Avodart & Proscar

BY MARK SCHOLZ, MD

Frequently I am asked about Proscar and Avodart, two medications that are FDA approved to reduce urinary side effects from prostate enlargement (BPH).  It turns out that these medications have a much wider spectrum of application than simply treating BPH. They function by blocking a type of testosterone called dihydrotestosterone (DHT) that occurs primarily inside the prostate. A short blog can’t summarize this vast field.  However, I think even a brief review might be helpful.  Here is a list of their potential applications:

• Lower the risk of being diagnosed with prostate cancer
• Improve the detection rate of high-grade prostate cancer
• Cause Gleason 6 cancer to regress or be suppressed
• Synergize with other hormone therapy medications (such as Casodex)
• Help maintain men on active surveillance to avoid surgery or radiation
• Prolong the “holiday period” in men on intermittent hormone therapy
• Reduce male pattern baldness
• Delay orgasm in men with premature ejaculation

The occasional side effects that can occur, such as reduced libido, impotence and breast enlargement, are manageable or preventable as long as the medication is stopped in a timely fashion when side effects occur.

In a randomized study comparing Proscar with placebo, 10,000 men underwent a prostate biopsy. The Proscar-treated men were diagnosed with cancer 25% less frequently compared to placebo. However, enthusiasm for the routine use of Proscar to prevent cancer was dampened when the same study reported a 1% increased incidence of diagnosing high-grade prostate cancer. Even though many experts hypothesized that Proscar was increasing the detection rate, not causing high-grade disease, Peter Scardino, a prominent urologist from Memorial Sloan Kettering published an opinion that Proscar could be causing high-risk cancer, raising all kinds of consternation and inciting the FDA to place a warning. Fortunately, subsequent follow up published in the August 15, 2013 issue of the New England Journal of Medicine showed that after 18 years of observation there was no increased prostate cancer mortality from Proscar.

Much of what is known about Proscar can also be said about Avodart. Both agents block 5- alpha reductase (5-AR), an enzyme that converts testosterone into DHT.  A possible advantage of Avodart is that it blocks two of the three forms of 5-AR whereas Proscar only blocks one.  No clinical trials, however, have been performed to compare clinical efficacy of the two agents.  In our in-house trials we have found that DHT blood levels are lower with Avodart than Proscar.

Since both Proscar and Avodart lower PSA by about 50%, the question arises, “Are they masking the capacity of PSA to signal cancer progression?”  Briefly, the answer is no. These medications do not stop a PSA rise in men with progressive cancer. However, after starting Proscar or Avodart the PSA baseline does reset 50% lower. On average, a man with a PSA of 6.0 before starting Proscar will drop to 3.0 within a few months. Subsequently, if the PSA rises consistently above 3.0, cancer progression should be entertained as a possible cause.

The rationale for concluding these agents are beneficial when added to other hormonal agents is based on the known fact that no pharmaceutical drug by itself can totally eradicate or block testosterone. So logically, the addition of a nontoxic 5-AR inhibitor to further lower DHT is likely to be helpful. Studies show that these agents suppress PSA in men with relapsed disease, delaying the rise in PSA, on average, for a couple of years.  It has also been shown that these agents can double the duration of the “holiday period” in men on intermittent hormone blockade.

Proscar and Avodart—mild agents with mostly reversible side effects—almost never interact with other medications.  They can be taken anytime of the day, with or without food. Proscar is available as a generic called finasteride and is very affordable. There is certainly an important role for these well-tolerated medications though in this era of new, high-powered hormonal agents such as Zytiga and Xtandi, Proscar and Avodart often get forgotten.  

Read another Prostate Snatchers blog written on Avodart & Proscar here:  http://prostatesnatchers.blogspot.com/2011/05/avodart-proscar-for-men-on-active.html
 

The Unending PSA Controversy

BY MARK SCHOLZ, MD

The controversy about PSA has been reignited by new data from Lancet and recently reported in the NY Times.  Even though PSA screening reduces mortality from the aggressive type of prostate cancer, the Lancet article again confirms that far too many men routinely receive unnecessary radical treatment for a low grade type of prostate cancer that is essentially harmless, an entity that should never have been called cancer in the first place.

