While EBRT combined with LDR brachytherapy is a common approach to treatment of prostate cancer, only two phase II studies conducted by cooperative groups have been completed, including CALGB 99809. The other study, RTOG 0019, similar to CALGB 99809, was designed to assess toxicity and participants were followed up to provide an initial assessment of treatment efficacy. RTOG 0019 included patients with clinical stage cT1c or T2a disease and either a Gleason score of 6 or lower and PSA levels of 10–20 ng/mL, or a Gleason score of 7 and PSA levels up to 20 ng/mL. All 138 patients were treated with EBRT to the prostate and seminal vesicles, which comprised 45 Gy three-dimensional conformal EBRT, followed 2–6 weeks later by LDR brachytherapy boost with 108 Gy I125
. Use of up to 6 months of androgen deprivation therapy (ADT) was left to the discretion of the treating physicians. Late genitourinary toxic effects were graded according to the Common Toxicity Criteria Version 2.0, and all other toxic effects were evaluated according to the RTOG and European Organization for Research and Treatment of Cancer late radiation morbidity scoring system. In an initial report, median follow-up was 19 months, and acute grade 3 toxic events were documented in 7.6% of patients. No grade 4 or 5 acute toxic events or late grade 4 or 5 toxic events were observed.4
Increased toxicity was noted in a subsequent report with a median follow-up of 49 months, but was deemed acceptable. Grade 3 genitourinary and gastrointestinal side effects occurred in 10.8% and 3.1% of patients respectively, and grade 4 genitourinary side effects occurred in 2% of patients. The rate of grade 3 or higher gastrointestinal and/or genitourinary toxic effects at 4 years was estimated to be 15%, which was higher than the estimate in RTOG series of EBRT or LDR brachytherapy alone. Biochemical recurrence was defined according to either the 1997 ASTRO consensus definition or the Phoenix definition. The estimated 4-year rate of freedom from biochemical recurrence according to the ASTRO and Phoenix criteria were 81% and 86% respectively.5
To date, expectations for treatment outcomes have been primarily based on retrospective, single-institution analyses. Sylvester and co-workers reported long-term results on 223 patients who underwent EBRT to 45 Gy, the majority of whom received treatment to a limited pelvic field followed by brachytherapy boost with either I125
(108 Gy) or Pd103
(90 Gy). Biochemical recurrence was defined according to a modified ASTRO consensus criterion of two consecutive rises in PSA levels. With median follow-up of 9 years, applying the D’Amico and Memorial Sloan–Kettering Cancer Center risk stratification criteria the 15-year rates of biochemical freedom from recurrence for patients at low risk in the Sylvester et al trial were 86% and 88%, for those at intermediate risk 80% and 80%, and for those at high risk 68% and 53%.6
Dattoli et al reported on patients with median follow-up of 9.5 years. Patients received a median dose of 41 Gy EBRT to a limited pelvic field up to the common iliac lymph nodes, followed by a brachytherapy boost with Pd103
Biochemical failure was assessed per the 1997 ASTRO consensus definition, nadir +2 definition, and absolute PSA >0.2 ng/ml at last follow-up. Actuarial rates of freedom from biochemical failure at 14 years were 87% for patients at intermediate risk and 72% for those at high risk without significant variance identified when applying the three definitions of biochemical failure. National Comprehensive Cancer Network guidelines were used for risk stratification (Intermediate risk: T2b to T2c, or Gleason 7, or PSA 10–20 ng/mL; High-risk: T3a or Gleason 8–10, or PSA > 20 mg/mL). Notably, the absolute risk of biochemical failure decreased progressively and fell to less than 1% after 6 years. Other researchers have reported similarly favorable findings in studies with shorter follow-up.8,9,10,11
There are three phase III trials inclusive of men with intermediate disease contempary with 99809 assessing external beam with or without ADT. A trial from the Dana-Farber Cancer Institute included 206 patients with cT1b–cT2b (AJCC 4th
edition criteria) with PSA ≥10 and ≤40 ng/ml or PSA ≥ 7 treated with 70 Gy +/− 6 months of total ADT. With median follow-up of 4.5 years a survival benefit was noted for patients receiving ADT with 5 year overall survival of 88% with no deaths due to prostate cancer. Survival without salvage ADT was 82% at 5 years for patients receiving ADT.12
An update with median follow-up of 7.6 years reported estimated 8 year overall survival of 74% with prostate cancer specific mortality of 3% for patients on the ADT arm of the trial.13
The Trans-Tasman Group reported results on 818 men cT2b-cT4 (AJCC 4th
edicition criteria) randomized to 66 Gy alone or with either 3 or 6 months of ADT. Only 18% of patients, however, were defined as intermediate risk. For patients receiving 6 months ADT, 5 year disease specific survival, freedom from salvage treatment, and prostate cancer specific survival were 52%, 78%, and 94% respectively.14
