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Could Anti-Inflammatory Drugs Work Against Prostate Cancer?

If, as we have seen, inflammation can lead to prostate cancer, could anti-inflammatory agents help protect against it?

The jury’s still out.  However:  Johns Hopkins epidemiologist Elizabeth Platz, Sc.D., has been intrigued by this possibility for many years.  She is senior author of a new study on the use of aspirin and statins, published in Cancer Prevention Research.  The study, of men in the placebo arm of the Prostate Cancer Prevention Trial, doesn’t answer this question once and for all – but adds more weight to the idea that, for lowering the risk of developing potentially fatal prostate cancer, fighting inflammation is a good thing.

Evidence from observational studies has suggested that when taken regularly over time, aspirin may lower the risk of prostate cancer.  These drugs block enzymes that play a key role in the body’s inflammatory response.  Other studies have linked long-term use of statins, prescription drugs that are used to lower cholesterol but that also are anti-inflammatory, to a lower risk of advanced and metastatic prostate cancer.

In this most recent study, the investigators looked for inflammation markers in benign prostate tissue samples.  “We compared the use aspirin and statins with the presence and extent of inflammation in the prostate tissue,” says Platz.  They also looked at prostate biopsy slides for the presence of certain immune cells that are involved in inflammation.

“Of 357 men, 61 percent reported aspirin use, and 32 percent reported statin use,” Platz continues.  “Aspirin users were more likely to have low FoxP3, a T regulatory cell marker, and statin users were more likely to have a low CD68, a macrophage marker.”  “Our results suggest these medications may alter the immune environment of the prostate. A next step is to determine whether these immune alterations may underlie the epidemiologic observations that taking an aspirin or statin may protect against getting advanced prostate cancer, and dying from it.”

Prostate Cancer Loves Fats          

Here’s some more recent research out of Johns Hopkins, a neat bit of  basic science that may help explain the findings of Platz’s recent study:  “Our work is mechanistic,” says investigator Marikki Laiho, M.D., Ph.D., director of the Division of Molecular Radiation Sciences, “and provides insight into how the tumor microenvironment senses the excess load of the lipids.  Diet and statins obviously relate to the amount and regulation of the lipids, and have shown those clear correlations to prostate cancer.  However, we need to understand why to be able to correct the problem. Our work provides at least one explanation how the lipids fuel cancer. One part of the work was just to feed the prostate cancer cells with cholesterol, which made them more invasive.”

It turns out that even on a cellular level, prostate cancer gravitates to its own kind of junk food – the tiny version of deep-fried Oreos with a side of chili cheese fries.  Laiho and colleagues have just figured out how the body enables prostate cancer’s terrible diet.

The culprit is a lipid-regulating protein called CAVIN1, the scientists reported in the journal, Molecular Cancer Research.  In lab studies, when CAVIN1 was removed from cells in and around the prostate tumor, the fatty acid that was in those cells spilled into the tumor’s microenvironment.   The effect on prostate cancer cells was dramatic:  the cancer cells soaked up the lipids, which then acted as turbo fuel to make the cancer spread more aggressively.

“In every prostate cancer cell line we tested,” says research fellow Jin-Yih Low, Ph.D., the study’s first author, “tumor cells universally had an appetite for the lipids, using them to strengthen the protective membrane around the cell, synthesize proteins and make testosterone to support and fuel the cancer’s growth.  The tumor cells then behaved more aggressively, exhibiting invasive and metastatic behavior.  Just having access to the lipids gave the tumor cells more power; the tumor’s behavior changed.”

But wait!  There’s more:  nearby cells changed, too.  Deprived of their lipids, normal stromal cells started to churn out inflammatory molecules, adding fuel of their own to the fire. 

Laiho’s team then confirmed their findings in mouse models, comparing tumors with and without CAVIN1 in the stromal cells.  In the mice, Laiho says, “although the presence or absence of CAVIN1 did not affect the speed of tumor growth, lack of CAVIN1 definitely caused the cancer to spread.  All of the mice with tumors that lacked CAVIN1 had a twofold to fivefold increase in metastasis.  The tumors also had a fortyfold to hundredfold increase in lipids and inflammatory cells.”

The investigators were surprised at these results, Laiho adds.  “We suspected CAVIN1 was important, but we didn’t realize how important.  The tumor’s microenvironment matters, and the amount of lipids matters a lot.”  Just changing the level of lipids “created a situation of rampant metastasis.”

What could come from this research?  One possibility is development of a new biomarker:  a loss of CAVIN1 in local or locally advanced cancer, for example, could signal a higher risk of metastasis.  The next step is to understand more about the inflammatory process in the tumor’s microenvironment.  “We want to understand why the inflammation brings in macrophages, immune cells that further exacerbate the inflammatory process, instead of T cells, which should attack the cancer.”  The more scientists know about how inflammation does its nasty work to inflame cancer, the closer we are to finding a way to stop it.

 

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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Infection, Inflammation, and Prostate Cancer

Why does it matter if you eat right and exercise?  Everybody knows the answer; in fact, we’ve all heard it so many times, it’s easy to tune it out:  diet and exercise are good for you.  Duh!  Who’s going to argue with that? Having a healthy lifestyle is right up there with world peace as a worthy goal!

Bear with me here:  With a topic such as this, I know I’m either preaching to the choir – people who are already exercising and eating a pretty good diet – or I run the risk of turning off the people I really want to hear this message, by seeming to preach at all: people who might think, “Go ahead, tell me what to do.  I really enjoy that.  Micromanage my life.  Maybe you’d like to come over and look at my closet and tell me what shirt to wear today.”

Okay, fine!  I’m not here to tell you what to do.  But I am going to try really hard to tell you why you might want to do certain things, and how good diet and exercise – or the lack thereof – can affect prostate cancer.

Please pardon the long set-up, but let’s begin with some facts, with plenty of links for further reading:

If you exercise, you are less likely to have cancer return after treatment, less likely to get metastatic prostate cancer and die of it.  What does exercise do?  A lot of good things for your vascular system, which, in turn, can help slow down prostate cancer metastasis.  But you know what it also does?  It helps you lose weight.

And it just so happens, men who lose weight are less likely to die of prostate cancer.

And sugar can make cancers grow faster.

And men who stop smoking are less likely to have cancer come back after treatment, and less likely to die of prostate cancer.

Exercise also helps control stress, and the stress hormone, cortisol, affects adrenal receptors, and can play a role in making cancer grow and spread faster.

Now, here’s why all this matters so much:  smoking, not exercising, quaffing sugary drinks, eating processed, fatty foods, and being overweight all contribute to inflammation.

