Hormone Therapy in Prostate Cancer

Stephen B. Strum M.D., Mark C. Scholz M.D., Glenn Tisman M.D.
March 20, 1997

Hormonal Pathways in Prostate Cancer

An understanding of the hormonal pathways involved in prostate cancer (PC) is important in the management of this disease. Knowledge of the biochemical steps that lead to testosterone and dihydrotestosterone synthesis may allow for therapeutic maneuvers that can result in more complete androgen blockade. The potential importance of progestins and their metabolism to androstenedione and from there to testosterone and/or DHT is also more evident if one becomes familiar with these hormonal pathways(diagram 1)

The hypothalamic-pituitary axis and its relationship to testicular and adrenal androgens is helpful in understanding sites of action of pharmacologic agents and their feedback loops(diagram 2). The testes and the adrenals are target tissues that produce androgens in response to hormonal stimulation arising from the control center in the hypothalamic-pituitary axis. The testicular androgens interact with the prostate cell directly and also via further enzymatic conversion that takes place within the prostate cell. The adrenal androgens are metabolized to testosterone within the prostate cell. The importance of the intra-prostatic synthesis of these androgens leads us to a more comprehensive appreciation of the role of adrenal androgens in the biology of the prostate cell.

The three pages that follow illustrate the above in diagram or table format. Diagrams 1, and 2 are graphic views of these pathways and Table 1 shows the hormonal effect of specific treatments, the site of hormone action, and reflex changes as a result of the hormonal effect.

Diagram 1. Metabolic Pathways of Hormones Involved in Prostate Cancer

Diagram 2. The Prostate Cell in Relationship to the Hypothalamic - Pituitary Axis

Table 1: Androgen deprivation therapies: site(s) of activity, hormonal effects and reflex increases

Hormone Therapy (HT) in the Treatment of D-1 and D-2 PC

Should androgen deprivation (AD) be reserved for advanced symptomatic disease or should AD be initiated earlier in the course of illness? As discussed above, PC is largely dependent on male hormones(androgens) for its growth. AD is a fundamental part of the treatment of PC. Most tumor populations of PC consistent of a large compartment of hormone-dependent cells.

Tumor burden, genetic mutation and clinical crises

There is literature that relates an increasing frequency of genetic mutation to an increasing amount of tumor. Therefore tumor burden or volume of tumor seems to be associated with changes in the genetic makeup of PC. This may be a part of the basis for the occurrence of androgen-independence or the so-called hormone refractory state. The development of androgen-independence does not seem to occur when patients with smaller tumor burdens are treated. Additional medical literature cites an increasing tendency toward aneuploidy (abnormal DNA) with time. All of these findings would support the concept of earlier treatment of PC rather than waiting until the disease is bulky and able to produce clinical symptoms. From a clinical standpoint of maintaining quality of life, treatment of PC should be an elective process & not evoked by a medical crisis such as bone pain, cord compression, or ureteral obstruction.

Importance of tumor burden on survival

Data from at least two studies confirm our concerns that PC should be treated earlier in the course of illness, not later. Labrie et al reported on the effect of tumor burden on efficacy of CHB (Lupron + Flutamide) in D-2 patients. There study showed a 60% survival at 8 years with CHB when the pretreatment bone scan showed 1- 5 bone lesions vs only a 20% survival at 8 years if more than 5 lesions on bone scan were found. If CHB was used when there were 1- 5 lesions there was a 4.4 year survival advantage compared to patients with 6-10 lesions versus a 6 year survival advantage compared to 11-40 lesions. ¹

The Intergroup #0036 data showed the effect of tumor burden on the efficacy of CHB vs monotherapy (Lupron or orchiectomy) in D-2 patients. The median survival was almost 20 months greater with CHB over that with monotherapy if minimal disease was seen on scan and the ECOG performance status was 0-2. The definitions of minimal and maximal disease and the ECOG scale is shown below. The actual median survivals were 61 months with combination therapy vs 42 months with monotherapy. The median progression-free survival was 48 months on the combination arm vs 19 months on monotherapy arm with a median follow-up period of greater than 5 years^2,3

Minimal disease = axial skeleton (spine) and/or pelvic bones or nodes
Maximal disease = above + appendicular skeleton (ribs, skull, long bones) or visceral disease (lungs, liver)

ECOG Performance Status
0= asymptomatic
1= restricted in strenuous activity but can do light work
2= up and about more than 50% of the time; unable to do work activities
3= bedridden more than half the time
4= completely disabled, totally confined to bed

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Importance of symptoms on survival Labrie et al presented survival data in relation to clinical symptoms of disease. Median survivals in D-2 patients were 5.47 years in the group having minimal symptoms compared to 2.71 years in those with moderate symptoms and 2.1 years in patients with severe symptoms.¹ The definitions for different levels of symptoms is shown below:

General symptoms: anorexia, weight loss, nausea, fatigue, neurological signs, or pain

Minimal symptoms: The absence of general symptoms + an ECOG performance status of 0 - 1.

Moderate symptoms: one general symptom of moderate severity and/or pain of moderate intensity and an ECOG status of between 0-2.

Severe symptoms: 1 general symptom of severe or very severe intensity, plus pain and an ECOG status of 1-3.

Results of HT on Survival in patients with D2 and D1 disease

Comparisons of survival in patients with D1 and D2 disease treated by HT are difficult to evaluate due to different patient populations and different HT regimens. A sense of survival data reported in various studies is shown in Table 2 below.

Table 2. HT in D2 and D1 Prostate Cancer

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Stage	# Pts	Rx	Median Survival (years)
			3	5	8	10
Labrie	Lupron + flutamide vs number of bone lesions on median survival
D2 11-40	50	CHB2	45	18	10
D2 6-10	45	CHB2	59	30	17
D2 1-5	105	CHB2	82	66	58
Zagars4	Effect of early orchiectomy on cause specific survival
	D1	111	O	93	85	57
Zincke5	Effect of early orchiectomy on cause specific survival
D1	294	O + RP	91	89	77	77
	86	RP	91	78	70	50
Zincke	Effect of ploidy status on cause specific survival
D1	69	D	96	87	83	72
	107	non-D	95	78	62	50
Zincke	Effect of EET and ploidy status on disease-free survival
D1	50	O+RP-D	100	100	100	100	100
	34	O+RP-non-D	85	68	62	62	0
	19	RP-D	90	70	62	42	0
	73	RP-non-D	62	18	10	10	no data

There are no long-term published studies on use of CHB in clinically localized PC. Most of the studies using CHB in earlier staged PC involve neoadjuvant studies. Some studies use CHB in early PC as part of an IHB (Intermittent hormone blockade) approach. Long term follow-up is not available in either of these two treatment groups.

