Chemoprevention of prostate cancer

CLINICAL REVIEW

CHEMOPREVENTION

OF PROSTATE

CANCER*

OTIS W. BRAWLEY, M.D. IAN M. THOMPSON, M.D. From the Division of Cancer Prevention and Control, National Cancer Institute, National Institutes of Health, and Brooke Army Medical Center, Fort Sam Houston, Texas

Prostate cancer is a significant cause of morbidity and mortality and is now the most common nondermatologic cancer in men in the United States. There are a number of areas of active investigation, such as the treatment of local and advanced disease as well as early detection and screening. These efforts have not as yet translated into reduced morbidity or mortality from the disease.‘-’ Recent leads in our understanding of the biology of the prostate gland and the synthesis of drugs that block the formation of androgenic growth factors make primary prevention strategies possible. Primary prevention is now a line of investigation being actively pursued. Epidemiologic studies demonstrate that much is not understood about the causes of clinically significant prostate cancer. Autopsy studies demonstrate a very high prevalence of indolent disease in older men dying of diseases other than prostate cancer and the prevalence of indolent low-volume disease is high even among young adult men.5 There is little variance in the prevalence of indolent disease among cultures and races, despite significant differences in clinically significant disease among those populations. These findings suggest that there are common initiators of prostate cancer found in all cultures but differing environmental and/or genetic differences that promote the occurrence of life-threatening prostate cancer. Before implementation can be advocated, a prevention strategy must be tested for efficacy Because of the high prevalence and varied biologic behavior of prostate cancer, a large-scale, randomized, controlled clinical trial is necessary to determine efficacy Any such trial would necessarily involve in excess of 10,000 men at risk of the disease and would require a significant period of followUP. *Thu opinions

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To be successful, intervention could function by preventing the occurrence of prostate cancer or by suppressing precursor lesions. Any agent that can successfully inhibit the progression of indolent, low-volume disease would be valuable. It would potentially save lives and could also spare a significant number of men the anxiety, morbidity, and mortality of cancer treatment. In order to be practical, the intervention must be safe and easily tolerated. An intervention would best have secondary benefits beyond prostate cancer prevention in order for it to be acceptable to a population of healthy men. DIET INTERVENTION

AND PREVENTION

A diet low in fat is an attractive intervention that has been suggested to decrease prostate cancer risk. The results of a number of dietary intake surveys support the concept that a high-fat diet may increase the risk of clinically significant prostate cancer. Dietary fat is presumably converted to androgens, leading to increased androgenie stimulation of the prostate. This may translate into an increased risk of hormonally induced tumors.6m8 Diets high in fat are associated with an increased production of sexual hormones. Black South African men fed a Western diet in one study had an increased excretion of both androgens and estrogens, while the opposite trend was demonstrated in African-American men fed a vegetarian diet in another study9,‘0 Epidemiologic studies do support the hypothesis that diet is linked to prostate cancer.“-14 These findings are similar to previous correlations of breast cancer mortality and fat intake. The higher amounts of dietary fat found in Western Europe, the United States, and Canada have been suggested to explain the higher prostate cancer mortality in these populations. I2 Armstrong and DollI studied fat consumption and prostate cancer death rates in thirty-two countries. They found a correlation of higher prostate cancer death rates with higher

average fat consumption. Populations with diets high in fiber and, therefore, presumably lower in fat have been associated with a lower incidence of prostate cancer.‘h-Li Overall, a diet in which 40-60 percent of calories come from fat appears to increase prostate cancer relative risk by a factor of 1.6 to 1.9.‘h.LtmL” There is relatively strong evidence that a population with a lifetime pattern of low fat consumption has a lower risk of prostate cancer. To date no definitive study has been conducted to determine if a change to a low-fat diet after years of a diet high in fat will lower prostate cancer risk. While American dietary habits are improving, the change is slow. Future generations may benefit from further scientific studies in this arena. DRUG THERAPY AND PREVENTION A number of potential chemopreventive agents have been studied in in vitro and in vivo carcinogenesis models.

