Intergroup Randomized Phase 3 Study of Androgen Deprivation Therapy (ADT) + Radiation Therapy (RT) in Locally Advanced Prostate Cancer (CaP) (NCIC-CTG, SWOG, MRC-UK, and INT: T94-0110; NCT00002633)
Authors: M.D. Mason, P.R. Warde, M.R. Sydes, M.K. Gospodarowicz, G.P. Swanson, P. Kirkbride, E. Kostashuk, J. Hetherington, K. Ding, W. Parulekar
Affiliations: Cardiff University. Cardiff, UK. Princess Margaret Hospital and University of Toronto. Toronto, ON. Clinical Trials Unit, Medical Research Council. London, UK. University of Texas Health Science Center at San Antonio. San Antonio, TX. Weston Park Hospital. Sheffield, UK. British Columbia Cancer Agency. Surrey, BC. Castle Hill Hospital. Hull, UK. NCIC Clinical Trials Group. Kingston, ON.
- Despite increased use of PSA screening, locally advanced or high-risk prostate cancer remains a significant public health problem comprising an estimated 24% of all newly diagnosed cases of prostate cancer in the US (Cooperberg et al. JCO, 2010).
- An analysis of patterns of practice with respect to the treatment of patients with high-risk prostate cancer found that approximately 45.5% of patients receive primary ADT alone (Cooperberg et al. JCO, 2010).
- Randomized evidence supports the addition of ADT to definitive RT for men with locally advanced prostate cancer (Bolla et al. Lancet, 2002)
- However, the benefit of RT in addition to ADT for such patients had until recently not been evaluated.
- The recently published SPCG-7 trial was a phase three study randomizing men with locally advanced prostate cancer to lifelong ADT alone vs. ADT + RT.
- With a median follow-up of 7.9 years, the authors reported a significant a reduction in overall mortality (39.4 % vs. 29.6%, RR 0.68, 95% CI 0.52-0.89) associated with the addition of RT to ADT (Widmark et al. Lancet, 2009).
- The currently reported study was similar in design to the SPCG-7 trial and was intended to assess the effect of RT on overall survival (OS) when added to lifelong ADT in men with locally advanced CaP.
- Patient eligibility criteria:
- Men with node negative adenocarcinoma of the prostate meeting one of the following criteria:
- T3/T4 (n = 1057) or
- T2, PSA > 40 ?g/l (n = 119) or
- T2, PSA > 20 ?g/l and Gleason ? 8 (n = 25)
- Eligible patients were then randomized to receive either:
- Lifelong ADT (consisting of either bilateral orchiectomy or LHRH agonist) plus RT (65-69 Gy to prostate ± seminal vesicles, +/- 45 Gy to pelvic nodes).
- Lifelong ADT alone
- The primary study endpoint was OS
- Secondary endpoints included disease specific survival (DSS), time to disease progression and quality of life.
- Although the majority of patients received pelvic RT followed by a boost to the prostate, the decision of whether or not to treat the pelvic nodes was left up to the individual treating physician.
- Between 1995-2005, 1,205 patients were enrolled in the study
- 602 patients were randomized to ADT, and 603 patients to ADT+RT.
- The study arms were well balanced with respect to baseline characteristics.
- A protocol specified second interim analysis on OS was performed in August 2009 (data cut-off December 31, 2008) and the review committee recommended release of the results for presentation.
- After a median follow-up of 6.0 years, 320 patients have died.
- 175 patients from the ADT arm
- 145 patients from the ADT+RT arm
- Ten percent of patients in this dataset had no follow-up data available beyond 2006.
- The addition of RT to ADT significantly reduced the risk of death (Hazard Ratio (HR) 0.77, 95% CI, 0.61-0.98, p = 0.033). The reported 7 year OS was 74% in patients receiving ADT +RT vs. 66% in patients receiving ADT alone.
- 140 patients have died of disease and/or treatment (89 on ADT and 51 on ADT+RT).
- The disease-specific survival HR was 0.57 (95% CI, 0.41-0.81, p = 0.001) favoring ADT+RT.
- The 10-year cumulative disease-specific death rates were estimated as 15% with ADT+ RT and 23% with ADT alone.
- Overall treatment related toxicity was not significantly increased by the addition of RT. Grade ?2 late GI toxicity rates were similar in both arms (proctitis, 1.3% ADT alone, 1.8% ADT+RT).
- The results indicate substantial benefits in overall survival and disease specific survival for the combined modality approach (ADT+RT) in the management of patients with locally advanced prostate cancer, with no significant increase in late treatment toxicity.
- These results are consistent with the findings previously published in the SPCG-7 trial.
- Therefore, ADT+RT should be the standard treatment approach for these patients.
- This was a well conducted phase III randomized trial examining the benefit of RT when added to ADT for patients with locally advanced CaP.
- With a relatively short median follow-up of 6 years, the results of the study have shown that the addition of RT was associated with an approximate 23% reduction in the risk of death, and a 43% reduction in the risk of death due to prostate cancer.
- When examining the reported survival curves, there appears to be a separation in survival curves between the two arms at approximately 5 years from treatment. Therefore, as Dr. Howard Sandler suggested during the plenary session, it would be reasonable to consider ADT +RT for any patient with High-Risk CaP with an estimated life expectancy of at least 5 years.
- Limitations of the study include:
- The dose of RT used in the study (65-69 Gy) is below what is typically prescribed with modern radiotherapy techniques. The magnitude of benefit associated with dose-escalated RT may be even greater than that observed in the study.
- The study design was for patients to receive lifelong ADT, but the authors did not report compliance with respect to ADT use. The optimal duration of ADT needed remains controversial. This may be particularly important because recent work has demonstrated that long-term ADT is associated with increased cardiovascular and metabolic risk.
- This study provides level I evidence supporting the use of RT in addition to ADT for patients with locally advanced CaP and combined modality treatment should be considered the standard of care for these patients.