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Does Shockwave Therapy Work for ED?

If you’re struggling with ED, you may be wondering whether the latest miracle cure is actually a miracle cure.  You’re right to wonder.  The world of treatment for erectile dysfunction (ED) is complicated; add in emotional stuff like frustration and hope, and it can be even tougher to figure out what to do.  And here’s this new approach that’s making – well, waves.  It’s called shockwave therapy.  You may have seen ads for it on TV or the internet.

Maybe shockwave therapy deserves all the hype it’s been getting, and maybe it doesn’t:  more comprehensive research is needed, and it has not been approved by the Food and Drug Administration (FDA) as a treatment for ED. 

The good news:  shockwave therapy is noninvasive, doesn’t require pills or pumps or injections, and it doesn’t seem to cause any harm.

However:  Despite what the enthusiastic commercials and Youtube videos say, it’s not clear how well shockwave therapy works for ED.   It’s also not clear which men would benefit the most; doctors can’t give percentages of real success yet, nor can they predict how long the treatment’s effects will last.  However, “the suggestion that it works on everybody is highly questionable,” says Johns Hopkins neuro-urologist and Professor Arthur Burnett, M.D.  I have worked with Arthur Burnett for more than 25 years, at Johns Hopkins, here at VJ, on various editions of the book and most recently, as part of my work writing for the Prostate Cancer Foundation’s website.   For all that time, he has been not only a world-renowned investigator authority on the science and medicine of ED, including ED after surgery or radiation for localized prostate cancer; he’s been a voice of reason and hope for thousands of men.

Burnett is also part of a panel for the Sexual Medicine Society of North America (SMSNA) that released a position statement in March 2019, cautioning men about shockwave therapy and other new treatments for ED that aren’t FDA-approved.  The statement also mentioned stem cell therapy, platelet-rich plasma (also called the “P shot,” or Priapus shot), and even amniotic fluid.  Without FDA approval, the SMSNA states, “the use of any novel therapy is considered off-label.”

And yet, despite the lack of definitive medical evidence supporting its use, Burnett says, shockwave therapy is “being heavily advertised, a lot of urologists are very interested in this, and it’s caught on in a big way in South America and Asia as a treatment option for ED.”  In the U.S., shockwave therapy is being offered by a growing number of urologists, particularly in Florida.

What is it, exactly?   It’s low-intensity, extracorporeal shockwave therapy (Li-ESWT), “a machine that delivers acoustic signals and a shock to tissue, much like the lithotripsy machines used to treat kidney stones.”  The idea, Burnett says, is that “you can generate a mechanical energy effect on tissues, and have a potential benefit – stimulating angiogenesis (the growth of new blood vessels) in the penis, and stimulate local chemical factors in the tissues – growth factors, paracrine signaling (cell-to-cell communication), maybe even somehow activating stem cells.”

In other areas of medicine, shockwave therapy is used to treat problems ranging from diabetic foot ulcers to heart disease.   And “for the past few years, in the world of sexual medicine, there have been some studies and literature reports presented at national meetings on the potential role of this therapy in men with ED,” says Burnett.  “There’s a lot of buzz.”

The problem:  “It’s very controversial.”  Does it work? “That’s the big question.  There may be some evidence of a short-term benefit, probably in men with mild to moderate ED.  But the treatment settings, the outcomes – it all remains investigational.”

You might not get that bit of information from the commercials on TV and the internet.  “The ads are out there.  Doctors are buying these machines, saying, ‘Plop down your $2,500, and we’ll treat you.’”

In theory, shockwave therapy is “potentially restorative,” says Burnett, in that it “might regenerate erectile tissues.”  In animal models, shockwave therapy has shown some success.  However, he notes, “there is a lack of clinical trial evidence to support its effectiveness and long-term safety” in men with ED.   No study has determined the basic parameters: energy dosage, frequency, or duration of treatment.

Who knows?  It may turn out to be great — but again, probably not for everybody.  Shockwave therapy is “potentially an exciting new therapy in the world of ED management,” Burnett continues.  “But the best patients to expect a benefit from this have not been fully well-defined. The long-term success remains uncertain. People are thinking this is some sort of fountain of youth, or magical cure to correct their ED, but that has not yet been proven.”

What about ED after prostate cancer surgery?  The men most likely to be helped by shockwave therapy after prostatectomy are also the men who are most likely to benefit from pills such as Viagra: younger men whose erectile nerves have been spared, who don’t have cardiovascular problems or other diseases, such as diabetes, that can affect either blood flow or nerve function, or both.  “Men with more severe ED, men with significant diabetic or vascular disease-related ED, men who have very poor or nonexistent responses to the pills, probably won’t benefit from it.  These men should look at other therapies – the vacuum device, penile injections, or penile prosthesis surgery.

“The real truth is that we just don’t understand who should be using this. It seems safe; there are no obvious concerns about men having complications with it.  But patients should be informed that this may not be successful, and that it’s expensive.  To say, ‘Try it, because it might work for you, even though you already had ED before your radical prostatectomy,’ creates a false hope, and that’s not good.”

Burnett and colleagues on the SMSNA concluded that until there is FDA approval, the use of shockwaves or any restorative therapies for the treatment of ED “is experimental, and should be conducted under research protocols in compliance with Institutional Review Board approval.”  Men considering such therapies should be fully informed “regarding the potential benefits and risks. Finally, the SMSNA advocates that patients involved in these clinical trials should not incur more than basic research costs for their participation.”

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

© Janet Farrar Worthington

 

 

 

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The Long, Wet Road: Conquering Incontinence After Prostatectomy

Incontinence after prostatectomy is one of the most feared complications.  The good news is that for nearly all men, it goes away.  For the very small percentage in whom it doesn’t, there is help.  This story is a very strong case in point.

In my work for the Prostate Cancer Foundation’s website,  I was lucky enough to interview JP Mac, who has had a particularly difficult struggle with incontinence after prostatectomy.  JP (real name: John P. McCann) is a novelist and an Emmy award-winning animation writer who worked for Warner Bros. and Disney.

He is also very funny.  So, when he wrote a short ebook (coming soon in paperback form) about his experience with prostate cancer – including his diagnosis in 2014 at age 61, the rush to find the right treatment and get it done before his health insurance was going to expire, his laparoscopic-robotic prostatectomy and the complications afterward, and his five-month battle to recover urinary continence after the surgery – he could legitimately have written a soap opera, or maybe even a tear-jerker; but he didn’t.

Instead, his ebook has a title that sounds like 1950s pulp fiction: They Took My Prostate: Cancer, Loss, Hope.  It’s not “Prostate Cancer Lite,” and it doesn’t minimize what he or anyone else has gone through to get back to normal after radical prostatectomy.  Far from it; in fact, his “short, hopeful essay” is a testament to what it takes to recover from this difficult but life-saving surgery: a balanced perspective, a good sense of humor, a great support system, and plain old hard work and persistence.

Here’s a message you hardly ever hear about prostate cancer, or any illness, for that matter:  It’s okay to laugh!   That doesn’t mean it’s not scary, and that it doesn’t wear you down, or that you’re not afraid you won’t ever get back to normal.

But if it’s laugh vs. cry, Mac would rather laugh.  Although no cancer is great, he says, prostate cancer is “especially seedy,” and in his case, it involved  “bloody urine, black feces, incontinence, impotence, vomiting, and various other bodily malfunctions that shouldn’t be discussed before supper.”  But he does discuss them, with the hope of helping other men and their families.  Mac knows that talking about what’s happening gives the cancer less power over your life, and helps you focus on the light at the end of the tunnel – getting your life back after the cancer is cured.

Mac is speaking out about one area, in particular, that doesn’t get talked about much: urinary incontinence.  For many men who suffer from it, in fact, there might as well be a Cone of Silence over this subject, and that’s a shame, because there is always help for urinary incontinence after radical prostatectomy.

When Mac was diagnosed with prostate cancer, his surgeon told him to buy our book, Dr. Patrick Walsh’s Guide to Surviving Prostate Cancer.  Mac did, and he referred to it a lot – especially our review of the male plumbing, which explains why at least some temporary incontinence is just about inevitable for men after radical prostatectomy.

Note: Long-term urinary incontinence is very rare after radical prostatectomy.  Results differ depending on the surgeon; also, some men have quirky anatomy — very subtle anatomical variations (not like a leg where an arm should be, or anything like that, but even tiny differences can be important in surgery, and good surgeons know this and look for such variations).  This is why, if you are considering radical prostatectomy, it is essential to find out how many of that surgeon’s patients have long-term complications.  If your surgeon doesn’t know, consider this a red flag.

The best surgeons keep track of their patients after radical prostatectomy. “In young (men in their forties, fifties, and early sixties), healthy men operated on by an experienced surgeon,” Walsh says, “about 80 percent should be wearing no pads – or at most, a security pad to catch the occasional drop – by three months after surgery, and at 12 months, 95 to 98 percent should be continent.”  Walsh considers a man continent “if he wears no pad or if he wears a pad that is dry.  “Many men continue to wear a small pad just to be safe,” he explains.  Your surgeon may have a different definition of continence, and you should find this out before surgery.  “Most men, even at three months, are not very wet.  It’s hard to believe, but urinary control does continue to improve over two years, and occasionally, even longer than that.”

But don’t lose hope, he adds:  “For many men, the recovery of urinary control is a slow process. The most important thing you can do is not get discouraged.  If your doctor told you there is only a 2 percent chance that you will have a long-term, serious problem with urinary control, believe it.  This means there’s a 98-percent chance that you’ll be back to normal someday, even if nobody can say exactly when.”

From Three Sphincters to One

Why is urinary control an issue after surgical removal of the prostate?  Normally, Walsh says, men have not one, not two, but three separate anatomical structures to control urine.  There is a sphincter in the bladder neck, one in the prostate itself, and then there’s the external sphincter (also called the striated sphincter), below the prostate. Radical prostatectomy knocks out two of these, leaving only the external sphincter to do the work of three.

Because of the other two sphincters, in most men this external sphincter is never tested or even used much; there is no way to know before radical prostatectomy how strong it really is.  Also, like every other muscle, this sphincter loses its tone with age.  A complicating factor is that older men are more likely to have some benign enlargement of the prostate (BPH), too. This could make the bladder thicker and more muscular – and much more powerful than a sphincter that may not have been that effective to begin with.

Mac didn’t really think about this in a lot of detail until his catheter came out after the surgery.  “A nurse handed me a thick cotton pad to put in my underwear.” Mac’s urologist “warned me that the urine was coming, as surely as a Cambodian rice farmer predicting the monsoon. Little could be done, he explained, until I underwent physical therapy. There I’d learn exercises to strengthen the underused muscles of my external sphincter.”

