Pisansky, Thomas M.

60 Background: Mapping algorithms informing economic evaluations are often derived using baseline data from clinical trials. It is unclear if these algorithms can predict health utilities accurately in post-intervention data. Thus, this study examines the longitudinal predictive ability of mapping algorithms derived from baseline trial data and explores the factors associated with prediction errors. Methods: This methodological study utilized data from an international, multicenter, randomized controlled trial of patients with low-risk prostate cancer (PC), conducted by NRG Oncology (NCT00331773). In addition to patient demographic and clinical data, this study utilized PRO data collected at baseline and 6, 12 and 24 months post-intervention. The Expanded Prostate Cancer Index Composite (EPIC) questionnaire measures health-related quality-of-life (HRQoL) and has four domains (urinary, sexual, hormonal, and bowel) and two subdomains per domain (function and bother); EuroQOL-5D-3L (EQ5D) captures health utilities. Ordinary Least Squares (OLS) regression models were used to map EPIC scores to EQ5D utilities in the baseline data through 5-fold cross-validation. Predictive performance was tested in the post-intervention data; predicted and reported utilities were compared using t-tests, and the absolute prediction error was modeled using fixed effects, as a function of baseline demographic and clinical covariates, as well as observed and predicted EQ5D utilities. Results: A total of 267 (199) patients had complete EQ5D and EPIC domain (or subdomain) data at baseline and all subsequent assessments. In the EPIC domain sample, mean ± standard deviation observed EQ5D utility was 0.90±0.13 at baseline, 0.92±0.11 at 6 months, 0.90±0.13 at 12 months and 0.89±0.14 at 24 months. Mean absolute differences (MDs) between reported and predicted were lower for models using EPIC subdomain data compared to EPIC domain data, and generally decreased as the time of assessment increased. The mapping functions over-predicted utilities for patients in perfect health while the prediction errors were increasingly negative for lower reported EQ5D scores. According to the fixed effects model for EPIC domain data, lower observed and predicted baseline EQ5D scores, and time of assessment were significant predictors of the absolute prediction error; for EPIC subdomain data, lower observed and predicted baseline EQ5D scores, hormonal bother and function, and bowel function significantly predicted the absolute prediction error. Conclusions: This study is the first to demonstrate the longitudinal validity of EPIC questionnaire, and builds upon existing research on longitudinal validity of mapping functions. The low MDs in prediction errors in post-intervention data indicate that the mapping functions are sensitive to treatment effect, thereby increasing confidence in their use in economic evaluations in PC.

PURPOSEThere remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa.METHODSMEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS).RESULTSThe median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups.CONCLUSIONThe sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

AbstractPurposeTo prospectively assess acute differences in patient‐reported outcomes in bowel and urinary domains between intensity‐modulated radiotherapy (IMRT) and proton beam therapy (PBT) for prostate cancer.Methods and MaterialsBowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC‐26 were collected in patients with T1‐T2 prostate cancer receiving IMRT or PBT at a tertiary cancer center (2015‐2018). Mean changes in domain scores were analyzed from pretreatment to the end of and 3 months post‐radiotherapy for each modality. A clinically meaningful change was defined as a score change >50% of the baseline standard deviation.ResultsA total of 157 patients receiving IMRT and 105 receiving PBT were included. There were no baseline differences in domain scores between cohorts. At the end of radiotherapy, there was significant and clinically meaningful worsening of BF and UO scores for patients receiving either modality. In the BF domain, the IMRT cohort experienced greater decrement (−13.0 vs −6.7, P < .01), and had a higher proportion of patients with clinically meaningful reduction (58.4% vs 39.5%, P = .01), compared to PBT. At 3 months post‐radiotherapy, the IMRT group had significant and clinically meaningful worsening of BF (−9.3, P < .001), whereas the change in BF score of the PBT cohort was no longer significant or clinically meaningful (−1.2, P = .25). There were no significant or clinically meaningful changes in UO or UI 3 months post‐radiotherapy.ConclusionsPBT had less acute decrement in BF than IMRT following radiotherapy. There was no difference between the two modalities in UO and UI.