I’m going to be writing a lot about inflammation in the next few posts, because it is becoming increasingly evident that inflammation can lead to cancer – and it’s quite possible that if we can prevent inflammation, we may prevent or at least slow down cancer.

What Inflammation Does

In a landmark study, Karen Sfanos, Ph.D., and scientists at Johns Hopkins have shown for the first time that bacterial infection can cause prostate cancer.  The study was led by Sfanos and her former graduate student, Eva Shrestha, Ph.D., in collaboration with Angelo De Marzo, M.D., Ph.D., Jonathan Coulter, Ph.D., and colleagues.  Infection? That’s not the same as inflammation!  True… but bear with me.

The bacterial culprit found in this study belongs to the family Enterobacteriaceae, which includes E. coli. Better known as a nasty gastrointestinal bug, E. coli causes inflammation in the urinary tract and is a known cause of bacterial prostatitis.  As the scientists discovered, colibactin, a genotoxin produced by some strains of E. coli, can also instigate a series of unfortunate events in the prostate.  Bacterial infection leads to acute and chronic inflammation, which can lead to the development of a lesion in the prostate called proliferative inflammatory atrophy (PIA), first described by pathologist De Marzo, oncologist William (Bill) Nelson, M.D., Ph.D., and other Johns Hopkins scientists; it can also cause DNA damage. The presence of colibactin is even more ominous, because it can directly lead to double-stranded DNA breakage. 

Sfanos suspects that this combination leads, in turn, to another development:  fusion of two genes, TMPRSS2 and ERG, that normally should remain separate, but in this case get abnormally spliced together.  Now, it may be that by themselves, TMPRSS2 and ERG are like Robert Leroy Parker and Harry Alonzo Longabaugh:  put them together, and they became Butch Cassidy and the Sundance Kid, and together, they got into much worse trouble than either one managed alone.  This TMPRSS2/ERG fusion – found in as many as half of all prostate cancers – is thought be an early event leading to the development of prostate cancer.

“We found evidence in human tissues (from prostatectomy specimens) that bacterial infections are initiating the TMPRSS2/ERG fusion,” says Sfanos.  “We don’t think this is the only way bacterial infections contribute to cause prostate cancer.  But in this particular study, the way we looked at it was by tracking the presence of these TMPRSS2/ERG fusions.”

It is entirely possible, notes De Marzo, “that other types of mutations or events could also be caused by bacterial infections or inflammation.  But looking at these fusions gave us ‘smoking gun’ evidence that bacterial infection was the initiating event.”  Sfanos adds that “the colibactin-producing bacteria, TMPRSS2/ERG fusions, PIA, and tiny buds of cancer were all there, in the same place at the same time, a snapshot of prostate cancer being born.”  The team’s early findings are available online in BioRxiv, a scientific data-sharing website, and a manuscript for publication is undergoing peer review.

Bacterial infection is a known cause of other cancers.  H. pylori, for example, is a well-established cause of stomach cancer.  “We believe that many different types of microorganisms, certain types of sexually transmitted infections (STIs), and other infections in the prostate can certainly cause the same chain of events,” says Sfanos.

How did the bacteria get into the prostate?  They could have come from the urethra.  “These bacteria are good crawlers,” Sfanos says.  De Marzo recalls what the late Don Coffey, Ph.D., the longtime director of the Brady’s scientific labs, used to say: “The urethra is like the Holland Tunnel for bacteria.”

Note:  These tiny cancers are not the cancers that were biopsied and that led to the diagnosis of prostate cancer; they’re too young even to achieve a Gleason grade.  They’re just baby sites of cancer cropping up, in addition to the more mature cancer that was already there.  Prostate cancer is multifocal:  in most men with prostate cancer, several sites of cancer develop at the same time.  But because of the unique molecular tools used in this study – looking for TMPRSS2/ERG fusions and “ERG-positive PIA” – Sfanos, De Marzo and colleagues were able to catch the formation of these invasive cancers in real time.  “This might start to explain the multifocal nature of prostate cancer,” says Sfanos. “There might be multiple infections or other inflammatory events that occur throughout a man’s lifetime.”

Sfanos suspects that the men whose tissue was used for this study “likely all had undiagnosed infections.”  These findings may lead to development of a new test, using urine or prostatic fluid, to look for colibactin or markers of inflammation in the prostate.  Future studies may look at urine samples along with prostate tissue for such markers, and  new imaging technology may one day be able to detect inflammation, as well.

For more than 20 years, De Marzo and Sfanos, with Brady scientists Bill Nelson, Srinivasan Yegnasubramanin, M.D. Ph.D., Elizabeth Platz, Sc.D., and William Isaacs, Ph.D., have studied inflammation as a risk factor for prostate cancer, particularly looking at PIA.  Sfanos “has also been the major champion of infection” as a risk factor, De Marzo says.  Now, these two paths of investigation have come together.

Could dietary changes make a difference?  “Bill Nelson showed years ago that loss of expression of the GSTP1 gene rendered prostate cells more susceptible to DNA damage caused by a chemical compound that is found in charred meat,” says De Marzo.  “Infection plus a bad diet might make this worse, and then combine that with the underlying genetics.  There might be multiple culprits, a constellation of things over years.”  We’re going to look more at diet in future posts.

Coming up next:  Could anti-inflammatory drugs help?

 

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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Metastasis Is a Spectrum

News flash:  All metastasis is not alike, and the basic category of “metastatic prostate cancer” is being redefined by doctors and scientists even as we speak.  It’s not just either-or anymore – either cancer is confined to the prostate area, or it has escaped.  It’s actually more of a spectrum, and it is very likely that there’s wiggle room – and still the potential for cure – between cancer escaping the local area around the prostate and full-blown, widespread, metastatic cancer, if we can catch it in time.

I’ve written previously about the work of Johns Hopkins radiation oncologist Phuoc Tran, because I really like what he’s trying to do:  widen the window of curability of prostate cancer.  Great news:  he’s not alone!  Doctors all over the world are rethinking metastasis in prostate cancer and other cancers, as well.  Recently, Tran was one of several experts to take part in a seminar the Prostate Cancer Foundation (PCF) put together.  I was lucky enough to be able to cover it for the PCF, and now I want to make sure you know about the kind of go-getters there are out there who don’t just accept that, if cancer leaves its primary organ, it can’t still be treated and maybe even cured with local treatment.  Better imaging is making it possible to see these cancers sooner than we ever could before.  The reason I want you to know this: if your doctor says you have a couple bits of cancer outside the prostate, so it’s time to start your lifetime of ADT – I want to encourage you to ask around and see if there’s another possibility.

