A Phase III Randomized Trial of Intermittent vs. Continuous Androgen Suppression for PSA Progression after Radical Therapy (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/ UK Intercontinental Trial CRUKE/01/013)

Reporter: Abigail Berman Milby
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 3 de octubre del 2011

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Presenting Author: J. M. Crook
Affiliation: University of British Columbia, Kelowna, BC, Canada,

Background

  • Conventional radiotherapy is associated with up to a 30% biochemical failure rate at 5 years.
  • Biochemical failure after either definitive radiotherapy or after post-RP radiotherapy is treated with androgen deprivation.
  • There has been basic science support for the concept of intermittent androgen suppression (IAS): androgen withdrawal benefits a proportion of patients with hormone-refractory disease, suggesting that the tumor is still androgen-dependent (Bruchovsky 1990).
  • IAS for PSA recurrence after radical radiotherapy (RT) may improve quality of life (QoL) and delay hormone resistance (HR) but has an unknown effect on survival.
  • This study compares overall survival (OS) for IAS vs. continuous androgen deprivation (CAD) in a non-inferiority randomized trial in patients who received radical radiotherapy and do not have overt metastatic disease.

Materials/Methods

  • Eligible patients:
    • Patients with adenocarcinoma of the prostate who have completed radical radiotherapy either as primary RT or salvage RT status post radical prostatectomy (RP) to the area of the prostate:
      • More than 12 months between the last day of radical radiotherapy treatment (more than 30 months from the date of brachtherapy implant) and randomization.
    • Patients must have a rising PSA level (current PSA > 3 ng/ml more than 1 year following RT and > nadir following radiotherapy)
      • Initial PSA entrance criteria was > 3 ng/ml, however this was lowered from originally 10 ng/mL and subsequently 6 ng/mL prior to the final PSA entrance criteria.
    • No definite evidence of distant metastasis (assessed by radiological studies or clinically)
    • No previous hormonal therapy except neo-adjuvant, concurrent, or adjuvant androgen deprivation (AD) given for cytoreduction in association with either radical radiotherapy or prostatecomy for a maximum duration of 12 months and completed at least 12 months prior to randomization.
    • ECOG PS 0 or 1
    • Total testosterone greater than or equal to 5
  • Patients were stratification on the following factors: time since RT (1-3 vs. >3 years), initial PSA (<15 vs. >15 ng/ml), prior radical prostatectomy, and prior ADT in association with radical RT or prostatectomy.
  • Patients were randomized 1:1 to the following two arms:
    • IAS arm: Patients received an LHRH analog and a non-steroidal antiandrogen for 8 months and if the PSA < 4 ng/mL and less than the baseline PSA, patients were observed until critera of progression was met and then they were re-started.
    • CAD arm: Patients received an LHRH analog and a non-steroidal antiandrogen OR bilateral orchiectomy +/- non-steroidal antiandrogen.
      • The use of non-steroidal antiandrogen was optional if a patient underwent bilateral orchiectomy.
  • Primary endpoint was OS.
  • Secondary endpoints included: quality of life (QoL), time to hormone resistance (HR), cholesterol/HDL/LDL in each arm at 3 years compared with baseline, duration of treatment and non-treatment intervals, and time to testosterone and potency recovery, putative translational research prognostic factors.
  • PSA levels were monitored every 2 months regularly in both arms.
  • In the CAD arm, hormone resistance (HR) was defined as: clinical disease progression, castrate testosterone level, PSA> 4 ng/mL or PSA risk > 1 ng/ml.
  • In the IAS arm, if PSA fell to normal during the 8-month treatment period, therapy was stopped until levels rose to 10 ng/mL, at which time IAS was resumed for another 8-month period. IAS continues as long as PSA levels are controlled. At the time of disease progression, patients begin continuous hormonal treatment similar to arm II.
  • The study was designed as a non-inferiority study, with a p value for non-inferiority indicating a difference in overall survival at 7 years of less than 8%, i.e. HR IAS vs. CAD ? 1.25.

Results

  • A total of 1386 patients entered the study between January 5, 1999 and November 30, 2005.
    • 690 patients were randomized to IAS ; 696 to CAD.
    • Median age was 74.2 years; follow up 6.9 years.
    • Baseline factors were balanced, including 11% prior prostatectomy.
  • IAS patients completed a range of 1-9, 8-month cycles, with a median of 2 cycles.
    • Patients completing 1 cycle had a median time to HR of 22 months, 2 cycles 13 months, 3 cycles 10 months and 5 months for patients receiving 4-9 months of IAS.
    • Time to HR was statistically significantly improved on the IAS arm (HR 0.80, 95% CI 0.67-0.98, p=0.024).
  • IAS patients had reduced hot flashes but no differences in other AEs, including myocardial events or osteoporotic fractures.
    • Hot flashes were identical in both arms for the first 8 months, then significantly better at 2 years in the IAS arm, and by 5 years, the difference in the two arms is reduced.
  • 35% of IAS cases had full testosterone recovery.
  • QoL analysis showed a range of benefits for IAS at different time points.
    • QoL was assessed every 4 months for 2 years and then every 8 months until development of hormone resistance, at the time of hormone resistance, and then annually thereafter.
    • The authors used a 10 point change from baseline score as clinically meaningful.
    • IAS patients had better QoL in physical function, fatigue, urinary problems, hot flashes, desire for sexual activity, and erectile function (all p values < 0.01).
  • 524 patients died (268 IAS vs. 256 CAD). Median OS was 9.8 vs. 10 years on IAS and CAD arms respectively (HR 1.02, 95% CI = 0.86-1.21; p for non-inferiority = 0.009).
  • IAS arm had more disease related (41% vs. 34%) and fewer unrelated (50% vs. 57%) deaths.

Author's Conclusions

  • For PSA recurrence after radical radiotherapy for prostate cancer, overall survival of patients receiving IAS as per this algorithm is not inferior to CAD.
  • The time to castration resistance longer (improved) in the IAS arm, although this may not be clinically significant given the different definitions of castrate resistance.
  • QoL measures improved in the IAS arm over CAD.

Clinical Implications

  • The findings of this study imply IAS should be the standard of care in non-metastatic patients with a rising PSA following primary or post-RP salvage RT.
  • This study only addresses the radiotherapy population. It does not address the use of androgen deprivation in patients who have undergone surgery only, where salvage RT to the prostate bed is an important treatment modality.
    • RTOG 0534 will help answer this question: A Phase III Trial of Short Term Androgen Deprivation With Pelvic Lymph Node or Prostate Bed Only Radiotherapy (SPPORT) in Prostate Cancer Patients With a Rising PSA After Radical Prostatectomy
  • Relatively few numbers of patients in this study were treated post-RP (11%) and therefore the applicability to this group is not known.
    • The PSA failure values for this group theoretically should also be lower than for patients who only underwent definitive radiotherapy. This did prompt lowering of the PSA entrance criteria.
  • One important subset analysis not presented is benefit of IAS vs. CAD according to Gleason's Score. It could be hypothesized that a higher Gleason's score patient may benefit less from IAS than a lower Gleason's score.
  • There were 9% more prostate cancer deaths on the IAS arm but fewer "unrelated" deaths. Defining these unrelated deaths would help interpret this data.
  • Cardiovascular disease from androgen deprivation is an important long-term concern of CAD, and it will be interesting to see if the two arms of this study show a difference in the future.

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