Rethinking Metastasis

News flash:  It’s a spectrumAll metastasis is not alike, and the basic category of “metastatic prostate cancer” is being redefined by doctors and scientists even as we speak.  In fact, 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.

That makes sense, right?  And yet, 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 therapyandrogen 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., discussed here.   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?

Earlier this year, 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.  The man 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 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.”

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 with other physician-researchers 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?

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.”

Janet Worthington
Janet Farrar Worthington is an award-winning science writer and has written and edited numerous health publications and contributed to several other medical books. In addition to writing on medicine, Janet also writes about her family, her former life on a farm in Virginia, her desire to own more chickens, and whichever dog is eyeing the dinner dish.

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