Our New Book

The new book is out and it’s better than ever, if I do say so myself!   This is the Fifth edition of a book that, in various forms, has been a number one bestseller on Amazon since Dr. Patrick Walsh and I wrote the first one in 1993.

That first book was called The Prostate:  A Guide for Men and the Women Who Love Them.  Dr. Walsh came up with the title because in his vast experience, many men don’t want to think about their health at all, much less think about prostate cancer.  In fact, it is often the women – wives, girlfriends, daughters, sisters, mothers, friends – who get them to go to the doctor.  In my own case, which I’ve written about here and elsewhere, when my dad was diagnosed with prostate cancer, he never read his own daughter’s book!  Instead, it was my mom who highlighted passages and read them aloud on the drive up to Baltimore to see Dr. Walsh from their home in South Carolina.

In that very first book, we covered all three things that can go wrong with the prostate:  prostatitis, benign enlargement (BPH), and prostate cancer.  We don’t do that anymore (although we do talk a bit about prostatitis, which is so often misdiagnosed and mistreated), because there’s so much new to say on prostate cancer alone.

Through my work with Dr. Walsh, the Brady Urological Institute at Johns Hopkins, and the Prostate Cancer Foundation, I have had a ringside seat at the forefront of prostate cancer research and treatment for three decades. I have interviewed and worked with some of the world’s best urologists, scientists, pathologists, radiation oncologists, medical oncologists, and epidemiologists in the field of prostate cancer.  What a privilege!  I was there, Gandalf, as Elrond says in The Fellowship of the Ring.  I’ve seen where it was then, and I marvel at where it is now.    

            Back in the day, we didn’t know nearly as much about diagnosis.  There was no routine screening for prostate cancer.  The PSA test was brand new and doctors didn’t really know how to use it (some still don’t, unfortunately).  There were no second-line blood tests like the 4k score or PHI test, which can help distinguish whether an elevated PSA score is most likely coming from cancer or BPH.  We have so many good updates on diagnosis, in a chapter written with the help of Weill Cornell urologist Jim Hu, M.D.  (Note: I use this information so often, in talking with men at various stages of diagnosis, that I have certain pages of this chapter earmarked and keep it on my desk, ready to go.)

Even if there had been regular screening back then, the treatments were not great.  Radiation was not nearly as effective and caused many more side effects compared to today, and before Dr. Walsh transformed radical prostatectomy, surgery was brutal (more on that in a minute).

In the early 1990s, prostate MRI was not a thing. There was only one standard approach for prostate biopsy (through the rectum), and infection was a big problem.  Hormonal therapy was not nearly as good then as it is now.  A lot of men, including my grandfather, got estrogen at too-high doses that raised the risk of a fatal heart attack.  There were no escalating hormonal therapies, no androgen receptor (AR)-blocking drugs.  No enzalutamide, no abiraterone.  No PARP inhibitors – and nobody had connected the dots between prostate cancer and inherited mutated genes such as BRCA 1 and BRCA 2.

Nobody thought much about PSMA (prostate-specific membrane antigen), and even if they did, there was no way to attach it to a radioactive tracer to light up tiny bits of cancer that had spread beyond the prostate, as we can do today with PSMA-PET.   And there definitely wasn’t a way to link PSMA to cancer-killing radioactive molecules that could target and attack individual prostate cancer cells.  There is now, and more of these radioligands are being developed.

There was no immunotherapy to speak of.  Focal therapy (see below) was wishful thinking.  We made no distinction in treatment between gay and straight men – not realizing that the treatment considerations are not the same for these men.  We know this now, and devoted a whole chapter to these considerations.

Active surveillance as it is today – carefully monitoring slow-growing localized cancer, and then treating at the first sign of growth with surgery or radiation – did not exist; instead, it was “watchful waiting,” which was much less hopeful.  It is so much better today, and we have a great chapter written with the help of Vanderbilt urologist Jeffrey Tosoian, M.D.

Before PSA screening became widespread in the 1990s, most cancer was diagnosed by rectal exam, when prostate cancer had grown large enough to be felt by a doctor’s gloved finger.   Widespread use of the PSA test moved up diagnosis by five years, at least.  But there was a learning curve.  At first, doctors thought there was a magic PSA number: 4.  If PSA was below 4, they thought, the man’s okay.  But then we learned that men could have deadly prostate cancer with a very low PSA score.  Scientists wrestled with PSA, trying to figure out how to make best use of it.  I watched concepts like PSA velocity and PSA density come into play in real time.  Northwestern urologist Hiten Patel, M.D., helped us write this chapter.

I have worked with the legendary urologic surgeon-scientist Patrick Walsh, M.D., since 1992.  I started working with him 10 years after he performed the first purposeful nerve-sparing radical prostatectomy.  The operation (the “Walsh procedure,” in fact) became the gold standard and changed the field of prostate cancer treatment forever.  In 1982, only 7 percent of men with prostate cancer underwent surgery.  That’s because the operation, as Walsh described it, used to be a bloodbath.  Surgeons couldn’t see what they were doing.  They operated in “a sea of blood,” he said, and men who underwent the old radical prostatectomy had to bank their own blood ahead of time, for the transfusion they would probably be needing.  Every man who underwent the procedure wound up impotent and incontinent, and often, the operation didn’t even cure the cancer, because it had been diagnosed too late in that pre-PSA era.

