Killing the Cancer, Not the Prostate

            Focal therapy, although not the standard of care, is emerging as a way to treat localized prostate cancer in carefully selected patients.  I recently interviewed one of the leaders in this field, urologist Arvin K. George, M.D., Director of Prostate Cancer Programs at the Brady Urological Institute at Johns Hopkins.

            Focal treatment is just one part of George’s clinical practice, which spans the diagnosis and management of prostate cancer and other genitourinary cancers; he is an expert surgeon who performs robotic prostatectomy and kidney surgery.  His research focuses on the use of imaging and biomarkers in diagnosis, risk stratification, and management of prostate cancer.

            Why is focal therapy a tricky subject?  As we have discussed here and elsewhere on this website and in the book, Prostate cancer is a multifocal disease:  like dandelions in a field, cancer can spring up in several places within the prostate at the same time.  That is why the gold standard for localized disease is to treat the entire prostate through surgery or radiation.

            Focal therapy – killing, or ablating, only the known spot or spots of clinically significant cancer within the prostate – has been around for decades in various forms; the most common approaches are cryo (freezing) therapy and high-intensity focused ultrasound (HIFU), and other technologies are emerging.  But for years, urologists have had questions about the idea of focal therapy itself, including:

  • What if you kill cancer in one spot, but miss another tiny site or sites of cancer?
  • Urine exits the body through the urethra, which runs right through the prostate, like a road through a tunnel. To protect it during focal therapy, doctors maintain its normal temperature with either a heating or cooling tube.  What if there is cancer near the urethra that is also spared?
  • What if one spot of cancer is ablated, but a new one starts to grow? Can the prostate tolerate multiple courses of the same type of focal therapy, should a different approach be used, or should the patient shift to surgery or radiation?

Why is Johns Hopkins now investigating and offering focal therapy?  What has changed?

            First and foremost, says George, the reason is imaging. “The better imaging gets, the better and more precise our treatments become.”  Improvements in MRI have been game-changing.  “We can see where a lesion is, how far it extends, and apply a treatment to just that area.”  That’s true, although some cancers just don’t show up on MRI, as discussed here. There is also a potential for PSMA-imaging technology to play a role in the treatment of localized disease, although so far it has not routinely been used in patients who are considering focal therapy.  PSMA-PET is more of a “big gun” brought out when it’s suspected that cancer has escaped the prostate.

            Risk stratification has gotten a lot better, too.  PSA density, second-line biomarker tests like the 4K score and Prostate Health Index (PHI,) and molecular pathology findings (from the biopsy tissue) help doctors create a “profile” of the cancer, to evaluate its potential to be aggressive or more slow-growing.

            Thus, says Mohamad Allaf, M.D., Director of the Brady Urological Institute (and, incidentally, the Hopkins surgeon who took out my husband’s prostate and saved his life, thank God!), “as we are understanding the biology of the disease more and our ability to see the cancer has gotten better – even though MRI and PSMA-PET aren’t perfect – there may be a role for focal therapy.”  This remains to be proven, he adds, and “Arvin is perfectly suited to doing this.  Doctors out in the community are already providing focal therapy, and somebody needs to take the lead to study it in a very rigorous way, tracking the cancer control long-term.  We see the Brady as a steward of treatment and as a leader in defining the role of focal therapy.  The unique thing Arvin brings is the academic rigor to study and implement focal therapy and anything image-guided within prostate cancer, including new MRI fusion transperineal biopsies.”

“We Definitely Have Some Bridges to Rebuild”

            One important priority is improving the public understanding of focal therapy, says George. “We definitely have some bridges to rebuild,” because of physicians worldwide over the last 20 years who have not been as responsible or, regrettably, as skillful as they should have been.  “We didn’t know what we didn’t know.  There was a learning curve to this new technology: how we apply it, and how we follow men afterwards.  We have some clarity regarding this with updated surveillance protocols, but we still have much to learn!”

