How Do You Treat Prostate Cancer That Has Progressed On Primary Androgen Deprivation Therapy? Part 2 of 2: Secondary Hormonal Treatment Approaches
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Revised October 1998

 

 



TABLE OF CONTENTS – PART 2

Page(s)
Table of Contents

4
Overview

5
The antiandrogen withdrawal response (AAWR)

5-6
High-dose bicalutamide after flutamide withdrawal

6-7
High-dose ketoconazole (HDK) with hydrocortisone (HC)

7-13
Aminoglutethimide (AG) with hydrocortisone (HC)

12-13
Megestrol acetate

13-15
Corticosteroids

16
Estrogen therapy

17-18
Summary and a view towards the future

18-21
References

21-26

OVERVIEW

The treatment approach for prostate cancer that has progressed on primary androgen deprivation therapy (ADT) has recently undergone a significant and fundamental transformation. The reason for this changing paradigm is not simply due to novel therapeutic interventions, but to more to the recognition that the term “hormone-refractory” does not adequately define the nature of the disease for all patients. In fact, there is significant heterogeneity in the “hormone-refractory” patient population such that some men retain some degree of hormonal sensitivity. In this booklet, we will review biologic and clinical characteristics to identify men who retain hormone sensitivity and their choices of secondary hormonal therapies.

THE ANTIANDROGEN WITHDRAWAL RESPONSE (AAWR)

We now know that an androgen receptor mutation can cause an antiandrogen to paradoxically stimulate tumor growth. Withdrawal of antiandrogen therapy has been shown to result in tumor regression, on average, in approximately 20% of patients. This phenomenon is called the Antiandrogen Withdrawal Response (AAWR).

A PSA decline with flutamide withdrawal was first reported in 1993 by Scher and Kelley.1 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 flutamide withdrawal. Twenty-five of these patients received CHB as initial treatment, of whom 10 (40%) had an AAWR. None of the 11 patients who received flutamide after PSA relapse on “monotherapy” (orchiectomy or LHRH-A treatment alone) showed an AAWR.

Figg, et al2 and Small, et al3 subsequently published two other studies of flutamide 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 flutamide was begun. Eight (14%) of 57 patients who received concomitant flutamide with ADT had an AAWR while 4 (16%) of 25 patients who received flutamide after PSA progression on monotherapy had an AAWR. Patients who responded were treated with flutamide for a longer time than non-responding patients (median duration 21 months vs 12 months, respectively, p = 0.2).

Withdrawal of bicalutamide (Casodex®) has also been reported to result in an AAWR.4,5 Interestingly, the time until PSA begins to decline after antiandrogen withdrawal appears to be shorter with flutamide than with bicalutamide, perhaps reflecting the longer half-life of elimination from the body with bicalutamide (1 week) vs flutamide (5.2 hours).5 Withdrawal responses do not appear to be limited to non-steroidal antiandrogens. A withdrawal response was reported in a patient receiving the progestin, megestrol acetate (Megace®), which also binds to androgen receptors6 and in patients withdrawn from diethylstilbestrol (DES).7

HIGH-DOSE BICALUTAMIDE AFTER FLUTAMIDE WITHDRAWAL

As described in part 1 of this booklet series, Veldscholte, et al, described an androgen receptor gene mutation in a LNCaP human prostate cancer cell line that could be activated by estrogen, progesterone and flutamide.8 This same point mutation and growth stimulating effect by flutamide was noted by other investigators.9-11 However, some mutant androgen receptors were found to be paradoxically antagonized by the structurally different antiandrogen, bicalutamide (Casodex®). Similarly, LNCaP cell growth was inhibited by bicalutamide.12

Based upon these observations, Joyce, et al, conducted a pilot study of high-dose bicalutamide (150 mg/day) in 30 patients who failed ADT that included flutamide.13 Fourteen (48%) received flutamide as part of the primary ADT whereas the other 16 received flutamide after PSA progression on monotherapy. Although 70% of patients had received at least one prior non-hormonal therapy prior to study entry, all patients had a rising PSA after flutamide 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 bicalutamide. Six (43%) of the 14 patients receiving flutamide as part of primary ADT were responders, whereas only 1 (6%) of 16 patients receiving flutamide at PSA progression on monotherapy were responders (p = 0.03). There was no correlation between patients having a response to high-dose bicalutamide and those having had a prior antiandrogen response.

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 bicalutamide at this dose is modestly effective for patients with AIPC, particularly for those treated with long-term flutamide.

