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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation were randomly assigned to conventional radiation therapy (CRT) or IMRT. Toxicity and quality of life were assessed using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domains, and Functional Assessment of Cancer Therapy–General. Between 2012 and 2015, 279 eligible patients were enrolled to the study with a median follow-up of 37.8 months. There were no differences in overall survival ( P = .53), disease-free survival ( P = .21), or locoregional failure ( P = .81). One year after RT, patients in the CRT arm experienced more high-level diarrhea frequency (5.8% IMRT v 15.1% CRT, P = .042) and a greater number had to take antidiarrheal medication two or more times a day (1.2% IMRT v 8.6% CRT, P = .036). At 3 years, women in the CRT arm reported a decline in urinary function, whereas the IMRT arm continued to improve (mean change in EPIC urinary score = 0.5, standard deviation = 13.0, IMRT v –6.0, standard deviation = 14.3, CRT, P = .005). In conclusion, IMRT reduces patient-reported chronic GI and urinary toxicity with no difference in treatment efficacy at 3 years.

PURPOSE Because of the negative impact of cancer treatment on female sexual function, effective treatments are warranted. The purpose of this multisite study was to evaluate the ability of two dose levels of extended-release bupropion, a dopaminergic agent, to improve sexual desire more than placebo at 9 weeks, measured by the desire subscale of the Female Sexual Function Index (FSFI), and to evaluate associated toxicities. METHODS Postmenopausal women diagnosed with breast or gynecologic cancer and low baseline FSFI desire scores (< 3.3), who had completed definitive cancer therapy, were eligible. Women were randomly assigned to receive 150 mg or 300 mg once daily of extended-release bupropion or a matching placebo. t-tests were performed on the FSFI desire subscale to evaluate whether there was a significantly greater change from baseline to 9 weeks between placebo and each bupropion arm as the primary end point. Sixty-two patients per arm provided 80% power using a one-sided t-test. RESULTS Two hundred thirty women were randomly assigned from 72 institutions through the NRG Oncology NCORP network. At 9 weeks, there were no statistically significant differences in change of the desire subscale scores between groups; participants in all three arms reported improvement. The mean changes for each arm were placebo 0.62 (standard deviation [SD] = 1.18), 150-mg once daily bupropion 0.64 (SD = 0.95), and 300-mg once daily bupropion 0.60 (SD = 0.89). Total and subscale scores on the FSFI were low throughout the study, indicating dysfunction in all groups. CONCLUSION Bupropion was not more effective than placebo in improving the desire subscale of the FSFI. Subscale and total scores of the FSFI demonstrated dysfunction throughout the 9 weeks of the study. More research is needed to support sexual function in female cancer survivors.

PURPOSE In oncology trials, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) is the standard tool for reporting adverse events (AEs), but it may underreport symptoms experienced by patients. This analysis of the NRG Oncology RTOG 1203 compared symptom reporting by patients and clinicians during radiotherapy (RT). PATIENTS AND METHODS Patients with cervical or endometrial cancer requiring postoperative RT were randomly assigned to standard 4-field RT or intensity-modulated RT (IMRT). Patients completed the 6-item patient-reported outcomes version of the CTCAE (PRO-CTCAE) for GI toxicity assessing abdominal pain, diarrhea, and fecal incontinence at various time points. Patients reported symptoms on a 5-point scale. Clinicians recorded these AEs as CTCAE grades 1 to 5. Clinician- and patient-reported AEs were compared using McNemar’s test for rates > 0%. RESULTS Of 278 eligible patients, 234 consented and completed the PRO-CTCAE. Patients reported high-grade abdominal pain 19.1% ( P < .0001), high-grade diarrhea 38.5% ( P < .0001), and fecal incontinence 6.8% more frequently than clinicians. Similar effects were seen between grade ≥ 1 CTCAE toxicity and any-grade patient-reported toxicity. Between-arm comparison of patient-reported high-grade AEs revealed that at 5 weeks of RT, patients who received IMRT experienced fewer GI AEs than patients who received 4-field pelvic RT with regard to frequency of diarrhea (18.2% difference; P = .01), frequency of fecal incontinence (8.2% difference; P = .01), and interference of fecal incontinence (8.5% difference; P = .04). CONCLUSION Patient-reported AEs showed a reduction in symptoms with IMRT compared with standard RT, whereas clinician-reported AEs revealed no difference. Clinicians also underreported symptomatic GI AEs compared with patients. This suggests that patient-reported symptomatic AEs are important to assess in this disease setting.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

187 Background: Intraprostatic radiation dose escalation is an area of clinical interest. Dose escalation within the prostate must be balanced with maintaining acceptable dose to the organs at risk, OAR (bladder, rectum, and urethra). Treatment planning therefore requires simultaneous consideration of multiple competing plan optimization goals, for which iterative, interdisciplinary treatment planning tasks may take significant physician, physicist, and dosimetrist time. Semi-automated treatment planning using artificial intelligence has the potential to significantly reduce treatment planning time for technically complex treatments. Methods: A prostate SBRT planning template was created using the Varian ETHOS treatment planning system (TPS) combined with an in-house RapidPlan SBRT prostate model. Prostate dose was prescribed to 36.25 Gy over 5 fractions with 95% coverage to the PTV. To respect standard SBRT normal tissue toxicity constraints while simultaneously escalating intraprostatic dose, the TPS automatically created an intraprostatic boost structure (PTV_SIB), derived from the PTV by excluding OARs with a pre-determined margin. Physicians were trained to perform treatment planning using the prostate SBRT planning template. Treatment planning was performed on 5 unique patients. The time spent from initiation to end of treatment planning and dosimetric parameters were recorded. Results: For each patient, the ETHOS TPS generated two SBRT plans (9 field static IMRT and 3 VMAT arc) with intraprostatic dose escalation in an average of 9.3 minutes [range 8.4-11.8]. Static field and VMAT plans were comparable. PTV_SIB was escalated to above 50 Gy in all cases. Relevant dosimetry for each patient’s static IMRT plan is shown. Conclusions: Physician-driven ETHOS treatment planning was able to produce boosted internal PTV doses using autosegmented volumes. The ETHOS TPS was able to generate dose-escalated plans that reconciled complex OAR and PTV goals within 8-12 minutes. Hence, the ETHOS TPS opens the possibility of rapid physician-driven treatment planning throughput. [Table: see text]