            That said, he adds:  “Some practitioners of focal therapy out there have been frankly sketchy,” he says, “providing inadequate coverage of the cancer, exorbitant out-of-pocket costs, no follow-up, learning on patients as the technology developed, causing fistulas and other complications.  We are still suffering from that hangover of offshore treatments and cash pay.” 

            But focal therapy is not the same today as it was then.  With rigorous follow-up, George says, focal therapy can be a good option for some men with localized cancer.   “Tens of thousands of cases of focal ablation have been performed,” he says.  “While we have less data than that, we do have five- to seven-year median outcomes on more than 1,300 patients that have been published.” He believes focal therapy is here to stay.  “It’s all about choosing the right patient.”

            Right now, the “sweet spot” for focal therapy, as we discussed here,  is a patient with favorable intermediate risk. “Less aggressive cancer may require no treatment at all, and more aggressive disease requires more aggressive treatment.”  The ideal patient “has cancer that is visible on imaging but is not near vital structures like the urethra, rectum, or neurovascular bundles, and has no high-risk features such as extracapsular extension or seminal vesicle invasion.”

            George is the Principal Investigator of two clinical trials of focal therapy. One is the PRESERVE study, involving prostate tissue ablation through irreversible electroporation (IRE).  IRE is largely “athermal.”  It doesn’t use either heat or cold; instead, it generates an electrical field across tissues between two electrodes.  The electricity creates holes in the cells on a microscopic level, causing them to die.  “Because IRE doesn’t harm the scaffolding, or connective tissue, theoretically, it can treat closer to the nerves.”  The other study is the VAPOR 2 trial, using water vapor to destroy tissue.  “This is an extremely hopeful time for men with prostate cancer.”

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

            Is focal therapy for every man with localized prostate cancer?  Absolutely not.  In fact, says Northwestern University urologic surgeon Ashley Ross, M.D., Ph.D., it’s not even a good option for the majority of patients.  But for a few carefully selected men, with close follow-up, “it can be a curative option with minimal side effects.”

Ross, one of the leaders in the developing field of focal therapy, is the expert I interviewed for the 5th edition of our book –where we not only talk about focal therapy for localized prostate cancer; we devote a whole chapter to it!   This is a significant milestone, especially if you look at all the previous editions of our books dating back to 1993, where we basically offered zero encouragement for taking this approach.

But – but – focal therapy is out there!  It is here to stay!  It’s available all over the world!  Yes, that’s true.  Does it work long-term?  Nobody knows yet.  The current National Comprehensive Care Network (NCCN) guidelines state that “cryotherapy or other local therapies are not recommended as routine primary therapy for localized prostate cancer, due to lack of long-term data comparing these treatments to radical prostatectomy or radiation.”  Also, except for follow-up biopsy, there is no way to prove cure with focal therapy.  PSA does not become undetectable because much of the prostate is still untouched, and that prostate tissue is still making PSA.

This is why long-term follow-up is critical:  you have to keep watching the PSA, and if it changes, you need a repeat MRI.  So, no matter what anyone says, focal therapy is not the standard of care; it is still considered investigational.

The last post (part 1 of this series) was devoted to all the reasons why men interested in this approach should proceed with a whole lot of caution.  This post starts to look at who might consider focal therapy.

            Why am I talking about it now?  What has changed?  Imaging, for one thing; prostate MRI and targeted MRI fusion (also called mpMRI) biopsies.  Also, there are intelligent blood and urine tests that can help determine whether a cancer is clinically significant (we have updated information on this in the 5th edition of the book).

Taken together, maybe with genetic testing if there’s a strong family history of cancer, it is possible to get a decent idea of the kind of cancer you’re dealing with.  You can’t just say, oh, I have localized cancer!  You need a more nuanced understanding of this cancer, and that requires putting together every available piece of information you can get.  Don’t just put all your faith in the biopsy.  Remember, a biopsy only looks at 1/10,000th of the prostate.  Yes, that’s one ten-thousandth.  Not a lot of tissue!  Just because the biopsy says Gleason 6 doesn’t mean there’s not some higher-grade cancer in your prostate; many men are “upstaged,” that is, a higher grade of cancer is found after prostatectomy when the pathologist examines the removed prostate tissue.

