Metformin and Statins for Prostate Cancer

BY MARK SCHOLZ, MD

As an internist and an oncologist, throughout my long career treating prostate cancer patients, I have periodically been asked by patients, “What do you do?  Surgeons (urologists) operate, and radiation doctors give radiation, but what do prostate oncologists do?”  My day-to-day, bread and butter is giving medical advice and prescribing oral medications. Unfortunately, I think this leads to some patients seeing me as a “pill pusher.” As such, I think I need to explain my motives for recommending the use of metformin and statins to my patients with prostate cancer.

One of the things that the last 20 years of my career treating prostate cancer has taught me is that a good diet has a favorable effect on inhibiting prostate cancer progression.  What converted me from a nonbeliever to a believer?  My patients.  A number of men have come to me through the years whose PSA was rising after surgery and who subsequently embarked on stringent vegan or macrobiotic diets. Lo and behold, as long as they stayed on their diets their PSA levels would stabilize. Subsequently, T. Colin Campbell published a very convincing book called The China Study that evaluated the connection between increased animal protein intake and cancer rates.  His findings conclusively demonstrated that high animal protein intake increases cancer risk.

How can diet make such an impact?  We don’t have all the answers but there are some very logical suppositions.  First, cancer cells “hurt” people by the process of cellular multiplication, ultimately spreading throughout the body and causing organ malfunction. It’s logical to assume that “better fed” cancers, the ones that get plenty of protein and energy, will grow faster and better than cancers that are relatively deprived.  Animal protein not only provides all the necessary amino acids for the construction of new cells, animal protein is invariably accompanied by substantial amounts of a potent energy source—fat (People forget that the average hamburger is over 50% fats). High protein diets also increase the level of insulin in the blood. And high insulin levels drive sugar and protein uptake into the cancer cells, further promoting growth. And lastly, dietary cholesterol is not only a type of “fat,” but it is also a hormonal precursor, a building block for DHEA and testosterone.

Unfortunately, few of us have the ability to follow strict vegan diets. It’s a lot of work and requires constant self-denial.  Certain medications, however, can achieve some of the same effects. Metformin, a generic medication approved for the treatment of diabetes, suppresses insulin levels in the blood. Studies in diabetic men with prostate cancer who are treated with metformin have shown lower prostate cancer mortality rates compared to diabetic men who are treated with other types of diabetic medications besides metformin.  Statins pills, medications such as Lipitor and Crestor, dramatically lower cholesterol levels.  Numerous studies have reported higher cure rates in prostate cancer patients receiving radiation who are treated with statins compared to radiation-treated patients who don’t receive a statin.

Regular exercise prolongs life in cancer patients.  If we had a pill that could accomplish what exercise can do—improved energy levels, sleep, digestion, memory, longevity and less depression—everyone would take it.  Many patients are lukewarm about prescription pills like metformin and statins, probably mainly due to concerns about side effects.  But side effects can be anticipated with careful monitoring.  When a medication side effect occurs it can be detected early and when the medication is stopped the problem is almost always resolved.  Following a rigorous macrobiotic diet for the rest of your life is beyond the reach of most of us. Taking an FDA-approved pill, while using careful precautions against potential side effects, is achievable for almost all of us. 

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Scare Tactics about the “Symptoms” of Prostate Cancer

MARK SCHOLZ, MD

In this week’s blog I was supposed to finish out the “Helpful Medications” theme started at my last blog. Specifically I need to make a case for using statin drugs and metformin, a generic diabetes drug, to help suppress prostate cancer.  However, that blog has been temporarily postponed in place of the following:

When Ralph and I wrote Invasion of the Prostate Snatchers we knew our highest priority was to calm people down so they could begin to think rationally.  Obviously the word “cancer” freaks everyone out. People get so scared that all rational thought ceases.  They immediately jump into the arms of the nearest doctor who is willing to offer a quick fix.  With prostate cancer that just happens to be a surgeon.

Scare tactics are effective from a business point of view since in business “time is money.” Frightened people act quickly and decisively, thus saving everyone time.  The psychology of fear is also quite commonly used in advertising.  You have heard these mottos and mantras many times before: “Time is Running Out,” or, “Space is Limited.”  No one wants to miss a one-time opportunity.

The threat of losing a one-time chance for cure naturally drives newly-diagnosed prostate cancer patients to act quickly. And there is after all a certain type of logic to people unfamiliar with prostate cancer.  With almost any other type of cancer a delay in treatment will reduce cure rates. Surprisingly with prostate cancer this is only rarely the case. However, the idea of a “harmless cancer” is certainly foreign to us all. It will take some time for newly-diagnosed patients to absorb this unexpected fact.

