What We Should Have Learned About Prostate Cancer (PC) in the Past 10 Years: Part Two
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by Stephen B. Strum, MD, FACP
Medical Oncologist and PCRI Co-founder
Ashland, OR

Edited from PCRI Insights May, 2008 v 11.2

Editor’s Note: In the Part 1, Dr. Strum illustrated his thesis, “what we should have learned about PC prevention”, with a case study of the Prostate Cancer Prevention Trial (PCPT).

Explanation of High-Grade PC in Finasteride Arm of PCPT

One explanation that has been published to explain the increased frequency of high-grade (link to Gleason grade) prostate cancer (HGPC) in the finasteride arm relates to the observation that finasteride reduces gland volume and enhances the biopsy sensitivity to detect HGPC.1,2  This belief relates to the effectiveness of finasteride in reducing BPH tissue as well as having an anti-PC effect on the PC cell population that has a relatively higher component of steroid 5-alpha-reductase type II (SRD5A2) enzyme. This is the low-grade component of PC (LGPC). Thus, what appears to be a more appropriate explanation is that the finding of greater frequency of HGPC in finasteride-treated men is a manifestation of the lower biologic activity of finasteride against HGPC.1,3 In fact, there is a relatively greater percentage of the enzyme 5-alpha reductase Type I (SRD5A1) in HGPC compared to the Type II enzyme than in low grade PC (LGPC).4 Thus, the effects of finasteride (anti-SRD5A2 enzyme) are significant in Grade 3 PC, but minimal in Grade 4 and absent in Grade 5 PC.5,6

The study by Lucia et al should be considered a landmark study because it clarifies the controversial issues that arose from the results of the PCPT and it resolves the concern about the HGPC found in greater amounts in the finasteride-treated patients. First, it showed that the morphology changes in patients found to have HGPC were found to occur at equivalent frequencies whether the patient received finasteride or placebo. This puts to rest the earlier publications that described and illustrated morphologic changes ascribed to finasteride in men with PC.5,6

Second, despite the fact that more GS 7 or higher was found in the finasteride-treated patients at biopsy, the follow-up findings of PCPT in those men undergoing RP (radical prostatectomy) showed statistically more PC in the placebo arm than in the finasteride arm. Increased PC activity was reflected in an increased percent of positive cores, bilaterality of PC, and in the occurrence of perineural invasion. (See Table 1). Third, the majority of HGPC was found only in the first year after the PCPT was begun and not thereafter. Fourth, the amount of HGPC at RP was not statistically different in the two treatment arms.

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Table 1: Findings at Biopsy and at RP in Men in the PCPT Study
Biopsy identified a greater proportion of patients with high-grade disease (later confirmed at RP) in the finasteride group than in the placebo group (69.7% versus 50.5%, p = .01). But the rate of upgrading from low-grade PC at biopsy to high-grade PC at RP as well as the pathologic stage at RP were similar in both groups.1

Assuming that the biopsy findings within the PCPT are now properly explained and confirm that finasteride does not initiate HGPC, what might be the impact on human life by using finasteride as an agent to prevent PC? Unger et al estimated the number of person-years saved assuming a 24.8% reduction in the incidence of prostate cancer for five years among United States males age 55 years old or older. The results indicated that 316,760 person-years would be saved due to finasteride use for the chemoprevention mode in the treatment of PC in the United States alone. This result was compared to eight therapeutic clinical trials in which 114,641 person-years were saved over the first five years using chemotherapy and/or immunotherapy — both highly expensive treatments and with significant morbidity and negative effects on the quality of life typical of chemotherapy.7

The case is no longer arguable if indeed it ever was. In light of the severity of the epidemic of PC, and what I consider a travesty to men at risk (one out of every six men) for PC, I have written to some of the key scientists involved with the PCPT to present you with their written responses (See the insert at end). I would consider these statements the “nitty-gritty” or “take home lessons” to discuss with friends and family who remain at risk from PC, and also to put the findings of the PCPT and the BCPT (see below) into proper perspective.