489 Background: To determine if SBRT followed by sorafenib (SBRT/S) improves overall survival (OS), progression free survival (PFS) and quality of life (QOL) vs. sorafenib alone (S), in patients (pts) with HCC. Methods: Eligible pts had new or recurrent HCC, unsuitable for surgery, ablation or TACE, with Zubrod performance status (PS) 0-2, Child-Pugh (CP) A, BCLC stage B or C, ≤ 5 HCCs, sum of hepatic HCCs ≤ 20 cm, and distant metastases ≤ 3 cm. Pts were randomized 1:1 to S 400 mg BID vs. SBRT (27.5-50 Gy in 5 fractions) followed by S 200 mg BID, increased to 400 mg BID after 28 days. Primary endpoint was OS; reported secondary endpoints - PFS, adverse events (AEs - CTCAEv4), and QOL (improvement in FACT-Hep score by ≥ 5 points from baseline to 6 months). Planned sample size was 292 pts (238 OS events, HR=0.72, 80% power, 1-sided α=0.05). Accrual closed early, due to a change in HCC standard of care. Statistics were amended to report as of 7/1/2022, projecting 155 OS events, with 65% power and the same α. OS and PFS were estimated by Kaplan-Meier and arms compared using log-rank test. Cox proportional hazards models were used to analyze treatment effect. Secondary endpoints were tested with 2-sided α=0.05. Results: Of 193 pts accrued from April 2013 to March 2021 from 23 sites, 177 eligible pts were randomized to S (n=92) vs. SBRT/S (n=85). Median age was 66 yrs (27-84); 41% had Hep. C; 19% had Hep. B or B/C. 82% were BCLC stage C. 74% had macrovascular invasion (MVI), 63% with VP3 or VP4 MVI. 4% had metastases. Median sum of max diameter of HCCs was 8.2 cm for S and 6.7 cm for SBRT/S; 40% had a single HCC. Median follow-up for all and alive pts was 13.2 and 33.7 mo. 22% of S pts received SBRT after discontinuing S. With 153 OS events, median OS was improved from 12.3 mo. (90% CI 10.6, 14.3) with S to 15.8 mo. (90% CI 11.4-19.2) with SBRT/S (HR=0.77, 1-sided p=0.0554). After adjusting for PS, M stage, CP A5 vs. 6, and degree of MVI, OS was statistically significantly improved for SBRT/S (HR=0.72, 95% CI 0.52-0.99, 2-sided Cox p=0.042). Median PFS was improved from 5.5 mo. (95% CI 3.4-6.3) with S to 9.2 months (95% CI 7.5-11.9) with SBRT/S (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). 8 grade (G) 3+ bleeds were seen: 5 in S arm (1 G3 variceal, 2 G3 upper GI, 1 G3 hepatic, and 1 G4 abdominal) and 3 post SBRT/S (2 G3 upper GI, 1 G3 lower GI). Treatment-related G3+ AEs were not significantly different (S - 42%; SBRT/S - 47%; p=0.52), with 3 G5 AEs (S - 1 hepatic failure, 1 death NOS; SBRT/S - 1 lung infection). 83 (47%) pts consented to QoL. Of 20 S and 17 SBRT/S pts with QoL assessments at baseline and 6 months, 10% on S improved in FACT-Hep score vs 35% on SBRT/S. Conclusions: Compared to S alone, SBRT improved OS & PFS in patients with HCC, with no observed increase in AEs, and a strong suggestion for QOL benefit at 6 months. Supported by U10CA180868 (NRG Onc. Op., U10CA180822 (NRG Onc. SDMC), UG1CA189867 (NCORP), and U24CA180803 (IROC) from the NCI. Clinical trial information: NCT01730937 .

7 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EAs) in LARC. EAs are not intended for direct comparison, but rather to concurrently randomized control arm (CA) patients. Primary endpoint (EP) and available secondary EPs (from EA1 using veliparib [V], PARPi; and EA2 using pembrolizumab [P], anti-PD-1) have been previously reported. We present long-term outcomes of all pts enrolled (NCT02921256). Methods: Stage II/III pts with MSS LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to CA (neoadjuvant FOLFOX [x 4mo] → chemoRT [capecitabine with 50.4Gy] → surgery 8-12 wks later). EA1 added V (400mg PO BID) and EA2 added P (200mg IV Q3 wks x 6 doses) each concurrent with chemoRT. Primary EP: 4-point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α=0.10, 80% power. NAR compared by linear model controlling for clinical T4 at entry (Y/N). Secondary EPs: OS, DFS. p-values are two-sided. Results: From 10/2016-2/2018, 178 pts were randomized (88 CA, 90 EA1). From 8/2018-5/2019, 185 pts were randomized (95 CA, 90 EA2). Baseline characteristics were previously reported. Median follow-up is 3.50 yrs for the 1st comparison. Median follow-up is 3.15 yrs for the 2nd comparison. Updated primary and long-term secondary outcomes are in the table. Conclusions: With longer follow-up, addition of V to TNT provided no significant differences in the NAR score or 3yr outcomes. The addition of P to TNT was associated with a statistically significant improvement in 3yr OS, but not DFS. Correlative molecular analyses are ongoing. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie; Merck. Clinical trial information: NCT02921256 . [Table: see text]

TPS3631 Background: Adenomatous polyps are the acknowledged precursors of colorectal cancer (CRC). Identification and removal of adenomas is the mechanism by which screening is effective in reducing CRC incidence and mortality. Patients with 1-2 non-advanced adenomas ( < 1 cm with neither villous components nor high grade dysplasia) are recommended to return at a timing ranging from 5-10 yrs. However, evidence for the benefit, optimal timing, and recommended frequency of surveillance colonoscopy is not available. A randomized, clinical trial to demonstrate the difference in results between 5- or 10-yr surveillance for participants with non-advanced adenoma can guide clinical practice. Methods: NRG-CC005/FORTE is a prospective, randomized, non-blinded, Phase III, non-inferiority clinical trial comparing CRC incidence in participants randomized to recommendation for a 5- and 10-yr vs. a 10-yr only surveillance colonoscopy exam schedule. Other pre-defined exploratory endpoints include incidence of advanced adenomas, CRC mortality, and incidence of stage III-IV CRCs. Stratification factors include age, gender, and time from qualifying colonoscopy to randomization. Participants ≥50 and < 70 yrs of age at the time of randomization with a first-time diagnosis of 1-2 non-advanced tubular adenomas from the qualifying colonoscopy within 4 yrs prior to randomization will be eligible. Participants with a clinical diagnosis of a significant genetic risk for CRC or with a family history of CRC diagnosed at ≤60 yrs in a first degree relative or in two first degree relatives diagnosed at any age are ineligible. Other ineligibility criteria include prior history of CRC or colorectal adenomas, a hyperplastic polyp measuring ≥1 cm or traditional serrated adenomas, or life expectancy < 10 yrs due to comorbid conditions. Collection of blood, stool, and tissue samples is planned. Statistics: The primary endpoint for the trial is CRC incidence. The trial is focused on CRCs diagnosed between year 5 and year 10. By incorporating a window of +/- 1 yr to allow for somewhat earlier and later procedures, as typically occurs in clinical medicine, the primary endpoint will include incident cancers identified in years 4 through 11. A crude 4- to 11-yr incidence rate of 0.387% is assumed for the 5- and 10-yr schedule arm. The study is powered at 90% to detect a non-inferiority margin difference of 0.387% at alpha 5% in CRC incidence rate between two schedules. 9,500 participants are to be enrolled. Support: U10CA180868, -180822, UG1CA189867, U24CA196067 Clinical trial information: NCT05080673.