HIGH-DOSE KETOCONAZOLE (HDK) WITH HYDROCORTISONE (HC)

HDK (trade name Nizoral®) plus hydrocortisone (HC) is a reasonable treatment approach for men with prostate cancer whose PSA has increased on ADT. HDK rapidly lowers serum testosterone to castrate levels by 48 hours by mechanisms that are different than LHRH agonists and antiandrogens (see figure below).

strum2a

HDK and and other drug, aminoglutethimide (AG, trade name Cytadren®), block the production of testosterone produced by the testicles and other androgens produced by the adrenal glands via a number of enzymatic pathways (see figure on next page). Since HDK can reduce cortisol production in approximately 25% of patients, a small percentage of patients develop symptoms consistent with mineralocorticoid deficiency. Patients are usually given HC along with HDK to prevent this potential side effect and also because of the known antitumor effect of HC against AIPC.

Other anti-cancer effects demonstrated with HDK treatment

HDK possesses other anticancer properties independent of its testosterone-lowering effects. In laboratory studies, HDK showed synergistic (more than additive) cell-killing effects when used with the chemotherapy drugs vinblastine (Velban®) and etoposide (VePesid®) in cancer cell cultures.15

Link to Diagram – Hormonal Pathways Involving Adrenal Androgens

HDK acts on cytochrome P-450 dependent 14-demethylation and decreases conversion of lanosterol to cholesterol, blocks 17,20-desmolase (or lyase) resulting in a decrease in serum testosterone, androstenedione, & dehydroepiandrosterone (DHEA). 24-hr urinary free cortisol is reduced 25% but still remains within the range of normal. Recent studies indicate that HDK also blocks 17 alpha hydroxylase.

Velban is an active agent in AIPC, and is used with HDK, doxorubicin (Adriamycin ®) and estramustine (Emcyt®) in the “Logothetis protocol.” HDK also has a direct cytotoxic effect on the prostate cancer cell (see figure below). In 2 human cell lines of AIPC, PC-3 and DU-145, HDK had direct cell killing effects at serum values that were attainable with oral doses used clinically (1.1 to 10.0 mcg/ml).16

strum2c

HDK has additional anticancer effects. It has been proven to block the Multi-Drug Resistance (MDR) gene that is largely responsible for cancer cells developing resistance to many types of chemotherapy drugs. In a 1994 paper by Siegsmund, et al, HDK added to in-vitro cancer cell cultures was effective in overcoming MDR to Velban and Adriamycin.17

Results using HDK + HC in patients with AIPC

Published clinical trials of HDK involved studies in the pre-PSA era. In the current era, PSA is used as a surrogate biomarker of disease response. In the pre-PSA era, Dupont, et al, reported an 88% decrease or disappearance in pain in 17 previously untreated men with metastatic prostate cancer. Two of these patients remained in complete remission with no evidence of disease after 30 months of treatment.18 Muscato, et al, reported results with HDK + HC in 21 patients considered hormone-refractory. Seven (33%) of 21 patients had a greater than 90% fall in PSA, with 6 of these 7 maintaining remissions lasting greater than 12 months (range 14-35+ months).19

In a recent paper, Small, et al reported the results of HDK + HC therapy in men with progressive disease on ADT and after anti-androgen withdrawal. Of 48 evaluable patients, 30 (63%) had a PSA decrease of greater than 50% for at least 8 weeks while 23 of these (48%) had a decrease in PSA of greater than 80% also maintained for at least 8 weeks. For all patients, the median PSA decrease was 79% (range 0-99%). The median duration of response was 3.5 months with 23 of the 48 patients having ongoing responses (range 3.3+ months to 12.8+ months). No difference was seen in response rates despite the presence or absence of an AAWR. The median survival of all patients had not been reached at 6+ months.20

In a recent report, Small, et al, treated 20 consecutive patients with simultaneous antiandrogen withdrawal and HDK + HC. The median PSA at entry was 13 ng/ml (range 1.9 to 1,000 ng/ml). Eleven of 20 patients (55%) met their criteria for response, i.e., a greater than 50% decline from baseline PSA. The median duration of response was 8.5 months (95% confidence interval 7-17 months) and the median overall survival was 19 months.21

Due to its effects on the MDR gene, HDK has been studied in combination with chemotherapy.

Patient guidelines for HDK + HC:

We start HDK at a half-dose of 200 mg 3 times a day for one week, then increase the dose to 400 mg (2 tablets) 3 times a day thereafter. HC should be given at a dose of 20 mg with breakfast and 20 mg with dinner. If symptoms suggest HC excess (ankle swelling or diabetes in poor control) we decrease the dose to 20 mg with breakfast and 10 mg with dinner.

