Living in Prostate Limbo

Ask Rob Gray* to talk about how prostate cancer came into his life, and he has the best possible response: “I prefer to talk about how it came out of my life.”

For nearly a decade, among other tests and procedures, Rob underwent 17 PSA tests, five PCA3 tests, and nine MRIs. He endured five prostate biopsies, some of them saturation biopsies, that made him feel like a human pincushion.   He remained steadfast in prostate limbo – when doctors couldn’t find cancer, but they couldn’t rule it out, either, because of some abnormalities in his MRIs and biopsies. Because he kept looking for answers when it would have been so easy to assume everything’s okay and leave it alone for a few years, Rob is cancer-free today.

He is only 49 years old – the age when many men just start to think about prostate cancer.

Rob’s ordeal started back when he was in his thirties. When he asked for a PSA test, his family doctor thought he was worrying too much: “We don’t traditionally order that test until you’re 50,” he told Rob. Note: The National Comprehensive Cancer Network recommends that men start getting screened for prostate cancer in their forties, and at age 40 if they have a family history of the disease. But Rob didn’t have a strong family history of prostate cancer, just a slight one. His grandfather developed it in his eighties, and wasn’t even treated for it because he had other significant health problems.

All Rob had at first was a minor urinary problem and the need to know why it was happening, which led him to read about possible causes, which led him to the prostate, which led him to the PSA test.

He also had a heck of a lot of persistence and maybe was even a bit of a pain in the medical butt because he wouldn’t just let it go. Thank goodness he didn’t. He is cancer-free because of his tenacity.

Over a remarkable nine-year gauntlet, Rob basically did hyper-vigilant active surveillance before the disease was ever diagnosed. He and his doctors followed his prostate, as best they could, in real time. He had so many biopsies that scar tissue developed in his prostate, which made it more difficult to interpret the abnormal MRI results, and if it weren’t for technology that recently became available, an MRI-guided fusion biopsy, his cancer still might not have been found.

When it was finally diagnosed, and when his prostate was removed – with more difficulty than it should have been for a man his age because of all that scar tissue – his Gleason grade turned out to be a 7 (3+4), higher than the Gleason 3 + 3 score found on his biopsy.

And here’s the really amazing part: During this time, Rob developed a strong family history of prostate cancer which did not exist before he began his active surveillance, the kind that should make most doctors take notice and say, “You need to be screened early for prostate cancer.” His father developed it at age 70, and a few years later, so did his maternal cousin, at age 56. In just a few years, he went from having hardly any family history to having three men (and maybe four, if Rob himself developed it) in the family with prostate cancer. It is very important to tell your doctor when your family history changes for exactly this reason: it should upgrade your risk, and you should be followed more closely.

Prostate Purgatory

It all started in 2005 with a drip; actually, a few drips after urination from time to time. “It wasn’t substantial,” he says, “but it was enough to raise an eyebrow for any guy,” particularly an active, otherwise healthy, 38-year-old man. “It started to weigh on me so much, so that I would need to be conscious about what I would wear.” Rob started reading up on his symptoms, trying to figure out what could be the cause.

In 2008, at his yearly physical, Rob asked his family doctor for a PSA test. “It came back at 1.6,” higher than it should have been.   The doctor said, “’I thought you would have been below 1.0. This may be something we want to explore,’” and referred Rob to a local urologist. His urologist in Connecticut performed several diagnostic tests for urinary problems, including a Uroflow test, a renal ultrasound, and a cystourethroscopy, in which a lighted tube is threated through the penis to examine the urethra. This was his least favorite, says Rob, of all the tests he’s had. “It was like Alien Autopsy,” he laughs. “I’d never experienced anything in my life like that, and it was just the beginning of the barbaric things I had to experience!”

And so it began. Five months later, in March 2009, the next PSA test came back with 1.9 and a rectal exam detected some swelling of the prostate, which the urologist suspected was prostatitis.   Rob had his first biopsy that same month, and three of the 12 samples showed high-grade PIN (prostatic intraepithelial neoplasm); this pathological finding is not cancer, but it’s not normal, either. In fact, where high-grade PIN is found, cancer is often lurking nearby – except the needle didn’t find it.

The next two PSAs were 1.9 and 1.8, taking us to 2010, and at this point, Rob decided to go to an academic medical center with expertise in treating prostate cancer. “I’ve been known to research things ad nauseam and then research them again to validate my original findings,” he says. “I thought, ‘if there’s any possibility that something’s developing, I have got to find who’s the best in this field.’” He sought a second opinion on his biopsy slides at Columbia University in New York; the results were confirmed.

The next few years saw more PSA tests, with the results ranging from a high of 2.3 down to 1.36. Ash Tewari, M.D., now Director of Urology at Mount Sinai, ordered Rob’s first PCA3 test. PCA3, like PSA, is a blood test and it is not a replacement for PSA, but an adjunct to it. The PCA3 test is more cancer-specific; the lower the score, the lower the odds of a positive biopsy. In Rob’s case, however, the PCA3 was not the crystal ball he’d hoped for; the first result was a false score of 58.8; the second was 18.3, the third was 18.7, and the fourth was 12.4. Another PSA test showed a free PSA ratio of 27 percent – again, not terribly helpful in Rob’s case. Generally, in men with a PSA lower than 4, a free PSA greater than 25 percent is more likely related to benign enlargement of the prostate, or BPH.

Rob had his first of nine MRIs – three of them endorectal – in 2010 before moving to the 3T MRI. It was not until he had a fusion biopsy conducted by urologist Ardeshir Rastinehad, M.D., at Mount Sinai – in which the needle biopsy is guided by MRI and ultrasound combined – done in June 2017, that cancer was finally detected – just a little, low-grade, Gleason 6. Rob had his prostate removed by urologist Ketan Badani, M.D., director of robotic surgery at Mount Sinai. His surgical margins were negative – no cancer was left behind. His nerve bundles were preserved. When the pathologist examined the prostate specimen after surgery, Rob’s cancer turned out to be of a slightly higher grade, Gleason 7 (3 + 4) – a finding that “validated my decision to have the surgery,” Rob notes.

“Literally, the first thing out of my mouth when I woke up in recovery from surgery was, ‘Was it contained?’ I was still groggy, and I must have asked my wife that question a dozen times. She was at my bedside when I awoke, and she said that it was – with a smile that said more than you could imagine for me and my family. I knew it had taken longer than it should have, based on when I went into surgery and the time estimated to wake up in recovery, which contributed to my concern. But this delay turned out to be because of the extra time it took to work around and cut away the buildup of scar tissue from all the biopsies. “There was so much scar tissue that it also contributed to the abnormal MRI results, which led to the increased number of biopsies. If I hadn’t had the fusion biopsy, it might not have been found. I would be living with it in me undetected and with a false sense of security – the thought of which is truly unsettling for me.”

We just fast-forwarded through years of worry, of waiting, of inconclusive tests – none of which Rob probably would have gotten if his pesky PSA had been where it should have been. As the volatility in his PSA persisted, so did Rob’s mission to stay ahead of anything that might have been developing.

In the meantime, because Rob and his wife didn’t have children during the early days of his ordeal, he banked his sperm just in case he ended up with prostate cancer. “Here I was, still young, and I didn’t know what tomorrow was going to bring. I had this sense of urgency to be prepared for the worst.” He even duplicated PSA tests with different doctors just to double-check; or as Rob puts it, “stress-test the results against one another.” A recent family photo, taken outside, shows Rob, his lovely wife and three beautiful young children, all looking healthy and happy.

Why was he so worried? Because of his dad and his cousin. Both developed prostate cancer. In tests in 2011, his dad’s PSA showed up as 10.3 and 7.56 – both numbers much higher than they should have been for a 70-year-old man. By this point, Rob knew the drill, and he plugged his father into the best system he could, with the same doctors he had come to know so well. An MRI and two biopsies later, Rob’s dad was diagnosed with Gleason 6 prostate cancer. He had a prostatectomy in 2013. In 2016, Rob’s cousin had a PSA of 8.9, was diagnosed with Gleason 9 disease, and once again, Rob’s experience helped him show his cousin the path forward; he, too, had a prostatectomy.