Rethinking Metastasis

For a very long time, many doctors believed, and many still believe, that if we don’t cure cancer while it’s confined to the prostate, then that’s it.  Game over, it’s not curable.  Note:  That doesn’t mean it can’t be treated, sometimes for many years!   But in terms of treatment, traditionally, metastasis has meant bye-bye, local therapy, and hello, systemic therapy – androgen deprivation therapy (ADT), androgen receptor-blocking drugs such as apalutamide or enzalutamide, and chemotherapy.  For patients with metastatic prostate cancer who see their doctors every three months for just a few minutes at a time, that can feel, as one patient’s son put it, like “Lupron and a handshake.”

But a lot of things have come together recently to make doctors and scientists say, “Not so fast!  Maybe there’s a window, and maybe the window is wider than we thought.”  One of these things is the recent ORIOLE study, led by Johns Hopkins radiation oncologist and PCF-funded investigator Phuoc Tran, M.D., Ph.D.  Another is the development over the last decade of better imaging, such as PSMA-PET, which allows tiny bits of cancer to be seen months before they could be seen on conventional imaging, such as a CT scan or bone scan.   Better imaging has sparked an idea:  “If we can see it, we can treat it.”

Is it true?  Can treating little spots of cancer, before full-blown metastasis develops, prolong life?  Recently, the PCF brought together some of the country’s best and brightest – experts in radiation oncology, oncology, urology, and basic science – for a worldwide exchange of knowledge, a webinar attended by more than 300 scientists around the world.  The topic was oligometastasis.  Oligometastasis is just a little bit of metastasis; definitions vary, but generally, scientists who use this word are generally talking about fewer than 3 or 5 spots of cancer that have escaped from the main tumor.  It’s not widespread; it’s limited.  That doesn’t mean it can’t go on to cause trouble later.  If your kids or grandkids are into Pokémon, it’s like catching a little monster before it evolves into something more powerful.

Is oligometastasis treatable?  It is in some other cancers.   In colon cancer, for example, oligometastasis is treated with surgery or spot radiation in addition to removing the primary tumor, and sometimes it’s cured!   Phuoc Tran’s ORIOLE study, and now promising early results from other studies, including ORIOLE’s successor, the RAVENS study, suggest that treating oligometastasis – in Tran’s case, with SABR (stereotactic ablative body radiation, also called SRBT, a highly focused, intense dose of radiation therapy) – in addition to treating the primary prostate tumor can change the course of metastasis in some patients.

Patients reach oligometastasis in different ways.  Some reach it by biochemical recurrence – the dreaded rise of PSA after treatment of the primary tumor in the prostate with surgery or radiation.  Others are diagnosed from the get-go with cancer that has already spread outside the prostate.  The standard of care for most of these latter patients is not only not to treat the main tumor, but not to zap or surgically remove the few sites of metastasis. 

Why not?  Why the heck not?  Or, as Tran says, “It makes so much sense, so why don’t we do it?  Because we have tried periodically over the past five decades to treat metastatic disease aggressively with local therapies, and because of lack of imaging, treatment technology and just general lack of our ability to take care of patients, this approach did not work.”  In fact, he continues, “it was actually a resounding failure, and made many who lived through these periods very scared of doing much more harm than good.  One of the first texts on this concept, called ‘Solitary Metastases,’ actually started out with a chapter called “Illusion or Reality.’”

But that was then.  Even now, there’s not yet definitive proof that it works.  But take heart:  the winds of change are blowing! 

This brings us to the PCF 2020 Global Knowledge Exchange on Oligometastatic Prostate Cancer.  Eric Klein, M.D., Chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic, who moderated the discussion, set the stage with a story about a patient, seen by him and medical oncologist Howard Scher, M.D., of Memorial Sloan Kettering Cancer Center (MSKCC).  The patient was in his 50s, diagnosed with Gleason 9 cancer that extended slightly past the prostate, into the seminal vesicles.  He also had cancer in a lymph node.  The man received ADT for six months, had a radical prostatectomy, then was on abiraterone plus prednisone for a year afterward.  A bone scan showed one spot of cancer; it was treated with radiation at MSKCC.  “He’s about eight or nine years out now,” says Klein.  “He has an undetectable PSA and a normal testosterone.”

As the PCF’s CEO, Jonathan Simons, M.D., says, “One clinical case well studied can change the course of medical history.”  This patient’s exceptional clinical course has led Klein ask to the big question:  “If we can seemingly cure one man with metastatic prostate cancer, can we cure others?  And are we at a place now in the field to be asking the right questions, with the right trial behind them?”

Ralph Weichselbaum, M.D., Chair of the Department of Radiation and Cellular Oncology at the University of Chicago, is the radiation oncologist who coined the term, “oligometastasis.”  He specializes in treating it in various forms of cancer.  Not only does metastasis represent a spectrum of disease, he says, “depending on the number of metastases, the organs involved, and the pace of progression,” but patients represent a spectrum, too.  “There are subsets of patients who are potentially curable with metastasis-directed therapies” (treating breakout tumors directly, and not relying on systemic therapy alone).  What accounts for these subsets?  Genetic factors, and also the robustness of the patient’s immune system.  Weichselbaum’s research suggests that patients with a well-functioning immune system are better able to hold metastasis in check than others.  In other words, whether oligometastasis responds to treatment depends on “the complex relationship between tumor and host.”

It May Require the Proverbial Kitchen Sink

Scher and Mary-Ellen Taplin, M.D., medical oncologist and Director of Clinical Research at the Dana-Farber Cancer Institute’s Lank Center for Genitourinary Oncology, collaborated on the design of a multi-arm, multi-modality therapy clinical trial with funding from a PCF Challenge Award.  “Our focus is the patient with high-risk localized disease, or low-volume or recurrent metastatic disease,” said Taplin. The trial will be looking at many things, including potential biomarkers for sensitivity and resistance to treatment.  But one of the objectives is of particular interest:  “to eliminate all disease in patients largely incurable with any single treatment.” 

In other words: to kill prostate cancer that has escaped the prostate, these doctors and others believe, in addition to targeting the primary tumor with prostatectomy or radiation, it may well take a short course of ADT, perhaps also chemotherapy, maybe further external-beam radiation to the area around the prostate, and then radiation or radiofrequency ablation to the metastatic sites themselves.   But then, the hope is that these patients will have an undetectable PSA and that they will get their testosterone back.

There are several other important trials underway to treat oligometastasis in prostate cancer.  Of all the things scientists hope to learn from these trials, perhaps most important, says medical oncologist Ana Aparicio, M.D., of MD Anderson Cancer Center, is “how do these site-directed therapies work?”  Will the success come from messing up the circulating tumor microenvironment?  One idea is that, as cancer spreads, it sends messengers back for supplies to the other sites where cancer is already established, using the bloodstream as a liquid version of Fed Ex.  “Or, are we modulating the immune response?  Does the primary tumor have an immunosuppressive effect that limits the ability of the patient’s immune system to control the disease?  Or, are we having an immune-stimulatory effect with treatments?  We may need to build on that, and combine radiation with some novel immunotherapies.  Or, are we decreasing the tumor burden,” by zapping sites of oligometastasis?

