BERKELEY, CA (UroToday.com) - In the post-PSA era, the patient population with biochemical relapse (BR) has become a large portion of clinical practice in the United States. Twenty to 80% of men experience BR within ten years of local therapy and patients with BR are considered to harbor micrometastatic disease.[1, 2] Prognosis of BR is diverse due to the heterogeneity of the disease. Some patients don’t require intervention while others with a high Gleason score (≥ 8), short PSA doubling time (PSA-DT), and short time to relapse are at higher risk for early metastases and prostate cancer death (e.g., prostate cancer-specific mortality up to 75% 5 years after BR in post-RT men with PSA-DT of less than 3 months).[1, 2, 3] Those high-risk patients are an appropriate cohort with which to investigate aggressive intervention before the development of systemic disease.
This phase II trial was conducted in the late 1990s when docetaxel started to demonstrate favorable results in metastatic castration-resistant prostate cancer (CRPC).[4, 5] We hypothesized that an earlier intervention with the addition of chemotherapy to androgen deprivation therapy (ADT) would maximize cytotoxic effect at a time when tumor burden is minimal and patients are relatively healthy, before the development of CRPC. Ninety percent of enrolled patients had high-risk disease (≥ T2c, or PSA ≥ 20 ng/ml or Gleason ≥ 8). Based on PSA remission with recovered testosterone, we believe that the adjuvant chemo-hormonal therapy in this trial cured up to 24% of patients. Considering that adjuvant chemo-hormonal therapy in breast cancer prevents systemic relapse by approximately 20-30%, we believe 24% with long-term remission is within the expected range for effective therapy for BR. There were seven prostate cancer-specific deaths (PCSM) (11%), with a median follow-up of 8.6 years. In published data by Zhou et al., PCSM 5 years after BR were ~31% (post-radical prostatectomy) and ~75% (post-radiation therapy) for patients with PSA-DT of less than 3 months. Low PCSM of 11% in our study further supports the possible positive outcome of this aggressive approach. Yet, the data need to be validated by phase III studies.
In conclusion, our multi-institutional phase II study demonstrated that adjuvant chemotherapy plus ADT is a feasible approach in men with hormone-sensitive micrometastatic disease. The study is among the first to evaluate a long term follow-up of chemo-hormonal therapy for men with BR. Patient eligibility, predictors of response, timing of therapy, and the treatment regimen will need to be optimized. We used the agents available in late 1990s; however, options now exist to explore, more potent second generation hormonal therapies (abiraterone and enzalutamide) and immunotherapy (sipuleucel-T) which have been approved for metastatic CRPC based on survival benefit. With more therapeutic options, chemotherapy may have less of a role in early stage prostate cancer; however, certain subtypes of prostate cancer (low PSA-expressing tumor for example) may benefit from early systemic therapy, including chemotherapy, and proper trials should be designed to investigate these hypotheses.
After more than a decade since initiation of this study, there is no standard treatment for BR. Only randomized phase III trials will be able to validate the efficacy of adjuvant or early salvage therapy for BR compared with standard ADT. Clinicians are encouraged to discuss clinical trials with BR patients -- especially those with high-risk features (e.g. Gleason score ≥ 8 and short PSA-DT).
- Ward JF, Blute ML, Slezak J, Bergstralh EJ, Zincke H. The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol. 2003; 170(5): 1872-6.
- Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999; 281(17): 1591-7.
- Zhou P, Chen MH, McLeod D, Carroll PR, Moul JW, D'Amico AV. Predictors of prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Clin Oncol. 2005; 23(28): 6992-8.
- Savarese DM, Halabi S, Hars V, Akerley WL, Taplin ME, Godley PA, et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol. 2001; 19(9): 2509-16.
- Beer TM, Pierce WC, Lowe BA, Henner WD. Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Annals of Oncology : official journal of the European Society for Medical Oncology / ESMO. 2001; 12(9): 1273-9.
- Early Breast Cancer Trialists Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005; 365(9472): 1687-717.
Mari Nakabayashi, MD, PhD and Mary-Ellen Taplin, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School Boston, MA 02115
Mary-Ellen Taplin, MD
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute
44 Binney Street, Boston MA 02115
Funding support: Supported by a grant from Sanofi-Aventis and funding from the Fairweather Foundation, Sally and Michael Fairweather Fund, and Uribe Family Fund (to Mary-Ellen Taplin).
MET: Consulting Sanofi-Aventis