And don’t put all your faith in the MRI.  As good as MRI is, some prostate cancers still don’t show up on it; they’re spread out, like plankton on the ocean, instead of all knotted up in one dense ball.  But if you put the imaging, the biopsy, and the other tests together, you can get a pretty good handle on the kind of cancer you have.

            Do you have the kind of cancer that needs to be treated right away?  If not, active surveillance is a great initial option.  It buys you time and has zero side effects.  If you have Gleason 3+3 (low-risk or very low-risk) or 3+4 (favorable intermediate-risk cancer), with not a lot of pattern 4, and the cancer seems safely contained within the prostate, then be thankful!  You have some breathing room.  Plenty of time to make a treatment decision when and if your cancer needs to be treated.

            If you have localized cancer but there’s a lot of Gleason pattern 4, or any Gleason pattern 5, (4+3=7, 4+4=8, 4+5, 5+4 or 5+5), then you have cancer that is not only clinically significant, but likely to spread, and the prostate needs to go – either with surgery or radiation, and if it’s higher-grade, higher-volume, and close to the borders of the prostate and you are deemed at high risk, you may need to escalate with a temporary course of hormonal therapy, as well.   We discuss all of these scenarios in detail in the book.

Who is the Ideal Candidate for Focal Therapy?

            Ross believes there is a “sweet spot” for focal therapy:  men with high-volume low-risk disease (Gleason 3+3) and favorable intermediate-risk prostate cancer (a little bit of Gleason pattern 4), “provided their disease is localized to one area of the prostate,” he says.  Preferably with just one lesion and ideally, “a lesion that is more anterior (above the urethra), as that allows for sparing of the neurovascular bundle.”

            Ideal candidates for focal therapy, he continues, should have a life expectancy of 10 years or greater.  They should be willing and able to undergo an MRI and biopsy, or should consider a saturation biopsy to make sure there aren’t areas of higher-grade cancer lurking in the prostate.  “Men also have to be willing, in my opinion, to undergo a confirmatory biopsy,” to make sure the focal treatment worked.  “They must have a very low chance of lymph node involvement, because obviously you’re not going to treat with focal therapy a disease that has spread to the pelvis.”

            The bullet points here:

  • 10-year or higher life expectancy
  • Unilateral cancer (one area, or focus), preferably away from the neurovascular bundles on both sides. A man who has multifocal disease (several bits of cancer sprouting simultaneously within the prostate; like seeds on a strawberry) “has a higher propensity for developing more prostate cancers,” and should not be considered for focal therapy.
  • You need a follow-up biopsy to make sure you’ve been cured.
  • Also, says Ross, you should undergo genetic testing if recommended. In the book, Ross mentions two kinds of genetic tests:  one looks for mutations in genes such as BRCA2, which raise the risk of developing aggressive cancer.  “Patients with genetic risks are potentially poor candidates for focal therapy,” says Ross.   There’s another kind of genetic test: one that looks for multiple genetic variations that are known to raise the risk of getting prostate cancer.  These are not mutated genes, but mutated sequences of DNA.  Men with high polygenic risk scores are more likely to have multifocal disease, and “also may be poor candidates for focal therapy.”

            Here is a case study Ross presented at Northwestern, which we used in the book.

            “Daniel” is 74, with a PSA of 7.1  No cancer was felt on his rectal exam, but an MRI showed one lesion, with a PI-RADS score of 5, in the right transitional zone.  His MRI-targeted prostate biopsy found cancer, Gleason 3+4=7 – but not much of it.  Cancer was only found in three out of 12 cores of the biopsy, but in two of those cores, 40 percent of the cancer was Gleason pattern 4.