Difuoromethylornithine (DFMO) is a potential prostate cancer chemopreventive agent. It thwarts cell proliferation by inhibiting polyamine synthesis. Polyamines are normal cell constituents important for cell proliferation. The enzyme ornithine decarboxylase (ODC) is responsible for the first and rate-limiting step in mammalian synthesis of polyamines. ,4n increase in ODC activity is thus necessary for cell proliferation. DFMO is a suicide substrate that inactivates ODC by irreversibly binding to it.“’ DFMO may be especially effective in the prevention of prostate cancer because the prostate has very high concentrations of polyamines and of polyamine synthetic enzymes.3’ DFMO has been shown to have chemopreventive activity in several animal tumors. Kadmon and associates’L have found chemopreventive activity in Dunning R3327 rat prostatic carcinoma models. There are currently several small human trials involving DFMO. These trials are designed primarily to assess adverse effects of tested drugs, but also to assess for activity in bladder and colon cancer prevention. Unfortunately, at this time a largescale study, of this agent would be difficult to mount for a number of reasons: the optimal oral dose has yet to be identified (current studies use from 0.125 to 1 .O g/day), only a relatively small number of men have yet to receive the drug, and toxicity including thrombocytopenia (dose-limiting) and ototoxicity proportional to the cumulative dose have both been noted.3’-‘5

RF I IXVOII)S

Retinoids are a class of agents includtng retinal and its analogs that interact with a class of specific receptors and can induce differentiation in a wide variety of tumors. The exact mechanism of action is unknown, but in rodent models retinoic acid (all-trans) administration leads to dramatic increases in transforming growth factor (-PGF)-beta expression. “’ Following ca.stration and associated with apoptosis (programmed cell death) of rat prostate cancer cells, significantly increased levels of TGF-beta mRNA can be detected.” Using the methods of Pollard, an androgen-sensitive cancer can be induced in Lobund-Wistar rats. Q+Sporn and colleagues have demonstrated that. the retinoicl 4hydroxyphenylretinamide (4-HPR) inhibits the occurrence of this malignancy.” Several clinical trials are underway primarily to assess the tolerability of 4-HPR. It is currently being tested in Italy as an adjuvant treatment in women who have had low-stage breast cancer surgically resected. In the United States, it is being studied for tolerance and prostate cancer chemoprcventive activity in men with a history of elevated serum prostate-specific antigen levels and negative prostate biopsies. A major concern regarding the use of retinoids for prostate cancer prevention is the risk of side effects associated with these agents: central nervous system (CNS) symptoms, impaired dark adaptation, dry mucous membranes, and Iethargy/fatigue. Because these agents must of necessity be administered to generally healthy men, compliance could be seriously compromised due to these side effects. Because in any chemoprevention trial among healthy men compliance must bc very high, and since it is doubtful whether this could be achieved with an agent with the spectrum of side effects that 4-HPR has, at this time a large-scale rctinoid chemoprevention trial is probably not possihlc. HORMONAI MANIP[UTIONS

Androgenic inhibition is an attractive approach to prostate cancer prevention. The precise role of androgens in the causes of human prostate cancer is unclear, but evidence is accumulating to suggest that androgenic stimulation promotes prostate carcinogenesis. It is well established that androgens do promote cell proliferation and inhibit prostate cell death?’ The hormonal sensitivity of prostate cancer has been exploited clinically since 1941, when the Nobel prize-winning ,work of Huggins and HodgesJ’ established the suppressive effects of castration on prostate cancer. Most hormonal therapies are similar in efficacy: responses are noted in most patients with

metastatic disease but for widely variable periods. It is controversial whether hormonal manipulation prolongs life when therapy is started for widely metastatic disease. Disease generally becomes refractory to hormonal manipulation within two years. Animal models of prostate cancer suggest that hormonal manipulation may be more successful in prolonging survival if begun when the tumor burden is less. Hormonal manipulation may remain an effective form of chemoprevention even if androgen-insensitive clones survive initial manipulation. It has been estimated that most 1 cm3 prostate cancers contain 10” cells and have undergone thirty tumor population doublings over five to fifteen years.‘l The mechanism of tumor resistance to hormonal manipulation is thought to be through mendelian selection.43 Even if androgen insensitive clones do survive, the patient may still benefit by tumor regression. Currently employed forms of hormonal manipulation used to treat advanced disease would likely be very effective preventive agents. Unfortunately, the adverse effects of these drugs are so significant that their use in chemoprevention would be impractical.

