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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

 

What is Prostatitis, Anyway?

Thousands of men are diagnosed with prostatitis every year.  But guess what? Most of them don’t actually have it.

Maybe you’re one of those men, and you’ve been taking antibiotics for weeks because your doctor told you that’s what you had. How are your symptoms? Are they any better? And here’s an important question: Did your doctor get a culture to make sure there’s a bacterial infection in your prostate?  

If you got a culture of your prostatic fluid, you would know it; it’s not like swabbing your throat looking for strep or taking a simple urine test.  No, checking the fluid that is inside the prostate begins with a rectal exam.  “We push on the prostate, fluid comes out the tip of the penis, and we capture this on a slide and look at it under the microscope,” says Sarah Flury, M.D., urologist at Northwestern University, one of the world’s experts on prostatitis and one of the experts we interviewed in the newest (2018) edition of our book on prostate cancer (prostatitis is NOT prostate cancer, but because it involves the prostate, that most troublesome gland, we put it in there).

If you didn’t have a culture of your prostatic fluid, but your doctor told you that you have prostatitis and put you on a powerful antibiotic like Ciprofloxacin, then it’s no wonder if your symptoms haven’t gotten any better. (Actually, taking a long course of antibiotics could even be bad for you; keep reading.)

Imagine if you had chest pain, and you went to the hospital, and the doctor in the Emergency Room said: “Chest pain? That’s a heart attack.” But in fact, your particular chest pain is because you have acid reflux – major backup of your stomach acid into the esophagus – and it hurts so bad that your esophagus is having a spasm. What you really need is a heavy-duty acid reducer or even a proton pump inhibitor, but instead you’re getting pumped full of blood thinners and expensive medicine to dissolve a nonexistent blood clot.

This is a terrible example, but it makes the point: In medicine, you can’t assume, and you can’t put people on medication that isn’t going to help them. If you don’t actually have prostatitis that is caused by bacteria, all the antibiotics in the world aren’t going to help you, and they may cause other serious problems.

Prostatitis is a grab-bag diagnosis; a catch-all where a variety of symptoms are often chucked together when doctors “don’t know what is going on,” says Flury. Pain in the testicles? Prostatitis. Pain in the penis? Prostatitis. Pain in the bladder or rectum? You guessed it. Burning when you urinate or ejaculate? Prostatitis. It’s like the diagnostic Island of Misfit Toys from the classic TV special, “Rudolph the Red-Nosed Reindeer.”

And yet: “Bacterial Prostatitis itself is actually very rare,” says Flury.

Which begs the question, what is it? For the vast majority of men, “prostatitis” is just what the symptoms sound like: Chronic Pelvic Pain Syndrome (CPPS). But what’s causing the miserable symptoms in one man with CPPS might not be what’s causing them in another man. Everybody’s different, and you need to see a doctor who specializes in this, at a medical center where they see a lot of men with these symptoms and know how to treat them.

For example, in some men the cause of pain or tenderness in the scrotum or lower back is actually the pelvic floor muscles in spasm– like a hard muscle knot in the neck or back, except it’s close to the rectum. “There’s treatment for it,” says Flury, “specialized physical therapy, where they do a pressure point release.” Other men have bladder symptoms that are related to interstitial cystitis, which is the “irritable bowel” of the bladder, with muscle spasms. Some men with frequent or burning urination get better with Flomax or another drug in the category of “alpha blocker.” These drugs relax the muscles in the prostate and bladder and help relieve symptoms. Some men get better by changing their diet – because for them, spicy foods seem to set off the symptoms. Men who have difficulty or pain when urinating are often helped by biofeedback and physical therapy.

“Chronic pelvic pain is the broadest diagnosis,” says Flury. “It’s the base of the pyramid. Prostatitis is one of the diagnoses that can cause pelvic pain – not the other way around. Prostatitis is completely misunderstood and misused as a diagnosis. There are many different causes, and it is incredibly rare that it’s actually a bacterial infection in the prostate.”

So, if you have these symptoms, or if you’ve been told that you have prostatitis, what should you do?   “First, know that you’re not alone,” says Flury. “You have something real, but it’s quite possible that you’ve been given the wrong terminology for your diagnosis. CPPS is a heterogeneous syndrome; it’s not a specific disease, and ‘one size fits all’ doesn’t work. It’s a framework, and men have different symptoms within that framework: urinary symptoms, psychosocial symptoms like depression, muscular problems, neurological symptoms, organ-specific problems – in the penis, or testicles, or bladder, or prostate. All those things fit into CPPS.”

Flury is troubled by the number of men who have come to see her after another doctor told them, “You have prostatitis. Try these antibiotics for six weeks and see how you feel.” It’s not that easy. “People treated for six weeks on Cipro, without a diagnosis of infection? It’s terrible. You have to take a history. There may be 10 different causes for these symptoms, and 20 possible treatments.” Many of these men never even had a culture to confirm the diagnosis; they just got put on antibiotics.