The first thing Walsh did was figure out how to control the bleeding.  Then he could see what he was doing – always useful in surgery!  He developed techniques to preserve urinary continence.  Then he had a patient who absolutely floored him:  this man told Walsh that soon after prostatectomy, he had an erection!  How could this be?  And if this guy could have one, why didn’t all men after prostatectomy?

Nobody knew where the nerves that controlled erection lived.  Surgeons assumed they were within the prostate. But Walsh, with Dutch urologist Pieter Donker, discovered the location of these microscopic nerves, which are in two neurovascular bundles that sit outside the prostate.  (Side note: the official name is actually the “Neurovascular bundle of Walsh.”)  Once Walsh found out where these extremely delicate bundles were, he figured out how to preserve them (as he inadvertently had in that one patient), and when it was safe to do so.  Today the Walsh procedure is performed worldwide, usually done using a da Vinci robot (but also performed as open surgery in parts of the world where they don’t have a robot).

            Edward (“Ted”) Schaeffer, M.D., Ph.D., trained by Walsh, is one of the world’s best urologic surgeons.  He is Director of Urology at Northwestern University, a surgeon-scientist who, like Walsh, constantly works to improve his surgical procedure, to save lives from prostate cancer, and to improve quality of life after treatment.  I am proud to tell you that he joined us for this edition as senior editor.  He is terrific!

As a surgeon, Schaeffer has worked to improve the robotic nerve-sparing prostatectomy, and has developed a fascia-sparing technique that is producing exciting results in the early return of urinary continence.  As the Chair of Urology, he has built a world-class prostate cancer program.  He was the first in the world, in fact, to create a urology clinic specifically for gay and bisexual men.  Our new chapter on special treatment considerations for these men was written with the help of Northwestern urologist Channa Amarasekera, M.D., who directs that clinic.

Also new in this edition is a chapter on focal therapy, and this is a big milestone for us.  Why is this? Because prostate cancer is a multifocal disease.  It tends to spring up in several places within the prostate at once, like seeds inside a strawberry.  Thus, any treatment that aims at treating just a spot of cancer might miss another spot growing nearby.  But we know a whole lot more about risk stratification – nuances based on a bunch of factors – and imaging is vastly better than it used to be.  Focal therapy is not yet standard of care, but for highly selected patients, it can be a good option.  We picked the brain of Northwestern urologic surgeon Ashley Ross, M.D., Ph.D., who is conducting trials of focal therapy in several forms, for this chapter.

There is so much in this new edition!  New treatments for advanced cancer., written with the help of Johns Hopkins medical oncologist Michael Carducci, M.D.  Going for a cure by treating oligometastasis with SBRT, which we wrote about with the help of University of Maryland radiation oncologist Phuoc Tran, M.D., Ph.D.  The causes of prostate cancer, and things that lower your odds of dying of it, written with the help of Johns Hopkins epidemiologist Elizabeth Platz, Sc.D.  The genes involved in prostate cancer.  Interviews with Northwestern genetic counselor Brittany Szymaniak, Ph.D., and with Johns Hopkins molecular geneticist William Isaacs, Ph.D.  Genetic tests, and who should get them.

What high-risk men (men with a family history, and men of African descent) need to know, and when to start screening.  Hint:  If you have a family history of cancer, including prostate cancer, you need to get a baseline PSA reading at age 40.  It’s a simple blood test.  Then, depending on your PSA, you may not need another one for a while.  But I beg you, please get that baseline!  Prostate biopsy:  we discuss the two approaches (traditional transrectal and transperineal, which has basically zero risk of infection), and we have a great discussion with Johns Hopkins pathologist Jonathan Epstein on how to interpret your biopsy findings.  Recovery of sexual function, with helpful advice from Northwestern urologist Nelson Bennett, M.D.

We also have a new chapter on survivorship:  getting on with your life after a cancer diagnosis, written with the help of Mandi Buss, LCSW, of Northwestern.  And we offer practical help for living with ADT and managing the side effects of medication.

Thirty years ago, when we wrote that first book, there was not much encouragement for men with advanced prostate cancer.  That’s not true today; in fact, some of the most exciting advances in the field of prostate cancer are new treatments for advanced disease.  There is more hope now than ever before.

In addition to the book, I have written 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.”  I firmly believe that 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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Gleason 6: Sugar-Coated Prostate Cancer?

It may never need treatment – but then again, it might.  So why do some doctors want to sugar-coat it?

“Don’t worry about Gleason 3+3=6 (Grade Group 1)!  It’s harmless!  We shouldn’t even call it cancer!  In fact, let’s call it IDLE (indolent lesion of epithelial origin)!”  Many patients have heard reassurances like these, and yes, if you have to have prostate cancer, Grade Group 1 is the best kind to have.

