A Multi-Institutional Pilot Study of Adjuvant Docetaxel for Patients with Prostate Cancer at High Risk for Relapse After Radical Prostatectomy

OPTIMIZING TREATMENT FOR ADVANCED PROSTATE CANCER A Multi-Institutional Pilot Study of Adjuvant Docetaxel for Patients with Prostate Cancer at High Risk for Relapse after Radical Prostatectomy Mario A. Eisenberger, MD Departments of Oncology and Urology, The Johns Hopkins Medical Institutions, Baltimore, MD The management of patients with high-risk, early-stage, prostate cancer represents a major challenge to all disciplines involved in the treatment of this common malignant neoplasm. A definition of the natural history of this disease—including the identification of key prognostic factors—and the availability of active systemic therapeutic modalities for patients with advanced disease are among the basic requirements needed to provide for early intervention in high-risk patients. Several cytotoxic chemotherapy regimens have demonstrated significant antitumor effects in patients with hormone-refractory disease. Docetaxel (Taxotere®, Aventis Pharmaceuticals, Bridgewater, NJ), a widely used taxane with broad antitumor activity, likely represents the most active single agent in prostate cancer treatment. Current data indicate that 40%–60% of patients treated with docetaxel have exhibited evidence of benefit from treatment with docetaxel, both alone and in combination with estramustine, with acceptable toxicity. In this review we describe a pilot study that is currently entering patients at high risk for relapse after radical prostatectomy. This study was designed to evaluate the safety, feasibility, and preliminary efficacy of docetaxel given postoperatively for 6 months. The main study endpoint is time-to-biochemical-relapse, which will be assessed against a matched group of historical controls. [Rev Urol. 2003;5(suppl 2):S42-S47] © 2003 MedReviews, LLC Key words: Adjuvant chemotherapy • Hormone-refractory prostate cancer • Radical prostatectomy • Docetaxel • Nomograms rostate cancer remains the most common malignant neoplasm diagnosed in adult males in the United States.1 During the past 15 years, widespread clinical utilization of the prostate-specific antigen (PSA) test has resulted in earlier identification of evidence of disease activity, and this has resulted in a P S42 VOL. 5 SUPPL. 2 2003 REVIEWS IN UROLOGY Study of Adjuvant Docetaxel in High-Risk Radical Prostatectomy Patients the rates for regimens employed for the treatment of diseases such as breast cancer and colon cancer, for which adjuvant chemotherapy has been shown to prolong survival. Active treatment regimens should be selected that are associated with acceptable toxicity and can be easily administered in the ambulatory setting. In this review, we discuss the background and rationale of an ongoing multi-institutional pilot study designed to evaluate the feasibility, safety, and preliminary efficacy of a surgical adjuvant chemotherapy program for patients who demonstrate pathologic evidence of extensive local/regional disease and are at high risk for biochemical and eventual systemic relapse following radical prostatectomy. Table 1 Univariate and Multivariate Cox Proportional Hazards Analyses of Variables Predicting for Biochemical Recurrence (The Johns Hopkins Series) Hazard Ratio 95% CI P 6.58-13.90 0.001 Univariate Analysis (+) Lymph nodes 9.56 (+) Extraprostatic extension 7.58 4.27-13.44 0.001 (+) Seminal vesicles 7.48 5.23-10.68 0.001 (+) Surgical margins 4.25 2.96-6.09 0.001 Modified Gleason score 2.50 2.17-2.88 0.001 Clinical stage 1.47 1.27-1.70 0.001 Prostate-specific antigen 1.06 1.04-1.07 0.001 Age 1.03 1.01-1.07 0.004 (+) Lymph nodes 4.20 2.68-6.58 0.001 (+) Surgical margins 3.17 2.19-4.60 0.001 Modified Gleason score 2.02 1.72-2.36 0.001 (+) Seminal vesicles 1.66 1.07-2.59 0.02 Multivariate Analysis Prediction of Relapse After Radical Prostatectomy CI, confidence interval. Adapted from Roberts et al.13 significant increase in the proportion of patients initially presenting with early stages of disease. Currently, over 50% of newly diagnosed patients have clinically localized disease treated either with radical prostatectomy, external beam radiation, or brachytherapy, alone or in combination.2,3 Data from uncontrolled studies suggest that 40%–60% of patients treated with local modalities will demonstrate evidence of biochemical relapse during a 10-year follow-up period.4 The relative risk for the development of biochemical recurrence is dependent on