There are several take-home messages here:

  • It’s up to you. Many doctors don’t order PSA screening during a routine physical, especially in men who don’t have a family history of the disease or in men younger than 50. If you’re age 40 or over, you should get a baseline PSA test, and then get it checked regularly afterwards. It’s easy: if you’re getting your blood checked anyway for cholesterol, lipids, etc., adding PSA to the list of things to be looked at is just a matter of your doctor checking a box on the lab form.

  • Do what you need to do. Rob really needed to know what was going on. At one point, his family suggested that he “was becoming a bit of a PSA junkie,” Rob recalls, and he asked himself: “Am I actually losing my mind? Am I looking for a problem?” But when his father and cousin were diagnosed with prostate cancer, “suddenly everyone in the family realized this was genetic” and appreciated Rob’s efforts.

  • Find doctors you have confidence in, and go to the best place you can. Many studies have shown that if you get treated for a disease – any disease – at a large-volume hospital where they treat a lot of people with this same problem, you will do better. Your cancer will be less likely to return, and you are less likely to have complications from treatment because they are really good at treating it there.

  • PSA fluctuates. There are many reasons why; if you have an infection in your prostate, engage in some form of intense physical activity, or have intercourse one to three days before your blood is drawn it could result in a higher PSA than normal. BPH and prostatitis can also drive up the PSA level.

  • Be prepared, or as Rob says, “Stay in front of the 8 ball.” Rob not only banked sperm ahead of time just in case he had his prostate removed; he researched various forms of treatment and – very important – got himself in the best possible shape for surgery. During the almost two months between his conclusive biopsy and prostatectomy, “I worked out every day as if I was training for a marathon,” he said. “I never missed a day at the gym. So when it was game time, aka the surgery, I was going to be in the best possible shape I could be and ultimately recover faster. In fact, just two hours after I was in my hospital bed post-surgery, I was up and walking laps around the unit in the hospital while some men were literally unable to get out of bed for a day or two because of their physical condition going into surgery.”

  • Take care of your family. “I have a brother, and three young sons, ages six, four, and two. God willing, nothing will happen to them,” but Rob will be on guard, making sure they get regular PSA screenings. He also made his sister aware that her risk of breast cancer may be higher, too, “once I started reading about the correlation between breast and prostate cancer I recommended that both she and my brother take the germline test. ”

  • Help your friends. Rob didn’t tell many friends before surgery that he had been diagnosed with prostate cancer. “I didn’t want it to become a ‘Woe is me’ situation and I certainly didn’t want to expend any energy fielding dozens of phone calls asking how I was doing, even though I know it was because they genuinely cared. I just needed to focus on preparing for the surgery and the recovery process.” He also told his wife, “I want to be the guy you can confidently point to regardless of where we are after you overhear somebody saying, ‘I’m scared, my husband is scared; he’s just been diagnosed with prostate cancer.’ It’s at that very moment you can say, ‘See that guy over there? Go talk to him. He had his prostate out X months ago and you would never know it.’ That’s the value I can take away from this recent journey: an experience I can share with others who find themselves in a similar situation.

“I was fortunate enough to dodge a bullet, and I want to – I feel obligated to – pay it forward. Any chance I can get to alleviate the fear that is most often fueled by uncertainty is something I want to offer. The anxiety that people are living with because they simply don’t know what to expect, where to start, or better yet, the incredible resources that are available to them as long as you know where to look;; the playbook, if you will. I did the Kegel exercises religiously as prescribed before and after surgery, which led to my getting off the pads after just two months, Sexual function is also fine, which was a welcome surprise.”

  • Reach out. Rob, who couldn’t let it go during the search for prostate cancer, isn’t about to let go now; in fact, he hopes that other men will be helped by his story. “This disease affects one in eight men over a lifetime – and more specifically, my grandfather, my father, my cousin, and me.   When I talk to friends who don’t know what a PSA test is, it proves there needs to be an even louder rally call and greater effort to educate and increase awareness around prostate cancer – so that like me, others can stay ahead of it, make the right decisions, and live long, healthy lives after detection and surgery.”

*Name has been changed, at Rob’s request, to protect his privacy.  The names of the doctors in this story have not been changed.

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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Coffee and Prostate Cancer: Go Ahead, Have Another Cup

Here’s some news about coffee, the good, the bad – actually, there is no bad to this story. Coffee is good! If you can’t drink caffeinated coffee, decaf is good, too! Here’s why:

Although most scientists are not yet willing to step out on a limb and proclaim definitively that drinking coffee prevents cancer (this story is mostly about prostate cancer, but beneficial effects have been seen in other types of cancers, too) or makes you less likely to have aggressive, high-grade disease if you do get it, undeniable evidence from several new studies suggests that this may indeed be the case.

Best of all, there’s no downside. If you drink coffee, keep right on drinking it. Fill it to the brim! And if you don’t already drink it, you may want to consider it.

What’s going on here? What about coffee has us so – pardon the pun – perked up? Well, there’s a latte to consider, so let’s look at the grounds for optimism starting with these findings, published in the International Journal of Cancer:

In a study from the Moli-sani Project, investigators looked at coffee consumption in nearly 7,000 men, age 50 and older, in the Molise region – a mountainous, mostly rural part of Italy. They followed them, on average, for more than four years, and during this time 100 of these men were diagnosed with prostate cancer. (Note: unlike many American men, these men were not getting routine screening, so it’s possible that some of them may have had not-yet diagnosed prostate cancer.) The average age at diagnosis was 67, and of these men, half had cancer that was Gleason grade 7 or higher; 8 percent had distant metastases, and 6 percent had local metastases. In separate studies, the Italian investigators also showed that both coffee and caffeine can slow down the growth rate and spread of prostate cancer cells in the laboratory.

But what about actually drinking coffee? It turns out that there was an inverse association between coffee intake and prostate cancer risk. In other words, the more coffee the men drank every day, the less likely they were to develop prostate cancer. In this study, the men who drank more than three cups a day had the lowest risk of getting prostate cancer.

Note: The investigators define more than three cups as drinking 90 grams or more per day. This actually turns out to be just 3.17 ounces; in Italy, coffee consumption tends to be in cute little espresso cups, and the cultural tendency is not to sit for hours nursing a cup at a café, but to just knock it back and get on with your business. So a dose of coffee here is more like a shot of espresso to us. In comparison, the smallest size at Starbucks, a Short, is 8 ounces; a Tall is 12 ounces, and a Grande is 16 ounces.   At Dunkin’ Donuts, a Small is 10 ounces, a Medium is 14 ounces, and a Large is 20 ounces.

It’s also worth noting that these men most likely took their coffee black, or maybe with a bit of milk or cream. In other words, they didn’t have a pump of hazelnut, five shots of whipped cream, ice cream, soy milk, almond milk, sugar, stevia, Nutrasweet, Sweet & Low, or any of the many things we can think of in America to add to our coffee.

So just think pure coffee here. Also, their coffee was unfiltered – not brewed or instant, as coffee is for many of us on this side of the pond.   This means that it may have some other prostate cancer-suppressing molecular components that get filtered out in other forms of coffee.

Still, the results are striking. Of all the foods and potential things you could take to lower your risk of getting prostate cancer – scientists believe the most promising of these include taking a baby aspirin a day, eating lots of tomatoes cooked in olive oil, taking vitamin D, or being on statins to lower cholesterol; all of these lower the inflammatory environment in your body and make it less likely for cancer to develop – coffee in this and other studies seems to have the best hazard ratio; that’s a scientific term that ranks the probability of being true in real life, and not just in the study.

So why aren’t we standing from the rooftops shouting: Coffee for everyone! Run, don’t walk, to the nearest percolator! Because, says Harvard nutritional epidemiologist and PCF-funded investigator Kathy Wilson, Sc.D., it is just so darn hard to know exactly what’s going on when you look at things in the diet. I recently interviewed her for the Prostate Cancer Foundation’s website.

For example: How do we know that the vast majority of these men didn’t get prostate cancer just because they downed a lot of coffee? Maybe it was what they were eating – which was almost certainly the Mediterranean diet, high in fruits and vegetables and olive oil, and low in red meat? Did they drink tea or eat chocolate? Both of these substances are chock full of antioxidants, as well.

Or maybe it was what they were not eating – high-fat, high-carb stuff like bacon cheeseburgers and chili fries. Or maybe it was what they were not drinking – super-sized sodas, energy drinks, or sweet tea?