            Daniel is still working and fairly active.  Ross estimates his life expectancy to be around 10 years.  Daniel has some health issues, including atrial fibrillation, and is on a blood-thinning drug, Eliquis.  Before coming to see Ross, he met with another urologist to discuss robotic prostatectomy, and with a radiation oncologist.  “He wasn’t interested in radiation therapy,” says Ross.  “He was worried about bleeding episodes” because of the Eliquis.  “He also worried about surgery.”

            Daniel underwent cryoablation, killing cancer cells with extreme cold – creating an “ice ball” of tissue, which then dies).  This focal procedure spared both neurovascular bundles (the nerves on either side of the prostate that are responsible for erection) and, because of the location of the tumor, did not affect the urethral sphincter.  It was done as an outpatient procedure, and Daniel went home the same day.  “He had an uneventful recovery, had immediate continence, which was complete, when the catheter was removed in seven days.  He had no decline in sexual function,” although Daniel had already experienced some ED before the procedure.  Three months later, Daniel’s PSA dropped to 0.94.  “We will continue PSA monitoring, and have an MRI and confirmatory biopsy at 12 months.”

            Part 3 of this series will be my interview with Johns Hopkins urologist Arvin George, M.D., who is investigating several different types of focal therapy and believes this treatment is going to be helpful for a wider window of patients.

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

Why I agonized over writing about it, and why I have (cautiously and for very selected men) altered my opinion.  In three parts.

            Four years ago, I wrote a VJ post on focal therapy.  I didn’t publish it.  I just couldn’t.  It started off:  “Dear Readers, if you ever want to start a veritable spitstorm in the world of prostate cancer, here’s a grenade:  it’s called focal therapy.  It’s like the idea of a lumpectomy; just treating the part of the prostate with cancer, and leaving the rest alone.”

Back then, in 2020, I wrestled with the story for months.  A wonderful man named Bill had contacted me on Facebook and wanted to tell his story.  A happily married man in his early 50s with young kids and an active life, he had undergone focal cryotherapy and was thrilled with the results.  He wanted me to write his story so he could help other men.

I turned him down.

Why would I do that?  I will tell you, but first, a couple things you need to understand:  First, if you don’t know it already, I agonize over you guys.  I do.  I worry about so many men, some I know personally, some I have interviewed, and some I’ve just corresponded with or talked to on the phone.  I’ve been writing about this disease for a long time, and I have known way too many men who died of it.  That’s why I push for you to get screened for prostate cancer, to get a second opinion if your PSA is going up and there’s no good reason for it, to get MRI or second-line blood tests even though your doctor says “it’s probably fine,” and that’s why I have been very cautious about any treatment that sounds too good to be true.  I have been very wary of focal therapy because there aren’t long-term results and, although it is becoming more common, I don’t know that it’s a long-term cure.

            Second:  On this website, I answer only to you, to myself, and to God.  Not in that order.  But nobody else.  I don’t make a dime from VitalJake.com.  As you may have noticed, I don’t accept medical ads.  Actually, I don’t have any advertising; I don’t even know how to go about it.  I’m not saying I would turn down an ad for clothing, or dog toys, gardening tools or fishing lures.  In fact, it would be a novelty to actually make money from this site, but that’s not why I do this; I do have a day job.  What I will turn down, and have turned down many times, are medical ads.  I get a lot of offers, and I always say no.  Because if I let somebody else sponsor these pages, they might think they get to control the content.  No. It’s just me, agree with me or not.

Now… back to the grenade.

I told Bill what Patrick Walsh and I said in our book – back then, the 4th edition – about it.  Actually, we devoted 10 pages of the 4th edition (I keep mentioning this because the 5th edition discussion of focal therapy is different, as we will discuss).  The bottom line is this:  Prostate cancer is a multifocal disease:  like dandelions in a field, cancer can spring up in several places within the prostate at the same time.  That is why the gold standard for localized disease is to treat the entire prostate through surgery or radiation. 

The average prostate specimen, when examined by a pathologist after prostatectomy, has between three and seven separate sites of cancer cells.

Focal therapy doesn’t kill the whole prostate, and thus it has minimal side effects.  That’s why so many men are really interested in it.  I would be, too.

