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Continued from PROSTATE CANCER: LATE STAGE

We have used the DHEA-S, a more stable blood level, to assess the presence of an AAWR. If the androgen receptor is regarding the anti-androgen as a growth stimulator (agonist), then the brain (hypothalamus) will sense adequate androgen levels and down-regulate the stimulatory hormones that are involved with T production. Such hormones would include LH and ACTH. LH stimulates the Leydig cells in the testicles to make T. This mechanism is already blocked by the LHRH-A. ACTH stimulates the adrenal cortex to make adrenal androgen precursors such as DHEA-S and androstenedione. Both of these are converted within prostate cells, be they benign or malignant, to T and then to DHT. If an ARM is operative, ACTH will be turned down and so will the levels of DHEA-S and androstenedione. Therefore, when we find suppressed levels of these two adrenal androgen precursors, we are suspicious of an ARM and proceed with anti-androgen withdrawal.

A PSA decline with flutamide withdrawal was first reported in 1993 by Scher and Kelly (J. Clin. Oncol., 1993). Defining an AAWR by a greater than 50% decline from baseline PSA, the authors reported an AAWR in 10 of 36 (28%) patients after 3 months of Eulexin withdrawal. Twenty-five of these patients received ADT as initial treatment, of whom 10 (40%) had an AAWR. In this study, none of the 11 patients who received Eulexin after PSA relapse on "monotherapy" (orchiectomy or LHRH-A treatment alone) showed an AAWR.

Figg et al. (Am. J. Med., 1995) and Small et al. (Cancer, 1995) subsequently published two other studies of Eulexin withdrawal responses, the latter of which evaluated a large cohort of advanced disease patients. In contrast to Scher et al., Small et al. showed similar rates of response regardless of when Eulexin was begun. Eight (14%) of 57 patients who received concomitant Eulexin with ADT had an AAWR, while 4 (16%) of 25 patients who received Eulexin after PSA progression on monotherapy had an AAWR. Patients who responded were treated with Eulexin for a longer time than nonresponding patients (median duration 21 months versus 12 months, respectively, p = 0.2).

Withdrawal of Casodex has also been reported to result in an AAWR (Small and Carroll, Urology, 1994; Small et al., Proc. Am. Soc. Clin. Oncol., 1996). The time until PSA begins to decline after anti- androgen withdrawal is shorter with Eulexin than with Casodex, reflecting the longer half-life of elimination from the body with Casodex (7 days) versus Eulexin (5.2 hours) (Small et al., Proc. Am. Soc. Clin. Oncol., 1996).

Withdrawal responses do not appear to be limited to nonsteroidal anti-androgens. A withdrawal response was reported in a patient receiving the progestin, megestrol acetate (Megace), which also binds to androgen receptors (Dawson and McLeod, J. Urol., 1995) and in patients withdrawn from Diethylstilbestrol (Bissach and Kaczmaiek, J. Urol., 1995).

High-dose Casodex after Eulexin Withdrawal

As described earlier, Veldscholte et al. (Biochem. Biophys. Res. Commun., 1990) described an androgen receptor gene mutation in a LNCaP human PC cell line that could be activated by estrogen, progesterone, and Eulexin. This same point mutation and growth stimulating effect by Eulexin was noted by other investigators (Culig et al., Mol. Endocrinol., 1993; Taplin, et al., N. Engl. J. Med., 1995; Fenton et al., Clin. Cancer Res., 1997). However, some mutant androgen receptors were found to be paradoxically antagonized by the structurally different anti-androgen, Casodex. Similarly, LNCaP cell growth was inhibited by Casodex (Olea et al., Endocrinology, 1990). Based upon these observations, Joyce et al. (J. Urol., 1998) conducted a pilot study of high-dose Casodex (150 mg/day) in 30 patients who failed ADT that included Eulexin. Fourteen (48%) received Eulexin as part of the primary ADT, whereas the other 16 received Eulexin after PSA progression on monotherapy. Although 70% of patients had received at least one nonhormonal therapy prior to study entry, all patients had a rising PSA after Eulexin withdrawal and were progressing on their last treatment. Using a response criteria defined as a > 50% decline from baseline PSA maintained at least 2 months, 7 (23%) patients responded to high-dose Casodex. Six (43%) of the 14 patients receiving Eulexin as part of primary ADT were responders, whereas only 1 (6%) of 16 patients receiving Eulexin at PSA progression on monotherapy were responders (p = 0.03). There was no correlation between patients having a response to high-dose Casodex and those having had a prior anti-androgen response. Therefore, in this study, it appears that patients progressing on ADT that includes Eulexin as part of combination hormone blockade are candidates to receive high-dose Casodex at 150 mg a day, regardless of whether or not they had an AAWR upon discontinuing Eulexin. Treatment was generally well tolerated. The primary side effects reported included exacerbation of hot flushes (40%), nausea (10%), fatigue (10%) and gynecomastia (5%). There were no liver function abnormalities seen. The authors concluded that Casodex at this dose is modestly effective for patients with AIPC, particularly for those treated with long-term Eulexin.

In the setting of PSA progression, the above evaluations should be undertaken to properly diagnose the patient's situation. If such an analysis is not done, the patient may be inappropriately labeled as having "hormone refractory disease" when in fact he may have an ARM, or perhaps excessive production of adrenal androgen precursors, or perhaps insufficient suppression of LH. Once this analysis is complete and the above causes of PSA progression have been excluded, the physician and patient can focus on therapies used in the treatment of AIPC.

I have divided these therapies into two major categories that reflect ease of treatment administration. This is a separation based on quality of life issues and not on the magnitude of response to treatment. As we improve in our treatments of AIPC, this separation may disappear. The treatment strategy is shown below.

Table 2

Continuation of PROSTATE CANCER: LATE STAGE