The Need to Derive Valid Conclusions

Despite literature clarifying the results of the PCPT presented above, many of the major forces in the world of PC still have shied away from using finasteride. Indeed, many clinicians appear to be frightened to use this effective pharmacologic tool to prevent PC. This is a classic example of what we haven’t learned about the prevention of PC, e.g. despite subsequent clarifications that clearly and scientifically “cleared” finasteride of the misunderstandings that were publicized in the 2003 article, for some reason, the misunderstanding, not the corrective clarification, persists as the popular dogma that has virtually excluded the use of finasteride as a PC preventative. In all the patients that I have seen since the original PCPT article by Thompson et al was published, I have yet to see a single patient who has been placed on finasteride or dutasteride as a preventative agent. I have not seen one conference agenda where an update of the PCPT was presented, with emphasis on the studies cited above. In fact, I have heard virtually nothing about the chemoprevention of PC with finasteride in all of the emails, P2P postings, patient calls, and even families where PC has involved a father &/or a son and left other immediate family members at greater risk of developing PC.8-17

The bottom line is that given the benefits of finasteride versus the risks, there is no justification for not using this form of chemoprevention to alter the natural history of PC. It will be those men who are treated with finasteride for BPH who will receive both the benefits of reduction in lower urinary tract symptoms (LUTS)  as well as a 25% decreased incidence of PC. What a waste not to use finasteride in the most important context of healthcare–prevention!

Breast Cancer Prevention Trial (BCPT)

While the finasteride debacle is sobering, it is not the only example of what we have simply never learned about cancer prevention. I have seen the same negative press affecting breast cancer prevention in women when the highly significant effects of the breast cancer prevention trial were published. Monumental results — a 49% reduction in new cases of BC — were found in large-scale trials (over 13,000 women) using tamoxifen (Nolvadex®), a blocker of the estrogen receptor. (See Figure 1) The impressive benefits of tamoxifen were essentially discarded due to the relatively infrequent side effects related to the induction of endometrial cancer, which only occurred in the post-menopausal subset.18,19 In the many years I practiced general medical oncology, prior to specializing in PC, I never directly encountered or heard of a single case of endometrial cancer related to tamoxifen use. In addition, when there is a monumental advance in preventing a common malignancy such as PC or BC, rational people look at the downside issues and determine ways to maximize the benefits and minimize adverse effects to enhance the therapeutic index.20

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Figure 1: The BCPT (Breast Cancer Prevention Trial). These results showed a 50% reduction in invasive BC after five years. However, this major advance in the chemoprevention of BC seems to have been ignored by most physicians and patients.19 Graph from article by Fisher et al.18

All of life, of biology, is a two-edged sword. Our job as physicians is to maximize the positive and minimize the negative. This issue is routinely ignored with most, if not all, the major advances made in contemporary medicine. Instead, we summarily throw the baby out with the bath water.

The REDUCE (Reduction by Dutasteride of Prostate Cancer Events) Trial

Subsequent to the PCPT, the REDUCE trial was initiated. Preliminary findings in this study indicate that the incidence of PC detected versus placebo was lower in men receiving dutasteride (Avodart®) with a PC risk reduction of 43% at 24 months and 51% at 27 months (See Figure 2).22 This study should yield interesting results in that dutasteride inhibits both 5-alpha reductase enzymes SRD5A1 and SRD5A2 (See Tables 2 and 3). Given the significant expression of SRD5A1 in HGPC, the superior results (to date) of the REDUCE trial would be expected. Also, I would anticipate that the issues which arose and initially confounded the results of the PCPT will not be an issue with the REDUCE trial.

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Figure 2: Preliminary Results of the REDUCE Trial. At 27 months, the probability of PC is reduced by approximately 50%. These findings are strikingly similar to the BCPT results reported in 1998 by Fisher et al — a study that is 10 years old and in which the impressive reduction in breast cancer (BC) with tamoxifen chemoprevention has seemingly been forgotten. (See Figure 1.)

