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Cancer’s Sweet Tooth

Cancer loves sugar, and sugar really loves cancer.  Isn’t that sweet?  Actually, no, it’s more like a match made in hell – because sugar (glucose) makes many types of cancer grow faster.

Scientists have long known that cancers soak up glucose like a sponge; in fact, German physiologist Otto Warburg, who found that tumors extract glucose at a rate 20 to 50 times higher than do normal cells, won the 1931 Nobel Prize for for his research on metabolism.  Lew Cantley told me that.  Cantley, Ph.D., is a world-renowned scientist and Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.  I recently interviewed him for the Prostate Cancer Foundation’s website, pcf.org.

Cantley has spent much of his career studying the interplay between sugar and cancer.  His studies suggest that it’s not so much the amount of glucose in your bloodstream that helps promote cancer, as it is the level of insulin, the hormone made by the pancreas that controls glucose.  Insulin helps turn glucose into immediate energy, and also helps your body pack it away for longer-term storage.  Briefly, when you eat, your blood sugar goes up; this causes your pancreas to say, “Hey! We need to make more insulin!”  Insulin, like Paul Revere, then travels rapidly throughout the land, telling the cells to let the glucose in, either to be used right away or saved in muscles, fat cells, and the liver.

Why does a tumor suck up more glucose?  “The main reason,” says Cantley, “is that insulin can turn on the glucose transporters (proteins on cell membranes that carry glucose into cells), similar to those in the liver, muscle and fat.  The presence of those glucose transporters on tumor cells is in part regulated by insulin.  That’s why I keep focusing on the insulin.”

Cantley began studying the insulin receptor in the 1980s, when he was on the faculty at Harvard University.  A few years later, after moving to Tufts University, he discovered an enzyme called phosphoinositide-3-kinase (PI3K); PI3K signals cells that insulin is present; the cells, in turn, open the valve that lets in sugar.  Normally, PI3K does good and vital work, helping cells survive, grow and proliferate.  But sometimes it goes awry; in Type II diabetes, this PI3K pathway becomes sluggish, cells don’t respond appropriately to insulin and become insulin-resistant.  But in cancer, even in someone who’s insulin-resistant, PI3K does its job too well; glucose floods in, tumor cells feast on sugar and grow faster.  “What we now know is that mutations in the PI3K pathway make tumor cells hyperactive in response to insulin.”

In many cancers – sugar-loving cancers; not all cancers are addicted to sugar, but many are – PI3K is like a power switch that drives growth.  “PI3K is the most frequently mutated cancer-promoting gene in humans,” says Cantley.  It may be involved in as many as 80 percent of cancers, including breast cancer, bladder cancer, and certain brain tumors.

What about prostate cancer?  Well, one of the most common genetic events in prostate cancer is the loss of a gene called PTEN; cancer just knocks this gene out.  “PTEN makes an enzyme that reverses what PI3K does.  PI3K makes a lipid, and PTEN destroys that lipid; you have to have a balance between those two enzymes to keep growth under control.  But in prostate cancer, and in breast cancer , the loss of PTEN activates production of this lipid that drives cell growth.

“This tells us we probably should try to keep insulin levels as low as possible if we have cancer, to try to keep the tumor from growing.   If we can keep the diet under control, or exercise to keep glucose levels and insulin levels low, we have a much better chance of slower growth of the tumor.  Our research would also argue that pharmacological intervention would be more effective if we keep insulin levels low.”

Even better:  Keep insulin levels as low as possible anyway, whether you have cancer or not.  “This is a powerful potential cancer-prevention mechanism,” says Howard Soule, Ph.D., Executive Vice President and Chief Science Officer for the PCF.  “Reducing processed sugar may turn out to be even more important for cancer prevention than treatment.”

Can we learn to use cancer’s sweet tooth as a weapon against it?  Cantley’s research has already led to the development of several PI3K-inhibiting drugs: idelalisib, approved by the FDA in 2014 for treatment of lymphoma and leukemia and alpelisib, approved in 2019 for treating breast cancers with mutations in PI3K.  But Cantley also believes that changing the diet – to one low in sugar, but also low in other carbohydrates, which can cause blood sugar to spike – can make cancer-fighting treatments work even better.  In a landmark 2018 paper published in Nature, Cantley and colleagues showed in mice that by severely restricting carbohydrates “and keeping the insulin level low, tumors would respond much more dramatically to drugs that are already approved to treat them.  Tumors we had never been able to shrink in mice, we could shrink with a low-glucose diet.

“That’s my obsession now, to get that message out there.  Endocrinologists tell patients to exercise more and eat less sugar to keep diabetes under control, but for me, it’s even more critical to keep insulin levels low in order to get better outcomes for cancer patients.”  Cantley’s research suggests that “if you have a mutation in the PI3K pathway that causes cancer, and you’re eating a lot of simple carbohydrates, every time your insulin goes up, it’s making the tumor grow.”

How can this knowledge help slow the growth of prostate cancer?  Here’s one example:  “For prostate cancer patients with low Gleason scores who are on active surveillance, it makes perfect sense to pay a lot of attention to what you eat.  Try to keep your consumption of sugary drinks as low as possible.  Keeping sugar down is the best thing you can possibly do.”  It used to be, Cantley notes, Japanese men hardly ever got prostate cancer.  “But second-generation Japanese Americans have prostate cancer in similar rates to Caucasians.  It’s clearly lifestyle,” the Western diet.  “The truth probably is that some Japanese men in their 90s had some level of prostate cancer, but didn’t consume enough sugar for the cancer to advance.”