565 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a minority of patients (pts) eligible for curative resection. Currently, systemic treatment options for down-staging pts with borderline resectable or locally advanced PDAC is extrapolated from the metastatic setting and modified FOLFIRINOX (FFX) +/- radiation (RT) is the most widely used regimen. Herein, we report the outcomes of combination gemcitabine, docetaxel, and capecitabine (GTX) +RT as compared to FFX +RT in the neoadjuvant (NA) setting via a single institution retrospective cohort review. Methods: We retrospectively reviewed the outcomes of pts with PDAC who underwent surgical resection at Columbia University Irving Medical Center (CUIMC) between 2011-2020. We evaluated demographics, treatment, clinical, surgical, and pathological outcomes. Statistical analysis includes Kaplan-Meier analysis and paired t-tests. Results: We reviewed 717 pts who underwent surgical resection at CUIMC of which 227 pts were confirmed to have received NA chemotherapy. Of those 227 patients, 133 pts also received RT. In total, 39 pts received GTX+RT and 42 pts received FFX+RT. Median age at diagnosis of pts who received NA GTX+RT or FFX+RT was 65 and 63 years, respectively. All pts were AJCC stage III at diagnosis and ECOG 0 or 1. There was a significantly greater percentage of pts who achieved R0 resection after GTX+RT as compared to FFX+RT, 35 (89.7%) vs 29 (69.0%), respectively (p=0.022). Significantly more pts achieved N0 lymph node status after GTX+RT as compared to FFX+RT, 29 (74.4%) vs 22 (52.4%), respectively (p=0.041). No statistically significant difference was detected in recurrence-free survival (RFS) or median overall survival (mOS) in pts who received GTX+RT and achieved R0 resection as compared to FFX+RT. See Table for summary. Conclusions: GTX appears to be a viable and active NA regimen in Stage III PDAC. In our small cohort study, more patients who received GTX+RT achieved R0 resection and N0 status as compared to FFX+RT. No difference in survival was detected but this may be due to inadequate power or choice of subsequent therapies. Larger prospective studies evaluating GTX+RT as an alternative treatment in the NA setting are warranted.[Table: see text]

8 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk pt population with correlative biomarkers. Here we report the primary and available secondary endpoints (EPs). Methods: Stage II/III LARC pts (with ONE or more of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy +/- pembrolizumab 200mg IV Q3 wks x 6 doses) → surgery 8-12 wks following last dose of radiotherapy. Primary EP: Improvement in Neoadjuvant Rectal Cancer (NAR) score for EA v control potentially representing a 3-4% absolute OS improvement. Secondary EPs: Comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter sparing surgery (SSS), and exploratory assessments of molecular and radiographic predictors of response and distant failure. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 8/2018-5/2019, 185 pts were randomized to control (n=95) or pembrolizumab (n= 90). Baseline characteristics were relatively well balanced. 137 pts were evaluable for NAR (68 control, 69 pembrolizumab). Mean NAR was 14.08 for control (95% CI: 10.7-17.4) v 11.53 for pembrolizumab (CI: 8.5-14.6) (p=0.26). pCR=29.4% v 31.9% (p=0.75); cCR=13.6% v 13.9% (p=0.95); and SSS=71.0% v 59.4% (p=0.15). The side effects on Arm 3 were consistent with both CRT and pembrolizumab safety profile. Grade 3/4 AEs were slightly increased on the pembrolizumab arm during and after CRT (48.2 v 37.3%). There were 2 deaths during FOLFOX, one on the control arm due to sepsis; the other on the EA due to pneumonia. There were no statistically significant differences in RT (fractions, dose, boost fractions, or boost dose), FOLFOX or capecitabine doses. Conclusions: Pembrolizumab added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. The secondary endpoints including PFS and OS have not been reached. Correlative analysis for both T-cell and myeloid cell populations in the tissue and blood in addition to comprehensive cytokine analysis is ongoing. NCT02921256. Support: U10CA180868, -180822; UG1-189867; U24-196067. Clinical trial information: NCT02921256.

Purpose Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. Patients and Methods Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test–Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. Results Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, −4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. Conclusion Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series.

Patient comorbidities may affect the applicability of performance measures that are inherent in multidisciplinary cancer treatment guidelines. This article describes the distribution of common comorbid conditions by disease site and by patient and facility characteristics in patients who received radiation therapy as part of treatment for cancer of the breast, cervix, lung, prostate, and stomach, and investigates the association of comorbidities with treatment decisions.Stratified two-stage cluster sampling provided a random sample of radiation oncology facilities. Eligible patients were randomly sampled from each participating facility for each disease site, and data were abstracted from medical records. The Adult Comorbidity Evaluation Index (ACE-27) was used to measure comorbid conditions and their severity. National estimates were calculated using SUDAAN statistical software.Multivariable logistic regression models predicted the dependent variable "treatment changed or contraindicated due to comorbidities." The final model showed that ACE-27 was highly associated with change in treatment for patients with severe or moderate index values compared to those with none or mild (P.001). Two other covariates, age and medical coverage, had no (age) or little (medical coverage) significant contribution to predicting treatment change in the multivariable model. Disease site was associated with treatment change after adjusting for other covariates in the model.ACE-27 is highly predictive of treatment modifications for patients treated for these cancers who receive radiation as part of their care. A standardized tool identifying patients who should be excluded from clinical performance measures allows more accurate use of these measures.

2009 Background: NRG CC001, a phase III trial of WBRT plus memantine (WBRT+M) with or without HA, sought to evaluate the neuro-protective effects of lowering the hippocampal radiation dose. Methods: Patients (pts) with BM were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module and analyzed using mixed effects models and t-tests. Results: From 7/2016 to 3/2018, 518 pts were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted hazard ratio (HR) = 0.74, p = 0.02) due to lower risk of deterioration in executive function at 4 mos (p = 0.01) and encoding (p = 0.049) and consolidation (p = 0.02) at 6 mos. Age≤61 predicted lower NCF failure risk (HR = 0.60, p = 0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p = 0.036), difficulty speaking (p = 0.049) and problems remembering things (p = 0.013) at 6 mos favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p = 0.011) and symptom interference (p = 0.008) at 6 mos. Treatment arms did not differ in toxicity, overall survival, or intracranial progression. Conclusions: HA during WBRT+M for BM better preserves NCF and patient-reported symptoms, while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute. Clinical trial information: NCT02360215.

3505 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of hypotheses in a consistent high-risk pt population with correlative biomarkers. Primary endpoint (EP) and available secondary EPs from the first EA using veliparib (a PARPi) are reported. NCT02921256. Methods: Stage II/III pts with LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX (x 4mo) → chemoRT (cape with 50.4Gy +/- veliparib 400mg PO BID) → surgery 8-12 wks later. Primary EP: 4 point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α = 0.10 and 80% power. NAR compared by linear model controlling for stratification and possibly other factors. Secondary EPs: OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, and SSS. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 10/2016 - 2/2018, 178 pts were randomized (88 control, 90 veliparib). Baseline characteristics were balanced except for candidate for SSS at entry (39% control, 61% veliparib). 140 pts were evaluable for NAR (72 control, 68 veliparib). Mean NAR was 12.6 control (95% CI: 9.8–15.3) vs 13.7 for veliparib (CI: 10.2–17.2). Controlling for stratification (p = 0.69) or stratification and candidate for SSS (p = 0.78), NAR difference was not significant. pCR = 21.6% vs 33.8% (p = 0.14); cCR = 28.2% vs 33.3% (p = 0.60); and SSS = 52.5% vs 59.3% (p = 0.43). Most common grade 3/4 AEs were diarrhea and cytopenias. The EA had two deaths (cardiac arrest [FOLFOX]; enterocolitis [chemoRT]). Conclusions: Veliparib added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie. Clinical trial information: NCT02921256.