“The Italian investigators adjusted for other factors in their study – such as total energy intake, smoking, BMI (how fat the men were) – and found that the coffee benefit was independent of those things,” says Wilson.

Wilson’s work focuses on understanding the role diet plays in prostate cancer, and she has been zeroing in on coffee for years. In fact, she was first author of a large Harvard-led study published in the Journal of the National Cancer Institute in 2011, in which investigators also showed an inverse association between coffee and prostate cancer. “The Italian authors put a lot of weight on the unfiltered coffee that’s consumed in Italy, but I don’t think we can rule out that the lowered risk is just an effect of coffee itself, filtered or unfiltered.”

In their study, Wilson and colleagues also found that coffee was associated with a lower risk of getting prostate cancer, and of developing aggressive, potentially lethal cancer. Men who drink one to three cups a day 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. “The findings were similar for caffeinated and decaffeinated coffee,” says Wilson.  This was perhaps even more remarkable because they also found that heavy coffee drinkers also tended to be smokers – and smoking cigarettes is known to raise the risk of getting prostate cancer, and of developing a more aggressive form of the disease.

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

What does coffee do in the prostate? This is very difficult to study. Ideally, in men who decide to have their cancer treated with surgery, scientists might look at the biopsy tissue from men at the diagnosis of prostate cancer, then have those men drink several cups of coffee every day until their surgery, and compare the tissue from the entire removed prostate with the biopsy. Maybe they would find a change in aggressiveness, or in inflammatory markers, or in some other measurable thing that might show more precisely what coffee does in the prostate.

What’s in coffee, anyway? Well, that’s another tough one. There are actually thousands of compounds. Metabolites found at high concentrations in caffeine. Roasting products. Polyphenols. Diterpenes, products in the oil of the coffee bean (these are strained out in filtered coffee). Which one is the golden ticket to better health? There may be more than one, maybe more than a hundred. Nobody knows for sure.

Okay, well then, maybe the key is in what coffee does in the body. Just what does it do, anyway?

Coffee has powerful antioxidant effects. As Wilson notes, “coffee is the number one source of antioxidants in the diet of the American man.” This is very interesting, and also pretty sad; it means the average American man is not loading up on antioxidants in fruit and vegetable form in his daily meal plan.

Coffee is also anti-inflammatory, says Wilson. “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. “It reduces blood glucose levels, reduces intestinal glucose absorption, and reduces liver glucose output.”

Coffee cuts lipids, the body’s fatty acids. “It reduces fasting cholesterol and triglyceride levels.”

Coffee helps the gut’s microbiome. It increases diversity in the microbiome, the millions of bacteria living happily in your gut. “There are a lot of immune cells along the gut, and the increased diversity in the microbiome may inhibit inflammation elsewhere in the body.” There may be some important interplay between the gut flora and inflammation, and it may be that coffee tips the balance away from inflammation and the development of cancer.

How much coffee should you drink? For how long do you need to drink coffee to be protected from cancer? Do men who cut down on caffeine later in life because of urinary problems (from BPH, benign enlargement of the prostate) lower this protective shield and somehow open the door to cancer?

Add these and a whole bunch of other questions to the large list of things nobody knows the answers to – for now. But scientists are working on it, and the Prostate Cancer Foundation is funding studies in four labs in the UK and U.S., says medical oncologist Jonathan Simons, M.D., CEO of the PCF. “Scientists who have expertise in pharmacology, biochemistry are curious about this unfiltered Italian coffee phenomenon. They’re undertaking the detective work needed to figure out the biochemistry and gene signaling of it.” Such work has paid off before, he adds. “Two of the most important drugs in internal medicine, digoxin and aspirin, come from leaves and tree bark plus intensive and persistent detective work by pharmacologists who were sure the clinical effects were real.”

One thing does seem pretty clear, notes Wilson: “There’s a perception that coffee is not good for you, that it’s a habit you should kick, or that you should cut back. But all the evidence is that if anything, coffee is beneficial. It’s really quite striking.”

And yet, she adds, “it’s probably premature to actively recommend coffee, or tell guys who don’t drink coffee that they should start drinking it. But coffee is not bad for you in terms of chronic health. If people are already drinking coffee, they should feel fine about it – not, ‘this is bad for me in the long run.’ In long-term health, coffee seems like it’s doing good things.”

One group not particularly well represented in the Harvard Health Professionals study or the Italian study is men of African descent. Prostate cancer is different in these men; it is more aggressive, it develops in a harder-to diagnose part of the prostate, different genes are involved in its development and progression, and some of the biomarkers that help monitor the disease do not work as well in these men. However, Wilson notes: “It is interesting that in overall U.S. diet data, black men do drink less coffee than white men.” File that one away for future studies; it’s hard to know what to make of that one fact on its own.

Because trying to find the magic pill – whether it’s beta carotene or selenium, or any of the millions of compounds that could potentially be isolated from the diet and sold as a supplement – has not worked yet, your best bet is just to err on the side of healthy. Eat lots of fruits and vegetables, particularly tomatoes, don’t eat a lot of red meat, don’t load up on carbs and sugar. Watch your weight; obesity is linked to a higher risk of prostate cancer. Don’t smoke.

And feel free to have another cup of Joe.

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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PSMA-PET and Prostate Cancer

Remember these letters:  PSMA.  If you haven’t heard of PSMA-targeted agents yet, you probably will soon.

Imagine a heat-seeking missile – except the tiny target locked onto by this particular missile is PSMA (prostate-specific membrane antigen), a protein that sits on the surface of prostate cancer cells.  The weapon itself is a small molecule, originally designed as an imaging agent by a team led by Johns Hopkins investigator Martin Pomper, M.D., Ph.D., and scientists are still discovering what it can do.

How specific is it? Imagine a bit of tissue the size of a teardrop.  Two of the cells inside it are prostate cancer cells; the rest are not.  With a PSMA-targeting tracer, like Pomper’s small molecule or any of its next-gen relatives, only those two cells would light up.

We’re talking molecular LEGOs here: With Pomper’s small molecule, PSMA can be linked to different chemical bricks.  One kind of brick is a radioactive tracer that can show on a PET scan exactly where small bits of cancer are hiding.  But wait!  There’s more:  PSMA can also be hooked up to a radiopharmaceutical agent, called a radionuclide, that can seek out and kill those tiny pockets of cancer and potentially even stop metastatic disease.

It’s like the old commercial for the miracle product called Shimmer on “Saturday Night Live.” It’s a floor wax! It’s a dessert topping! No, it’s both!

“It truly has excellent potential and we are just scratching the surface here of what PSMA-targeting can do,” says medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, “in metastatic disease and also in localized disease.”   I recently interviewed Simons and Pomper for the PCF’s website, and Pomper for the newly released Fourth Edition of my book with Patrick Walsh.

This momentum has been building for two decades. “We started working on PSMA-based imaging agents back in the late 1990s,” says Pomper, Director of Nuclear Medicine and Molecular Imaging at Johns Hopkins. Pomper’s team was not the first to try to harness PSMA as a way to get to prostate cancer; in 1996, scientist Neil Bander created an antibody that can target PSMA and used SPECT imaging to see hidden prostate cancer cells.  But antibodies are cumbersome; it takes several days from the time they are administered until they clear the bloodstream and reach the target cells. They are also very large. Continuing the building-block theme here, it’s like trying to attach toddler-friendly DUPLO blocks to the much more svelte LEGOs. “We want to be able to scan within an hour or so after injection,” Pomper explains. “We prefer the small molecules for therapy, too.”

Pomper’s versatile small molecule and derivatives of it have galvanized the field of nuclear medicine. PSMA-targeted imaging and therapy has generated huge interest worldwide – especially in Europe, where scientists have linked the small molecule to radionuclides (both alpha- and beta-emitting particles) and are reporting long-term remissions in some men with metastatic prostate cancer. “You just switch what’s attached to the small molecule, and you can go from imaging to irradiating the cancer – cancer you can’t even see, potentially. This would be impossible using external-beam radiation.”