Here’s another:  If you are on ADT for metastatic prostate cancer, you are more likely to gain weight, and also to develop insulin resistance.  One way to fight this is by limiting your sugar and simple-to-digest carbs.  Bonus: keeping insulin down may also help slow down the cancer.  Watch out for protein drinks, too; many are loaded with sugar.

What about the ketogenic diet?  It’s low in carbs and high in fats.  “I’m not preaching the ketogenic diet; I don’t eat it myself,” says Cantley, who says he weighs the same now as he did in high school.  “I eat what my grandparents ate:  a healthy diet, lots of raw vegetables, some animal fat, healthy vegetable fats, an intermediate amount of protein.  I don’t avoid fats, but I prefer olive oil on salads, and healthy fats from fish and avocado,” instead of loading up on butter and cheese.  “I eat more protein than the ketogenic diet would recommend, and I do occasionally eat rice and pasta.”

But here’s the kicker:  “The one thing I’m fanatic about is not drinking anything with sugar:  no orange juice, no apple juice, no soda.  I’ll eat an orange, but I won’t grind it up and drink it.”  Sugar in liquid form is rapidly digested, which results in “glucose peaks, followed by insulin peaks.”

What about alcohol?  “A dry martini is probably safer than wine; there’s not much sugar in there.”  However, Cantley adds, “I do drink wine, but as low in sugar as possible.”

Exercise is a great way to divert sugar into someplace safe:  the muscles.  “Muscle is where you store a lot of sugar in your body.  If you drink a sugary drink after exercising, your insulin goes up, and you drive all that glucose into your muscle.  Whether you’re exercising at the time you drink a sugary drink, or you just put on muscle from exercise in general, there’s still a benefit: insulin won’t spike.”   However, exercise doesn’t make it safer to drink a lot of sugary drinks, because…

Sugary drinks are bad.  It’s not just sodas; sweet teas and coffee drinks have more sugar than you may realize.  Even sports drinks are loaded with sugar.  In 2019, Cantley and colleagues published another landmark paper in Science, involving mice with polyposis syndrome (mice genetically predisposed to developing polyps in the colon).  They demonstrated that sugary drinks can dramatically drive the growth of intestinal polyps.  “We gave mice high-fructose corn syrup, and their polyps grew two to three times faster.”  Fructose is a different sugar from glucose, and although “fructose is not consumed by tumors, it goes straight to the liver and turns into fat.  Fructose makes you fat.  But the other issue is that intestinal epithelial cells can directly consume fructose.  We think this explains why there has been a doubling to tripling rate of colorectal cancer in young adults.”

Consuming sugar in liquid form is worse than having that same amount of sugar in solid form.  Cantley explains:  “If you eat an apple, it takes a long time to get to the colon.  By the time it gets there, all that sugar has leached out.  But if you have that same amount of sugar in a drink, that watery sugar gets to the colon pretty quickly.  That’s independent of the insulin elevation (discussed above), and it’s another scary reason why young people should avoid drinking sugary drinks, no matter how much you exercise.  You may be a champion marathon runner, but if you’re drinking sugary drinks all the time to keep up your energy, this is a real warning that you should pay attention to.”

Now, back to prostate cancer:  Would taking a PI3K-inhibitor help slow cancer’s growth?  As is often the case with prostate cancer, it’s not that simple.  It turns out that there are two different kinds of PI3K, an alpha and a beta form that can contribute to prostate cancer.  “When prostate cancer loses PTEN, it uses PI3K alpha and beta form redundantly to drive the tumor.”  This means that a drug that targets only the alpha form probably won’t be as effective in prostate cancer as in other forms of cancer, where only the alpha form of PI3K is involved.

However, “our preclinical findings are overwhelmingly supportive, and the retrospective data in patients strongly suggests” that one day, in addition to surgery, radiation, hormonal therapy or other treatments for prostate cancer, patients will be prescribed a precision diet to make the treatment more successful.  “The more we learn about cancer metabolism, we are understanding that cancers are addicted to particular things.  For many cancers, that thing is sugar.”

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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COVID-19 and Male Hormones: What’s the Connection?

Why has the COVID-19 virus killed many more men than women?  What does the virus have to do with male hormones?  Well, quite a lot, it turns out, and a lot of what scientists now know about this male hormone (androgen)-virus interaction comes from scientists studying prostate cancer.  Scientists whose research happens to have been funded by the Prostate Cancer Foundation (PCF).

Suddenly, the genetics of prostate cancer have also become the key to finding new treatments for this terrible coronavirus.  I write for the PCF’s website, so I’ve been lucky enough to learn about some of this research from the scientists first-hand.

It all has to do with genes and proteins:  That’s how the virus sneaks into the nose, throat and lungs, and does its evil work; how it enters the cells in the airway and starts reproducing like crazy, causing the cells to burst open.  The explosion of respiratory cells causes terrible inflammation, swelling, and congestion.  Worse, oxygen can’t get into the bloodstream.  This devastation can result in a ventilator in the ICU, or in death.

Think of this nasty virus as a con man who looks normal – like Fred MacMurray as Steve Douglas, the beloved dad in “My Three Sons.”  He seems benign, and he walks right into your house through your front door.  But oh, no! It’s actually Fred MacMurray as Walter Neff, the murderous insurance salesman in the iconic film noir, Double Indemnity!  By the time you realize he’s a bad guy, it’s too late! You’re in trouble.

COVID-19 does the same thing.  It attaches itself to a certain receptor called ACE2, which then tells cells, “This guy’s legit.  Let him in.”  ACE2 is the doorknob; that’s how the virus enters cells in the nose, airway and lung.

