The annual meeting of the American Urological Association was rocked this year by the release of PIVOT (Prostate Cancer Intervention Versus Observation Trial). Journalists at the event stated that the presentation of the data brought a “collective gloom” over the hall filled with urologic surgeons. The reaction is not surprising as the study basically concluded that radical prostatectomy is not necessary for the management of anything other than aggressive prostate cancer. So does this study mark the beginning of the end for the widespread use of radical prostatectomy for the management of prostate cancer? I think that in order to answer this question we first need to take a closer look at the design and results of the study.
PIVOT Study
The PIVOT study was created in 1994 to determine whether the use of prostatectomy in treating prostate cancer added to overall survival and cancer specific survival. The study was designed to recruit 5000 men (less than 75 years of age) with newly diagnosed, localized prostate cancer. Men eligible to proceed were then randomized into one of two groups:
1) Prostatectomy: Actually, only 78% of men in this group underwent prostatectomy while the rest underwent other therapies
2) Observation: Patients in this group did not undergo any treatment aside from palliative therapy for symptomatic management of metastatic disease
The patients in the two groups were then followed for an average of 10 years .
Results of the PIVOT Study
Before I get into the results of the study, I want to stress that just the basic data has been provided and, until the actual paper is published, the nitty gritty of the data cannot be really assessed. Nonetheless, even the basic data that is available definitely provides a starting point for discussion.
Out of the 5000 patients recruited for the study, only about 700 of the eligible patients actually agreed to proceed. These 700 men were then divided into two groups with, on average, similar characteristics in terms of age and degree of prostate cancer. After an average of about 10 years of follow up, the results reported by the study were definitely eye opening:
1) While 48% of the men in this study died within the 10 years of follow up, only 7% died from prostate cancer
2) Prostatectomy led to an insignificant, absolute 2.9% increase in overall survival.
3) Prostatectomy led to an insignificant, absolute 2.7% increase in prostate cancer specific survival.
4) For high risk patients with PSA greater than 10, prostatectomy provided a significant, 7.2% increase in survival.
Initial Reaction to the Results
Upon first glance at these results, it is not unreasonable to come to the conclusion that radical prostatectomy is an unnecessary procedure for the majority of men diagnosed with prostate cancer. After all, with PSA screening, most men are diagnosed with low or moderate risk disease and a PSA well below 10. This trend towards early stage disease is also demonstrated by the study itself in that 70% of men participating in the study had a Gleason score of 6 or less and 72% were classified as either low or intermediate risk. If we take the study population as a microcosm of the general population, we would argue that over 70% of men simply do not need to undergo prostatectomy (or any other treatment for that matter) to treat prostate cancer. We would argue that men should not expose themselves to the significant risks and quality of life impacts of prostatectomy for only a minimally higher chance of surviving prostate cancer. We would then conclude that treatment for prostate cancer should be reserved only for those men with high risk cancer and a PSA greater than 10. With the general data provided, these conclusions may very well all be true. Before hanging up the scalpel for good, however, I thought I would take a closer look at the data.
Digging a Little Deeper
After my initial shock from these results wore off, two big questions became prominent in my mind:
1) How healthy were the men in the study? As I noted above, approximately half of the men in the study died within the 10 years of follow up. Only a small percentage of these men died of prostate cancer. There are two possibilities to explain the small number of men dying from prostate cancer:
A) The low risk prostate cancer that afflicted most of the men in the study was just not that lethal.
B) The men in the study had other health problems that were more lethal than prostate cancer.
The answer is probably a mix of both. Men with significant medical problems (heart disease, stroke, diabetes) often do not live long enough to be affected by or to die from prostate cancer. At this point you are probably thinking that I am proving the point of the study: most low or intermediate prostate cancer does not need to be treated. However, not all men have significant medical problems. Healthy men, particularly healthy young men, may well live long enough to suffer from and even die from prostate cancer. A famous, large European study recently demonstrated that, when looking at men as a whole, 50 men with prostate cancer would need to undergo prostatectomy to save one life from prostate cancer. HOWEVER, a follow up study then went on to demonstrate that, when looking at HEALTHY men, only 4 men with prostate cancer would have to undergo prostatectomy to save one life from prostate cancer. Quite a difference! Unfortunately, I believe that the PIVOT study is too small to demonstrate this type of distinction. Nonetheless, I hope that when the final, more specific, data from the trial is published, information about the overall health of these men is included to help us determine whether their overall health precluded them from benefiting from prostate cancer treatment.
2) Why was the study only carried out for 10 years? During my residency training I, like most other urologists-to-be, learned that men with a life expectancy less than 15 years probably should not undergo aggressive treatment for low risk prostate cancer. Studies have demonstrated that prostate cancer typically takes around 15 years to create metastatic disease significant enough to be lethal. As a result, men that did not expect to live that long would not derive any benefit from treatment. This previous data makes it not very surprising that, at 10 years, only a minimal survival advantage was noted in PIVOT for men undergoing treatment versus those men that chose to observe their cancers. At 10 years, metastatic prostate cancer starts to present itself but usually not to the extent that can kill. I would imagine that, like in previous studies, metastatic disease was found more often in men in the observation arm of the PIVOT trial. I am not sure, however, that this was an endpoint recorded for the trial. I would bet that if the investigators running the PIVOT trial would continue to collect data up to the 15 and 20 year marks, the tiny difference demonstrated in the survival curves of men in the treatment versus observation arms of the study would prove to be only the initial separation point of two very divergent curves.
Of course, the average age of the men in the study was 67. Men in this age group have a life expectancy of about 15 years so, for them, a survival benefit achieved 15-20 years after surgery is pretty useless. But what about a 50 year old man? His life expectancy is over 30 years. For him, a survival advantage 15 years after surgery can mean the possibility of 15 extra years of life. I don’t think the value of this survival advantage is really debatable. This concept was demonstrated in a recent study of Scandinavian men with prostate cancer which, after 15 years of follow up, demonstrated a 38% survival advantage for men younger than 65 years of age undergoing surgery as opposed to observation. For this reason, I feel that while the 10 year survival data from this study may be helpful in guiding a treatment (or no treatment) decision for a man in his late 60s or 70s, the data is not relevant to a healthy man in his fifties.
Take Home Message
The purpose of this post was not to criticize the PIVOT trial. Any well run, randomized trial evaluating 700 men deserves significant attention and must be taken very seriously. The study, indeed, reaffirms many important concepts in the management of prostate cancer. First, men with low risk prostate cancer should definitely be advised of the option of active surveillance, particularly if they are in their 60s or older and/or if they have significant medical problems. These men, as the study demonstrates, may not derive significant benefit from prostatectomy or other treatments. In the same vein, men with aggressive prostate cancer should be offered treatment, even if they are older or may have some other medical problems. These aggressive cancers, as demonstrated by PIVOT, can lead to premature death even within a 10 year time frame.
What the PIVOT trial does NOT prove to me, however, is that prostatectomy is useless for YOUNG, HEALTHY men with low or intermediate risk prostate cancer. Of course, these young men need to be counseled on the risks and quality of life implications of treatments such as prostatectomy. They need to be told that any survival advantage from surgery or other treatments would not be enjoyed for more than a decade. They also need to be advised of the risks and benefits of active surveillance as well. However, until large, randomized, long term studies prove otherwise, I believe that these young, healthy men should not be told that treating their prostate cancer is unnecessary.
