Oliver M. Bautista

Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo.

PURPOSEnWe analyzed data from the placebo arm of the MTOPS trial to determine clinical predictors of BPH progression.nnnMATERIALS AND METHODSnA total of 3,047 patients with LUTS were randomized to either placebo, doxazosin (4 to 8 mg), finasteride (5 mg), or a combination of doxazosin and finasteride. Average length of followup was 4.5 years. The primary outcome was time to overall clinical progression of BPH, defined as either a confirmed 4-point or greater increase in AUA SS, acute urinary retention, incontinence, renal insufficiency, or recurrent urinary tract infection. We analyzed BPH progression event data from the 737 men who were randomized to placebo.nnnRESULTSnThe rate of overall clinical progression of BPH events in the placebo group was 4.5 per 100 person-years, for a cumulative incidence (among men who had at least 4 years of followup data) of 17%. The risk of BPH progression was significantly greater in patients on placebo with a baseline TPV of 31 ml or greater vs less than 31 ml (p <0.0001), a baseline PSA of 1.6 ng/dl or greater vs PSA less than 1.6 ng/dl (p = 0.0009), a baseline Qmax of less than 10.6 ml per second vs 10.6 ml per second or greater (p = 0.011), a baseline PVR of 39 ml or greater vs less than 39 ml (p = 0.0008) and baseline age 62 years or older vs younger than 62 years (p = 0.0002).nnnCONCLUSIONSnAmong men in the placebo arm, baseline TPV, PSA, Qmax, PVR and age were important predictors of the risk of clinical progression of BPH.

Study design of the medical Therapy of Prostatic Symptoms (MTOPS) trial

Alpha-blockers and 5-alpha-reductase inhibitors are medical therapies that are being used as alternatives to surgical interventions to relieve symptoms of benign prostatic hyperplasia (BPH). Taken as monotherapy, alpha-blockers and 5-alpha-reductase inhibitors have each been shown to provide relief from BPH symptoms. Treatment with finasteride over 4 years has been shown to reduce both BPH symptoms and the likelihood of acute urinary retention and the need for surgery. Direct comparison of the alpha-blocker terazosin with finasteride has been done, but only for a period of 1 year. The Medical Therapy of Prostatic Symptoms (MTOPS) trial is a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to evaluate the long-term efficacy of the alpha-blocker doxazosin and the 5-alpha-reductase inhibitor finasteride, whether taken as a monotherapy or in combination, in preventing or delaying the progression of BPH. We describe in this paper the design of the MTOPS trial, the concept of BPH progression, the definition and methods of determining the primary outcome events and the proposed statistical analysis methods. A unique feature of MTOPS is the inclusion of prostate biopsies on a subgroup of randomized participants. Volunteers among randomized participants are to undergo a biopsy of the prostate at predetermined time points during the trial. Studies that will be conducted using the tissue specimens collected in MTOPS can potentially provide information at the molecular level on the natural history of BPH among medically treated and untreated men with moderate to severe symptoms of BPH.

A 9-Valent HPV Vaccine in Women.

To the Editor: Joura et al. (Feb. 19 issue)1 report that the 9-valent vaccine against human papillomavirus (9vHPV) had an efficacy of 96.7% to prevent high-grade cervical, vulvar, or vaginal dysplasia related to HPV types 31, 33, 45, 52, and 58 in women. Men who are positive for the human immunodeficiency virus and who have sex with men (HIV+MSM) have a strongly increased risk of persistent anogenital HPV infection and associated anal or penile intraepithelial neoplasia (AIN or PIN) and cancer.2,3 The quadrivalent HPV vaccine effectively prevents disease related to HPV types 6, 11, 16, and 18 in both women and men.4,5 We have analyzed the HPV spectrum in 451 biopsy specimens of AIN, PIN, and anal and penile cancer obtained from men categorized as HIV+MSM (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).2 Although only 45% of the lesions carried HPV types covered by the quadrivalent HPV vaccine, 68% of the HPV types are likely to be covered by the 9vHPV vaccine. Most important, 55% of anal and penile cancers carried the five HPV types that are included only in the 9vHPV vaccine. Unfortunately, HPV vaccination of boys and male adolescents is not yet recommended in several countries that cover HPV vaccination of girls in their national vaccination programs. If future studies show that the 9vHPV vaccine is as effective in men as in women, this vaccine should not be withheld from males.

A Flexible Stochastic Curtailing Procedure for the Log-Rank Test

For safety and ethical reasons, a data monitoring committee of a clinical trial may wish to assess the futility of continuing a trial if the currently available data at an interim look show no beneficial effect due to treatment, especially when accompanied by mounting evidence of treatment emergent adverse effects. Stochastic curtailing whereby conditional power is evaluated given currently observed data is one way of evaluating futility. In clinical trials that look at time-to-event as the primary outcome, difference between treatment groups with respect to the primary outcome is commonly evaluated using the log-rank test. Although the unconditional power function for the log-rank test has been described previously, its conditional power has not been widely investigated. We describe a method for evaluating conditional power when the log-rank test is used to assess the difference between the survival distributions of two treatment groups with respect to some failure-time outcome. The method is useful under a wide range of assumptions regarding the underlying survival distribution, patient entry distribution, losses to follow-up, and (if applicable) noncompliance, drop-ins, lag in treatment effect, and stratification. This level of applicability is attained by generalizing a flexible Markov chain approach to unconditional power computation, described previously, to compute conditional power.

Stratified-adjusted versus unstratified assessment of sample size and power for analyses of proportions

In any scientific investigation, it is important to evaluate the adequacy of sample size with regard to one’s ability to provide clear answers to the questions posed. In many cases, this assessment is based upon the power of a statistical test for the comparison of two groups with respect to the probability of some event or characteristic in two independent samples of subjects. In the simplest case, the proportions of subjects with some characteristic are compared between the two groups using a standard chi-square or Z-test for a 2 × 2 table. Various authors have described expressions for the approximate power of the large sample chi-square test, the most widely used being the expression based upon the large sample Z-test for two proportions of Halperin et al. [1]. This and other widely used procedures for the evaluation of sample size on the basis of power are reviewed by Lachin [2] and Donner [3], among others. This approach is based upon an unconditional or marginal assessment of the treatment group difference without consideration of other covariate effects.