Background

The objective of this study was to assess the impact of a prostate-specific antigen (PSA) complete response (PSA-CR), measured at the end of external-beam radiotherapy and short-term hormone therapy, on treatment outcomes.

Methods

The phase 3 Radiation Therapy Oncology Group 9413 trial, as part of its original protocol, used the assessment of PSA-CR (ie, PSA ≤0.3 ng/mL) at the end of short-term HT as a secondary endpoint. Short-term HT consisted of futamide plus a lutenizing hormone-releasing hormone agonist for 4 months. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival. Cumulative incidence was used to estimate biochemical failure, distant metastasis, and disease-specific survival. Univariate and multivariate analyses were performed to correlate PSA-CR after short-term hormone therapy with all endpoints, and the following variables were considered for analysis: PSA at baseline, Gleason score, treatment arm, age, and baseline testosterone status. Phoenix consensus definition was used to define PSA failure.

Results

For 1070 evaluable patients, the median PSA at the end of short-term hormone therapy was 0.2 ng/mL. In total, 744 patients (70%) had a PSA-CR. At a median follow-up of 7.2 years, failure to obtain a PSA-CR was associated significantly with worse disease-specific survival (P = .0003; hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.38-2.97), with worse disease-free survival (P = .003; HR, 1.28; 95% CI, 1.09-1.50), and with a higher incidence of distant metastasis (P = .0002; HR, 1.92; 95% CI, 1.37-2.69) and biochemical failure (P < .0001; HR, 1.57; 95% CI, 1.29-1.91). Other factors that were associated with worse disease-specific survival were Gleason scores from 8 to 10 (P = .0002; HR, 3.06; 95% CI, 1.71-5.47) and PSA levels >20 ng/mL (P = .04; HR, 1.55; 95% CI, 1.02-2.30).

Conclusions

The current results indicated that failure to obtain a PSA-CR (PSA ≤0.3 ng/mL) after short-term hormone therapy and external-beam radiotherapy appears to be an independent predictor of unfavorable outcomes and could help identify patients who may benefit from the addition of long-term androgen ablation.

Purpose

The purpose of this study was to quantify the frequency and clinical severity of quality deficiencies in intensity modulated radiation therapy (IMRT) planning in the Radiation Therapy Oncology Group 0126 protocol.

Methods and materials

A total of 219 IMRT patients from the high-dose arm (79.2 Gy) of RTOG 0126 were analyzed. To quantify plan quality, we used established knowledge-based methods for patient-specific dose-volume histogram (DVH) prediction of organs at risk and a Lyman-Kutcher-Burman (LKB) model for grade ≥2 rectal complications to convert DVHs into normal tissue complication probabilities (NTCPs). The LKB model was validated by fitting dose-response parameters relative to observed toxicities. The 90th percentile (22 of 219) of plans with the lowest excess risk (difference between clinical and model-predicted NTCP) were used to create a model for the presumed best practices in the protocol (pDVH0126,top10%). Applying the resultant model to the entire sample enabled comparisons between DVHs that patients could have received to DVHs they actually received. Excess risk quantified the clinical impact of suboptimal planning. Accuracy of pDVH predictions was validated by replanning 30 of 219 patients (13.7%), including equal numbers of presumed "high-quality," "low-quality," and randomly sampled plans. NTCP-predicted toxicities were compared to adverse events on protocol.

Results

Existing models showed that bladder-sparing variations were less prevalent than rectum quality variations and that increased rectal sparing was not correlated with target metrics (dose received by 98% and 2% of the PTV, respectively). Observed toxicities were consistent with current LKB parameters. Converting DVH and pDVH0126,top10% to rectal NTCPs, we observed 94 of 219 patients (42.9%) with ≥5% excess risk, 20 of 219 patients (9.1%) with ≥10% excess risk, and 2 of 219 patients (0.9%) with ≥15% excess risk. Replanning demonstrated the predicted NTCP reductions while maintaining the volume of the PTV receiving prescription dose. An equivalent sample of high-quality plans showed fewer toxicities than low-quality plans, 6 of 73 versus 10 of 73 respectively, although these differences were not significant (P=.21) due to insufficient statistical power in this retrospective study.

