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.