But wait: Let’s not call it “not cancer,” says Johns Hopkins urologic pathologist Jonathan Epstein, M.D.  “There are some very good reasons to keep the cancer designation for Grade Group 1.”  Epstein should know; he is the originator of the Grade Group system of prostate cancer grading, a system that has been adopted worldwide.  I recently interviewed him about this for the upcoming Fifth Edition of our book.

“Under the microscope,” he explains, “Grade Group 1 cancer has some of the same behaviors as higher-grade cancer.”  Even though it is not aggressive, it can still “invade nerves, go out of the prostate, and rarely, can invade the seminal vesicles.  Molecularly, it has many of the hallmarks associated with higher-grade cancer, and has certain features that you do not see in benign prostate glands.”

So why do some doctors try to sugar-coat Gleason 6 cancer?  The thinking here, Epstein explains, is that “if you remove the cancer label, it could reduce unnecessary treatment of low-grade disease,” and ease the uncertainty for men on active surveillance living with a cancer diagnosis.  For some men, this is very stressful: “In the Johns Hopkins active surveillance program, 8 percent of men undergo definitive therapy – even though they still qualify for active surveillance,” because of anxiety.  They just don’t want a cancer diagnosis hanging over their heads.

Another problem: many men who are diagnosed with Grade Group 1 cancer who have a prostatectomy actually turn out to have higher-grade cancer in their prostate.  “It was just missed during the biopsy.  If we had a crystal ball or could look at the prostate with some other imaging or molecular test, and see that all a patient had was pure Gleason 6, I would feel more comfortable saying we should potentially change the name.”

Epstein worries that if men believe they don’t have cancer, they won’t feel a strong need to get regular follow-up monitoring.  “If you tell a man that he doesn’t have cancer, yet you’re telling him you want to see him every year and get a repeat biopsy multiple times, he may think, ‘It’s not cancer, so why do I have to keep coming back?  I’m fine!’”  And then, if he stops regular follow-up monitoring, “potentially, his cancer could progress and that would be missed.”  One more thing, Epstein warns: “The excellent prognosis of treated Grade Group 1 cancer is not the same if it is called noncancer and is not treated.”  

Note: If you have very low-risk disease (basically, just a tiny amount of Gleason 3+3=6 cancer), or you have low-volume low-risk disease (a little more cancer, but still not much), your likelihood of dying of prostate cancer is less than 1 percent.  Jeffrey Tosoian, M.D., a urologist at Vanderbilt University, told me that (also for the book, the chapter on Active Surveillance). He tells his patients with very low-risk or low-risk, Gleason 6 (Grade Group 1) prostate cancer that active surveillance is the preferred treatment, because: “‘Your risk of dying from something else versus having metastatic cancer is 24 to 1.’  If the patient still wants to undergo treatment (with surgery or radiation), I question whether we did a good job of educating and counseling!”  For men who are lucky enough to have slow-growing cancer, active surveillance gives the gift of time, a delay in surgery or radiation and the side effects of those treatments.

Let’s just take a brief look here at active surveillance:  Many men don’t stay on active surveillance forever.  Eventually, they need treatment.  Now, you might say, some of these men don’t have very low- or low-risk, but favorable intermediate-risk (Grade Group 2; Gleason 3+4=7) cancer, ideally mostly Gleason pattern 3 with just a little bit of Gleason pattern 4 disease.  But some men on active surveillance who end up needing treatment do have Gleason 6 disease: it’s still very curable; it just grew.  “About 50 to 70 percent of men selected for active surveillance will avoid treatment and its potential side effects for at least 10 years,” says Tosoian.  Ideally, these men are monitored carefully, and at the first sign that cancer is growing or changing to the point of needing treatment, they undergo surgery or radiation.  With safe monitoring, “while 32 to 50 percent are treated by 10 years, the treatment delays do not seem to affect the cure rate,” and it is very unlikely – though still possible – that cancer will progress beyond the prostate or that it will leave the region and go to a distant site.  This is why it’s so important to have regular check-ups if you’re on active surveillance.

Finally, changing the name of Gleason 6 cancer may not even be that meaningful today, Epstein continues.  “Grade Group 1 is more intuitive to patients as lowest-grade cancer.  With greater acceptance of active surveillance, patients are understanding that not all cancers are the same, that not everyone needs treatment right away – or ever – and that low-grade cancer can be followed carefully and safely.” The key word here is “followed.”

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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Going After High-Risk Localized Prostate Cancer

Can intense hormonal suppression before surgery keep potentially aggressive prostate cancer from coming back?

