Nitroglycerin for the treatment of progressive prostate cancer?

According to a group of researchers at Queen’s University in Kingston, Ontario, a very low dose of nitroglycerin may be able to delay the progression of prostate cancer in men with a rising PSA after standard first-line treatment with radiotherapy or surgery.

These data were originally presented in 2009 at the annual meeting of the American Urology Association, where Siemens et al. presented the initial results of a 24-month-long, prospective, Phase II clinical trial in 29 men with a rising PSA following prostate surgery or radiation for localized prostate cancer. To be eligible for entry into the trial, men must have had three consecutive rises in their PSA levels following their first-line therapy.

Eligible patients were then treated with a low-dose, slow-release, transdermal patch formulation of nitroglycerin (glycerol trinitrate or GTN). The patients’ PSA doubling times were compared before and after initiation of treatment, and were also compared to those of a matched control group of patients who received no immediate treatment for their PSA recurrence.

The results of the study (as presented in a recent media release) showed that:

  • 29 patients were enrolled into the study.
  • 17/29 patients completed the 24-month trial
  • 1/17 patients who completed the study experienced clinical progression of their cancer within the 24-month follow-up period.
  • No serious adverse events were reported.
  • The PSA doubling time of patients prior to GTN treatment group was 13.3 months
  • The PSA doubling time of the men in the matched control group was 12.8 months.
  • The end-of-study PSA doubling time for the treatment group was 31.8 months.

Nitroglycerin has been used to treat angina for > 100 years, and in significantly higher doses than those given in this trial. We know that GTN is a relatively safe drug, and there are plenty of data establishing its tolerability over time.

Dr. Siemens, the lead author is this study, is quoted as stating that, “We were very excited to see a significant slowing in the progression of the disease as evidenced by the men’s PSA levels, and to see this result in many of the men who completed the study.”

Now it would be a wonderful finding if GTN could really be proven to be effective as a second-line treatment for prostate cancer that could delay the need for other forms of therapy (e.g., hormone therapy) that are known to have significant side effects. However, The “New” Prostate Cancer InfoLink will need to see a great deal more data than that which has been presented to date before we are convinced about the value of nitroglycerin therapy for treatment of prostate cancer.

Just to give a couple of examples, in the abstract of the paper published in the Journal of Urology, the authors state that 2/18 patients who were on treatment for the full 24 months had progressive disease. However, in yesterday’s press release it states that only 1/17 patients who completed the study had progressive disease. Perhaps more worrisome, in neither article is there any explanation of what happened to the 11 or 12 patients (37.9 or 41.4 percent of patients respectively) who did not complete the 24 months on therapy. Did they have progressive disease before completing 24 months on therapy? Did they simply move on to another therapy for some reason? We are given no information.

If the technology licensee (Nometics, Inc.) hopes to be able to market GTN for the treatment of prostate cancer in the U.S.A., we hope that the next step will be randomized, double-blind, Phase II clinical trial comparing nitroglycerin to placebo in the second-line treatment of prostate cancer. Such a trial would probably need at least 50 patients in each arm — and those patients should be stratified by age and by PSA doubling time, to be sure we are comparing apples to apples.

This does also raise the question of whether it is ethical to give patients with a rising PSA a placebo (effectively “no treatment”) in comparison to any investigational therapy. Some form of salvage therapy (e.g., external beam radiation after first-line surgery or surgery after first-line external beam radiation) has historically been regarded as customary care for a man with a rising PSA.

2 Responses

  1. What about those who refuse standard treatment on the grounds of fear of side-effects? Should they not be included in the trials also? If not, why not?

  2. It seems likely that the ethical issues can be resolved easily because the PSA velocity of prostate cancer is easily measured at either 3- or 6-monthly intervals. Thus for a trial, those who wish could enroll, and there is no need for a double-blind trial or for use of a placebo. The stabilization of PSA velocity is what matters, and the previous track record of PSA velocity is presumably known. This is the course I have personally pursued for 17 years. Selenium and Vitamin E had a minimal impact. No impact with pomegranate juice. A fatty acid synthase inhibitor (Orlistat) caused a NEGATIVE DECLINE in PSA velocity of 40% during the following 12 months. It would be most interesting to combine Orlistat with a nitro patch AND POSSIBLY Estrogel. I should add that my PSA at [diagnosis] was 9.6 ng/ml, with a Gleason of 7. Obviously there may be limitations of any treatment for patients with a Gleason score of 7 or greater.

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