Mac was so happy to have the catheter out that he thought the worst was over.  Cotton pad in place, he made an appointment to come back in three weeks, and took his wife out for breakfast.  “Rising an hour later after three cups of coffee,” he gushed urine “as if putting out a fire in a wastebasket.”  It turns out that the worst was just beginning.  “Basically, the bladder holds urine until a series of reflexes causes a bathroom urge.  Bladder and sphincters then receive a message from the brain to check flow until an appropriate time. When you’re incontinent, any time is just dandy.  You can experience stress incontinence with activities that suddenly increase pressure inside the abdomen, like lifting or standing. Then there’s urge incontinence, which is a sudden uncontrollable need to leak.  Finally, there’s overflow incontinence when you can’t sense if the bladder was filling.  I had all three.”

Suddenly, Mac’s new normal was a life with absolutely no bladder control.  “Movements gross and subtle, lying on my back, it didn’t matter. Everything ended in a demoralizing urine surge. I really needed that physical therapist. But our new insurance had other ideas.”

While he “moped around home like the Incredible Surging Man,” his wife, Joy, spent hours on the phone wrangling with the old and new insurance companies, whose bureaucracies were “sharp as a paper cut,” Mac comments. Meanwhile, he experimented with leakage protection:  “I tried packing my regular underwear with cotton pads. That idea cratered in less than a day. Not only were ‘man diapers’ necessary, but they required cotton pads inside as well. I was soaking through three pads a day minimum. Each morning, I’d wake up drenched, smelling like an interstate washroom.”

Days passed until, Joy finally convinced the insurance company that “we were, indeed, customers and had paid for a specific plan.” Then, the insurance company insisted that the physical therapist wasn’t covered by the plan.  Mac was desperate; his urologist’s office staff stepped in to wrangle with the insurance and finally got the go-ahead for the physical therapist. While all this was happening, “I lived the life of the urine free spirit.  Avoiding coffee or soda mattered little. No internal spigot staunched the constant flow.”  Mac got sick of smelling urine, of feeling that he was “marinating in pee.”

Three or more times a night, he says, “I’d awaken with man diapers soaked and pressure on my bladder. Sitting up, I’d whiz into a hand urinal, change, clean myself, then lie back down and hope for a little sleep before the next voiding.”

At last, Mac could see a physical therapist.  Mac drove to the appointment – his first time behind the wheel since the operation – hopped out of the car, and soaked himself again.  Then he met Eva, his physical therapist, who used biofeedback to help him identify the right muscles to use.

“She hooked my perineal and abdominal muscles to a laptop via adhesive pads, and for the next hour, gave instruction in finding, then clenching and unclenching my striated sphincter in order to control urination. On the computer screen, I could monitor my efforts. A moving graph alerted me when I targeted the correct muscles.”  Mac learned how to do Kegels – clench-and-release exercises to strengthen the pelvic floor muscles below the bladder.

“I found biofeedback to be of great value,” and for Mac, it helped him start to regain bladder control.  “I know a guy who underwent the same radical robotic prostatectomy,” he says.  “Afterwards, his urologist tossed him a few sheets of diagrammed Kegel exercises and said ‘Vaya con Dios.’ No one told my friend you could overdo these exercises. While other factors may’ve been in play, his continence recovery turned out to be longer and messier than mine. Maybe a little biofeedback could’ve improved his condition quicker.”

Eva gave Mac daily exercises with frequency and duration goals.  She also encouraged him to walk daily.  Psychologically, the Kegels were important,” he notes.  “I lived with a constant dribble that could transform into a flood. Eva’s exercises provided me concrete specific actions. She also warned me against overtraining that could fatigue the striated sphincter, rendering it too tired to work.”

Five days later, at his next PT session, “I saw progress.”  For the first time, he could stand up without urinating.  Next, he learned to anticipate the “go” urge – and not wait until he felt pressure in his bladder.  “I could then reach the toilet with something left in the bladder.”  Mac discovered that, in order to stand up without putting excess pressure on his bladder, he had to walk bent over, “like Groucho Marx.” At first, he could go maybe three or steps without a surge.

Joy noticed improvement before Mac did; so did his urologist, who told him, “a lot of the discomfort you’re feeling now will pass. Once you strengthen the striated sphincter, your bladder urges will stabilize.”

There was some good news:  Two months after surgery, Mac’s PSA was undetectable.  His cancer was gone!  And finally, after much hard work, his bladder control began to return.  “With persistence, I sensed how to locate and activate my new bladder-control muscles.  Eva suggested I aim to eliminate jug peeing (with the handheld urinal at night) and excessive bathroom visits.  Using the striated sphincter, I should school the bladder, aiming for fewer, but more productive, bathroom trips. In the meantime, I discovered a cost-effective method of cutting down on cotton pads out in public. By inserting several sheets of double-ply toilet paper into my man diaper, I caught the wild leaks. Just toss and replace the tissue. It was easier than finding a stall and swapping out cotton pads.”

Then, for two nights in a row, he only urinated once. By mid-November, nearly two months after his surgery, “I’d slept an entire night without awakening to pee.  In the morning, I loped ape-like to the bathroom and urinated. Just after Thanksgiving, I stopped wearing man diapers and returned to underwear, albeit with a cotton pad and toilet paper inside.”

For Christmas, Mac and Joy flew to the Pacific Northwest to visit his sister.  Traveling was “an adventurous time, with me unable to cross forty feet of airport concourse without running into a washroom jackknifed over.  I grew to be an expert at identifying tile patterns.”

But even his “odd potty walk” would not last forever. By March 2015, “ I could check flow and walk upright to the bathroom.  My newly discovered striated sphincter knew the routine and exceeded expectations.  I’d finally turned a corner.”

It might not seem like it now, if you’re going through the worst of what Mac endured, but remember: only about 2 percent of men have long-term incontinence after radical prostatectomy, and if you’re in that percentage, there is still hope. Talk to your urologist about biofeedback, which made all the difference for Mac.  Other options include collagen injections, a mesh sling to help take some of the pressure off of the sphincter, and for severe incontinence, an artificial urinary sphincter.

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

© Janet Farrar Worthington

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Block SRCs, Kill Prostate Cancer?

This is part of On the Horizon:  a series written with the sole purpose of sharing hope:  showing you some of the new treatments that are being developed to fight cancer that has defied everything else.  Because I write for the Prostate Cancer Foundation’s website, I get to interview scientists developing highly promising treatments that aren’t widely available yet, but they’re in the works.  Salma Kaochar, of Baylor College of Medicine, is one of these scientists.

How do you stop a runaway train?  Take a few seconds and think about it; feel free to draw from any runaway-themed movies you might have seen.

Well, you could go after the track: rip it up: a train can’t go very far without a track.  Get rid of its fuel:  this was an idea in “Air Force One,” where Harrison Ford dumped jet fuel in mid-air.  Slow it down:  in “Unstoppable,” Denzel Washington and Chris Pine tried to halt a runaway by pulling it from behind with another engine. This didn’t work for very long; next, they tried to engage the brakes – first on the individual cars, and then on the main engine.  Blow it up: If you didn’t really care about innocent bystanders or collateral damage, you could just take a rocket-powered grenade or heat-seeking missile and try to destroy the runaway engine… if you happened to have such a weapon, if you knew how to use it – and if, of course, this weapon actually works like you hope it will.

Metastatic prostate cancer is like a runaway train. Every day, scientists are getting closer to stopping it, with a drug or treatment that targets one of cancer’s weak spots.  Cut off its fuel:  That’s the reason for ADT (androgen deprivation therapy), shutting down testosterone and other androgens (male hormones) that drive the cancer; and also for androgen receptor-blockers, drugs like abiraterone and enzalutamide.  Hinder its ability to grow:  that’s the purpose of chemotherapy, and of drugs that target angiogenesis – like the tracks for the train, there are pathways cancer needs before it can get rolling.  But these types of drugs often don’t work for long.

Wouldn’t it be nice to target several of these ideas at once?  Not an either-or situation, but a “this mechanism and this one, too, and also this one.” 

That has been the dream.  What could be even better?  A drug that would not mess with the male hormones; something that would enable men to keep their testosterone and prevent the side effects of ADT.

We may have found one.  It’s preliminary, and probably two years away from clinical trials, but Salma Kaochar, Ph.D., Nicholas Mitsiades, M.D., Ph.D., and colleagues at Baylor College of Medicine seem to have found a promising new strategy that rips up the track, and dumps the jet fuel, and turns on the brakes – and causes, at least in mice, no collateral damage. 

It shortstops prostate cancer at the protein level and at the same time, turns up the immune system – in a way unlike any form of immunotherapy currently available– and doesn’t affect testosterone at all.

“We are developing a first-in-field approach to target the previously undruggable family of cancer-promoting genes for the treatment of both androgen receptor-dependent and androgen receptor-independent castrate-resistant prostate cancer (CRPC),” says Kaochar.  She presented her findings at the 2018 Scientific Retreat of the Prostate Cancer Foundation.

What is this secret weapon, and how does it work?  If we continue with our movie analogies – and pardon me for doing so, but otherwise this stuff is hard to explain – then it’s like that scene in “Raiders of the Lost Ark,” where Indiana Jones, faced with a fearsome, sword-wielding assailant, pulls out a pistol and shoots him.  He doesn’t try to out-fence a master swordsman.   He changes the game.

Kaochar and colleagues have found a potential game-changer, a target that no one has ever tried in cancer before: p160 SRCs, or “steroid receptor coactivators.”  These are “master regulators of transcription factor (key proteins) activity necessary for cancer cell proliferation, survival, metabolism, cell motility, invasion and metastasis,” she explains.  “In prostate cancer, they are required for the function of the androgen receptor and its variants.”

Transcription factors are proteins that act as a key to turn on a gene – just like a key in the ignition of a car.  Except here, if you have more keys, you can make the engine go faster.   “In CRPC, there is frequent overactivation of p160 SRCs,” Kaochar continues. “This results in increased androgen receptor activity, faster growth of the prostate cancer cell (more powerful and determined cancer cells), resistance to therapy, and bad outcomes.  Increased levels of these SRCs are associated with very poor prognosis.  SRCs are also important for the energy homeostasis (energy balance) in prostate cancer.”

The most deadly prostate cancers are addicted to SRCs.  They’re like crack for cancer. 

But guess what?  “SRCs can be reprogrammed.  They can be suppressed.”  And this can happen in localized tumors as well as in metastatic cancer.  Theoretically, there is no point in cancer at which this couldn’t start to work.  “Our goal is to find something to hit cancer at that late stage, where there’s absolutely no other treatment, where it’s all over, everywhere.”

In mice, Kaochar and colleagues are using “pulses” of treatment, not one continuous treatment.  Each pulse shuts down all the machinery cancer needs to grow, and also energizes the body’s immune system to fight the cancer.

Overactivation of SRCs appears to be extremely common in prostate cancer, and in other forms of cancer, as well.  So far, in laboratory tests using various types of aggressive, hormone- and chemotherapy-resistant prostate cancer cells (because men with prostate cancer don’t all have the same genetic mutations), 100 percent of prostate cancer cell lines tested in a dish have tested positive (see below) as being driven by SRC.