Inhibitors of Sa-reductase may inhibit prostate cancer occurrence and growth while causing very few side effects. +I These drugs decrease androgenie stimulation of the prostate while having negligible effects on other androgen-dependent organs. Sa-reductase inhibition blocks conversion of testosterone (T) to the more potent androgen dihydrotestosterone (DHT).45 Although both T and DHT can bind to the cellular prostate androgen receptor and induce androgen-mediated effects, DHT is far more potent than T. When compared to T, DHT exhibits a higher binding affinity for and lower dissociation rate from the androgen receptor. The DHT-receptor complex also has greater stability and a higher binding affinity for DNA. The observation that 5a-reductase activity is low in populations at low risk for prostate cancer, such as Japanese and Chinese men, when compared with American men gives further support to the hypothesis that reduced androgenic stimulation of the prostate may decrease prostate cancer risk.46,+7 Laboratory testing of the Sa-reductase hypothesis is difficult. Rodent carcinogenesis models are not well suited for this purpose. All major, accepted, rodent prostate cancer models involve administration of a chemical carcinogen followed by chronic administration of high doses of andro-

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gens.4” The very fact that androgens are necessary to promote prostate cancer growth in laboratory animals is in itself supportive of the theory that decreasing androgenic stimulation can lower prostate cancer risk. Several studies have demonstrated that Sa-reductase inhibitors can reduce the growth of several human prostate cancer cell lines in tissue culture and rodent implant models.49z50 A decrease in androgenic stimulation, such as DHT inhibition, would likely exert its greatest influence at the earliest stages of tumor development and progression. There is evidence, however, that Sa-reductase inhibition causes minor decreases in the serum PSA of men with Stage D disease. While the clinical significance of this decline is unknown, it demonstrates that DHT inhibition may exert some influence even on undifferentiated metastatic prostate cancer.5’ Although Sa-reductase inhibitors have some antitumor activity, anticancer activity is not necessary in order for a drug to prevent cancer. Carcinogenesis is a process rather than an event. Decreasing the androgenic stimulation of prostate cells over a period of time may diminish the probability that these cells will enter or progress along the carcinogenic process. The fact that androgenic stimulation of the prostate is only partially decreased suggests that finasteride therapy may not cause a tumor to become resistant to more “standard” forms of hormonal manipulation. A number of 5a-reductase inhibitors have been synthesized. Finasteride (Proscar) was the first Sareductase inhibitor to enter clinical trials. It is a steroidal analog of testosterone that functions as a reversible competitive inhibitor of Sa-reductase. It has been studied extensively for the management of benign prostatic hyperplasia (BPH) and it has been approved by the U.S. Food and Drug Administration for that indication. Finasteride (5 mg/day, orally) causes a 75 percent decrease in serum DHT levels, an 80 percent decrease in intraprostatic DHT, and a 10 percent increase in serum T. Despite the 10 percent increase in serum T, all values were within the clinically normal range in several large trials. While very high concentrations of T can interact with androgen receptors similar to dihydrotestosterone, the increased T levels found in male pseudohermaphrodites are not high enough to promote prostate growth.52 In a number of clinical trials for the treatment of BPH, finasteride has been demonstrated to be a very safe drug with minimal side effects. Given its excellent safety profile and the possibility that it may also prevent BPH, finasteride would be very

UROLOGY

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1994 / VOI I’hlt 4.3, ~VIWIItR 5

suitable for long-term administration as a cancer chemopreventive agent. The National Cancer Institute and several of its cooperative oncology groups are sponsoring a randomized, double-blind, placebo-controlled trial to determine if 5a-reductase inhibition will reduce the incidence of prostate cancer. The trial will enroll 18,000 men, fifty-five years of age and older, in good health. with no evidence of prostate cancer. Participants will be randomized to receive finasteride 5 mg/day orally or placebo and evaluated for seven years. The primary objective is to demonstrate a decreased incidence of prostate cancer in the treatment group compared to the placebo group. The trial design allows for a 90 percent power to detect a 25 percent difference in prostate cancer incidence between the two groups. There are a number of hypothetical problems associated with the use of finasteride in a chemopreventive setting. The effect of finasteride upon the ability of the examiner to detect abnormalities on digital rectal examination (DRE) is unknown. One possibility is that the reduction of gland size will preclude the ability to palpate subtle abnormalities, but another possibility is that the reduction in size of the adenoma may result in an enhanced ability to detect nodularity or induration of the gland. Since the study’s design enrolls men with a prostate-specific antigen (PSA) level less than 3.0 ng/mL and a normal DRE, based upon the experience of Labrie and colleagues,‘i it is expected that the majority of interval biopsies will be prompted by PSA changes and not by abnormalities in DRE. Because the trial design calls for an equal number of interval biopsies in finasteride-treated subjects as in subjects receiving placebo, the problem of PSA change in finasteride-treated subjects is eliminated. Another concern for any trial which uses a hormonal intervention for the prevention of prostate cancer IS the possible selection of androgen-resistant clones of cancer cells. This concept is analogous to the appearance of bacterial resistance as described by Luria and Delbruck.“’ It is reassuring that this has not been the case in the initial clinical experience with finasteride. In the North American Phase III trials using finasteride for the treatment of benign prostatic hyperplasia, a small number of patients have subsequently been found to have prostate cancer. In patients treated thus far, tumors have responded to standard hormonal therapy. Studies using animal models of prostate cancer also dispute whether finasteride would prompt emergence of androgen resistant strains. In Dunning G and H tumors (androgen-responsive), in-