Stomach acid is needed to enhance HDK absorption (bioavailability). We advise patients to take HDK on an empty stomach since food reduces acid. Over-the-counter histamine-2 blockers (Zantac®, Tagamet®, Pepcid®, Axid ®) decrease HDK absorption by 75%. Prescription proton-pump inhibitors such as omeprazole (Prilosec®) and lansoprazole (Prevacid®) reduce stomach acid even more. Antacids and the presciption anti-ulcer agent sucralfate (Carafate®) will also interfere with HDK absorption. Other drugs that have the potential to interfere with HDK absorption by decreasing stomach acid through anticholinergic mechanisms are listed below. Drugs commonly used in prostate cancer patients appear in boldface type.

Artane (trihexyphenidyl) Cystospaz (hyoscyamine) Lomotil (has atropine)
Atrovent (ipratropium) Ditropan (oxybutynin) Pro-banthine (propantheline)
Beelith (has magnesium) Donnatal (has belladonna) Robinul (glycopyrrolate)
Bellergal (has belladonna) Levsin, Levbid, Levsinex (all have hyoscyamine) Antispasmodic tablets (has belladonna)
Bentyl (dicyclomine) Transderm-V (scopolamine) Urised (has hyoscyamine)
Cogentin (benztropine) Librax (has clindinium) Urispas (has hyoscyamine)

If you have a particular medical condition under a doctor’s care that requires you to take any of the above drugs to lower your stomach acid, we recommend taking HDK with Coca-Cola, Pepsi, 1,000 mg Vitamin C, lemonade or orange juice. In a recent study done in AIDS patients receiving acid-reducing drugs, the oral absorption (bioavailability) of ketoconazole was increased by 50% by the concurrent intake of Coca-Cola or Pepsi.22

It is now possible to measure ketoconazole levels in the serum using a new assay method. We recommend monitoring serum drug levels at the onset and periodically on HDK therapy. A level blood between 3 and 5 mcg/ml is considered therapeutic when drawn 4 hours after a dose of HDK.


Side effects of HDK + HC
Nausea

10%
Fatigue

6%
Leg Swelling

6%
Skin rash or changes

4%
Abnormal liver function

4%

Side effects of HDK + HC:

The main side effects of HDK are nausea and loss of appetite in 10% of patients. Concurrent administration of HC may reduce the frequency of this side effect. A number of skin changes including rash, dry, cracked lips and an unusual “sticky skin” syndrome has also been reported in approximately 5% of patients. This can usually respond to topical application of vitamin E. Photophobia (sensitivity to light) is rarely seen in patients taking ketoconazole for fungal infections, but may be more common with HDK. Liver function test (LFT) abnormalities (elevations in SGOT, SGPT and/or alkaline phosphatase) are generally mild usually return to normal without intervention. Patients on HDK must have LTFs checked monthly. Although rare, a rise in serum bilirubin indicates that HDK must be discontinued. Intolerance of nausea, fatigue or abnormal liver function tests is the most common reason patients stop HDK treatment. AG rarely causes these side effects, thus it can be easily substituted for HDK in such patients.

 


Drugs that interact with HDK and should not be taken together:

Interacting drug Possible drug interaction
Loratadine (Claritin ®)

Astemizole (Hismanal ®)

Cisapride (Propulsid ®)

HDK significantly increases blood levels of these drugs that can potentially cause a severly irregular heartbeat. Glipizide (Glucotrol ®)

Glyburide (Diabeta ®, Glynase ®,
Micronase ®)

Metformin (Glucophage ®)

Chlorpropamide (Diabinese ®)

HDK may increase the blood sugar-lowering effects of these drugs, which may result in severe hypoglycemia (low blood sugar).

 


Drugs that may need dose changes if HDK is taken concurrently

Drug with dosage affected Precaution/Dosage adjustment
Warfarin (Coumadin®) Monitor prothrombin time – reduce dose if needed to prevent possible bleeding.
Phenytoin (Dilantin®) Monitor blood levels and toxicity of both drugs – reduce doses if levels become elevated.
Isoniazid (INH, Rifamate®) Both drugs may need to be stopped if liver function tests become abnormal.
Rifampin (Rimactane®, Rifamate®) Monitor ketoconazole blood levels – if levels are below therapeutic range, increase dose.
Triazolam (Halcion®)Midazolam (Versed®) Blood levels of both drugs may become increased and lead to excess sedative effects.
Methylprednisolone (Medrol®) Blood levels are increased, but no adjustment in dosage is needed unless toxicity occurs.
Cyclosporin (Sandimmune®) Monitor blood levels of both drugs and adjust doses if needed.
WARNING:HDK should not be taken with alcohol! Concurrent use of HDK and alcohol-containing beverages may cause an “Antabuse reaction” (skin flushing, rash, swollen legs, nausea, vomiting and headache).