various preoperative and postoperative clinical and pathologic factors. Multivariate analyses indicate that the most significant independent predictors are preoperative PSA, pathologic T stage, and final Gleason score (based on the prosta- tectomy specimen).4-8 Various investigators have developed nomograms and mathematical models to estimate the relative risk of biochemical recurrence in patients with clinically localized disease treated with radical prostatectomy. These models can be Several studies have reported on various prospective and retrospective factors that may assist in defining the risk for relapse after radical prostatectomy. The most commonly reported statistically significant, independent predictors are preoperative PSA, percent of positive (initial) biopsy, pathologic stage, surgical Gleason score (based on the prostatectomy specimen), and possibly a number The experiences with cytotoxic chemotherapy in patients with advanced hormone-refractory disease indicate consistent response rates of approximately 40%–60% with taxane-based regimens. utilized in the selection of patients and the design of clinical trials The experiences with cytotoxic chemotherapy in patients with advanced hormone-refractory disease indicate consistent response rates of approximately 40%–60% with taxane-based regimens.9 These response rates are comparable to or better than of molecular markers that define the biology of the disease.4-8 Various independent groups of investigators have developed mathematical models and nomograms that allow for postoperative prediction of biochemical recurrence and for the definition of risk groups based on preoperative and surgically determined prognostic VOL. 5 SUPPL. 2 2003 REVIEWS IN UROLOGY S43 Study of Adjuvant Docetaxel in High-Risk Radical Prostatectomy Patients continued Table 2 Predicted Biochemical Recurrence-Free Survival Probabilities After 5 and 7 Years in Patients with Non–Organ-Confined Disease After Radical Prostatectomy (The Johns Hopkins Series) Gleason Score PSA 0.0–4.0 ng/mL (95% CI) PSA 4.1–10.0 ng/mL (95% CI) PSA 10.1–20.0 ng/mL (95% CI) PSA > 20.0 ng/mL (95% CI) Gleason 5 5 years 7 years 0.98 (0.93-0.99) 0.97 (0.89-0.99) 0.95 (0.87-0.98) 0.93 (0.82-0.98) 0.91 (0.77-0.97) 0.87 (0.67-0.95) 0.83 (0.56-0.95) 0.77 (0.42-0.92) Gleason 6 5 years 7 years 0.94 (0.84-0.98) 0.92 (0.78-0.97) 0.90 (0.75-0.96) 0.86 (0.66-0.95) 0.84 (0.61-0.94) 0.77 (0.48-0.91) 0.74 (0.41-0.90) 0.64 (0.26-0.86) Gleason 3 + 4 5 years 7 years 0.87 (0.67-0.95) 0.81 (0.55-0.93) 0.81 (0.55-0.93) 0.73 (0.41-0.89) 0.72 (0.40-0.89) 0.62 (0.26-0.84) 0.61 (0.23-0.84) 0.48 (0.12-0.78) Gleason 4 + 3 5 years 7 years 0.71 (0.38-0.89) 0.60 (0.24-0.84) 0.63 (0.28-0.85) 0.51 (0.15-0.79) 0.54 (0.17-0.80) 0.40 (0.08-0.73) 0.43 (0.09-0.75) 0.29 (0.03-0.66) Gleason 8–10 5 years 7 years 0.44 (0.09-0.75) 0.30 (0.03-0.66) 0.37 (0.06-0.71) 0.24 (0.02-0.60) 0.31 (0.03-0.67) 0.18 (0.01-0.55) 0.25 (0.02-0.63) 0.13 (0.00-0.51) PSA, prostate-specific antigen. Adapted from Han et al.14 parameters.4-8 In addition to the standard pathologic examination, various histopathologic determinants and molecular markers have been evaluated for prediction of PSA recurrence and survival.10,11 In recent reports, Johns Hopkins investigators12,13 updated a previously described biostatistical model12 that was developed in an attempt to define the risk for biochemical recurrence of patients with clinically localized disease (T1c and T2). The data outline many of the same prognostic factors that are important predictors of biochemical relapse: extraprostatic involvement, prostatectomy Gleason score, surgical margins, lymph node status, and seminal vesicle involvement (see Table 1). A modified Gleason score was developed to further distribute the mid-range scores. Multivariate analysis yielded an equation that estimates S44 VOL. 5 SUPPL. 2 2003 the relative risk for biochemical recurrence. Coefficients and hazard ratios were then calculated in a multivariate Cox proportional hazards analysis employing four selected variables (shown in Table 1) and yielded an equation employed for defining the patient population of this study: RW' = lymph node involvement (0/1)  1.43 + seminal vesicle involvement (0/1)  0.51 + surgical margin status (0/1)  1.15 + modified Gleason score (0–4)  0.71. Patients at high risk for recurrence were defined as having a value of > 2.84, which was selected because it resulted in a > 50% rate of biochemical recurrence by 3 years. Interestingly, in this model the pretreatment PSA was not shown