Risk Should Dictate the Aggressiveness of Prostate Cancer Treatment

Greg Kennelty

Matthew Cooperberg, MD genitourinary cancer specialist, University of California San Francisco (UCSF), discusses the varying management techniques for both low- and high-risk prostate cancers, including radiation therapy, surgery, hormonal therapy, and active surveillance.

Matthew Cooperberg, MD

The optimal treatment strategy for men with prostate cancer has evolved dramatically, with a growing acceptance of multimodal approaches that include surgery, hormonal therapy, and radiotherapy for patients with high-risk prostate cancer, according to Matthew Cooperberg, MD. Furthermore, in the low-risk population, active surveillance is now being utilized more appropriately and effectively.

In an interview withTargeted Oncology, Cooperberg, genitourinary cancer specialist, University of California San Francisco (UCSF), discussed the varying management techniques for both low- and high-risk prostate cancers, including radiation therapy, surgery, hormonal therapy, and active surveillance.

TARGETED ONCOLOGY:What are some of the contemporary management techniques for high-risk prostate cancer?

COOPERBERG:Historically, men with what looks like clinically localized but high-risk prostate cancer were quite frequently managed with androgen deprivation therapy. These men were not offered any chance at local therapy.

One of the findings we had with the CAPTURE registry is that the proportion of men who are getting hormonal therapy alone had been rising consistently over a 15-year period up to 2010. It was as high as 50%, and has now fallen down to 25%, which is good news. It means we are seeing more appropriately aggressive management in men with clinically localized, high-risk disease.

Until recently, when those men got local treatment it was usually radiation therapy. In the last 5 years or so, it was relatively uncommon to see surgery, which is part of the paradigm for high-risk disease. What we are seeing now is a change, based in part on a growing body of evidence that surgery may be a more effective local therapy than radiation therapy alone for men with high-risk disease.

One of the other papers I believe is relevant to this is a meta-analysis that recently came out in European Urology that summarizes 19 different studies—all retrospective. This meta-analysis showed a consistent two-fold improvement in cancer-specific survival and overall survival when surgery is part of the management paradigm.

The question in many cases should not be “surgery or radiation therapy?” and should be “how can these treatments be best combined?” In that regard, for high-risk prostate cancer, we are probably behind a lot of other solid tumors. When you think about how aggressively breast cancer is managed, or rectal cancer or gastric cancer, the answer is yes — you get surgery, radiation therapy, and systemic therapy.

So we are quite a bit behind the curve in still having these debates.

TARGETED ONCOLOGY:What is being done to get the treatment of prostate cancer out from “behind the curve?”

COOPERBERG:There is increasing recognition, at least in academic circles and at academic centers, that a more aggressive approach to men with high-risk disease is in fact appropriate. When appropriate, these men will do well with surgery, which is very often followed by adjuvant radiation therapy and is often combined with systemic therapy.

The questions come down to the details of those combinations, such as when secondary radiation therapy should be used, if it should be adjuvant or if it could be early salvage, and should hormonal therapy be given with salvage radiation therapy. There are trials going on now to answer some of those questions.

Some of the questions not being answered yet that would be of great interest is when should we give immunotherapy early, together with surgery, for example, as a neoadjuvant treatment.

We had a small study at UCSF, and a couple other centers looking at Provenge as a neoadjuvant treatment to prove that there is an immune infiltrate in the primary tumor. It was too small of a study to show any clinical benefit, but it makes sense that the best time to use immunotherapy would be earlier.

There are studies that have been accrued that are looking at adjuvant and neoadjuvant chemohormonal therapy for men with high-risk disease. Those trials have been completed and are in follow-up, but neither has been reported yet.

TARGETED ONCOLOGY:How should surgery be viewed, when determining the best treatment for prostate cancer?

COOPERBERG:Surgery has always been one of the mainstays for prostate cancer, though patients tend not to want it and men with low-risk prostate cancer don’t need it. Most men with low-risk disease will do well with active surveillance and don’t need to go straight to surgery or radiation therapy.

If you need treatment and showcase a tumor that is a risk to your life, then the question comes down to managing the possibilities of side effects and how patients react to those possibilities rather than saying one is more or less invasive. Invasiveness is not the question — the question is what is the long-term impact on their quality of life. That is going to vary from individual to individual, and the differences need to be weighed against the cure likelihood when it comes to different disease.

TARGETED ONCOLOGY:For men with low-risk prostate cancer, how active is active surveillance?

COOPERBERG:Right now, the definition is evolving. What we’re seeing in pragmatic, real-world practice is that most protocols say you do a biopsy every one to two years. What’s starting to happen a little more is that interval is modulated depending on what we see and the overall clinical picture.

For a young man who is a borderline candidate for active surveillance in the first place and has a Gleason score of 3+3 or 3+4, that is someone who truly needs to be on active surveillance. He needs very close PSA surveillance and he needs regular biopsies because he is at some risk of progression. That is someone who would benefit from further testing like MRI and genomic testing.

On the other hand, if you have a 78-year old gentleman who has cardiac disease and has Gleason 3+3 in a single core, that is someone who did not need to be diagnosed in the first place. Recognizing that, his surveillance regimen can be less active. At UCSF, we would typically do a confirmatory biopsy to make sure that the cancer is low-grade, low-volume, and organ-confined. If it were, we would try to maximize the interval between biopsies unless there is some sign of clinical progression.

TARGETED ONCOLOGY:When there is a sign of progression in active surveillance, would you immediately move on to treatment?

COOPERBERG:When you look at studies of long-term active surveillance, the likelihood of staying on active surveillance for 10 or 15 years is around 50%, depending on which cohort you look at and how long of a follow-up period you look at. With men who stay on for anywhere between 6 months and 5 years, we see progression in their disease, then yes, we move on to surgery or radiation, or other treatments.

In some cases, patients just get anxious and opt for treatment even though everything looks like it’s fine. This category is getting less common as time goes on and the whole community is getting more comfortable with the idea of active surveillance. We used to see that about a third of men who went on to receive treatment after starting surveillance did so in the absence of any objective sign of progression. Their Gleason was still low, their PSA hadn’t risen very much, and everything seemed fine.

In my mind, that is often a failure of counseling, though there are some men who are just extremely anxious, though there are a lot of men who could have avoided that with counseling.