Grade 6 “cancers” are harmless. However, it’s hardly surprising that men (and doctors) push for immediate treatment anyway.  No amount of reasoning seems to ease the instinctual fears generated by this venomous word.  Despite warnings about impotence and incontinence—and reassurance that low-grade prostate cancer can be safely monitored— 85% of these low-risk men undergo radical treatment anyway.

Unfortunately, outrage against the genuine harms of overtreatment is routinely directed at PSA when the real culprit is the 12-core random prostate biopsy. I have previously weighed in on this matter in various blogs and videos, but the prostate cancer intelligentsia continues to be totally clueless, routinely blaming PSA rather than the ridiculous policy of randomly jabbing needles into the rectums of a million men annually.

Random biopsy could perhaps be justified if prostate scans were unreliable. In fact prostate imaging does often miss small, low-grade cancers; the very ones we now know are harmless. But for high-grade disease, color Doppler ultrasound and multiparametric, three-tesla MRI, are very accurate. Evaluating an abnormal PSA with an imaging study rather than a biopsy greatly reduces the chance of diagnosing grade 6 disease, the type that so commonly leads to unwarranted treatment.

Low grade cancers are incredibly common. However, higher-grade cancers also occur.  When imaging detects a high grade lesion, a targeted biopsy (a limited number of cores aimed directly at the lesion) should be performed. Lesions that are biopsy-negative or show low-grade cancer, can be monitored without treatment.  If high-grade cancer is confirmed, further staging followed by treatment counseling is needed.

Trained doctors using state-of-the-art technology read the scans and summarize their overall impression which falls into one of three categories:

1.        No evidence for high grade disease, no need for biopsy

2.        A suspicious lesion is detected, a targeted biopsy is necessary

3.        An ambiguous area is detected. Either a targeted biopsy can be considered or alternatively, ongoing monitoring with another scan in 6-12 months can be considered

Imaging “sees” all sorts of things besides cancer, including scar tissue, areas of active prostatitis, and nodular areas from BPH. Lesions of greater concern are located in the peripheral zone, over a centimeter in size, show bulging of the prostate capsule or are associated with increased blood flow or diffusion. An ambiguous lesion should be targeted for biopsy if it enlarges over time during observation on subsequent scanning. Expert judgment that takes each individual’s characteristics into account comes into play during a discussion between the patient and doctor about whether or not a targeted biopsy is indicated.

Color Doppler ultrasound and multiparametric MRI are complementary. In our experience, the imaging findings between these two modalities match 80% of the time. However, in a minority of cases, one imaging modality illuminates a specific lesion more clearly. Therefore, with ambiguous lesions using one modality, we usually consider additional imaging with the other modality before recommending targeted biopsy.

One would think that new advances in imaging would lead to an immediate revolution in prostate cancer management. Unfortunately many doctors are either unaware of what’s available or unacquainted with the full capabilities of the latest technology.  Finally, even well informed doctors may be reluctant to embrace imaging when they are well paid to do random biopsies.

Random biopsy continues to fly unscathed under the radar while people mistakenly blame PSA for the great misfortune of having thousands of men undergo unnecessary surgery or radiation every year. Forgoing PSA screening altogether is both foolish and dangerous. State-of-the-art prostate imaging, rather than random biopsy, should be the first step in evaluating men with elevated PSA levels.

The Power of a Word

BY MARK SCHOLZ, MD

At an Active Surveillance Consensus Conference in 2007, it was openly bemoaned that the word “cancer” profoundly overstates the significance of low risk prostate cancer.  The pathology experts who were present, however, shot down the idea of a name change saying, “Under the microscope it looks like a cancer, so it’s cancer.” At that time no one had a rebuttal, so the subject was dropped. Now studies confirm that Gleason grade six prostate cancer never metastasizes.