AMINOGLUTETHIMIDE (AG) WITH HYDROCORTISONE (HC)

AG (Cytadren ®) blocks the conversion of cholesterol to pregnenolone, which not only decreases production of adrenal androgens, but also blocks the secretion of cortisol and the mineralocorticoid, aldosterone. AG is also a potent inhibitor of the enzyme aromatase, which converts androstenedione to estrone and testosterone to estradiol. HDK and AG both decrease plasma levels of testosterone, androstenedione and DHEA, whereas AG also reduces plasma levels of aldosterone, estrone and estradiol.

The reduction in serum cortisol levels by AG, and to a lesser extent by HDK, leads to a compensatory increase in pituitary production of adreno-corticotropic hormone (ACTH). ACTH stimulates the adrenal glands to produce more adrenal hormone, which, over time, may eventually override the effectiveness of AG therapy. Oral synthetic glucocorticoid medications, such as hydrocortisone (HC), prednisone or dexamethasone will effectively block this secondary ACTH increase. HC is the agent of choice, because AG increases the metabolic breakdown of prednisone and dexamethasone so that much larger doses of these drugs are required over time.23

Since AG inhibits aldosterone synthesis, patients require mineralocorticoid replacement therapy to prevent a deficiency syndrome manifested by dizziness, weakness, weight loss, low sodium, high potassium and low blood pressure upon standing. The concurrent administration of HC at standard replacement doses (30 mg a day, 20 mg in the morning and 10 mg in the evening) provides an adequate level of mineralocorticoid effect for most patients receiving AG.

The pure mineralocorticoid, fludrocortisone (Fluorinef ®) can be used for certain patients with deficiency symptoms that persist despite HC supplementation. The Fluorinef dosage must be titrated to an effective dose that can range from as little as 0.1 mg twice a week up to 0.1 mg per day.

Results using AG + HC in patients with AIPC

Most clinical trials involving AG + HC were published before PSA came into use and before antiandrogen medications were available. In a trial reported by Drago, et al, 7 (16%) of 43 patients with AIPC had an objective response and 24% had disease stabilization with AG. One responding patient remained in complete remission for more than 4 years.24 In 1985, Murray, et al, reported results using AG in 58 patients with AIPC. Objective responses were noted in 11 (19%) patients and stabilization of disease in 6 others (14%). The mean duration of response in all patients was 10+ months. The mean survival in patients who achieved an objective response was 15 months compared to only 4.7 months for those who did not achieve an objective response.25

Dupont, et al reported results using simultaneous flutamide withdrawal and AG + HC. These authors observed an AAWR in 30 of 40 (75%) patients after flutamide was stopped. One patient achieved a complete response, 3 had partial responses and 26 others had stabilization of their disease. The average duration of PSA response was 14.5 months, ranging from 3.6 to as long as 29.9 months. Patients in this study developed PSA progression after a long period of ADT response (average 46.8 months).26

Sartor, et al, reported results with simultaneous flutamide withdrawal coupled with AG + HC in 29 patients. Using a stricter criteria for response of a > 80% decline from baseline PSA, 14 (48%) of 29 patients responded. The PSA level normalized for 4 or more weeks in 7 (24%) of 29 patients. The median PSA nadir was 73% below the pretreatment baseline and the median time to reach the PSA nadir was 40 days (range 0-265 days). Three of 12 patients with measurable disease achieved an objective response (tumor shrinkage on bone scan, chest x-ray or CT scan). Fifteen (56%) of 27 patients who had symptoms referable to prostate cancer reported subjective improvement lasting 4 or more weeks.

The median duration of response in all 29 patients was 4 months. For responding patients, median response duration was 8 months whereas for non-responding patients, median response duration was only 2 months. Median survival duration had not been reached, but was estimated to be 12+ months at the time of the report.27

Dawson AG + HC + AAW + Suramin vs without AAW.28

Patient guidelines for AG + HC:

We start AG at a dose of 250 mg orally 3 times a day for 3 weeks, then we increase the frequency of dosing to 4 times a day. HC is given in the same manner as with HDK, above. If either HDK or AG is stopped, the HC dosage must be tapered gradually over 2 weeks rather than stopped abruptly so that possible symptoms of adrenal suppression are avoided.

Side-effects of AG + HC:

Most symptoms with AG are transient and improve or disappear over time. A rash that is commonly seen is peculiar in that it usually begins on the 10th day of therapy and subsides within a week without treatment. Occasionally, the rash may be associated with fever. There have been rare reports of thrombocytopenia (a low platelet count), leukopenia (a low white blood cell count) and anemia due to AG, but these side effects usually resolve after AG treatment is stopped. If leukopenia, anemia or thrombocytopenia are severe, they can be treated with growth factors that stimulate bone marrow, e.g., filgrastim (Neupogen ®), erythropoietin (Procrit ®) or oprelvakin (Numega ®).