TPS8578 Background: Multiple clinical trials have shown that prophylactic cranial irradiation (PCI) prevents brain metastases and may prolong survival in small cell lung cancer (SCLC). However,prophylactic cranial irradiation can lead to decline in cognitive function. Preclinical evidence suggests that the pathogenesis of this toxicity includes inflammatory injury to proliferating neuronal progenitor cells in the peri-hippocampal stem cell niches. We hypothesized that conformal avoidance of the hippocampal neural stem cell compartment during brain irradiation using intensity-modulated radiotherapy (IMRT) would decrease the likelihood and/or severity of this toxicity. This hypothesis was recently validated by positive results from NRG Oncology CC001, a phase III trial of hippocampal avoidance during whole-brain radiotherapy for patients with brain metastases. NRG Oncology CC003 is an ongoing randomized phase II/III trial of hippocampal avoidance during prophylactic cranial irradiation (HA-PCI) for small cell lung cancer, conducted in parallel with NRG Oncology CC001. Methods: The primary endpoints of the phase IIR and III components are 12-month intracranial relapse rate and 6-month deterioration in Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall, respectively. This is a seamless phase IIR/III trial, with the phase IIR designed to demonstrate non-inferiority. If the non-inferiority margin of the phase IIR component is not exceeded, then the trial would transition to the phase III component. Following accrual of 182 of planned 172 patients on the phase IIR component, the trial closed to accrual on 10/13/17 to assess the phase IIR primary endpoint. The DSMB evaluated the IIR outcomes, and on 1/9/19, the trial was reactivated to accrue an additional 122 patients to the phase III component. Eligibility criteria include: 1) small cell lung cancer with at least partial response to chemotherapy; 2) contrast-enhanced thin-slice volumetric MRI scan; and, 3) Zubrod performance status 0-2. Supported by grant UG1CA189867 (NCORP) from the National Cancer Institute. Clinical trial information: NCT02635009.

TPS721 Background: Locally advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers is needed to advance treatment outcomes. This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EA) in LARC. The EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk patient (pt) population with correlative biomarkers. Success of any EA will be determined by achievement of pathologic endpoints compared to a control arm. Methods: The NRG-GI002 trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC with any ONE of the following: distal location (cT3-4 ≤ 5 cm from anal verge, any N); bulky (any cT4 or tumor within 3 mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, pts receive neoadjuvant FOLFOX x 4 mo→chemoRT (capecitabine with 50.4 Gy)→surgical resection 8-12 wks later. The first EA will assess activity of veliparib with standard chemoRT. Enrollment to this EA is complete (results anticipated late 2019). The second EA, testing pembrolizumab concurrently with and following chemoRT, is currently active, with several other EAs in development. Primary endpoint is demonstrated improvement in Neoadjuvant Rectal Cancer score for the EA v control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including QOL, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts/arm with additional EAs added through protocol amendments. NCT02921256. Support: U10CA180868, -180822, UG1-189867, U24-196067; AbbVie, Merck. Clinical trial information: NCT02921256.

649 Background: This study sought to compare adverse events (AEs) of older and younger adults with lower gastrointestinal (GI) malignancies treated on NRG studies. Methods: Data from six NRG trials (RTOG 9811/0012/0247/0529/0822 & NSABP R-04), testing combined modality therapy (radiation and chemotherapy) in patients with anal or rectal cancer, were collected to test the hypothesis that older age was associated with increase in acute ( ≤ 90 days from treatment start) AEs. AEs were defined as GI, Genitourinary (GU), hematologic, or skin. AEs and compliance with protocol-directed therapy were compared between patients aged ≥ 70 years and < 70 years. Categorical variables were compared across age groups using the chi-square test. The association of age on AEs was evaluated using a covariate-adjusted logistic regression model, with odds ratio (OR) reported. To adjust for multiple comparisons, a p-value < 0.01 was considered statistically significant. Results: Data from 2525 patients were collected (43% female, 72% rectal cancer). There were 380 patients ≥ 70 years old (15%). Older patients were more likely to have worse baseline performance status (PS 1 or 2) (23% vs. 16%, p

Purpose There are no data on how complication rates after accelerated partial-breast irradiation delivered by three-dimensional conformal radiotherapy are affected by treatment technique. We therefore examined the risk of pneumonitis in relation to lung dose-volume parameters. Patients and Methods Our prospective dose-escalation trial enrolled 198 treated patients from 2003 to 2007. Patients received 32 or 36 Gy in 4-Gy fractions, given twice daily: 29 (14%) were treated with pure photons; 149 (77%) with mixed photons and electrons; and 20 (10%) with protons. Results There were four cases of pneumonitis at 4, 4, 7, and 9 months after treatment. All were in the 36-Gy cohort and were treated with pure photons. The risk of pneumonitis for the two cohorts combined was: 17% (four of 24) for an ipsilateral lung volume (ILV) receiving 20 Gy or higher (ILV, 20 Gy) of 3% or higher (P = .0002 for comparison to ILV 20 Gy < 3%, Fisher's exact test); 20% (four of 20) for an ILV 10 Gy of 10% or higher (P = .0001); and 15% (four of 26) for an ILV 5 Gy of 20% or higher (P = .0002). Conclusion The risk of pneumonitis appeared related to the ILV treated. This volume can be reduced by using mixed photons and electron when possible. We recommend that the ILV 20 Gy should be lower than 3%, the ILV 10 Gy lower than 10%, and the ILV 5 Gy lower than 20% when purely coplanar techniques are used.

Purpose A Patterns of Care Study of patients treated from 1996 to 1999 evaluated the national practice for patients receiving radiation therapy for carcinoma of the esophagus in the United States. Methods A national survey was conducted at 59 institutions in a stratified random sample selected from a master list of radiation therapy facilities throughout the United States. Patient, tumor, and treatment characteristics were evaluated. Multivariate comparisons of survival times were made using the Cox proportional hazards model. Results Adenocarcinoma was diagnosed in 51% of patients and squamous cell carcinoma in 49% of patients. Sixteen percent of patients were clinical stage (CS) I (using the 1983 American Joint Committee on Cancer system), 39% were CS II, and 33% were CS III. Significant variables in the multivariate analysis of survival times included clinical stage, treatment approach, and facility size. Patients with CS III disease had a higher hazard risk of death as compared with CS I patients (hazard ratio [HR], 2.01; P = .001), whereas those treated with chemoradiotherapy followed by surgery (HR, 0.32; P < .0001) had a decreased risk of death compared with chemoradiotherapy-only patients. Patients at small centers had a higher risk of death (HR, 1.32; P = .03) compared with patients treated at larger facilities. Conclusion Concurrent chemoradiotherapy continued to be the most commonly utilized treatment approach during the time period studied. The observation that patients undergoing surgical resection following chemoradiation have a decreased HR or chance of death compared with other treatment schemes supports the need for a randomized trial comparing these strategies.

TPS876 Background: Locally-advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms (EA) in LARC. The EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk patient (pt) population with correlative biomarkers. Success of any EA will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC with any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, all pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. The first EA will assess the activity of veliparib with standard chemoRT. A second EA, testing pembrolizumab concurrently with and following chemoRT, is in development. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score for the EA vs control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional EAs added through protocol amendments. NCT02921256. Support: U10 CA-180868, -180822, UG-189867, U24CA196067; AbbVie Clinical trial information: NCT02921256..

