The Potential Benefits of Caloric Restriction

BY RALPH BLUM

There has been a lot written about the benefits to prostate cancer patients of eating mindfully. Boiled down to simplest terms, the notion translates as “Just eat less.”

I am always a bit uncertain when I read how mice prosper on some regime or treatment. Like the diet known as “caloric restriction,” which has all the normal healthy ingredients and food groups, but contains 30 percent fewer calories than usual. A New York Times article of July 10, 2009 stated that “mice kept on such a diet from birth have long been known to live up to 40 percent longer than comparison mice fed normally.”

Well and good. Further up the chain than flatworms. But still a long step from human results with caloric restriction. The next step was to use such a diet with rhesus monkeys to learn whether primates responded the same way as rodents. However, since rhesus monkeys have an average life span of 27 years and a maximum of 40, these experiments require patience.

Dietary restriction seems to set off an ancient strategy written into all animal genomes, that when food is scarce resources should be switched to tissue maintenance from breeding.

The rhesus monkey experiment requires another 15 years before the last monkey is expected to die. An eon, compared to flatworms, which have a life expectancy of about three weeks.

Twenty years after the experiment began, two studies, conducted by a team led by Ricki J. Colman and Richard Weindruch at the University of Wisconsin, reported in Science that the monkeys were showing many benefits, including significantly less diabetes, cancer, and heart and brain disease. “These data demonstrate that caloric restriction slows aging in a primate species,” the researchers wrote, which makes it likely that one could expect the biology of caloric restriction to produce similar benefits for humans.

While caloric restriction holds great promise, few people can keep to a diet with 30 percent fewer calories than usual. So biologists have been looking for drugs that might mimic the effects of caloric restriction, conferring the gain without the pain, so to speak. In recent years researchers have had considerable success in identifying the mechanisms by which cells detect the level of nutrients available to the body. The goal is to find drugs or compounds that trick these mechanisms into thinking that famine is at hand, hence the need for a severely restricted diet.

One such compound is resveratrol, a substance that can, apparently, duplicate in people some of the effects of caloric restriction. A member of a group of plant compounds called polyphenols, resveratrol is thought to have antioxidant properties that protect the body against the kind of damage linked to increased risk for conditions, including cancer since resveratrol is thought to limit the spread of cancer cells and trigger the process of cancer cell death or apoptosis.

The problem was that resveratrol, found primarily in the skin of red grapes (other sources include peanuts and berries) and, hence, in red wine, is present in quantities too small to have any effect, unless you drank about three bottles at a sitting. I have long been a fan of reveratrol, although I have despaired of acquiring enough of the compound to have a measurable effect on my system.

When it comes to resveratrol supplements, there isn't any specific dosage recommendation, and dosages can vary from supplement to supplement, although they are typically far lower than the amounts that have been shown beneficial in research studies. Most supplements contain 250 to 500 milligrams of resveratrol. To get the equivalent dose used in some animal studies, you would have to consume 2 grams of resveratrol (2,000 milligrams) or more a day. Not impossible. And arguably not a risk.

Now, Sirtris, a company based in Cambridge, Mass., has developed several chemicals that mimic resveratrol and can be given in concentrated doses. One such compound, the drug rapamycin, was reported to significantly extend life span in elderly mice, though it is not yet clear whether rapamycin sets off the same circuits as those that increase longevity in caloric restriction when ingested by humans. But there’s hope!

I remember when I was growing up, my Catholic classmates, like Dicky Doyle, ate no meat on Fridays. I reckon that at the very least, the meatless 24 hours gave their digestive systems a rest. Seen as a mild form of caloric restriction, meatless Fridays might well have had an impact on human longevity.

Perhaps if I can find a copy of the Beverly Hills High School alumnae, I can discover who is still around as we enter our 80s. And if they are still in possession of their faculties, perhaps I can learn what and how they’ve been eating for the last half century.

Meanwhile, there is evidence that those of us who eat as our ancestors ate do better in avoiding or fighting a variety of ills, prostate cancer among them.

In my upcoming blogs, I will revisit the eating habits of cave dwellers.

