A question that I have repeatedly heard from readers has been about the length of time hormonal therapy needs to be given in conjunction with radiation to treat prostate cancer. As I replied to these readers, the answer, like most aspects of prostate cancer treatment, is not very straightforward and remains somewhat controversial. In this post I will attempt to clarify which men actually need hormonal therapy in addition to radiation, the benefits of this additional hormonal therapy, and the ideal duration of the therapy.
Why Add Hormones to Radiation Therapy?
The benefits of adding hormones to radiation therapy for prostate cancer were first demonstrated through animal experiments. These studies evaluated the added efficacy of androgen deprivation (hormonal therapy) when combined with radiation therapy in treating prostate tumors in mice. The studies scientifically demonstrated that the hormonal therapy reduced the amount of radiation necessary to destroy and control the growth of the tumors. These and other studies have proposed that radiation and hormonal therapy work synergistically to destroy prostate cancer cells and keep them from spreading locally and into the bloodstream.
The added benefits of hormonal therapy were then tested in the clinical setting on real patients. One of the seminal studies testing the theory was conducted in Europe over a decade ago. The study compared the outcomes of men with locally advanced prostate cancer who underwent either radiation therapy alone or radiation therapy combined with a 36 month course of hormonal therapy. The study demonstrated that, 10 years after treatment, men undergoing combination therapy enjoyed superior overall survival (58% vs 39%) and a much lower chance of dying specifically from prostate cancer ( 11% vs 31%) when compared with those men undergoing radiation alone. Studies such as this ushered in the wave of hormonal therapy that has been becoming more and more popular in the treatment of localized prostate cancer.
As more and more patients were placed on hormonal therapy, it soon became apparent that this additional treatment does not represent a free lunch. As I described in my previous post, hormonal therapy comes with significant risks to your heart while increasing your chance of developing diabetes. In addition, hot flashes and sexual dysfunction can have a dramatic impact on quality of life for men on the therapy. As such, many began to wonder if 3 years of hormonal therapy is really worth the benefits. Studies have been conducted comparing the combination of radiation plus short term hormonal therapy (4-6 months) with radiation alone. One such study demonstrated a superior 8 year overall survival for men undergoing the combination therapy (74% vs 61%) as compared to men undergoing radiation therapy alone. The presence of this new data subsequently begged the question of whether long term hormonal therapy yielded any benefits above and beyond those achieved with short term hormonal therapy. Excellent, randomized studies were conducted to answer just this question.
Optimal Duration of Hormonal Therapy
Two large, randomized trials have been carried out comparing short term with long term hormonal therapy in combination with radiation therapy. These studies were carried out specifically in men with HIGH RISK prostate cancer. Only men with either locally advanced prostate cancer (T2c-T4) or positive lymph nodes were evaluated. I emphasize this point because, as I shall explain later, the results and conclusions can not and should not be applied to treatment decisions for ALL men with prostate cancer.
The first trial, known as Radiation Therapy Oncology Group 92-02 studied over 1500 men with T2c-T4 prostate cancer (cancer which took over both lobes of the prostate and/or extended out of the prostate to varying extents) with or without positive lymph nodes. Men in the study were randomly enrolled into one of two treatment protocols:
1) Radiation plus 4 months of hormonal therapy (starting 2 months prior to radiation)
2) Radiation plus 28 months of hormonal therapy(starting 2 months prior to radiation)
The study demonstrated that, after 10 years, men undergoing long term hormonal therapy enjoyed better cancer specific survival (89% vs 84%), lower chance of metastatic disease (15% vs 29%), and a lower chance of further local spread ( 12% vs 22%) than those undergoing short term hormonal therapy . What the study did not demonstrate, however, was a significantly improved overall survival rate for men undergoing the long term versus the short term hormonal therapy. The study then analyzed a particularly high risk subset of men with Gleason 8-10 prostate cancer. In this subset of patients, in contrast, a significantly superior overall survival rate (45% vs 32%) was seen in men undergoing long term hormonal therapy.
The second study was conducted by the European Organization for Research and Treatment of Cancer. This trial evaluated 970 men with either locally advanced prostate cancer (T2c to T4) or men with positive lymph nodes and any local stage. The study divided the patients randomly into two treatment groups:
1) Radiation therapy plus 6 months of hormonal therapy (starting the first day of radiation).
