Continued from PROSTATE CANCER: LATE STAGE
Corticosteroid Therapy in AIPC
Corticosteroids are a family of semisynthetic and synthetic compounds that mimic the anti-inflammatory effects of cortisol. Corticosteroids are produced naturally by the adrenal glands. The most commonly prescribed agents include cortisone acetate (Cortef), hydrocortisone (Hydrocortone), prednisone (Deltasone), and dexamethasone (Decadron or Hexadrol). It has been recognized for many years that corticosteroids have a definite palliative (symptom improving) and sometimes objectively beneficial effect on the clinical course of patients with AIPC.
Tannock et al. (J. Clin. Oncol., 1989) studied the clinical benefit of Deltasone given at a dose of 7.5 to 10 mg a day in 13 patients with AIPC. Results of this study showed objective responses in 5 (38%) patients lasting a median of 3 months. The authors attempted to correlate patient response with suppression of the adrenal androgens DHEA-S and androstenedione. Twelve (92%) of 13 patients had significant suppression of either one or both hormones, with levels of < 1 mM/L and < 1 nM/L for DHEA-S and androstenedione, respectively. The authors concluded that low-dose Deltasone provided excellent suppression of adrenal androgen levels, which results in good palliative benefits for patients with AIPC. In a subsequent randomized trial by the same principal investigator, the response rate to Deltasone alone was lower, but still significant at 13.5%. The median duration of response to single, agent Deltasone in this trial was 4.5 months (Tannock et al., J. Clin. Oncol., 1996).
Harvey et al. (Proc. Am. Soc. Clin. Oncol., 1994) studied Decadron at a weekly dose of 10 mg intravenously in six patients with advanced-stage PC who had failed at least two prior hormone maneuvers and who also had received chemotherapy. Using a response criteria of a > 50% decline of PSA from baseline, 5 of 6 (83%) of patients responded. They also demonstrated a decrease in pain and an improved performance status. The median duration of survival was 9 months (range of 4 to 20+ months) with 5 patients still responding at the time of the report.
Storlie et al. (Proc. Am. Soc. Clin. Oncol., 1994) evaluated the effectiveness of oral Decadron in 38 patients with progressive disease after orchiectomy. The Decadron dose was 0.75 mg twice a day. Responses were seen in 23 of 38 (61%) of patients evidenced by a greater than 50% PSA decline. Thirteen of 38 (34%) of patients had a greater than 80% decline in PSA. In two of 23 responding patients, the possibility of an AAWR could not be excluded. However, 21 (55%) of 38 patients still had a greater than 50% decline in PSA if these two patients are excluded from analysis. The authors unfortunately did not mention the duration of response in this abstract.
Kelly et al. (Cancer, 1973) conducted a prospective study in which patients with AIPC were initially treated with Hydrocortisone alone, and then were progressively given suramin. Patients treated with suramin require Hydrocortisone to replace the loss of adrenal cortisol production caused by suramin. In that report, only 10% of patients derived an independent benefit from suramin, suggesting that the use of Hydrocortisone may have accounted for the high rates of antitumor response previously reported in suramin trials for AIPC.
In our opinion, all of these studies should have measured DHEA-S and androstenedione levels at baseline and during steroid treatment. If the observations of Tannock et al. were correct in their initial study, the suppression of these hormone levels values may possibly identify which patients may respond best to corticosteroid therapy.
Estrogen Therapy for AIPC: Diethylstilbestrol (DES)
Estrogens have significant effects on the PC cell. Estradiol has been shown to localize irreversibly to the nuclear membrane of the tumor cell within 2 hours of exposure (Sinha et al., Cancer, 1973). Diethylstilbestrol, a nonsteroidal estrogen, has been shown to inhibit RNA polymerase activity in prostatic tissue and inhibit DNA synthesis in both benign and malignant prostate tissue (Davies and Griffiths, J. Endocrinol., 1973; Lasnitzki, J. Steroid Biochem., 1979). All estrogens also exert a competitive inhibitory effect on androgen-dependent cancers by suppressing LH secretion at the level of the pituitary-testicular axis.
Until the advent of LHRH agonists, estrogens and Diethylstilbestrol were extensively used in the treatment of advanced PC. In the initial Veterans Administration Cooperative Urologic Research Group (VACURG) studies, Diethylstilbestrol was found to be as effective as orchiectomy for PC, but at a dose of 5 mg/day, carried a significant risk of cardiovascular morbidity (Byer, Cancer, 1973).
More recently, single and cooperative group studies have evaluated the effectiveness of Diethylstilbestrol at dosages of 3 and 1 mg a day (Blackard, Cancer Chemother. Rep., 1975; Pavone-Macaluso et al., J. Urol., 1986; Emtage et al., Eur. J. Cancer, 1990).
Both dosages were found to be as effective as the 5 mg/day dosage with considerably fewer cardiovascular toxicities. Although serum T levels were not consistently suppressed to castrate levels using the 1 mg/day dose, this dosage showed an equivalent anticancer effect compared to the 5mg/day dosage (Byer and Corle, NCI Monogr., 1988). It should be noted that the regression of metastatic disease can occur without maximal suppression of serum T levels (Scott et al., Cancer, 1990).