Side-effects of AG + HC
  • Lethargy (sleepiness) – 41%
  • Skin Rash – 36%

Patients will develop tolerance to lethargy and sleepiness commonly seen with AG. AG was initiatially studied as a sleeping medication, but studies were stopped when its effects on adrenal steroid synthesis were found.

Drugs that may need dose changes if AG is taken concurrently

Drug with dosage affected Precaution/Dosage adjustment
Warfarin (Coumadin®) Monitor prothrombin time – increase dosage if the blood thinning level is inadequate.
Diphenhydramine (Benadryl®) Additive sedative effects that can result in severe coordination difficulties.
Carbamazepine (Tegretol®)Phenobarbital (Luminal®)Mephobarbital (Mebaral®) Drug levels of all drugs may be reduced requiring an increase in drug dosage. Phenobarbital and mephobarbital have sedative effects are increased by AG.
Alcohol, all sleeping pills, sedating antihistamines and tranquilizers AG will add to the sedating side effects of these drugs and can potentially cause serious coordination difficulties.

MEGESTROL – A PROGESTERONE ANALOG

Megestrol acetate (Megace®) appears to have activity in AIPC. Megestrol inhibits the release of LH, blocks androgen receptors and inhibits the enzyme 5alpha-reductase, which converts testosterone into its more active form, dihydrotestosterone. In addition, some investigators have suggested that it may have cytotoxic effects on prostate cancer cells at high doses.

To test this hypothesis, the Cancer and Leukemia Group B (CALGB) conducted a randomized controlled trial comparing standard dose megestrol (160 mg/day) vs high-dose megestrol (640 mg/day). In a 1996 abstract, Dawson, et al presented preliminary results in the first 149 patients entered. Using a response criteria of a > 50% decline from baseline PSA, the overall response rate was 12% and the objective response rate for patients with measurable disease was only 3%. There were no significant differences in the proportion of patients responding or in the duration of survival between patients who received standard dose megestrol vs high-dose megestrol.

In 51 patients, antiandrogen withdrawal was undertaken, and in 14 (31%) patients an AAWR occurred 8 weeks after stopping flutamide. No correlation was found between patients having an AAWR with a response to megestrol although there was a suggestion that patients who had an AAWR had a longer duration of survival (p = 0.08). The authors concluded megestrol at 160 or 640 mg/day had only modest activity in AIPC patients.29

We do not recommend using megestrol to treat AIPC because it can bind to androgen receptors and potentially stimulate prostate cancer growth. The small percentage of patients who responded to megestrol in the above study most likely experienced a paradoxical antagonistic effect upon cancer cell growth due to a mutation in the androgen receptor gene. We have safely used medroxyprogesterone acetate injection (Depo-Provera®) to treat severe, intractible hot flushes in our patients.

CORTICOSTEROID THERAPY IN AIPC

Corticosteroids are a family of semi-synthetic and synthetic compounds that mimic the antiinflammatory effects of cortisol. This is produced naturally by the adrenal grands. 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 effects of the clinical course of patients with AIPC.

Tannock, et al studied the clinical benefit of prednisone given at a dose of 7.5-10 mg per day in 13 patients with AIPC. Results of this study showed objective responses in 5 (38%) patients lasting a median of 12 weeks. The authors attempted to correlate patient response with suppression of the andrenal androgens DHEA-sulfate & 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-sulfate and androstenedione, respectively. The authors concluded that low dose prednisone provided excellent suppression of adrenal androgen levels and results in good palliative benefits for patients with AIPC30 In a subsequent randomized trial by the same principal inveastigator, the response rate to prednisone alone was lower, but still significant at 13.5%. The median duration of response to prednisone alone in this trial was 18 weeks.31

Harvey, et al, studied dexamethasone (Decadron®) at a dose of 10 mg intravenously once a week in 6 patients with advanced-stage prostate cancer that failed at least 2 prior hormone maneuvers and also received chemotherapy. Using a response criteria of a > 50% decline from baseline PSA, 5 (83%) patients responsded and also demonstrated a decrease in pain and an improved performance status. The median duration of survival was 9 months (range of 4-20+ months) with 5 patients still responding at the time of the report.32

Storlie, et al evaluated the effectiveness of oral dexamethasone in 38 patients with disease progression post­orchiectomy. The dose was 0.75 mg twice a day. Responses were seen in 23 (61%) patients evidenced by a greater than 50% PSA decline. Thirteen (34%) patients had a greater than 80% PSA decline. In 2 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 when we exclude these 2 patients. The authors did not mention the duration of response in this abstract.33