Imaging is Superior to Random Biopsy

BY MARK SCHOLZ, MD

Recently, our attention has been directed at the overtreatment of low-grade prostate cancer.  While PSA screening has been fingered as the problem, overuse of random needle biopsies is the real culprit. Over a million men undergo biopsies every year to address concerns about the possibility of underlying cancer.  Few people realize, however, that random biopsy reveals low-grade prostate cancer in one out of five men in the general population—even if PSA is normal.

 

Most of these “cancers” are harmless. Even so, it’s hardly surprising that patients with “cancer” want immediate treatment.  The words “low grade” or “microscopic” can’t offset the instinctual fears generated by this venomous word.   Despite dire warnings about the risks of treatment-induced impotence and incontinence—and reassurance from experts that low-grade prostate cancer can be safely monitored—studies show that 85% of men still throw caution to the wind and get treatment anyway.

 

Imaging is “Blind” to Small Low-Grade Cancers

While latent prostate cancers are more common, aggressive prostate cancer is also a reality. After all, 30,000 men die every year of prostate cancer. Back when doctors believed that all types of prostate cancer were universally dangerous, prostate imaging, which often misses small, low-grade lesions, was deemed inadequate. However, now with a more modern perspective we know that color Doppler ultrasound or multiparametric, three-tesla MRI overlook low grade disease while still detecting high-grade disease accurately.  Imaging spares men the shock of an unnecessary cancer diagnosis and unwarranted treatment.

 

Targeted Rather than Random Biopsies

When an overtly suspicious lesion is detected by imaging, a targeted biopsy (a limited number of cores aimed directly at the lesion) is typically recommended. Lesions that are biopsy-negative or show low-grade cancer can be monitored without treatment.  If high-grade disease is diagnosed, further staging followed by counseling about treatment is needed.

 

The doctor who reads the scan summarizes his 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

When to Biopsy Ambiguous Lesions
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, bulge the prostate capsule or are associated with increased blood flow or diffusion. An ambiguous lesion may require biopsy if a subsequent scans show an enlarging lesion. Expert judgment that takes individual patient characteristics into account comes into play during a discussion between the patient and doctor about whether or not a targeted biopsy is indicated.

“Cross Checking” Ambiguous Lesions
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.

New Technology Brings Growing Pains
You might think that new technological advances would immediately revolutionize prostate cancer management. Not necessarily. Many doctors simply don’t know what’s now available. Those that are aware are often unacquainted with the full capabilities modern imaging can achieve. And finally, even the well informed doctors may be reluctant to venture outside their comfort zone to embrace imaging as a substitute for doing a random biopsy.

Final Thoughts
Lack of awareness about how random biopsy leads to the over diagnosis of harmless, low grade cancers is resulting in a 100,000 men undergoing unnecessary surgery and radiation every year. Forgoing PSA screening altogether is both foolish and dangerous. State-of-the-art prostate imaging, not random biopsy, should be the first step in evaluating men with elevated PSA levels.

Join us in Long Beach, CA at Barnes & Noble Marina June 26, 2014 @ 7pm- Ask the Author: Mark Scholz, MD will be discussing his book, Invasion of the Prostate Snatchers and Men's Health. More June events and details here: https://groups.google.com/forum/#!topic/prostateoncology/H1AE5oeW2jc 

The Art of Being a Patient

BY RALPH BLUM

In an essay entitled Complications: Surgeon’s Notes on an Imperfect Science, Atul Gawande, surgeon, writer and professor at Harvard Medical School wrote: “Just as there is an art to being a doctor, there is an art to being a patient. You must choose wisely when to submit and when to assert yourself.”

 

This advice is especially important if you have just been diagnosed with prostate cancer. Because prostate cancer is so common, and in most cases so slow growing, that to submit to any form of radical treatment could be a huge mistake, and hugely detrimental to your quality of life. Yet most doctors you consult will advocate some form of radical treatment. It’s what they know, what they do. And it goes against the grain for both doctors and patients alike not to treat cancer.

