Let’s move on to the treatment of advanced prostate cancer. Hormonal therapy remains the standard and the strategy here involves lowering testosterone levels or blocking androgen levels. The tried and true methods for doing this are orchiectomy or LHRH analog. Some more recent innovations that are not standard are peripheral androgen blockade, using an antiandrogen like flutamide or Casodex with or without a 5-alpha reductase inhibitor. There are a number of phase II studies, no comparative studies. This is not a standard in the United States, nor is intermittent hormonal therapy where a patient goes on orchiectomy, LHRH analog or combined androgen blockade for some period of time, stops it, starts it, stops it, starts it. No randomized studies yet although there is one randomized study that is accruing patients right now, looking at this strategy. Combined androgen blockade remained the standard in the United States for many years for patients with advanced prostate cancer. Based on a large Intergroup study that was published in the New England Journal in 1988 comparing daily injections of Lupron versus Lupron plus flutamide demonstrating an improved relapse rate and survival rate associated with combined androgen blockade. Amazingly, since that time, there have been 28 or 29 other randomized studies, including this one that has looked at the concept of combined androgen blockade. This is the largest study that I know of. Patients had metastatic disease, randomized to orchiectomy or orchiectomy plus flutamide. In this study there was a slight improvement in the ability to render the PSA less than 4 with combined androgen blockade, but no overall difference in progression free or overall survival. When one combines all the studies in a metaanalysis there appears to be a very very modest improvement associated with combined androgen blockade, which is statistically significant but arguably, is it really clinically significant?

So for patients with advanced prostate cancer, that is D2 disease – overt metastases in the bones or lymph nodes above the aortic bifurcation – there is probably only a modest impact on overall survival. So the use of an anti-androgen combination with an orchiectomy or an LHRH analog is particularly important in the symptomatic patient in order to block the flare pattern early in the disease when an LHRH analog is used. The combination approach may promote the selection of clones that have an altered androgen receptor, which is a problem, but the use of combined androgen blockade is still a wide open question in earlier forms of the disease, locally advanced disease, the rising PSA patient, etc. But for D2 disease we are moving away from the routine use of long term anti-androgen in addition to orchiectomy or LHRH analog.

This is a fairly typical scenario of a patient with advanced prostate cancer who was treated with hormonal therapy. The patient had a PSA of 600. Started on combined anti-androgen blockade. His PSA rapidly decreased to near undetectable levels. The decrease in PSA is a reflection of several things. One is an artificial decrease in PSA. The PSA gene is partially androgen stimulated so when one removes androgen, the biochemical production will go down automatically without anything happening to the cells themselves. Part of this reduction is due to cell loss. There is some apoptosis that is going on and there is some dormancy as well. So this is some combination of effects that include a biochemical effect as well as a true cellular effect causing dormancy or apoptosis. The PSA is an incredibly reliable test in predicting relapse in this disease after hormonal therapy. The PSA will remain at some level for some period of time, which may be a few months or many many years. The earliest sign of relapse will be a rising PSA which will predate the radiographic or symptomatic progression. In this case, by a few months. Sometimes by many many years. Very good predictor of relapse and obviously a controversial issue is when to institute further therapy here. There is no consensus on this right now. In general patients should go on clinical trials when this happens.

Prostate cancer