What does this have to do with prostate cancer?  The specific gene that makes it possible for the virus to grab onto ACE2 and keep entering and killing respiratory cells is called TMPRSS2.  PCF-funded scientists have studied this gene extensively in prostate cancer since 1988.  They know, from 32 years of research, what controls the TMPRSS2 gene that unlocks the receptor that lets in the virus:  androgens (male hormones).  TMPRSS2 is an androgen receptor-controlled gene.  

            Scientists believe they can stop the virus’s attack on the body by targeting TMPRSS2.

“In about half of all prostate cancer patients, TMPRSS2 is involved in a genetic event that can drive prostate cancer,” PCF-funded investigator Matthew Rettig, M.D., told me in a recent interview.  Rettig is a medical oncologist at UCLA and Chief of Hematology and Oncology at the VA Greater Los Angeles Healthcare System.  “The gene is tightly regulated by male hormones in prostate cancer.”  Male hormones, primarily testosterone, activate the androgen receptor and cause more TMRPRSS2 to be available on the surface of cells for the virus to enter.  “The question is, does TMPRSS2 in lung tissue behave in the same fashion as it does in prostate tissue?  We have good, correlative evidence that it does.

One way to do it is to shut down testosterone for a few weeks (being tested in TMPRSS2-targeted clinical trials discussed here, midway down the article).  “It turns out that if you suppress male hormones, that will suppress the production of the receptor,” Rettig says.  Basically, explains medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the PCF, “if you suppress male hormones, you reduce the total number of door handles the SARS virus can use to enter.”  Imagine evil, Double Indemnity Fred MacMurray, trying to get into the car where he commits the murder; there were no power door locks, so as he gets to each door, you push the lock down:  one, two, three, four!  You locked him out!

“Conversely,” says Rettig, “if you add male hormones to lung tissue, it will increase the expression of the receptor.  There is a lot of molecular/biochemical/scientific evidence that supports this concept: that the receptor for the virus is regulated in at least a similar manner in lung tissue as it is in prostate cancer tissue.”

Rettig continues:  “It is not a stretch for someone doing prostate cancer research to immediately see this connection and say, ‘Why don’t we temporarily suppress male hormones,” with available, FDA-approved drugs, “in male patients who are suffering from COVID-19, to see if we can immediately ameliorate the severity of the illness?’”

Don’t women have at least a small amount of testosterone?  “Yes,” notes Simons, “but while thousands of women have been infected, men are still more likely to become infected and die from COVID-19.”  Rettig adds:  “A striking study just reported that a huge proportion of women test positive who have no symptoms.  We think they actually may be protected by a combination of low androgens and high estrogen.  Work done by some of our colleagues at Columbia suggests that female hormones – estrogen and estrodiol – actually suppress the expression of the receptor.”  Then why not give estrogen to men?  “It does seem to suppress the receptor, but when it’s first given, in the first few hours,” there’s a temporary backlash, “a transient rise in the expression of the receptor that could make the disease more severe.”

This begs another question, and the answer has changed since I first interviewed Rettig a few weeks ago.  I asked him:  If shutting down the male hormones can stop the virus from invading the lungs, are men who are on androgen deprivation therapy (ADT) for prostate cancer protected?  He said, “Nobody knows yet.”  And that was true.  But since that time, another PCF-funded study of men with prostate cancer in Italy found that men who were on ADT were four times less likely to be infected with the coronavirus than men who were not on ADT, and five times less likely to die.  You can read about that here. And another approach, also being tested in clinical trials, involves a drug used in Japan to treat pancreatitis.  It is also a TMPRSS2-blocker.

It is amazing that in a matter of weeks, scientists have learned so much about this virus, including good potential avenues for treating it.

 

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

 

 ©Janet Farrar Worthington

 

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Whack-a-Mole and Prostate Cancer

Oligometastasis:  Good News from the ORIOLE Study

To the growing and hopeful list of strategies for attacking prostate cancer, let us add this approach:  Whack-a-Mole.

That’s how Johns Hopkins radiation oncologist Phuoc Tran, M.D., Ph.D., describes it to his patients.  The actual scientific name for this highly sophisticated strategy is stereotactic ablative radiotherapy (SABR, highly focused, intense doses of radiation), for men with oligometastasis – up to three small bits of cancer that have broken away from the main prostate tumor and started to grow elsewhere.

Previously, I wrote on Vital Jake and also on the Prostate Cancer Foundation’s website, about the Baltimore ORIOLE study, led by Tran, who also contributed greatly to our book.  Tran was enrolling patients in a small study to see if men with oligometastasis would benefit from SABR in addition to treatment of their primary tumor.

His strategy was a new one – part of a general rethinking of what represents curable prostate cancer.  The boundary used to be very clear:  prostate cancer was either confined to the prostate or prostate bed, or it wasn’t.   Like a light switch with no dimmer, there was no in-between:  a man with only one metastasis was believed to face the same fate, eventually, as a man with widespread metastases.  It was just a matter of time.

But Tran believed that the lines of prostate cancer were not so clear-cut as scientists had assumed; that instead of two circles – localized and metastatic cancer – that didn’t connect, we might be dealing with a Venn diagram, with oligometastasis as the critical area where the two circles overlap.  “It may be that the window of curability is wider than we thought,” he said last year, and we all hoped that he was right.

Tran and colleagues at Johns Hopkins, Stanford, and Thomas Jefferson University recently published results of the ORIOLE Phase 2 clinical trial in JAMA Oncology.  The results are promising:  54 men with oligometastasis were randomly assigned either to treatment with SABR or to observation.  To detect and keep track of the oligometastases, the study used PSMA-PET scanning, which uses a small molecule linked to PSMA (prostate-specific membrane antigen, found on the surface of prostate cancer cells) as a radioactive tracer.  This PSMA-targeting tracer can highlight areas of cancer as small as a BB – much smaller than can be seen on regular PET or CT imaging.  “PSMA-PET allows us to treat lesions we otherwise couldn’t see,” Tran explains.  “A CT or bone scan would miss those lesions, and patients would presumably not do as well.”