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Tables 2 and 3: Comparison of Dual Inhibitor of Both SRD5A1 and SRD5A2 (dutasteride) Versus Mono Inhibitor of SRD5A2 (finasteride). These two tables compare the three major types of 5-alpha reductase enzymes and also compare the two commercially available agents that inhibit these enzymes – type I and/ or type II. The tables were constructed from data from Thomas et al4 and Uemura et al.23

So despite the number of patients enrolled in the BCPT, PCPT and REDUCE trials, it is a rarity to come across any men or women who are being or have been treated proactively with tamoxifen, finasteride or dutasteride, respectively. It is difficult to understand why. The adverse effects of these agents are relatively small and can be reduced further by being selective in the patients chosen for chemoprevention. With the use of finasteride, there is a small percent of men having decreases in libido, but the reduction of urinary symptoms that plague men age 50 and older more than makes up for the relatively minor downsides of finasteride or dutasteride. Over and over, it would seem, we have tossed out savings, not only of lives but of valuable healthcare dollars, at a time when our nation’s economy is at its lowest ebb since the great depression.

Additional Biological Activity of SRD5A Inhibitors

It would be simple to totally explain the results of the PCPT and REDUCE trials on the basis of what we have learned about the “intracrinology” of PC. Fernand Labrie, the scientist most responsible for emphasizing this concept, has pointed out that the enzymatic machinery necessary to convert testosterone to dihydrotestosterone (DHT) resides within prostate tissue — both benign prostate epithelial and stromal cells but also malignant epithelial cells.24 Therefore, any effect of drugs like finasteride or dutasteride could reflect this inhibition of enzyme activity in the conversion of testosterone to the more potent metabolite dihydrotestosterone (DHT). The sites of testosterone production and action of both testosterone and DHT are shown in Figure 3 along with various pharmaceutical compounds that block those actions.

 

Figure 3. The Hormonal Pathways Involved in PC. This is a very comprehensive illustration of the multiple hormones involved in PC proliferation. It depicts the trophic hormones that stimulate PC growth, e.g. LH g T g DHT as well as the various agents that are in use to block these pathways, e.g. LHRH agonists, antiandrogens, 5-alpha reductase inhibitors, HDK, estrogens, steroids, etc.

The fact is, however, that there are many publications published in the preceding 15 years that show a dose-response relationship of finasteride against BPH and PC.25-34 In clinical practice, this reduction in serum DHT levels correlates well with reductions in the PSA level. My use of SRD5A inhibitors has been primarily in the context of PC in the induction and maintenance (time off) phases of ADT (androgen deprivation therapy) and IAD (intermittent androgen deprivation). The combination of an LHRH agonist plus an anti-androgen and a SRD5A inhibitor has been termed ADT3 by Strum and Scholz. This is equivalent to the term “triple therapy” by Leibowitz and Tucker.

In the late 1980s, a number of physicians were in attendance at a special gathering in the home of Lloyd Ney, the founder of PAACT, the first organization to actively empower & support PC patients. At this meeting, we discussed the use of finasteride with our mentor, Fernand Labrie, who should be recognized as the scientist responsible for igniting the idea of clinical trials using finasteride as part of ADT. This idea was subsequently incorporated into my practice as well as the practices of Leibowitz, Roy Berger, and Israel Barken in the late 1980s and early 1990s. Later the use of ADT3 was also enthusiastically adopted by “Snuffy” Myers. The publications by Strum and Scholz, and by Leibowitz and Tucker on the use of 5AR inhibitors as part of ADT have shown a significant increase in the off-time interval of IAD.35-37

Despite these articles, many mainstream PC medical oncologists continue to deny the value of SRD5A inhibitors during ADT or IAD. Recently, Eggener et al used a mouse model to explore various treatment possibilities to answer the question “Do 5AR inhibitors add anything to ADT?”. Using a LNCaP tumor model, the group castrated the mice and then treated them with continuous androgen ablation (CAA), continuous androgen ablation plus finasteride (CAA + F), intermittent androgen ablation (IAA), or intermittent androgen ablation plus finasteride (IAA + F).

After one cycle of therapy, mice treated with IAA + F had significantly less tumor growth than the other treatment groups (P = 0.002). Mice treated with IAA + F had the best survival (P = 0.048) and were 3-5 times more likely to be alive 70 days following treatment initiation.38 Given our recently published article in Urology that described the utilization of finasteride in the induction phase of ADT and in the maintenance off-time interval, plus the findings of the Eggener article, and the results of the PCPT and REDUCE trials, I believe it is high time for other physicians to incorporate the findings of the published literature on this subject into their treatment approach for men with PC. More details on this topic will be discussed later.