It is worth it, Flury adds, to go to a center of excellence. She recommends that you start with this link: http://www.mappnetwork.org. There is a network of centers across the country, where physicians and scientists are doing research on the entire spectrum of CPPS. Even if you don’t want to participate in a clinical trial, physicians at those centers know how to figure out what’s actually causing your symptoms, and plan the treatment accordingly. “CPPS is a common condition, but many traditional therapies fail,” she says. Undoubtedly, that’s because the wrong thing is being treated. Find a doctor who can figure out what you really have. If you’ve been given a diagnosis of prostatitis, the first thing to do is to make sure you actually have it. If you have an infection, you need antibiotics, but if you don’t, you don’t need antibiotics. Many more men have CPPS than prostatitis.”

            Antibiotics: There Are Risks

Some people have the idea that – because in the 1940s when they first came out, these truly were miracle drugs – everything’s better with antibiotics. But here’s why it’s not good to be put on six weeks of a powerful antibiotic if you don’t really need it:

In July 2016, the FDA issued a warning to doctors. It advised restricting the use of fluoroquinolone antibiotics for certain uncomplicated infections – because the “serious side effects … generally outweigh the benefits for patients.” People with some conditions – such as sinusitis, bronchitis, and a simple urinary tract infection – have other options; there are lots of antibiotics that treat those problems. However, men with acute or chronic bacterial prostatitis don’t have as many other choices, so for them, the risks of fluoroquinolones are probably worth it.

But you sure don’t want to be taking these drugs if you don’t need them – and if you haven’t even had a proper culture to determine if you even have an infection.

“An FDA safety review has shown that fluoroquinolones, when used systemically… are associated with disabling and potentially permanent serious side effects that can occur together. These side effects can involve the tendons, muscles, joints, nerves, and central nervous system.” Some of these side effects include “tendon, joint and muscle pain, a ‘pins and needles’ tingling or pricking sensation, confusion, and hallucinations. Patients should talk with your health care professional if you have any questions or concerns.”

  

What if You Actually Do Have Bacterial Prostatitis?

No getting around it: if you do have bacteria-caused prostatitis, you need to take antibiotics for six weeks.

Acute Bacterial Prostatitis. If you have this, you know it, because it’s debilitating – so much so, that you are probably reading this in the hospital. You most likely also have a fever, chills, and extreme pain. This is not the time to be a macho man and suffer through it. You need immediate treatment. Go to the doctor or, after hours, an emergency center.   This is very important: If you have acute bacterial prostatitis and you don’t get help right away, you could develop a life-threatening infection in the blood (called sepsis), or not be able to urinate (urinary retention, which requires a temporary catheter), or develop an abscess within the prostate (an infected area of pus under pressure; as you can imagine, this is very painful).

“Acute bacterial prostatitis is an infection that can have very severe symptoms,” says New York University urologist Stacy Loeb, M.D. “It requires immediate treatment with antibiotics. It is also one of the potential risks of a prostate biopsy: this is why all men who undergo a prostate biopsy require antibiotics before and after to reduce the risk of a symptomatic urinary tract infection – and acute bacterial prostatitis is really an acute urinary tract infection. In fact, recent studies show that acute prostatitis after a biopsy can be more severe than other cases.”

The good news is that once you start taking antibiotics – usually in the category called fluoroquinolones; an example is Ciprofloxacin – you will start to feel better fairly quickly. The thing is, you will need to stay on antibiotics much longer than you might expect. If you just take a course of antibiotics for a week to 10 days and then stop, and even a tiny amount of infection remains in the prostate, guess what? It is likely that the prostatitis will come back – this time as a chronic infection, which is harder to get rid of.   If you have an episode of acute bacterial prostatitis, then, you should stay on antibiotics for about six weeks. Be steadfast with the antibiotics and wipe it out the first time. You don’t want to go through this ever again if you can help it.

Chronic Bacterial Prostatitis. This is rare. Here, too, the treatment is antibiotics. The “chronic” part is that this form of prostatitis can come back every so often for years if an episode of acute bacterial prostatitis is not adequately treated the first time. The treatment is the same: six weeks of antibiotics.

More about prostatitis 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.”  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

 

Do Statins Prevent Lethal Prostate Cancer?

Statins are toying with prostate cancer scientists.

Study after study hints at a tantalizing connection between taking these cholesterol-lowering drugs and protection from getting lethal prostate cancer.

But an actual magic pill guaranteed to do this just keeps hovering just over the horizon, like the Goodyear Blimp, taunting scientists and oncologists who would love to have something to give to men and say, “Here, take this every day, and you won’t get aggressive prostate cancer.” Or, “This will lower your chances of having your prostate cancer come back after treatment.” Or. “This will help you stay on active surveillance and not develop a higher grade of cancer that needs treatment.”

The link between statins and all these scenarios hasn’t been definitively proven yet. On the other hand, it won’t go away, either.

The problem is, there’s a big difference between suspecting that statins might have a protective effect against aggressive prostate cancer and being willing to go out on a limb and recommend that all men start taking them.

So far, not a single scientist is prepared to do that.

And still, statins won’t go away. What is it about these drugs, anyway? Is it the fact that statins lower cholesterol, and that this in itself somehow changes the body’s susceptibility to prostate cancer? Or is it some other biochemical action of these drugs?

