To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer.
One thousand five hundred seventy-nine men with ...intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up.
There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8- and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio HR, 0.81; P = .45), respectively, and 10-year overall survival rates were 66% (95% CI, 62.0% to 69.9%) and 67% (95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8- and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen-based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively.
Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate-risk prostate cancer.
There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and ...resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores.
NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test.
The study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity.
This study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.
Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this ...holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer.
NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; BF1) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; BF2), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average
between treatment hazard ratios for ICE and OS).
BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated (
= 0.67), but this was not true for BF1 (
= 0.09), BF2 (
= 0.12), or DM (
= 0.18) and OS.
MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.
There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and ...resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores.
NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 week and a day twice a week) or 12 fractions (4.3Gy in 2.5 weeks 5 times a week). Secondary objectives assessed patient-reported toxicity at 5 years using the EPIC. Chi-square tests were used to assess the proportion of patients with a deterioration from baseline of >5 points for bowel, >2 points for urinary, and >11 points for sexual score.
The study enrolled 127 patients to 5 fractions (121 eligible) and 128 patients to 12 fractions (125 eligible). The median follow-up for all patients at the time of analysis was 5.38 years. The 5-year frequency for >5 point change in bowel score were 38.4% (P = .27) and 23.4% (P = 0.98) for 5 and 12 fractions, respectively. The 5-year frequencies for >2 point change in urinary score were 46.6% (P = .15) and 36.4% (P = .70) for 5 and 12 fractions, respectively. For 5 fractions, 49.3% (P = .007) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points; for 12 fractions, 54% (P < .001) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points. Disease-free survival at 5 years is 89.6% (95% CI: 84.0-95.2) in the 5-fraction arm and 92.3% (95% CI: 87.4-97.1) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity.
This study confirms that, based on long-term changes in bowel and urinary domains and toxicity, the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.
Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer.
To ...validate the GC in the context of a randomized phase 3 trial.
This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network-approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer-specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019.
Salvage radiotherapy (sRT) with or without 2 years of bicalutamide.
The preplanned primary end point of this study was the independent association of the GC with the development of DM.
In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median interquartile range age, 64.5 (60-70) years; 314 White 89.2% participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio HR, 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (-7.8% vs 4.6%).
This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT.
ClinicalTrials.gov identifier: NCT00002874.
The natural history of microinvasive (T1mi) breast cancer is uncertain. The objective was to evaluate long-term local and distant recurrence rates following breast conserving surgery (BCS) in a ...prospective cohort of patients with T1mi compared to T1a-2 disease who received whole breast irradiation (WBI) in the context of a randomized trial of hypofractionation.
1234 patients with T1-2 N0 breast cancer were randomized to receive adjuvant WBI of 42.5Gy in 16 daily fractions, or 50Gy in 25 daily fractions after BCS. An analysis of patients with T1mi tumors compared with T1a-2 disease was performed. Kaplan-Meier estimates of local recurrence (LR), distant recurrence, and overall survival (OS) were compared using the log-rank test.
Median follow-up was 12 years. T1mi was found in 3% (n = 38) of patients. The 10-year LR rate was 22.6% in T1mi vs. 6.9% in T1a-2 breast cancer hazard ratio (HR) = 3.73; 95% confidence interval (CI): 1.93, 7.19; p < 0.001. The 10-year risk of distant recurrence was 5.1% for T1mi, and 12.1% for T1a-2 disease (HR = 0.56; 95% CI: 0.19, 1.84; p = 0.36). Ten-year OS was 91.5% in T1mi and 84.4% in T1a-2 disease, (HR = 0.48; 95% CI: 0.18, 1.30; p = 0.14). Rates of LR did not differ whether treated by hypofractionation or conventional fractionation (HR = 1.21; 95% CI: 0.35, 4.18; p = 0.77).
The risk of LR was considerably higher in patients with T1mi compared to T1a-2 tumors, but OS remained very good. Future research should evaluate the utility of wider local excision and boost radiation to optimize local control for microinvasive breast cancer.
•Patients with microinvasive breast cancer have a high risk of local recurrence.•Both the rate of invasive and non-invasive local recurrences are increased.•The risk of distant recurrence and death is not increased.•Methods to reduce the risk of local recurrence should be considered.
