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Risk Factors Predicting Failure and Prostate Cancer Mortality in High Risk Prostate Cancer Patients Treated with Definitive External Beam Radiation Therapy

Reviewer: Geoffrey Geiger, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 3 de noviembre del 2010

Authors: Q. Nguyen, L. B. Levy, A. K. Lee, S. Choi, S. J. Frank, K. Hoffman, S. McGuire, D. A. Kuban
Institution: M.D. Anderson Cancer Center, Houston, TX

Background

• Prostate cancer is the most common non-cutaneous malignancy in men and is the second most common cause of cancer deaths in the United States.
• High-risk prostate cancer is a complex and diverse disease with several available treatment modalities.
• The definition of high-risk prostate cancer has evolved throughout the PSA era as earlier screening has identified patients with less advanced disease at the time of diagnosis.
• The current NCCN guidelines include the following under the high-risk category: T3a or GS 8-10 or PSA >20.
• In locally advanced prostate cancer, the combination of radiation therapy (RT) and androgen deprivation therapy (ADT) has been demonstrated to provide superior outcomes when compared to RT or ADT alone in multiple randomized studies.
• Dose escalation in prostate cancer has also been demonstrated to yield improvement in biochemical progression free survival in six randomized studies.
• In this study, the authors set out to evaluate risk factors predicting for treatment failure and prostate cancer death in high-risk prostate cancer patients treated with external beam radiation therapy.

Materials and Methods

• Study design: retrospective.
• The authors evaluated 929 high-risk prostate cancer patients treated with external beam radiation therapy at the University of Texas, M.D. Anderson Cancer Center from 1987-2004.
• Patients were considered high risk if they had clinical stage ?T3, Gleason ?8, or PSA ?20 ng/mL.
• Multivariate analysis was performed using a Cox proportional hazard model. Kaplan Meier survival curves were compared using a log rank test.

Results

• The median follow-up was 7.8 yrs.
• Patient characteristics:
• 43% were stage T1-2, 57% stage T3-4.
• Gleason score: 27% GS 6, 25% GS 7, 48% GS 8-10.
• Pretreatment PSA: <10 35%, 10-20 22%, >20 43%.
• Age: <70 (60%) >70 (40%).
• RT dose: Low (<75.6 Gy) 59%, High (>75.6 Gy) 41%.
• ADT+ 48%, ADT- 52%. Median duration ADT: 2.1 years.
• The 5 year and 10 year actuarial overall survival rates were significantly decreased at 82% and 57% for patients treated with external beam (EBRT) dose <75.6 Gy and without ADT compared to 94% and 71% for patients treated with EBRT dose >75.6 Gy and ADT (p <0.0001).
• At 5 years, few patients died of prostate cancer:
• 7% of patients treated with <75.6 Gy and no ADT compared to 3% of men treated with >75.6 Gy and ADT.
• However, at 10 years this rate increased to 18% and 8%, respectively (p = 0.014).
• Patients with a local failure had a 3 fold increase risk for a lymph node (p = 0.0022) or distant failure (p <0.0001).
• Patients experiencing a PSA or distant failure were more likely to die of prostate cancer with hazard ratio (HR) = 64.7 and HR = 82.9 (p <0.0001).
• Multivariate analysis demonstrated PSA >20 ng/mL (p <0.0001), Gleason 8-10 (p = 0.0002), age >70 yrs (p <0.0001), and no ADT (p <0.0001) as predictors for worse overall survival, and PSA 10-20 ng/mL (p = 0.025), PSA >20 ng/mL (p <0.0001), Gleason 8-10 (p <0.0001), and no ADT (p = 0.0003) for higher risk for prostate cancer mortality.
• The 10-year rate of symptomatic local failure was 2% for all patients.
• The cause of deaths (n = 170) were 37% prostate cancer, 16.8% cardiac, 5% pulmonary, 7.5% CNS/neurologic, 2% vascular, 2% GI, 1% GU, 1% infectious, 0.3% hematologic, 10% secondary malignancies, 16% unknown, and 1.7% other etiologies. Comparisons between different causes of death did not yield statistical significance.

Author's Conclusions

• PSA ? 20, Gleason 8-10, and lack of ADT were risk factors predicting for increased prostate cancer specific mortality.
• High-risk prostate cancer patients treated with ADT+ EBRT dose >75.6 Gy had improved rates of freedom from PSA failure and increased prostate cancer specific mortality.
• High-risk prostate cancer patients treated with ADT + dose escalation had few symptomatic local recurrences with long-term follow-up.

Clinical Implications

• In this retrospective analysis, the authors elucidate several risk factors predicting for treatment failure and prostate cancer death in high-risk prostate cancer patients treated with external beam radiation therapy.
• The data corroborates the available literature and demonstrates on multivariate analysis that pretreatment PSA ? 20, Gleason 8-10, and lack of ADT are associated with increased prostate cancer specific mortality. Furthermore, very few patients overall suffer from symptomatic local failure.
• High-risk prostate cancer patients (T3a or GS 8-10 or PSA >20) patients being treated with external beam radiation therapy benefit from dose escalation and androgen deprivation therapy with a 10% cause specific survival benefit at 10 years.
• This supports use of dose-escalated radiotherapy with ADT in this high-risk patient population.