At six months, 61 percent of the men in the observation group progressed – compared to only 19 percent of the men who received SABR.  “We also saw a significantly decreased risk of new metastatic lesions using PSMA PET-CT” says Tran.  “The men in the SABR group did considerably better.  This is a definite signal that we can perhaps modify metastatic disease.”

This was a Phase 2 study, and “we need larger Phase 3 trials,” he says.  “But this is very positive, and we hope that in the future, we will be able to change the course of metastatic disease in some men.” 

Some interesting points here:  First, Tran and colleagues hope that “complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).”  The key question, Tran says, is, “can we alter the natural history of metastatic prostate cancer with metastasis-directed therapy (MDT)?”  They don’t know the answer yet.  Most men with oligometastatic disease who get these spots of cancer zapped don’t experience a complete drop in PSA.  This, Tran says, suggests that “residual micrometastases are present but undetectable.” Does SABR simply reset the clock – does it keep pushing the snooze button?  Or, as the scientists hope, does it make the cancer less likely to form new metastases?

Bad Pioneers on a Bad Journey:  Tran and other scientists theorize that the spread of cancer is a story of colonization.  A few pioneers set forth on a journey to a new land.  At first, it’s touch-and-go; their survival is tenuous.  Just think of the early colonists in the U.S., from England, France, or Spain.  Until they took root in the new land, these nascent colonies were frail:  they needed reinforcements from their mother countries – medicine, weapons, tools, food – and “eventually they did survive.”  So it may be with the seeds of cancer; either the cancer cells themselves, or their messages (in the form of genetic and chemical telegrams) are dispatched to the primary tumor, the mother country.  If the mother country is no more – if it has been eradicated by surgery or radiation – then small cancer outposts might get similar support from visiting each other.  But if those outposts are destroyed by SABR, even if there are a few cancer cells remaining in the tissue or bloodstream, it doesn’t matter:  the environment is too hostile, and the numbers are too few for new colonies to survive – “or, if they did, it would take much longer.”

“It’s like Whack-a-Mole”:  In the ORIOLE trial, Tran and colleagues looked for circulating tumor DNA (ctDNA), and identified certain gene signatures that can tell if a man is more likely to respond to SABR.  “Patients who don’t have these mutations responded very well,” he says.  They also have learned from this and other research that men with oligometastasis fall into three basic groups.  “Some men do really well after one course of SABR,” with no recurrence of cancer.  A second group of men have a small recurrence.  “Another site pops up; a microscopic metastasis that we couldn’t see before establishes itself into a macroscopic metastasis.  It’s a limited return of cancer and it responds to another round of SABR.”  Then some men, after a few months, have multiple new areas of cancer.  “For these men, the SABR doesn’t control the disease at all.”

Imagine a green lawn, with one or two dandelions, Tran tells his patients:  “You can pluck those two or three weeds, and wait and see.  Sometimes you get lucky; sometimes another weed or two pops up, and you pluck them.  It’s like Whack-a-Mole.  You can do that for a while,” with repeated SABR treatments.  As the scientists reported:  “If a single round of MDT arrests the progression of some, but not all, lesions, subsequent rounds of MDT might salvage the remaining disease, until what remains is inadequate to support a metastatic phenotype.” Basically, for some men, a treatment strategy might be to keep knocking the cancer down until, like a prizefighter who’s taken one too many blows to the head, it can’t get back up.  Imagine:  punch-drunk prostate cancer that may still be staggering around, but can’t raise a fist.  Wouldn’t that be nice!

That probably won’t work in every man, Tran says.  “Unfortunately, sometimes there will be a whole bunch of seeds all at once, and at that point, you need weed killer all over the lawn,” or systemic therapy.  However, SABR plus ADT, androgen-blocking drugs, or chemo might one day provide “the multipronged attack required to cure this disease.”

Looking ahead:  In a follow-up trial, called RAVENS, men with oligomestatic prostate cancer are randomly given either SABR alone, or SABR plus radium-223 (Xofigo).  “What we have seen in the men in that second group – the ones who have more isolated spots of cancer popping up – is, they’re not recurring where they received the SABR, but in areas that were microscopic, and commonly in the bone.”  Radium-223 targets cancer in bone.  “It releases a radioactive particle that is very toxic but is so focused that it only kills in a radius of two-three cell depths.  It’s ideal for microscopic disease.”

More and larger studies are needed, but in the future, Tran envisions, men with oligometastasis will require more vigilant monitoring, and ideally, regular follow-up PSMA-PET scanning.  “This has the potential to be practice-changing.  We are very excited by our results, and by the potential to modulate the course of metastatic prostate cancer.”

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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The Other Survivors

When it comes to disrupting your life, prostate cancer cuts quite the swath.   We don’t know exactly how big this trail of disruption is.  We don’t know how bad it is, either.

Let’s start with the numbers.  In the U.S. alone, there are more than 3 million men out there who are prostate cancer survivors.  Although we can speculate, we don’t know exactly what these guys are going through; everybody’s experience is different.  It doesn’t help, either, that many men are reluctant to discuss the side effects of treatment.

But these men are just the tip of the iceberg.  An estimated 73 percent of men aged 65 to 80 are married or have partners, says New York University urologist Stacy Loeb, M.D.  “It’s safe to say that if there are more than 3 million prostate cancer survivors and approximately three-fourths of them are partnered, that’s a lot of people who are being affected by this disease.”