Prevention of clinical and biochemical flare

What is flare?
We know that when an LHRH agonist is first started, it paradoxically causes a rise in the pituitary hormone LH. The LH rise stimulates the testicles to make testosterone during the first 5-12 days after initiation of the LHRH agonist. This increase in testosterone stimulates prostate cancer cell growth and is termed flare.

Why is flare prevention important?
In patients with advanced disease with subclinical spinal cord compression, flare can precipitate full cord compression and paralysis. If there is PC growing close to a nerve root then flare could result in pain in the distribution of that nerve. In patients with PC involving lymph nodes close to the ureters, flare could increase nodal disease and cause early compression of the ureter(s). Obstruction of both ureters could lead to kidney failure. Increasing disease in bony sites often leads to bone pain during times of flare.

What is clinical flare vs biochemical flare?
When this increase in tumor burden causes signs of bone pain, or compression of a nerve root or spinal cord compression, or blockage of ureter(s) this is called clinical flare. If the increase in tumor burden does not result in symptoms but does result in an increase in PSA alone, this is caused biochemical flare. We would like to avoid any stimulation of tumor cell growth whether or not it is associated with clinical symptoms. The purpose of Flutamide, Casodex, Nilutamide or any anti-androgen prior to Lupron or Zoladex should be to block all flare reactions. Other agents like Nizoral that turn off testosterone production from the testes or DES or Cyproterone acetate that decrease LH also have been used to prevent flare.

Can we prevent flare?
If we saturate the androgen receptors with Casodex or Flutamide we can prevent both clinical and biochemical flare. What we propose is to study not only LH and testosterone levels after starting Lupron but also to measure PSA levels. We propose that patients first beginning hormone blockade therapy use Casodex or Flutamide for one week before starting Lupron or Zoladex and allow us to draw blood for PSA, Testosterone and LH at least at baseline and for the first 7 days after Lupron or Zoladex is given. If there is no rise in PSA then there is no biochemical flare despite the elevation of LH and Testosterone that is initially seen after starting Lupron or Zoladex. If flare prevention is complete, the use of an anti-androgen prior to LHRH agonist therapy should deter any biological effect of increased testosterone until the binding of the LHRH agonist to the LHRH receptor results in decreased LH production.

What if initial anti-androgen therapy does not block flare?
If there is block in PSA production by pretreatment with anti-androgens prior to use of LHRH agonists, then biochemical flare can be eliminated. If this is not possible, then the use of agents that decrease LHRH such as DES could be considered for flare prevention or the use of agents to decrease testosterone production such as Nizoral could be considered. The combined use of either agent with an anti-androgen prior to the use of LHRH agonist therapy would have to be studied to determine the optimal dosing for biochemical flare prevention. The possible use of combined anti-androgen and 5 alpha reductase inhibitor prior to use of an LHRH agonist would also be a consideration since this combination would block DHT production and also prevent Testosterone and remaining DHT from binding to the androgen receptor. No one has studied these approaches in preventing flare.

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Hormone Therapy in Prostate Cancer

Part 2

Neoadjuvant CHB In recent years numerous television shows have depicted our judicial system. All of us are now familiar with the principle of the Miranda.......... You have the right to remain silent, you have the right to an attorney..... Conceptually, the Miranda is frequently applied in medical practice but perhaps not enough. It would go something like this:

 

You have the right to know your diagnosis, ---

You have the right to understand principles of evaluation and treatment, ---

You have the right to be familiar with the pros and cons of available treatment options.

Too often patients are not read their medical Miranda (MM). We believe that patients with prostate cancer (PC) should have their MM. This MMPC or medical Miranda for prostate cancer patients should, at the very least, communicate the fundamental concepts involved in the evaluation and treatment of PC. We believe that your MMPC should involve your right to understand the following:

The concept of organ-confined disease
Is the PC likely to be confined to the prostate or is there a high risk that it is not? We know that systemic disease cannot be cured with local therapies such as: radical prostatectomy (RP), external beam radiation (EBRT), brachytherapy, or cryosurgery. Patients are entitled to know what group they belong to in regards to risk for systemic disease. Are you in a high, middle or low risk group? Using three pieces of information, the baseline PSA, Gleason’s score and clinical stage, we can relay to the patient their likelihood of having organ-confined disease, capsular penetration, seminal vesicle and lymph node involvement.

We have termed these tables, The Partin Tables, from the work of Alan Partin MD of the Johns Hopkins Medical Center.⁶ We consider the Partin Tables to be the major prognostic paradigm for the 1990’s.

Perhaps the addition of RT-PCR or Complexed PSA may enhance the value of these tables or surpass them; this should be evaluated. For now, we consider a discussion of the findings of the Partin Tables an absolute must in the physician’s initial or early discussion with the patient. In addition, in these days of concern regarding the cost of medical care, the Partin Tables will save millions of dollars in needless expense that involves inappropriate use of local therapy in the setting of overwhelming risk of systemic disease. Moreover the Tables are also able to indicate negligible risk for lymph node disease which might spare the patient the need for lymph node sampling and/or perhaps the need for pelvic CT or MRI. These studies would have a minimal chance of detecting such low-risk disease. Similarly, other reports have been published relating to risk-benefit and cost-savings in PC and relate to lymph node⁷ and bone involvement⁸. We have currently reviewed the work of other investigators that have employed this concept of combined modality staging as used originally by Partin. We have assimilated these reports into software programs that predict the likelihood of clinical and pathologic outcomes. These are reviewed separately on our homepage in a paper called: Predictive and Prognostic Information in the Counseling of Patients Newly Diagnosed with Prostate Cancer. These publications include the work of Narayan, Bluestein, Lerner, Kleer, Pisansky and D’Amico and their colleagues.

The concept of determination of extent of disease or stage
This is intimately related to the first item noted above of the MMPC. How has the diagnosis of PC been evaluated? Has there been a comprehensive history and physical examination and basic laboratory tests that may have implications for my ability to receive treatment? Have the determinations of Gleason’s score, clinical stage and PSA been made? Do I need a bone scan, endorectal MRI, pelvic MRI or pelvic CT? Is a determination of RT-PCR status for PSA relevant to treatment decisions in my case? We believe these are reasonable questions to ask your evaluating physician with the expectation of answers.