Introduction: The biennial meeting of the Genitourinary Radiation Oncologists of Canada (GUROC) took place November 22-23, 2019. A consensus-building session was held during the meeting addressing ...topics of emerging interest or controversy in the management of genitourinary malignancies. Methods: Draft statements were debated among all meeting attendees in an open forum with anonymous live voting. Statements for which there was at least 75% agreement among attendees were adopted as GUROC consensus. Results: Four evidence-based consensus statements were developed. First, the use of prostate radiotherapy is recommended in the setting of de novo low-volume metastatic hormone-sensitive prostate cancer to improve overall survival. Second, the support of ongoing randomized trials evaluating metastasis-directed ablative local therapy in oligometastatic prostate cancer is recommended; where such trials are available, off-trial use of oligometastasis-directed ablative radiotherapy at this time is strongly discouraged. Third, routine use of prostate-rectal hydrogel spacer devices in patients with localized prostate cancer planned to receive external beam radiotherapy is not recommended; instead, selective use in patients at highest risk of rectal toxicity may be considered. Finally, multidisciplinary consultation is recommended for all patients with newly diagnosed localized muscle-invasive bladder cancer. Conclusions: The GUROC consensus statements provide practical guidance to clinicians in areas of current controversy in the management of prostate and bladder cancer, and it is hoped that their implementation will contribute to improved outcomes in real-world practice and greater support of clinical trials.
To validate whether prostate-specific antigen (PSA) level after neoadjuvant androgen suppression (neoAS) is associated with long-term outcome after neoAS and external beam radiation therapy (RT) with ...concurrent short-term androgen suppression (AS) in patients with prostate cancer.
This study included 2404 patients. The patients were treated with neoAS before RT and concurrent AS (without post-RT AS) and were pooled from NRG Oncology/RTOG trials 9202, 9408, 9413, and 9910. Multivariable models were used to test associations between the prespecified dichotomized post-neoAS, pre-RT PSA level (≤0.1 vs >0.1 ng/mL) groupings, and clinical outcomes.
The median follow-up for surviving patients was 9.4 years. The median post-neoAS, pre-RT PSA level was 0.3 ng/mL, with 32% of patients having levels ≤0.1 ng/mL. Race, Gleason score, tumor stage, node stage, pretreatment PSA level, and duration of neoAS were associated with the groups of patients with PSA levels ≤0.1 and >0.1 ng/mL. In univariate analyses, post-neoAS, pre-RT PSA level >0.1 ng/mL was associated with increased risks of biochemical failure (hazard ratio HR, 2.04; P < .0001); local failure (HR, 2.51; P < .0001); distant metastases (HR, 1.73; P = .0006); cause-specific mortality (HR, 2.36; P < .0001); and all-cause mortality (HR, 1.24; P = .005). In multivariable models that also included baseline and treatment variables, post-neoAS, pre-RT PSA level >0.1 ng/mL was independently associated with increased risk of biochemical failure (HR, 2.00; P < .0001); local failure (HR, 2.33; P < .0001); and cause-specific mortality (HR, 1.75; P = .03).
Patients with a PSA level >0.1 ng/mL after neoAS and before the start of RT had less favorable clinical outcomes than patients whose PSA level was ≤0.1 ng/mL. The role of post-neoAS, pre-RT PSA level relative to PSA levels obtained along the continuum of medical care is not presently defined but could be tested in future clinical trials.
Although radical cystectomy is considered the standard of care for muscle-invasive bladder cancer (MIBC), recent data has suggested comparable survival outcomes for bladder-sparing trimodality ...therapy (TMT). We conducted a retrospective, single-institution analysis of MIBC patients to evaluate the efficacy of TMT as an alternative, curative approach to surgical intervention.
We conducted a retrospective analysis of MIBC patients assessed by a multidisciplinary team at the Juravinski Cancer Centre from 2010-2016. Patients underwent transurethral resection of bladder tumor (TURBT) followed by radiotherapy with or without concurrent chemotherapy. Patients could receive neoadjuvant treatment. Clinical data and response rates were summarized, and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method.
Our analytic cohort included 115 patients, of whom 53 underwent TMT and 62 underwent radiotherapy alone following TURBT. Median age at diagnosis was 79 years and median followup was 21 months. Complete response rates in those receiving TMT and radiation without chemotherapy were 84.4% and 66.7%, respectively. For TMT patients, three-year OS and DFS were 68.5% and 49.6%, respectively. Patients who received TMT had reduction in risk of mortality (hazard ratio HR 0.49; p=0.026) and disease recurrence (HR 0.55; p=0.017) compared to those who had radiation without chemotherapy. Overall, four patients had grade 3 or higher late toxicity.
In this single-institution analysis, TMT appears to be a safe and effective approach in the short-term management of MIBC in appropriately selected patients. Extended followup and analysis are necessary to validate these results.
PDF