German doctors – who, thanks to a regulatory loophole were able to move right into using PSMA-targeted radiotherapy without having to conduct the clinical trials required in the U.S. – have even reported cures in a few men – but also some side effects, including the loss of the salivary gland, where some PSMA-bearing cells also live. That’s because, although scientists called it “prostate-specific,” PSMA is not solely confined to prostate cancer.

Scientists worldwide are trying to figure out how to tackle the “collateral damage” problem of PSMA. Is there some way to protect the salivary gland, like using potassium iodide to protect the thyroid in the event of a nuclear attack? Some of the salivary-protecting options being explored include botox and anticholinergic drugs.

The Great Promise of PSMA-Targeting Agents

“PSMA is present in the normal prostate, present in the brain, the kidney and the intestines,” Pomper notes, “but it’s really expressed much higher in malignant prostate tissue. It’s also expressed in the neovasculature – the vessels tumors need in order to grow in place or metastasize.”

PSMA is present in many different cancers, too. “Renal cell carcinoma, glioblastoma, pancreas cancer and other cancers have PSMA in the blood vessels around them – not in the tumor itself,” and this is an exciting potential avenue for future research: finding a way to target and kill PSMA-bearing areas around some terrible cancers that desperately need effective treatment.

Pomper keeps tinkering with the molecule and agents that link to it.. Recent work with Hopkins colleagues in Radiology and Radiation Oncology has led to the first published small-molecule alpha-particle emitting agent to treat prostate cancer. A team led by radiation oncologist Ana Kiess, M.D., Ph.D., linked an alpha-particle emitter to Pomper’s small molecule. “Alpha particles are emitted from certain molecules as a consequence of radioactive decay,” explains Pomper. “They are useful for treating cancer because they provide a lethal punch to the DNA of malignant cells – more so than other forms of radiation. The key is to enable the alpha emitter to reach the cancer cells selectively, leaving normal tissues unharmed.”

In the lab, “using this agent, we were able to prolong the lives of immunocompromised mice bearing human prostate tumors,” says Pomper. This study lays the groundwork for future clinical trials in men with prostate cancer, and for the design of even safer, next-generation alpha particle agents. Also, it “represents a pivot by our group from developing imaging agents to finding better agents for therapy.” The group is now leading a phase I clinical trial for beta particle-emitting agents it has developed.

The very good news for men with advanced prostate cancer is that numerous clinical trials are opening in the U.S. and Australia to test similar PSMA-targeted radiopharmaceutical agents. In fact, the PCF is funding three research projects – in Australia, at UCLA, and Weill Cornell – and all of these have clinical trials.

PSMA-PET Can Help Clarify Localized Prostate Cancer, Too         

So far, efforts with PSMA-targeting molecules have mostly been focused on what ancient Romans called the disjecta membra, the scattered bits and pieces of cancer that started out in the prostate and moved to the lungs, bone, liver, or someplace else.

But what about the cancer that’s right there in the prostate – cancer that hasn’t spread yet?  That’s what investigator Steve Cho, M.D., has been working to find out.  Cho, on the faculty at Johns Hopkins before joining the faculty at the University of Wisconsin, led the first human imaging study of Pomper’s PSMA-targeting agent.   He showed how well PSMA-PET could pick up metastatic prostate cancer – better than a bone scan and CT combined. Then he thought: “There’s a low level of PSMA in the prostate itself. How well does this agent pick up primary prostate cancer?”   With Movember funding through the Prostate Cancer Foundation, Cho led another study for prostatectomy patients – men with localized prostate cancer who have it taken out surgically. The benefit here is that Cho and colleagues could compare what they saw on the PSMA-PET images with what the pathologists found in the needle biopsy tissue and in the actual removed prostate specimens. They learned a couple of very important things:

One, in localized disease “this specific agent doesn’t show up in all prostate cancer patients.” (Note: other PSMA-targeting molecules might be found to work better in this situation.) But “it does show up in men with higher-grade cancers,” Gleason grade 8 or 9 tumors.

As it turns out, PSMA-targeting molecules have discernment.

This is really important, because many men need some extra help. “One of the problems with MRI,” Cho explains, “is that it can pick up a lot of lesions – but sometimes they are benign.” Calculi, stones in the prostate (like kidney stones, but tiny), and enlargement of the prostate (BPH) can show up on an MRI, too, and it’s not always apparent what needs to be treated and what doesn’t.

MRI is sensitive, but not always very specific; it’s “user-dependent, in terms of interpretation and experience.” Understandably, a radiologist who looks at nothing but prostate images all day probably has more expertise at spotting prostate cancer than does a radiologist who looks at images of all sorts of body parts. “PSMA-PET was specific in our study,” says Cho. “If you see a signal by PSMA-PET in the prostate, it typically ends up being a site of prostate cancer, and ends up being clinically significant.”

This could be particularly helpful for men with an elevated PSA but a negative biopsy (or biopsies), or men considering Active Surveillance for prostate cancer. Men who are told they have low-grade disease – because the biopsy needle hasn’t picked up anything different – could have extra peace of mind if a PSMA-PET comes up negative for high-grade disease. Or, men who have had one or more inconclusive biopsies may decide to undergo surgery or radiation therapy if PSMA-PET shows high-grade cancer that the needles missed.

Even if a biopsy shows cancer, “the biopsy needle is not always accurate,” Cho notes. “It might show Gleason 6 disease, but maybe there’s Gleason 8 cancer somewhere hidden. ” Similarly, during a rectal exam, “the urologist’s finger can’t always feel cancer in the apex or anterior of the prostate. That’s where I think this technology can really help: it can provide a better way of targeting a specific region of the prostate so the needle has a higher probability of a true hit.”

Combining PSMA-PET with MRI may result in even more accurate and predictive scans, as well.

But wait again! There’s even more! Cho is exploring PSMA-PET in several different studies, aimed at helping men with different stages of prostate cancer.

One of these is for men with high-risk prostate cancer, “we currently have a clinical trial here at the University of Wisconsin, a Department of Defense-supported grant, with medical oncologist Joshua Lang, M.D., urologist David Jarrard, and biomedical engineer David Beebe, Ph.D., who studies the microenvironment of tumor cells. “In these high-risk patients, at the time you take the prostate out, they already have a high probability of having cancer outside the prostate.” But if the disease could be attacked systemically, with three months of hormonal therapy (Degarelix) and chemotherapy (Docetaxel) before prostatectomy, would that help – and could PSMA-PET images show that tiny bits of cancer have disappeared?

In future studies of men with advanced prostate cancer, Cho envisions using PSMA-PET to monitor treatment – any kind of treatment – to make sure it’s working. “Can we tell early on whether a patient is responding or not responding well, so we don’t have to continue to give treatment that’s not working, and we can quickly change course?” Molecular imaging can help doctors “be more nimble” and respond more quickly – either to intensify treatment or, if it’s working, perhaps to dial it back and spare the patient multiple cycles of hormonal therapy or chemotherapy. This is already happening in other cancers, such as lymphoma.

“This whole area is evolving,” says Cho. “We have barely scratched the surface.”

We’ll be talking more about PSMA in future posts.

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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ED After Prostate Cancer Treatment: Old School Approach Not Good Enough

Just when everything should be getting better – you’ve been diagnosed with prostate cancer, gotten curative treatment with surgery or radiation, and now you’re looking forward to getting your life back – there’s another bump in the road: ED (erectile dysfunction). You don’t need that!

Darn it, here’s yet another “reluctant brotherhood” – a club, like that of prostate cancer, that you never wanted to join. Take heart: You’re not alone, and it’s going to get better.  But your road to success may not be a little blue pill.

Maybe you’re like a lot of men who, before treatment, envisioned themselves boldly striding forward toward recovery of potency – perhaps temporarily using Viagra, Cialis, or another pill in the class of PDE5 inhibitors as a crutch until erections returned on their own.

Unfortunately, for some men, these might as well be sugar pills. They just don’t work as promised. And instead of striding forward boldly, they find themselves making uncertain progress like the Wayfarer, a character painted by Renaissance artist Hieronymous Bosch: a poor guy just trying to get somewhere down a troubled path.

For too many men, the road back to potency is a lot more difficult, confusing, and frustrating than it has to be. This makes me mad, because I have talked to men and their families who just don’t need another health burden to deal with. It makes Johns Hopkins urologist Arthur Burnett, M.D., mad, too, and he is doing something about it.  