The concept of neoadjuvant hormone blockade (NHB)
The use of upfront combination hormone blockade (CHB) with an anti-androgen (such as Casodex, Flutamide or Nilutamide) in combination with an LHRH agonist (such as Lupron or Zoladex), has been shown to decrease the frequency of positive surgical margins at the time of RP. This has been reported in at least 5 published studies, 4 of them randomized. Patients proceeding directly to RP without NHB have had approximately a 39% chance of positive surgical margins while those receiving NHB with CHB have had an average of ~ 13% positive surgical margins.

Study Group	% Surgical margins without NHB (# of patients)	% Surgical margins with NHB (# of patients) with 3 mos CHB
Labrie et al.9 1993	38.5% (65)	13% (77)
Fair et al.10 1993	33% (72)	10% (69)
Solomon et al.11 1993	35.3% (119)	11.5% (156)
Fair et al.12 1995 update	36% (92)	11% (92)
Gleave et al.13 1995	Not randomized	5% (36)-- 8 mos CHB
Soloway et al.14 1995	47% (144)	17% (137)
Totals	39.2% (420)excluding Fair’s 1st group	13.5% (462)excluding Gleave

Thus, in 4 randomized studies from different institutions, the percentage of pathologically positive surgical margins (PPSM) in patients undergoing RP without NHB has been essentially identical. The benefit of 3 months of NHB with a reduction to approximately 13.5% from 39% of PPSM in all 4 studies attests to the validity of these findings. The reduction to 5% in one non-randomized study raises the issue of what is the optimal treatment time with CHB in a neoadjuvant setting.¹³

The use of the Partin Tables may also allow us to possibly bypass NHB in patients with favorable Gleason scores(2-4), low PSA readings(0-4) and clinical stages T1a to T2a. Predictions of organ-confined in such a setting is 85 to 100%. However, the prediction for capsular penetration of 22% in the T1c patients in the above group is still worrisome and would warrant a clinical trial to evaluate the need for NHB. The Partin Tables, if reviewed routinely for each patient being considered for local therapy with any current modality, would point out the risk for capsular penetration, seminal vesicle and lymph node involvement thus highlighting the need for NHB.

The long-term effects on survival with NHB are not available. The time in follow-up of patients receiving NHB has been too short for this determination. In Fair’s study, the NHB subgroup with pathologically organ-confined disease (no surgical margin +, seminal vesicle + or node + patients) have shown the identical biochemical PSA relapse rate as those patients having RP only with pathologically organ-confined disease.¹² Therefore 3 months of upfront CHB before RP appears to be having a biological effect on relapse. It appears to be not just masking disease as some opponents to CHB and NHB claim. In fact, in Walsh’s book The Prostate neoadjuvant therapy is criticized with the statement: hormone therapy is not a vacuum cleaner-it can’t suck the cancer cells back into the prostate once they’ve escaped.¹⁵ If this really were the case then no neoadjuvant therapy for cancer should work. The data on converting non-resectable lung cancer to resectable with neoadjuvant chemotherapy or significantly improving survival with neoadjuvant therapy for head and neck cancer, breast cancer or soft-tissue sarcoma testifies to the validity of the concept of neoadjuvant therapy, be it hormonal or non-hormonal.

The median follow-up time in the Fair et al study is 24 months. Further follow-up over the next 5 years will be critical in the assessment of the value of NHB on survival. However, since NHB does increase the number of men who are found to have surgical margin negative disease, then this increasing benefit should in and of itself justify the use of NHB. This latter observation seems to have been largely ignored by many critics of NHB.

Let's look at 3 populations of "virtual" PC patients each comprised of 100 patients eventually going to RP. The first 100 receive no CHB and based on the literature 39 men will have positive margins and 61 will have negative margins. Those 61 men will have no biochemical evidence of progression at a rate of, let's say, 80% at 4 years (this is purely for discussion's sake but in truth depends on the preoperative PSA, Gleason’s score and ploidy status 16). Therefore 49 men (80% of 61) will be doing great at 4 years after RP. We won't discuss the margin + men. Their prognosis is worse.

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The second group of 100 men will get 3 months of CHB prior to RP. Based on the literature from 4 different studies 13 men will have positive margins and 87 will have negative margins. Of these 87, 80% or 69.6 will be doing great after 4 years. They won't be doing any better than the men without CHB and negative margins, but instead of 49 of them there are 21 more men in this category of negative margins. The 13 with positive margins who received CHB will be doing worse, per the remarks of Dr. Fair, then those with positive margins and no CHB. I have no idea whether the degree of worseness in the 17 men (5 more than control group of 12) outweighs the benefit of the ~ 70 (21 more men than the control group) in the margin negative group who do better with CHB. As far as absolute numbers however, almost 16 men are now doing better thanks to only 3 months of CHB prior to RP.

The 3rd group of 100 men receive 8 months of CHB prior to RP. 95 have negative margins at RP with only 5 with + margins at RP. 80% of those 95 men or 76 are doing well at 4 years compared to the 49 without CHB having RP. That indicates benefit to an additional 27 men. Only 5 have positive margins and they possibly do worse than the 39 men without CHB who have positive margins. This seems to me, if all above is confirmed and stated accurately, of showing potential major benefit to neoadjuvant CHB.

Findings in 3 groups of 100 men treated with and without CHB before RP

Treatment Group	Margins +	Margins -	80% BFFP	20% BP	Net Difference BFFP- BP
No CHB	39	61	48.8	12.2
3 m CHB	13	87	69.6 (+20.8)	17.4 (-5.2)	+15.6
8 m CHB	5	95	76 (+27.2)	19 (-6.8)	+20.4

BFFP = biologic freedom from relapse

BP = biologic progression

CHB = combination hormone blockade

Margin findings for the no CHB arm are based on multiple randomized studies of NHB prior to RP with the no treatment group having about an average of 61% with negative margins.