complete androgen withdrawal (a small amount of androgen replacement) in castrated animals leads to tumor growth curves identical to castrated controls.‘? Since the appearance of androgen-insensitive cell clones is the invariable cause 01 tumor recurrence, this pattern suggests that partial androgen withdrawal does not accelerate the growth of androgen resistant clones. Further evidence from the Dunning tumor model finds that animal survival is directly related to earlier androgen withdrawal. Because castration in these animals is, by definition. “incomplete” androgen withdrawal (other androgens persist but at lower concentrations), this similar “early incomplete therapy” does not promote growth of androgeninsensitive cells but indeed delays this event.” Summarizing this conclusion in 1986. Schnipperi’ suggested that although there exists a strong relationship between the dose of antineoplastic agents and the cytotoxic effect on tumors. such has not been the case for hormonal therapy. A large randomized trial can have a number of other benefits. Prospectively following a group of aging men can yield valuable data on the epidemiology, risk factors for, and natural history of prostatic cancer; the screening and diagnosis of prostate cancer; and quality of life in the aging malt. The study is also a unique opportunity to assess finasteride‘s ability to prevent benign prostatic hyperplasia. SUMMARY Primary prevention of prostate cancer is a relatively new concept. Through large-scale studies it is possible that we may be able to define better the risk for prostate cancer and identify those who would benefit from an intervention to lower their risk of disease. As risk for prostate cancer is better defined, a number of interventions ma). cventuall) be tested. Several interventions are sufficiently mature that they can be implemented in large-scale trials. Diet modification is an intervention that is ready for evaluation. It may also have additional benefits by decreasing mortality from other malignancies and cardiac disease. Sot-reductase inhibitors are also ready for testing. The National Cancer Institute and its clinical cooperative groups have begun a large trial to assess finasteride in the prevention of prostate cancer.

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noma m NB rats following prolong”1 5~s hljrmonc adminlstratlon. Cancer Res 27: IYZY-1033, IYi’T. $9. Kadohama N, Karr JP_Murphy GP, and janclherg AA: Selective Inhibition of prostatic tumor 5-alpha-reductasc hj a 4-methyl-+azasteroid. Cancer Res 44: 4Y47-4Y54, 1084. 50. Petrow V, Padilla GM. Mukhcrjl 3, and Marts SA Endocrinc depcndencc of prostatic cancer upon tlihydrotcstosteronc and not upon testoStcrone ] Pharm t’harmacol 36: 352-353, 1984. 5 I. Presti JC Jr. I:air WR. Andrlole C;, Soganl PC , Seldman EJ, Ferguson D. Ng J, and Gormle) CI Multicenter, randornlzed, double-blind, placebo controllrd study to Investigate the effect of finasteride (MK-906) on Stage D prostate cmccr J Ural 148: 1201-1204, 1042. 52. Gormley GJ: Role of 5-alpha-rcduc tasc ~nhlb~t~~rs in the treatment of advanced prostatic carcinom;t. lirol Clan North Am 18: 9%Y8. 1991. 53. Lahric F, DuPont A, Suburu ER. Gomcz ]I_, Cusan I_, Lemay M, Koutsilier1s M. and Diamond P- %rum prostatic specific antigen (PSA) is a highly eflicicnt press rcening test for prostate cancer. J Lirol 149: 4 I )A. lYY3 54. Luria SC. and Delbruck M: Mutation of bacteri,l from virus sensitivit) to virus resistance.
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