And hardly anybody knows what these wives and partners are experiencing; in part, because hardly anybody has asked them.  Loeb and colleagues are hoping to shine some light on these other survivors.  Loeb was first author of a study recently published in the Journal of Sexual Medicine, called, “A Call to Arms: Increasing our Understanding of the Impact of Prostate Cancer on the Sexual Health of Partners.”  I recently interviewed her for the Prostate Cancer Foundation’s website.

Loeb and colleagues found that sexual disruption for these couples often starts with biopsy!  “One of the potential effects of sampling the prostate with needles is blood in the semen, which can be off-putting to both patients and their partners.  It usually doesn’t last more than a few weeks, and it’s not medically dangerous. “However, seeing blood can certainly be disruptive of the sexual encounter – so even from the process of diagnosing prostate cancer, there can be an impact on sexual health for the couple.  There is controversy over whether biopsies – or repeated biopsies – are associated with erectile dysfunction (ED).”  Some evidence suggests that undergoing multiple biopsies can cause scar tissue to develop in the nerves responsible for erection, but the medical literature is “a bit conflicting, Loeb says.  It’s also difficult to study, because many men getting multiple prostate biopsies are also getting older, and have other health conditions that can affect sexual health.

And that’s just diagnosis of prostate cancer.  “All forms of prostate cancer treatment can have a potential impact on sexual health,” says Loeb.   For example:  “With surgery, the greatest insult to the body is at the beginning, and then function can gradually recover over time.  With radiation, ED can take several years to develop.”  But what about the men – and there are thousands each year – whose cancer requires more than one form of treatment?

“Surveys from both the U.S. and the UK show that many men who undergo various forms of prostate cancer treatment have sexual complaints,” says Loeb.  “However, many of them are not getting any treatment for their ED or other issues.  This really has a huge impact for the partner.  ED is one of many possible sexual consequences.  Penile curvature (Peyronie’s disease) is another.  There’s the potential for penile shortening (note: use of a vacuum erection device to stretch the penis can help prevent this) and there are issues with libido.” Men who have had prostatectomy may also struggle with urinary incontinence, and some may experience sexual incontinence (leaking urine during sex).  “There are changes in orgasm after prostate cancer treatment, as well,” Loeb adds.

Men who undergo short- or long-term androgen deprivation therapy (ADT) experience a loss of libido and complications including gynecomastia (breast swelling; this can be treated with radiation).  Does this affect their partners?  Of course!  But by how much, nobody knows.  The doctor visits are typically “focused on the patient,” says Loeb.  “There’s a significant unmet need for greater support for partners.”

Many prostate cancer treatment centers offer their patients help with penile rehabilitation for recovery of sexual function.  “In some practices, there is a different urologist, nurse practitioner, or physician assistant who manages sexual health issues than the urologist who did the surgery, whose main expertise is in cancer control.”  The good news is that sexual medicine subspecialists can provide a lot of help.  The not-so-good news is that many men don’t take advantage of what these experts can offer.  There’s still a lot of stigma.  In the study, Loeb and colleagues found that a significant number of patients were not seeking help with sexual recovery.  Shame or unwillingness to discuss sexual issues may account for some of the reluctance; another barrier may be financial.  “Some of the treatments are very expensive.”  For example, erection-assisting drugs can be expensive, and many insurance plans don’t offer reimbursement for a VED (although the Veterans Administration does cover VEDs).

The other not-so-good news is that “there’s a lot of work to be done with the partners, defining their experience and the unmet needs that they have, and finding ways to provide additional support to them.”

In one way, these survivorship issues are a good sign – they’re happening because more men with localized disease are being cured of prostate cancer, and more men with cancer that has escaped the prostate are living for many years, says Loeb.  “But what comes with that is having a large pool of survivors who are living for years with the impact of the disease.  This impact does not only affect the patients, but also the people around them.”  In the study, some of the partners described “problems with relationship dynamics,” arguments or the opposite: isolation.  “They feel they can’t discuss it with their partner.”  Some describe making changes, like using a certain type of condom to deal with sexual incontinence.  “In some cases, there’s a real feeling of grief; people feel cut off from their partner, and they can’t discuss some of the sexual issues easily. There really is a great need for more research in this area, and help for the partners of prostate cancer patients.” Many of the partners, by the way, may be having sexual health issues of their own, including going through menopause.

So:  Men, be kind to your partners.  They’ve been through a lot with you.  Even though it’s not in their bodies, it’s their cancer, too.  

All of this said, I just want to add a personal note:  As the wife of a prostate cancer survivor, I‘m just so happy, and so very grateful, that the cancer is gone!  This doesn’t mean the recovery hasn’t been a drag; it has.  But that weight of fear that felt so crippling, for me at least, was much worse.  

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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OMG!  My Treatment is Delayed! 

So, you’ve got localized prostate cancer, you’ve decided to get it treated with either surgery or radiation, and you have steeled yourself to just bite the bullet and get on with it.

You’ve been through a lot already: the PSA and physical exam, the biopsy, and just coming to terms with the fact that you have prostate cancer.   You did your research, decided on the right treatment, found a good doctor, and you’re all ready to go – and, looking past the treatment and recovery, you’re looking forward to getting on with the rest of your life.

And now there’s a global pandemic.  OMG! 

At many hospitals around the country, non-emergency procedures have been bumped, including treatment for localized prostate cancer.  And maybe you’re feeling a little stressed by this, or even flat-out panicky, thinking that cancer’s ticking away inside your body like a time bomb – or like the creature that burst out of John Hurt’s chest in “Alien.”  You’re not alone.  I recently wrote about this for the Prostate Cancer Foundation’s website, pcf.org., because so many men are worried about treatment delays.

