New England Journal of Medicine Volume 352:1977-1984, May 12, 2005, Number 19

Anna Bill-Axelson, M.D., Lars Holmberg, M.D., Ph.D., Mirja Ruutu, M.D., Ph.D., Michael Häggman, M.D., Ph.D., Swen-Olof Andersson, M.D., Ph.D., Stefan Bratell, M.D., Ph.D., Anders Spångberg, M.D., Ph.D., Christer Busch, M.D., Ph.D., Stig Nordling, M.D., Ph.D., Hans Garmo, Ph.D., Juni Palmgren, Ph.D., Hans-Olov Adami, M.D., Ph.D., Bo Johan Norlén, M.D., Ph.D., Jan-Erik Johansson, M.D., Ph.D., for the Scandinavian Prostate Cancer Group Study No. 4

ABSTRACT

Background In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results.

Methods From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression.

Results During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test).

Conclusions Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.

Risk of Prostate Cancer-Specific Mortality Following Biochemical Recurrence After Radical Prostatectomy

JAMA. 2005;294:433-439

Stephen J. Freedland, MD; Elizabeth B. Humphreys, BS; Leslie A. Mangold, MS; Mario Eisenberger, MD; Frederick J. Dorey, PhD; Patrick C. Walsh, MD; Alan W. Partin, MD, PhD

Context The natural history of biochemical recurrence after radical prostatectomy can be long but variable. Better risk assessment models are needed to identify men who are at high risk for prostate cancer death early and who may benefit from aggressive salvage treatment and to identify men who are at low risk for prostate cancer death and can be safely observed.

Objectives To define risk factors for prostate cancer death following radical prostatectomy and to develop tables to risk stratify for prostate cancer-specific survival.

Design, Setting, and Patients Retrospective cohort study of 379 men who had undergone radical prostatectomy at an urban tertiary care hospital between 1982 and 2000 and who had a biochemical recurrence and after biochemical failure had at least 2 prostate-specific antigen (PSA) values at least 3 months apart in order to calculate PSA doubling time (PSADT). The mean (SD) follow-up after surgery was 10.3 (4.7) years and median follow-up was 10 years (range, 1-20 years).

Main Outcome Measure Prostate cancer-specific mortality.

Results Median survival had not been reached after 16 years of follow-up after biochemical recurrence. Prostate-specific doubling time (<3.0 vs 3.0-8.9 vs 9.0-14.9 vs 15.0 months), pathological Gleason score ( 7 vs 8-10), and time from surgery to biochemical recurrence ( 3 vs >3 years) were all significant risk factors for time to prostate-specific mortality. Using these 3 variables, tables were constructed to estimate the risk of prostate cancer-specific survival at year 15 after biochemical recurrence.

Conclusion Clinical parameters (PSADT, pathological Gleason score, and time from surgery to biochemical recurrence) can help risk stratify patients for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. These preliminary findings may serve as useful guides to patients and their physicians to identify patients at high risk for prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy to enroll them in early aggressive treatment trials. In addition, these preliminary findings highlight that survival in low-risk patients can be quite prolonged.

Long-Term Outcomes Among Localized Prostate Cancer Survivors: Health-Related Quality-of-Life Changes After Radical Prostatectomy, External Radiation, and Brachytherapy

Journal of Clinical Oncology, Vol 23, No 12 (April 20), 2005: pp. 2772-2780 © 2005 American Society of Clinical Oncology

David C. Miller, Martin G. Sanda, Rodney L. Dunn, James E. Montie, Hector Pimentel, Howard M. Sandler, William P. McLaughlin, John T. Wei

PURPOSE: We sought to elucidate long-term changes in health-related quality-of-life (HRQOL) outcomes by prospectively re-evaluating a well-characterized cohort of prostate cancer (PC) survivors 4 to 8 years after primary treatment.

PATIENTS AND METHODS: Patients who had been evaluated previously at a median of 2.6 years after radical prostatectomy (RP), external radiation (three-dimensional conformal radiation therapy [3-D CRT]), or brachytherapy (BT) were recontacted at a median of 6.2 years after treatment. The clinical relevance of long-term HRQOL impairment among survivors was established by comparison with controls of similar age. Factors associated with HRQOL changes during this interval were evaluated.

RESULTS: Of the 964 eligible men, 709 (73.5%) completed measurable questionnaires. In four domains (urinary irritative-obstructive, urinary incontinence, bowel, and sexual), significant HRQOL differences were detected for at least one of the therapy groups, compared with controls (all P < .05). During the 4-year interval, significant improvement was observed for the urinary irritative-obstructive (P < .0001) and bowel (P < .0001) domains among BT patients, whereas urinary incontinence HRQOL worsened for both the BT (P = .0017) and 3-D CRT (P = .0008) treatment groups. Overall sexual HRQOL deteriorated for the 3-D CRT cohort (P = .0017), as well as for controls (P = .0136). Among RP patients, significant HRQOL changes were not observed.

CONCLUSION: During a 4-year interval from earlier to longer-term phases of PC treatment survivorship, sexual, urinary, and bowel dysfunction remain significant concerns among early-stage PC treatment survivors, compared with control men. Although postprostatectomy HRQOL remains relatively stable during this interval, disease-specific HRQOL continues to evolve among men treated with BT and 3-D CRT.

FAILURE AFTER PRIMARY RADIATION OR SURGERY FOR PROSTATE CANCER: DIFFERENCES IN RESPONSE TO ANDROGEN ABLATION

The Journal of Urology Volume 172(2) August 2004 p 525-528

GREGORY P. SWANSON, MARK RIGGS, JOHN EARLE

ABSTRACT

Purpose: Androgen ablation is the standard treatment for recurrent and metastatic prostate cancer. Surprisingly few studies have documented the specific results for local and distant failure in patients treated primarily with radiation or radical prostatectomy. We report the long-term outcome of a series of those patients.