“These p160 SRC molecules are important in many cancers,” Kaochar says, “including uveal melanoma,” a particularly nasty form of melanoma that attacks the eye. “Uveal melanoma is a hormone-independent cancer, and it is heavily addicted to these molecules.”  Not only is uveal melanoma deadly; it is an “orphan disease,” rare, and lacking big financial support for research.  Kaochar’s research, funded by the Prostate Cancer Foundation, may lead to the first effective treatment for this disease, too.

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Could Controlling Metastatic Cancer Really Be Just a Matter of Tweaking?

If you’re a certain age – old enough to remember life before digital TVs – you probably know a lot about the fine art of tweaking.  If your picture was fuzzy, there were lots of ways to fiddle with the TV to try to fine-tune it.  There was the antenna, of course; actually, there were two, one up on the roof, and the rabbit ears on the TV set itself.  Then there were the knobs:  color, contrast, brightness, horizontal and vertical control.  It took a lot of trial and error, but tweaking was the key to a better picture.

Could controlling cancer be anywhere near that simple?  Well, in practice, it’s a heck of a lot more difficult, but the idea may be that simple:  tweaking the cancer cells, and also fine-tuning the normal cells.

Salma Kaochar and colleagues at Baylor are really developing several things at once: One is a sophisticated test to see if a man’s prostate cancer – and, quite possibly, anyone’s melanoma, breast cancer, pancreatic cancer, glioblastoma, ovarian cancer, etc. – is controlled by SRCs, which do various biological things, ranging from housekeeping chores like DNA repair, to controlling the metabolism, to controlling various proteins and driving cancer cell growth.  She is working on a simple test that works like a stoplight:  green means positive, yellow means maybe, and red means no. But the thing is, cancer might test red today, but as it continues to mutate and become more dangerous, it might test green in a few months. 

So far, 100 percent of the various prostate cancer and other cancer cell lines Kaochar has tested – in RNA sequencing and tests of more than 1,000 different genes – have come back green.  “More than 92 percent of the genome is coded by SRCs,” says Kaochar. “In prostate cancer and breast cancer, we have seen the same thing, and we believe it’s true in multiple different cancers.”

In cancer cells in a dish, “SRC 160 looks like a real vulnerability,” says Kaochar.  Jonathan Simons, M.D., medical oncologist and molecular biologist, and CEO of the Prostate Cancer Foundation, which has funded this work, describes it as “hitting the carotid artery.  If it works, it would be a stopper.”

But, “the more we learn, the more complicated the story gets,” Kaochar cautions.  “It’s exciting to have something that does so many things and has so much promise.  But at the same time, we have to carefully examine everything, and make sure there is no toxic effect.  That’s the spectrum where we’re really focused right now.”

Because this is first-in-field – a whole new class of drug – it will require a lot more testing before it can be tried in humans. Starting with cell cultures, then mice, then rats, then larger mammals.  “We just don’t know what their off-tumor effect,” on normal cells that are just minding their own business, “would be.”

Kaochar’s idea is that this drug would tweak the body: turn down SRC function in cancer – slowing down cancer cell growth, and also shutting down the cancer’s drive to metastasize – but also turn up the immune system at the same time, so the body can fight off the cancer.

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

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Regular Guy, Exceptional Responder

I’ve said it before, because this is what some of the finest researchers in prostate cancer have told me:  The goal for aggressive prostate cancer is to find out which genes are involved and treat with gene-specific medicine — ideally, even preventing the need for androgen deprivation therapy (ADT).  We’re not there yet, but some men are blazing the trail for the future.  Chris Seelye is one of them.  He just happens to have a mutation in a particular gene, BRCA2, that just happens to respond particularly well to platinum-based chemotherapy: a drug called carboplatin, given in combination with another chemotherapy drug, docetaxel.  Chris is an exceptional responder to this treatment.

The very best part of my work, including the writing I do for the Prostate Cancer Foundation, is getting to talk to men like Chris:  men who are beating the odds dramatically.  Men who weren’t expected to make it, who are, in fact, thriving because of treatments that didn’t exist a few years ago.

Not very long ago, the future looked pretty bleak for Chris.  At just 62, this professional photographer from Washington State thought he had maybe a year to live.   “I was facing a terminal illness and was reaching the time where I had to start making decisions,” he says.  Decisions like, “Do I continue pursuing my love of photography, or is it time to start selling equipment and cutting back and sitting on the couch dreaming of the days when I could do those things?”

Then Chris, a U.S. Navy Veteran who served in the Vietnam era, joined a clinical study.  His oncologist, Bruce Montgomery, M.D., is leading it at the Veterans Affairs (VA) Puget Sound Health Care System as part of a new partnership  between the VA and the Prostate Cancer Foundation.  Montgomery, who is also on the faculty at the University of Washington School of Medicine, Fred Hutchinson Cancer Center, and the Seattle Cancer Care Alliance, thought Chris might do well in this study because of the genetic makeup of his metastatic cancer.

He did not anticipate that Chris would go into complete remission,  because he had “metastatic, castrate-resistant prostate cancer,” Montgomery says, “the kind that kills men.  As part of the VA-PCF collaboration, we did deep (genetic) sequencing of his cancer and we found that he has a mutation in his BRCA2 gene.  Because we knew he had this, we got him in this study.  His PSA has gone from over 200 to 1.  The scans he had initially, which showed metastatic disease, are now essentially normal.  He’s had a complete radiographic response.”  In other words, scans are not able to find cancer in Chris Seelye.

What Helped Chris?  A Chemo Combo

Men in this study receive carboplatin (not a standard drug in the treatment of prostate cancer) along with docetaxel.  Small data sets from Montgomery’s group and others predicted an 80-percent likelihood of response to this treatment if a patient has a tumor with BRCA2, and those responses are likely to be “exceptional” – significant and long-lasting. On the other hand, the expected response to docetaxel alone (the standard chemotherapy Chris would otherwise have received) is 25 percent or less.

Exceptional responses are what ongologists wish for desperately but, too often, do not see in men with metastatic prostate cancer. “It’s hard to actually put into words, to be honest with you,” says Montgomery.  “We all, every day, hope for a miracle.  And this is as close to a miracle as we get right now.”

PCF funding helped develop gene-targeted therapy– a whole new way to approach cancer. Recent research, also funded by PCF, found that people with many different kinds of cancer share mutations in genes like BRCA1 and BRCA2, which are often linked to breast and ovarian cancer. This means that a drug that helps a woman with breast cancer who has a defective BRCA gene will also help a man with prostate cancer who has the same bad gene.  It’s treating the gene, not just treating the specific organ that has cancer.

“Not Going to Let Myself Get Depressed.”

 Chris joined the Navy when he turned 18, did a four-year hitch at the Naval Air Station in Alameda, California, was honorably discharged as a 3rd-class Petty Officer, went to school on the GI Bill to “learn about things I didn’t know,” and has spent his career doing mainly industrial, technical, and nature photography, plus professional printing and publishing.  “I learned of my prostate cancer in 2014,” he says, “after a year of working with my primary caregiver to diagnose a set of (urinary) symptoms.”  When he finally took a PSA test, it was “through the roof,” and a biopsy diagnosed high-grade cancer.

Although some men might go through “a period of denial, saying ‘why me,’ I never really had that,” Chris says.  “I knew that keeping a good attitude was paramount to successful treatment, so I refused to let myself get depressed, and even to this day, I have not gone down that road.  I just couldn’t get myself to make it worse.”  It helped him, Chris adds, early on when a doctor explained, “We’re not treating your cancer, we’re not curing your cancer.  We are managing.  That was very helpful in terms of my acceptance, not getting this false hope of, ‘maybe I’m the one, the first person to ever beat a terminal cancer.’”

And yet, here he is, the exceptional responder.  Chris is still getting used to the term.

At first, “my expectations were that realistically, this is my best last chance.  I was either going to be dead within a year or this was going to present a better alternative.  So far, the results have been pretty stellar.”  But Chris is cautious when he talks about the future. “I would phrase it that I have optimism, as opposed to hope.  I know that still, we’re not talking about cure, we’re talking about management – but I’m optimistic.  I had an expected expiration date.  Now, with participating in this study, that’s taken away.  I don’t see an expiration date any more– or if there is one, it’s years out, as opposed to months out.”

Although he’s not ready to call this combination therapy a life-saver, “it certainly is a life-extender.  I’m highly optimistic that this quite likely is going to keep me going long enough for the next round of treatments that are in the research phase now.”  One day, he believes, his doctors won’t be talking about a terminal illness anymore, but a chronic one.  “I’ll take chronic over terminal any day.”

If you have just been diagnosed with, or are battling prostate cancer, Chris has this advice for you:  “Don’t just hope, but know that new treatments are coming online practically as we speak.  Newly diagnosed patients actually have better treatment options than I had just three years ago.”  And if you have not been diagnosed with prostate cancer but are having urinary symptoms:  “Get the PSA test.  I was 59 when I was diagnosed.  Had a PSA been done when I was 55, maybe the outcome might have been different early on.”

And, if you can, participate in a clinical trial:   “It’s a life changer.  With this study, new questions are being asked and investigated. It happens that I have this specific genetic defect.  This alliance between the VA and the PCF looking at exactly that question has allowed me to participate in a study and my prognosis is very different than it was. I would strongly encourage the VA to participate in every cancer study that they can get their hands on, particularly as we’re moving away from  management to actual treatments” for metastatic cancer.  “I happen to be one of the very early patients who actually has optimism that in my course of treatment, we’re going to actually achieve the transition from terminal illness to chronic illness.”

For now, as for selling his beloved photography equipment: “That’s off the table!  I’m looking forward to the winter of (photographing) migratory birding season; that’s going to start up in less than a month. I’m ready to go and I’m ready to keep going.”

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

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My Prostate Cancer Talk

I’ve had a lot of requests to print a talk I recently gave. Here it is. — Janet

Recently, I took part in a large, two-day community cancer seminar in Prescott, Arizona, presented by Prescott United Methodist Church.   Many people have asked for copies of my talk, so here it is.  Readers of this blog will find some of this material familiar, but I’ve collected it all into one place.  I would call it “Prostate Cancer in a Nutshell,” but that doesn’t sound very good… I’m sharing it with you now because I want you to know that there really is hope.

I’m not a doctor.  But I have been writing about the very latest in prostate cancer research and treatment for more than 25 years. What I hope to do today is give you kind of a “state of the union” talk on the latest advances. Some of these are not yet available, but they are coming. Everything I have to talk about is very hopeful.

I started writing about prostate cancer when my father-in-law died of it at age 53.  I was the editor of the Johns Hopkins medical magazine at the time, and so I arranged to interview Patrick Walsh, Director of the Brady Urological Institute at Hopkins.  I had no idea that he was the surgeon who invented the nerve-sparing radical prostatectomy, the operation to remove the prostate but preserve continence and potency. We wrote an article about prostate cancer in 1993, it got 3,000 requests for reprints, and when my daughter, Blair, was born, I left Hopkins and Pat Walsh and I wrote our first book.  We’re now on our sixth book.  At that time, PSA, prostate-specific antigen, was new, and although there was a PSA blood test, nobody knew what to do with the results.  I made my dad start getting the PSA test, and my mom and I made him start getting his prostate checked.  He did not appreciate it, especially the rectal exam.  But he did it, and in 1997 was diagnosed with prostate cancer, even though his PSA was very low – 1.2.  Patrick Walsh took out his prostate.  He had no complications from the operation, and his PSA remains undetectable today.  That was 21 years ago, and he just happens to be visiting today.  Dad, hold up your hand. (VJ readers, my dad got a big round of applause here!)