This form of treatment – killing, or ablating, only the known spot or spots of clinically significant cancer within the prostate – has been around for decades in various forms; the most common approaches are cryo (freezing) therapy and high-intensity focused ultrasound (HIFU), and other technologies are emerging.  But it doesn’t kill the whole prostate.  So there is the strong possibility that some cancer could be missed, or inadequately treated, and $30,000 out-of-pocket later, there you are looking down the barrel of surgery or radiation.

In the first edition of our book, back in 1993, we wrote about the side effects of cryotherapy, and there were a lot.  There was a huge learning curve, and it was often not pretty.  There were also many cases of men who paid a lot of money for HIFU, whose PSAs didn’t go down because there was still cancer in their prostates.  Also they had some of the key side effects they were trying to avoid; in this study, at one year, nearly 30 percent were impotent after HIFU and 27 percent still had cancer in their prostate.

Then, for Discovery, a magazine I write and edit for the Brady Urological Institute at Johns Hopkins, I interviewed a urologist for whom I have great respect:  Michael Gorin (now at Mount Sinai), who saved my husband’s life with his amazing biopsy skills.  To my great surprise, he was doing studies of focal therapy.  He believed MRI imaging had gotten good enough for urologists to see what was actually clinically significant disease in the prostate, and to kill it.

So, I got on Facebook, messaged Bill and said, “I think I owe you an apology.”  I told him they’re doing this at Hopkins, and asked if his offer to let me interview him was still open.  He agreed.

But then, in the ping-pong nature of this saga, for the Prostate Cancer Foundation’s website, I happened to be interviewing a University of Michigan radiation oncologist and Prostate Cancer Foundation (PCF)-funded investigator, Daniel Spratt, M.D., on a different subject.  I asked him what he knew about focal therapy.  He knew plenty; he has had to treat men for whom focal therapy has failed.  I’m including some of what he had to say below.  This, in turn, prompted a man named Greg to write to me here at Vital Jake.  He had seen the story on the PCF website and was not happy with it.  He was a fan of focal therapy.

Enough with the Backstory

             Let’s get to it.  This three-part series is my effort at a balanced discussion.  The rest of this first part is from the interview with Dan Spratt.  If you’re looking for the quick story, it’s a no on focal therapy.  But stay with me.  Parts two and three are a qualified yes.  For some men.  Some very selectively chosen men.  Men who must then receive rigorous, long-term follow-up monitoring.  The bottom line here is that this story is evolving.  Here’s that PCF interview:

If It Sounds Too Good To Be True…

            If you have been diagnosed with cancer that is contained within the prostate, you may be thinking:

            “Hey, there’s just a spot of cancer that showed up on the MRI,” or:

            “Only three of the needles came back with any cancer at all.”

            And this may lead you to think:  “Why do we have to treat the whole thing?  Why can’t I just get a prostate version of a lumpectomy?”

            Or:  “Why not just zap that one spot of cancer?”

            Wouldn’t that be great? 

            This is called focal therapy – just treating part of the prostate.  In just a few seconds’ search on the internet, you can see that there’s a lot of this focal therapy out there, and it all sounds great!  No erectile dysfunction (ED) or urinary incontinence!  If your PSA rises, no problem!  Treat it again!  A lot of doctors are offering focal treatment, using methods including cryotherapy (freezing the tissue), high-intensity focused ultrasound (HIFU), or even with highly focused radiation.

            There’s just one problem with every type of focal therapy for prostate cancer, says University of Michigan radiation oncologist and Prostate Cancer Foundation (PCF)-funded investigator Daniel Spratt, M.D.:  “I would say, strongly, that it’s experimentalThere’s a very high risk of recurrence, usually within the first three years and it may increase your risk of side effects if you later need curative treatment.  There is a reason it is not considered a standard-of-care treatment by most national and international guidelines.”