My goal in writing about prostate cancer is to offer reassurance and hope, and also a nudge or two when it’s time to take action.  I have been very excited in past posts to write about the broader window of curability for oligometastasis,  catching cancer when it first escapes the prostate and is big enough to be seen on conventional imaging.  Now, with PSMA-PET imaging, at the first sign of a rising PSA after treatment, men can see where renegade cancer may be hiding when it’s too small to be picked up by other imaging, and seek further treatment sooner than ever, still hoping for a cure.  But maybe we can be even more proactive, which brings us to the work of National Cancer Institute medical oncologist Fatima Karzai, M.D.  I interviewed her recently for the Prostate Cancer Foundation.

What does it take to make sure high-risk localized prostate cancer never comes back?  A new Phase II clinical trial aims to find out, and it is noteworthy in two ways:  One, as Karzai, the study’s principal investigator, puts it, “We’re being aggressive.”  And two, with the help of PSMA-PET imaging, the investigators can observe the effects of anti-cancer medications – three powerful forms of hormonal therapy, in addition to surgery – on the cancer in real time.

Three steps further than surgery:  This is a no-holds-barred, all-out attack on localized prostate cancer that has the potential to be aggressive and to recur after treatment.

Karzai and colleagues are taking high-risk cancer – even though it’s localized – very seriously, and rightly so:  more than half of patients diagnosed with high-risk prostate cancer have a recurrence, sometimes years later, and more than 20 percent of men with high-risk prostate cancer die of their disease within 15 years.  Note:  these numbers have not yet caught up with the use of PSMA-PET scanning, which many doctors believe is a game-changer.

What will a short-course of triple hormone therapy do?  The researchers hope this systemic (throughout the body) treatment before surgery will strike any stray cancer cells while they are most vulnerable, and reduce the risk of full-blown metastases.   A similar trial showed promising results after more than three years of follow- up.

The trial is still recruiting patients.  So far, Karzai says, the average participants are in their mid-60s, with Gleason scores of 8 or 9, but the trial is open to men of any age with high-risk or even intermediate-risk prostate cancer that has not spread to other parts of the body (up to stage N1 cancer) who are planning to be treated with prostatectomy.

For six months before surgery, men in the trial undergo “intense androgen deprivation therapy,” says Karzai, who serves as Clinic Chief and Inpatient Director of the Genitourinary Malignancies Branch of the Center for Cancer Research at the National Cancer Institute.  This includes: Goserelin (Zoladex),which shuts down testosterone, and two drugs that target the androgen receptor:  abiraterone (given with prednisone), and enzalutamide.  “We’re really driving down the male hormones as low as we can.”  The cancer is imaged with MRI and serial PSMA-PET scans – before treatment, two months after starting treatment, and again before surgery – and patients may be asked to undergo an additional prostate biopsy two months into the study.

Note:  The loss of testosterone is temporary!  As the patients are recovering from surgery, testosterone starts to come back.  “It takes six months to a year from the second shot (given midway through the study), and all the patients will recover their testosterone.  Their libido will be affected temporarily, but as they start to recover testosterone, libido will return.” 

During the six months, “we see the PSA levels become very low or undetectable,” says Karzai.  She and colleagues are also looking for corresponding changes in the tissue (in biopsy samples and in the prostate tissue itself after surgery), studying genetic mutations in the cancer and – for the first time – observing how the effects of intense hormonal therapy are manifested on PSMA-PET imaging.  “We are seeing some patients who are exquisitely sensitive to androgen deprivation, and some who aren’t; the difference really has to do with the unique biology of their cancer.”  On PSMA-PET, “usually what we see is that the area that lights up becomes less.  In some patients with disease that’s pretty aggressive, it won’t go away completely in six months,” but it does diminish.  “We’re not looking to cure them completely with this treatment, but to get them to the surgery,” and to maximize their chances of cure.

One goal of the study is to learn how to incorporate PSMA-PET scans into the treatment of men diagnosed with high-risk prostate cancer.  “Right now, these men don’t routinely get PSMA-PET scans.  We’re also trying to see, up front, if you do more androgen suppression, what does that mean for the overall outcome?”  Is it possible to hit aggressive cancer hard enough at the localized state to keep it from coming back?  “We’ll follow these patients for a long time.”

For more information about this study, please contact the study’s research nurse, Katherine O. Lee-Wisdom, R.N. at (240) 858-3525, or email: katherine.lee-wisdom@nih.gov.

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 BAT Works

Driving Prostate Cancer “BATty”

Part Two: How BAT Works

Several years ago, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, and colleagues came up with a remarkable concept for attacking prostate cancer: alternating ADT with high-dose testosterone.  Recently, he took the time to explain to me how and why this works, in an interview for the Prostate Cancer Foundation’s website.  See part one of this interview here.

Patients have asked Denmeade if this treatment, called Bipolar Androgen Therapy (BAT), could be used as initial therapy for metastatic cancer instead of androgen deprivation therapy (ADT), or even as primary therapy instead of prostatectomy or radiation.  “No and no,” he says.  “BAT was designed to work against castration-resistant prostate cancer (CRPC).”