SCREENING

I’m starting with screening, because it just makes me mad.  Screening is the best thing you can do to avoid dying of prostate cancer.  But ever since 2012, millions of American men haven’t been screened for prostate cancer because their doctor said they didn’t need it, because that’s what the U.S. government told them.  And yet: About one out of seven American men – about 160,000 this year alone – will be diagnosed with prostate cancer at some point in his life.  Not all prostate cancer needs to be treated; many men with low-risk cancer can safely do Active Surveillance.  But many men do need treatment.

American men need a baseline PSA test and rectal exam to check for prostate cancer in their forties, and then they need follow-up screening at regular intervals.  Men who are at higher risk – men with a family history of prostate cancer and other cancer, and African American men – need to start screening earlier, ideally at age 40.

In 2012, the government – the Congressionally funded Band of Geniuses known as the U.S. Preventive Services Task Force, USPSTF for short –recommended against routine screening for “men of average risk” for prostate cancer.  There was not a single urologist on this panel, by the way. The USPSTF placed fear of overtreatment over the value of detecting curable disease.

Many urologists and oncologists believe the USPSTF made some bad assumptions. One is that many men are treated overzealously; that men who have slow-growing disease are subjected to surgery or radiation and suffer side effects from treatment they didn’t need. And it is absolutely true that, back in the 1990s when scientists were just beginning to figure out PSA, many men were treated who probably didn’t need it.

But that’s not the case today.

The other bad assumption was that all men are the same.  They’re not.  Some men are a lot more likely to develop the kind of prostate cancer that really needs to be treated.  These include men with a family history of prostate cancer and men of African descent.  Also, we now know that just having a history of cancer in your family – even if it’s not prostate cancer – raises your risk of getting prostate cancer.  Also, all men of average risk are not alike:  men who smoke cigarettes, for example, are at higher risk; so are men who are obese. We’ll get to that.

This summer, my boss at the PCF, medical oncologist and molecular biologist Jonathan Simons, sent me an article in the World Journal of Urology.  The senior author was Jim Hu, urologist and urologic oncologist at Weill Cornell Medicine.

The title: “Unintended Consequences of Decreased PSA-based Prostate Cancer Screening.” The article begins: “In May 2012, the USPSTF issued a grade D recommendation against PSA-based prostate cancer screening,” which is why so many family doctors stopped screening men for prostate cancer.

So, how is that working out for us?

To find out, Hu and colleagues looked at nearly 20,000 men at nine high-volume referral centers in the U.S. from 2008 to 2016.  They broke these men into two groups– from 2008-2012, and 2012-2016.  Before and after the Band of Geniuses.  From 2012-2016, they found fewer men were diagnosed with low-grade cancer, the kind that is easiest to kill.  Unfortunately, what this really shows is that these cancers were not caughtwhen they were low-grade.  They also found across the board that high-grade cancers increased by 24 percent.

Between 2008 and 2012, 6.2 percent of men had a biochemical recurrence, a return of PSA after treatment, which is not supposed to happen.  Between 2012-2016, that number had nearly tripled to 17.5 percent. All centers experienced consistent decreases of low-grade disease and absolute increases in intermediate and high-risk cancer.

The new guidelines give a grade of C, which is not exactly encouraging but is better than a D, to prostate cancer screening in men aged 55 to 69.  This is still not good enough.    

If you want to know the value of PSA screening, ask the 45-year-old guy diagnosed with metastatic prostate cancer who’s just starting ADT, androgen deprivation therapy, the suppression of male hormones including testosterone.  Oh, wait – 45-year-old men aren’t even mentioned in these guidelines.  Some men are diagnosed with prostate cancer in their early forties, and a few are diagnosed in their late thirties.  For many men, age 55 is too late to start screening.  And 69 is too early to quit.  

Pat Walsh and other Hopkins scientists recently reported that even using age 75 as a blanket cutoff for PSA screening is missing some significant prostate cancer. Men diagnosed at 75 or older account for 48 percent of metastatic cancers and 53 percent of prostate cancer deaths.  So basically, if you’re in good health and are 75 and over and you don’t want to die of prostate cancer, you should keep getting screened.

Also: many men don’t know their family history.  You may be at higher risk and not know it.

Do you need screening for prostate cancer?  Well, Do you want to know, or not?  If you do, ask your doctor to start checking you for prostate cancer, with a PSA blood test and a physical exam.  If you don’t, then don’t.

But remember: If you are diagnosed with prostate cancer, that doesn’t necessarily mean that you need treatment.  You may be that guy who can safely live his life with a little bit of cancer that will never spread beyond his prostate.

If you are diagnosed with cancer that needs to be treated:  Prostate cancer that’s localized, confined to the prostate, can be cured with surgery or radiation; however, both treatments have a risk of side effects, including erectile dysfunction (ED) and, with surgery, the risk of incontinence. With an experienced surgeon at a high-volume center, the risk of complications is much lower.  These side effects are often temporary, and they can be treated.  With ED, where there’s a will, there’s a way:  in other words, if you want to have your sex life back, there are treatments that will restore it.  And don’t let anyone tell you that men who get radiation instead of surgery dodge the ED bullet.  They don’t. But again, there are good treatments, and I have specifics in the book and on my website.

Incontinence is usually temporary after surgery, and gets better as your muscles get stronger.  If it persists, there are treatments for this, as well.  

Maybe you’re thinking, “The treatment is not worth it. I don’t want the side effects. I’ll take my chances and just deal with cancer if I have to.”  If it turns out that you do have it, and that the cancer has spread outside the prostate, it may not only be very difficult to cure:  In this case, side effects aren’t just a “maybe.”  You will definitelyhave side effects from ADT– androgen deprivation therapy, the shutting down of male hormones including testosterone.  These can include impotence, breast swelling, weight gain, bone density changes, a higher risk of metabolic syndrome, diabetes, heart attack, stroke, or cognitive changes.   Note: These side effects can and should be fought with diet and exercise, and many men do very well on ADT for decades. But catching the disease early and treating it while it’s confined to the prostate, is better.

 

DIAGNOSIS 

Very briefly:  The whole point of getting regular PSA tests is to watch what the number does.  It should not be going up.  If it is, you should have a prostate biopsy.

Biopsies are not infallible.  Even with 12 or 14 cores of tissue (it used to be 6), cancer can still be missed.  Why?  Prostate cancer is multifocal– that means, there’s not one obvious tumor that sticks up like a marbleand screams, “Here I am, I’m cancer!”  The average prostate that has cancer in it has seven individual spots of cancer– and if you think of the prostate as a strawberry, these spots of cancer are like the little black seeds on it.  Just little dots.  They’re easy to miss.  African American menhave an even tougher situation; their prostate cancer tends to develop in an out-of-the-way place at the apex of the prostate – the attic, instead of the basement, where the needle comes in, so it’s harder to reach.

Several new forms of MRI can help target a biopsy and detect cancer.  I recently wrote about a man named Rob who was a human pincushion; he had endured five prostate biopsies, some saturation biopsies – all inconclusive.  But his PSA kept rising.  In fact, he had developed scar tissuein his prostate that masked the presence of cancer.  But a fusion biopsy, guided by MRI and ultrasound, found cancer.  Robhad his prostate out, the cancer turned out to be intermediate grade; it was confined within the prostate, and he’s fine now.  Rob is just 49 years old.

MRI is even more effective when combined with PHI – the Prostate Health Index.  This is a “second-line” blood test that combines three molecular forms of PSA into a single score.  There are other “second-line” biomarker tests, and more on the horizon, including tests for circulating tumor cells in the blood, urine tests, and molecular and genetic tests of biopsy sample tissue. One of these, developed by Hopkins pathologist Angelo De Marzo, is called the PTEN IHC test.  IHC is immunohistochemistry, and it involves using antibodies to stain cells.  PTEN is a “tumor suppressor” gene; it puts the brakes on cancer.  But cancer doesn’t like brakes, so in about half of all lethal prostate tumors, PTEN is knocked out. The loss of PTEN is a powerful predictor of aggressive cancer.  This test is not widely available yet.

Second opinion on pathology:

Another thing you can do is get a second opinion on your biopsy slides.  You can send your biopsy tissue to an experienced tertiary-level hospital to have a urologic pathologist take a look at it.  At Hopkins, world-class pathologist Jon Epstein and colleagues do second opinions on 15,000 cases a year, sent from all over the world.  They can also do IHC and other tests.

 WHAT CAUSES PROSTATE CANCER? 

Chronic Inflammation.  One cause of chronic inflammation is charred meat.

When meat is cooked at a high temperature – when a steak, burger, hot dog, or even a piece of cooked fish gets those grill marks that most of us really like to see – it produces a bad ingredient called PhIP.   PhIP is a “pro-carcinogen,” a chemical that turns into something that can attack and mutate your DNA.  PhIP is known to cause prostate and other cancers in rats.  However, when scientists feed rats tomatoes and broccoli along with PhIP, the rats live longer and have fewer prostate and other cancers than the rats that ate the PhIP alone.  Vegetables help counteract PhIP.  In the entire world, those least likely to get prostate cancer are men in rural Asia, who eat the traditional anti-inflammatory diet – low in meat, high in fruits and vegetables, with hardly any processed carbs.  No soda, lots of green tea.  No fries, lots of rice.  No burgers, lots of vegetables.  However,when those same men with their low risk come to America, over time, their risk goes up to the level of an American man’s. You are what you eat.

Good news: Men of any age can benefit from eating anti-inflammatory foods.

The opposite is also true: Obesity and one of its consequences, diabetes, make these flames of inflammation burn even higher.   This may be one reason why ruralAsian men are less likely to get prostate cancer: they have a lower body mass index, BMI, which means less stress on their cells.  If you are overweight or borderline diabetic, you turn on more insulin to try to control your blood sugar.  Insulin secretes molecules called cytokines, which can encourage inflammation.  This can put added stress on the body and perhaps tip the balance toward cancer.

The prostate is particularly vulnerable to inflammation because it’s just chock full of inflammatory cells called prostaglandins. So the prostate is already a tinderbox.

Bad genes:  We’ll cover this more in a minute, but the good news even with bad genes is that they are not automatically your destiny: we know this from studies of identical twins.  There are many cases where one twin gets cancer, and one does not.  Their genes are the same, so it must be something in their diet or lifestyle, too.

High blood sugar: Men who have diabetes are not more likely to getprostate cancer, but they are three times more likely to die of it if they do get it. Nondiabetic men who have high blood sugar have almost a five-times greater risk of dying from prostate cancer.  If you are pre-diabetic or diabetic, you can lower your risk of lethal prostate cancer by getting your blood sugar under control, improving your diet, and exercising.