The 8 month data for NHB is based on non-randomized data from Vancouver group. The 80% BFFR (biochemical freedom from PSA relapse) is a hypothetical prediction applied to all groups to show effect on improving outcome in regards to absolute numbers of men. The 80% BFFR at 4 years was chosen arbitrarily as noted in the text above. For example, in the group receiving 3 months of CHB prior to RP there would be 87 men with negative margins and of these 80% or 69.6 are hypothetically going to remain free from biochemical progression (no PSA progression). This 69.6 is 20.8 men greater than that seen in the control group with 48.8 men (80% of 61) biochemically free from relapse. It is 5.2 men worse than that of the control group as well since 20% of this larger pool of men are predicted to relapse. (The 20% BR (biochemical relapse) relates to those men who would show failure at 4 years.) The numbers in parentheses for BFFR and BR reflect net change compared to the "no CHB" group. The net difference column shows effect of NHB on the group insofar as improving the hypothetical outcome in men with 3 months of CHB and 8 months of CHB by subtracting the number who will demonstrate BR at 4 years from the number who will show BFFR at 4 years.

I am puzzled by why anyone would be opposed to neoadjuvant therapy that kills tumor cells, decreases chance of margin positivity, probably decreases ability to disseminate tumor as a result of surgery and definitely has been shown to downstage the disease.

The reasons cited NOT to use neoadjuvant hormone blockade have been that it makes surgery and separation of gland more difficult due to fibrous tissue buildup. Also , while shrinkage may occur the data show that "time to PSA relapse" is the same with and without CHT(CHB). The first statement above seems related to the experience of the urologist performing radical prostatectomies in patients who have received CHB. Fibrosis around the capsule of the prostate and seminal vesicles may make the RP more technically difficult in some patients. Complication rates were however higher in control patients not receiving CHB. There appears to be no question that margin positivity is much less with CHB. The survival data is way too early to discern differences. The PSA relapse data is about the same. My understanding of that data is that those patients who have not received CHB and who have negative margins as well as those patients who did receive CHB and who have negative margins are doing the same in regards to PSA relapse. In addition, those patients who received CHB and who have positive margins are doing worse than those patients who had no CHB with positive margins.

It would seem to me that if those patients getting CHB and having negative margins are showing the same PSA relapse rate as those with no CHB and negative margins then CHB is doing something valuable.

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The understanding of the pros and cons of different local and systemic therapies
Has your MD explained the pros and cons of treatment based on statistics from his practice or is he quoting the expertise of a physician(s) at a major medical center or another community practice? Too often we hear about physicians telling patients that incontinence after RP is only 1%, implying that that is their statistic, when in reality they have 40-50% incontinence rates. Make sure that your doctor is relating his experience, not that of others. Ask for the names and telephone numbers of the last 5 patients who had RP's and speak with those patients.

Have the pros and cons of various treatment options been explained to you and do you have a copy of these in writing? Have you requested a copy of your consultation(s)- a consultation that either you and/or your insurance company have paid for? Our belief is that patients are to be the primary recipients of consultation reports; it is the patient's mind and body that are being affected. In our experience we have found the consultation report to be a wonderful teaching tool that significantly elevates the patient's understanding of his illness and raises it to a level closer to that of the doctor. The patient and doctor become a team working towards the best possible outcome for the patient.

The MMPC is a concept that is of key importance to your welfare. You have the right to be informed of matters that relate to your health and welfare. You have the right to know.

CHB 2 vs CHB 3 vs 4 drugs vs 5 drugs

Additional agents that may have value include Bromocriptine, Serotonin uptake inhibitors, and Proscar.

The rationale for Bromocriptine is to inhibit prolactin. Prolactin interacts at the receptor level on the PC cell. Prolactin increases cell sensitivity to androgens by enhancing androgen receptors. Bromocriptine stimulates dopamine which antagonizes Prolactin.

A study by Rana¹⁷ et. al. examined the use of Bromocriptine + orchiectomy + Hydrocortisone (HC) (Arm 3) vs orchiectomy + flutamide (Arm 2) vs orchiectomy alone (Arm 1). There were 10 patients in each arm of the study. Serum testosterone was reduced by more than 90% in all arms. There was an 84% reduction in androstenedione in Arm 3 and a 76% reduction in serum Prolactin in Arm 3 as well as a maximal reduction in prostate volume in Arm 3. The authors reported a better clinical outcome with 40% of patients showing disease progression in Arm 3 vs 60% in Arm 1 at 3 years. We have had no patient that could tolerate bromocriptine in terms of side-effects of nausea and vomiting and/or hypotension. However, we did not routinely use hydrocortisone in conjunction with bromocriptine in these patients; this should be evaluated.

The use of serotonin uptake inhibitors¹⁸ are based on culture studies showing that serotonin receptors are found on the PC cell and on in vitro studies showing decrease in PC growth with high doses of serotonin uptake inhibitors. Serotonin inhibition in the central nervous system may result in reflex increase in dopamine which is the basic mechanism of bromocriptine activity.

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Proscar in the treatment of PC

There are no studies that compare LHRH + anti-androgens(AA) ± 5AR inhibitors such as Proscar re: progression-free survival or cause -specific survival. Proscar (the generic is finasteride) is an FDA-approved medication used for the treatment of benign growth or hyperplasia of the prostate. It is a well-tolerated, nontoxic medication. Proscar blocks the enzyme 5-alpha reductase which converts testosterone (T) into the 4x more potent form, dihydrotestosterone (DHT). In the adult DHT is the major growth hormone of the prostate cell. The prostate gland needs the ongoing presence of DHT and testosterone to exist and function. When the prostate experiences a decline in DHT it begins to shrink.

Prostate cancer, which is derived from the same cells that make up the prostate gland also needs testosterone and DHT to grow and flourish. Testosterone and DHT receptors are found in prostate cancer cells. Medications used to treat prostate cancer such as Lupron, Zoladex, Flutamide, Casodex, Nilutamide, Cyproterone, and others express their anti-cancer activity via some manner of testosterone-blocking. Since Proscar is an agent that can limit the formation of testosterone in its most potent form, dihydrotestosterone, it is a likely candidate for anti-cancer activity.

