Early Patterns of Failure in a Prospective Trial of Concomittant Docetaxel and Proton Therapy for High-risk Prostate Cancer
Reporter: Annemarie Fernandes, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 31, 2012
Presenter: Nancy Mendenhall, MD Presenter's Affiliation: The University of Florida Proton Therapy Institute, Jacksonville, FL
Patients with high-risk prostate cancer are at increased risk of distant metastases and death related to prostate cancer progression. These patients are typically treated more aggressively, with definitive radiation therapy and long-term androgen suppression
Docetaxel is an anti-mitotic chemotherapeutic agent that has been shown to improve overall survival in patients with metastatic, castrate-resistant prostate cancer. The efficacy of docetaxel in the locally advanced setting has not been well established. Phase II data using docetaxel in the adjuvant setting and phase I data using paclitaxel concurrently with androgen deprivation and radiation therapy have been promising.
The purpose of this prospective trials was to evaluate the early outcomes of a novel approach to high-risk prostate cancer using concomitant docetaxel and proton therapy
Materials and Methods
This prospective trial enrolled men with high-risk prostate cancer
Inclusion criteria: PSA > or equal to 20 and/or Gleason Score > or equal to 8 and/or clinical stage T3 disease
Patients were treated with proton therapy to a total dose of 78 CGE in 39 fractions with concomitant docetaxel followed 6 months of androgen deprivation therapy. Docetaxel was delivered weekly at 20 mg/m2, intended for radiation sensitization.
Toxicity was evaluated using IPSS, CTCAE v3 and EPIC toxicity assessments, performed at baseline and at 6-month intervals after treatment
PSA values were followed and patients underwent restaging with bone scan, pelvic imaging and PET/CT scanning if there was evidence of PSA progression
40 men were enrolled
The median follow-up was 5.1 years,
The freedom from biochemical or clinical disease progression at 5 years was 74%
Overall survival at 5 years was 85%
5 patients developed PSA-only failures. 2 patients developed PSA-failures and distant metastases and 1 patient developed a PSA failure and pelvic node recurrence
Patterns of failure were largely out of the proton field
Predictors of disease progression included:
Increasing number of high-risk factors (high risk factors: stage T3/T4, Gleason score >8 and PSA>20)
T-stage (T3/T4 (80% with disease progression) vs. T1/T2 (8.6%))
Gleason score of 9 (35.7% with disease progression) vs. Gleason score of 6-8 (7.7%)
Toxicity: there were no Grade 4/5 toxicities.
Grade 3 GU toxicity was noted in 2 (5%) patients (1 patient experienced urinary incontinence requiring collagen implant and the other patient required hyperbaric oxygen for urinary symptoms).
Grade 3 GI toxicity was noted in 1 (3%) patient (this patients required a transfusion for spontaneous rectal bleeding).
Grade 3 hot flashes were noted in 5 patients.
There was no hematologic toxicity
The authors conclude that this novel approach of concomitant weekly docetaxel and proton therapy followed by 6 months of androgen deprivation was well-tolerated and the clinical outcomes at 5-years are promising
Patients with multiple high-risk factors may need more aggressive treatment with longer androgen deprivation or higher doses of docetaxel
The authors note that future studies from their institution will include 2 years of ADT for patients with many high risk factors. Additionally, the use of whole pelvis radiation therapy is being explored for patients with >15% risk of lymph node involvement
The authors present interesting and promising data regarding the use of concurrent docetaxel with definitive radiation therapy in patients with high-risk prostate cancer.
The data presented represent 5 years of follow-up. Because prostate cancer is a relatively indolent disease, additional follow-up is necessary to make stronger conclusions about this novel treatment approach.
The dose of the docetaxel (20 mg/m2) has been established through phase I data as a safe dose with concurrent high-dose radiation therapy in prostate cancer. This dose of docetaxel is also thought to be an effective radiosensitizer. Concurrent androgen deprivation with radiation therapy is a known radiation sensitizer in prostate cancer. Docetaxel has not been compared to androgen deprivation to determine which its efficacy as a radiation sensitizer. The patients in this study received adjuvant, not concurrent androgren deprivation. Docetaxel needs to be established as a more effective radiation sensitizer than androgen deprivation. This should be studying in a randomized prospective trial.
The dose of the docetaxel (20 mg/m2) resulted in low chemotherapy related toxicity, which is promising. There was no hematologic toxicity in this study.
This study treated patients with 6 months of adjuvant androgen deprivation. Typically, patients with high-risk prostate cancer are treated with 2-3 years of adjuvant androgen deprivation. This study resulted in adequate 5-year overall survival rates, however the rates of disease progression were high in patients with multiple high risk factors. The authors note that patients with multiple high risk factors should probably receive longer androgen deprivation and the authors are planning to conduct future studies that implement long-term androgen deprivation.
It is feasible, however, that patients with less aggressive high-risk prostate cancer can be treated with the approach used in this study. This approach would spare patients from long-term androgen deprivation, which adds significant morbidity and adversely affects patients’ quality of life.
The authors treated patients with proton beam radiation therapy and reported favorable toxicity profiles. There are few proton therapy centers in the country. However, this data can potentially be extrapolated to radiation treatment with conventional IMRT (intensity-modulated radiation therapy).
Further prospective randomized studies are needed to evaluate the efficacy of this novel treatment approach with the current standard of care (definitive radiation therapy with long-term androgen deprivation). We agree with the authors that futures studies should evaluate using long-term adjuvant androgen deprivation in patients with multiple high-risk factors. Additionally, the use of whole pelvis radiation therapy should be explored in this setting.
Future studies should also evaluate the efficacy of using docetaxel concurrently with androgen deprivation and radiation therapy. This has been shown to be feasible and safe in a previously published phase I study.
Oct 4, 2010 - Men with advanced prostate cancer that has resisted prior chemotherapy with docetaxel survive a median 2.4 months longer if they take cabazitaxel instead of mitoxantrone, according to the results of a phase III trial published in the Oct. 2, cancer-themed issue of The Lancet.