A slightly different story with radiation therapy. Three RTOG studies looking at hormonal therapy followed by radiation, versus radiation therapy alone. I just want you to look at these two studies down here, comparing Zoladex or LHRH analog versus no concomitant radiation therapy. Difference in local control rates in disease free survival, so far no difference in overall survival when combined androgen blockade was used in combination with radiation. Once again, local control rates improved, disease free survival rates improved. As of yet, no difference in overall survival. The most important study though was a study published in the New England Journal last year, a European study that looked at high risk, localized prostate cancer treated with radiation versus radiation therapy plus three years of androgen deprivation; 455 patients. Local control improved with hormonal therapy, relapse rates improved with hormonal therapy and there was a 20% actuarial five year difference in survival. So the concept of using hormonal therapy plus radiation appears to have some support at the present time. It appears that longer term hormonal therapy is required. Whether that will work for surgery or not remains to be seen. But the standard of care in the United States for locally advanced prostate cancer, I think at the present time – this is T3 tumors, high grade tumors – remains combination therapy with hormonal therapy plus radiation therapy or more, which I’ll come back to.

So we can sort of design how patients should be treated based on their risk group. Good risk patients – lower PSA’s, lower grade tumors, lower clinical stage, fewer biopsies that are positive. If cure is necessary, that’s a hard question to answer, but if it is necessary the standard of care remains radical prostatectomy but what we would like to do is minimize morbidity, and that’s why brachytherapy or seed implants have become popular over the past few years because of the sentiment that this therapy may in fact be equivalent in terms of outcome or close to equivalent, and less morbid. There are some patients in this subgroup that can be watched and external beam radiation still remains an alternative therapy here. For intermediate risk patients; some patients will be cured with radical prostatectomy, 50% will not and therefore multi-modality therapy should be contemplated here. Either standard multi-modality therapy with hormonal therapy plus external beam therapy, or in the context of a clinical trial. For high risk patients; these patients are not going to be cured, for the most part, with local therapy with external beam radiation or surgery. So the current strategy is these patients should be enrolled in clinical trials, with some experimental agent, hormonal therapy, chemotherapy, etc. prior to surgery or prior to radiation therapy.

Now if a patient is treated with surgery or with radiation and they are not cured, as evidenced by a rising PSA, this presents a huge clinical dilemma for the physician and a quandary for the patient as well. A very heterogeneous group of patients, how do we determine what to do with these patients? Should they undergo immediate hormonal therapy or delayed hormonal therapy? Well, the things that help us make a decision here are the rate change of the PSA and the tumor grade which will clearly determine prognosis on the basis of several studies now. The absolute PSA level is less predictive, although we use that as a benchmark for patients in terms of saying, let’s say, “When your PSA gets to this level then it is reasonable to start therapy.” But probably the dominant determinant of when therapy is instituted is the balance between the anxiety of the patient with a rising PSA versus the quality of life aspects of starting a patient on hormonal therapy. So it’s still a wide open area and there are no answers here yet, but we individualize therapy as best we can here.

Now what about treatment for this disease? Well, hopefully we have progressed a little bit from this “voice-mail” answer for patients a few years ago. Once again, there are a number of different ways to treat this disease. There are some patients that don’t need to be treated. There are no randomized studies that compare treatment to no treatment. The standard in the United States though, for organ-confined prostate cancer, remains a radical prostatectomy and different forms of radiation therapy remain an alternative, and in general a quality of life alternative. Hormonal therapy could be used in some patients and cryosurgery as well.

Prostate cancer

Now how do people do with treatment? Well, we can say something about their likelihood of being cured. There are now two large studies, one from the Cleveland Clinic and one from our institution, looking at the comparison – this is not randomized data, but controlled retrospective data looking at different factors at baseline – and looking at the comparison of external beam radiation to surgery. What one can say is that no matter what one does with localized prostate cancer, the likelihood of being alive at five years is good and equivalent between both of these different types of treatment. And the same can be said at 10 years as well. The outcome appears to be similar with surgery and with radiation in these retrospective, non-randomized types of studies. What the outcomes will look like at 15 and 20 years after treatment remains to be seen. Another thing that we can tell patients is something about the morbidity of treatment. So we can tell people the likelihood of being cured, we can tell people the morbidity of different treatments – we have some good data there – what we cannot tell people is what is their need to be treated. That remains largely unknown. This is a study that we did. This is the only prospective study that looked at treatment outcomes after radiation and surgery in which questionnaires were given to the patients prior to treatment as well as after treatment. The leader of the study was Jim Calcott in our group. We are only looking at radical prostatectomy and external beam radiation here. When asked the question of whether the patients are developing urinary incontinence, radiation does not cause urinary incontinence where surgery does. Fully one-third of individuals two years after having a radical prostatectomy were still wearing absorptive pads because of concern of leakage or true leakage. And 13% of men said that they had a lot of incontinence. One of the disappointing findings in this is that sexual dysfunction was very high with either form of therapy. With radical prostatectomy the majority of patients were rendered impotent as a result of surgery, by the definition of inadequate erections for sex. It really did not matter whether or not they had the nerve-sparing procedure. It is only the subset of individuals who had bilateral nerve-sparing procedures, who were relatively young, where the results were reasonably high. About 50% of those individuals maintained potency. Radiation has its problems as well, although radiation does not cause immediate impotence, it does cause comparable levels of impotence which occurs slowly over a several-year period of time.

An issue that comes up in the treatment of early prostate cancer in under-staging. This is best illustrated, I think, from this paper that was published in JAMA a few years ago. Once again, out of the SERE cancer registry looking at 3,000 men who had undergone a radical prostatectomy in the late 80’s, early 90’s. The important finding here is that over one-third of patients who were treated with radical prostatectomy required some other form of therapy within the next five years; either hormonal therapy or radiation therapy because they had relapsed or there was some concern of relapse. So what had become popular 5-10 years ago were strategies to combine hormonal therapy with either surgery or radiation to try to improve the cure rates of these particular forms of local therapy. In the context of surgery, there were three randomized studies comparing surgery to preoperative hormonal therapy followed by surgery. In these studies hormonal therapy was given for a short amount of time, generally three months. In all the studies there was a reduction in the likelihood of having positive margins when hormonal therapy was used, but no difference in disease free or overall survival. So at the present time, preoperative hormonal therapy is not the standard of care. Now it may be that this concept is completely flawed, or alternatively one requires longer term hormonal therapy in order to see an effect in relapse and overall survival. But that remains unanswered.