PURPOSE To update the efficacy of a selective multimodality bladder-preserving approach by transurethral resection (TURBT), systemic chemotherapy, and radiation therapy. PATIENTS AND METHODS From 1986 through 1993, 106 patients with muscle-invading clinical stage T2 to T4a,Nx,M0 bladder cancer were treated with induction by maximal TURBT and two cycles of chemotherapy (methotrexate, cisplatin, vinblastine [MCV]) followed by 39.6-Gy pelvic irradiation with concomitant cisplatin. Patients with a negative postinduction therapy tumor site biopsy and cytology (a T0 response, 70 patients) plus those with less than a T0 response but medically unfit for cystectomy (six patients), received consolidative chemoradiation to a total of 64.8 Gy. Surgical candidates with less than a T0 response (13 patients) and patients who could not tolerate the chemoradiation (six patients) went to immediate cystectomy. The median follow-up duration is 4.4 years. RESULTS The 5-year actuarial overall survival and disease-specific survival rates of all patients are 52% and 60%, respectively. For clinical stage T2 patients, the actuarial overall survival rate is 63%, and for T3-4, 45%. Thirty-six patients (34%) underwent cystectomy, all with evidence of tumor activity, including 17 with an invasive recurrence. The 5-year overall survival rate with an intact functioning bladder is 43%. Among 76 patients who completed bladder-preserving therapy, the 5-year rate of freedom from an invasive bladder relapse is 79%. No patient required cystectomy for treatment-related bladder morbidity. CONCLUSION Combined modality therapy with TURBT, chemotherapy, radiation, and selection for organ-conservation by response has a 52% overall survival rate. This result is similar to cystectomy-based studies for patients of similar age and clinical stages. The majority of the long-term survivors retain fully functional bladders.

3522Background: SCCAC is a human papilloma virus (HPV) associated cancer that is potentially curable with CMT, commonly associated with HIV infection, and characterized by high local regional failu...

573 Background: Squamous cell carcinoma of the anal canal will be diagnosed in 28,000 individuals globally. Considered a rare cancer, the incidence of anal carcinoma continues to rise annually. Majority of patients present with locally advanced disease in which concurrent chemoradiation (CRT) will be provided with curative intent. The Anal Cancer IRCI Working Group was created to pursue novel approaches to the diagnosis, treatment, and surveillance of patients. Yet, surveillance following completion of CRT is not well established and varies as per NCCN (v2.2015) and ESMO guidelines. Methods: A 22-question survey provided to anonymous international GI subspecialists in various fields. Questions pertained to timing and type of diagnostic imaging, surveillance interval, approach to detection of complete response (CR), and prevention of sexual dysfunction. Results: Survey distribution was initiated in March 2015 and still ongoing. Thus far, 96 physicians responded. Conclusions: Carcinoma of the anal canal continues to rise in incidence annually. Surveillance following completion of CRT is warranted; however, global variability in practice patterns for surveillance exists. As such, the IRCI Anal Cancer Working Group intends to provide an international consensus surveillance statement. [Table: see text]

27 Background: The considerable interest in short UHR 5-12 fractions(fr) in management of CaP is based on potential radiobiological advantages, patient convenience & resource allocation benefits. Prior to comparison with standard RT regimens (SRTR), a study was undertaken whose primary objective was to demonstrate that 1-year health-related quality of life (HRQOL) for at least one UHR arm was not significantly lower than baseline as measured by the Bowel & Urinary domains EPIC instrument(EPIC B&U). Secondary objectives included acute & late GI & GU toxicity. Methods: RTOG 0938 is a randomized phase II study of CaP patients(pts), (Gleason score 2-6, stage T1-2a & PSA < 10 ng/mL) receiving 36.25 Gy (5 fr of 7.25 Gy in 2 wks), or 51.6 Gy (12 fr of 4.3 Gy in 2.5 wks). Pts were stratified according to RT technique – Cyberknife vs IMRT/VMAT or protons. A change in EPIC bowel domain score (baseline to 1-year) > 5 points & in EPIC urinary domain score > 2 points were felt to be clinically significant. The frequency for > 5 point change in bowel score (FREQE-B) in ≤ 35% of pts was considered acceptable, with the frequency ≥ 55% unacceptable. Similarly, the frequency for > 2 point change in urinary score (FREQE-U) in ≤ 40% was considered acceptable, with the frequency ≥ 60% unacceptable. A sample size of 156 pts was needed for 95% power with one-sided significance level of 0.025 to preserve an overall level of 0.05. Results: 240 pts were enrolled to ensure adequacy of data for analysis. The compliance for HRQOL completion was good ( > 80%). The 1 year FREQE-B for 5 fr was 23.5% (p < 0.001) & 12 fr was 23.1% (p < 0.001). The 1 year FREQE-U for 5 fr was 35.3% (p < 0.001) & 12 fr was 34.7% (p < 0.001). Conclusions: This study confirms that based on changes in EPIC B&U (baseline to 1-year), acute & late toxicity, both the 5 & 12 fr regimens are well tolerated. These UHR need to be compared to current SRTR in the context of a RCT with efficacy & toxicity endpoints. Supported by grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, UG1CA189867 from the National Cancer Institute (NCI). Clinical trial information: NCT01434290. [Table: see text]

4007 Background: RTOG 0436 is a randomized Ph III trial evaluating cetuximab added to concurrent chemoradiation for patients (pts) undergoing non-operative management of esophageal carcinoma (EC). ...