And the supportive literature doesn’t stop here. For example, we know that testosterone (T) and dihydrotestosterone (DHT) up-regulate PC growth by stimulating the androgen receptor, which in turn sends messages to the androgen response element (ARE) within the nucleus to turn on protein synthesis by DNA replication via the cell cycle (See Figure 3). However, recent studies have indicated that high doses of finasteride or dutasteride appear to inhibit the growth of PC by other mechanisms of action beyond the effect of lowering DHT. In the 2007 Prostate Cancer Symposium in Orlando, Florida, Mostaghel et al showed that 7-times the 0.5mg standard dose of dutasteride would have major effects on gene expression — revealing 98 genes to be down-regulated and 32 genes to be up-regulated. Examples of the down-regulated tumor promoting (oncogenes) are TMPRSS2 and TF3 (trefoil factor 3) (See Figure 4). TF3 promotes PC invasiveness and protects the PC cell from apoptosis. The tumor-suppressing gene that showed 3.8-fold increased activity with high-dose dutasteride was IGFBP-3 (insulin-like growth factor binding protein-3). IGFBP-3 decreases the availability of IGF-1, a PC stimulating growth factor.39

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Figure 4: Effect of High Doses of Dutasteride (SRD5A2 inhibitor) on Gene Expression. In a human study, seven times the usual dose of dutasteride (Avodart®) were shown to either down- or up-regulate 130 different genes. Three that highly affect PC growth are TMPRSS2, TFF3 and IGFBP3. From Mostaghel et al.39

This means that in all likelihood we have not fully appreciated the mechanisms of action of the SRD5A inhibitors in the chemoprevention of PC, and, we have also failed to understand their contribution to ADT and intermittent androgen deprivation (IAD). Now, perhaps, the dose-response literature per Bologna et al26 from 1995 is being appreciated insofar as the utility and mechanism of action of the SRD5A inhibitors are concerned. Finally, we are making substantial inroads that hopefully will translate sooner, not later, into more evolved care for men with PC. We seriously need to expedite the clinical translation of important inroads that have been previously reported. It is my belief that this will only happen – as evidenced by the huge progress made by the AIDS community – through similar concerted efforts of intellectually empowered PC patients and their support teams.

The subsequent parts of this article that will appear in upcoming issues of Insights will extend this thesis beyond PC prevention to also discuss the status of diagnosis, staging, treatment, supportive care and end-of-life services for men with PC. In summary, I hope to clarify for PC patients where we are today, where we could have been, and where we have the ability to go in our campaign against prostate cancer.

Part III extends Dr. Strum’s thesis to the use of PSA, PSA Velocity, PSA Doubling Time, and PSA Density in the diagnosis and staging of prostate cancer.

Sidebar: The Opinions of Three Scientists Involved With the PCPT

Stephen Strum: I believe we are again blowing away the positive effects of significant chemoprevention with these agents, as we have done in the past with tamoxifen in breast cancer,18 because of the concerns of HGPC (high grade PC) which by no means negate the major benefits of finasteride and apparently even greater benefits with dutasteride. The explanation of the greater frequency of HGPC (high grade PC) in the finasteride arm would make sense based on the relatively increased amounts of SRD5A1 (not affected by finasteride) when comparing BPH to PC. Thomas et al also reported significant activity of SRD5A1 in the context of HGPC.

Therefore, it would make sense that there would be more HGPC remaining (not affected by a selective SRD5A2 enzyme inhibitor like finasteride) in those men treated with finasteride. However, peer-reviewed publications state that the reduction in volume caused by finasteride is the explanation for the increased amounts of HGPC in men so treated. I find this explanation, by itself, hard to accept. It would make a lot more sense to hypothesize that if there is HGPC present (or developing) that the nature of HGPC makes it more resistant to the effects of a SRD5A2 inhibitor – especially if SRD5A1 expression increases in PC and in the HGPC subset. It is this residual subset of PC, coupled with a smaller gland volume, which leads to an increased frequency in the biopsy diagnosis of HGPC in the context of finasteride treatment. Maybe the real answer is a combination of factors: an effect of finasteride on selecting out more PC that is low grade and leaving relatively more HG behind to be biopsied more frequently in a target volume (prostate gland) that has been made smaller. This results in a higher cancer density, i.e. cancer per unit volume. If there is a better explanation(s) I would appreciate your sharing it with me.