to be an independent REVIEWS IN UROLOGY predictor of biochemical relapse (defined as PSA levels of > 0.2 ng/mL and rising); this may, however, reflect the patterns of the pretreatment PSA levels of the patient population evaluated. The 3-, 5- and 10-year biochemical relapse-free survival rates were 42%, 35%, and 18%, respectively, in the high-risk group and 95%, 91%, and 82%, respectively, in the low-risk group. A recent publication of the Johns Hopkins series, which included 2091 patients with clinically localized disease, described a nomogram (corrected for decreasing relative risk of biochemical recurrence over time) for the prediction of biochemical relapse after radical prostatectomy.14 The figures for patients with non– organ-confined disease describing actuarial cancer-specific survival probabilities at 5 and 7 years are shown in Table 2. Study of Adjuvant Docetaxel in High-Risk Radical Prostatectomy Patients Table 3 Clinical Trials of Docetaxel as a Single Agent and in Combination with Estramustine Efficacy (PSA decline ≥ 50%), % Measurable Disease Response Rate, % Study No. of Patients Kreis 17 Docetaxel 40–80 mg/m2 q 21 d Estramustine 14 mg/kg/d divided tid qd 82 17 Savarese 47 Docetaxel 70 mg/m2 Estramustine 10 mg/kg/d  5 d q 21 d 69 22 Petrylak 35 Docetaxel 70 mg/m2 Estramustine 280 mg, tid  5 d q 21 d 74 57 Copur 18 Docetaxel 35 mg/m2/wk Estramustine tid  3 d 420 mg for 4 doses 280 mg for 5 doses q wk  2 of 3 wk 72 50 Sinibaldi 32 Docetaxel 70 mg/m2 Estramustine 280 mg q 6 hr  5 doses q 21 d 45 23 Picus 35 Docetaxel 75 mg/m2 q 21 d 46 24 Berry 61 Docetaxel 36 mg/m2/wk  6 wk, followed by 2-wk break 41 33 Beer 23 Docetaxel 36 mg/m2/wk  6 wk, followed by 2-wk break 47 N/A Treatment PSA, prostate-specific antigen. Adapted from Laufer et al.18 Rationale fo r the Selection of Systemic Treatment Docetaxel is a semisynthetic taxane that has been approved by the Food and Drug Administration for the treatment of metastatic breast cancer as well as for first-line therapy for lung cancer and second-line therapy for platinum-refractory non-small cell lung cancer. Docetaxel acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells.15 The inactivation of bcl-216 and the induction of cyclin-dependent kinase p27/Kip-1 expression17 have also been suggested as possible mechanisms of the antitumor effect of docetaxel. Docetaxel has been combined with estramustine in the treatment of hormone-refractory prostate cancer, and the combination has been shown to achieve 50% PSA reductions in a range of 45%–82% of patients (see Table 3).18 The combination of docetaxel and estramustine is currently being studied in a randomized, phase III study in hormone-refractory prostate cancer. Of note, however, is the fact that this combination has been associated with a significant rate of thrombotic complications, generally around 10%. As the thrombotic events have been largely attributed to the administration of estramustine, a number of investigators have studied single-agent docetaxel in hormonerefractory prostate cancer. Picus and colleagues19 administered single-agent docetaxel at a dose of 75 mg/m2 every 3 weeks, with 46% of patients achieving a 50% decline in PSA (Table 3). The treatment was associated with grade 3/4 neutropenia in 43% of these patients. Other VOL. 5 SUPPL. 2 2003 REVIEWS IN UROLOGY S45 Study of Adjuvant Docetaxel in High-Risk Radical Prostatectomy Patients continued investigators have chosen to administer docetaxel on a weekly schedule because of its relatively low incidence of acute toxicities, including myelosuppression, compared with the every-three-weeks schedule. In separate studies, Berry20 and associ- currently entering patients across the United States. Docetaxel administered weekly has been selected for this adjuvant study, based on the regimen’s efficacy and relatively favorable side-effects profile. Favorable results in this phase II Two studies treated patients with single-agent docetaxel at a weekly dose of 36 mg/m2 for 6 consecutive weeks followed by a 2-week rest; the PSA-response proportions were 41% and 47%, respectively. In both studies the grade 3/4 neutropenia rate was < 10%. ates and Beer21 and coworkers treated patients with single-agent docetaxel at a weekly dose of 36 mg/m2 for 6 consecutive weeks followed by a 2-week rest; the PSA-response proportions were 41% and 47%, respectively (see Table 3). In both studies the grade 3/4 neutropenia rate was < 10%. Study Synopsis A multicenter, open-label, phase II trial of adjuvant docetaxel in patients at