In retrospect, I wish the conference attendees had been able to rise up to the name-change challenge. Back when the makers of 7-Up wanted to emphasize the distinctness of their product compared to other soft drinks, they came up with the name “Un-Cola,” a stroke of marketing genius. Since the pathology experts insist that low-risk disease is a cancer—we should undo the negativity of this word by renaming it: “The Un-Cancer.” Alternatively, the SHADES of Blue classification system calls this harmless type of prostate cancer SKY BLUE.

Misinterpreting the significance of the word cancer leads everyone to think, “I had better be safe and remove the gland.”  The biggest challenge of educating people about prostate cancer is overcoming their preconceived notions, what they already think they know about cancer.  Random biopsies are detecting cancers that are so small that even if they grow while under observation, they will still be curable.  And for the minority of men on active surveillance who develop progressive disease, at least they have real proof that their cancer truly needs intervention, for this minority, it’s not a paper tiger and undergoing treatment is justified.

Defining the Un-Cancer—The Basic Components of SKY

	Favorable	Ambiguous Zone	Unfavorable
Color Doppler or Multiparametric-MRI	< 10 mm  in maximum tumor dimension	11-17 mm  maximum tumor dimension	> 18 mm max tumor dimension
Highest Gleason Grade	Grade 3 + 3 = 6	3 + 4 = 7	4 + 3 = 7 or higher
PSA Density	Under 0.13	0.14 to 0.17	Over 0.18

Further In-depth Testing for SKY
New technology is also providing new insight into how favorable cancer can be distinguished from unfavorable cancer. The biggest advance is better imaging of the prostate. Other new blood and genetic tests such as Prolaris, Oncotype, MDx, OPKO 4K and Mitomics, can also ferret out the cancers that are prone to behave more aggressively or have been missed on the initial random biopsy.

The Drawbacks for Active Surveillance
The main concern is that the initial random biopsy missed a higher grade tumor somewhere else in the prostate. Most centers address this problem by doing random biopsies over and over. Repeated random biopsies are unpleasant and they can cause serious infections.  Multiple biopsies have also been associated with higher impotence rates and worse urinary symptoms. A better way is to rely on modern imaging with color Doppler ultrasound or multiparametric MRI (MP-MRI). Also, because with active surveillance prostate gland is left intact, there is the possibility of a new, higher grade cancer developing. The privilege of keeping the prostate intact entails the responsibility of close monitoring. Then, if a new higher grade cancer subsequently develops, it can be detected and treated at an early stage.

Anxiety and uncertainty about living with untreated cancer is also a problem, one that is often magnified by the treating physicians, surgeons or radiation doctors who often send an ambivalent and lukewarm message about active surveillance to their patients.  This half-hearted attitude is probably rooted in the doctor’s own uncertainties about untreated cancer. Despite all these very real issues, however, studies show that men on an active surveillance program are no more anxious than men who have had surgery or radiation and are being monitored after therapy to make sure their cancer stays in remission.

It’s Hard to Teach an Old Dog New Tricks
It’s easier to teach a proper golf swing to a true beginner than to someone who has previously developed bad habits.  The mind of a child learns a new language much more easily than the cluttered mind of the adult.  Good first impressions are valued so highly because we all know how hard it is to undo a bad first impression.  Changing the mindset of doctors and patients about how to treat something called CANCER is going to be a slow process.

Men need to realize that survival rates with low-risk prostate cancer managed with observation are extremely favorable.  Studies show that survival with active surveillance matches the survival of men getting immediate surgery. Men need to guard themselves from being rushed into unnecessary treatments that have irreversible side effects.

Abstracts from the Meeting of the American Urological Association

BY MARK SCHOLZ, MD

Each year in May the American Urology Association meeting provides a treasure-trove of new scientific information.  As noted in my reviews from earlier scientific meetings, the results of new studies are communicated in 350-word Abstracts which concisely summarize the efforts of a team of scientists working on a specific clinical question.  Several thousand abstracts are published in the proceedings of the meeting, amounting to over a million published words.  On the topic of prostate cancer there were merely hundreds. This year I selected 46 for comment. This blog briefly comments on only a few of these abstracts. Each bullet point is for a separate abstract.