Imagine that tomorrow you develop some minor rectal bleeding. Your primary care physician refers you to a gastroenterologist who performs a colonoscopy finds a 3-cm moderately differentiated adenocarcinoma beginning at 8 cm from the anal verge. Staging computed tomography scans show no evidence of distant metastases. Pelvic magnetic resonance imaging (MRI) confirms a 3-cm mass, and a small part of the smooth black line of the muscularis propria is violated by the tumor on two contiguous MRI slices. There is no perirectal lymphadenopathy. Is preoperative chemoradiotherapy the right initial treatment for your clinical stage of disease? Our current uncertainty regarding the optimal adjuvant therapy for all clinically staged T3, N0, M0 rectal cancers was not always the case. More than two decades ago, the results of two randomized North American trials (the Gastrointestinal Tumor Study Group Protocol 7175 and the Mayo/North Central Cancer Treatment Group Protocol 79-47-51) demonstrated an increase in local control, disease-free survival, and overall survival when long-course radiation was administered concurrently with fluorouracil (FU) -based chemotherapy after surgical resection for patients with stage II and III rectal cancer. The National Surgical Adjuvant Breast and Bowel Project R01 trial then established that adjuvant FU chemotherapy after a rectal cancer resection was associated with improved survival compared with surgery alone or surgery with postoperative radiation. After the publication of these studies, it became standard of care for all patients with completely resected stage II or III rectal cancer to be treated in the postoperative setting with both FU-based chemoradiotherapy and FU chemotherapy for the best possible chance of achieving local control and overall survival. More recently, before preoperative chemoradiotherapy and total mesorectal excision (TME) emerged as a new standard of care, investigators evaluated whether there was a select group of patients in which adjuvant chemoradiotherapy could be safely omitted. Retrospective data from the non-TME era suggest that there may be a favorable subset of patients with pathologic T3, N0 disease (well to moderately differentiated histology, extending 2 mm or less into the perirectal fat, without lymphatic or vascular invasion, upper rectal location, and adequate node dissection) who may not benefit from adjuvant treatment. Furthermore, subset analyses of the largest postoperative trials evaluating adjuvant chemoradiotherapy demonstrate significantly improved local control and survival outcomes for patients with T3, N0 or T1/2, N1 disease. It is reasonable to expect even better results in the TME era. The landmark German Rectal Cancer Study, which directly compared preoperative versus postoperative chemoradiotherapy in the setting of modern clinical staging with endorectal ultrasound (ERUS) and modern surgical resection with TME, transformed our postoperative treatment standard and challenged our growing consensus that not all pathologically staged T3, N0 cancers require adjuvant therapy. This large randomized trial demonstrated that local control, rate of any grade 3 or 4 acute or late toxicity, and treatment compliance were significantly improved when chemoradiotherapy was administered preoperatively. Although preoperative chemoradiotherapy was the clear winner, new concerns emerged. First, 18% of the patients on the postoperative treatment arm who were clinically staged by ERUS as having T3 or N cancer, were found at resection to have T1-2, N0 disease and did not need adjuvant therapy. Second, due to preoperative chemoradiotherapy downstaging, we lost accuracy in predicting which patients may not benefit from adjuvant therapy, such as those with good-risk pathologic T3, N0 tumors. It is important to note that administering chemoradiotherapy and additional chemotherapy comes with a price: increased treatment-related deaths, and enhanced morbidity including radiation enteritis, diarrhea, ileus, bowel obstruction, and hematologic toxicities. In addition, functional anorectal outcome such as number of bowel movements per day, fecal continence, and sexual function have been demonstrated to be worse in patients receiving radiation. Guillem et al, in this issue of the Journal of Clinical Oncology, admirably address the question regarding the necessity of adjuvant therapy for all patients with T3, N0 rectal cancer in this new era of preoperative therapy. Although we are now aware of the potential overstaging risk from the German study, how often do we miss more advanced disease for patients with ERUSor MRI-staged T3, N0 rectal cancer? In this large multicenter review, 22% of the patients believed to have clinically node-negative T3 disease were identified after chemoradiotherapy at the time of resection to have positive mesorectal lymph nodes. Although this analysis may be criticized for its retrospective nature, heterogeneity in the treatment techniques among institutions, as well as for the lack of central staging and pathology review, it still strongly emphasizes the significant degree of understaging that can occur with modern ERUS and MRI practice at some of the best JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 3 JANUARY 2

LBA6 Background: RTOG 0436 is a randomized Ph III trial designed to evaluate the benefit of cetuximab added to the concurrent chemoradiation for patients undergoing non-operative management of esophageal carcinoma. Methods: Pts with biopsy-proven squamous cell or adenocarcinoma of the esophagus (T1N1M0; T2-4 AnyN M0; Any T/N M1a) were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions ± weekly cetuximab (400 mg/m2 day 1 then weekly 250 mg/m2). Patients were stratified by histology, tumor size (< 5 cm vs > 5cm), and the status of celiac lymph nodal involvement. Overall survival (OS) was the primary endpoint, with a planned accrual of 420 pts to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided 0.025 alpha. An interim analysis of cCR was planned for the first 150 of each histology. Results: The study accrued 344 pts from 2008-2013 and 328 were eligible. Based on interim analyses, the study stopped accruing adeno pts in 5/2012 and SCC pts in 1/2013. Pts were well matched for pretreatment characteristics: 80% with T3/4 disease, 66% N1, and 19% with celiac nodal involvement. Incidence of grade 3/4/5 treatment (tx) related AEs was 45%, 22%, 4% in Arm 1 (cetuximab) and 49%, 17%, 1% in Arm 2 (no cetuximab). A cCR rate of 56% was observed in Arm 1 vs 59% in Arm 2 (p=0.72). No differences were seen in cCR between tx arms for either histology. The 12 and 24 mo OS rates for cCR pts were 79% and 58% vs 53% and 30% for those with residual disease (p

460 Background: Radiation Therapy Oncology Group (RTOG) 0529 assessed feasibility of dose-painted intensity-modulated radiation therapy (DP-IMRT) to reduce the acute morbidity of chemoradiation with 5-fluorouracil (5FU) and mitomycin-C (MMC) for T2-4N0-3M0 anal cancer. This secondary analysis was performed to identify patient (pt) and treatment factors associated with acute and late gastrointestinal (GI) adverse events (AEs). Methods: RTOG 0529 treatment plans were reviewed to extract dose-volume data for tightly contoured small bowel (SB), loosely contoured anterior pelvic contents (APC), and uninvolved portions of colon outside the clinical target volume (UC). T-tests were performed to evaluate differences in the mean absolute volumes of each critical structure receiving doses ≥ 5 to 60 Gy (V5-V60) in 5 Gy increments between pts with and without ≥ grade (G) 2, acute and late GI AEs, and ≥G3 acute GI AEs using the NCI Common Terminology Criteria, version 3. Acute is defined as ≤ 90 days from the start of treatment and late is > 90 days. Additional factors (age, location, gender, race, Zubrod, grade, size, stage, prone vs supine position) were also evaluated in multivariate (MV) logistic regression (acute AEs) or Cox proportional hazards models (late AEs) to evaluate correlation with GI AEs. Results: Among 52 evaluable pts, ≥G2 acute, ≥G2 late, and ≥G3 acute GI AEs were observed in 35, 17, and 10 pts, respectively. Trends (p4cm, and worse Zubrod. SB and APC dose parameters remained correlated with GI AEs on MV analysis. Treatment in the prone vs supine position correlated with lower SB V10-V35 and APC V5-V20, although no significant differences in GI AEs were observed. Conclusions: Acute and late GI AEs from 5FU/MMC chemoradiation using DP-IMRT correlates with RT dose to the SB and APC. Further analysis is underway to determine critical structure cut-point parameters that may aid treatment plan optimization for anal cancer DP-IMRT. Supported by RTOG U10 CA21661, CCOP U10 CA3742 and ATC U24 CA 81647 NCI grants. Clinical trial information: NCT00423293.

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.