That’s why it is critically important to encourage men to take time to gather their senses and calm down.  Given some space to reflect they will learn that with prostate cancer they need to weigh the potential for treatment-related side effects against the tiny amount of increased survival surgery or radiation offers in men with low-risk disease.

As noted above, the fears and confusion incurred by a recent prostate cancer diagnosis have a certain type of logic. But what is totally illogical is the proliferation of articles I keep coming across on the internet that purportedly describe the “Symptoms of Prostate Cancer.”  Invariably these articles present a long list of symptoms such as urinary frequency, nighttime urination, slow urination, and blood in the urine as possible indications of prostate cancer.

These articles are completely false! EARLY PROSTATE CANCER ALMOST NEVER HAS SYMPTOMS.  This is why the PSA blood test has been so revolutionary.  PSA can detect prostate cancer before symptoms of advanced disease occur. The most common symptom of prostate cancer—bone pain—only occurs after the disease has spread to the bones. Prostate-related symptoms, when they are present, signal another diagnosis such as prostatitis or prostate enlargement. These prostate problems have nothing to do with prostate cancer. Symptoms such as these may need evaluation and treatment but there is no reason to scare people with the suggestion of cancer.

Competition on the internet has become so fierce that just about any scare tactic is considered acceptable, up to and including bald-faced lying.  But let’s put this falsehood to rest.  The myth that early-stage prostate cancer causes urinary or sexually related symptoms is an exploitative tactic that can lead to all kinds of harm, creating anxiety and fear that results in unnecessary diagnostic testing such as random needle biopsies that lead to the over-diagnosis of low-risk prostate cancer.

Medications for Prostate Cancer that Might Help and Probably Won’t Hurt

BY MARK SCHOLZ, MD

Do we have confidence in our prescription pills?  How can we really know that they are helping?   It partly depends on whether or not there is a benefit.  Fever disappears soon after starting an antibiotic.   PSA declines in men with prostate cancer who undergo hormone blockade.  Blood pressure is better after starting a new blood pressure medication.

We have confidence in these medications because there is a measurable benefit.  Seeing a benefit offsets our suspicions about potential side effects. Medication choices really boil down to a simple equation: balancing the benefit against the risk of side effects.

But sometimes it’s difficult to see the benefit, especially if the medication is being used because of the benefits were only reported in a population study showing and advantage of one group of people over another.  Baby aspirin is a good example. How do you really know that the pill you took today helped you dodge a heart attack?

Science and the Media
Interpreting scientific studies requires skill and training. But these days, the challenge is even greater because scientific studies are primarily reported in the media.  Unfortunately, media experts face tremendous temptations to make their stories more interesting. So they tend to overstate their importance.  As a result the general public is becoming very wary of supposed scientific finding.   

Considering Risk, What about Low Risk Medications that “Might” Work?
Few people have the time or skills to do their own research. But deciding “yea” or “nay” on a new medication can also be based on its perceived risk. If a medication is considered relatively safe, people with a chronic illness like prostate cancer may start thinking along the following lines: “I can’t be sure it will help, but at least it won’t hurt.”  This is a common mindset with vitamins and supplements because they are generally perceived to be harmless.*

Modifying the Down-Side Risks
This “why not” mindset comes into play when considering certain common generic medications that have been on the market so long their potential side effects are well known.  Specifically I am referring to four medications—aspirin, metformin (a diabetes medication), 5-alpha-reductase inhibitors like Avodart and Proscar, and Lipitor (a cholesterol drug).

In previous blogs I have presented arguments in favor of aspirin, Avodart and Proscar. In my next blog I’ll review some of the arguments for using metformin and Lipitor in patients with prostate cancer.

However, in the remainder of this blog I would like to outline an approach for reducing the risk of experiencing serious side effects:

1)     The greatest vigilance is necessary in the first few weeks after a new medicine is started.  When a medication causes side effects they usually appear fairly quickly.

2)     Generally, there is no rush. So why not begin at half dose? If after a few weeks or a month there are no negative side effects, the dosage can be gradually increased.

3)     Medication side effects follow specific patterns. Aspirin, for example, can cause intestinal bleeding.  So patients need to be carefully informed about the significance of any new symptoms of heartburn and the meaning of having black stools should they appear.

4)     Some side effects are only detected with blood tests.  Everyone who starts a cholesterol drug—Lipitor for example—needs to have liver function tested within a month or so.  Liver problems heal quickly if the side effects are detected and the medication is stopped in a timely fashion. It can be dangerous if negative effects persist undetected.       

*Ironically, in the absence of overt deficiency, when vitamin supplementation is subject to careful testing it sometimes has been shown to be deleterious.   Vitamin E is one good example. In a large randomized, double-blind placebo-controlled trial, prostate cancer mortality was higher in the men who took vitamin E compared to those who took a placebo. 

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