Most studies of Proscar in prostate cancer have occurred in very advanced disease at a time when other cancer agents have already failed. Results of those studies have demonstrated minimal benefit from Proscar. More recently an abstract has been published using Proscar as the first and only treatment in men who develop rising PSA levels after having undergone radical prostatectomy. Such a situation is equivalent to progressive cancer. These were men who had undergone radical prostatectomy and who had postoperative rises of PSA to levels between 1 and 10. This range of PSA would be consistent with a relatively low volume of disease. The study evaluated two groups, one of which received Proscar and the other which received placebo. Comparisons in the PSA levels between the two groups were made after 12 and 24 months. PSA levels in the Proscar treated group dropped and took an average of one year to climb back up to the original starting level for that particular patient. The placebo group, however, had a steady rise in PSA levels. Interestingly the patients who initiated treatment with Proscar at a time when their PSA level was less than one took 24 months before the PSA level returned to its starting value.

An additional study by Francisco Civantos and Mark S. Soloway from the University of Miami evaluated the effects of finasteride on the pathologic findings in patients with prostate carcinoma. Five men who had undergone radical prostatectomy after having taken finasteride from three months to two years prior to the diagnosis of prostate cancer were evaluated. The radical prostatectomy specimens from these 5 men were compared to 60 radical prostatectomy specimens controlled by age and clinical stage without hormonal therapy and 113 in which the patients received leuprolide +/- flutamide. Apoptosis of tumor cells, vacuolization, small tumor glands separated by stroma, empty or mucin filled spaces and an inflammatory response were present in the finasteride treated carcinomas but were less prominent than with leuprolide. Atrophy of non-neoplastic glands, basal cell prominence and transitional metaplasia allowed recognition of androgen deprivation in the non-neoplastic prostate but unlike leuprolide, the finasteride treated cases had unaffected hyperplastic glands. PIN was detected in all five finasteride treated cases. Androgen deprivation effect was marked in Gleason grade 2 or 3 tumor areas but was minimal in grade 4 and absent in grade 5 tumor. The authors concluded that finasteride's general effect on carcinoma is similar to that seen with leuprolide but less marked and specifically more prominent in well differentiated (Gleason grade 2 or 3) carcinoma. Capsular penetration and tumor at the resection margin in high grade tumor was unaffected by finasteride. Finasteride did not result in reduction of PIN to the extent seen with an LH-RH analogue. Civantros, F & Solloway MS: Finasteride (Proscar) effect on prostate cancer. J Urol, A- , 1996.

We believe that one can conclude from these studies that Proscar definitely has anticancer activity though it may be modest. This modest activity however may not be inconsequential. It has already been demonstrated in the studies with Lupron and Flutamide that more complete testosterone deprivation can translate into a longer life even in men with very advanced disease. Presently more and more men are now being treated with testosterone-blocking agents at earlier stages of disease (low PSA levels). These early stages are substantially more susceptible to hormone blocking than are the advanced stages. It is possible that even the modest effects of Proscar when used on top of the traditional agents such as Lupron and Flutamide might translate into significantly increased cell kill. Fundamental oncologic principles support this sort of argument. A variety of different cancers have been studied in which relatively weak anti-cancer agents were evaluated in the advanced stages of breast and colon cancer and found to be of limited benefit. When these same agents were utilized at the earliest stages, i.e. high risk patients after surgery, studies have proven that a portion of these patients are cured!

Success in these studies of breast and colon cancer has usually been based on the principal of using maximal therapy at the earliest stage of disease. The same line of thought has led us to considering that the additional blocking effect of Proscar may ultimately prove to be of real clinical benefit when it is added to the already established treatment of Lupron and Flutamide. Unfortunately there is absolutely no scientific support for this premise. We are not aware of any studies presently ongoing to try to answer this question. We did submit a randomized protocol to Merck in 1991 that would have answered this question but at that time this protocol was rejected by Merck. In the absence of any conclusive studies we feel it is our job to make our patients aware of the possible but unproven benefit of Proscar in this situation. It is our judgment that it is highly unlikely that Proscar will cause harm or significant side effects based on its extensive evaluation in the treatment of BPH (benign prostatic hyperplasia). Unfortunately in the absence of any good science, the responsibility for the decision to use Proscar in the treatment of prostate cancer will have to rest with our patients.

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PSA as a modulator of PC growth

Prostate-Specific Antigen Stimulates Proliferation of Human Prostatic Cancer and Fibromuscular Cells and facilitates human prostate cancer invasion¹⁹

Prostate-specific antigen (PSA) is currently used as a specific diagnostic marker for the early detection of prostate cancer. Human prostatic epithelial cells secrete PSA. PSA is an enzyme, a kallikrein-like serine protease, which is a normal component of the seminal plasma; it helps to liquefy the seminal coagulum. PSA's action as a protease allows it to cleave Insulin-like growth factor (IGF) from binding-protein 3(BP3). Dissociation of the IGF-BP3 complex renders IGF available to bind to its receptor and stimulate tumor growth. One study evaluated the potential mechanism of cellular proliferation in human prostatic fibromuscular stromal fibroblasts (FMS) and in DU-145 androgen-independent prostatic cancer cell lines. Using this model, IGF concentration-response relationships were defined for DU-145 and FMS cells. When DU-145 and FMS cells were incubated with IGF at submaximal stimulatory concentrations in the presence of varying levels of IGF-BP3, a concentration- dependent inhibition of IGF-induced cellular proliferation was observed. PSA- dependent DU-145 and FMS cellular proliferation increases were evident when PSA was incubated in the presence of IGF and IGF-BP3. Under the same conditions, PSA per se stimulated increases in DU-145 and FMS cell numbers in a concentration-dependent fashion. These results suggest that that both IGF and PSA have direct stimulatory effects on both cell types. IGF-BP3 can antagonize IGF stimulation and PSA can counteract these inhibitory effects . These data provide evidence that the biological activity of PSA is tightly regulated in the prostate and that PSA has the potential to induce proliferation of prostatic cancer cells & their surrounding fibromuscular stroma.

Another study demonstrated that PSA degrades the extracellular matrix glycoproteins: fibronectin and laminin. This degradation of basement membrane substances may facilitate invasion by prostate cancer cells. Blocking of PSA proteolytic activity with a PSA-specific monoclonal antibody resulted in a dose- dependent decrease (in vitro) in the invasion of the reconstituted basement membrane Matrigel by LNCaP human prostate carcinoma cells which secrete high levels of PSA. The authors hypothesized that: (a) because of the dysplastic cellular disorganization in prostatic intraepithelial neoplasia (PIN), PSA may be secreted not only at the luminal end but also at the cell-basement membrane interface, causing matrix degradation and facilitating invasion; and (b) PSA, along with urokinase, another serine protease secreted by prostatic epithelium, may be involved in the proteolytic cascade during prostate cancer invasion and metastasis. This discovery of the extracellular matrix degrading ability of PSA not only makes it a marker for early detection but also a target for prevention and intervention in prostate cancer.²⁰

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Intermittent CHB (IHB)

The concept of using CHB intermittently arises out of 2 key issues: 1] can we maintain the androgen dependent state of PC and prevent androgen independence thereby prolonging survival? and 2] can we improve the quality of life of patients by an approach that allows for restoration of the normal androgenic environment that is so critical to many biologic functions?