Nobody’s entirely sure about that, either. Meanwhile, here statins sit, blowing raspberries and waggling their ears at scientists trying to find the answers.

The latest study to tease prostate cancer scientists comes from Denmark: scientists looked at nationwide Danish registries and identified 31,790 men who were diagnosed with prostate cancer from 1998 to 2011; of these, 7,365 died of the disease.   (Note: the study does not describe how these men were treated, nor whether they were diagnosed by regular screening. Also, there are more and better treatments for prostate cancer now than there were back then – so don’t get distracted by these numbers; that’s not the point of this article.) Then they looked to see which of these men had also taken statin drugs, and how these men fared compared to the men who had not taken them. In secondary analyses, they looked at the use of statins before prostate cancer diagnosis, and at one year or five years after diagnosis. They concluded that men who took statins after diagnosis were less likely to die from prostate cancer. “However,” the scientists reported, “it remains to be established whether this association is causal.”

Yeah.  In an accompanying editorial in the Journal of Clinical Oncology, Harvard epidemiologist Lorelei Mucci, Sc.D., M.P.H., and Memorial Sloan Kettering oncologist Philip Kantoff, M.D., note that “cholesterol is a precursor of androgens (male hormones) and…can act by reducing androgen bioavailability, thereby limiting tumor growth.” In other words, cholesterol feeds androgens, which in turn, feed a prostate tumor.

Statins act on this pathway, but they also act in some other, cholesterol-independent ways that affect prostate tumors. “Given the multiplicity of possible mechanisms by which statins might work,” the editorial said, “it would be of clinical interest to know whether nonstatin lipid-lowering drugs have the same effect as statins on prostate cancer mortality.

“Taken together, the data from (this and other statin studies) point toward a substantial salutary effect associated with statins, with hazard ratios (a way to measure the effect of a treatment) comparable to many of the more toxic and more expensive agents that now are used for advanced prostate cancer.” And now here comes the uncertainty: With studies like this, the editorial continues, “there is a risk that systematic error… may explain the observed associations.” In other words, are there complicating factors that could be messing up how these results are viewed?

Almost certainly there are, says Johns Hopkins epidemiologist Elizabeth Platz, Sc.D., M.P.H. “You can’t rule out bias in these studies. Even though the investigators tried to take other factors into account, when you look at the patients who were taking a statin and those who were not, they’re very different people. So I worry about saying to all men, ‘Take a statin just because you have prostate cancer and want to be able to do something.’”

That said, “I think there actually is something in statins that protects against prostate cancer. But until we can rule out confounding factors, I can’t say that men should take a statin even if they don’t have a cardiovascular need.”

On the other hand, she adds, if you’re already taking a statin because a doctor has put you on one to help prevent a heart attack or stroke, you may also get some bonus protection against lethal prostate cancer.

Why shouldn’t you just start taking a statin? Because these drugs can have complications, including inflammatory arthritis, muscle weakness, and inflammation of the colon. “If you take a huge group of men who don’t have prostate cancer,” says Platz, “or men who have survived prostate cancer but who have a risk of it coming back, you certainly would not want to tell them to take a statin to prevent lethal prostate cancer, because you would cause a ton of side effects.”

Just about every drug has side effects – even aspirin, which many people take as a preventive measure against stroke, heart disease, and colon cancer. But aspirin also raises the risk of gastrointestinal bleeding, among other things. So there’s a balance: is it better to run a slight risk of a GI bleed and lower your risk of having a stroke?

“Everyone wants to do a trial to prove that statins work,” says Platz. But that’s a lot easier said than done. “So many men are already taking a statin. It wouldn’t be ethical to take them off of that medicine to get them into a trial. We also need more basic science to understand the mechanisms of statins, and the mechanisms of the side effects, too.” At some point, she believes, someone will do a big clinical trial that will answer the question of statins as adjuvant therapy or prevention for prostate cancer once and for all – but it’s going to be really hard. “You might have two guys who look just the same, but one will have a different inflammatory milieu than the other; one will be more pre-diabetic.”

Here’s the kicker: No drug, ever, has proven to be as effective at protecting against prostate cancer and pre-mature death in general as having a healthy weight and being physically active. “If you want to reduce your risk of lethal prostate cancer while increasing your well-being, improve your diet and increase your activity level. Improving your diet is good for reducing your heart attack risk, too. It’s good for your overall health. “

Men who have diabetes are not more likely to get prostate cancer, but they are more likely to die of it if they do get it, “probably due to some very complex pathways that may have to do with glucose itself, or insulin, or the inflammatory environment that seems to result in diabetes,” continues Platz. “So another important thing for men to think about, if they are at risk, pre-diabetic, or diabetic, is to get their blood sugar under control, improve their diet, and exercise to put on lean mass,” and get rid of excess body fat.

There are no shortcuts here. There is no magic bullet. And in Platz’s opinion, shortcuts may not be the way to go, anyway. “If you take a pill, you’re messing with the system. There are going to be side effects, and it’s not holistic. Changing your diet and lifestyle will benefit many aspects of your health, including your mental wellbeing. You’ll feel better if you lose weight and exercise.”

 

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