TPS9150 Background: Skeletal related events (SREs) diminish quality of life (QOL) as well as overall survival (OS) in patients with bone metastases, a common event in breast, lung and prostate cancer. SREs can be reduced or delayed by the use of bisphosphonates. It is postulated that the radiopharmaceuticals, Strontium-89 (Sr89) and Samarium-153 (Sm153), when added to a bisphosphonate can decrease the incidence of SREs. Methods: RTOG 0517 randomized patients with breast, lung and prostate cancer and blastic bone metastases to either Zoledronic acid (ZA) alone or ZA plus a single standard dose of either Sr89 or Sm153. No limitations were placed on additional therapy such as chemotherapy or hormonal treatment. The projected median time to SRE [pathological bone fracture, spinal cord compression, surgery to bone, or radiation to bone] for the ZA arm was 10.4 months requiring 257 SRE events to detect a 33% relative reduction for the radiopharmaceutical arm in the time to development of an SRE with 90% power. Other study objectives included quality of life, pain control, OS and toxicity. Results: 261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued from July 2006 through February 2011 (4.6 patients/month). Due to a lower than expected rate of SREs in the control (ZA) arm, the study was closed early and therefore did not reach the targeted accrual. 28 (17.4%) patients in the ZA arm and 27 (16.8%) in the radiopharmaceutical arm experienced an SRE. Median time to development of an SRE in the ZA and radiopharmaceutical arms was 11.60 and 16.74 months, respectively (p=.47). Median OS in the ZA arm and radiopharmaceutical arm was 15.95 and 11.18 months, respectively (p=0.12). Cox proportional hazards regression model showed that baseline characteristics, including gender, race, ethnicity, primary disease site or number of bone metastases, had no significant impact on OS. There was no difference in QOL parameters or toxicities between the two arms. Conclusion: Patients receiving ZA only experienced a much lower SRE rate than was hypothesized. The addition of Sr89 or Sm153 did not result in a difference in SREs, OS, or QOL

4030 Background: Epidermal growth factor receptor (EGFR) expression and HPV infection are common in SCAC. We therefore initiated 2 phase II studies to evaluate the safety and efficacy of the EGFR inhibitor CX given concurrently with CDDP/5-FU/RT in HIV-positive (AMC045) and immunocompetent (E3205) patients with SCAC. Methods: All patients received CX (400 mg/m2 loading, then 250 mg/m2/wk IV x 6-8 wks) plus CDDP (75 mg/m2 IV q28 days x 2) and 5-FU (1000 mg/m2/day IV infusion days 1-4 q 28 days x 2) concurrently with RT (45-54 Gy) beginning with CX dose 2. Patients in E3205 also received 2 cycles of CDDP/5-FU alone prior to CX/CDDP/5-FU/RT; this was discontinued on recommendation of the NCI Anorectal Task Force after 28 patients. Both trials were powered to detect a reduction in 3-year local-regional failure (LRF) rate from 35% to 17.5% (alpha=0.10, beta=0.10), the primary end point. Other endpoints included progression free survival (PFS) and overall survival (OS). The results below include complete toxicity and preliminary efficacy data (including only the first 28 patients from E3205). Results: Expedited reporting was required for type I (any grade 5, grade 4 cardiac) or II (grade 4 RT skin, diarrhea) adverse events, with prespecified rates of >5% or >20%, respectively defined as unacceptable. Early stopping rules were not invoked for either trial. LRF rates data will be presented after more detailed case review is completed. Conclusions: CX plus CDDP/5-FU/RT is feasible in patients with SCAC, including patients with HIV infection. Preliminary safety and efficacy data appear encouraging, but accrual without neoadjuvant CDDP/5-FU continues in E3205, and additional followup of both study cohorts is required in order to determine whether pre-specified efficacy endpoints were met. [Table: see text]

435 Background: Pre- and post-treatment FDG-PET imaging parameters may be useful for predicting pR following neoadjuvant CRT for LARC Methods: Between 2006 and 2010, 18 patients (pts) receiving preoperative CRT (5FU or capecitabine with concurrent 50.4 Gy conformal radiation) for LARC underwent a pre- (0-14 days before) and post-CRT (4 to 6 weeks after) PET/CT. Total mesorectal excision was performed 6 weeks post CRT. pR was dichotomized into complete (pCRs) and partial responders as reference standard. Pts with pathologic microscopic disease were classified as pCRs for this analysis. Changes in FDG metabolic parameters between pre and post-CRT scans, including maximum Standardized Uptake Value (SUVmax), metabolic tumor volume (MTV) and total glycolytic activity (TGA), were investigated as predictive imaging biomarkers for pR. Fixed SUVmax percentage threshold (30%, 40% and 50%) and gradient-based segmentation (PET Edge) were used to calculate the MTV and TGA. Receiver Operator Curve analysis was performed Results: Median pt age was 57.5 years (31-87); 67% M; 61% AJCC 2010 stage II, 33% III and 6% IV. pCR achieved in 44%. The 30% SUVmax threshold MTV best correlated with PET Edge MTV (Pearson r 0.99). Using ROC analysis, % change in SUVmax and PET edge TGA between pre and post-CRT scans were comparable and the most accurate parameters for predicting pR. SUVmax % change yielded an area under the curve (AUC) of 0.7125 (95% CI 0.4318-0.9932), while the AUC for PET Edge TGA % change was 0.7000 (95% CI 0.4209-0.9791). Based on ROC analysis, a cutoff of 78.9% change of PET Edge TGA had a likelihood ratio of 2.4, with a sensitivity of 90% and a specificity of 62.5% for predicting pCR. A cutoff of 88.7% change of PET Edge MTV yielded a likelihood ratio of 2.00 with a sensitivity of 50% and a specificity of 75%. Conclusions: The % change pre- to post-CRT in SUVmax and PET Edge Total Glycolytic Activity appears to be the most suitable FDG metabolic parameters for predicting pR following neoadjuvant CRT for LARC. As such, these PET-FDG biomarkers of CRT response should be validated in future prospective trials.

565 Background: HIV-infected patients are reported to experience increased treatment toxicity with standard concurrent chemoradiation (CRT) protocols for anal cancer. IMRT is a novel radiation (RT) delivery technique that allows the oncologist to conform or “dose paint (DP)” the RT dose to the tumor while sparing surrounding normal organs. We report our multi-institutional experience with DP-IMRT in regards to acute toxicities and treatment outcomes in HIV positive (HIV+) patients on highly active antiretroviral therapy (HAART). Methods: From August 2005 to December 2010, 63 patients, (10 HIV+), were treated with CRT for biopsy-proven, squamous cell carcinoma of the anal canal at two academic medical centers. HIV+ and HIV- patients received a median DP-IMRT dose of 50.4 Gy over 43.5 and 42.0 days, respectively. Acute toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events, version 3.0. Two year actuarial control and survival rates were calculated using the Kaplan-Meier method. Results: The median follow-up was 29.3 and 24.3 months for HIV+ and HIV- patients, respectively. No significant differences were noted in acute grade 3+ toxicity in HIV+ versus HIV- patients: dermatologic 10.0% vs. 13.21%, p=1.0; genitourinary 10.0% vs. 3.77%, p=0.410; gastrointestinal 20.0% vs. 15.09%, p=0.653; and hematologic 80.0% vs. 64.15%, p=0.474. Multivariate analysis confirmed that HIV infection was not predictive of acute grade 3/4 toxicity. No significant differences were noted in 2-year local control (90.0% vs. 95.0%), distant control (90.0% vs. 89.7%), overall survival (90.0% vs. 89.2%), and colostomy-free survival (90.0% vs. 83.7%) rates among HIV+ vs. HIV- patients. Conclusions: HIV+ patients on HAART receiving concurrent chemotherapy with DP-IMRT for anal canal cancer showed similar two-year outcomes and no significant differences in acute toxicity compared to HIV- patients. As such, HIV+ patients with anal cancer should be considered eligible for all national trials in which IMRT is employed.