In CRPC, the cancer’s environment is significantly different than it is in earlier- stage cancer.  As CRPC cells learn to adapt to the lack of testosterone with ADT, “they crank up the androgen receptor (AR) to high levels,” and make themselves comfortable in the new environment.  But with high levels of AR, the cancer cells are sitting ducks, vulnerable to the shotgun blast of a hefty dose of testosterone.  “Flooding the prostate cancer cell with testosterone gums up the works:  suddenly, the cancer cells have to deal with too much androgen (male hormone) bound to the receptor.   This disrupts their ability to divide.  They either stop growing or die.”

It’s all about creating chaos in the environment, so the cancer cells can’t thrive, and timing is critical.  “ADT initially works because prostate cancer cells are suddenly deprived of testosterone, and most of them can’t survive this shock.”  Cancer cells die by the thousands, PSA plummets, imaging scans show cancer shrinking, and symptoms improve.  But prostate cancer, like the Road Runner, is elusive.  Over time, the hardy band of surviving cells regroups, adapts to living in the low-testosterone environment, and begins to grow again.  “BAT is a similar type of hormone shock – just in the opposite direction,” says Denmeade.  “A key feature of BAT is the rapid change from a very high- to low-testosterone level.”  Men remain on ADT, and receive monthly shots of high-dose testosterone, which gradually fades, then bumps back up again with the next monthly shot.  That’s the bipolar part of Bipolar Androgen Therapy (Denmeade uses the illustration below to explain to his patients).  “The repeated shocks of BAT cycling don’t give the cancer cells time to adapt, “because the underlying environment is always changing.”

So far, in four clinical trials at Hopkins, Denmeade and colleagues have given BAT to about 350 men with CRPC, most of whom have also received enzalutamide (Xtandi), abiraterone (Zytiga), or both.  For men with CRPC whose disease is worsening on ADT or on AR-blocking drugs like enzalutamide or abiraterone, BAT is highly promising. In the recent TRANSFORMER study, “we compared BAT head-to-head with enzalutamide” in patients with CRPC who had progressed on ADT and abiraterone.  “It was kind of a weird study, comparing a drug to its exact opposite: an androgen vs. an anti-androgen.  I don’t know if anybody’s ever done a study like that.  To our amazement, BAT and enzalutamide were nearly identical in terms of their effect.”  PSA levels dropped in about 25 percent of men on either treatment, and for both treatments, the response lasted about six months.

However, the real difference between the treatment arms was seen after cross-over – when men on BAT were switched to enzalutamide or vice versa.  “If we gave BAT first and then enzalutamide, almost 80 percent responded, and the response lasted almost a year.  That’s quite an improvement in the rate of response and duration.”  Among patients who received enzalutamide first, followed by BAT, the response rate to enzalutamide was only 23 percent.

This begs the question:  Why stop after one round of BAT then enzalutamide?  Why not just keep going?  “We should be able to cycle back and forth over and over again,” says Denmeade.  The STEP-UP trial, of 150 patients at Johns Hopkins and eight other centers nationwide, is looking at just this, “sequencing androgen and anti-androgen.  There are two BAT treatment arms: in one, the patients just switch every two months – two months of testosterone, two months of enzalutamide.  In the other, the men stay on testosterone until their PSA goes up, and then switch to enzalutamide, and stay on that until their PSA goes up,” then repeat.  Cancer response is also monitored by regular CT and bone scans.   Patients stop treatment if scans show cancer progression.

The BAT studies thus far have been small, Denmeade says.  “We need a big phase 3 study; we’ve just been nipping at the edges.”  For now, BAT remains investigational; positive results from larger randomized trials are needed for it to be considered standard of care. While not a cure for advanced prostate cancer, BAT may become an option for extending life and, importantly, improving quality of life.

Note:  BAT is not recommended for men with symptomatic bone pain from metastatic prostate cancer, because it can make that pain worse.  “This pain increase occurs within hours of testosterone injection, and resolves as testosterone levels in the blood decline over the first cycle of BAT,” says Denmeade.  “The worsening pain is not due to rapid growth of prostate cancer, but more likely to testosterone-stimulated release of inflammatory factors.”

BAT and the Immune System

Some men are exceptional responders to BAT.  Denmeade has a few patients who have remained on BAT alone for several years.  But for many men, the response is temporary; just a few months.  Why?  Could it have something to do with mutated genes?  What about the immune system?

“One of the things observed in the lab by our colleague, Dr. Sushant Kachhap, is that when we give testosterone, the prostate cancer cells get stressed and turn on all these immune factors,” says Denmeade. “Testosterone activates immune pathways.”  When three men who had participated in BAT trials later had “dramatic” responses to immunotherapy – 100-percent decreases in PSA, and one man remains in long-term remission – “we thought that might be the secret: androgen plus immunotherapy.”