We have used this approach primarily in older patients as an alternative to intensive local therapies such as RP or EBRT. We are more reserved about the use of IHB in younger patients since we do not know how survival is affected by this approach. We do believe that HT in PC will become integrated with many other treatment modalities since it appears that androgen deprivation therapy is synergistic with other conventional modalities.

Goldenberg et. al. treated 47 patients with CHB for at least 6 months until a serum PSA nadir was observed. Medication was at that time withheld until the PSA reached between 10-20 ng/ml at which time CHB was reinstituted. This cycle was then repeated. The first 2 treatment cycles lasted 18.25 months and 18.75 months. The mean time off treatment was 7.5 months and 8.25 months for cycles 1 and 2 respectively. This would represent ~ 30% for the mean percentage time off treatment. The clinical stages of the patients in this study were 14 D-2, 10 D-1, 19 C, 2 B-2 and 2 A-2.²¹

Prolonged Non-detectable PSA in Patients Treated by Androgen Deprivation May Allow for Discontinuation of Hormone Blockade (IHB)
Stephen B. Strum, Mark Scholz, Jonathan McDermed, Glenn Tisman

Introduction
We entertained the hypothesis that a prolonged period of non-detectable PSA might be associated with sufficient tumor cell kill to allow discontinuation of combination hormone blockade (CHB). This might be especially valuable in patients unfit for RP or EBRT, patients unwilling to undertake any invasive treatment of prostate cancer and perhaps those old enough to survive PC with only hormone blockade therapy. Supporting literature for this approach included reports from Dupont et al that D-2 patients treated with CHB have an average initial period of positive response of 46.8 +/- 4.5 months. 22 The Intergroup Study also showed that CHB in a subset of patients with minimal D-2 PC is associated with a survival advantage of ~ 20 months over patients receiving monotherapy with either orchiectomy or LHRH agonist therapy.³

Results of Study: CHB 1
As part of a community practice of oncology subspecializing in PC, we evaluated 21 patients with T1c to T4 prostate cancer that have been treated with combination hormone blockade using Lupron + Flutamide. These patients received CHB as either initial therapy (11) or after relapse from RP (3), EBRT (3) or both RP followed by EBRT (4). An arbitrary period of at least 12 months on CHB was planned, followed by an observation period that involved monitoring the PSA along with the clinical status of the patient. Patients' ages at diagnosis ranged from 54 to 84. The clinical stage was: T1c in 1 patient, T2a-c in 15 patients, T3c in 1 patient, T4 in 3 patients and not documented in one patient.

The mean/median PSA values at the start of first CHB were 36.3 and 7.2 months. The mean and median times to non-detectable PSA were 3.9 and 2.5 months(range 1 to 10). The mean/median duration's of CHB was 21.8 and 16 months. Following discontinuation of CHB the mean/median times of non-detectable PSA were 7.5 and 7 months. The average time off CHB is > 20 months. 16 patients continue to remain off CHB with the mean/median PSA values being 0.9 and 0.3 respectively. The average time off CHB for those patients presenting with clinically localized disease and treated initially with CHB was ~20 months (September 96).

CHB2
5 patients had a rise in PSA to 4.5, 5.12 and 5.24, 5.5 and 9.06 at which time CHB was resumed ("CHB2"). Those 5 patients had been off 10, 13, 19, 27 and 33 months with 1st CHB. 4 of these patients have again achieved non-detectable PSA's at 3,3,7 and 9 months. The remaining patient has a PSA decline from 5.24 to 2.72 at 1 month. To date, no patient that has initiated therapy using the above approach has developed evidence of non-responsive or refractory PC.

Suppression of testosterone production
Prolonged CHB may result in suppression of testosterone production as long as 24 months after discontinuation of CHB. Of 11 patients evaluated with serum testosterone levels, 1 patient had a low testosterone 6 months off CHB, 4 patients 12 months off CHB, 1 after 18 months off treatment and 1 patient after 24 months off therapy. Median time off CHB in this group of 7 patients is >19 months. None of these patients has required CHB2. In affected patients either a prolonged down regulation at the LHRH receptor site and/or a secondary effect resulting in prolonged testicular atrophy may have occurred resulting in low testosterone levels. Measurement of LH levels suggests that variations in the time to recovery of the LHRH agonist: LHRH receptor complex after discontinuation of CHB is the most likely explanation for prolonged testosterone suppression.

The favorable clinical course of patients treated with discontinuation of CHB after prolonged periods of non-detectability may reflect a patient population that is highly sensitive to tumor cell kill with androgen deprivation. This might be especially valuable in patients unfit for RP or EBRT, patients unwilling to undertake any invasive treatment of prostate cancer and perhaps those old enough to survive PC with only hormone blockade therapy.

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Hormone Therapy in Prostate Cancer

Part 3

Anti-androgen Withdrawal Response (AAWR) (by InfoMed)
Prostate cancer can be treated in various ways including surgery, radiation therapy, chemotherapy, and hormone manipulation with drugs or surgery that removes the testosterone-like hormones ( androgens) from the body. These drugs that decrease androgens are called antiandrogens and include several drugs such as Flutamide, Casodex, Nilutamide (Anandron) and Cyproterone (Androcur).

It has been noted that in patients with prostate cancer treated with one of these antiandrogen drugs, if the prostate cancer starts to grow again, this growth can be stopped by simply stopping the previously effective antiandrogen drug. This unusual response to stopping the antiandrogen drug is referred to as the anti- androgen withdrawal response (AAWR) and is probably caused by a mutation or genetic change in the prostate cancer that may actually be caused in part by prolonged exposure to the anti-androgen drug. More research is needed but the current recommendation is that in patients treated and responding well to an antiandrogen drug who later stops responding to that medication a trial of stopping the drug is warranted before considering other types of treatment.