 

But prostate cancer is unique among cancers because the mortality rate is so low. Autopsies reveal that more than 50% of older men have the disease, live with it, and die from something else—sometimes without ever knowing they had a life threatening condition. Furthermore, the life expectancy of men with recurrent prostate cancer stretches out well past a decade. And yet the radical prostatectomy, one of the most complex and challenging surgeries because the prostate is located in absolutely the wrong place for a simple surgical solution, is still the most widely recommended treatment option. It is also the most unnecessary, and the one most likely to leave you incontinent and/or impotent.

 

My own experience with urologists has not been a happy one. Twenty years ago, a doctor who wanted nothing but patient compliance, told me that if I did not agree to immediate surgery I would be dead in two years. His recommendation and prognosis were not only wrong, but in my opinion violated the ancient medical precept incorporated in the Hippocratic Oath: “First do no harm.”  Fortunately I was not the kind of patient to be easily intimidated.

 

A significant part of any doctor’s job is to create a relationship based on trust, confidence and hope. And as patients, our job is to put ourselves in charge of our recovery. It is our job to do the research, and give ourselves permission to say “No” if we feel the recommended treatment—for what ever reason, or simply instinct— is not right for us.  My decision not to be intimidated by what, in effect, was a death threat, but to monitor the cancer and take the time to educate myself, has given me many years of quality time with my wife that almost certainly would have been lost or diminished if I had committed to immediate surgery.

 

Doctors have busy lives. They believe in what they do. But often they tend to treat the disease and not the patient. Traditionally we’re encouraged to go along with whatever they recommend, and asking questions, or refusing to follow advice is unpopular.  But this passive attitude does not serve us well. The feisty, “difficult,” assertive patient, the one who challenges the doctor, is the one who has the best outcome.

Prostate Cancer Clinical Trials

MARK SCHOLZ, MD

Clinical studies are primarily performed on men with advanced prostate cancer (the Royal Shade of Blue). Why?  The FDA.   FDA only approves new drugs when survival is proven to be prolonged compared to similar men treated with a placebo. The FDA’s insistence on a survival endpoint forces pharmaceutical companies to limit their research to men with a short life expectancy. If survival has to be the endpoint and the study participants live a long time, the cost of performing the study goes up exponentially.

Undergoing experimental therapy with a new medication is reasonable consideration when standard treatment is either no longer working or is causing unacceptable side effects.  However, it’s rare for doctors to recommend an experimental medication before other FDA-approved drugs on the market have been tried.  The commercially available treatments already proven to extend survival are Lupron, Provenge, Xtandi, Zytiga, Xofigo, Taxotere and Jevtana.

Getting Involved in a Trial Can Be Challenging

Eligibility requirements for participation can be rigorous. Trials have carefully specified pretreatment and health status criteria: Eligibility may be denied if the patient is either too sick or not sick enough, if there is too much previous treatment or not enough previous treatment. Criteria are pre-specified so that the final results of the trial are not skewed by a lack of uniformity among patients.  Other requirements designed to achieve trial uniformity include stopping all other anti-cancer medications and the use of placebos, both of which at times may be at variance with a patient’s best interest.

An additional challenge is finding the right trial that matches a patient’s need. The clinical trials landscape changes quickly.  New trials are initiated with limited fanfare and close as soon as they have met their pre-specified number of participants. Trials available at one center may not be so at another.  Another difficulty patient’s face is how to determine the effectiveness of a prospective study drug. Is it likely to work or not?  Due to a study drug’s newness, its functional characteristics are often unclear to patients and doctors alike.

There are different types of study designs to consider each with different goals.  Phase I studies, for example, are primarily designed to learn more about a drug’s side effects. Phase I studies sequentially escalate medication dosages up to determine the point of dosage intolerability. Phase II studies treat a group of patients at a fixed dosage to get a preliminary sense of a drug’s response rates. Phase III studies are the final step that leads up to FDA approval.  Phase III trials are the placebo-controlled trials.

The Business of Clinical Trials

Patients contemplating participation in a clinical trial should be aware that the clinical trial world functions like a business.  It’s funded primarily by the pharmaceutical industry. As such, doctors working in academia are highly motivated to find participants in their research.  If trials are not completed in a timely fashion funding for new trials will be harder to come by in the future.