COMBAT, a small, phase 2 study supported by PCF, co-led by Hopkins investigators Mark Markowski, M.D., Ph.D., and Emmanuel Antonarakis, M.D., (now Director of Genitourinary Oncology at the University of Minnesota) tested the combination of BAT and immunotherapy in 45 men with metastatic castration-resistant prostate cancer (mCRPC).  The men were treated with BAT in combination with nivolumab (an immunotherapy agent).  “We saw an impressive clinical response rate of 40 percent,” says Markowski.  “We also observed a durable benefit, lasting over a year, in a few patients who had received extensive prior therapies.”  The results suggested that BAT alone has significant efficacy, while nivolumab improves responses in some patients.  The combination of BAT with nivolumab was safe and well tolerated by the participants.  Markowski and Antonarakis are designing a randomized Phase 3 study to compare combined BAT plus nivolumab versus standard treatments for patients with mCRPC.

In the COMBAT trial, “we treated a group of incredible men who agreed to have tumor biopsies before and after three cycles of BAT,” says Denmeade.  “We are studying the heck out of these biopsies,” looking for specific biomarkers or gene mutations that might help predict who will have the deepest and longest-lasting responses.  The team is also performing additional studies of the interactions between BAT and the immune system to discover how this treatment can be improved.

 

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In addition to the book, I have written 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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Driving Prostate Cancer “BATty”

BAT: The Opposite of Conventional Wisdom

Could the flat-out opposite of conventional wisdom prove to be effective against metastatic prostate cancer?

 Androgen deprivation therapy (ADT) has been the bedrock of treatment for advanced prostate cancer for more than half a century.  But investigators at Johns Hopkins are rethinking it – in a way that sounds counterintuitive – and driving new approaches to tackle treatment resistance.  They’re discovering that shaking up prostate cancer with high-dose testosterone makes it more vulnerable to other treatments. 

ADT slows prostate cancer’s progress by shutting off testosterone.  Eventually, however, cancer adapts to this new environment and PSA levels start to rise; this stage is called castrate-resistant prostate cancer (CRPC).  ADT is not a curative treatment, and long-term ADT causes significant side effects, including fatigue, hot flashes, weight gain, and loss of sexual function.

Several years ago, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, and colleagues came up with a remarkable concept for attacking prostate cancer: alternating ADT with high-dose testosterone.  I have interviewed Denmeade several times over the years for Johns Hopkins publications, and recently I was lucky enough to talk to him in-depth for the Prostate Cancer Foundation’s website.

“It had been known for a long time that something weird happens when you give testosterone to prostate cancer cells,” says Denmeade.  “With low doses you can get the cancer cells to grow,” which nobody wants.  “But plenty of reports said that paradoxically, at high doses the cancer cells don’t grow as well, or they die.  Even Charles Huggins, who won the Nobel Prize for discovering hormonal therapy, said in his Nobel acceptance speech (see below) that another way to kill cancer would be to give too much hormone.  I was always interested in that idea.”

About 10 years ago, Denmeade conducted a small study at Hopkins to test the concept of using testosterone against prostate cancer.  “At the time, it seemed like all the data and literature suggested that the dose was really important; it had to be a high dose.”  The hypothesis:  Prostate cancer cells adjust to a very low-testosterone environment (created by ADT) by making very high levels of the androgen receptor (AR).  And here, as he says, “too much of a bad thing can be a good thing.”  These high levels of the AR now make cancer vulnerable to very high levels of testosterone.  Cancer cells that survive this respond to high-dose testosterone by turning the AR back down – and making the cancer once again susceptible to very low testosterone.”

The idea is “to screw up the cancer cell’s ability to adapt.”  Denmeade and colleagues coined the term, Bipolar Androgen Therapy (BAT), “to capture these polar extremes of very high and very low.  Not just making the testosterone high, but cycling between high and low.”  It’s this cycling that seems to be the key to keeping the cancer off-balance, slowing its ability to flourish.  In BAT, men experience high testosterone levels that decrease over a 28-day period, then bounce back up with the next testosterone injection.

In that early study, of just a handful of patients, “we were very cautious, because we didn’t want to make the disease worse.  We built in all these safety parameters.  But we were surprised:  it didn’t seem we made anybody worse.  It seemed very safe.  The patients did very well, and some of them stayed on the testosterone for a year or more.  Most of them felt really good.  A number of them did not want to come off of it when it seemed they were progressing:  they were just so happy to have more energy, and some of them could have sex again.”

Armed with this initial clinical data to show that BAT was safe and to show some response, Denmeade received funding for additional proof-of-concept studies from PCF, among other sources. Larger studies at Johns Hopkins have followed, including RESTORE, TRANSFORMER, and COMBAT.  Other trials testing this concept have been completed or are under way at the University of Washington, University of Colorado, and in Australia, Brazil, and the Netherlands.

Next:  How BAT Works

“Certain cancers are hormone-dependent and these cells die when supporting hormones are eliminated.  Certain cancers succumb when large amounts of hormones are administered.”–Urologist Charles Huggins, M.D., whose discoveries led to hormonal therapy for cancer and earned him the 1966 Nobel Prize for Physiology and Medicine, shared jointly with virologist Peyton Rous.

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In addition to the book, I have written 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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MRI’s Future Role in Prostate Cancer Treatment

Prostate MRI’s ability to show what’s happening in the prostate is already transforming how prostate biopsies are done.  Will it change treatment for prostate cancer, as well?