Kelly, et al conducted a prospective study in which patients with AIPC were initially treated with hydrocortisone alone and then, on progression were given suramin. Patients treated with suramin need hydrocortisone to replace the loss of adrenal cortisol production caused by this drug. 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.34

In our opinion, all of these studies should have measured DHEA-S and androstenedione levels and baseline and during glucocorticoid treatment. If Tannock et al’s observations in their initial study were correct, 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 prostate cancer cell. Estradiol has been shown to localize irreversibly to the nuclear membrane of the tumor cell within 2 hours of exposure.35 DES, 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.36,37 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 DES were extensively used in the treatment of advanced prostate cancer. In the initial Veterans Administration Cooperative Urologic Research Group (VACURG) studies, DES was found to be as effective as orchiectomy for prostate cancer, but at a dose of 5 mg/day, carried a significant risk of cardiovascular morbidity.38 More recently, single and cooperative group studies have evaluated the effectively of DES at dosages of 3 and 1 mg per day.39-41 Both dosages were found to be as effective as the 5 mg/day dosage with considerably fewer cardiovascular toxicities. Although serum testosterone 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.42 It should be noted that the regression of metastatic disease can occur without maximal suppression of serum testosterone levels.43

In a more recent study, Jazieh et al, reported results using oral DES treatment in 14 patients with progressive AIPC. DES was given at a dose of 1 mg 3 times a day along with routine anticoagulation with warfarin (Coumadin®). In this study, 9 (64%) patients responded with a greater than 75% decline in baseline PSA. PSA levels normalized in 5 (36%) patients, however, 2 of these patients may have had an antiandrogen withdrawal response. In patients with symptomatic disease, 50% showed improvement with DES treatment. The median duration of response was 8 months (range 2-24 months) and the median time to reach a PSA nadir was 3 months (range 1-10 months). There were no cardiovascular or thrombotic (blood clotting) events reported.44

More recently, Smith, et al reported results of a phase II study of DES at a dose of 1 mg/day in 21 patients failing ADT. All patients were withdrawn from antiandrogen therapy and started DES at PSA progression. LHRH agonist therapy was stopped simultaneously. In this study, response, defined as a > 50% decline from baseline PSA, was seen in 9 (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.45

Intravenous estrogens (fosfestrol or stilbestrol disphosphate)

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 prostate cancer cell. In theory, stilbestrol diphosphate 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, DES destroys the cell by inducing apoptosis (programmed cell suicide).46

Selenomethionine75 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 prostate cancer cells was inhibited 20%. At DES levels of 5 mcg/ml, isotope incorporation was inhibited by 69.6%.47 DES blood levels of this magnitude can easily be achieved in the clinical setting. Using high-pressure liquid chromatography, a one gram intravenous injection of stilbestrol diphosphate resulted in a mean plasma DES level of 3.6 mcg/ml 30 minutes after injection.48

Ferro et al conducted a prospective trial of high-dose intravenous stilbestrol diphosphate in 29 patients with symptomatic AIPC metastatic to bone. At baseline, all patients has elevated PSA levels, 24 (83%) had elevated PAP levels and 28 (97%) had elevated alkaline phosphatase levels. Stilbestrol diphosphate was administered as a dose of 1,104 mg intravenously over 5 minutes daily for 7 days. A subjective response, e.g., improvement in bone pain, mobility and/or decreased analgesic requirements, was seen in 22 (76%) patients. Significant decreases in serum PSA were noted in 13 (45%) patients, with PSA reductions ranging from 44-93%. 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.49

Fosfestrol is a European formulation similar to stilphostrol diphosphate known by the names of Honvan, Fosfostilben, Honvol and ST-52. In a study by Droz et al, 16 AIPC patients received fosfestrol, 4 grams per 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 7 (43%) patients. The median duration of survival was longer in responding patients (10 months vs 5 months, respectively). Cardiovascular complications occurred in 6% of patients.50

A slower rate of intravenous administration appears to reduce the risk for perineal discomfort, nausea and vomiting. Intravenous stilphosterol disphosphate has not been reported to cause cardiovascular or thrombotic complications when the duration of treatment is limited 7 days.51 Therefore, anticoagulation does not appear to be necessary in this setting.

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.

SUMMARY AND A VIEW TOWARDS THE FUTURE:

“Hormone refractory” prostate cancer clearly does not accurately describe the true nature of this disease when it progresses on primary ADT. Antiandrogen withdrawal is the first step to identify patients who may have had disease progression due to an androgen receptor gene mutation. Although not uniformly reported, an AAWR appears to identify a subset of patients who may respond to a number of secondary hormonal maneuvers.