Hold up there, friend:  a few weeks is not going to mean that your golden opportunity for a cure has closed.  Let’s take a deep breath and think about this:

First, nobody, ever, has instant treatment for localized prostate cancer.   The reason is that your prostate must heal after the supreme insult of having multiple needles stuck in there and little bits of tissue removed.  After the biopsy, the prostate is riddled with tiny holes – like perforated paper.  And, like perforated paper, it’s easier to tear, which means it will be more difficult to remove that damaged tissue in surgery.  Also, it’s inflamed; it’s not going to respond the same way to radiation, and it’s going to be a lot more difficult for a surgeon to operate.  If there’s swelling, or if the tissue inside the prostate is adherent to the rectum – a common, temporary occurrence after biopsy – the surgeon may inadvertently leave cancer cells behind.   The inflammation needs to heal and the punctures need to heal.   That’s why you have to wait a minimum of six to eight weeks after biopsy before you can get surgery or radiation.

“We have studied hundreds of patients who underwent surgery and evaluated the delay between diagnosis and cure,” says my longtime coauthor, Johns Hopkins urologist Patrick Walsh, M.D.  “With long follow-up, we found no significant difference in the 10-year cancer control rates of these men.”  This is reassuring: “There is no immediate urgency to perform surgery after you are diagnosed with prostate cancer, especially if you have stage T1c disease and a biopsy Gleason score lower than 7.”

Second:  every single statistic about men being cured of prostate cancer you’ve ever seen:  those men all had to wait a few weeks or months, and they did great!  Many of those men got repeat biopsies.  They got second opinions.  They took their sweet time just wrapping their minds around the fact that they had cancer.  They still had their cancer cured.  If you were diagnosed by a change in PSA, here’s more good news:  PSA screening has given us a five- to ten-year lead time in diagnosis.  It used to be that prostate cancer wasn’t diagnosed until it had grown big enough to be felt in an exam, or until it caused symptoms.  You’re already ahead of the game!

Third, the average prostate tumor at diagnosis has been growing for years.  Prostate cancer tends to grow very slowly within the prostate.  It has a slow doubling time.  So, even if it’s an aggressive cancer that needs to be treated, just remember:  that sucker has been in percolating away in there for a long time.  It’s not going to suddenly take off and sprint out of the prostate in the next few weeks.  You are going to get it treated; it’s just not exactly when you planned.

Two more things to consider:  Stress is bad for the prostate.  Worrying about not getting your treatment right away is not good for you.  And finally, you may want to take advantage of this brief delay to lose a few pounds.  The prostate is not terribly accessible in the best of situations, because of its location deep in the pelvis.  If you have a lot of belly fat, it can make it more difficult for a surgeon to perform a good cancer operation, preserve urinary control, and preserve potency.  “The best advice I can give an overweight man seeking radical prostatectomy is to lose weight through a healthy program of diet and exercise,” says Edward Schaeffer, M.D., Ph.D., contributor to our book and director of urology at Northwestern University.  “For those who are severely overweight, robotic surgery is extremely challenging and should be performed only by experienced surgeons.  In men who are very overweight or morbidly obese, it can be very difficult for the anesthesiologist to ventilate the lungs because of the weight of the abdomen pressing on the diaphragm.”  If this applies to you, your best bet – besides having an experienced surgeon – is to take this time to change your diet and get some exercise.

And don’t despair!

 

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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Stress and Prostate Cancer

Here we are in a global pandemic; we’re all stressed, and we all need to fight it.  If you have prostate cancer, you need to fight it even harder, because the stress hormone, cortisol, may be affecting your cancer, AND because lowering your stress may help your cancer respond better to treatment.  

Having prostate cancer is stressful, even today, when there is more hope of successful treatment than ever before.  But it’s not just the cancer itself.  It’s the hassle of wrangling with an insurance company, and the worry about medical bills or taking time off for treatment; it’s frustration over a slower-than-expected recovery of urinary continence or sexual potency.  It’s anxiety about the next PSA test.  It’s unanswered questions and uncertainty, and worry that life will never get back to normal.  Yes, there’s stress, and plenty of it.    

Does stress make prostate cancer worse?  This one’s not so easy to answer.  “Everybody has an individual response to stress,” says medical oncologist Suzanne Conzen, M.D., Chief of Hematology and Oncology at the University of Texas Southwestern Medical Center in Dallas.  And that’s the key, she adds:  it’s not so much the stress itself but the physiological response that can take a toll, and that may hinder our ability to fight cancer.  Conzen is studying stress pathways in cancers, including prostate cancer.  I recently interviewed her for the Prostate Cancer Foundation (PCF), which is funding some of this research.

The body responds to stress with a surge of corticosteroids; primarily cortisol.  When our ancient ancestors were running for their lives from a savage beast, it was this stress hormone, cortisol – along with adrenaline – that kicked in and saved their bacon.  “We are hard-wired to respond to stress with this ‘fight or flight’ response.”  Unfortunately, many of us react to everyday troubles with the same surge of stress hormone as if we were facing a sabertooth tiger – as if we were under attack.  Our hypothalamus, located in the most primitive part of the brain, tells our adrenal glands, “This is the big one! Go to Defcon 3.”  And cortisol, revving up in its effort to save us – a chemical version of someone running around in a panic, shouting, “Ohmygod, ohmygod,” can cause harm instead, affecting normal functions including the immune system, and even changing genes that are expressed in cancer cells.

“Some people have a higher stress response than others.  It could be an inherited tendency; or they haven’t necessarily developed effective ways of coping with exposure to stressors,” says Conzen.  “However, not all people who have a high stress response get cancer; and a lot of people are under stress and don’t get cancer.  But that’s the complexity: not everybody who smokes gets lung cancer, but smoking is a risk factor.  What you want to do is reduce your risk factors,” and your response to stress – like a bad diet, or smoking, or being overweight – is a risk factor for prostate cancer that can be changed.