Materials and Methods: We followed until death 94 patients in whom primary radiation therapy failed and 67 in whom radical prostatectomy failed. All patients received androgen ablation.

Results: Statistically (p = 0.04) more patients in the radiation group (78%) died of prostate cancer than in the radical prostatectomy group (63%). Of the radiation group with local failure alone 63%, died of prostate cancer at a median of 5.03 years. Of the surgery group with isolated local failure 50% died of cancer at a median of 9.83 years. Of the patients treated with radiation with distant metastasis 93% died of cancer with a median time to death of 2.34 years. Of the patients treated with surgery 69% died of prostate cancer at a median of 3.27 years. The differences in survival between the 2 groups was significant.

Conclusions: This study is unique in providing followup until death of patients treated with radical prostatectomy and radiation who had clinical failure and were treated with androgen ablation. Compelling is the finding that survival after androgen ablation after surgical failure is superior to that for radiation. If confirmed, this would be a significant consideration for future studies of patients in whom primary therapy fails.

Key Words: androgens, prostatic neoplasms, radiotherapy, prostatectomy

Pretreatment PSA Velocity and Risk of Death From Prostate Cancer Following External Beam Radiation Therapy

JAMA. 2005;294:440-447

Anthony V. D'Amico, MD, PhD; Andrew A. Renshaw, MD; Brenda Sussman, RN, OCN; Ming-Hui Chen, PhD

Context Men with localized prostate cancer and a preoperative prostate-specific antigen (PSA) velocity greater than 2.0 ng/mL per year experience a 10-fold increase in prostate cancer-specific mortality despite surgery.

Objective To assess whether a greater than 2.0-ng/mL increase in PSA level during the year prior to diagnosis was significantly associated with prostate cancer-specific mortality following radiation therapy (RT).

Design, Setting, and Patients Between January 1, 1989, and December 1, 2002, 358 men treated with RT for localized prostate cancer formed the study cohort (median age at treatment, 71.2 [range, 43.2-83.5] years). A Cox regression multivariable analysis was used to evaluate whether a PSA velocity greater than 2.0 ng/mL per year was significantly associated with prostate cancer-specific mortality and all-cause mortality after controlling for prognostic factors available at diagnosis.

Main Outcome Measure Time to prostate cancer-specific mortality for the 125 men with low-risk prostate cancer (clinical tumor category T1c or T2a and PSA level <10.0 ng/mL and Gleason score 6) and the 233 men with higher-risk disease, stratified by the PSA velocity.

Results A PSA velocity greater than 2.0 ng/mL per year was significantly associated with a shorter time to prostate cancer-specific mortality (adjusted hazard ratio [HR], 12.0; 95% confidence interval [CI], 3.0-54.0; P = .001) and all-cause mortality (adjusted HR, 2.1; 95% CI, 1.3-3.6; P = .005) when compared with men whose PSA velocity was 2.0 ng/mL per year or less. Men presenting with low-risk disease and a PSA velocity greater than 2.0 ng/mL per year had a 7-year estimate of prostate cancer-specific mortality of 19% (95% CI, 2%-39%) compared with 0% for men whose PSA velocity was 2.0 ng/mL per year or less. The corresponding values for men with higher-risk disease were 24% (95% CI, 12%-37%) and 4% (95% CI, 0%-11%), respectively.

Conclusions A greater than 2.0-ng/mL increase in PSA level during the year prior to diagnosis is associated with a significantly higher risk of death due to prostate cancer following RT despite having low-risk disease. Such men who are planning to undergo RT and are in good health could be considered for RT combined with androgen suppression therapy because this approach improves survival in men with higher-risk disease.

20-Year Outcomes Following Conservative Management of Clinically Localized Prostate Cancer

JAMA. 2005;293:2095-2101.

Peter C. Albertsen, MD, MS; James A. Hanley, PhD; Judith Fine, BA

Context The appropriate therapy for men with clinically localized prostate cancer is uncertain. A recent study suggested an increasing prostate cancer mortality rate for men who are alive more than 15 years following diagnosis.

Objective To estimate 20-year survival based on a competing risk analysis of men who were diagnosed with clinically localized prostate cancer and treated with observation or androgen withdrawal therapy alone, stratified by age at diagnosis and histological findings.

Design, Setting, and Patients A retrospective population-based cohort study using Connecticut Tumor Registry data supplemented by hospital record and histology review of 767 men aged 55 to 74 years with clinically localized prostate cancer diagnosed between January 1, 1971, and December 31, 1984. Patients were treated with either observation or immediate or delayed androgen withdrawal therapy, with a median observation of 24 years.

Main Outcome Measures Probability of mortality from prostate cancer or other competing medical conditions, given a patient's age at diagnosis and tumor grade.

Results The prostate cancer mortality rate was 33 per 1000 person-years during the first 15 years of follow-up (95% confidence interval [CI], 28-38) and 18 per 1000 person-years after 15 years of follow-up (95% CI, 10-29). The mortality rates for these 2 follow-up periods were not statistically different, after adjusting for differences in tumor histology (rate ratio, 1.1; 95% CI, 0.6-1.9). Men with low-grade prostate cancers have a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2-4, 6 deaths per 1000 person-years; 95% CI, 2-11). Men with high-grade prostate cancers have a high probability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8-10, 121 deaths per 1000 person-years; 95% CI, 90-156). Men with Gleason score of 5 or 6 tumors have an intermediate risk of prostate cancer death.

Conclusion The annual mortality rate from prostate cancer appears to remain stable after 15 years from diagnosis, which does not support aggressive treatment for localized low-grade prostate cancer.