Elsevier

Urology

Volume 74, Issue 4, October 2009, Pages 878-883
Urology

Oncology
Phase II Study of Nitric Oxide Donor for Men With Increasing Prostate-specific Antigen Level After Surgery or Radiotherapy for Prostate Cancer

https://doi.org/10.1016/j.urology.2009.03.004Get rights and content

Objectives

To evaluate the effect of low-dose glyceryl trinitrate (GTN) on men with biochemical recurrence of prostate cancer after primary therapy. Preclinical, proof-of-principle studies have demonstrated that nitric oxide signaling plays a significant role in the hypoxia-induced progression of prostate cancer.

Methods

A prospective, open-label clinical trial of men with an increasing prostate-specific antigen (PSA) level after surgery or radiotherapy was conducted. Men with PSA recurrence were enrolled in a 24-month trial investigating the effect of a low-dose, slow-release transdermal GTN patch. The PSA doubling time (PSADT) was compared before and after treatment initiation, as well as with a matched control group that received no immediate treatment for their PSA recurrence.

Results

A total of 29 patients were enrolled in the study. Of the 29 patients, 62% completed the 24-month protocol, with 10% experiencing clinical disease progression. The calculated PSADT of the treatment group before initiating GTN was 13.3 months, not significantly different from that of the matched control group at 12.8 months. In an intention-to-treat analysis, the end-of-study PSADT for the treatment group was significantly different at 31.8 months (P < .001).

Conclusions

We report the first clinical trial of a GTN patch in patients with prostate cancer. The prolongation of the PSADT and the safety of the drug, coupled with the corresponding preclinical in vitro and in vivo data documenting the ability of nitric oxide to attenuate hypoxia-induced progression of prostate cancer, warrant further testing in a placebo-controlled study.

Section snippets

Material and Methods

This study was a prospective Phase II, open-label clinical trial of men with PSA recurrence after primary treatment of prostate cancer. The patients were enrolled from May 2001 to June 2004. The institutional review board of Queen's University reviewed and approved the study, which was investigator initiated, without industry sponsorship.

The patients included in the present study were those who had undergone previous treatment with definitive radiotherapy (n = 10) or radical prostatectomy (n =

Results

Of the 29 patients enrolled in the study, 17 (58%) completed the entire 24 months of the study medication. Only 3 of the 29 patients (10%) had documented disease progression at 3, 9, and 21 months during the trial. Of these 3 patients, 2 had documented asymptomatic bony metastases on bone scan performed for suspicious PSADTs. One patient had bony metastases confirmed on magnetic resonance imaging 3 months after initiation of the study. Magnetic resonance imaging was performed for an equivocal

Comment

PSA is widely accepted as the most useful prognostic marker of prostate cancer progression, particularly after primary therapy with radical surgery or radiotherapy.17 Despite the improved cancer control rates with definitive management of early-stage prostate cancer, PSA recurrence is common (25%-50%) in most large case series.2, 3, 4 However, given the generally prolonged natural history of prostate cancer, this biochemical recurrence predates radiologic or clinical evidence of disease by a

Conclusions

The results of our study suggest that low-dose GTN has a consistent, inhibitory effect on PSA progression in men with recurrent prostate cancer after primary treatment failure. These significant effects on the slowing, and even stabilization, of the PSADT suggest a non-random drug effect of GTN. Implementation of strategies that could prolong the PSADT, thereby delaying the time to treatment with hormonal therapy and to death, would be of great benefit to patients. Our findings appear to

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