Radiologist Peter Choyke, M.D., believes it will.  He is Senior Investigator and Director of the National Cancer Institute’s Molecular Imaging Branch, and I recently interviewed him for the Prostate Cancer Foundation’s website.  He gave me some good examples of what MRI is already doing, and what’s on the horizon:

 Active surveillance:  “You can monitor patients on active surveillance with MRI,” says Choyke, but there’s a caveat:  “What you’ll typically see is not much change over two to three years.  But if you do biopsies over time, it’s not uncommon to see grade migrations, like Gleason 6 to Gleason 7, with no visible change on the MRI.”  Is that a significant change for the patient?  Does that mean that active surveillance has to stop and the man needs treatment right away?  “As far as I can see, there’s no right answer.  A lot of people are trying to substitute MRI for biopsies.  The danger there is that you will miss patients who are converting from Gleason 6 to 7.  Just because the MRI is unchanged doesn’t mean the histology (what’s happening within the cancer) is unchanged; that’s not a good assumption.”  Choyke suspects that MRI changes actually reflect growth of the tumor, “and are related to the number of cancer cells that are present – which is a really good index of how aggressive the tumor is.  If there are more cells, that’s a bad sign.  But if the cells are about the same in number, that’s not such a bad sign.”

One important role for MRI is before a man starts on active surveillance.  “You want an MRI to see what the extent of the disease is, to make sure you get a targeted biopsy of the lesion or lesions, and to make sure that you’re not putting someone on active surveillance who needs treatment instead.  By doing this, you get the patients who really should be on active surveillance, and can stay on it for much longer.”

 On the horizon:  Local treatment for prostate cancer:  MRI-guided treatments are being tested in clinical trials at the NIH and elsewhere.  The idea here is that MRI is getting so good, it may be able to provide a roadmap for treatment within the prostate.  Instead of removing or irradiating the entire gland, “we have a few protocols where we are trying to treat the lesions that we see on MRI.”  One approach is focal therapy, with MR-guided laser ablation “just to the lesion.”  If this works, there are some big advantages:  “We could significantly reduce the side effects from surgery and radiation,” says Choyke.  “We’re also very interested in, and are about to open enrollment for a trial of, local deposition of anti-androgen therapy – essentially putting androgen deprivation therapy (ADT) directly into the spot of cancer seen on the MRI – so the patient doesn’t have to undergo systemic ADT while receiving radiation therapy.”  Unlike, say, taking Bicalutimide by mouth, which affects the entire body, a micro-dose of Bicalutimide within the prostate tumor “only goes a certain distance before it’s washed away, and it’s in such a low concentration that the systemic effect is negligible.”   This will be tested in men with localized, intermediate-grade cancer, “where ADT is useful but not mandatory,” Choyke adds.  “There may come a time when this can be advanced to higher-grade tumors.”

Another trial in the works will test MR-targeted focal radiation.  “We’re very excited about this because with radiation, you can really do dose painting.  With a laser, you either kill or you don’t kill; you either burn it or you don’t burn it.  But with radiation, you can taper the dose around the edges of a tumor, where there’s a large expectation of cancer.  That’s good for the patient, because you’re not giving the same dose throughout and irradiating things that don’t need to be irradiated, like the rectum, urethra, or bladder base.”  This trial is “awaiting good planning software,” to help plot precisely where and how much the dose should be.

But much more testing is needed.  “First, do no harm.”  If it turns out that “we can treat the cancer successfully without a lot of side effects, that’s a good outcome.  All of that is enabled by the MRI providing the spatial information to direct these therapies.”

Artificial intelligence and MRI:  “We have a very good correlation between what’s on the MRI and the actual pathology of the radical prostatectomy specimen,” says Choyke.  “We have thousands of cases where we’ve compared the pathology to the MRI.  So now, with pretty good accuracy, we can predict the pathology from the MRI.”

But sometimes, MRI can’t see every bit of a tumor.  Sometimes normal tissue is interspersed with cancer, “at the resolution that MRI can’t detect; cancer is sort of hidden in all that normal tissue.”  Sometimes, tumors have stroma (noncancerous connective tissue cells), that masks the cancer cells.  And then there are some higher-grade tumors that simply don’t show up on MRI.  “In our studies, it’s 5 percent, but I’ve seen it as high as 15 percent of patients with intermediate or high-grade disease who have negative MRIs.  We’re looking to see whether artificial intelligence (AI) can pull out these lesions that the human eye can’t detect.”  No one knows why this is; under the microscope, “the pathology of those lesions doesn’t look that different.

“You’d think by now we would understand this very well,” but because the vast majority of tumors do show up on MRI, “it’s hard to accumulate enough cases to make bold statements about what’s going on.  We are continuing to look at it – so stand by for more information!”

This is part3 of 3 stories on MRI, MRI’s role in cancer screening, and MRI’s potential use in treatment.