Burnett is a surgeon-scientist, a neuro-urologist and pioneer in the understanding of erectile dysfunction (ED). His research on the biochemical mechanisms of nitric oxide in erectile tissue contributed to the development of Viagra and other PDE5-inhibiting drugs.

Burnett is also a world-recognized authority on treating the problems in sexual function that can occur after surgery or radiation for prostate cancer – and there are several. “ED is one thing,” he says, but it’s not the only potential roadblock to sexual recovery. “Some men also develop scarring in the penis, a condition known as Peyronie’s syndrome. Some men have climacturia, where they may release a little urine during sexual stimulation or climax, so that’s problematic. There’s a whole host of things that can go wrong,” and all of these problems can be treated.

By far the most common problem after prostate cancer treatment is ED, difficulty achieving or maintaining a penile erection. The American Urological Association has just revised its guidelines on treating this. Burnett, who co-chaired the committee to change these recommendations, says they were brought about by an evolution in thinking. “Treatment should be based on shared decision-making,” he states. “Patients should have the opportunity to have a full discussion on ED with their doctor – the variety of options to treat it, the likelihood of success – and options should exclude those that may have contraindications,” that aren’t recommended in their particular case, or that probably won’t help them.

Makes sense, right? And yet, Burnett has seen thousands of patients from all over the world who have not had such a discussion with their doctor, or whose doctor has continued treatment that not only isn’t working, but never was going to work.  

The old model – the one that emerged close to two decades ago with availability of PDE5 inhibitors – had well-defined steps to follow.   “We initiated therapy along the lines of first line, second line, and third line,” explains Burnett.   The first-line treatment was the pills, “the least invasive form of therapy.”

Erection is a vascular event; it involves blood flowing into the penis, being held inside there, and then flowing back out. The nerves that are responsible for erection lie in fragile neurovascular bundles on either side of the prostate, a discovery made by my co-author on the books, Johns Hopkins surgeon Patrick Walsh, M.D., who found that if men had one or both bundles preserved during prostatectomy, it was still possible for them to recover erectile function. However, he reported that patients who were older or who had one bundle were not always successful in recovering erections, and even men who had both bundles preserved, if they had vascular problems or other health issues, were more likely to have trouble.

Burnett has spent years studying these nerves, and he has found that the surgery itself – the traction on the nerves, and the stress of having an invasive procedure – can damage them. Often they recover, but sometimes they don’t. So even if, theoretically, a man should be able to produce an erection, it’s not guaranteed.

Many men – even though their nerves have been spared – “are not likely to respond to PDE5 inhibitors,” Burnett notes. These patients, particularly men with significant vascular disease, “need to be counseled in realistic terms on their likelihood of responding to these pills, balanced with their preferences, to try to get to the most effective therapy sooner rather than later,” says Burnett.   “Vacuum pumps and injections have traditionally been second-line treatments, but perhaps that should just be put on the table up front. Even penile prosthesis surgery should be put on the table early on for patients with more severe forms of ED. If men are already struggling with erections before surgery, after radical prostatectomy, they’re going to have even more trouble, and more frustration.” In other words, if you were relying on Viagra before treatment, the pill probably isn’t going to have the same effect that it used to.

“I see patients in my clinic who might best have been fast-tracked to a penile prosthesis early.” Burnett even sees men who had “non nerve-sparing” surgery – that is, both neurovascular bundles were removed (which is the right thing to do if cancer has reached these nerves) – who have been “done a disservice,” by being offered medicine that is simply not going to work for them. “Oral therapy depends on a necessary degree of intact nerve function,” Burnett explains. In other words, the pills augment what the nerves are already trying to do. “Their doctor says, ‘Let’s just try PDE5 inhibitors,’ but there are no nerves for penile erection. They start the first-line therapy. Then it’s, ‘Let’s wait another six months; keep trying.’” And that is not acceptable, in Burnett’s opinion. “We have to understand how these different therapies work, think about the clinical presentation of the patient, the variables that may impact his erectile physiology.”

Just having “all guys get first-line treatment, no matter what, and seeing how they do, then ‘maybe we’ll consider vacuum pumps and see how that goes for several months, and if it doesn’t work, we’ll consider injections’ – that’s not good enough. “It’s a much more practical model we’re evolving, one that’s focused on the patient’s desires and what is most likely to be effective.”

Make no mistake, Burnett adds, “if the patient has undergone a good-quality nerve-sparing radical prostatectomy, we should give his nerves the opportunity to recover function,” and not just jump to the third-line treatment, the penile prosthesis, right away. Nerves can continue to recover and erections can continue to improve even as long as four years after surgery. But that doesn’t mean a man should just stoically wait to resume his sex life until the day he achieves a decent erection, either. Maybe try a PDE5 inhibitor and a vacuum erection device, for instance.

Why do so many doctors insist on starting with the pills? Maybe they don’t take the time to find out how well the man’s erections were before surgery; maybe they don’t take heart disease or other health problems (again, some illnesses can hinder blood flow to the penis) into consideration – or maybe, as Burnett suspects, “they think, ‘the pills don’t have much of a negative impact,’ even though the patient will be frustrated for months.” Or maybe “they think, ‘More invasive therapies carry risks. Let’s see how he does,’ and they don’t consider that his sexual dysfunction can have a real impact on his health and wellbeing.” Too many doctors, he adds, “just pat ‘em on the back and say, ‘Things will be fine; you’ll be all right.’”

            But months and months of an unrestored sex life can be demoralizing, Burnett continues. “That’s why I think it’s more humane and appropriate to proceed with effective management of patients – not just treating ED by recipe. If somebody really is not predisposed to do well with PDE5 inhibitors, why push that on him?”

Similarly, injections work very well for some men, but not for others; men who have a large belly or who have poor hand-eye coordination, for instance, have difficulty. Other men simply “don’t feel that doing a needle injection is something that appeals to them. Why would we tell a man that’s all he’s got, instead of referring him to a penile prosthetic surgeon?”

Vacuum erection devices also have their pros and cons. “On the pro side, it’s noninvasive, and it’s fully under the control of the patient,” says Burnett. “But on the downside, it’s cumbersome and mechanical, it involves trying to draw blood into the penis, there’s a constriction band, it feels cold, and it can feel unnatural. Just put it on the table, and try to figure out what will work for one patient at a time – not some rote approach.”

Most men who get a penile prosthesis are happy with the result, says Burnett. “The erection feels natural, and they wonder why they didn’t get it sooner.” Why don’t more men with severe ED choose this option? “Part of it depends on how we in the medical community have presented it to patients.” Many of Burnett’s patients come to him after years of feeling frustrated with the first- and second-line treatments. “All too often, I hear patients say, ‘My internist said never get a penile implant; they get infected, and mechanically they don’t work.’ That’s unfortunate that this is what they’re being told.” In the 1970s and 1980s, penile prosthetics were not as reliable and were more prone to malfunction, but they have vastly improved since then.  

“Just like every other option, the prosthesis has its pros and cons. There is a 1 percent infection risk with prosthetic devices.” Burnett notes that doctors who are “infrequent implanters” tend to have higher infection rates, while “for expert surgeons, high-volume implanters, the infection rate is very low.” Burnett implants 80 or more penile prostheses a year, and “if I see an infection even once a year, it’s very rare.”

Patrick Walsh has told his patients for years, “if there’s a will, there’s a way,” and if they want to have a sex life after surgery, they can. Burnett, Walsh’s longtime colleague, adds to that message of hope from the doctor’s standpoint: “Never give up on a man who wants to preserve and restore his opportunity to be intimate with his partner.   We should try to explore options to help him achieve that.”

There’s one other important message here: Watch out for shysters. “Don’t waste your time or money with over-the-counter treatments or supplements,” says Burnett. They don’t work. Also, be very suspicious of high-cost experimental treatments. “The Sexual Medicine Society has taken a stand about some of this, and in our new ED guidelines for the AUA, we make it very clear that some things are investigational and require further evidence to show that they work.” These include shock wave therapy, stem cells, and platelet-enriched plasma injected into the penis. “Guys are being told, we’ll give you a couple of shots, and you’ll be fine. They pay out of pocket – $10,000 for as yet unproven therapy. It’s reprehensible, people out there trying to exploit these men. It is really terrible.”