It is also clear that the anticancer effects of some of the “secondary hormonal treatments” are not simply due to a hormonal effect. The direct cytotoxic effects observed with HDK and oral and high-dose intravenous DES support this contention. The fact that these agents have different types of toxicities than chemotherapeutic agents make them attractive agents to use in combination with active chemotherapy agents for patients with AIPC.

REFERENCES:

  1. Scher HI, Kelly WK: Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol 11:1566-72, 1993.
  2. Figg WD, Sartor O, Cooper MR, et al: Prostate specific antigen decline following discontinuation of flutamide in patients with stage D2 prostate cancer. Am J Med 98:412-14, 1995.
  3. Small EJ and Srinivas S: The antiandrogen withdrawal syndrome: Experience in a large cohort of unselected advanced prostate cancer patients. Cancer 76:1428-34, 1995.
  4. Small EJ and Carroll PR: Prostate-specific antigen decline after Casodex withdrawal: Evidence for an antiandrogen withdrawal syndrome. Urology 43:408-10, 1994.
  5. Small EJ, Schelhammer P, Venner P, et al: A double-blind assessment of antiandrogen withdrawal from Casodex (C) or Eulexin (E) therapy while continuing luteinizing hormone releasing hormone analogue (LHRH-A) therapy for patients (Pts) with stage D2 prostate cancer (PCA). Proc Am Soc Clin Oncol 15:255, 1996 (abstract).
  6. Dawson NA and McLeod DG: Dramatic PSA decline in response to discontinuation of megestrol acetate in advanced prostate cancer; Expansion of the antiandrogen withdrawal syndrome. J Urol 153:1956-7, 1995.
  7. Bissada NK and Kaczmarek AT: Complete remission of hormone refractory adenocarcinoma of the prostate in response to withdrawal of diethylstilbestrol. J Urol 153:1944-5, 1995.
  8. Veldscholte J, Ris-Stalpers C, Kuiper GGJM, et al: A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 173:534-40, 1990.
  9. Culig Z, Hobish A, Cronauer M, et al: Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocr 7:1541, 1993.
  10. Taplin M-E, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, et al: Mutation of the androgen receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 332:1393-8, 1995.
  11. Fenton M-A, Shuster TD, Feris A, Taplin M-E, Kolvenbag G, Bubley GJ and Balk SP: Anti-androgen activation of mutant androgen receptors from androgen-independent prostate cancer. Clin Cancer Res 3:1383, 1997.
  12. Olea N, Sakabe K, Soto AM and Sonnenschien C: The proliferative effect of “anti-androgens” on the androgen-sensitive human prostate tumor cell line LNCaP. Endocrinology 126:1457, 1990.
  13. Joyce R, Fenton M-E, Rode P, Constantine M, Gaynes L, et al: High dose bicalutamide for androgen independent prostate cancer: Effect of prior hormonal therapy. J Urol 159:149-53, 1998.
  14. Trachenberg J, et al. J Urol 130:152-3, 1983.
  15. Eichenberger T, Trachenberg J, Chronis P, et al: Synergistic effect of ketoconazole and anti-neoplastic agents in hormone-independent prostatic cancer cells. Clin Invest Med 12:363-6, 1989.
  16. Eichenberger T, Trachenberg J, Toor P, et al: Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells. J Urol 141:190-1,1989.
  17. Siegsmund MJ, Cardarelli C, Aksentijevich I, et al, Ketoconazole effectively reverses multi-drug resistance in highly resistant KB cells. J Urol 151:485-491, 1994.
  18. Dupont A, et al: Long-term experience with high dose ketoconazole therapy in patients with stage D2 prostatic carcinoma. J Urol 137:902-4,1987.
  19. Muscato JJ, Ahmann TA, Johnson KM, et al: Optimal dosing of ketoconazole (Keto) and hydrocortisone (HC) leads to long responses in hormone refractory prostate cancer. Proc Am Soc Clin Oncol 13:229, 1994 (abstract).
  20. Small EJ, Baron AD, Fippin L and Apodaca Dl: Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol 157:1204-7, 1997.
  21. Small EJ, Baron A and Bok R: Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in patients with advanced “prostate carcinoma. Cancer 80:1755-9, 1997.
  22. Coke or Pepsi and ketoconazole article in AIDS patients.
  23. Santen RJ, et al: J Clin Endocrinol Metab 45:469-79, 1977.
  24. Drago J, et al, Cancer 53:1447­50, 1984.