Scott Lucia: Your assessment is correct: we also conclude that two factors must be working simultaneously – a reduction in prostate volume combined with a relative reduction in low grade cancer (leaving a disproportionate number of high grade tumors left). Therefore, when you stick a needle into a smaller prostate (due to finasteride) you are more likely to hit a small tumor. If only high-grade cancer remains after treatment with finasteride, then that small tumor will be high grade on biopsy.

Lynn Thomas: Your hypothesis regarding the increased incidence of high-grade cancer in the PCPT is similar to ours. We think there is sufficient evidence to indicate that this is unlikely to be due to either a true induction of more aggressive tumors or to a histological artifact caused by treatment with finasteride. Instead, it is likely that an ascertainment bias existed for PC in the finasteride group, deriving from two factors: 1) a finasteride-induced reduction in average prostate volume and 2) an increase in the sensitivity of PSA testing for detection of PC. As you suggested, such biases would have led to increased detection of all prostate cancers in the finasteride arm of the study.

However, it is clear that finasteride had a differential effect on high and low-grade cancers. The increased number of high-grade tumors was due primarily to an increase in PSA-initiated for-cause biopsies, which may have occurred because finasteride suppressed PSA less in high grade tumors. Finasteride reduces serum PSA by approximately 50%, therefore a doubling algorithm was used as an adjustment factor and a biopsy was triggered by a serum PSA value > 4 ng/ml. If finasteride decreased PSA to a lesser extent in high grade versus low- grade tumors, then a greater number of for-cause biopsies would be performed on men with high grade cancer in the finasteride arm of the study. Since finasteride does not inhibit 5aR1 at clinical doses, the increased levels of 5aR1 in high grade compared to low grade cancer provide a potential explanation as to why finasteride would decrease PSA to a lesser extent in high grade versus low grade tumors.

Your data extrapolations regarding levels of SRD5A1 and SRD5A2 staining in high and low grade prostate cancer are correct. The exact values are given in our 2008 paper.4 You might also be interested to look at a paper by Serfling et al, which has a good analysis of the probability of detecting cancer in prostates from finasteride treated and untreated men.21

 

REFERENCES

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33. Presti JC, Jr., Fair WR, Andriole G, et al: Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer. J Urol 148:1201-4, 1992.
34. Tuttle RM, Loop S, Jones RE, et al: Effect of 5-alpha-reductase inhibition and dexamethasone administration on the growth characteristics and intratumor androgen levels of the human prostate cancer cell line PC-3. Prostate 24:229-36, 1994.
35. Leibowitz RL, Tucker SJ: Treatment of localized prostate cancer with intermittent triple androgen blockade: preliminary results in 110 consecutive patients. Oncologist 6:177-82, 2001.
36. Scholz MC, Jennrich RI, Strum SB, et al: Intermittent use of testosterone inactivating pharmaceuticals using finasteride prolongs the time off period. J Urol 175:1673-8, 2006.
37. Strum SB, Scholz MC, McDermed JE: Intermittent androgen deprivation in prostate cancer patients: factors predictive of prolonged time off therapy. Oncologist 5:45-52, 2000.
38. Eggener SE, Stern JA, Jain PM, et al: Enhancement of intermittent androgen ablation by “off-cycle” maintenance with finasteride in LNCaP prostate cancer xenograft model. Prostate. . 2005.
39. Mostaghel EA, Coleman IM, Coleman R, et al: Prostate gene expression changes after neoadjuvant 5α-reductase inhibition: identification of potential chemopreventative mechanisms. Prostate Cancer Symposium, Feb 22-24, Orlando, Florida Abstr #1:p72, 2007.