It’s particularly terrible when there are medically proven approaches that Medicare and insurance will pay for that can actually restore a man’s sex life.

 

How Common Is ED After Surgery or Radiation?

 

Answering this question is more difficult than you might think, for two reasons: First, every surgeon and radiation oncologist has different results, based on expertise and the number of times the doctor has performed the procedure. So that’s one variable. The other variable is huge – and that’s your personal health. Start with the SHIM score, which is based on a few simple questions. You must be honest here. No one else will see these answers but you and your doctor.

After surgery: “In general,” explains Burnett, “erections are temporarily lost in many men who have a radical prostatectomy. Even with nerve-sparing, the nerves can be traumatized.   It takes a while for these nerves to recover. Although men may have some sporadic erections, it is very common for men not to be able to have consistent erections during the first nine to 12 months after surgery, without help.”

In men who are able to be sexually active without the help of a PDE5 inhibitor before nerve-sparing surgery, the potency rate after surgery gets better over time. “The potency rate at six months is different than at 12 months, and it’s even better at 24 months,” says Burnett. “Most men who had nerve-sparing surgery are going to recover erections in the second year.” Over the long term, he continues, “probably 80 to 90 percent of men who have pre-operative erections have the potential to recover erections without PDE5 inhibitors – if they have no other co-morbidities.”

This is the key. Co-morbidities are other health problems that could affect blood flow – particularly, blood flow to the penis. Major risk factors for not recovering erections, even if you have nerve-sparing surgery, include being a cigarette smoker (cigarettes are vasoconstrictors; they cause your blood vessels to contract); having diabetes, and having cardiovascular disease. There are other conditions and medicines that can affect erections, as well; this is why you need to have an honest discussion with your doctor about your current health and sexual function before treatment.

What about after radiation treatment? It’s kind of the opposite situation. “Unlike surgery, where you have a major loss and then you recover, with radiation you’re pretty much fine and then many men tend to lose erectile function over time,” says Burnett. For these men, PDE5 inhibitors may help. “As many as 50 percent of men who undergo radiation experience a general decline after two or three years – but for the first two to three years, men do not experience any true erection impairment.” Unless, of course, they were already having problems before treatment. The honest SHIM score is important here, too, and so is the discussion of any risk factors that you may already have with your doctor.

Note: None of this means that sex is impossible after you have surgery or radiation treatment for prostate cancer. If you want it, you can absolutely have it, Burnett says – but you may need more than PDE5 inhibitors, especially if you are already experiencing some ED before treatment.

False expectations are cruel. “Patients need to recognize if they aren’t the optimal guy to fully recover potency after surgery without any help,” says Burnett.   “Today, I had a 56-year-old professional athlete in my office, who had a perfect SHIM score and stage T1c cancer.” This man is highly likely to have full recovery of erections after surgery, because his cancer is minimal, and his cardiovascular system is in great shape.

But another man with that same stage of cancer who is diabetic and a smoker might not have such an easy recovery of potency.   That man can still have a full and wonderful sex life, Burnett says, but it might require a penile prosthesis. Knowing this before treatment could spare that man months of frustration.

 

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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Cancer, Gut Bacteria, and Your Poop

What does your poop reveal about your gut bacteria (called the gut “microbiome”), and what does this have to do with your immune system’s ability to fight off cancer? Just how important is this gut flora, or bacteria, anyway?

Let’s look at the last question first. How important is your gut bacteria? It’s very important to your whole body: your brain, your heart, your immune system – and, although no one has proven it yet, we suspect that it is also very important to your prostate. Being able to empower the gut bacteria – to increase certain “good” bacteria that, in turn, 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. In still other work, scientists studying melanoma found that the presence of certain gut bacteria can change how cancer patients respond to immunotherapy.

I have written about understanding and tapping the power of the gut bacteria here, and here, as it relates to irritable bowel and depression. But cancer! This article mainly applies to prostate cancer, but the implications are rich for many types of cancer.

Could treating the bacteria help prevent cancer, make it less likely to spread, or make immunotherapy more effective against it? I recently interviewed Johns Hopkins scientist Karen Sfanos, Ph.D., whose work is shedding light on the role bacteria play in cancer – particularly, in prostate cancer – for the Prostate Cancer Foundation (PCF), which has invested $1 million in research to help explain the gut microbiome’s role in metastatic prostate cancer.  Call it a “gut feeling.”

Eight Pounds of Your Body Is Just Bacteria

Here’s something to consider about the megapopulation of bacteria in your gut: A lot of us have been exposed to bad bacteria, but these bugs don’t kill us. In our large intestine, we have about eight pounds or so of trillions of bacteria; in fact, we have more bacteria than cells in our bodies. Some of them are good, and some of them are not so good.

But some people die from bacterial infections in the gut; what happens to make them more susceptible? Dysbiosis: an imbalance, where the bad bacteria take over. For example: say you have an upper respiratory infection, and you get antibiotics. Antibiotics wipe out bacteria. They don’t distinguish between good and bad species; they just kill ‘em all. The good bacteria are collateral damage, and sometimes this scorched-earth result creates an opportunity for very bad bacteria to thrive in your gut. What’s going to fix that, more antibiotics? Maybe, but not always. In fact, when you wipe out the gut flora with antibiotics, an even worse form of bacteria – something nasty like C. difficile, for instance – can take over.

Again, what does this have to do with cancer? Here we go: If antibiotics fail, the most effective way to cure intractable C.difficile is with a fecal transplant: basically, taking the poop of someone who does not have C. difficile, who has a healthy gut microbiome, and inserting it in your colon. It’s gross, but it can also save someone from chronic, miserable illness.

Karen Sfanos is one of a few pioneering cancer researchers wondering if the same principle could apply to treating prostate cancer.   With colleagues at Hopkins and Thomas Jefferson, she is looking at gut bacteria – a heck of a lot of it, in at least a thousand patients undergoing various treatments for advanced prostate cancer. As principal investigator of the PCF grant, Sfanos is stockpiling gut bacteria and building a microbiome specimen repository that will serve as an international database for research.

Sfanos, a molecular microbiologist, has long been interested in the relationship between bacteria and prostate cancer; in fact, she is among a growing number of scientists who are proving that urine is not (as scientists supposed for decades) sterile, and was the first to describe the urinary microbiome in men with and without prostate cancer. Bacteria in the urinary microbiome may shed light on the presence of microbes that can cause prostate infections, including some that are sexually transmitted infections. These microbes may produce no symptoms but may lead to chronic inflammation – and this, in turn, may cause prostate cancer in some men.

Meanwhile, a few studies looking at other forms of cancer “started to indicate that the gut microbiome could have an influence on treatment response,” Sfanos says, “and that really got us thinking about whether the gut microbiome could influence how well men respond to prostate cancer treatment.”

In studies with medical oncologist Julie Graff, M.D., of Oregon Health & Science University, Sfanos has been working to see if there is a difference in the gut microbiome of men with widely metastatic prostate cancer who have responded dramatically well to the checkpoint-inhibiting immunotherapy drug, pembrolizumab.

Originally, Graff and colleagues suspected that the men in their studies who were exceptional responders to this drug had cancers with “microsatellite instability” (they had tumors with many genetic mutations) – which made the cancer cells stand out and be more easily recognizable as enemies to the immune system. And this is undoubtedly true, but it’s not the whole story.

In Graff’s initial small study, published in Oncotarget, three men out of 10 had dramatic responses: their metastatic tumors in the liver, brain, and elsewhere disappeared, and their PSA levels plunged. Tumor tissue from two of these men was available for further analysis and, indeed, one of the men’s tumors had microsatellite instability. But the other man’s tumor did not. The number of tumor mutations, explains Sfanos, “cannot fully explain those responses to immunotherapy,” in Graff’s and other studies. “People who do not have that phenotype are still having dramatic responses.”

For these men, “the gut microbiome could be contributing in several ways. If the immune system is blocked from recognizing the tumors,” because the cancer uses sneaky tricks and devious disguises to hide itself from the body’s roving immune system soldiers that would kill it, “the right mix of bacteria could help stimulate the immune system – and combining that with the immune checkpoint inhibitor might drive a robust anti-tumor immune response. So that could explain what’s happening in patients who do have this high mutational burden.”