Participating in a clinical trial has become more attractive over the last ten years as the pharmaceutical industry has made significant strides toward understanding cancer.  Now that they have access to cancer “blueprints” it’s feasible for brilliant biochemists to design “software patches,” new drugs that are far more effective and far less toxic than what has been traditionally available.  However, patients need be careful they don’t mistake a “new” drug for being an “effective” drug.  Despite the tremendous advances in research, most phase I and II drugs still fail to meet minimum standards of clinical effectiveness and never even advance to phase III testing. Sadly, many of the potential prostate drugs that have been tested in Phase III studies over the last ten years have failed to meet the FDA minimum threshold of showing a survival advantage.

Dr. Scholz is the Principal Investigator at Prostate Oncology Specialists - a list of the active trials are found at http://www.prostateoncology.com/clinical_trials

IMRT: The Gift that Keeps on Giving

BY RALPH BLUM

By 2013, I had lived with prostate cancer for almost 25 years without submitting to any form of radical treatment. I was fortunate that my cancer was the non-aggressive, slow moving variety. And over the years I became a strong advocate of a “Die with it not from it” policy.

I learned early on that a “Whatever you say, doc,” attitude can be dangerous, and I knew that the longer I could simply monitor the cancer and use the time to educate myself about the disease, the better off I would be. However, the main reason I resisted radical treatment was the book Mark Scholz and I wrote with the sub-title: “No More Unnecessary Biopsies, Radical Treatment or Loss ofSexual Potency.” I reckoned I’d better practice what I preached.

Then, a little over a year ago, when my PSA suddenly spiked to 26 for no reason I could determine (like BPH or an infection), I figured the cancer was finally on the move. And maybe, after all these years, my immune system was no longer the staunch ally it had been. Mark was reassuring. My cancer hadn’t changed—it was still the non-aggressive type. Which meant the odds of surviving were pretty much in my favor if I decided not to submit to treatment. Still, “To treat or not to treat” remained the question.

After determining that the cancer hadn’t spread to my lymph system or to my bones (big relief there!), I couldn’t help wondering if perhaps I was pushing my luck by sticking to my credo. And to tell the truth, I was getting tired of living with cancer. So as I am no fan of surgery, and anyway at my age (81) it was not an option, I decided to go for a cure with IMRT, Intensity Modulated Radiation Therapy.

It is now almost five months since I completed 45 sessions of IMRT, and I could not be more pleased with the results. At first, I was dismayed to see a rather snail-slow descent of my PSA. Then I learned—and this is the really big news—that cell death, or apoptosis, continues after treatment for another year to a year and a half. According to Lisa Chaiken, MD, an admirable and patient teacher, who is in charge of St. Johns Hospital’s IMRT program, “The cancer cells turn over slowly. More and more die off with the passage of time. There is an immediate impact of the radiation—the damage, is done—but the process takes time."

And get this: the cells only die when the time comes for them to divide! In trying to participate in the creative process of replication, cell death, apoptosis, is the result.  The cancerous cells are actually committing suicide: How’s that for irony?

To confirm with visual evidence what is taking place, I’ve been to see radiologist Duke Bahn, MD and compared his various ultrasound images of my prostate: the multiple red tributaries indicating angiogenesis (the flow of new blood to the tumor), once as thick as a busy river delta, are now reduced to a scattered few!

An unexpected bonus for me from undergoing IMRT is a new understanding of PSA function, about which I was always uncertain in the past. Now that I understand the process, the behavior of my PSA—post-treatment—makes total sense: As the cancerous cells die off, the PSA falls. I am now almost five months post treatment, and my PSA has dropped from 26 to 17 to 7.8 and a week ago, in the most recent PSA, to a gratifying 2.8! A level I haven’t seen in a quarter of a century!

Technically speaking, I still have prostate cancer. But my cancer is terminally feeble, itself waiting for the final cut by the Grim Reaper of cancers.

IMRT is truly the gift that keeps on giving!