Two Icebergs

Aparicio draws a picture for her patients to help explain:  There are two icebergs, one blue, one yellow.  “The blue one, most of it is above the water,” she notes.  “If you get rid of what you see, it is likely that the iceberg is going to take a long time to grow again and become a problem.  So, if what we see on the scans is most of the disease that’s present, then yes, addressing all the sites we can see can be beneficial.  But if it’s just the tip of the iceberg (like the yellow picture), and there’s a large burden of tumor we are not able to detect with our imaging tools, we’ll find that the disease grows very quickly.”

Better imaging, such as PSMA-PET, will undoubtedly help determine the true state of tumor burden, “particularly when the PSA is rising, but it’s less than 10; conventional imaging really is not useful when the PSA is 5 or 10,” says Phuoc Tran.  He believes the number of patients with oligometastasis in the U.S. is huge, “much higher than the number of men diagnosed each year.”  Right now, “systemic therapy is the standard of care for patients with metastatic disease,” says Tran.  “But in that gray area of biochemical recurrence (PSA creeping back up after prostatectomy or radiation of the primary tumor), as men are approaching low-volume metastasis, there’s a perfectly reasonable period in which you can ask the question, does local therapy change the metastatic process?” That was the question behind the ORIOLE trial.

“If the oligometastatic state didn’t exist, if this were not a spectrum, and if local therapy could not alter that natural history of metastasis, then we shouldn’t be able to affect progression at all with local therapy alone.  Patients should progress no matter what.  We did not see that.  Obviously, stronger evidence is needed,” but the results of the ORIOLE trial and early results of the RAVENS trial have been very encouraging.

It may be, says Weichselbaum, that we are dealing with multiple, different disease states, “requiring entirely different kinds of treatments.  We need to define really what metastasis is, and how the systemic treatments and ablative treatments fit together for optimal therapeutic outcome.”

And maybe one day, says Tran, “we can alter the natural history of metastasis, and cure these patients with formerly incurable disease.”

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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Two Changeable Risk Factors for Prostate Cancer Death

Hey, wait, come back!  This story sounds grim, but it’s actually hopeful!  There are two things you can do right now that raise your odds of not dying of prostate cancer: Stop smoking, and lose weight.  Both of these can make a big difference.

For several years now, doctors have known that there was a link between prostate cancer and smoking.  They couldn’t prove that smoking caused prostate cancer, but they knew that men who smoke cigarettes – if they developed prostate cancer – were more likely to have aggressive disease, and to die of it.

They know more now.  Scientists led by Johns Hopkins epidemiologist Elizabeth Platz, Sc.D., M.P.H., studied men who had prostatectomy for localized prostate cancer.  Those who continued to smoke after their diagnosis and treatment were more than two times more likely to have their cancer come back than men who never smoked.  But “men who had quit smoking had a similar risk of recurrence as men who never smoked.”

Let’s just stop for a second:  This is really important and hopeful, because it shows that when you quit smoking, your body starts to heal, and your risk of being cured of localized prostate cancer goes way up.

Platz puts it bluntly:  “Smoking is a risk factor for prostate cancer death.  If you start with a group of men who don’t have a diagnosis of prostate cancer, and they smoke, in the future they’re more likely to die of prostate cancer.  Men who have prostate cancer, if they continue to smoke, are more likely to die of prostate cancer.  Men who have been treated for prostate cancer, if they keep smoking, are more likely to die.  Even if they had surgery, the cancer is more likely to recur.”

Platz and other scientists know the connection between smoking and prostate cancer is powerful, but they don’t know exactly why and how smoking makes the body so susceptible to lethal prostate cancer.  “The reason why more is not known about the mechanisms at work here, frankly, is that nobody cares about smoking anymore —even though it accounts for most of the cancers in the United States and it really does explain a chunk of prostate cancer deaths.”   Smoking-related research funding is harder to come by.  “It seems like it’s an old story, so no one wants to talk about it anymore, despite it being so important: Smoking causes premature births, causes lung cancer, causes heart attacks, causes so many bad things.”

In a recent study, Platz and colleagues figured, “we know what’s happening to men who smoke who are followed as part of research studies.  What about larger groups – like entire states – where the prevalence of smoking has gone down?”  Several states have significantly lowered the number of people smoking, through cigarette taxes, indoor air pollution laws, workplace smoking bans, and “quit lines” (smokers call a number and receive many services, often for free, including nicotine patches or gum, counseling sessions, and a lot of help to quit – see below).  The investigators picked four states: Maryland, California, Utah, and Kentucky.  They found that in the states where smoking has decreased, the rate of deaths from prostate cancer has dropped, as well.

The bottom line:  At any point in your life, if you stop smoking, you are less likely to die of prostate cancer.

Note:  It is not clear how the “vape” or e-cigarettes figure in here.  There are a lot of chemicals in these products, and they haven’t been studied for very long, and as far as I know, there are no studies linking e cigarettes and prostate cancer.  That said, they may raise your general risk of getting cancer.

Fat and Prostate Cancer:  Another important risk factor may surprise you:  Obesity.  “Again, it sounds like old news, but we are a fat society,” says Platz.  The thing is, like smoking, obesity is “pretty convincingly associated with being diagnosed with more aggressive disease and death from prostate cancer.  For men who have prostate cancer, being obese and continuing to gain weight is associated with higher disease recurrence and death.”

Why is this?  People who are overweight tend to have higher glucose levels, higher insulin levels, and to produce cytokines – immune system boosters, which can encourage inflammation; sometimes inflammation is good, if it helps you fight off infection, but other times, it can put added stress on the body and perhaps tip the balance toward cancer.  “We need to understand the biology better, and then maybe if we knew the pathways affected, we could come up with ways to intervene directly,” says Platz.  “In the meantime, the better approach is to lose weight, even though it’s hard for many of us to do.”

The good news here is that at every phase of your life – just as with smoking – changing your lifestyle will help you.  If you’re a young man, losing weight might stop the disease from developing.  “If a tumor is already there, but very small, and not yet PSA-detectable, losing weight may delay the growth of cancer.  If you have a diagnosis of cancer, losing weight can slow or help prevent the cancer from growing to form metastases” (from spreading to other sites in the body).

“It’s never too late to lose weight or stop smoking.  If you quit now, or lose weight now, it will benefit you now and in the future.”