            Prostate cancer is usually a multi-focal disease, meaning it is in more than just 1 or 2 spots in your prostate.  This is true even if your biopsies or MRI show only 1 area being involved with cancer.  Some studies suggest more than 40 percent of patients have MRI- invisible tumors, and standard prostate biopsies sample less than 1 percent of your prostate gland.  This is why focal therapy is often ineffective:  it treats only part of your cancer.

            Also, a lot of what they promise about not having side effects is not true.  “Side effects are often lower than men experience with a radical prostatectomy, but there are side effects,” says Spratt.  “There’s still the potential for erectile dysfunction (ED) and other side effects, and one of the biggest concerns is that with subsequent treatment, if the patient needs surgery or radiation, sometimes you can have severe or unexpected side effects.  I’ve seen it in patients who previously had focal therapy,” including one man after HIFU, whose entire urethra (the tube that carries urine from the bladder through the prostate and into the penis) became necrotic – the tissue died.   “He had to have emergency surgery.  They killed healthy tissue.”

            That’s why focal therapy for prostate cancer is still considered experimental. As molecular biologist and medical oncologist Jonathan Simons, M.D., then-CEO of PCF put it:  “’Experimental’ means ‘not proven.’”

            How does something become proven?  It requires well-designed studies to see how patients do in the short run and then over several years.  “There’s so little evidence in the literature,” says Spratt and most are retrospective studies or small single arm trials.  “No well-powered trials with long-term follow-up have been done to even inform us of how effective these therapies are, and to show the safety of doing subsequent curative treatment (surgery or radiation).”

            Spratt has seen many men in recent years who have come from around the country to see him after focal therapy has failed.  “Most of the patients I see who have had it are very upset.  Insurance often does not cover it, and they have spent $20,000-$30,000 out of pocket, thinking they’re going to get a cure with no side effects.  But some do get side effects and all of them who see me were not cured.  And when I tell them, ‘Look, you need a second treatment and you’re at a higher risk of having more side effects,’ they are very upset.”

            The best way to try focal therapy, Spratt continues, is in a clinical trial, “where you are fully informed of all the risks.  Many top centers offer focal therapy, and they should be offering it in the context of a clinical trial.  If not, this is concerning.  These trials are critical to learn how to quantify and optimize focal therapy.  Maybe if they improve it, in the years to come, it will be better than surgery or radiation.  But right now, it’s definitely not.  We’re learning.  There’s a lot of misinformation out there. We must remember that if patients want a non-invasive option other than radical surgery, there are multiple forms of radiotherapy that are completely non-invasive and have better cure rates and long-term potency rates than focal therapy.”

            In a recent trial of HIFU, “within one year, about 30 percent of men developed ED and 25 percent still had cancer in their prostate.  Most of these men had low- or intermediate-risk disease, and could safely have been monitored on active surveillance.  In comparison, in a similar risk group of patients receiving radiotherapy one would expect close to zero percent chance of recurrence within one year, no incontinence, and fewer than 10 percent would experience ED so soon.  Similarly, surgical removal of the prostate would also have excellent long-term cure rates.

            “So why do centers and providers offer focal therapy?  This is very complex.  I fear it comes back to money, trying to advance one’s academic career with something different, and the pervasive avoidance of working as a multi-disciplinary team.  A lot of doctors are trying to offer something less invasive than removal of the prostate for patients looking to avoid the risks of incontinence or impotence, rather than simply offering radiotherapy.  Focal therapy is new and it entices patients – like they found the magic bullet.  However, external-beam radiotherapy has extensive, high-quality evidence with very long-term follow-up beyond 20 years, and has essentially zero percent incontinence and superior erectile function outcomes compared to the focal therapy literature.”

            Spratt says, “Bottom line:  the two standard-of-care treatments for prostate cancer are surgery and radiotherapy.  Lots of emerging treatments and technologies, including focal therapy and proton-beam therapy, may have a role for the management for prostate cancer.  Well-done randomized trials are necessary to determine what, if any, role they will have in the management of prostate cancer.  Until then…proceed with caution.”