“We think high cortisol levels are probably not a good thing in men who have prostate cancer.  At least a subset of those men may have tumors that respond to high levels of stress because the prostate cancer expresses a protein, the glucocorticoid receptor (GR), that is activated by cortisol,” and although Conzen is working on how to determine who these men are, right now, there’s no way to know for sure.

Cortisol, a hormone, attaches to a protein called the glucocorticoid receptor (GR) in cells throughout your body, and this is like flipping a switch that activates stress in all those cells, including cancer cells.  In ovarian cancer, Conzen has shown, higher levels of these receptors in the tumor tissue are linked to more aggressive, even lethal, disease.  And in prostate cancer, she has found that the GR “is more highly expressed in cancer that is resistant to androgen deprivation therapy (ADT).”

But it’s complicated, she adds:  “We think it’s not only how much GR your tumor has, it’s how active it is.”  With PCF funding, Conzen and colleagues in her lab are working to find a way to measure how active cortisol and GR are in a prostate tumor, “whether it’s turning on and off a lot of genes, or just a few genes.  The amount of GR does not necessarily correlate with the activity of the protein.”

So, how to fix it – if a man has aggressive prostate cancer, and high cortisol/glucocorticoid receptor activity?  “One hypothesis would be, deprive that tumor of your body’s stress hormone receptor activity, by keeping the stress hormones relatively low.”  This could happen with some type of medication – or, it could happen with stress reduction.  What is that, exactly?  It could mean making changes in your life, so there are fewer stressful factors in it.   It also could mean making changes in you – with the help of such things as exercise, yoga, meditation, and counseling, and other things to help reduce stress, like having a pet, and reaching out to family, friends or a support group, so you’re not coping with this alone.

Note:  Conzen does not believe that stress, all by itself, causes prostate cancer.  “My guess is that GR-mediated stress signaling in the tumor cells probably has more to do with promoting aggressiveness and progression of cancer,” and perhaps recurrence of cancer.   When Conzen talks about stress, she doesn’t mean a single traumatic incident, such as a car crash:  “The kind of stress we’re talking about is daily unremitting stress.”  Those countless little things that add up, day after day.

Also with PCF funding, Conzen and colleagues are working to identify which genes in prostate cancer cells are involved with the stress response, and what those genes are doing when the tumor cell GR is activated in a man who already has prostate cancer.  “If we knew that, we would know when it would be useful to give a drug (a GR-modulator) to block it,” especially if they could find a drug that would only work in prostate cancer cells.  Glucocorticoid receptors are expressed in a subset (about 20 percent) of castration-resistant prostate cancer.  Conzen and colleagues have initiated clinical trials testing GR-modulating drugs in breast cancer, prostate cancer, and other cancers. In advanced prostate cancer, there are at least three ongoing clinical trials testing GR-modulators: 1) enzalutamide alone vs. with the GR-modulator mifepristone; 2) the GR-modulator CORT125134 plus enzalutamide; and 3) the GR-modulator CORT125181 plus enzalutamide.

In the meantime, stress reduction may help achieve similar results for men with prostate cancer, by lowering circulating cortisol activity.  Clinical trials are needed, Conzen notes, to show the effectiveness of stress response-reducing measures including cognitive behavioral therapy, medication, yoga, and mindfulness in prostate cancer patients.  Such trials have been done in breast cancer, she says, “and have shown that there is a beneficial effect.”

 

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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Surgery, Radiation, and Resiliency

 

You’re minding your own business and happily living your life, as most of us are when there is a diagnosis of cancer.  What do you do now?

For Ric Siler, an actor and writer who was diagnosed with prostate cancer at age 64, the easy answer is that he went to Italy and wrote a one-act play that beautifully combines both of these life-changing journeys.  He has performed it in the New York area and a reading of it here.  His message is resiliency — a timely message for all of us, as I’m writing this during the global pandemic.

I was lucky enough to interview Ric for the Prostate Cancer Foundation’s website, pcf.org, and we have stayed in touch.  Ric did what many doctors believe is the most important thing you can do in a medical crisis:  he remained upbeat.  He practiced gratitude – for his wife and daughter, for a chance conversation that resulted in finding just the right surgeon, for the kindness and support of friends and the many medical professionals he would soon come to know, and especially for the beauty of nature and art, which he began noticing all the time.  He also kept his sense of humor.

Why does attitude matter?  Nobody understands the mind-body connection completely, but scientist Suzanne Conzen, M.D., has shown that stress involves the same pathways as cancer.  The stress hormone is cortisol, and just about every single cell in our bodies has a receptor for cortisol (this is called the glucocorticoid receptor, or GR).  There are many important implications to her work, but one of them is that decreasing stress lowers cortisol, and this can slow the growth of cancer.

Out of the blue:  When Ric’s prostate cancer was diagnosed, in June 2018, “I had no symptoms,” Ric says, “no idea that anything was wrong.  I had gone to my doctor for something completely unrelated, and he said, ‘We haven’t taken your blood for a while.  Maybe we should.’”  It turns out that in a year and a half, Ric’s PSA had doubled, from 4 to 8.

He went to a urologist near his home, in Rockland County, New York, and didn’t much care for him.  “He did nothing to instill confidence; I didn’t feel right about him.  There were four doctors at the practice, so I picked the one who was, available.  Funny how that works.”  The biopsy came back: cancer was present in all 12 tissue samples, and his Gleason score was initially thought to be 8; it later turned out to be 9.