            For More Help:  It’s hard to quit smoking, and it’s hard to lose weight.  The good news is that there has never been more help available for both of these challenges.

For smoking: You can call 1-800-QUIT NOW (1-800-784-8669) for help; this is a state “quit line,” and the services offered here are free.  Under the Affordable Care Act, insurance plans must cover some services to help people quit smoking. Depending on your insurance, you may be able to get help for free.  A couple of links you might want to check out are:  Smokefree.gov. and http://healthfinder.gov/HealthTopics/Category/health-conditions-and-diseases/diabetes/quit-smoking

For weight loss:  Here, too, under the Affordable Care Act, insurance plans must cover screening and counseling for obesity, and depending on your insurance plan, you might be able to get help for free.  Here’s a link to the government’s website;  http://healthfinder.gov/HealthTopics/Category/health-conditions-and-diseases/diabetes/watch-your-weight#the-basics_1.  It helps to talk to somebody, and don’t worry:  They’re not going to judge you; they are there to help you. Just about every medical center has some type of weight management center.  They wouldn’t have these centers if there weren’t millions of people who need to lose weight.  “Intensive weight loss counseling has been shown to be effective,” says Platz.

Caution:  Beware of any radical or fad diet that offers drastic results very quickly.  Those almost universally fail.  Instead, look for gradual, proven plans.  It’s the Tortoise vs. the Hare approach: Slow and steady wins the race.

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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TRexit:  The Movement to Leave Traditional Prostate Biopsy “Behind”

In Australia, and to a smaller but increasing extent in the U.S., urologists are moving away from the traditional transrectal (TR) biopsy.  A much lower risk of infection is a big reason why.  

Nobody wants a prostate biopsy, but we’re stuck with it.  Literally.  Multiple times.   And for the vast majority of men (more than 2 million in Europe and North America alone), those hollow, ultra-sharp biopsy needles go right through the rectum to reach the prostate.  Unfortunately, the rectum is just chock full of bacteria, and this, in turn, means a couple of things:  the risk of infection and sometimes sepsis, and the need for antibiotics, some of them quite powerful.

Because infection can be such a serious complication, urologists have gone to great lengths to try to minimize it – particularly for men with a chronic illness such as diabetes, men with prostatitis or a urinary tract infection, or men who use a urinary catheter.  These men at higher risk often need a longer course of antibiotics, or different antibiotics.  Some options to reduce the risk of infection are to use more than one antibiotic for extra coverage, or to try to tailor the antibiotic to the specific bacteria found in a man’s rectum.

Before a TR biopsy, “we routinely swab a man’s rectum to see what bacteria he has, and we give him antibiotics based on those bacteria,” says University of Pittsburgh-Western Maryland urologist Michael Gorin, M.D.  “But despite our best intentions, sometimes these antibiotics fail to prevent an infection. Additionally, antibiotics can cause complications on their own.”

If only there were alternative.  Wait!  There is!  It’s a different way to reach the prostate:  through the perineum, the area between the scrotum and rectum; this is called transperineal biopsy.  Now, don’t get too excited:  Neither kind of prostate biopsy is ever going to be fun.  However, the perineal approach has some important advantages.  One big one: zero risk of infection!  Zip.  Nada!  “With the transperineal approach,” says Gorin, we don’t have to give any antibiotics, because instead of passing through the rectum, the needles go through an area of skin, which can be thoroughly cleansed before the procedure.”  Gorin pioneered the transperineal approach at Johns Hopkins, and is second author of an article that is shaking up the world of prostate biopsy:  “TRexit 2020: why the time to abandon transrectal prostate biopsy starts now.”

The paper’s first author, and a leading proponent of the transperineal approach, is Australian urologist Jeremy Grummet, M.B.B.S., associate professor of Urology at Monash University in Melbourne.  Grummet made a formidable argument in favor of transperineal biopsy at the American Urological Association’s annual meeting in 2017, with a PowerPoint presentation that featured, memorably, a slide of an angry poop emoji with these talking points:  “TR biopsy is dirty,” and “We use antibiotics instead of basic hygiene.”

That image was followed by a picture of a headline from Bloomberg News, about fears of an “Antibiotic Apocalypse” being stoked by antibiotic-laden chickens.  What’s happening in big agriculture, Grummet says, “is a very close analogy to what we do in hospitals.  There’s an extraordinary lack of hygiene, replaced by the use of antibiotics.  It works in the short term, but it also produces an immense amount of antibiotic resistance.”  The antibiotics often used with TR biopsies are fluoroquinolones; however, “fluoroquinolone-resistant organisms, also known as ‘Superbugs,’ have been identified in 10 to 30 percent of patients undergoing rectal swab cultures before biopsies,” Grummet notes, “and the incidence of hospitalization due to severe infections after prostate biopsy is increasing.”  A 2015 study of 455 patients in a VA hospital in Boston found that 2.4 percent of the men developed sepsis after prostate biopsy, and 90 percent had fluoroquinolone-resistant bacteria.   In addition, side effects of fluoroquinolones can be serious or potentially disabling, including depression, disorientation and agitation, tendonitis and tendon rupture, pain in the muscles and extremities, and gait disturbances.

Lack of hygiene?  But… but… don’t men do an enema before biopsy?  That cleans it, right?  Sadly, not really.  An enema flushes out poop, but it does not eradicate rectal bacteria.  It can’t.  “You can imagine, sticking a needle into a rectum, which is purpose-built for feces, absolutely crawling with bacteria.  It’s a dirty procedure; you take a clean needle, and put it through a contaminated area: that’s what a TR does every time.  You’re playing roulette with your needles; you have no idea if you’re inoculating bacteria with rectal flora into the prostate.  We try to overcome that with antibiotics.”

Going through the rectum, Grummet continues, goes against the basic surgical principle of sterile technique.  “Why do we wear gloves, why do we wash our hands?  Yet we completely turn a blind eye to that whole principle when we do a transrectal biopsy.”

What if, he says, “we could eradicate prostate biopsy sepsis?  And what if we could do it without using big-gun antibiotics on a global scale?  We can and we have.”  In a multi-center study of transperineal biopsy in Australia, Grummet and colleagues showed that of 245 consecutive men who received transperineal biopsy, there were zero readmissions for infection.  “Our series has since grown to 1,194 consecutive cases at five centers across Melbourne, with no complications and zero hospital admissions for infection.”