In a more recent study, Jazieh et al. (Proc. Am. Assoc. Cancer Res., 1994) reported results using oral Diethylstilbestrol treatment in 14 patients with progressive AIPC. Diethylstilbestrol was given at a dose of 1 mg, 3 times a day along with routine anticoagulation with warfarin (Coumadin). In this study, 9 (64%) of 14 patients responded with a greater than 75% decline in baseline PSA. PSA levels normalized in 5 of 14 (36%) of patients. Two of these patients, however, may have had an anti-androgen withdrawal response. In patients with symptomatic disease, 50% showed improvement with Diethylstilbestrol treatment. The median duration of response was 8 months (range 2 to 24 months), and the median time to reach PSA nadir was 3 months (range 1 to 10 months). There were no cardiovascular or thrombotic (blood clotting) events reported.
More recently, Smith et al. (Urology, 1998) reported results of a phase II study of Diethylstilbestrol at a dose of 1 mg/day in 21 patients failing ADT. All patients were withdrawn from anti-androgen therapy and started Diethylstilbestrol at PSA progression. LHRH agonist therapy was stopped simultaneously. Response in this study was defined as a > 50% decline from baseline PSA. This was seen in 9 of 21 (43%) patients. In 13 patients who failed only one hormonal therapy, responses were seen in 8 (62%) patients. In the 13 patients who failed more than one prior hormone treatment, a response was seen in only 1 (13%) of 8 patients. Duration of response was not reported. Sixteen patients remained alive after a median follow-up of 82 weeks with a 2-year survival rate of 63%. Therapy was generally tolerated well. Nineteen (90%) patients complained of nipple tenderness, but none discontinued therapy because of this side effect. Three (14%) patients developed gynecomastia (breast enlargement), and one (5%) patient developed deep venous thrombosis.
Intravenous Estrogens (Fosfestrol or Stilbestrol Diphosphate)
Stilbestrol diphosphate (Stilphosterol) is a water-soluble formulation of nonsteroidal estrogen that can be injected intravenously. High-dose intravenous estrogens are thought to have a direct cytotoxic effect on the PC cell. In theory, Stilphosterol enters the cell, and free stilbestrol is liberated by an enzymatic action within the cancer. This enzyme, acid phosphatase, is abundant in malignant prostatic tissue and releases free stilbestrol via dephosphorylation. Within the cell, stilbestrol destroys the cell by inducing apoptosis (programmed cell suicide) (Colapino and Aberhart, Br. J. Urol., 1961).
Selenomethionine is a radioactive isotope that is used as a marker for protein synthesis by the cell. At DES plasma levels of 1 mcg/ml, incorporation of this isotope into PC cells was inhibited 20%. At DES levels of 5 mcg/ml, isotope incorporation was inhibited by 69.6% (Ferro et al., Br. J. Urol., 1988). DES blood levels of this magnitude can easily be achieved in the clinical setting. Using high- pressure liquid chromatography, a 1-gram intravenous injection of Stilphosterol resulted in a mean plasma DES level of 3.6 mcg/ml 30 minutes after injection (Abramson and Miller, J. Urol., 1982).
Ferro et al. (Urology, 1989) conducted a prospective trial of high-dose intravenous Stilphosterol in 29 patients with symptomatic AIPC metastatic to bone. At baseline, all patients had elevated PSA levels, 24 (83%) had elevated PAP levels, and 28 (97%) had elevated alkaline phosphatase levels. Stilphosterol was administered as a dose of 1104 mg intravenously over 5 minutes daily for 7 days. A subjective response was seen in 22 (76%) patients as evidenced by improvement in bone pain, mobility, and/or decreased analgesic requirements. Significant decreases in serum PSA were noted in 13 (45%) patients, with PSA reductions ranging from 44 to 93%. Duration of patient response or survival were not reported. Side effects consisted of perineal discomfort, nausea, vomiting, and bone pain in some patients, with widespread bony metastases. No cardiovascular or thrombotic complications were reported.
Fosfestrol is a European formulation similar to stilbestrol diphosphate and is known by the names of Honvan, Fosfostilben, Honvol, and ST-52. In a study by Droz et al. (Cancer, 1993) 16 AIPC patients received fosfestrol, 4 grams a day intravenously over 3.5 hours for 5 consecutive days. For the remainder of the month, patients received an unspecified oral dose of fosfestrol, with intravenous therapy repeated once a month. Response, defined as a > 50% decline in baseline PSA, was seen in seven (43%) patients. The median duration of survival was longer in responding patients (10 months versus 5 months, respectively). Cardiovascular complications occurred in 6% of patients.
A slower rate of intravenous administration appears to reduce the risk for perineal discomfort, nausea, and vomiting. Intravenous Stilphosterol has not been reported to cause cardiovascular or thrombotic complications when the duration of treatment is limited to 7 days (Ferro, Urol. Clin. N. Am., 1991). Since we use Stilphosterol over many weeks' duration, routine anticoagulation with Coumadin is advised.
Further studies with oral and intravenous estrogens are needed. The activity of both oral and high-dose intravenous therapy in AIPC patients who already have castrate testosterone levels clearly indicates their mechanism of action is different from simply effects upon the pituitary-testicular axis.