  25. Murray R, et al: Eur J Cancer Clin Oncol 21:453-58, 1985.
  26. Dupont A, Gomez J-L, Cusan L, Koutsilieris M and Labrie F: Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy. J Urol 150: 908-13, 1993.
  27. Sartor O, Cooper M, Weinberger M, et al: Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of “hormone-refractory” prostate cancer. J Natl Cancer Inst 86:222-7, 1994.
  28. Dawson AG + HC + AAW + Suramin article.
  29. Dawson NA, Small EJ, Conaway D, et al: Megestrol acetate (MA) in men with hormone-refractory prostate cancer (HRPC): Prostate sepcific antigen (PSA) response and anti-androgen withdrawal (AAWD): Cancer and Leukemia Group B (CALGB) 9181. Proc Am Soc Clin Oncol 15:241, 1996 (abstract).
  30. Tannock I, Gosbodarowicz M, Meakin W, et al: Treatment of metastatic prostate cancer with low dose prednisone: Evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 7:590-7, 1989.
  31. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian Randomized Trial with palliative end points. J Clin Oncol 14:1756-64, 1996.
  32. Harvey, et al: Proc Am Soc Clin Oncol 13:255, 1994 (abstract).
  33. Storlie JA, et al: Proc Am Soc Clin Oncol 13: 235, 1994 (abstract).
  34. Kelly WK, Scher H, Bajorin D, et al: The contribution of hydrocortisone to the observed response proportions of suramin. Proc Am Soc Clin Oncol 13:A710, 1994 (abstract).
  35. Sinha AA, Blackard CE, Doe RP, et al: The in vitro localization of 3H-estradiol in human prostatic carcinoma. Cancer 31:682-8, 1973.
  36. Davies P, Griffiths K: Hormonal effects in vitro on ribonucleic acid polymerase in nuclei isolated from human prostatic tissue. J Endocrinol 59:367-368, 1973.
  37. Lasnitzki I: Metabolism and action of steroid hormones on human benign prostatic hyperplasia and prostatic carcinoma grown in organ culture. J Steroid Biochem 11:625-630, 1979.
  38. Byer DP: The Veterans’ Administrative Cooperative Urological Research Group’s studies of cancer of the prostate. Cancer 32:1126-30, 1973.
  39. Blackard CE: The Veterans’ Administrative Cooperative Urological Research Group studies of carcinoma of the prostate: a review. Cancer Chemother Rep 59(Part 1):225-7, 1975.
  40. Pavone-Macaluso M, de Voogt HJ, Viggiano G, et al: Comparison of diethylstilbestrol, cyproterone acetate, and medroxyprogesterone acetate in the treatment of advanced prostate cancer: final analysis of a randomizaed phase III trial of the European Organization for Research on the Treatment of Cancer Urological group. J urol 136:624-30, 1986.
  41. Emtage LA, George J, Boughton BJ, et al: Haemostatic changes during hormone manipulation in advanced prostate cancer: a comparison of DES 3mg/day and Goserelin 3.6 mg/month. Eur J Cancer 26:315-9, 1990.
  42. Byer DP and Corle DK: Hormone therapy for prostate cancer: results of the Veterans Administrative Cooperative Urological Research Group studies. NCI Monogr 7:165-70, 1988.
  43. Scott WW, Menon M and Walsh PC: Hormonal therapy of prostatic cancer. Cancer 47(7 suppl):1929-36, 1980.
  44. Jazieh AR, et al: Proc Am Assoc Cancer Res 35:233, 1994 (abstract).
  45. Smith DC, Redman BG, Flaherty LE, Li L, Strawderman M and Pienta KJ: A Phase II trial of oral diethylstilbestrol as a second-line hormonal agent in advanced prostate cancer. Urology 52:257-60, 1998.
  46. Colapinto V and Aberhart C: Clinical trial of massive stilboestrol diphosphate therapy in advanced carcinoma of the prostate. Br J Urol 33:171, 1961.
  47. Ferro MA, Heinemann D, Smith PJB, et al: The effect of stilboestrol and testosterone on the incorporation of selenomethionine75 by prostatic carcinoma cells. Br J Urol 62:166-72, 1988.
  48. Abramson FP and Miller HC: Bioavailability, distribution and pharmokinetics of diethylstilbestrol. J Urol 128:1336-9, 1982.
  49. Ferro MA, Gillatt D, Symes MO, et al: High dose intravenous estrogen therapy in advanced prostatic carcinoma: Use of prostate specific antigen as a serum marker. Urology 24:134-8, 1989.
  50. Droz, et al, Cancer 71:1123-1130, 1993
  51. Ferro MA: Use of intravenous stilbestrol diphosphate in patients with prostatic carcinoma refractory to conventional hormonal manipulation. Urol Clin North Am 18:139-42, 1991.