The actual transperineal approach, itself, is not new, notes PCF-funded investigator Edward Schaeffer, M.D., Ph.D., Chair of Urology at Northwestern University’s Feinberg School of Medicine.  “Transperineal biopsies have been around for several decades, and offer an opportunity to sample all regions of the prostate very efficiently” (more on this below).  However, there was a good reason why they weren’t popular: “The limitations of transperineal biopsies in the past were that they required general anesthesia, as they are quite painful.  Newer techniques in regional prostate blocks have enabled the use of in-office, awake, transperineal approaches.”  Using the nerve block provides more protection from pain than local anesthetic alone.

This may prove to be the big selling point for many urologists, says Grummet.  “TR biopsy has been, certainly in Australia, a well-reimbursed procedure.  You can do it in five minutes in your office.  Because transperineal biopsy traditionally required a general anesthetic, it took longer and used hospital resources and personnel.  It has been less convenient.”

Although Gorin routinely does transperineal biopsy in the outpatient setting, using a nerve block and local anesthetic, it’s a little different in Australia.  In his home state of Victoria (over 5 million people), transperineal biopsy is more commonly performed than TR biopsy,” says Grummet.  “In our practice, no one gets a TR biopsy; the transperineal procedure is common across Australia.”  However, he adds, it is still done mainly in the hospital, under general anesthesia.  “Only a few of us over here have shifted to local anesthetic.  I have done only a handful with local anesthetic, and then COVID-19 hit,” and outpatient procedures were severely limited.  Now that the country is opening up, he plans to do more transperineal biopsies with the local anesthetic and nerve block.  “With the general anesthetic, transperineal biopsy is essentially perfect.  But with the local nerve block, even if the pain relief is not perfect, if the overall greater good is to avoid infection, that is by far a bigger win than some mild discomfort.  But if it’s too painful, we shouldn’t be doing it.”

Going in sideways:  But wait!  There’s more!  With Johns Hopkins urologist Mohamad Allaf, M.D., Gorin developed a technique to perform MRI-guided prostate biopsy through the transperineal approach that is “not only cleaner; there’s reason to believe the transperineal approach is more accurate,” better able to sample the prostate’s anterior region – the area where cancer commonly develops in African American men.  

Besides the risk of infection, there’s another big drawback to the TR approach:  it’s hard to cover the entire prostate.  Basically, as Schaeffer explains , if you think of a prostate as a house, the transrectal biopsy comes in from the basement.  It’s pretty good at reaching the main floor, but not that great at reaching the attic.  It’s a South to North approach.  The transperineal approach goes from West to East, and instead of a house, Gorin uses the analogy of a car:  “The needle comes in from the headlights to the tail lights, but it can go lower, from the front tires to the back tires, or higher, from the front windshield to the rear windshield.”

Is there a downside to the transperineal approach?  Although there is not any published evidence, Grummet says, “there seems to be increased scarring of the apex of the prostate in patients who have had transperineal biopsy.  That would make sense, because instead of moving the needle along the back of the prostate, which is what you do in TR biopsy, the needle in a transperineal biopsy is coming in at the apex.  I certainly haven’t seen any evidence that it actually affects the outcome of surgery.”  Another potential downside, as with TR biopsy, is of urinary retention, particularly in men with a large prostate who have more needle cores taken.  “The more cores you take, the more swelling there is.  Our published rate of retention is 2.5 percent; that is entirely reasonable.  Urinary retention is not life-threatening like sepsis is; you put a catheter in, and you take it out the next day.”  Another risk, as with the TR approach, is a “temporary, mild reduction of erectile function,” from inadvertently grazing the nerves involved in erection, “but this risk occurs in TR biopsy too.”

How can I get a transperineal biopsy?  Unless you live in Australia, or you happen to live near one of the few places in the U.S. where they are being performed, you probably can’t.  Yet.  But that is expected to change fairly soon.

Personal note here:  As I have written about earlier, a transperineal biopsy performed by Mike Gorin recently saved my husband’s life.  I am biased in favor of this approach, because several urologists have told me that because of its location in the anterior of the prostate, behind the urethra, Mark’s cancer would have been missed with a TR biopsy.  It was tiny, just 6 mm at the time of biopsy, 7 mm at the time of surgery, totally contained within the prostate, but very aggressive.  Gleason 9 cancer, diagnosed when he was just 58.  Thank God we got it out of there.   

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

©Janet Farrar Worthington

 

 

 

 

 

 

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How to Have Your Best Prostatectomy

Please Read This Before You Go Under the Knife.  Nobody thinks a prostatectomy will be a breeze; if anybody tells you that, take it with a big old mental grain of salt.  Even with the best surgeon in the world, there will still be some incontinence and erectile dysfunction.  But ideally, with exercises, biofeedback if necessary, and penile rehabilitation, these should be temporary, and you will be cancer-free and enjoying your life again soon.

The complications from prostatectomy ought to be minimal.   But often, they are devastating.  A bad surgeon can ruin your life.  

So please hear this advice and take it to heart:  Find the best surgeon you can.  Get it done right.

Radical prostatectomy is a very difficult operation.  It takes not only skill, but the kind of expertise you get only after being involved in a lot of procedures, first from the sidelines as a doctor in training, and then learning how to do it meticulously with the guidance of an expert surgeon.

The very best prostate surgeons specialize in the prostate.  That’s often all they do, and they do a lot of these procedures every year.  As Patrick Walsh and I said in the book, you don’t want to be part of the learning curve.

Another point:  Because there are so many bad surgeons out there, you can’t trust everything you read on the internet or from hospitals’ propaganda.

I would dearly love to weed out the bad surgeons, so they stop doing procedures they aren’t skilled enough to do.  Until that happens, well, this is your one shot at this.  Do your due diligence.  How can you find the right surgeon?  Here’s a checklist I developed and wrote about for the Prostate Cancer Foundation’s website, with the help of three experts.  Please.  Take the following things into consideration before you go under the knife:

  • Find a high-volume center that does a lot of these procedures. Often, this is an academic medical center.  An added benefit here is that if they do a lot of these, and do them well, then everyone is going to be better at helping you. The nurses know how to take care of recovering prostatectomy patients, and there is a wing or set of beds just for those men – and not also appendectomy or hysterectomy patients, whose post-op needs are very different.  How do you find a high-volume center?  Edward Schaeffer, M.D., Ph.D., Chairman of Urology at Northwestern University, says, “This can be hard, but I always refer patients to two websites that can help.”  One is the National Cancer Institute’s website, which designates “cutting-edge cancer treatments to patients in communities across the United States.”  http://www.cancer.gov/research/nci-role/cancer-centers/find And the other is a website showing National Comprehensive Cancer Network-designated cancer centers.  “NCCN Member Institutions pioneered the concept of the multidisciplinary team approach to patient care and lead the fight against cancer as they integrate programs in patient care, research, and education.”  NCCN writes the guidelines for how to screen and care for all types of cancers, including prostate cancer.  That website is:   https://www.nccn.org/patients/about/member_institutions/qualities.aspx
  • Look for a place where different specialties work together. Top centers have multidisciplinary teams – experts from different specialties including urology, radiation oncology, medical oncology, and pathology – working together on prostate cancer. Some men are perfect candidates for surgery; others might do better with radiation, and if you are one of those, you need at least to speak with a radiation oncologist before you decide on surgery. Other men need to talk to a medical oncologist, as well.  Prostate cancer is a complicated thing, and there is no “one-size-fits-all” answer for every patient.  With the multidisciplinary approach, you get the opinion of a team of experts, not just one, and the benefit is a more thorough and thoughtful approach to your treatment.
  • Ask the surgeon about results: Does he or she keep results? For how many years?  The best surgeons, like Patrick Walsh at Johns Hopkins, follow their patients for life – so they know, 25 years after the fact, whether the PSA is still undetectable, whether there was any incontinence, whether erections returned on their own or with help from medications or other treatments, etc.
  • Then double-check. “To be honest, in my experience some surgeons lie,” says urologic oncologist Trinity Bivalacqua, M.D., Ph.D., at Johns Hopkins, “and it’s hard to determine when someone is not being truthful.  The most important factor is the reputation of the institution and the department, as well as the surgeon.  One thing that helps is asking the surgeon to provide you with names of his or her patients who have agreed to speak to other patients about their experience.  This is very helpful, and will show that the surgeon has happy patients, cares enough to put this together, and knows the importance of a large support network to help a cancer patient decide what’s best for him.”
  • Are any of the surgeon’s patients willing to talk to you?  You can hear it from the “horse’s mouth” what recovery was really like.
  • How many radical prostatectomies has the surgeon done? The answer should be in the hundreds.  If it’s something like “several,” do not walk away – run!
  • Ask more than one doctor to recommend the best prostate surgeon in your area. (Note: Some doctors are in practice groups, and recommend the specialist in that group. This is why it’s good to ask different doctors in different practices.)
  • Beware of the reviews or ads on the internet. “It is unclear to me who actually goes to these sites and makes the comments,” says Schaeffer.  Maybe it’s the patients; maybe it’s a buddy of the doctor putting in a rave review to get the number of five-star listings up.  Or maybe it’s a disgruntled colleague, or a competitor hoping to drive business away from that surgeon.  Who knows?  For the most part, says urologist Stacy Loeb, M.D., M.Sc., at New York University, “Online reviews are totally unreliable, so I am hesitant to tell men to rely on them.”  Research has shown poor correlations between online reviews with outcomes, she adds, “so I am wary to recommend something that could be misinformative.  Speaking to other patients and local doctors is a much better idea.” Loeb also recommends that you check with prostate cancer support groups in your area, and ask these men about their own experience and advice on a surgeon. “The internet is full of false accusations and glamorization of surgeons and the hospital or department,” says Bivalacqua.  A lot of hospital websites, he adds, “advertise something that is often not present or real.  I know this is a sinister way of thinking about things, but it’s the reality of our society and medical profession.”
  • And finally, don’t worry about offending the doctor with questions or by getting a second opinion. You don’t get to be a surgeon without being something of a tough cookie.   People ask for second opinions all the time.  Patients ask questions all the time.  You are paying the doctor, not the other way around.  (Note: That doesn’t mean you should be rude or disrespectful; it just means you shouldn’t feel intimidated or like you are being a bad guy simply for doing your homework.)  If the situation were reversed, do you think your doctor would not make every effort to find the best possible surgeon?  It’s your prostate, it’s your recovery, it’s your life.  You don’t want to be one of those guys saying afterward, “My surgeon was not very good.”

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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Beyond PSA: “Second-Line” Tests for Prostate Cancer

Maybe you’re in your 50s, and your PSA is 3.  Maybe you’re in your 60s, and it’s 4.  Maybe you’re in your 40s, and it’s 2.  And maybe, unfortunately, your family doctor seems in no hurry to do anything about it, saying something complacent like, “Your PSA looks good,” or “the government guidelines don’t really recommend screening for prostate cancer, so we probably don’t even need to check it every year.”  Or, “You’ve got some enlargement of the prostate.  That’s probably what it is.”  Or, “It’s still pretty low.  Let’s just watch and see what it does.”

This makes me want to scream!  Right now I want to scream anyway, and cry.  I’m thinking a lot about one of the world’s nicest guys, whom I wrote about here, who was diagnosed at age 45, after many trips to the doctor for urinary problems, back pain, and other symptoms that should have raised red flags — especially because this man is Black, and automatically at higher risk for developing aggressive prostate cancer — but didn’t.  When he was diagnosed, his PSA was in the 200s, and the cancer was widely metastatic.  His wife, an amazing advocate and warrior for her husband, told me this week that he has now entered hospice care.  He should have started getting his PSA tested at age 40.  How different might his life be right now if his cancer had been diagnosed while it was confined to the prostate?  He was in and out of doctors’ offices for years, and nobody even looked at his PSA.

Dear Readers, I talk to a lot of men with prostate cancer.  Some of them have actually been diagnosed.  

Let’s just think about that for a minute.  So I’m going to tell you what I tell them.

Screening starts with the PSA test, and then it can escalate:  In our book, we talk about the great work by Johns Hopkins urologist Bal Carter, M.D., which I’ve also written about here, on PSA velocity.  Carter and my co-author, legendary Johns Hopkins urologist Patrick Walsh, M.D., were very troubled by a study showing that 15 percent of men with a PSA lower than 4 have cancer, and 15 percent of these men with cancer have high-grade cancer.  That’s because there is no safe, absolute cutoff above a PSA level of 1.0 where a man can rest assured that he is not harboring a high-grade prostate cancer that needs to be treated.  There’s just no guarantee.

The PSA number itself is not as important as what that number does over time, how fast it changes; this is PSA velocity.  But there are some numbers for men younger than 60 that are helpful as reference points: that is, whether you are above or below the 50th percentile for your age.  If you’re below the 50th percentile for your age, you may not need to take a PSA test every year — although, frankly, men, it’s a simple blood test, and if you’re getting your cholesterol checked, then what the heck?  Your blood is there at the lab anyway!  Get the PSA checked!  But if you’re above the 50th percentile for your age, you should have your PSA measured at least every two years during your 40s, and every year from age 50 on.  Men in their 40s who have a PSA level greater than 0.6 ng/ml are in this group, as are men in their 50s who have a PSA greater than 0.7.  Those are Carter’s numbers; in a large study, urologists Stacy Loeb, M.D., of New York University and the Manhattan Veterans Affairs (see below) and William Catalona, M.D., of Northwestern University, found the comparable numbers to be slightly higher, 0.7 for men in their 40s and 0.9 for men in their 50s.  What about men older than 60?  One study showed that 2.6 was a good PSA cutoff point.  This is still a lot lower number than many doctors seem to be troubled by.