What about the other people with various forms of cancer who do have microsatellite instability – the weird-looking, multi-mutated tumors that the immune system can see and say, “Hey, that’s not supposed to be here!” Why do only some of them respond well to immunotherapy? The gut may be helping them, too.   Is it diet? Do these people just eat better, and thus have a healthier gut microbiome?

“Certainly, diet does have a profound influence on the composition of your gut flora,” says Sfanos. To understand more, it’s time to look at your poop – or rather, at the poop of men with advanced prostate cancer who are contributing to this repository – in a very high-tech way. With each fecal sample, Sfanos and colleagues extract all of the bacterial DNA and RNA. They’re generating “microbiome profiles” that include bacteria, viruses, fungi, and protozoa. Then, they are correlating the gut flora with the treatment the men are receiving – and hoping to find answers to so many questions.

“I am extremely interested in the interplay between bacteria and circulating hormones,” says Sfanos. Does ADT – androgen-deprivation therapy, which deprives prostate cancer of the androgens, or male hormones, that nourish it – change the makeup of bacteria in the gut? “It’s an underappreciated relationship: they influence each other. The gut bacteria influence the circulating androgen levels, and vice versa. They’re talking to each other.”

In one ongoing study, “we looked at the gut flora of men across the prostate cancer spectrum,” Sfanos notes – men without prostate cancer, men with localized prostate cancer, men with recurrent prostate cancer, and men with metastatic prostate cancer. “We were really interested in determining if there are differences based on what treatments the men were being given. Oral anti-androgens, including abiraterone and enzalutamide, “may directly interact with the gut flora. We found that these men in our study had measurable differences in the composition of their gut flora. Something specific is going on in the men taking oral anti-androgens.” In further analyses, Sfanos and colleagues found that in men taking these drugs, “there are bacteria capable of hormone biosynthesis in the gut: microbes able to synthesize and metabolize precursors that can be hormones. This could potentially influence treatment response.” In other words, some gut bacteria can synthesize androgens that “could maybe even continue to nourish the tumor. We are very actively studying this right now.”

The gut flora, she adds, are “absolutely linked” to some of the other health problems that can accompany ADT, particularly metabolic syndrome. “This is very understudied in men with prostate cancer.” (Sfanos’s most recent work is currently in press, to be published soon in Nature’s journal, Prostate Cancer and Prostatic Diseases. In the meantime, here’s a link to a related study she did.

What might this research lead to? How could it help men with advanced prostate cancer fight their disease? Here’s one example Sfanos can envision. “Let’s say we discover a species of bacteria that’s capable of metabolizing an androgen,” a nasty bug that could counteract the effects of abiraterone by whipping up its own homemade batch of male hormones. “If depriving men of androgens leads to an outgrowth of some bacteria that can make their own androgen, we could check for them in a patient’s stool sample and try to get rid of them.”

Boosting the immune system: The epithelial barrier, the thin lining of the intestinal wall, is a virtual Checkpoint Charlie for immune system activity. This is a gateway with “a massive amount of immune cells on one side, and bacteria on the other side,” Sfanos notes. “Several studies have shown that certain species of bacteria are overrepresented in the gastrointestinal tract of people who respond to immunotherapy.” One research group has focused on a group of bacteria called Ruminococcaceae, and another is studying a microbe called Akkermansia muciniphila. Either of these, or both, may turn out to be very important. “The idea is that if, for whatever reason, the presence of these microbes is essential to generate a response to immunotherapy, you would want to introduce these bacteria,” in a fecal transplant or perhaps in the form of a targeted prebiotic or probiotic.

There probably won’t turn out to be one “magic bullet” form of bacteria, which is why a fecal transplant might be helpful. It is an intriguing idea: taking the gut bacteria from someone who responds extremely well to immunotherapy, and transplanting that – in poop form – into the colon of someone whose gut bacteria is not as beefed up for cancer-fighting. Would this stimulate the immune system so that it would knock out the cancer? Could it turn flabby, couch potato bacteria into ripped, mighty, cancer-fighting bacteria? And could this beefed-up bacteria help put your cancer into remission?

It’s early days yet. But if the bacteria within our bodies can shape how our immune system functions, if it can help determine how we respond to cancer treatment – or even whether we get cancer at all – then understanding the very complicated interplay between gut bacteria and cancer could be a game-changer.

“Historically, many prostate cancer biobanks have not included fecal samples,” says Sfanos. This means that nobody has correlated the other markers for how prostate cancer develops or progresses – PSA, Gleason score, genetic mutations, or clinical outcomes – with what’s happening in the gut.

Thanks to Sfanos and colleagues, that’s not the case anymore. 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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Oligometastasis in Prostate Cancer: Curable?

What if you have cancer that is confined to the prostate, with just a little tiny bit outside of it? Are you doomed? It used to be that doctors thought, “Oh, man, he’s a goner, the cancer’s spread outside the prostate.” But scientists are learning that not all out-of-the-prostate cancer is the same, and just because a spot of cancer has popped out of the prostate, doesn’t necessarily mean that it can’t still be cured.

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

This is pretty much the way it’s been for men were treated for localized prostate cancer with surgery or radiation who have a rising PSA.   The options have been: salvage radiation or surgery, maybe a short course of androgen deprivation therapy (ADT), a vaccine, maybe a clinical trial, and then… waiting for metastases, long-term ADT, and other forms of treatment.

But here’s some promising news:  The window of curability may be wider than anybody thought. Until very recently, the dividing line between prostate cancer that was considered curable and cancer that might not be was the prostate itself – whether the cancer was confined to the prostate or had spread beyond it to a distant site. That’s not the case anymore, says Johns Hopkins radiation oncologist Phuoc Tran, M.D., Ph.D. In the most recent (2018) edition of our book, Patrick Walsh and I wrote the section on radiation oncology with expert opinion from Tran, an innovative scientist working hard to save lives from prostate cancer.

“Clinically speaking, we prescribe treatments for men with prostate cancer as though prostate cancer presents in clear clinical states,” he says.

Think of a Venn diagram: in one circle are “men we believe to have purely localized disease, and they are curable by surgery or radiation.” In the other circle are men with metastatic disease, men who are considered “treatable but not curable with our current therapies.  In general, this old treatment paradigm says that men with localized disease benefit mostly from local therapies like surgery and radiation and very little from systemic treatment like hormones and chemotherapy.”

But Tran and Hopkins colleagues are among scientists who believe these circles intersect. 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 also the few metastatic lesions, 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.

This is a dramatic and very exciting change in scientific thinking, and it’s happening because several key advances have come together all at once. PSMA PET scanning now allows bits of cancer as small as a BB to be seen – and SBRT (stereotactic body radiation therapy) or SABR (stereotactic ablative radiation) make possible precision treatment. “SBRT and SABR are highly focused radiation given in an intense fashion,” says Tran. “I tell patients it’s like spot welding—focused on a small area, very intense, and theoretically ablative, meaning it kills all the cancer in that spot.”

The Baltimore ORIOLE Trial

Can this new SABR technology plus treatment of localized cancer help men with oligometastatic cancer? “We wanted to test our idea in a rigorous way,” says Tran.  “Our Baltimore ORIOLE trial is a randomized clinical trial in patients with oligometastatic prostate cancer (defined as three or fewer metastases).” To be eligible, men must have received either surgery or radiation for the primary prostate disease, and have had no hormonal therapy for their metastatic disease. “They can have had hormonal therapy in conjunction with treatment for their primary disease,” such as a short course of androgen deprivation therapy (ADT) with external-beam radiation therapy, “but not for their metastatic disease.”

Men are randomly assigned either to receive SABR to up to three metastatic sites, or to a short observation period of three to six months – but this doesn’t mean that the men assigned to observation can’t get SABR, Tran states. “The randomization is two to one to SABR, versus a short – no longer than one- to six-month – observation period, after which they can cross over to the SABR treatment.”

Other criteria for eligibility: small metastatic sites (less 250 cc) and a PSA doubling time of less than 15 months. “We chose less than 15 months because there are men who have biochemical failure or low-volume metastatic disease with long PSA doubling times, sometimes many years,” explains Tran. “These men probably don’t need any treatment immediately – or possibly, ever.  A PSA doubling time of less than 15 months allows us to zero in on patients for whom SABR treatment may make a difference.”