Ric’s daughter, Laurette, suggested that he get a second opinion.  “I hadn’t even thought of that,” says Ric.  But he didn’t know what to do, or how to find a good urologist.  “The next morning, I was working out at the Y,” and without realizing it, he networked.  The PCF recommends both of these strategies.  It is very important to find a doctor in whose clinical abilities you feel confident.  And networking – to find the right doctor, or to talk to men who are or have been in your same boat – can make a huge difference in how you approach your cancer treatment and look forward to your life after cancer.

Ric talked to his friends, Peter and Steve.  Steve said he knew men who had survived prostate cancer, and offered to ask around for a good surgeon.  And “Peter said, ‘Talk to Jerry.’  Jerry is the founder and CEO of the company Peter and I work for, and is a prostate cancer survivor.”  Ric talked to Jerry that same day.  “I saw Jerry in his office with the door open.  I asked if he had a minute,” and explained the situation.  “It just came out in a flood.  I hadn’t planned to be emotional;” in fact, “a sort of stoic resolve is usually my default mode.”  But Jerry understood, and said had felt the same way with his own diagnosis of prostate cancer.  “He said, ‘When I heard the news, I thought my life was over.’  And then he said, ‘A year from now, we’ll be laughing about it.’  It was great to talk to someone who had been in my shoes and come out the other side.  He offered any help, any time I needed to talk, and said, ‘You’ll do the same for people someday.’  Yes, I will.”

The next day, Steve texted Ric with a referral from one of his buddies to urologist Ash Tewari, M.D., at Mount Sinai.  “Time for a second opinion!  I was reading Don Quixote at the time, and I saw this quote the same day, a Latin phrase that translates into, ‘After the darkness, I hope for light.’”

While he waited to see Tewari, Ric, who had started to keep a written record about his experience, made a note of how he was feeling:  “Keeping it as normal and real as possible.  Not dwelling on it.  Staying positive, or trying my best to.  I never completely lose sight of what’s happening, but I am not letting it get me down.”

The date for the operation was September 17.  “I asked about the hospital stay, and he said that he did three surgeries yesterday, and they were all going home today!”  Ric recalls.  He mentioned the big trip to Italy, scheduled for November, that he and his wife, Bette, had been planning for years.   Tewari said it should be fine, and it turned out to be a wonderful trip.

Ric’s play, “How Do You Say Prostate in Italian?” covers what happened next in some detail:  the MRI, which had radio music piped in, including ad for Dunkin’ Donuts in between soothing classical music pieces; the hospital, where he was delighted to have a private room (“It could spoil a guy!”); walking the hospital floors after surgery, with his catheter, “pee bag,” and abdominal drain; important milestones, from passing gas after surgery to getting the catheter removed, to buying pads, getting biofeedback and learning to do Kegel exercises while he dealt with temporary urinary incontinence.  And it’s funny!  And enthusiastic, and full of gratitude.

Not so fast:  Ric’s PSA started to go up again after his surgery.  “I had thought I was out of the woods… not so fast, Kimosabe!  I had thought the PSA being elevated post-surgery meant that maybe there is cancer… nope.  It means yep, there’s cancer, and we have to deal with it.’”

Christmas of 2018 was a time for reflection.  Ric made a note:  “I’ve lived my life mostly feeling kind of indestructible, so it’s sobering to feel, well, destructible.  One thing that I know for sure as I sit here quietly with the dog and a beautiful tree with presents arrayed around it, under it and on it, and my wife and daughter sleeping peacefully upstairs, is that I want to be here next year to do it again, and the next and the next… and I’ll do whatever it takes to make that happen.”

Under the care of medical oncologist William Oh, M.D., and with the goal of “total eradication of the cancer,” Ric had a short course of hormonal therapy and eight weeks of external-beam radiation therapy, which had its own challenges.  When the eight weeks ended, Ric was surprised to find he had mixed feelings.  He wrote: “While the treatments have been happening, there has been a sense of rock-solid purpose.  We’re working together to eradicate this cancer.  I do my part by coming in with a full bladder, no gas and on time, and I get really good at it.  Now that it’s over, we have to wait six weeks – only then will we know for sure.  It’s all about PSA levels at this point.”  Laurette surprised him on his last day of treatment by showing up to ring the official bell – a rite of passage at many radiation therapy centers to say, “I made it through!”

Ric is cancer-free now, and getting on with the rest of his life.  “I was so fortunate,” he says.  “If I hadn’t mentioned my cancer to these guys at the Y, I wouldn’t have met Dr. Tewari,” and through Tewari, Dr. Oh.  “Everything fell together beautifully for me.  If I hadn’t gotten that blood test done, I’d be sitting here a year and a half later none the wiser, and the cancer would have continued to grow.

“The whole point of my play, aside from the personal reflections on living to see the art in Italy, and what it meant to me, and being here after this brush with cancer, is that early detection is really important.  You’ve got to get checkups regularly, and if something’s not right, you have to take the steps to see what’s wrong, go to the best people you can.  I wasn’t really going into this with any great message; I didn’t know what would come out of it or what the next step would be.  It is a cautionary tale for doing what you need to do, as soon as you can.  Silence is not golden when it comes to the prostate.”

Ric has not been silent; one man he spoke to about his experience said, ‘Wow, my wife wanted me to make an appointment with the doctor.  I didn’t go.  I’m going to do it right now.”  He hopes such encounters will be like “ripples in the pool,” men helping each other to be healthy.  When Jerry first told him that one day, he would laugh about his experiences, Ric didn’t believe him.  “I hoped he was right – and he is!  But it’s been quite a ride.”

Recently, Ric did a reading of his play in New York.  Afterward, a woman came up to him; her husband is a prostate cancer survivor.  “She took me aside and said, ‘This is very important, because men don’t talk about this stuff except in whispers.’”

 

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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