Smoking:  Men who smoke, even if they don’t have a diagnosis of prostate cancer, are more likely to die of prostate cancer in the future.  Men who have been treated for prostate cancer who keep smokingare more than twice as likely to die of it, too, because cancer is more likely to recur.  The good news: Recent smoking matters more than if you smoked 30 years ago.  Your risk of dying of prostate cancer starts going down the day you stop smoking!  In 10 years, it’s the same as if you had never smoked!  Quitting now can make a big difference.  If you smoke, you should quit, and if you have prostate cancer, you should definitelyquit. There is no point in the spectrum of prostate cancer where quitting smoking is not helpful.

No drug protects against prostate cancer as much as having a healthy weight and being physically active. 

Lose that gut. Like smoking, obesity is linked to more aggressive disease and death from prostate cancer.  For men who have prostate cancer, being obese and continuing to gain weight is associated with higher disease recurrence and death. Among 2,500 men with localized prostate cancer in the Physicians’ Health Study, a one-unit increase in body mass before cancer diagnosis was associated with a 10-percent increase in a man’s risk of dying of prostate cancer.  A five unit increase raised the risk of dying of prostate cancer by 20 percent.

If you’re a young man, losing weight might stop prostate cancer from developing.  If a tumor is already there, but very small and not detectable, losing weight may delay the growth of cancer.  If you have a diagnosis of cancer, losing weight can slow cancer or help prevent it from spreading.  “It’s never too late to lose weight.”

Drink coffee.  Coffee is good!  Regular or decaf!  Let’s look at this study from Italy, published in the International Journal of Cancer:  In the Moli-sani Project, investigators looked at coffee consumption in nearly 7,000 men, age 50 and up in rural Italy.  They followed them, on average, at least four years, and during this time 100 of these men were diagnosed with prostate cancer.  It turns out that the more coffee the men drank every day, the less likely they were to develop prostate cancer.  Men who drank more than three cups a day had the lowest risk of getting prostate cancer.

Note:  these men took their coffee black, or maybe with a bit of milk.  In other words, they didn’t have five shots of whipped cream, etc. Also, their coffee was unfiltered– not brewed or instant.

A Harvard study published in the Journal of the National Cancer Institutefound that coffee was associated with a lower risk of gettingprostate cancer, andof developing aggressive, potentially lethalcancer.  Men who drank one to three cups a day, regular or decaf, had a 29-percent lower risk, and the risk went down as the coffee drinking went up.  Men who drank at least six cups a day had a 60-percent lower risk.  Amazingly, the heavy coffee drinkers also tended to be smokers – so coffee seems to have helped counteract cigarettes.

In other studies, coffee has been linked to a lower risk of developing Type 2 diabetes; liver cancer, endometrial cancer, postmenopausal cancer and colorectal cancer.

Coffee has powerful antioxidant effects.  Coffee is the number one source of antioxidants in the diet of the American man. This is sad.

Coffee is also anti-inflammatory.  Many studies have shown that heavy coffee drinkers have lower levels of circulating inflammatory markers in their blood.

Coffee has helpful effects on insulin and glucose metabolism.

Coffee cuts lipids, the body’s fatty acids.  It reduces fasting cholesterol and triglycerides.

Coffee helps the gut’s microbiome.  It increases diversity in the microbiome, the eight pounds of bacteria living happily in your gut.  Bad gut flora may promote inflammation, and vice versa.

Exercise:  Your prostate doesn’t care about six-pack abs and “gun show” biceps.  But your cardiovascular health matters a lot.  Cardiovascular exercise can lower your risk of getting lethal prostate cancer, or of having cancer come back if it’s already been treated.   UCSF scientistJune Chan and colleagues found that vigorous exercise (jogging or bicycling) after diagnosis was associated with a lower risk of prostate cancer death in men with localized cancer. “Three or more hours a week of vigorous activity was associated with a 60 percent reduction in the risk of dying of prostate cancer.” Now they are looking to see if moderate exercise, the kind anybody can do, can lower the risk of dying of prostate cancer.  “Biochemically, exercise could help deter metastasis, spread of cancer, by changing the environment for the cancer.”  This is like spraying fire retardant on the tumor. Not necessarily extinguishing the flame altogether, but making it burn slower, and helping the body set up fire breaks to keep the cancer from spreading.

Here’s an odd thought:  Exercise seems to make prostate cancer fat and happy.  “Prostate cancer may be the most common cancer where exercise, used like a drug, can confer an increase in survival,” says Jonathan Simons. “There is no form of treatment that has this effect.”  It may be that just as it improves blood flow in the arteries, exercise gives cancer a better blood supply that keeps it happy where it is, “so the tumor has no motivation to leave.” So basically, exercise makes cancer feel like it’s at a nice hotel, with free cable TV and a pool.  It’s content to stay there indefinitely. “When tumors are stressed” – when they’re in a bad neighborhood, in effect – “they have genes that are programmed to help them survive by getting them to crawl away to someplace that better serves their needs.”  One of those genes, Simons discovered, not only pipes in more blood to supply the tumor; it gets rid of waste products – the cancer cells’ sewage.  “When tumors build a supply line of blood vessels, to bring in more nutrients, they also build their own plumbing system.  Once they have this infrastructure, they launch a genetic program that lets them grow and spread.  But giving the cancer a better blood flow might sabotage the cancer’s need to boost its own blood supply. It just may be that exercise makes cancer, rather than head for the door, sit back in the recliner and reach for the remote. A contrary notion, isn’t it – that in order to turn your prostate cancer into a couch potato, your best chance is not to be one yourself?

This doesn’t mean that men who exercise are immune to prostate cancer. “There are very fit athletes who have had forms of prostate cancer that are so aggressive, so genetically mutated, that they have proved fatal. However, those men are at one end of the spectrum of prostate cancer. There are many thousands of men at the other end or in the middle, for whom exercise may make a real difference.

Here are some other things that can lower your risk, which I cut out of this talk to save time.

Oligometastasis:  Is the Window of Curability Wider Than We Thought?  Now: What if you have cancer that is confined to the prostate, with just a little tiny bit somewhere else? Are you doomed? It used to be that doctors thought, “Oh, man, he’s a goner, the cancer’s spread.” But scientists are learning that just because a spot of cancer has popped out of the prostate, this doesn’t necessarily mean that it can’t still be cured.

Here’s the old-school thinking:  You’re lying on a chair at the dentist’s office, and the dentist says, “You’ve got a cavity, decay is inevitable. We’ll just wait and pull all your teeth in a few years.” Like the poor guy in “Monty Python” who is mistakenly left for dead:” “I don’t want to go on the cart!”

Until very recently, the dividing line between prostate cancer that was considered curable and cancer that might not be was the prostate itself. That’s not the case anymore, says Johns Hopkins radiation oncologist Phu Tran, also a contributor to our book.

New evidence suggests that in men with oligometastasis – just a few spots of cancer outside the prostate – by treating “not only the primary disease in the prostate or the pelvis, but alsothe few metastatic spots, perhaps men can actually live a long time without disease progression and even be cured.” It’s the difference between being reactive – waiting for the next shoe to drop, the rise in PSA or development of symptoms – and being proactive. In other words: not just suspecting cancer is there, but knowing its precise location and going after it.

Now, how do they know where these little bits of cancer are?  There is a new form of technology called PSMA PET scanning,which can showbits of cancer as small as a BB.  There is also highly focused radiation, called:  SBRT (stereotactic body radiation therapy) or SABR (stereotactic ablative radiation).  Tran says it’s like spot welding—focused on a small area, very intense, and theoretically ablative, meaning it kills all the cancer in that spot.” Tran is testing this in clinical trials at Hopkins.

PSMA-PET:  

Hopkins scientist Marty Pomper, who was one of my husband’s interns when he was Chief Resident at Hopkins, figured out how to engineer a small molecule that binds to PSMA, prostate-specific membrane antigen, which sits on the surface of prostate cells. He then used innovative biochemistry to glue F18, the radioactive fluorine that glows in a PET scan, to that small molecule.  What he achieved is a way to see cancer that no one could see before.

This is very exciting for two reasons: PSMA-targeting molecules can find prostate cancer.  But if you switch out the radioactive tracer for a radionuclide – a little grenade of radiation that is targeted precisely to PSMA – then this technology can also be used to kill prostate cancer.  This is in clinical trials in the U.S., but it has been used for several years in Europe and Australia. Germany got the leap on everyone, because they don’t have to go through all the rigorous testing that we do.  Some doctors in the U.S. are sending patients with widely metastatic disease out of the country for these treatments, and some of these men have gone into long-term remission.  There are still some bugs to be worked out.  There are different radionuclides, and we need to know which is better. Also, it turns out that PSMA didn’t know that its name was prostate-specific… it is also in the salivary glands, and so there has been a problem with men getting their cancer into remission but having no salivary glands, so this is not ready for prime time yet.  But it is extremely hopeful.

IF YOU HAVE ADVANCED PROSTATE CANCER

If you need to start ADT, androgen-deprivation therapy, thanks to several recent studies, you also need to start taking an androgen receptor blocker.  There are three:  abiraterone (which you also take with prednisone), enzalutamide, and apalutamide.

The LATITUDE study, released last summer at the ASCO meeting, showed that giving abiraterone (Zytiga) and prednisone along with Lupron to men who are just starting ADT increased survival by an average of 18 monthslonger than ADT alone. But the study found that 25 percent of men showed an increased survival of four years, and a small percentage of those men appear to be “exceptional responders” who have had no progression of cancer for at least six years. 

In real estate, it’s location, location, location. With cancer drugs, scientists are learning, the key to success may be timing, timing, timing.  Starting abiraterone earlier, while the cancer is more vulnerable – before it has had a chance to mutate, to develop resistance and strengthen its armor – makes a huge difference.

Who should be interested in these findings?  Between 50,000-60,000 American men just this year alone.  Men who are on ADT, whose PSA is rising rapidly and doubling every 10 months or less.  And men who are just starting ADT.

Apalutamide (Erleada) is the newest FDA-approved drug for advanced prostate cancer.  Enzalutamide (Xtandi) is the third.  These are game-changers, and the game they are changing is a terrible one, the agony of wait-and-see, played out with each PSA test by men whose cancer looks like it’s going to metastasize.  This game sucks.  Until now, men who did not yet have metastatic cancer did not have access to the next level of treatment.

The idea is that now, not only do you nothave to wait for metastasis, you may very well change the course of the cancer, delaying the time to metastasis by more than two years longer than ADT alone.  Again, for some men, doctors aren’t even sure how longmetastasis can be delayed, because their cancer stillhasn’t progressed.  The SPARTAN study, of apalutamide, was published February 2018 in the NEJM.  Its senior author, Eric Small of UCSF, told me that the idea behind this study was actually to see if we could somehow put advancing cancer in a holding pattern.  Maybe metastasis is not a done deal.  In fact, he says, “this was really the first metastasis prevention study.”

For the men in the apalutamide group, the average metastasis-free survival was 40.5months – and some of these men stillhaven’t developed metastasis.

