Menachem Laufer

Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma.

Recent clinical trials have shown antitumor activity with the combination of docetaxel plus estramustine phosphate (EMP) in the treatment of patients with androgen independent prostate carcinoma (AIPC). However, the most commonly employed treatment schedules with EMP have been associated with significant gastrointestinal, cardiovascular, and thromboembolic toxicity. The authors hypothesized that the therapeutic index of the combination of docetaxel plus EMP for patients with prostate carcinoma could be enhanced by reducing the incidence and severity of EMP‐associated toxicity, which could be accomplished by shortening the duration of exposure to EMP. To preserve the therapeutic synergism between docetaxel and EMP, they designed a regimen employing higher doses of oral EMP administered on the day of the docetaxel infusion.

COMPLETE ANDROGEN BLOCKADE FOR PROSTATE CANCER: WHAT WENT WRONG?

PURPOSE We summarized and critically assessed all available data from phase III clinical trials on complete androgen blockade versus surgical or medical castration alone. MATERIALS AND METHODS Published results in journals and abstracts of phase III trials, and published meta-analyses were reviewed. We also reviewed quality of life and toxicity issues associated with the addition of antiandrogens to medical or surgical castration. Finally, we discuss the original rationale for complete androgen blockade in the context of current knowledge. RESULTS A total of 27 clinical trials using various combinations of androgen deprivation were identified, of which 3 showed a statistically significant benefit for the complete androgen blockade arm. There were 5 publications of meta-analyses that each used different selection criteria for the inclusion of studies in the final analysis. Toxicity and quality of life have not been widely investigated in prospective fashion but the available data suggest a higher toxicity rate and decreased quality of life with complete androgen blockade. CONCLUSIONS The extensive body of data does not support routine use of antiandrogens in combination with medical or surgical castration as first line hormonal therapy in patients with metastatic prostate cancer.

Marimastat in the Treatment of Patients with Biochemically Relapsed Prostate Cancer: A Prospective Randomized, Double-Blind, Phase I/II Trial

Purpose: To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer. Experimental Design: Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred. Results: Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9% and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and −0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02). Conclusion: These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening antimetastatic agents.

MANAGEMENT OF PATIENTS WITH RISING PROSTATE-SPECIFIC ANTIGEN AFTER RADICAL PROSTATECTOMY

During the past 12 years, routine use of serum prostate-specific antigen (PSA) has resulted in a major rise in the proportion of patients initially diagnosed with clinically localized disease and the average age at diagnosis has declined. 1,2 These important demographic changes, coupled with major improvements in surgical technique, resulted in a sharp increase in the number of advocates for radical prostatectomy (RP) as definitive treatment for prostate cancer. 3,4 After curative RP, the serum PSA level should become undetectable, and the detection of elevated levels at any time after about 4 weeks postoperatively reflects evidence of disease recurrence. 5 The incidence of disease recurrence while PSA is undetectable is extremely low, although it might be observed in very poorly differentiated tumors or neoplasms of distinct histologic subtypes. 6,7 The first evidence of disease recurrence after RP is manifested by a consistent elevation of serial serum PSA tests, usually without any associated objective findings. 5 The probability of biochemical relapse at 5 and 10 years, reported in several large series, has ranged between 20% and 31% and 27% and 53%, respectively. 7‐10 Various factors, including differences in patient populations, duration of followup, and the definition of PSA recurrence (0.2 to 0.6 ng/mL), might account for the variance in the reported rates. On the basis of the number of RPs performed and the cumulative figures of biochemical relapse rates, it can be estimated that thousands of patients present annually to clinicians throughout the world with an elevated PSA level as the only evidence of disease. At present, the natural history of the patient with biochemical relapse after RP remains poorly defined, and no criteria are uniformly accepted for implementation of treatment for these patients. The management philosophy has been influenced primarily by physicians’ and patients’ biases, and it is becoming obvious that despite the lack of consensus, early interventions are more commonly applied than observation only. Our objective was to review the published reports dealing with the evaluation, natural history, and treatment of patients with a rising PSA after RP for clinically localized prostate cancer and to provide the necessary groundwork for the development of clinical research on this challenging problem.