Mistaken Judgment:  Prostate Cancer Hormone Treatment (IV)

The Original Huggins Article
The first was the original observation by Huggins himself that administration of testosterone to men caused “enhanced growth” of prostate cancer in men with metastatic disease. A second was a well-known 1981 article from the Memorial Sloan Kettering Cancer Institute in New York, authored by the most prominent prostate cancer expert of his era, Dr. Willet Whitmore, that reported near-universal poor outcomes when men with metastatic prostate cancer received testosterone injections. And the third was the phenomenon known as testosterone flare. Testosterone flare refers to the temporary increase in testosterone caused by the use of medications called LHRH agonists in men with advanced prostate cancer. Testosterone flare has been associated with a variety of complications attributed to the sudden growth of prostate cancer.

All three of these issues applied only to men with known metastatic disease, and because no one was suggesting that testosterone therapy be offered to men with advanced prostate cancer, the existence of this literature wasn’t terribly troubling. What was of concern to those of us prescribing testosterone therapy was the possibility that we might be putting our otherwise healthy patients at risk for prostate cancer, but so far all the data looked reassuring on this point. Metastatic disease was something quite different, and it would not have been shocking to learn that it responded differently to high levels of testosterone than localized disease within the prostate.

But I was still bothered. I had read all the relevant articles years ago during my training, but not with a critical eye toward the relationship of testosterone and prostate cancer. One day, I found myself with an unexpectedly free afternoon and decided to investigate. Everything changed for me the day I descended into the basement of the Countway Library, Harvard Medical School’s incredible archive of medical literature. It was the most exciting day of my professional career, a day that changed my views on testosterone, prostate cancer, and, even more, on medicine itself.

The basement of Countway Library is where the old volumes of medical journals are kept. Some of these, from august journals such as The Lancet, go back to the 1800s. It is an amazing collection, open to any member of the Harvard community.

I found the original article by Huggins from 1941. It was in the very first published volume of what is now a highly respected journal called Cancer Research. I read how Dr. Huggins and his coinvestigator, Clarence Hodges, used the new blood test called acid phosphatase to show that lowering testosterone by castration or estrogen treatment caused prostate cancer to regress, and how T injections had caused “enhanced growth” of prostate cancer in these men. And then I noticed something that made my heart race.

Huggins and Hodges had written that three men had received T injections. But results were given for only two men. And one of these men had already been castrated. This meant that there were results for only a single man who had received T injections without prior hormonal manipulation. Dr. Huggins had based his “enhanced growth” conclusion on a single patient, using a test—acid phosphatase—that has since been abandoned because it provides such erratic results!

I sat there in the basement of the library, reading the same lines over and over to make sure I hadn’t misread it. Later, I asked several colleagues to read it as well. Dr. Huggins’s assertion that higher testosterone caused greater growth of prostate cancer, repeated for so long and accepted as gospel, was based on almost nothing at all!

The Memorial Sloan Kettering Experience
I was still giddy when I decided to look up the article detailing the experience of testosterone administration to men with metastatic disease from the Memorial Sloan Kettering Cancer Institute, published in 1981 by the urologic giant of his day, Willet Whitmore, and his colleague, Jackson Fowler. The short summary of the paper was quite damning. Over a course of eighteen years, fifty-two men with metastatic disease had undergone treatment with daily T injections, usually as a last-gasp treatment for their cancer. Of these fifty-two men, forty-five had experienced an “unfavorable response,” most within the first month of treatment.

This seemed pretty grim. Maybe Huggins had been right after all, despite basing his conclusions on a solitary patient. But then I discovered something equally shocking in the fine print of this article. Of the fifty-two men studied, all but four had already been treated with castration or estrogen treatment to lower testosterone. And of these four previously untreated men, one had an early, unspecified unfavorable response, while the remaining three men continued to receive daily T injections for 52, 55, and 310 days without apparent negative effects. In fact, one of these men was reported to have had a “favorable response” to T administration.

Drs. Fowler and Whitmore were impressed by the difference in outcomes for the untreated group of four men compared with the men who had already undergone hormonal treatment to lower testosterone. To explain the lack of negative effects on the untreated men, the authors postulated the following: “Normal endogenous testosterone levels may be sufficient to cause near maximal stimulation of prostatic tumors.” In other words, raising testosterone levels beyond the normal range did not seem to cause any increased cancer growth, even in men with metastatic disease!

This important concept was lost in the headline of the study, which clearly indicated that giving testosterone to men with prostate cancer was associated with rapid onset of negative consequences in most men. One had to read the article closely to learn that the headline applied only to men who had been previously castrated. Although this article has been cited for many years as evidence that T administration causes rapid and near-universal growth of prostate cancer (PCa), the authors in fact clearly made the point that the worrisome effects of T administration did not appear to occur in their small group of men without prior hormonal treatment.

Testosterone Flare
It had been an amazing day in the library, which had long since turned to night. My head was spinning, but I wanted to tackle the last hurdle, the problem of testosterone flare. In the early 1980s, medications were developed to replace the need for surgical removal of the testicles for men with advanced prostate cancer. These medications are called LHRH agonists, and they continue to be used to this day. LHRH injections cause T concentrations to increase by 50 percent or more for seven to ten days, after which testosterone levels fall rapidly to castrate levels. This transient rise in testosterone is called testosterone flare.

Not long after LHRH agonists began to be used, there were reports of complications occurring after men began these treatments, and these complications were attributed to testosterone flare causing rapid growth of prostate cancer. These complications included the inability to urinate, worsening of bone pain, or, in the most tragic cases, paralysis due to collapse of a vertebra in which the cancer had eaten away the bone. As a result, for the last twenty years, it has been routine to add medications to block testosterone flare when starting a patient on treatment with LHRH agonists.

That night in the basement of Countway Library, I pulled all the original studies I could find of LHRH agonists, as well as reports of bad outcomes due to the flare. As I read, two things became apparent. First, many of the bad outcomes attributed to testosterone flare occurred a month or more after initiation of treatment. This meant that these complications occurred not when testosterone levels were high, but when testosterone levels had already dropped for some time to castrate levels.

Second, out of the substantial literature on LHRH agonists and prostate cancer, I could find only two articles that actually measured and reported PSA levels during the time of the testosterone flare. And here was the kicker: both articles showed absolutely no change in mean PSA values during the time of the testosterone flare! Curiously, neither article so much as mentioned this result.

PSA is an excellent indicator of prostate cancer growth. The fact that PSA did not rise in these men during the testosterone flare strongly suggested that the cancers did not grow during this time. Perhaps the complications attributed to testosterone flare were nothing more than the cancer progression that would have happened without any treatment at all.

It had been quite a day and night in the Countway Library. I left with my head spinning and a feeling that I had stumbled onto something very important. It was like the children’s story The Emperor’s New Clothes—we see what we want to see. And for two-thirds of a century, it had been assumed that raising testosterone increased prostate cancer growth. But maybe the emperor was naked.

Even in men with metastatic disease, there was no evidence I could find that raising testosterone made prostate cancer grow more than it would have anyway. Shockingly, the very publications cited so regularly to demonstrate a dangerous relationship between testosterone and prostate cancer contained evidence that this was not true

Dr. Raphael Nyarkotey Obu: PhD is a research Professor of Prostate cancer and Holistic Medicine at Da Vinci College of Holistic Medicine, Larnaca city, Cyprus and the National President of the Alternative Medical Association of Ghana(AMAG). He is also the President of Men’s Health Foundation Ghana