“We are talking about a 72-percent reduction in the risk of metastasis,” Small says.    What nobody knows yet is whether earlier treatment will lengthen overall survival. “We believe it will,” says Small, “but it’s way too early.”  For now, though, “We’re having a dramatic impact on delaying metastasis.”   At nearly four years, “50 percent of men in the apalutamide group still have not developed PSA progression.  They are doing well, they don’t have metastatic cancer, and haven’t been ravaged by extensive disease.  That’s remarkable.”

In July 2018, the FDA approved enzalutamide (Xtandi) for men with non-metastatic CRPC.  Same thing: this used to be second-line hormonal therapy, recommended only in men who developed metastatic cancer afterbeing on ADT.  This decision is based on the PROSPER clinical trial, led by oncologist Maha Hussein, M.D., of Northwestern.  In this study, 1,400 men with non-metastatic CRPC whose PSA levels were doubling every 10 months or sooner were randomly given either ADT with a placebo, or ADT plus enzalutamide.

Men who received enzalutamide had a delay in time to metastasis or death by an average of 21.9 months longerthan men in the placebo group, and some men haven’t had metastasis at all.

And now we get to Bad Genes and Immunotherapy

In 2016, a breakthrough study came out.  It was led by Fred Hutchinson Cancer Research Center medical oncologist Pete Nelson, and published in the New England Journal of Medicine. The study found that:

Prostate cancer is a lot more of an inherited disease than anybody thought;

There are 16 bad genes that we now know to look for; and

If you have a mutation in one of these genes, your sons and daughters and their children should get tested, so they can be considered high-risk for certain types of cancer, screened vigilantly, treated aggressively, and live to a ripe old age and not die of cancer.

These particular genes, called DNA-repair genes, are tiny quality control specialists; they’re the spell checkers.

Nelson’s study looked at 20 DNA-repair genes, in 692 men with metastatic prostate cancer in the U.S. and United Kingdom.  They found mutations in 16 of them, including some unexpected ones, like BRCA1 and BRCA2.

“Now wait,” you may be thinking, “aren’t they the breast cancer genes?”  Yes, and for years, nobody linked these genes to prostate cancer.  Now we know that the very same mutation that can cause breast and ovarian cancer in women can cause lethal prostate cancer in men.

Other bad DNA-repair genes include one that sounds like it should be at a bank, called ATM; and one that sounds like a roadie making sure the microphones work at a concert, called CHEK2; there’s also one that sounds friendly but isn’t at all, PALB2, which is strongly involved in pancreatic cancer.

Nelson and colleagues estimate that one in nine – 12 percent – of men with metastatic cancer have one of these bad genes.

In another study led by William Isaacs of Johns Hopkins, investigators did a genetic analysis of 96 men who died of prostate cancer at an early age – younger than 65.  Billy Isaacs says: “Surprisingly, we found that more than 20 percent of these patients carry inherited mutations in genes responsible for repairing damaged DNA.”

  Why Genes Matter:  There are entirely new kinds of cancer-fighting drugs that target specific genes.  One class of drugs is known as PARP inhibitors like Olaparib, which is being used to treat women with BRCA mutations in ovarian cancer. It has now been approved as a treatment for advanced prostate cancer in some men.  Men with BRCA mutations also respond well to carboplatin, nota standard drug in prostate cancer.

What should you do?  If you have high-risk or metastatic prostate cancer, or if you have a strong family history of prostate or other cancers, ask your doctor about genetic testing. One of them is made by Color Genomics, and it costs $250.  You just spit into a test tube.

Checkpoint Inhibitors

In July 2016, a small but very exciting study led by investigators at the Oregon Health & Science University and Johns Hopkins, was published in the journal, Oncotarget.  It involves checkpoint inhibitors.

Basically, your immune system can do great and powerful things: like cause an autoimmune disease to devastate your body.  Ideally, it should only attack bad things, like cancer. But cancer has a lot of devious tricks.

T cells are some of the body’s most powerful warriors. They kill enemy cells.  But prostate cancer basically makes a nice cup of chamomile tea for these T cells, and puts them to sleep.  If you look at a sample of prostate cancer tissue, you can see the T cells right there next to cancer cells, and the T cells are asleep.  They have checkpoints on them; these are like a straitjacket.  Here, the cancer is hijacking a normal process that happens in every pregnant woman, so she doesn’t make an immune reaction to her unborn child.

Checkpoint inhibitors are a class of drugs, invented by Jim Allison with funding from the Prostate Cancer Foundation; in fact, he just shared the Nobel Prize for this work this month!  Checkpoint inhibitors take off the straitjacket and unleash the T cells.

But not every checkpoint inhibitor works for every cancer.  Also, compared to other kinds of cancer, prostate cancer looks pretty normal.  It doesn’t have many mutations.  Some forms of cancer have so many mutations – think of any villain in Batman – that the immune system says, ‘Hey, that guy looks weird. Let’s kill him.”  But prostate cancer can blend in, so this is one problem: getting the immune system to recognize prostate cancer as the enemy.

There’s a lot of work that needs to happen. However: some people have had spectacular success with checkpoint inhibitors. Tumors that should have killed people with metastases in their lungs, liver, and brain, have melted awayinstead.

In this study, led by Julie Graff of Oregon, they used a checkpoint inhibitor called a PD-1 inhibitor.  The results were so dramatic, and so unexpected, that they published the results early.  Julie Graff was working with immunologist Chuck Drake, of Columbia University.  Previously, she had seen two men with advanced prostate cancer who responded exceptionally well to a PD-1 inhibitor:  their PSA went away, and their cancer appeared to be undetectable.   Chuck Drake suggested that maybe enzalutamide, which targets the androgen receptor, might stimulate the immune system to make the PD-1 inhibitor work better.

So they did this study, of men who were taking enzalutamide but whose cancer was still progressing.  The men continued to take enzalutamide as they receive four doses of a PD-1 inhibitor called pembrolizumab. The first 10 patients were enrolled from March 2015 to January 2016.  Their ages ranged from 61 to 80, and their PSA ranged from a little over 4 to nearly 2,503.

In three men, the disease did not change; it did not get noticeably better, but it didn’t get noticeably worse, either.  Four men did not have any evidence of a benefit, and one of these men died of his cancer.  So that’s seven men; what about the other three?  Their response blew the investigators away:  Their PSA – including the man with the PSA of nearly 2,503 – dropped to the undetectable rangeof less than 0.1.  Two of these men had been on narcotics for pain, and stopped taking them.  One man’s liver metastases went away.  “These three men had a complete response,” says Graff.  “Their tumors shrank radiographically” – meaning that they couldn’t be seen in imaging – “in the lab” – their PSA falling to nearly nothing – “and clinically,” with the need for pain medication going away.  “None has had a recurrence.”

Another very promising form of immunotherapy, on the horizon, is Tumor-targeting CAR T cell immunotherapy.  This is custom-tailored for each patient:  they take a patient’s T cells, and engineer a gene that enables the T cell to pick a cancer cell out and kill it.

Now here’s a question you are probably wondering:  How is cancer affected by my gut bacteria? It may be that being able to increase “good” bacteria will help the immune system do a better job of fighting off disease – may soon help people with some types of cancer respond better to immunotherapy.  Recently, scientists studying colon cancer found that certain bacteria are found in half of all colon tumors and when the cancer spreads, the bacteria spread right along with them. In another study, scientists found that two different forms of bacteria work together, like fertilizer, to help colon cancers grow.  Scientists studying melanoma found that the presence of certain gut bacteria can change how cancer patients respond to immunotherapy.  Karen Sfanos of Johns Hopkins is working on this in prostate cancer.   It may be that special probioticsor even a fecal transplantmay help immunotherapy work better.

Gene-Targeted Therapy

Already, at major academic medical centers, getting treatment for advanced prostate cancer involves a talk with a genetic counselor.  Heather Cheng, a medical oncologist at the University of Washington and Fred Hutchinson, was the first one.  She started the world’s first prostate cancer genetics clinic.  Here is a story about one of her patients, an amazing guy I interviewed named Mark Meerschaert.

In a matter of weeks, Mark went from being an athlete to someone who could barely walk; metastatic prostate cancer had come from nowhere and spread like wildfire throughout his body. Mark is a university math professor – the kind who fills up the blackboard in his classroom with calculations to answer questions of probability, and statistics.  So when he got sick, he did what he does best: looked at the numbers. Men with widespread prostate cancer that is not responding very well to standard treatment don’t live very long.

So then Mark did what I hope everyone with a challenging diagnosis will do: He became his own advocate. He did some research and found Heather Cheng.

It turns out that Mark has a mutated BRCA2 genethat runs in his family.  Cheng immediately focused on this gene and suggested a very different type of treatment – off-label use of olaparib, approved by the FDA to treat ovarian cancer. Olaparib is a PARP inhibitor; it blocks a protein that cancer cells need to repair themselves, and works especially well in people with defects in the BRCA2 gene. Olaparib and other PARP inhibitors are being studied in clinical trials for prostate cancer.

Cheng also got genetic sequencing of tissue from Mark’s metastatic cancer.

Cancer can change over time. If you have metastatic cancer, there may be different mutated genes than in the cancer that was originally diagnosed from the needle biopsy. This matters because there may be a new medicine that works well with your particular mutated gene or genes. She told him it could get worse before it got better.

It did.  Mark said: “I started olaparib in October 2016. Two months later, “we did a bone scan, and saw that there was cancer all over the place: my ribs, hips, legs, some lymph nodes.”  He became very weak.  He used a cane, then a walker, then a wheelchair. He took a leave of absence from his job. Now he is looking forward to going back.

Starting early in 2017, he says, “I just slowly started to feel better and better.  At some point, I said, ‘Maybe I can go for a walk again. I had a little numbness in my foot, but I said, ‘I’m going to keep walking,’ so I did. I walk my dog every day, a couple of miles. Now even the numbness is gone.”  In a matter of six months, he said, “I’ve gone from shockingly, disastrously ill to feeling – I’m still cautious, still waiting for the other shoe to drop; nobody knows how long this is going to work.  There’s no data on people like me. Now I feel great.”

Mark had known he was BRCA2 positive; after his brother was diagnosed with breast cancer several years earlier, he got genetic testing. But he never expected to get prostate cancer.  In fact, although he’d gotten a PSA test every year, he had stopped. “My doctor said, ‘We don’t need to do PSAs.’ For two years I didn’t get a PSA.”  Which brings us full circle to the Band of Geniuses.

In 2013, Mark developed some urinary symptoms and went to see a urologist. Cancer was found.  He also learned that his father had been treated for prostate cancer when Mark was away in college, and his parents never said a word. “Had I known, I would have kept PSA screening.”

Mark underwent external-beam radiation therapy and a two-year course of ADT, which ended in March 2016. “By July of 2016, something just felt a little off. I went to see a urologist.  A biopsy showed high-grade cancer.