The prostate specific antigen ( PSA) decline response after anti-androgen withdrawal was first noted with the antiandrogen Flutamide, and reported in 1993 by Kelly and Scher at Memorial Sloan Kettering.²³ Three case reports were presented in which PSA declines of 37% to 89% after 3 months of Flutamide withdrawal were observed. The decrease in PSA levels was associated with improved symptoms in the only patient with symptoms. Later in 1993 a similar response was reported by Small and Carroll ²⁴ at UCSF and Nieh ²⁵ at the Lahey Clinic this time for Casodex withdrawal providing evidence that the PSA decline was a general response to withdrawal of multiple classifications of AA meds, and was then labeled the "antiandrogen withdrawal syndrome".

The generalization of the syndrome was further supported by a paper from Japan in which the AA, Chlormadinone acetate, was withdrawn in 2 cases with a greater than 50% decline in PSA levels, with significant symptom improvement.²⁶ In addition, Dawson and McLeod²⁷ from Walter Reed Army Medical Center in Washington DC reported a similar response to Megestrol acetate further generalizing the AA withdrawal response to both steroidal and non-steroidal AA's. A summary of findings and a discussion of the mechanisms behind this phenomenon was presented by J. Moul et. al. ²⁸ in May 1995. In 3 series of patients reported by Kelly and Scher at MSK, a Canadian group from Laval University and the NCI group, a total of 105 patients in which various AA medications were withdrawn showed from 50% to 75% of patients responding with a greater then 80% decline of PSA with remission of many objective symptoms lasting for 5-14 months. While the molecular mechanism behind the AA withdrawal syndrome is unknown, several mechanisms have been postulated. The most popular mechanism has centered on mutations occurring in the androgen receptor. While clonal differences among prostate cancer cells may be partially responsible for the time-limited response to AA's observed in some prostate cancers, it has been shown that during or as a consequence of progression to an androgen independent state upward of 20% to 30% of tumors develop mutations in the androgen receptor. Clinically the frequency and degree of the AA withdrawal response has been somewhat correlated to the duration of AA exposure in a low androgen state. This exposure to an AA may influence an increased rate of androgen receptor mutations and lead to a partial agonist activity of the AA's and resultant decline in clinical activity. These assumptions have been supported by in-vitro studies of the LNCaP prostate cancer cell line in which codon 877 reveals a mutation also seen in several other codon point mutations in exon H that have been similarly observed in clinical prostate cancer tissue. Other proposed mechanisms for the AA withdrawal response include AA induced tumor enzyme changes that affect local hormonal milieu and/or AA metabolites acting with other developing genetic changes as the prostate cancer progresses. Regardless of the molecular mechanisms behind the AA withdrawal response in prostate cancer, the response is reproducible and clinically significant in a large portion of patients. In 2 review articles by Mcleod et.al.²⁹ and Scher et.al.³¹ the issues of patient management and the AA response are discussed. Although no specific factors could predict which patients would show a clinical response to AA withdrawal significant responses were seen in patients with a history of long initial exposure to the AA drugs.

In summary, Scher et. al. recommend that a trial of AA withdrawal therapy is warranted in patients with relapsing prostate cancer prior to the initiation of more toxic therapy. The expected clinical response to AA withdrawal is correlated with a significant decrease in PSA levels usually occurring within several weeks of AA withdrawal and potentially lasting up to 1-2 years. AAWR after Casodex may take up to 4-8 weeks due to the long half-life of Casodex. Additionally, previous and future studies of prostate cancer relapse treatment with chemotherapy should be interpreted in light of these AA withdrawal response effects.

Additional Data regarding AAWR
The first logical step in the management of a patient with a progressively rising PSA after primary hormonal blockade is anti-androgen withdrawal. Wilding et al (Prostate 14:103,1989), Wolf et al (Brit J Cancer 64:47, 1991) and Schuurmans et al (J Steroid Biochem Molec Biol.,37:849,1990) have shown point mutations in the hormone-binding domain of the androgen receptor. In LNCaP cells this mutation may lead to paradoxical stimulation of growth after incubation with hydroxyflutamide, Nilutamide, Cyproterone acetate and progestins. In humans, PC cell mutation may result in the stimulation of cancer cell growth by the anti-androgen. Stopping the anti-androgen in such patients often results in an anti-androgen withdrawal response or AAWR. Dupont et al, (J Urol 150:908-13, 1993) noted an AAWR in 30/40 or 75% of patients (1 CR, 3 PR, 26 Stable). A decrease in serum PSA was seen in 34/40 or 85% of patients. The average duration of AAWR was 14.5 with range 3.6-29.9 mos. The authors reported an average response of 46.8 +/- 4.5 months using CHB prior to AAW.

Scher and Kelly (Scher et al JCO 11:1566-72, 1993) documented an AAWR in only 10/35 (29%) of patients defined by a PSA decline of 50% or more. Their median response was 5+ months in contrast with Dupont's median response of 14.5 months. Of the 10 patients that had an AAWR, all had received CHB as initial therapy. Therefore, of the 25 patients that had received CHB as initial treatment the frequency of AAWR was 10/25 or 40%. None of the patients (10) who received Flutamide as a later addition after failure of monotherapy showed an AAWR.

Herrada et al (ASCO 13:237, 1994) in a preliminary report, noted that patients with higher adrenal androgen levels may predict for non-response to AAWR. If the DHEA value was above 75 there was little chance of response. This would suggest that if the anti-androgen were acting as an agonist as occurs in those having an AAWR, then the pituitary would respond to this agonist by turning down ACTH and decreasing adrenal androgen production resulting in lower levels of androstenedione and DHEA. If the AA were not causing an AAWR then the pituitary would sense a lack of androgen and try to overcome this by increasing ACTH resulting in high levels of adrenal androgens such as DHEA and androstenedione. DHEA levels > 75 would therefore indicate that an AAWR would not be likely.

Anti-Androgen withdrawal should be the first step in patients progressing under CHB. Whether this should be done as a solitary maneuver or in conjunction with initiating a secondary hormonal manipulation such as Nizoral + hydrocortisone or Cytadren + hydrocortisone is unknown. We have seen prolonged responses to such secondary treatments when these regimens are instituted simultaneously with discontinuation of the anti-androgen. Sartor et al have reported the same. 31 In this report all patients had received Suramin, hydrocortisone, Flutamide and either surgical or medical castration immediately prior to Flutamide withdrawal. 14 of 29 or 48% of patients had a PSA decrease of more than 80% for 4 or more weeks.