BackgroundThe goal of this study was to assess the impact of trastuzumab on locoregional failure.METHODSThe analysis included 2763 patients with HER2‐positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis.ResultsThe median follow‐up was 13.0 years. The first site of failure was local‐only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%‐5.7%). LFR10 was 5.5% (95% CI 4.3%‐7.2%), 4.9% (95% CI 3.7%‐6.4%), and 2.8% (95% CI 1.9%‐4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor–positive patients, LFR10 was 3.7% (95% CI 2.8%‐4.8%) and for estrogen receptor–negative patients, it was 6.1% (95% CI 5.0%‐7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%‐7.8%), 3.0% (95% CI 2.1%‐4.3%), and 5.5% (95% CI 4.0%‐7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%‐8.9%), 4.1% (95% CI 2.4%‐7.0%), and 4.3% (95% CI 2.9%‐6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6).ConclusionLow 10‐year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.

5584 Background: The timing of systemic therapy in relation to radiotherapy (RT) is important in most malignancies. In contrast, androgen deprivation therapy (ADT) has largely been investigated in relation to its duration rather than its sequencing with RT. Herein, we conduct the first combined individual patient analysis of two phase III randomized trials to determine the optimal timing of ADT with RT in localized prostate cancer (PCa). Methods: Individual patient data was obtained from the Malone et al trial (JCO 2019), which randomized patients to receive neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only RT. This was combined with the prostate only RT arms of RTOG 9413 that randomized patients to 4 months of neoadjuvant/concurrent or adjuvant ADT. The neoadjuvant/concurrent arms of both trials were combined into the “neoadjuvant” group, and the concurrent/adjuvant (Malone) and adjuvant arm (RTOG 9413) were combined in the “adjuvant” group. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Cumulative incidence of distant metastasis (DM), PCa-specific mortality (PCSM) and biochemical failure (BF) were calculated using the Fine-Gray method with non-PCa deaths as competing events. Late genitourinary (GU) and gastrointestinal (GI) toxicity are also reported. Results: The median follow-up was 14.9 years (yrs) and 1065 patients were included (n=531 neoadjuvant, 534 adjuvant). Groups were well balanced for all baseline characteristics. Adjuvant ADT was superior to neoadjuvant ADT in terms of BF (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), DM (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04), and PFS (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01). Adjuvant ADT yielded lower PCSM (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10), but did not reach statistical significance. This approached statistical significance in high risk PCa (HR 1.39 (95%CI 1.00-1.93), p=0.053). OS was not significantly different between arms (15yr: 39% vs 34%, HR: 1.11 (95%CI: 0.95-1.30), p=0.20). There was no significant difference in either late grade ≥3 GI (p=0.21) or GU (p=0.98) toxicity. Conclusions: We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized PCa, favoring an adjuvant rather than neoadjuvant approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design. Clinical trial information: NCT00769548 .

9525 Background: Determine if prophylactic tadalafil maintains spontaneous (off-drug) erectile function (EF) compared to placebo in patients (pts) treated with radiotherapy (RT) for prostate cancer. Methods: Double-blind 1:1 randomization to tadalafil 5mg daily for 6 mos vs placebo starting with RT. Primary outcomes measured by International Index of Erectile Function (IIEF). Eligibility included pre-RT IIEF Question [Q] 1 response “sometimes/most times/always” able to get an erection. Ps treated with hormones were excluded. Primary outcome was response to IIEF Q1 at 30 wks (6 wks off drug). Pts were stratified by RT modality (external vs. brachytherapy) and age (≤65 vs. >65 years). 182 pts were needed in an intent-to-treat analysis to show a difference from 20% responders with placebo to 40% with tadalafil based on a 2-sided Fishers exact test with α=0.05 and 80% power. Results: We report on 155/222 analyzable/eligible pts. Median age was 63 years, white (73%), and external RT (63%). Mean total dose for external RT was 77.23 Gy and 136.74 Gy for brachytherapy with penile bulb D50 of 24.46 Gy and 31.24 Gy respectively. Most pts completed treatment per protocol (84% tadalafil, 70% placebo). Spontaneous EF at 30 wks from drug start was not different (p=0.99) between arms based on IIEF Q1 response, total IIEF score (52.5 drug vs 52.8 placebo), or score change from baseline (-8.0 drug vs -8.8 placebo). No difference in these outcomes was noted at 1 year. Non-responders at 30 wks were likely to be older (age≥65; p=0.432), but there were no significant predictors at 1 year. About 80% of pts maintained spontaneous EF in both arms. Conclusions: Low-dose daily tadalafil did not preserve EF within the first year of RT for prostate cancer. If tadalafil positively influences delayed RT-induced vasogenic injury, additional time may be needed to observe a benefit to tadalafil as a preventive agent. Alternatively, tadalafil dose modification or altered dosing schedules may be needed to demonstrate a protective effect of this agent when used with RT. Clinical trial information: NCT00951184.