When Mark went to Seattle, Heather Cheng got that biopsy tissue and sequenced it. Cheng told him, ‘Your cancer is very aggressive, but that might work in your favor.’ That turned out to be absolutely correct. It got bad really fast, and it got better really fast.” He says: “The question is, what happens next?  I’m very interested in the five-year survival rate for people like me. They’ve only been using this since 2015, and the studies were on ovarian cancer.  My God, what if this had happened five years ago?”

So, right now, immunotherapy drugs only help men with certain mutated genes: mainly BRCA 1 and 2, and ATM.  But this is just the beginning.

Imagine a waiting room full of 100 men with advanced prostate cancer.  Some of those men have mutated BRCA genes; those genes can also cause breast and ovarian cancer, so let’s color them pink.

Some have a mutated PALB2 gene, also the bad gene in pancreatic cancer.  Let’s color them green.

For about eight of those men, the bad gene is WNT. That’s also the gene involved in 100 percent of aggressive colon cancers.  Let’s color those men blue.

About half have a bad ERG gene.  This is found in children’s leukemia and in sarcoma. Let’s color those men purple.

About one-fourth have a mutated PTEN gene.  That can also cause some brain cancers, endometrial cancer, breast cancer, and ovarian cancer. Let’s color those men orange.

One guy has a mutated IDH1 gene; this only affects 1 percent of men with prostate cancer, but it affects 100 percent of people with a glioblastoma, like Senator John McCain.  Let’s color that man red.

Eventually, our imaginary waiting room looks like an Easter Egg hunt.

Each color represents a subgroupof advanced prostate cancer.  The drug that works best on the men with the bad BRCA genes probably won’t work best on the men with the faulty ERG genes.  The drugs work differently because the men’s cancers are different – but they’re different in groups. A man in the yellow group may not be helped by a drug that works well for the guy in the purple group.  But he probably will be helped by a drug that helps other men in the yellow group.

You know who else will be helped?  People with other cancers who have that same mutated gene. So very good things are happening, and there has never been so much hope for prostate cancer, and cancer in general, as there is now.

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

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How Inflammation Sparks Prostate Cancer

Believe it or not, there once was a time when the Grand Canyon was just a ditch.  Before that, it was a rough patch in the desert with a river running through it.  It took a very long time for that canyon to form, and the conditions had to be just right to allow water, blazing sun and wind to chip away through layers of fragile rock.

On a very much smaller scale, this is what happens to cause cancer when the conditions are just right.

Now, if you will:  While we’re thinking about the Grand Canyon, let’s pan the camera a few miles away. We’re near some tall pine trees, and there’s a campfire.  Some cowboys are sitting around it.  Let’s imagine that they all have white hats; they’re good guys.  (They’re also much quieter than the cowboys around the campfire in “Blazing Saddles,” so don’t go there!)

If you’ve ever sat around a fire, you know that wood sometimes pops unexpectedly and sends out sparks.  That’s exactly what happens at our little campfire, and it happens to hit one of the cowboys square on the arm.  He brushes out the sparks, then goes back to his seat.  Nothing’s really changed; he laughs it off.

Wouldn’t you know it, the fire sparks up again – right on that same poor guy.  This time, he’s a little more scorched; his shirt has a hole in it and his eyebrows got singed.  He’s also a little irritated.

It happens a few more times, and he is no longer the proverbial happy camper.  He’s moving around, no longer sitting quietly, he’s got some burns that will leave scars, and he’s angry.  His hat is so charred now that it’s almost black.  One last spark, and he’s out of there.  He leaves the campfire, saddles up his horse, and rides away, fighting mad and looking for trouble.

This little scene plays out a lot, every day, in our bodies.  There are countless campfires – like stars dotting the sky – that flare up, burn quietly, get snuffed out, and never cause harm.  The campfires are little flares of inflammation.  

Commenting on this analogy is medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation.  “The future of fighting prostate cancer,” he says, “is either to stop the sparks from flying, or to put fire retardant on the flames – or better yet, to bring in the fire retardant really early in life.  It’s all about the sparks, and what makes the sparks, and then spark interception or spark interdiction.”

Expect to Hear a Lot More About Inflammation

Inflammation is our own version of Dr. Jekyll and Mr. Hyde: When it works the way it’s supposed to – when you skin your knee or get a paper cut on your finger, for instance – inflammation is what protects your body from bacteria and germs that find their way through the open wound.  The immune system kicks in; zealous home soldiers like killer T cells spray chemicals on the intruders, puncture their armor, or even eat them whole.  You notice some redness, a little heat, maybe some swelling or even a bruise, and you know that your body is healing.  There’s a scab, new skin covering the hole or tear, and all is well. The inflammation goes away.

But what if it doesn’t go away?   Here’s where the dark side of Dr. Jekyll, his alter ego Mr. Hyde, starts to show itself.  Chronic inflammation is bad.  

“The story of inflammation is absolutely the heart of what causes prostate cancer,” says Simons.  “Inflammation lowers your defenses,” and changes the DNA.  Going back to the angry cowboy at our campfire scene: If only he had moved away from the fire, or if someone had poured a little water on the fire to cool it down and keep the flames low.  He might have had a few scars, but he would have been okay.  Instead, he began moving around, and eventually he left the campsite; if he were a prostate cell, he would have become cancerous – but still there at the site, still easily treatable.   But as he became more scorched, he became metastatic.  The continued exposure to those flames turned him from a cell sitting quietly into a metastatic cancer cell.

“We estimate that 30 percent of all cancers are caused by this kind of chemistry,” Simons adds.  The little fires hurt genes that are nature’s own tiny fire retardants, so without their subduing effect the flames burn hotter; the fires then go after the body’s normal first responders.  So the firefighters don’t stop the burning; the paramedics don’t heal the injured victims.  The inflammation draws other cells called macrophages and granulocytes to the scene; they’re supposed to be part of the body’s cleanup crew.  “Unfortunately, in cleaning up, they actually make the flames burn hotter and further damage the area.”

What causes the fires? 

One huge cause is our diet.  Fat, charred meat, processed carbohydrates, chemicals in junk food, and sugar.  Basically, what we know as the Western diet – high in meat and bad carbs, low in fruits and vegetables.   How do we know this?  Because the men in the entire world least likely to get prostate cancer are men in rural Asia, who eat the traditional Eastern diet – low in meat, high in fruits and vegetables, with hardly any processed carbs.  No soda, lots of green tea.  No fries, lots of rice.  No burgers, lots of broccoli.  But when those men come to America, their risk of getting prostate cancer goes up.  Diet matters. 

“The rural Asian diet is anti-inflammatory,” says Simons.  “It may be that these men would eventually develop prostate cancer if they lived to be 120.  But they don’t.”  If you think about our campfire analogy, maybe cells still get singed, but they’re few and far between.  That critical momentum never develops.

“We are now learning that it’s essential for men to have a healthy diet when they’re young – say, between 14 and 30.”  But men of any age can benefit from turning down the inflammation with “fire-fighting” foods.

The opposite is also true:  Obesity and one of its consequences, diabetes, make these flames burn even higher.   (In fact, this may be one reason why rural Asian men are less likely to get prostate cancer: because of their diet, they have a lower body mass index, which means less stress on their cells.) “If you are overweight or borderline diabetic, you turn on more insulin to try to control your blood sugar,” says Simons.  Insulin secretes molecules called cytokines, which – thinking of our cowboys at the campfire – are like the chuck wagon, bringing in oxygen, new blood vessels and nutrients to feed the cancer.

“Some men have more sparks flying around, and men who are overweight are in this group.  The good news is that you can reduce your insulin level with exercise,” says Simons.  “There’s a lot of evidence that just being sedentary is a terrible setup for trouble later, if you have a slightly inflamed prostate and higher insulin level.”

The prostate is particularly vulnerable to inflammation, Simons adds, because it’s just chock full of inflammatory cells called prostaglandins, most likely nature’s way of protecting the fluid that makes up semen.  So the prostate is already a tinder box.

What else makes it worse?  A big one is genetics.  Some men are born with  their own fire-starter – genes they inherited from their father or mother.  If you are of African descent, or if you have a family history of prostate cancer or cancer in general, you are at higher risk of developing prostate cancer.  That doesn’t mean that you’re bound to get it, and it may be that with cancer-fighting diet, exercise, not smoking, and plain old good luck that you will never have prostate cancer.

Other causes of sparks:  Infection.   Cigarette smoking.  Emotional stress.  Not being circumcised: several stories have shown that circumcision has a protective effect, lowering your odds of developing prostate cancer, and of dying from it.  This ties in with what we’re still just learning about the role infection plays in changing the prostate’s microenvironment, and making it more susceptible to cancer.

            Okay, then what puts out the fires?

We’re still figuring this out.  A good diet, exercise, and other flame retardants such as Vitamin D.  Dietary supplements such as turmeric seem to help, as do broccoli and tomatoes cooked in olive oil (which brings out the lycopenes).  Meditation: new research suggests that this may help calm the tiny sparks and lower the chances of cancer catching fire.

And finally, there’s a huge question mark. What else helps?  “This area of research is woefully underfunded,” says Simons. There may be a bacterial equivalent of H.pylori– the nasty bacteria found to cause stomach ulcers.   New research suggests that probiotics – “good” bacteria that change the microflora in the gut – may prove helpful in preventing cancer.  Does this mean that there are bad bacteria that do their share of causing it?  Could this be related to the link between infection and inflammation?

We don’t know.  Stay tuned.

 

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

 

 

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Immunotherapy for Prostate Cancer, Part 2

Checkpoint Inhibitors

Miracle Drugs for Some, But Not Yet All

Checkpoint inhibitors have one mission: to unleash the immune system.  They wake up the sleeping T cells, and in some people with cancer, they have done this spectacularly well. But right now, they don’t help more than a fraction of patients. In other words, for every extraordinary responder – a man whose metastases in the liver and brain simply melt away, whose PSA drops from the thousands to undetectable – there are six or seven men who don’t get any better.

Doctors and scientists desperately want to change this.

A brilliant scientist and investigator named Jim Allison, with initial funding from the Prostate Cancer Foundation, was the first to discover molecules on T cells called checkpoints. He figured out that these molecules were putting T cells into an induced coma, stopping them from carrying out their mission as assassins of cancer cells, and he worked to develop the first checkpoint-inhibiting drug, ipilimumab, which has had great success in treating some cancers, particularly melanoma.  In fact, he just shared the  2018 Nobel Prize in Physiology or Medicine for this work.

Why don’t checkpoint inhibitors work better in prostate cancer? Chuck Drake, M.D., Ph.D., director of genitourinary oncology and the associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at New York Presbyterian/Columbia University Medical Center, explains: “When a T cell moves into tissue, it installs a brake.” It doesn’t necessarily apply the brake; it just has one ready to go.

I wish these brakes had convenient names, like “Bob,” or “Annette.”  But they don’t; they have pesky initials and numbers, so just hang in there and power through.  This is important:  One of those brakes is a molecule called PD-1, which sits right on the surface of the T cell. “Many tumors have T cells inside them, but they’re not working, because they have PD-1 on their surface.” The T cell with the PD-1 is just sitting there. But cancer cells make sure that cell isn’t going to move by adding a molecule called PD-L1. “That’s the foot on the brake. PD-L1 binds to the PD-1 on the T cell.” Imagine a car with several unpaid parking tickets under the windshield wiper; now imagine a traffic cop coming along and putting a parking boot on the car’s front tire. That car isn’t going anywhere.

