initiated with cyproterone acetate (100 mg/d) and diethylstilbestrol (0.1 mg/d) and then maintained with cyproterone acetate in combination with the luteinizing hormone-releasing hormone agonist, goserelin acetate (3.6 mg/month). After 6 or more months of suppression of serum prostate-specific antigen (PSA) into the normal range, treatment was interrupted for 2 to 11 months. After recovery of testicular function, androgen-withdrawal therapy was resumed when serum PSA increased to a level of about 20 micrograms/l. This cycle was repeated sequentially to a total of two to four times over treatment periods of 21 to 47 months with no loss of androgen dependence.

CONCLUSIONS. These results demonstrate that intermittent androgen suppression can be used to induce multiple apoptotic regressions of a tumor; they also suggest that the cyclic effects of such treatment on prostate cancer can be followed by the sequential measurement of serum PSA levels.

EXCERPTS FROM THE ARTICLE: The article states that:

Whether intermittent androgen withdrawl and its effects on tumor progression alter survival in a beneficial or adverse way is unknown, although the possibility of an improved outcome has been considered by Klotz et al. (A hyperlink to this article is forthcoming.) No unfavorable effects on survival have been suggested by our experience with such therapy. However, it would be of considerable interest to compare the results of intermittent versus continuous androgen suppression in patients in whom the PSA is lowered into the normal range by initial therapy.

Owing to the fact that the function of the testis and the concentration of serum testosterone return to normal slowly over a period of 8 to 14 weeks when the patient is off treatment, it is unlikely that acute symptoms and signs of tumor flare will be precipitated by intermittent androgen suppression. Under such conditions of deliberate and gradually increasing hormonal stimulation, a greater chance exists that the androgen-dependent (apoptotic) state of the tumor will be restored, thus setting the stage for another response to androgen deprivation. This is in contrast to the adverse effects of androgen priming on androgen-independent (Stage D3) prostate cancer. Sudden clinical deterioration may be observed owing to accelerated growth of tumor cells which remain androgen-sensitive but irreversibly nonregressing.

WellnessWeb Comment: What this means in layman's terms is that continuous therapy may allow cancer cells that have mutated to a state where they are independent of testosterone to reach a state where they are irreversibly independent. With intermittent therapy, even though cells have mutated to a state of hormone independence, during the time when the drugs are withdrawn and the hormones are allowed to gradually return
to pre-therapy levels, the mutated hormone independent cells may again become hormone dependent. If true, the conventional wisdom that once a patient is put on hormone therapy he must remain on it for life may be counterproductive.

The article goes on to say that:

More obvious advantages of intermittent androgen suppression include an improved quality of life with recovery of sexual function and apparent prolongation of the androgen-dependent state of the tumor. This treatment may, in addition, provide more favorable conditions for response to chemotherapy, applications to the management of disease in earlier stages, and reduced cost of treatment.