When Prostate Cancer Returns After Surgery: My New Thoughts

So a surgeon told you to cut it out because you shouldn't live with cancer living in your prostate. You listened to him and a few years later the tumor raised its ugly head as indicated by a slow elevation of the PSA blood test. Now what?

Well in the old days if the PSA level at the time of recurrence was  less than 2 ng/ml most radiation therapist recommended irradiating the prostate and surrounding lymph nodes. Seemed that that was associated with a slight increase in survival. 

Now we can look at two newer studies that suggest adding to this recommendation will save more lives. 

Shipley (N Engl J Med 2017;376:417-28. DOI: 10.1056/NEJMoa1607529 )  studied 760 eligible patients who had undergone surgical removal of the prostate gland and lymph nodes. At the time of surgery patients had a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no lymph nodes were involved with tumor, and  PSA levels ranged between 0.2 to 4.0 ng per milliliter. Within three months of prostatectomy, those patients experiencing persistence of an elevated PSA (failure of prostatectomy) received bicalutamide (Casodex) at a higher than standard dose of 150 mg daily or daily placebo tablets during and after "salvage" radiation therapy. The primary end point was the rate of overall survival. This randomized trial showed that the addition of 24 months of high-dose bicalutamide to salvage radiation therapy resulted in higher rates of overall survival and other important end points among surgery-treated patients with persistent or recurrent disease that was detected only because of an abnormal PSA level. See chart above.

The STAMPEDE clinical trial of nearly 2,000 men revealed that immediately adding abiraterone acetate (Zytiga) with prednisone to a standard androgen deprivation therapy (ADT) initial treatment regimen (usually Lupron) for high-risk, advanced prostate cancer lowered the relative risk of death by 37%. The 3-year survival rate was 76% with standard therapy alone vs 83% with standard therapy plus the immediate addition of abiraterone + prednisone. This is the largest study of abiraterone and prednisone as first-line therapy for advanced prostate cancer. The study was presented  by James et al. at the 2017 ASCO Annual Meeting (Abstract LBA5003) and recently published in the prestigious New England Journal of Medicine ((June 4, 2017, at NEJM.org. DOI: 10.1056/NEJMoa1704174). The early addition of abiraterone to usual ADT not only prolonged life, but also lowered the chance of relapse by 70% and reduced the chance of serious bone complications by 50%. This study tells us that adding maximal androgen withdrawal all at once is better than using androgen withdrawal sequentially!

Thinking Out Loud

It is well established that the use of androgen deprivation therapy (ADT) concurrently with radiation, improves overall survival in patients with locally advanced disease compared with patients who received radiation alone. Potential reasons for this include the anti-angiogenic and pro-apoptotic effects of ADT, as well as to cytoreduction and control of small tumor clusters. (Prostate Cancer and Prostatic Diseases (2010) 13, 39–46)

So what if we treat patients that fail initial surgical therapy as outlined in the Shipley study but modified as in the STAMPEDE study with either:  Immediately administer Casodex + Abiraterone + prednisone androgen deprivation added to radiation therapy or with the immediate use of Lupron + Abiraterone + prednisone androgen deprivation with radiation therapy. My guess is that either combination will produce results superior to those reported by Shipley and certainly will best the use of  radiation alone. The reason this should best Shipley's results is because it "maximizes" anti-androgen deprivation (more than his high-dose Casodex alone). 

Now Here is the Problem

Academicians will concede that my thinking out loud may be reasonable in theory however it will take several years of clinical trials to prove that such is most effective. Medical therapy frequently resists change. But what to do for patients at risk today. Do they want to try to maximize potential for cure NOW or do they  wait until the window of opportunity for better survival closes? My guess is that there would be several obstacles confronting a patient willing to roll the dice for the newer combination including: 1) their private practice urologist, always cognizant of the potential threat of a malpractice suit, may be unwilling to treat the patient other than in a classical, possibly inferior, but community standard 2) the patient's insurance company may refuse to reimburse the patient for the combination of therapies not FDA approved for combination use etc. 

Decision Time

So what should you as a patient do? Have a serious discussion with your doctor. Present him with the facts as presented above. If he is not aware make him aware. Present your thoughts and ask him what he thinks. You will ultimately be your best advocate. Do your homework! Speak out.

Glenn Tisman, M.D.