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Proactive Therapy: Widening the Window of Curability

Imagine you’re lying on a chair at the dentist’s office, and the dentist says, “You’ve got a cavity, and decay is inevitable.  We’ll just wait and pull all your teeth in a few years.” 

Like the poor gentleman in “Monty Python and the Holy Grail” who is mistakenly left for dead,” you might be thinking, “I feel fine!  I don’t want to go on the cart!”  

This is pretty much the way it’s been for men were treated for localized prostate cancer with surgery or radiation who have a rising PSA.   The options have been:  salvage radiation or surgery, maybe a short course of androgen deprivation therapy (ADT), a vaccine, maybe a clinical trial, and then… waiting for metastases, long-term ADT, and other forms of treatment. 

            That is changing.

It may be that the window of curability is wider than we thought.  Not too long ago, the dividing line between prostate cancer that was considered curable and cancer that might not be was the prostate itself – and whether the cancer was confined to the prostate or had spread beyond it to a distant site.  That’s not the case anymore, says Johns Hopkins radiation oncologist and Movember- and Prostate Cancer Foundation-funded scientist Phuoc Tran, M.D., Ph.D.

“Clinically speaking, we prescribe treatments for men with prostate cancer as though prostate cancer presents in clear clinical states,” he says.

Think of a Venn diagram:  in one circle are “men we believe to have purely localized disease, and they are curable by surgery or radiation.”  In the other circle are men with metastatic disease, men who are considered “treatable but not curable with our current therapies.  In general, this old treatment paradigm says that men with localized disease benefit mostly from local therapies like surgery and radiation and very little from systemic treatment like hormones and chemotherapy.”

But Tran and Hopkins colleagues are among scientists who believe these circles intersect.  New evidence suggests that in men with oligometastasis – just a few spots of cancer outside the prostate – by treating “not only the primary disease in the prostate or the pelvis, but also the few metastatic lesions, perhaps men can actually live a long time without disease progression and even be cured.”  It’s the difference between being reactive – waiting for the next shoe to drop, the rise in PSA or development of symptoms – and being proactive.  In other words: not just suspecting cancer is there, but knowing its precise location and going after it.

This is a dramatic and very exciting change in scientific thinking, and it’s happening because several key advances have come together all at once.  PSMA PET scanning now allows bits of cancer as small as a BB to be seen – and SBRT (stereotactic body radiation therapy) or SABR (stereotactic ablative radiation) make possible precision treatment. “SBRT and SABR are highly focused radiation given in an intense fashion,” says Tran. “I tell patients it’s like spot welding—focused on a small area, very intense, and theoretically ablative, meaning it kills all the cancer in that spot.”

The Baltimore ORIOLE Trial

Can this new SABR technology plus treatment of localized cancer help men with oligometastatic cancer?  “We wanted to test our idea in a rigorous way,” says Tran.  “Our Baltimore ORIOLE trial is a randomized clinical trial in patients with oligometastatic prostate cancer (defined as three or fewer metastases).”  To be eligible, men must have received either surgery or radiation for the primary prostate disease, and have had no hormonal therapy for their metastatic disease. “They can have had hormonal therapy in conjunction with treatment for their primary disease,” such as a short course of androgen deprivation therapy (ADT) with external-beam radiation therapy, “but not for their metastatic disease.”

Men are randomly assigned either to receive SABR to up to three metastatic sites, or to a short observation period of three to six months – but this doesn’t mean that the men assigned to observation can’t get SABR, Tran states.  “The randomization is two to one to SABR, versus a short – no longer than one- to six-month – observation period, after which they can cross over to the SABR treatment.”

Other criteria for eligibility:  small metastatic sites (less than 250 cc) and a PSA doubling time of less than 15 months.  “We chose less than 15 months because there are men who have biochemical failure or low-volume metastatic disease with long PSA doubling times, sometimes many years,” explains Tran.  “These men probably don’t need any treatment immediately – or possibly, ever.  A PSA doubling time of less than 15 months allows us to zero in on patients for whom SABR treatment may make a difference.”

This study was funded by the Movember Foundation and the PCF.   “Thanks to Movember support, the PCF funds more innovative, higher-risk, higher-return projects for patients and science,” says medical oncologist Jonathan Simons, M.D., CEO of the PCF.  “The Baltimore ORIOLE trial had no preliminary data when we funded it, and without private funding, it would not have been possible.  Generally, the federal government requires that you have one-third of the work done in advance, then they fund the other two-thirds of it.  That’s a real deterrent to highly innovative projects, and this one goes after a central and potentially practice-changing question:  Can these men be cured now, and be spared ADT and metastases later?”

The potential implications here are huge:  “The data suggest that two-thirds of men – or perhaps even more – who progress from biochemical failure to metastatic disease progress first with oligometastatic disease,” says Tran.  “The number of men who could be helped by this could be as high as 20,000 to 25,000 every year.”

Because of the possibility of long-term remission or even cure, the study has been filling up fast, Tran adds.  “We have been enrolling quickly and have 35 men out of 54 total.  Thus far, as expected, we have seen only minimal side-effects from the SABR, and all men continue to work and are able to resume their normal activities during the short treatment,” which generally lasts less than three weeks.  Early results “look promising.  The trial also has a number of cutting-edge genetic, blood and imaging studies associated with it that men would not have access to otherwise.”

The Baltimore ORIOLE trial is a collaborative effort involving Hopkins radiation oncologists Theodore DeWeese, Danny Song, Curt DeVille and Stephen Greco; medical oncologists Mario Eisenberger, Ken Pienta, Emmanuel Antonarakis, Michael Carducci, Sam Denmeade Channing Paller and Mark Markowski; urologists Ashley Ross and Michael Gorin; radiologists Steven Rowe and Martin Pomper; and statisticians Hao Wang from Johns Hopkins and Adam Dicker from Thomas Jefferson University.

If you are eligible and are interested in joining this study, please contact Tran directly at [email protected].

 

 

 

 

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.