So we’ve got our superhero in a stupor, like Superman staggering around or unconscious because Lex Luthor put a big chunk of Kryptonite in the room. But wait! Checkpoint inhibitors are coming to the rescue! “If you block either PD-1 or PD-L1 with a drug, a monoclonal antibody, you can wake up the T cell, take off the boot,” T cells can come roaring in and “do what they were designed to do, which is kill specific cells, including tumor cells.” And this is happening with checkpoint inhibitors in kidney cancer, bladder cancer, melanoma, and lung cancer.

Why not so much in prostate cancer? It may have something to do with the number of mutations on the prostate cancer cell. “Some melanomas have over 500 mutations; squamous cell lung cancer can have 200 to 500 mutations; garden variety lung cancer has 150 mutations, kidney cancer has about 70,” says Drake. “But prostate cancer only has about 30 mutations.”

Basically, the more mutations a cancer cell has, the more freakish it looks to the immune system, and the easier it is to recognize as an enemy. Think about any villain in Batman – the Joker, with his green hair and white pancake makeup, for instance. The villainous disguises are really helpful to crime fighters, because they say, “This guy’s dangerous.” But prostate cancers, even the very worst ones, are more like James Bond villains; they don’t look that much different from anybody else.

Timing may be a key factor, too.   Drake recalls a study he took part in when he was at Johns Hopkins, of a PD-1 blocker called nivolumab, which has worked well in other cancers. The patients were men with late-stage prostate cancer who had been through ADT and chemotherapy. “We had zero responses in 17 patients.” He recalled some anecdotal evidence from another trial, where a man who was on enzalutamide got Provenge , “his PSA went down to nearly undetectable, and his response lasted a very long time.”

In talking with Julie Graff, the lead investigator on a recent trial where Drake was a co-investigator, “we said, why don’t we try this same thing with pembrolizumab,” another PD-1 blocker. “We wanted to have patients who initially responded to enzalutamide but were progressing, and we didn’t stop the enzalutamide, but added on the pembro. Maybe there’s something funky about tumors progressing on enzalutamide that allows the immune system to recognize them. Whatever it is, maybe it’s better to stay on the enzalutamide and just add the PD-1 blocker.”  This strategy worked in a few men who were “exceptional responders.”

This study, published in Oncotarget, showed in just a few men with the most devastating prostate cancer – cancer that has metastasized, cancer that has invaded the bones, cancer that got better for a while on hormonal therapy but came back with a vengeance when the hormonal therapy stopped working – what might actually be cures.  It’s high time!  Why shouldn’t this happen in prostate cancer, number of mutations aside?  What is it, exactly, that has been happening in those other cancers:  Tumors that should have killed people with lung cancer, melanoma, kidney or bladder cancer have melted away instead, because checkpoint inhibitors allowed the T cells to recognize the cancer that’s been growing – invisibility-cloaked in plain sight – right beside them.  The results with pembrolizumab were so dramatic, and so unexpected, that the investigators decided to publish the early results.

Oncologist Julie Graff, M.D., at the Knight Cancer Institute of Oregon Health & Science University, explains:   “PD-1 inhibitors on their own have not seemed to have much of an effect on prostate cancer.”  But Graff, Drake and colleagues saw two exceptions to the rule, two men with “castrate-resistant prostate cancer” (their hormonal therapy stopped working) who responded exceptionally well to immunotherapy:  their PSA went away, and their cancer appeared to be undetectable.   “We wondered whether enzalutamide, which targets the androgen receptor, might stimulate the immune system to make the PD-1 inhibitor work better.”

The team designed a study of 28 men who are taking enzalutamide but whose cancer is still progressing.  The men continued to take enzalutamide as they received four doses of  pembrolizumab. The first 10 patients were enrolled from March 2015 to January 2016.  Their ages ranged from 61 to 80, and their PSA ranged from a little over 4 ng/ml to nearly 2,503.  Here’s what happened to them:  in three men, the disease did not change; it did not get noticeably better, but it didn’t get noticeably worse, either.  Four men did not have any evidence of a benefit, and one of these men died of his cancer.  So that’s seven men; what about the other three?  Their response blew the investigators away:  Their PSA – including the man with the PSA of nearly 2,503 – dropped to the undetectable range of less than 0.1 ng/ml.  Two of these men had been on narcotics for pain, and stopped taking them.  One man’s liver metastases went away.  “These three men had a complete response,” says Graff.  “Their tumors shrank radiographically” – meaning that they couldn’t be seen in imaging – “in the lab” – their PSA falling to nearly nothing – “and clinically,” with the need for pain medication going away.  “None has had a recurrence.”

With Emmanuel Antonarakis, M.D. of Johns Hopkins, Drake is looking at ipilimumab, which blocks a different checkpoint called CTLA-4.   “It turns out that within tumors there’s another population of bad guy lymphocytes (white blood cells), called regulatory T cells. These cells have a number of ways to turn off the immune response.”  In addition to blocking CTLA 4, ipilimumab interferes with the function of these regulatory T cells. Which begs the question: “What if you help the killer T cells by blocking PD-1, and at the same time block CTLA4?”  Blocking two checkpoints at once!  “In animal models, this works brilliantly,” says Drake. “The first data with melanoma were just magical; tumors shrank in four to six weeks.” Antonarakis and Drake “took turns petitioning the drug company” to do a clinical trial in prostate cancer for several years, with no luck. Then Antonarakis and Hopkins colleague Jun Luo, Ph.D., published an important paper in the New England Journal of Medicine showing that men who have a particular variant androgen receptor, called ARV7, don’t respond to enzalutamide and abiraterone. “We said, “If we can’t try this with everybody with prostate cancer, can we at least give it to guys who have the mutation? What if we took ARV7 patients and treated them with both anti-PD-1 and –CTLA 4 (blocks CTLA-4?),” says Drake.  “Emmanuel wrote the trial,” which just finished, and was published in Oncotarget.  “That’s the first clinical trial ever to combine anti PD-1 and anti-CTLA-4 in prostate cancer. It’s very promising.”  It’s also the first study to look at a specific, very bad, form of prostate cancer.  Let’s look at that study:

Combination Immunotherapy Combats AR-V7+ Prostate Cancer:  In this Hopkins-led study of men with very aggressive prostate cancer, this combo of two immunotherapy drugs has made a significant difference – shrinking tumors partially or completely – and two of 15 men have shown exceptional responses.

Once again, no one is suggesting that these drugs would produce the same promising results in all men with aggressive prostate cancer.   But this is an exciting example of precision oncology– finding the right drug (or combination of drugs) to work for the right patient and the right cancer.  The idea is that one drug might just help a few people; but another drug might help a few different people, and if we just keep chipping away at it, eventually we’ll help everybody, one subgroup of patients at a time.

The 15 men in the study had AR-V7-positive prostate cancer; AR-V7 is an aggressive variant of the androgen receptor, first discovered at Hopkins several years ago by Jun Luo and Antonarakis (this can be diagnosed by a blood test, available at Hopkins and through a company called EPIC Sciences).  They were given a combination of ipilimumab and nivolumab.  This specific form of prostate cancer, “can lead to fatal disease in only six to nine months and has inadequate treatment options,” says Antonarakis.

Patients received treatment by IV infusion:  3 mg per kilogram of nivolumab plus 1 mg per kilogram of ipilimumab every three weeks for four doses, followed by a maintenance regimen of 3 mg per kilogram of nivolumab alone every two weeks thereafter. The patients were enrolled between December 2016 and October 2017.

Two of the 15 men (13 percent) experienced a significant drop in PSA – by at least 50 percent.  “More encouragingly,” notes Antonarakis, “one-quarter of patients achieved an objective response, meaning that their tumors shrank partially or completely with combination immunotherapy.  These responses were durable and typically lasted more than nine to twelve months.”  But here’s the most exciting part:  “At least two of these patients remain alive for more than 18 months, which is much longer than expected for patients with AR-V7+ prostate cancer.”  Which means that Antonarakis and Luo don’t even know how long the response will last, because it’s still happening.

Genetic mutations affect response, too:  The men in this study were already different from many patients with advanced prostate cancer because of their AR-V7 variant.   Were there other differences that might help predict which men will respond best to this double checkpoint inhibitor approach?  Yes:  the specific genetic mutations are very important.

“Interestingly, six of 15 patients (40 percent) harbored damaging mutations in at least one DNA-repair gene,” notes Luo.  These mutations were either germline (inherited) or somatic (mutations that just developed spontaneously as the cancer advanced).  “In these six men, we detected gene mutations of BRCA2(3 men), ATM(2 men), and ERCC4(one man).

The job of DNA repair genes is to fix mistakes that occur in the DNA as cells divide – to keep a mistake from being repeated over and over again.  “Remarkably,” notes Antonarakis, “most of the benefit from ipilimumab plus nivolumab appeared to occur in patients who had one of these gene mutations, particularly in two men with BRCA2 mutations.”  If this proves true in larger studies, “it will have profound implications for other diseases such as breast and ovarian cancers, where these genes are more frequently mutated.”  An estimated 20 percent of men with metastatic prostate cancer have mutations in BRCA2or related DNA-repair genes. “This study suggests that these gene mutations may be even more common in men with the AR-V7+ form of prostate cancer, perhaps as high as 40 percent.”

The study also showed that the combination of nivolumab plus ipilimumab was safe and tolerable in men with AR-V7+ advanced prostate cancer.  “We did see some important side effects including colitis, pneumonitis and hepatitis – all caused by an over-activated immune system. These side effects were managed with prompt administration of steroids, which often resulted in reversal of these conditions.”

Encouraged by these preliminary findings, Antonarakis and his team are now expanding the study to include more patients.  This larger study is currently open to enrollment (https://clinicaltrials.gov/ct2/show/NCT02601014?cond=NCT02601014&rank=1), and is actively seeking participants.  If you are interested, please call Mrs. Rana Sullivan at (410) 614-6337.

So where do we go from here? Medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, quotes Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” In other words, it’s just getting good. “We are learning so much about the immune system.”

There may be a dozen or more potential checkpoints to block. “We only have drugs for about half, and we have a lot more being investigated.” It may be that for the T cells to eradicate prostate cancer, it will require one or more checkpoint inhibitors, plus one or more vaccines. “When we’ve really got a checkpoint inhibitor that allows these T cells to wake up, PSAs will fall, tumors will melt away. When one of these works, man does it work!”

Immunotherapy-induced changes in how we kill cancer are happening so fast, it’s hard to keep up. In lung cancer, for instance, 30 percent of patients now get a checkpoint inhibitor, nivolumumab, before they get chemotherapy, and about half don’t even need standard chemotherapy.   “We don’t even know what some of the antigens are,” says Simons. “We’ve got to make this work for every patient.”

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

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