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

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

Rethinking Metastasis

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

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

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

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

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

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

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

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

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

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

It May Require the Proverbial Kitchen Sink

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

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

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

Two Icebergs

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

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

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

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

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

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

 ©Janet Farrar Worthington

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

©Janet Farrar Worthington