Conclusions

Plan quality deficiencies in RTOG 0126 exposed patients to substantial excess risk for rectal complications.

Background

The NRG/RTOG 9413 study showed that whole pelvic radiotherapy (WPRT) plus neoadjuvant hormonal therapy (NHT) improved progression-free survival in patients with intermediate-risk or high-risk localised prostate cancer compared with prostate only radiotherapy (PORT) plus NHT, WPRT plus adjuvant hormonal therapy (AHT), and PORT plus AHT. We provide a long-term update after 10 years of follow-up of the primary endpoint (progression-free survival) and report on the late toxicities of treatment.

Methods

The trial was designed as a 2 × 2 factorial study with hormonal sequencing as one stratification factor and radiation field as the other factor and tested whether NHT improved progression-free survival versus AHT, and NHT plus WPRT versus NHT plus PORT. Eligible patients had histologically confirmed, clinically localised adenocarcinoma of the prostate, an estimated risk of lymph node involvement of more than 15% and a Karnofsky performance status of more than 70, with no age limitations. Patients were randomly assigned (1:1:1:1) by permuted block randomisation to receive either NHT 2 months before and during WPRT followed by a prostate boost to 70 Gy (NHT plus WPRT group), NHT 2 months before and during PORT to 70 Gy (NHT plus PORT group), WPRT followed by 4 months of AHT (WPRT plus AHT group), or PORT followed by 4 months of AHT (PORT plus AHT group). Hormonal therapy was combined androgen suppression, consisting of goserelin acetate 3·6 mg once a month subcutaneously or leuprolide acetate 7·5 mg once a month intramuscularly, and flutamide 250 mg twice a day orally for 4 months. Randomisation was stratified by T stage, Gleason Score, and prostate-specific antigen concentration. NHT was given 2 months before radiotherapy and was continued until radiotherapy completion; AHT was given at the completion of radiotherapy for 4 months. The primary endpoint progression-free survival was analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769548. The trial has been terminated to additional follow-up collection and this is the final analysis for this trial.

Findings

Between April 1, 1995, and June 1, 1999, 1322 patients were enrolled from 53 centres and randomly assigned to the four treatment groups. With a median follow-up of 8·8 years (IQR 5·07-13·84) for all patients and 14·8 years (7·18-17·4) for living patients (n=346), progression-free survival across all timepoints continued to differ significantly across the four treatment groups (p=0·002). The 10-year estimates of progression-free survival were 28·4% (95% CI 23·3-33·6) in the NHT plus WPRT group, 23·5% (18·7-28·3) in the NHT plus PORT group, 19·4% (14·9-24·0) in the WPRT plus AHT group, and 30·2% (25·0-35·4) in the PORT plus AHT group. Bladder toxicity was the most common grade 3 or worse late toxicity, affecting 18 (6%) of 316 patients in the NHT plus WPRT group, 17 (5%) of 313 in the NHT plus PORT group, 22 (7%) of 317 in the WPRT plus AHT group, and 14 (4%) of 315 in the PORT plus AHT group. Late grade 3 or worse gastrointestinal adverse events occurred in 22 (7%) of 316 patients in the NHT plus WPRT group, five (2%) of 313 in the NHT plus PORT group, ten (3%) of 317 in the WPRT plus AHT group, and seven (2%) of 315 in the PORT plus AHT group.

Interpretation

In this cohort of patients with intermediate-risk and high-risk localised prostate cancer, NHT plus WPRT improved progression-free survival compared with NHT plus PORT and WPRT plus AHT at long-term follow-up albeit increased risk of grade 3 or worse intestinal toxicity. Interactions between radiotherapy and hormonal therapy suggests that WPRT should be avoided without NHT.

Funding

National Cancer Institute.