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Sequential androgen blockade: Anti-Androgen + Proscar

Patients who exhibit progressive disease and who were initially treated with monotherapy using an LHRH agonist or orchiectomy, should consider the use of combination finasteride (Proscar) + flutamide (Eulexin). This approach considers the block of T to DHT by the use of finasteride which inhibits 5-alpha-reductase, the enzyme that helps to convert T to DHT. It also considers blockade of DHT & T to the AR(androgen receptor) by the use of flutamide. Flutamide blocks DHT and T by action at the androgen receptor site. Animal studies show that the combination of finasteride and flutamide is equivalent to Lupron + flutamide³².

In a human study involving 10 patients this combination of finasteride and flutamide resulted in an 89% drop in PSA by the 3rd month³³. 5-alpha-reductase inhibitors(finasteride or Proscar) should not be used alone due to the secondary increase in testosterone (T) which may overcome the 5-alpha-reductase blockade³⁴.

Toxicity of CHB: The Androgen Deprivation Syndrome

Not all patients exhibit these toxicities. There is considerable variation from patient to patient.

Toxicities
Anemia of androgen deprivation may occur especially in men > 73.
Muscle wasting with prolonged use > 1 year (may be helped with exercise)
Hot flashes
May cause arthritic symptoms possibly due to acute osteoporosis
Memory loss
Weight gain
Increase in cholesterol and triglycerides by ~ 10%
Emotional lability with easy crying
Aggravation of incontinence
May cause diarrhea (Flutamide) or liver enzyme abnormalities (Flutamide or Casodex)
Night adaptation problems with Nilutamide
Alcohol intolerance with Nilutamide, Casodex, and Flutamide
Will cause testicular atrophy (decrease in size of testicles)
Will cause decrease in pubic and axillary hair and facial hair
Impotence in virtually all patients

Management of toxic symptoms

Anemia if severe or symptomatic can be treated with Epogen or Procrit.
Muscle wasting can be diminished or prevented by exercise and weight lifting.
Hot flashes can be treated with homeopathic agents like Lachesis or Chinese herbs like TCB 3 and TCB 7. If patients are severely affected the use of depo-provera injection can be considered after discussion with the patient about potential concerns of the use of a progestin. This concern may not be justified but should be explored. The injection of depo-provera, 200-400 mg im can eliminate hot flashes. The issue is whether the effect of this drug is due to its metabolism to androstenedione or to an effect on a receptor that involves the mechanism for hot flashes i.e. the LHRH receptor. Perhaps depo-provera may stabilize the LHRH receptor.

Osteoporosis/Arthritis may be prevented and treated with bisphosphonate compounds such as Fosamax or Aredia. These should be used in conjunction with calcium citrate supplements (1000 mg per day) and vitamin D. The latter can be given as vitamin D-3 at 400 units per day or more aggressively as 1,25 dihydroxycholecalciferol (Rocaltrol),a much more potent synthetic vitamin D, as 0.5 micrograms per day with this dose increased to 1 microgram assuming calcium levels remain normal. This latter agent requires a prescription. Slow-release sodium fluoride will help with bone formation. This is usually given as 25 mg twice a day. Currently this drug has not been approved by the FDA.

Memory loss could possibly be helped by the use of Gingko at 60 mg three times a day. Agents such as Hydergine could be used as well as Nicotine gum to increase cerebral blood flow. Other smart drugs such as Deprenyl, Piracetam or Vinpocetin could be tried. Clinical studies are needed.

Weight gain, cholesterol/triglyceride increases could be managed by exercise and a low fat diet. We may be exploring the use of fenphen (phenteramine/fenfluramine) in patients with this problem.

Other Areas of Interest
This overview on hormone therapy is not intended to cover all important aspects in PC understanding and management. Just recently a report on the reduction of angiogenesis by hormone blockade was reported by Ennis , Katz et. al. in 58 patients with clinically localized PC going for RP. Most of these patients did not receive hormone blockade (43) and of the 15 that did only 3 received CHB while 11 received single agent flutamide. Despite this, a significant anti-angiogenesis effect was noted in patients receiving hormone blockade³⁵. As additional studies of interest are published we will try to update this review. Please note that a detailed discussion of secondary hormonal treatments can be found in other papers we have written on our PCRI Papers page.

Stephen B. Strum M.D.
Mark C. Scholz M.D.
Glenn Tisman M.D.
March 20, 1997

REFERENCES

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13. Gleave M, Goldenberg L, Jones E, et al. Maximal biochemical and pathological downstaging requires 8 months of neoadjuvant hormonal therapy prior to radical prostatectomy. J Urol 153(4):392A, 1995.
14. Soloway M, Sharifi R, Wood D, et al. Randomized comparison of radical prostatectomy alone or preceded by androgen deprivation for cT2b prostate cancer. J Urol 153(4):391A, 1995.
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27. Dawson NA, McLeod DG: Dramatic PSA decline in response to discontinuation of Megestrol acetate in advanced prostate cancer; expansion of the antiandrogen withdrawal syndrome. J Urol, 153:1946-1947.
28. Moul JW, Srivastava S, and McLeod DG: Molecular implications of the antiandrogen withdrawal syndrome. Semin. Urol., 13:157-163.
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31. Sartor, O. , Cooper M, Weinberger M et. al. Surprising activity of flutamide withdrawal, when combined with aminoglutethemide in treatment of "hormone refractory" prostate cancer. JNCI 86: 222-227, 1994.
32. Labrie C, et al, Combination of an antiandrogen and a 5-alpha-reductase inhibitor: a further step towards total androgen blockade, Endocrinology 128: 1673-1675, 1991
33. Fleshner et al, Sequential androgen blockade, J Urol, 148:1928-1931, 1992.
34. Labrie et al, Eur Urol 3:94-105,1993.
35. Ennis RD, Katz AE, Da Silva M, Martin AR Clayton EC, et. al. Tumor angiogenesis in prostate tumors is decreased by preoperative hormonal deprivation. Proc Annu Meet Am Soc Clin Oncol 15:A603, 1996.

From the Daniel Freeman Marina Hospital Medical Center. Supported in part by PCRI.

Prostate Cancer Research Institute (PCRI)

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