Active Surveillance

·        A large registry in Michigan that tracks prostate cancer treatment reports that about 50% of men with low-risk prostate cancer who are eligible for active surveillance actually undergo active surveillance (the other half get radical therapy). As sad as this sounds, 50% is double the reported active surveillance rates from 3-4 years ago, showing progressively increasing acceptance of active surveillance by doctors and patients. 

·        Laurence Klotz, the father of active surveillance and the lead investigator of the longest study of over a thousand men on active surveillance, reports that after more than ten years of monitoring, 3.6% of patients have developed metastatic disease and 1.7% have died of prostate cancer. Dr. Klotz points out that these statistics are similar to the expected mortality in low-risk patients that get treated with initial surgery or radiation.

Can Gleason 3 + 3 = 6 Metastasize?

·        2500 surgical patients were reviewed to determine if Gleason grade 6 can spread outside the prostate into the seminal vesicle.  In this study not a single case of seminal vesicle invasion was documented when the cancer was exclusively grade 6.

·        Out of 173 men with Gleason grade 6 who had their lymph nodes removed, not a single case of lymph node spread was observed. After an average of five years of observation, no patient has developed metastases.

Metformin and Statins

A number of previous reports have suggested that metformin and statins have anticancer effects. The anticancer effects of metformin have been only studies in diabetics but there is no reason to believe that metformin would be ineffective as an anticancer agent in non-diabetic men. Four abstracts at the AUA elaborate further on this active area of interest.

·        In Denmark, men taking metformin (for diabetes) were at one-third lower risk of being diagnosed with prostate cancer compared to men who were not taking metformin.

·        Men undergoing surgery for prostate cancer who were taking both metformin plus a statin had a reduced risk of cancer relapse—from 30% down to 15%.

·       In Finland, prostate cancer survival was evaluated in 6000 men depending on whether they were taking statins. Statin use reduced prostate cancer mortality by two-thirds.

·       In a study from Europe, there was a 60% reduction in overall mortality in men with advanced prostate cancer who were taking statins compared to those who were not. Both cancer mortality and cardiovascular mortality were reduced by a similar increment.

 Benefits of Surgery

·       In Denmark, the estimated length of life gained with surgery compared to the general population was only 0.4 years after 10 years of observation.

·       In France within 60 days following surgery, the mortality rate was one in a thousand surgeries. Mortality after surgery was nearly twice as high in hospitals performing less than 10 prostate operations a year compared to more experienced centers.

Treatment of a PSA Relapse

Here I quote directly from two abstracts on the topic of a rising PSA after surgery or radiation:

·        “We found that salvage radiation was associated with decreased use of salvage hormone therapy, as well as lower risks of local recurrence, systemic progression, and death from prostate cancer.”

·        “Approximately 16% of patients with a detectable PSA after radical prostatectomy may have false biochemical failure. Repeating the serum PSA in all patients with a detectable level is paramount before making treatment recommendations, especially if the patient had Gleason score 6, negative margins, and the cancer was organ−confined.”

Accuracy of Prostate MRI

One of the problems with random biopsy is that it finds too much grade 6 disease, leading to too much unnecessary radical treatment. Previous studies have indicated that multiparametric MRI finds high-grade disease quite well, only missing small tumors.  However, multiparametric MRI “sees” low-grade tumors much less, which is a good thing. Below are two new reports on this important new technology.

·       A multiparametric prostate MRI showing no cancer in the prostate is accurate 82% of the time for grade 6 cancer and 98% of the time for grade 7 or higher using a 12-core biopsy as the reference standard.

·       A multiparametric prostate MRI showing no high-grade cancer is accurate 74% of the time when using surgical removal and pathologic dissection of the prostate as the reference standard. The types of high-grade cancers that were missed by MRI tended to be smaller, secondary tumors that were organ confined.

I was encouraged to see so many abstracts on active surveillance at this year’s meeting. Also gratifying were the numerous reports on imaging, which in my opinion is the technology of the future that will eventually supplant random biopsy. All the 46 abstracts I judged interesting have been posted here: http://goo.gl/ZzwmpB