Preliminary results of RTOG 9408 were reported in 2009. 1,979 men were enrolled including 1,068 patients with intermediate-risk disease, defined as Gleason score 7 or Gleason of 6 or less and either a PSA of 10–20 or T2b disease. Patients received 66.6 Gy +/− 4 months of ADT. Eight year overall survival with vs. without ADT was 72% vs.66% which was statistically significant.15
A challenge in evaluating efficacy of combined modality therapy inclusive of ADT is the potential for misinterpretation of PSA rise due to testosterone rebound after cessation of ADT with biochemical failure. Distinguishing benign rise in PSA from biochemical recurrence is further complicated by the well documented phenomenon of PSA bounce after brachytherapy.16,17,18
The 1997 ASTRO consensus definition of biochemical failure has been shown to over call biochemical failure for patients who are treated with either ADT or brachytherapy when longer term analyses allowing for subsequent decline in PSA are performed.19,20
To address this concern, the protocol definition of PSA failure, 3 consecutive PSA rises over 1.0ng/ml after 18 months from start of treatment, was developed and applied in analysis. Subsequently, the Phoenix definition, nadir +2, was found to have improved accuracy in defining biochemical failure.20
To facilitate comparisons with past and future studies both the 1997 ASTRO consensus definition and the Phoenix definition were assessed along with the protocol definition. The finding of a lower rate of biochemical control in the current study using the 1997 ASTRO consensus definition in comparison with the other two definitions is therefore not unexpected. Ultimately, impact on survival is the most important assessment of efficacy and only a phase III trial will satisfactorily assess survival.
Treatment efficacy is important, however the impact of any treatment on disease control or eradication has to be considered in the larger context of toxicity and quality of life. Given that prostate cancer presents without significant symptoms for most men with clinically localized disease and that survival is typically protracted, treatment related toxicity is an important factor to be considered in choosing an approach to disease management. The long-term rates of grade 2 and 3 toxicity in the current study compare well to the other completed co-operative group study.5
We previously reported on the primary study endpoint, rate of grade ≥3 toxicity with 39 months median follow-up.21
Now with nearly double the median follow-up time only a modest increase in toxicity was noted, and only in the grade 2 category, with an increase from 13% in our initial report to 21% in this report. It is noted that median time to late GU and GI toxicity is approximately 18 months.22,23,24,25
Therefore, with 73 months median follow-up we believe it is very unlikely that significantly more toxicity will manifest with further follow-up. It is also important to recognize that IMRT was not allowed on CALGB 99809 as guidelines for use of IMRT in cooperative group trials had yet to be developed at the time of study inception. The use of IMRT and improved brachytherapy techniques has potential to further reduce toxicity.
The excellent results of CALGB 99809 in terms of both DFS and toxicity are notable, however there are several limitations of the study that should be recognized. Enrolling institutions all had experience with use of TPPB as there was a requirement that each participating site have a minimum of 50 prior cases in order to accrue patients on this study. Implant quality was excellent as assessed on central review with a median V90 of 98% and only one implant did not meet the minimum study criteria for V90 of 80%. Therefore, the results may not be applicable to centers with less prostate brachytherapy experience. The study also required the use of ADT. While ADT has been shown to improve overall survival in three randomized studies of intermediate risk patients treated with external beam radiation,12,14,15
no randomized studies investigating the use of hormonal therapy have been performed for patients undergoing brachytherapy. Given the modest doses of external beam radiation used on these trials, one hypothesis is that with dose escalation currently in common use, ADT will not be necessary. A new RTOG study, RTOG 0815, has been designed to address this question. Given the potential side effects of ADT, combined external beam and brachytherapy may be a more attractive therapeutic approach if ADT could be omitted. Impotentcy is a common concern for patients contemplating treatment for prostate cancer. Use of ADT coupled with lack of utilization of a validated instrument to assess sexual function made assessment of the impact of combined EBRT with brachytherapy boost difficult on the present study. The total number of patients is also modest albeit sufficient to address the primary study objective. Also, the favorable efficacy findings would be strengthened by confirmatory findings of other multi-institutional studies such as RTOG 0815 and RTOG 0232 which was designed to compare brachytherapy alone vs. external beam radiation with brachytherapy boost for patients with intermediate risk disease. Results from both of these studies will not be available for many years, however the current study provides valuable insight into results achievable with combined modality therapy across a broad range of institutions.