2) Radiation therapy plus 36 months of hormonal therapy (starting the first day of radiation).
After about 6 years of follow up, the study demonstrated a small but significant overall survival advantage for men on long term versus short term hormonal therapy (85% vs 81%). The difference in death rates (19% vs 15%) represented a 42% higher chance of death for men undergoing short term versus long term hormonal therapy.
While demonstrating slightly different impacts, both studies concluded that men with HIGH RISK prostate cancer should be considered for long term hormonal therapy.
Long Term Hormonal Therapy: Who Really Needs It?
While the above mentioned studies argue for adding long term hormonal therapy to radiation for treatment of HIGH RISK prostate cancer, they DO NOT conclude that all men undergoing radiation therapy for prostate cancer need hormonal therapy. Before discussing the suggested regimens for men without high risk disease, we should review the accepted “risk” categories for prostate cancer:
1) High Risk: Prostate cancer that is locally advanced (T2C-T4) and/or Gleason score 8-10 and/or associated with a PSA greater than 20
2) Intermediate Risk: Prostate cancer with moderate local stage (T2b) and/or Gleason score 7 and/or PSA 10-20.
3) Low Risk: Prostate cancer with low local stage (T1b-T2a) and Gleason score 2-6 and PSA less than 10.
These risk categories are very important to understand, particularly in context of prostate cancer studies. In relation to adding hormonal therapy to radiation for prostate cancer, the utility of the additional hormonal therapy depends on what risk group you are looking at. As I mentioned above, the added benefits of hormonal therapy, particularly long term hormonal therapy were demonstrated only in HIGH RISK prostate cancer patients. In contrast, no study has ever demonstrated any benefit of adding hormonal therapy to radiation of LOW RISK prostate cancer. The data for INTERMEDIATE RISK is more mixed. While no studies have specifically evaluated the added benefit of combining hormonal therapy with radiation therapy for INTERMEDIATE RISK prostate cancer, numerous patients with INTERMEDIATE RISK disease were included in the studies evaluating HIGH RISK patients. These studies did demonstrate a benefit of adding hormonal therapy to a radiation therapy regimen for patients with INTERMEDIATE RISK disease. No study, however, has demonstrated any significant additional benefit of long term over short term hormonal therapy for INTERMEDIATE RISK disease. As a result, many of the radiation oncologists performing these studies recommend a combination of short term hormonal therapy and radiation for men with INTERMEDIATE RISK prostate cancer. This recommendation, of course, is only valid if the risks of the additional hormonal therapy (heart risk, diabetes, osteoporosis) do not outweigh the benefits for a given patient. In addition, because no randomized studies have been carried out looking to answer this question in men with INTERMEDIATE RISK disease, the data and recommendations I have just mentioned for INTERMEDIATE RISK disease can be considered fairly trustworthy but not definitive.
Take Home Message
The controversy over the optimal duration of hormonal therapy to give in combination with radiation for prostate cancer again demonstrates the recurrent theme we hear about repeatedly in relation to prostate cancer therapy: prostate cancer treatment cannot be carried out with a “one size fits all” approach. While studies seem to demonstrate a modest although significant advantage to long term ( > 2 years) hormonal therapy in addition to radiation for HIGH RISK prostate cancer, there has been NO evidence demonstrating that hormonal therapy for LOW RISK prostate cancer is of any benefit at all. INTERMEDIATE RISK prostate cancer, in turn, may be optimally managed with a combination of radiation and short term hormonal therapy although we still await definitive studies to confirm this. In addition, even when keeping these risk groups in mind, the final decision of whether or not to add hormonal therapy to radiation (and, if so, for how long ) really rests on weighing the risks and benefits for each individual patient. In some men with HIGH RISK prostate cancer, cardiac and metabolic risk factors may make the risks of heart attack and diabetes posed by hormonal therapy far outweigh the benefits of the treatment. In contrast, some otherwise healthy men with HIGH RISK prostate cancer may derive significant benefits from the additional hormone therapy with minimal additional risks. The key to answering this question is to really understand your situation. Make sure that you understand your particular prostate cancer risk group. Also, make sure that you discuss your cardiac and metabolic risk factors with both your urologist/radiation oncologist and your primary doctor (who is more familiar with your overall health). Finally, make sure that your doctor weighs these competing factors with you so that you can be assured that, no matter what your given situation, the treatment course you chose truly provides you with more benefits than risks.