Maybe it’s because they don’t want to put a man through a prostate biopsy if it’s not necessary.  Well, sure, that makes sense.  But what many family doctors don’t seem to realize is that times have changed!  Good news:  You don’t have to move directly to having needles stuck in your prostate!  It’s not the Monopoly bad-case-scenario of “Do not pass Go, do not collect $200!”  There is a next step!  It’s a “second-line” test:  a blood or urine test that can provide other layers of information beyond the basic PSA test.  There are several good ones out there.  Which one do you need?  Well, as Marlon Brando said in the classic 1953 movie, The Wild One:  “Whadya got?”

There’s no shortage of options!  There are blood tests that provide more nuanced information than the basic PSA test, plus urine tests and even, if you’ve already had a biopsy, molecular biomarker tests, which aren’t done on body fluids but on tissue samples.  These tests can be helpful, not only in diagnosing cancer, but in risk stratification – predicting which cancer is more likely to be aggressive, and which cancer is less likely to need immediate treatment.

Helping us navigate these options is New York urologist Stacy Loeb, whom I recently interviewed for the Prostate Cancer Foundation.  “First and foremost,” Loeb says, “if a patient has an elevated PSA, the thing to do is to repeat the PSA test at the same lab.  It may feel like backtracking, but step one is to confirm that it even is elevated.”  This is why using the same lab as you’ve used in previous PSA tests is important; what might seem to be a rising PSA might just be a normal fluctuation between labs using different equipment.

However, Loeb adds, “many urologists will order the repeat test as a Free and Total PSA blood test,” because this test is inexpensive and readily available, and because it provides some additional information.   “Free PSA measures whatever PSA in the blood that is not bound to proteins.  The higher percentage of PSA that is free, the more likely you are to be free from cancer.”  This test provides context:  If the percentage of free PSA is higher than 25, then the elevated PSA is more likely to be caused by BPH, benign enlargement of the prostate.  If it’s lower than 25 percent, this doesn’t automatically mean that there’s cancer, but it does raise the likelihood that cancer may be present.

“It’s also important to rule out other causes of an elevated PSA.”  Having prostatitis can raise your PSA; so can having a urinary tract infection.  So can having sex within three days before getting your blood test, because sexual activity stimulates the prostate, which then can release more PSA into the blood.  Similarly – a big oops here for the doctor! – getting your blood drawn after the rectal exam, which stimulates the prostate and shoots PSA out into the blood stream, can make your PSA level temporarily higher.

And then there’s MRI.   “In our practice,” says Loeb, “we’re getting MRIs as the next step for patients who have an elevated PSA.  If the MRI shows a suspicious lesion, we recommend a targeted biopsy.  If the MRI is not suspicious, but we’re still worried because of the patient’s PSA and clinical picture, in that context, a biomarker test could potentially give the extra data point that could help us proceed with a biopsy anyway.  What’s nice about MRI is that it shows us suspicious areas – so in addition to providing information on the risk that significant cancer is present, it also gives us some information on where to look.  The data are very clear that performing targeted biopsies based on MRI findings is a superior strategy to only performing biopsies that sample various locations all around the prostate,” in which cancer is easy to miss.  Note:  The power of the magnet in MRI makes a difference; the stronger the magnet, the better the picture and the more the doctor can see.  You want a 3 Tesla (3T) MRI, not 1.5.

Now, about those other blood tests:  In addition to the free PSA test, here are two more that include free and total PSA, but look for other factors, as well:

PHI (Prostate Health Index):  PHI not only helps determine if cancer is present; it also can predict the likelihood of finding high-grade cancer on a prostate biopsy.  “PHI also predicts the likelihood of progression during active surveillance,” says Loeb, who with Catalona reviewed the effectiveness of PHI for the journal Urology.   “PHI is a simple and inexpensive blood test that can be used not only for biopsy decisions, but for risk stratification and treatment decision-making.” In a Johns Hopkins-led study, PHI outperformed PSA in predicting prostate cancer in general, but proved especially helpful in finding clinically significant (higher Gleason grade) cancer.  It was even better when combined with MRI; in the study, no men who had a PHI score lower than 27 and a PI-RADS of 3 or lower had clinically significant cancer.  For men who went on to have prostatectomy, a higher PHI score was associated with a higher Gleason grade of cancer and pathologic stage.   PHI also provided discernment, reduced the number of men who needed biopsies without overlooking clinically significant cancer.

4K score:  This blood test combines four prostate-specific biomarkers (three forms of PSA and also human kallikrein 2, a protein made by cells lining the prostate), plus clinical factors including age, to assess a man’s likelihood of having high-grade prostate cancer found at biopsy.  Studies at UCSF, reported in the Journal of Urology, evaluated 4K score and a prostate MRI scan, both for their ability to detect high-grade prostate cancer and to help patients avoid unnecessary biopsies.   “Both of these tests can predict the risk of finding a clinically significant prostate cancer,” cancer that needs to be treated. They found that MRI was a more able predictor of high-grade prostate cancer than the 4K score – however, MRI was not sensitive enough to detect all high-grade prostate cancer, “and 4K testing alone could be sufficient as the initial tool to select patients who may benefit from a biopsy.”  But even better, they found, was combining 4K and MRI:  “Using higher 4K cut points such as greater than 15, combined with MRI… allows for more avoided unnecessary biopsies with minimal missed high-grade prostate cancer cases.”

Loeb adds:  “About 12 percent of the time, MRI can miss something.  So, if we still suspect that cancer may be hiding, that’s a good case for using a biomarker test” like PHI or 4K.  “With a biomarker test and MRI combined, the chance of missing a significant cancer is exceedingly low.”

Urine tests:  One urine test, EPI, is done using a fresh-catch urine specimen.  This test can help predict clinically significant prostate cancer in men who have not yet had a biopsy.  Another, the PCA3 test, is done after “a vigorous rectal exam,” says Loeb.  It looks for mRNA levels of a marker, called prostate cancer gene 3, to help rule out other causes of an elevated PSA test, such as BPH or prostatitis.  “It’s FDA approved for use in men who have had a negative biopsy.”  Then there’s Select MDx, which measures mRNA levels of two biomarkers commonly expressed in prostate cancer, and MiPS, developed at the University of Michigan, which combines PSA with two biomarkers for prostate cancer.  “More head-to-head data is needed comparing all of the different blood and urine markers to find out which is best in different patient scenarios,” says Loeb.

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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