Still with me?  Okay, next, let’s look at two centers where they are proceeding with caution, with studies of focal therapy for localized prostate cancer.

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

Androgen deprivation therapy (ADT) is a double-edged sword.  It can do a lot of good:  in men with high-risk prostate cancer, for example, a two-year course of ADT can make the cancer more susceptible to radiation treatment, leading to a cure.  And in men with cancer that has spread beyond the prostate, ADT by itself or combined with other treatment can keep cancer at bay for years.

            But ADT can also cause health problems.  It can raise your risk of metabolic syndrome, diabetes, heart attack, stroke, cognitive impairment, loss of muscle mass, fractures, balance issues, and falling.

Now here’s the question:  Are these problems inevitable?  And the answer is:  We don’t know yet!  The Prostate Cancer Foundation (PCF) is funding efforts to help predict who is at higher risk.  What we do know is that you can fight ADT’s negative effects on your body.  With a PCF Challenge Award, a team of Harvard and Dana-Farber investigators led by Christina Dieli-Conwright, Ph.D., M.P.H., is leading a study to find out more:  the FIERCE trial (Debunking the Frailty-SarcopenIa-ADT Axis in MEtastatic Prostate CanceR with MultiComponent Exercise).

Fierce is what Dieli-Conwright, an expert in exercise oncology, would like you to be – and against ADT, a major way to be fierce is with exercise.   “Debunking” is an interesting word choice for the study’s title.  What kinds of things get debunked?  False or exaggerated claims; in this case, the claims of what is sure to happen with ADT.

I recently interviewed Dieli-Conwright about this award.  She is one of my favorite scientists in the field of prostate cancer because of her can-do spirit.  (If you missed this post on her DIY home fitness plan, it’s worth a read.  It’s got exercises anyone can do, anywhere!)  “The effects of exercise have been vastly understudied in men with metastatic prostate cancer,” Dieli-Conwright says, “particularly on how exercise can help prevent frailty and sarcopenia” (loss of muscle mass, strength, and function).  It also can help prevent metabolic syndrome, a precursor to diabetes and heart disease, and this is terribly important for overall health and quality of life – affecting the entire body, not just the bones and muscles.”

            There is a domino effect in ADT, and it starts with weight gain and metabolic syndrome.   ADT takes away testosterone, and without testosterone, your body is more likely to have higher blood pressure, higher blood sugar, more body fat around the waist, and higher levels of cholesterol and triglycerides.  All of these conditions, in turn, raise the risk of comorbid conditions such as heart disease, stroke, and diabetes.  These conditions can be debilitating on their own, and they also can create or encourage a pro-inflammatory environment that promotes the growth of cancer.

Dieli-Conwright has spent her career working to determine the underlying physiologic mechanisms by which obesity, sarcopenia, and metabolic changes affect recurrence of cancer, then coming up with and testing exercise interventions to fight obesity, diabetes, and cardiovascular disease among cancer surivors.  The goal in going after these simultaneous diseases is not only to prolong life in cancer survivors, but to improve it.

In the FIERCE study, men with metastatic prostate cancer who are receiving ADT will undergo a 16-week supervised exercise intervention (including resistance, aerobic, and functional training to improve balance and movement).  Men in the control group will undergo a stretching program and will be offered the exercise program after the 16 weeks.  The investigators will measure the effects on frailty and sarcopenia in both groups, and measure biomarkers of inflammation, muscle activity, and cancer response.  “We hope this study will establish an exercise treatment program to prevent the degenerative effects of ADT and significantly improve quality of life and outcomes in men with metastatic prostate cancer,” says Dieli-Conwright.

So:  exercise, in fighting metabolic syndrome, can help prevent other potentially serious conditions, and may help slow the growth of cancer, as well.  It even improves the cognitive effects of ADT, helping you think and function better.  Also, it can help keep you from losing bone density and muscle mass – and this, in turn, can help prevent falls and fractures.

Note: For more information on the FIERCE trial, call 877-DF-TRIAL (877-338-7425).

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

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 RingI’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 menWe 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

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

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