Final Report of a Canadian Phase III Trial of 3 vs. 8 months Neoadjuvant Androgen Deprivation Prior to 66 Gray External Beam Radiotherapy for Clinically Localized Prostate Cancer.

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 25 de septiembre del 2008

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Presenter: J. M. Crook, MD
Presenter's Affiliation: Princess Margaret Hospital, Toronto, ON, Canada
Type of Session: Scientific

Background

  • Data from prior RTOG and EORTC trials indicate that the combination of hormonal therapy to radiation treatment for prostate cancer may improve survival in certain subsets of patients.
    • However, questions still remain as to the onset and duration of hormonal therapy that is ultimately necessary. 
  • Previous research has shown that neoadjuvant hormonal therapy (NHT) improves the treatment outcomes of conventional-dose radiation therapy in patients with localized prostate cancer.
    • The RTOG 86-10 trial by Pilepich et al in 2001 demonstrated an improvement in DFS in all patients and in overall survival in patients with Gleason score 2-6 who received hormonal therapy for 2 months before and 2 months during RT. 
      • This formula of hormonal therapy then became the standard for cytoreduction in these patients. 
  • The authors of this study question whether longer duration of NHT (8 months) prior to concurrent RT will lead to increased local control (LC) and freedom from survival (FFS).
  • The purpose of this study was to evaluate the effect of 3 vs. 8 months of NHT prior to conventional dose radiotherapy (RT) on disease free survival for localized prostate cancer. 

Materials and Methods

  • Between 1995 and 2001, 378 men with clinically localized prostate cancer were randomized to 3 versus 8 months of flutamide and goserelin hormonal therapy. 
  • Patients participating were from 4 centers in Canada.
  • Patient were stratified by tumor stage (Stage T1 or T2a vs. T2b or T3 or T4), Gleason score (2–6 vs. 7–10), and pretreatment PSA level (0–9.9 vs. 10.0–24.9 vs. ≥25.0 ng/mL).
  • Eligibility included:
    • Histologic diagnosis of adenocarcinoma of the prostate, with all Gleason scores, PSA levels, and clinical T categories eligible
    • Life expectancy of > 5 years
  • The primary endpoints were disease free survival (DFS), patterns of failure, and biopsy status at 2-2.5 years after RT. Overall survival was also examined, although the authors duly noted that this study was not powered for OS. 
  • Assessment of disease status was mainly by digital rectal exam and PSA (using the Phoenix nadir +2 definition for recurrence) at every 2 months during NHT. After completion of radiation, the assessments were at 1 month, then every 3 months for 2 years, and every 4-6 months thereafter. 
  • Post-treatment prostate biopsies were scheduled at 24–30 months, and biopsy status was also used to assess disease status. Patients were graded as negative, positive, or indeterminate with severe treatment effect. Biopsies were centrally reviewed. 

Results

  • 361/378 patients were evaluable for data. Of those, 290 patients are still living. Of the deaths, 25% were from prostate cancer.
  • The median age of these patients was 72 years. 
  • Median follow up was 6.6 years (range 1.6 to 10.1). 
  • Median baseline PSA was 9.7 ng/mL (range 1.3 – 189) and 50% of patients had a Gleason score of <6. 
  • 25% of patients were low risk, 43% were intermediate, and 32% were high risk.
  • Patient characteristics between the 2 groups were well balanced with regards to Gleason score, age, clinical T stage, risk group and presenting PSA.
  • An overall survival difference was not seen between the two arms.            
    • Overall 7-year cause specific survival was 94% for the 3 month group and 93% for the 8 month group (p=0.24). 
    • Overall 7-year actuarial survival was 81% for 3 month group and 79% for the 8 month group (p=0.7). 
  • A difference in 7-year actuarial freedom from failure (FFF) between the 2 arms was not seen for patients overall. 
    • 3 month arm vs. 8 month arm: 58% vs. 58% at 7 years (p=0.18)
    • A subset analysis of FFF by risk group was also performed. 
      • For high-risk patients, there was a statistically significant difference seen between the 2 arms. The FFF in the 8 month arm was 59% vs. 35% for the 3 month arm, with a p-value=0.01.
      • There was no difference seen in the low and intermediate risk groups.
  • Post-treatment biopsies at 2 years were performed in 205 men. There were 106 men in the 3 month arm and 99 men in the 8 month arm who had biopsies performed. 68% of patients had negative biopsies, 14% had positive biopsies, and 18% had indeterminate biopsy results. 
  • 7-year FFF rate by biopsy status was also assessed. Patients with negative or indeterminate biopsy results had similar results, and were therefore grouped together. It was found that biopsy status (negative or indeterminate vs. positive) was a strong predictor of 5- and 7-year DFS. 
    • FFF rate was 66% for the negative/indeterminate group vs. 21% for the positive group, at 7 years, with a p-value of <0.0001. 

Author's Conclusions

  • There was no difference in OS or long-term FFF seen with a longer duration of HT compared to a short course. 
  • However, on subset analysis, the high risk prostate cancer patient group did have an increased FFF at both 5 and 7 years in the 8 month group compared to the 3 month group. 
  • In addition, biopsy status at 2 years was found to be a powerful predictor of disease-free status at 5 and 7 years. 

Clinical/Scientific Implications

  • Androgen deprivation therapy has emerged in the last decade or so as an important treatment option in the management of prostate cancer. The benefits were first shown in the adjuvant setting; however more recent data have demonstrated improved outcomes for NHT in combination with conventional radiation therapy. The optimal timing and duration of NHT remains an unanswered question.
  • This study was a well-designed randomized trial with significant follow up data to help answer the question of timing for NHT.   
  • The authors found that there was no difference in FFF or OS between the 2 arms, although there was benefit in 5 year DFS for patients with high risk prostate cancer. 
  • These results suggest that 3 months of NHT is likely sufficient for use with conventional-dose RT to improve outcomes, but that longer-term hormonal therapy may be required to benefit high-risk patients who are at greater risk for microscopic metastatic disease.
  • One important point to note is that the numbers in the trial were small and the trial may not have been sufficiently powered to demonstrate an advantage in DFS or OS for patients overall. 
  • In addition, more mature follow up data of this trial is needed, as patients with prostate cancer may not have recurrence for up to 10-20 years after initial treatment. 
  • The results of this trial should not change our current clinical practice.
  • It is arguable that there is little benefit in delaying the start of radiotherapy by even three months to allow for neo-adjuvant hormones in our current era of dose escalation. 
    • This study used 66 Gy as the RT dose delivered, and the combination of RT and hormonal therapy for cytoreduction was an area which needed to be explored. However in the modern era of high-precision, dose-escalated RT to doses of up to 80 Gy, it may not be necessary to delay a patient’s RT for even 3 months (much less 8) to give NHT to low/intermediate risk patients. However, for high risk patients, there seems to still be an added benefit in terms of control of micrometastatic disease, and the optimal duration of NHT in these patients is still undetermined. 
  • Future studies may focus on evaluating the effects of NHT with higher doses of RT which are currently being used in treating prostate patients. 

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