high risk of relapse following prostatectomy is being sponsored by the Roswell Park Cancer Institute and the National Cancer Institute and is study would support the investigation of docetaxel as adjuvant therapy in prostate cancer. Docetaxel will be administered at a dose of 35 mg/m2 as a 30-minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Patients will be treated for 6 cycles unless there is evidence of progressive disease, unacceptable side effects, or withdrawal of consent. Patients will be followed for disease progression for 3 years after the prostatectomy. Inclusion Criteria Patients with prostate cancer who are currently postprostatectomy and are at high risk of progression of disease as defined by an RW' > 2.84 will be included in this study. Duration of Treatment Patients will be treated for 6 cycles or until one of the following events occurs, whichever is first: • Disease progression • Unacceptable toxicity • Any medical or social situation that would make it unsafe and/or unethical to continue with treatment • Patient’s request to withdraw from the study for any reason. Criteria for Evaluation Efficacy analysis. The primary end points of the study will be the 2-year and 3-year progression-free survival rates. Safety. Clinical and laboratory toxicities will be graded according to the National Cancer Institute Common Toxicity Criteria, Version 2.0. Statistical Procedures To determine the 2-year progressionfree survival, we will compare the null hypothesis H0:P = 60% for the progression-free survival rate of the Main Points • The most commonly reported statistically significant independent predictors of risk for relapse after radical prostatectomy are preoperative prostate-specific antigen (PSA), percent of positive (initial) biopsy specimens, pathologic T stage, surgical Gleason score (based on the prostatectomy specimen), and possibly molecular markers. • Investigators have devised mathematical models and nomograms to predict biochemical recurrence after radical prostatectomy and define risk groups. • Patients with advanced hormone-refractory disease indicate consistent response rates of approximately 40%–60% with taxane-based regimens. • Docetaxel, a semisynthetic taxane approved by the Food and Drug Administration, as a single agent, for the treatment of metastatic breast cancer and first-line and second-line platinum-refractory non-small cell lung cancer, has been combined with estramustine in the treatment of hormone-refractory prostate cancer; the combination has achieved 50% PSA reductions in a range of 45%–82% of patients. • An ongoing multicenter, open-label, phase II trial of adjuvant docetaxel in patients at high risk of relapse following prostatectomy is described. The study was designed to evaluate the safety, feasibility, and preliminary efficacy of docetaxel given postoperatively for 6 months. Favorable results in this phase II study would support the investigation of docetaxel as adjuvant therapy in prostate cancer. S46 VOL. 5 SUPPL. 2 2003 REVIEWS IN UROLOGY Study of Adjuvant Docetaxel in High-Risk Radical Prostatectomy Patients historical group with the alternate hypothesis H1:P = 79% for the progression-free survival rate of the treatment group. To determine the 3-year progression-free survival, we will compare the null hypothesis H0:P = 50% for the progression-free survival rate of the historical control group with the alternate hypothesis H1:P = 69% for the progression-free survival rate of the treatment group. Confidence intervals for the response rates will also be estimated. The width of the confidence intervals for the progression-free survival rates is expected to be 24%. The KaplanMeier curves for the progression-free survival for the historical control group and the treatment group will be compared by using log-rank and/or Wilcoxon tests. A statistical analysis will also be performed using the Cox proportional hazards model to investigate the possible differences in progression-free survival for subgroups of the study participants. These subgroups will be examined retrospectively for the purpose of generating hypotheses. In summary, taxane-based, systemic chemotherapy regimens have shown a consistent rate of clinical benefit for patients with hormone-refractory disease. These data serve as further evidence of a non-hormonal, cytotoxic regimen’s antitumor activity and advance the possibility of a new modality of treatment that could be employed in the early stages of disease. 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