In addition to the book, I have written 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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MRI: No More “Hit-or-Miss” Biopsy!

Can MRI really make a difference in diagnosing prostate cancer?  Just ask Rob Gray.  It took nine years for his cancer to be diagnosed.  He felt like a human pincushion after going through numerous tests, exams, and five prostate biopsies – some of them saturation biopsies (each involving 20 or more needle samples!).  Doctors couldn’t find cancer, but they couldn’t rule it out, either.  The inconclusive “TRUS” (transrectal ultrasound) biopsies took their toll, as well: scar tissue developed in his prostate, making cancer even more difficult to detect with TRUS.   Rob is firmly convinced that, had it not been for an MRI-guided fusion biopsy, his cancer, which turned out to be Gleason 3 + 4, still might not have been found.  Today he is cancer-free.

Out with the “Hit-or-Miss” Biopsy!

With TRUS, unfortunately, Rob’s story is all too common, says radiologist Peter Choyke, M.D., Senior Investigator and Director of the National Cancer Institute’s Molecular Imaging Branch, and a pioneer in the rapidly evolving use of MRI to evaluate prostate cancer.  He is at the top of the MRI-prostate cancer field, and I was privileged to interview him recently for the Prostate Cancer Foundation’s website.

Why have so many men, like Rob, endured multiple inconclusive biopsies?  Choyke explains: “Let’s look at what until very recently was state of the art: 12 biopsies performed by the urologist under TRUS, six on one side and six on the other.  It really wasn’t targeted to anything in particular.”  The basic biopsy sampled the upper, mid and lower part of each side of the prostate (this, by the way, was an improvement over the old biopsies of 20 years ago, which took only six samples!).  Even with 12 samples, “there are a lot of opportunities to miss lesions.  And, because urologists don’t want to injure the urethra, which is in the center of the prostate, they tend to put the needles more towards the back of the gland, so the front part of the gland was relatively unsampled in a traditional TRUS biopsy.”

In other words, the traditional biopsy is largely hit or miss.  “Once we started doing MRIs,” says Choyke, “we realized that a lot of tumors are above where the needles usually went in; in fact, those lesions are more amenable to transperineal biopsy.  That was important in helping us detect the cancers in men who had multiple negative TRUS-guided biopsies.”

A targeted biopsy – done with TRUS, but using the MRI as a roadmap – can direct the needle to specific areas that look suspicious.  “Also, once you have the MRI, you realize how big the lesion is.  With TRUS, you just had a specimen that was positive.  You didn’t know if it came from a 3mm- or a 5 cm-sized lesion!  It was just ‘positive.’  Now with MRI, we have a much better feel: is this a big lesion, has it been there a long time, has it grown outside the prostate, possibly to the lymph nodes?  Are the seminal vesicles involved, is the bladder involved?  There’s a lot of anatomy that you can get from the MRI that you just don’t get from the biopsy information.  Was the needle in the center of the lesion, or the periphery – or did it biopsy something completely different than the main lesion?  Is this cancer caught very early, so it’s hard to see, or is it large and obvious?  That influences the discussion of treatment options, and allows the patient to make a much more informed decision.  With MRI, you’re way far ahead of the game.”

And this is why Choyke believes that “in the best of all possible worlds, every man with suspected prostate cancer would get an MRI.”  MRI is of even more benefit, he adds, as a man’s PSA rises.  “We did a study where we compared men with a PSA less than 5 with men with a PSA greater than 5.”  For men with a lower PSA, “the advantage of MRI was much smaller compared to a traditional TRUS biopsy.  But for those with PSA greater than 5, it was clearly superior to have an MRI.”

That said, there are some qualifiers:  Not every insurance policy pays for MRI, and good-quality MRI is not universally available.  The power of the MRI machine itself used to matter more, with 3 Tesla strength preferred.  But today, the major determinants are, “how old is the MRI unit, and is there a radiologist who is focused on prostate MRI, who has been to courses learning how to interpret it properly?  Or, is the radiologist a generalist without specific expertise?”  If you’re paying for part or all of the cost out-of-pocket, Choyke notes, “these scans are very expensive.  I don’t think it’s unreasonable to ask good questions.”

Another bonus to today’s prostate MRI:  With more sophisticated machines, very few men require the endorectal coil, a latex-covered probe, inserted in the rectum, that helped provide better-quality images of the prostate with earlier-generation equipment.  “We advocated for endorectal coils universally five years ago; but once we bought a new scanner, we now reserve coils for cases in which the patient’s already been treated and we’re looking for recurrent disease in the pelvis, which can be very subtle.”  With the recent approval of 18F DCFPyl PSMA-PET, which uses a highly specific molecular tracer to find prostate cancer cells anywhere in the body, “we’re using the coil less and less.  That’s associated with lower cost, better patient appreciation, and faster scans.  Nobody regrets to see the passing of the endorectal coil.”

This is part 1 of 3 stories on MRI, precision cancer screening, and MRI’s potential use in treatment.

In addition to the book, I have written 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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