This study was funded by the Movember Foundation and the Prostate Cancer Foundation (PCF).   “The Baltimore ORIOLE trial had no preliminary data when we funded it, and without private funding, it would not have been possible. says medical oncologist Jonathan Simons, M.D., CEO of the PCF. “Generally, the federal government requires that you have one-third of the work done in advance, then they fund the other two-thirds of it. That’s a real deterrent to highly innovative projects, and this one goes after a central and potentially practice-changing question: Can these men be cured now, and be spared ADT and metastases later?”

The potential implications here are huge: “The data suggest that two-thirds of men – or perhaps even more – who progress from biochemical failure to metastatic disease progress first with oligometastatic disease,” says Tran. “The number of men who could be helped by this could be as high as 20,000 to 25,000 every year.”

Because of the possibility of long-term remission or even cure, the study has filled up fast, Tran adds. “Thus far, as expected, we have seen only minimal side-effects from the SABR, and all men continue to work and are able to resume their normal activities during the short treatment,” which generally lasts less than three weeks.  Early results “look promising.  The trial also has a number of cutting-edge genetic, blood and imaging studies associated with it that men would not have access to otherwise.”

The Baltimore ORIOLE trial is a collaborative effort involving Hopkins radiation oncologists Theodore DeWeese, Danny Song, Curt DeVille and Stephen Greco; medical oncologists Mario Eisenberger, Ken Pienta, Emmanuel Antonarakis, Michael Carducci, Sam Denmeade Channing Paller and Mark Markowski; urologists Ashley Ross and Michael Gorin; radiologists Steven Rowe and Martin Pomper; and statisticians Hao Wang from Johns Hopkins and Adam Dicker from Thomas Jefferson University.

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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Exercise and Cancer: What Your Prostate Thinks

Hey, guys: If you think exercise is just about pumping iron and getting big traps, six-pack abs and “gun show” biceps, your prostate would like to disagree.

To your prostate, how ripped or shredded you are is not nearly as important as your cardiovascular health.

Now, you may be wondering, why should the prostate even care about cardiovascular exercise? Here’s a very good reason: exercise can lower your risk of getting lethal prostate cancer, or of having cancer come back if it’s already been treated.

Epidemiologist June M. Chan, Sc.D., an expert on lifestyle and cancer, heads a research program at the University of California San Francisco that seeks fixable risk factors for prostate cancer progression – things in your lifestyle that you can change to lower your odds of dying of prostate cancer. I recently interviewed her for the Prostate Cancer Foundation’s website.

In previous work, Chan and colleagues were the first to show that vigorous exercise (such as jogging or bicycling) after diagnosis was associated with a reduced risk of prostate cancer death in men with localized disease. “We observed that three or more hours a week of vigorous activity, as opposed to less than one hour a week, was associated with an approximately 60 percent reduction in the risk of dying of prostate cancer.” Chan and colleagues observed similar results among 1,455 men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). These findings suggest that “engaging in relatively vigorous physical activity and/or having higher cardiorespiratory fitness may protect against prostate cancer progression.”

Now, exactly why is this? That’s what Chan and colleagues are hoping to figure out. “We have a number of studies here at UCSF examining lifestyle and prostate cancer,” she says. “One trial is for men on Active Surveillance, and our main goal is to look at changes in prostate tissue.” Investigators are comparing prostate biopsy samples taken at diagnosis and again after a 16-week period in which men are randomly assigned either to continue their usual activities or to take part in a personalized exercise program that is designed to increase their cardiopulmonary fitness. The researchers also are measuring chemical processes involving circulation and metabolism, looking for specific differences in the two groups.

In this study, Chan is not as interested in studying the men who are already exercising a lot. “We anticipated that the biggest benefits would be observed in individuals who are relatively sedentary and who adopt moderate exercise. If men are already highly fit, they’re probably already exercising several hours a week, and we thought it would be harder to ask them to do more or spend more time, so that we could observe a relative change in fitness,” she says. “Our main goal is to increase the fitness levels gradually through a walking program in men who are at low to intermediate levels of fitness at the beginning of the study.”

The idea here is that even moderate exercise can help lower the risk of lethal prostate cancer. We’re talking about the kind of exercise that almost everyone can do. It is “purposely scaled to be relative to someone’s baseline fitness, and we are choosing men who are low- to moderate-fit,” Chan notes. Men in this study start out just by walking, and then walking faster, and then escalating – literally – to walking uphill.

The men aren’t going flat-out, like someone in a high-intensity workout. They’re just doing a little more than they could, and after they get used to that, they do a little bit more – slowly building up their fitness.

Chan speculates that the tissue samples in the exercise group will show changes in indicators of angiogenesis (cancer’s ability to build a scaffolding of blood vessels and other infrastructure so it can grow and move beyond the prostate); in inflammatory processes; in insulin and insulin-like growth factor signaling; in androgen receptor signaling pathways; and in oxidative stress mechanisms. “Biochemically, exercise could help deter metastasis of the tumor by changing the environment for the cancer” – in effect, 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 confined to its current location.

Making 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 medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation. “There is no form of treatment that has this effect, and certainly not one as beneficial to the entire body as exercise.”

It may be, Simons adds, that what exercise does – just as it improves blood flow in the arteries – is give 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, continental breakfast, and a pool. It’s content to stay there indefinitely, ordering room service. “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 found in research at Johns Hopkins, not only pipes in more blood to supply the tumor; it gets rid of waste products – the cancer cells’ sewage, in effect. “When tumors try to turn on blood vessel growth to get more nutrients, they also build their own plumbing for both intake and waste disposal. Angiogenesis is not just about getting oxygen and food – glucose and protein – to the cancer. It’s getting rid of byproducts, too. That kicks off a genetic program so the cancers can relocate” – start to spread.

But giving the cancer a better blood flow might subvert 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, of course, 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 have proved fatal,” notes Simons. 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. “What if you have a Gleason 8 cancer, you had surgery, your PSA was undetectable, and now it’s starting to creep up. And what if you could exercise and delay its colonizing in your bones by eight or nine years, because you so shifted the chemistry in your body that the cancer cells just sat there? That’s a very abstract concept, one that’s still not widely appreciated. But if we could get even three times as many men right now exercising, we could change the overall survival of the disease.” And if scientists like Chan can figure out precisely why this is happening, it may lead to development of new treatments that could make exercise even more effective in deterring the return or spread of prostate cancer.

Is it ever too late to start to exercise? No!

In other trials, including one funded by Movember, Chan and colleagues from around the globe are studying the benefit of aerobic exercise and also strength training in men with castrate-resistant prostate cancer, to see if these interventions can help men at a later stage of cancer live longer. “There are data in men with advanced disease also suggesting that exercise may impart not only quality of life but also clinical benefits” she says.

Body Size and Prostate Cancer

Prostate cancer loves fat. Fat increases inflammation in the body, lowers insulin resistance, and just generally makes a more inviting environment for prostate cancer.

But exercise burns fat. And this, in turn, lowers your body mass index (BMI).   “Increasing evidence suggests that being overweight, either before or at the time of diagnosis with prostate cancer, is strongly associated with the risk of cancer progression and of dying from prostate cancer,” says Chan. “For example, among 2,546 men diagnosed with localized prostate cancer in the Physicians’ Health Study, a one-unit increase in BMI before cancer diagnosis was associated with about a 10-percent increase in a man’s risk of dying of prostate cancer.”

BMI calculators are available on the internet, but briefly, if you are at a healthy weight, your BMI is between 19 and 24.9 kg/m2.  In the Physicians’ Health Study, having a BMI of 30 kg/ m2 or greater “was associated with a nearly twofold increased risk of prostate cancer death,” notes Chan. Further, “a meta-analysis of six studies in prostate cancer patients reported that a 5 kg/m2 increase in BMI raised the risk of dying of prostate cancer by 20 percent, and of biochemical recurrence (having the PSA start to rise again after treatment) by 21 percent.”

 More of this story and much more about prostate cancer are on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.” The PCF is funding the research that is going to cure this disease, and they have a new movement called MANy Versus Cancer that aims to crowd-fund the cure, and also empower men to find out their risks and determine the best treatment. 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 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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