3517 Background: The primary endpoint analysis of RTOG 0247 showed that preoperative pelvic RT plus C + O achieved a pathologic complete response rate (pCR) pre-specified threshold (21%) to merit further study, whereas the RT+ C + I arm did not (10%) (ASCO 2008). This current analysis reports on the secondary efficacy endpoints. Methods: A randomized phase II trial evaluated preoperative RT (50.4 Gy in 1.8 Gy fractions) with (1) concurrent C (1,200 mg/m2/d orally M-F during RT) and I (50 mg/m2 IV weekly x 4 doses) (Arm 1), and with (2) concurrent C (1,650 mg/m2/d orally M-F during RT) and O (50 mg/m2 IV weekly x 5 doses) (Arm 2) in patients with clinical stage T3 or T4 rectal cancer ² 12 cm from the anal verge. Surgery was performed 4-8 weeks following completion of chemoradiation. Four to 6 weeks after surgery, adjuvant chemotherapy (O 85 mg/m2; leucovorin 400 mg/m2 IV over 2 hours; 5FU 400 mg/m2 IV bolus; 5FU 2400 mg/m2/46 hr infusion) was administered every 2 weeks x 9 cycles. Disease-free (DFS) and ov...

77 Background: The specific aim of the ACR QRRO survey was to determine the national patterns of radiotherapy (RT) practice in patients (pts) treated for stage IB–IV (non-metastatic) gastric cancer (GC). Methods: A National Process Survey was conducted from randomly selected U.S. RT facilities to assess demographics, staging, geographic region, practice setting, and treatment through retrospective on-site record review of eligible GC cases treated from 2005-2007. Three clinical performance measures (CPMs): 1) use of CT-based treatment planning; 2) use of dose volume histograms (DVHs) to evaluate RT dose to the kidneys and liver; 3) completion of RT within the prescribed time frame were assessed. Three emerging quality indicators: 1) use of intensity modulated RT (IMRT); 2) use of image-guided tools (IGRT), other than CT, for RT target delineation; 3) use of preop RT were also assessed. Results: CPMs were computed on data collected through Aug, 2010 for 250 eligible pts at 45 institutions. Median age was 62 years; 66% male; 60% Caucasian. 13% were AJCC 2002 stage I, 29% II, 32% IIIA, 10% IIIB and 12% IV. Most pts (43%) were treated at academic centers with 32% at large non-academic centers and 25% medium-small facilities. Almost all (99.5%) pts underwent CT-based planning and 75% had DVHs to evaluate normal tissue doses to the kidneys and liver. 70% completed RT within the prescribed time frame. IMRT and IGRT were used in 22% and 17% of pts, respectively. IGRT techniques included: PET (n = 20), MRI (n = 1), respiratory gating and/or 4D-CT (n = 22) and on-board imaging (n = 10). 19% of pts received preop RT. Conclusions: Preliminary findings from QRRO's analysis of radiation practice patterns for non-metastatic gastric cancer indicate widespread adoption of CT-based planning with the use of DVHs to evaluate normal tissue doses. Moreover, most pts completed adjuvant RT in the prescribed time frame. Emerging RT techniques such as IMRT and IGRT were not routinely incorporated into clinical practice during the evaluated time period. These data will serve as a benchmark for future QRRO gastric cancer surveys. No significant financial relationships to disclose.

368 Background: 5-Fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer is associated with high rates of acute morbidity. We have previously shown that dose-painted IMRT (DP-IMRT) significantly reduces grade 3+ GI and dermatologic acute toxicity, as compared to the RTOG 9811 5FU/MMC arm, which used non-conformal radiation techniques. We now report on the two-year outcomes of this DP-IMRT approach. Methods: T2-4N0-3M0 anal canal cancers received 5FU (1,000 mg/m2/day 96 hour infusion) and MMC (10 mg/m2 bolus) days 1 and 29 of DP-IMRT prescribed as follows - T2N0: 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs), 28 fractions; T3-4N0-3: 45 Gy elective nodal, 50.4 Gy ≤ 3 cm and 54 Gy > 3 cm metastatic nodal and 54 Gy anal tumor PTVs, 30 fractions. The following two-year outcomes were assessed: local-regional (LRF) and colostomy failures (CF) using the cumulative incidence method, and disease-free (DFS), overall (OS) and colostomy-free survivals (CFS) using the Kaplan-Meier method. Results: Of 63 accrued patients, 52 were analyzable. Median age was 58 years; 81% female; 54% stage II; 25% IIIA; 21% IIIB. Median follow-up was 23.2 months (0.2-33). Two-year LRF, CF, DFS and 95% confidence intervals are 20% (9%, 31%), 8% (0.4%, 15%) and 77% (62%, 86%), respectively. The causes of death for the 7 patients that died are: anal cancer in 5, morbidity in one and second primary outside the radiation field in one. Two-year comparison data from the RTOG 9811 5FU/MMC arm are shown in the table below. Conclusions: DP-IMRT with 5FU/MMC for the treatment of anal canal cancer yields similar two-year outcomes as the RTOG 9811 conventional radiation, 5FU/MMC arm. Because of the associated acute toxicity sparing, DP-IMRT will be used as the platform, and may allow for radiation dose escalation, in future RTOG anal canal trials. Supported by RTOG U10 CA21661, CCOP U10 CA3742 and ATC U24 CA 81647 NCI grants. [Table: see text] No significant financial relationships to disclose.

4144 Background: Chemoradiation for anal cancer yields effective tumor control, but is associated with significant acute toxicity. We report our multi-institutional experience using dose-painted IM...

9521 Background: RTOG 97–14 [Hartsell et al, breast/prostate cancer patients (pts) with painful bone metastases randomized to 8 Gy/1 fraction or 30 Gy/10 fractions], revealed no difference in pain relief or narcotic use 3 months post randomization. The 8 Gy regimen resulted in fewer acute toxicities, but higher rates of retreatment for recurrent pain. Single 8 Gy fractions for painful vertebral bone mets have not been well accepted, possibly due to provider concerns about efficacy and toxicity. The present study evaluates treatment differences in the subset of pts treated specifically for painful vertebral bone mets (PVBM). Methods: PVBM were treated to the cervical, thoracic, and/or lumbar spine. Chi-square test was used to evaluate population differences between PVBM and non-PVBM. Amongst PVBM, differences in retreatment rates (cumulative incidence method, Gray's test) and in pain relief/BPI worst pain score, narcotic use, and toxicity 3 months post randomization (chi-square test) were evaluated. Results: Of 909 eligible pts, 235 (26%) were PVBM. PVBM and non-PVBM pts differed in % of males [55% vs. 47%,p=0.03] and pts with multiple painful sites [57% vs. 38%,p No significant financial relationships to disclose.

4021 Background: Preoperative chemoradiation for distal rectal cancer is an effective treatment strategy in which achievement of pathologic complete response (pCR) may be associated with a favorabl...

9560 Background: Little is known about the frequency and types of spiritual issues that arise for advanced cancer patients and the responses of clinicians to them. Methods: Randomly-sampled, advanced cancer patients receiving palliative radiotherapy at Beth Israel Deaconess Medical Center, Boston Medical Center, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute were interviewed about spiritual issues arising in the cancer experience and desires for spiritual care from oncology physicians and nurses. Results: We approached 80 patients and 59 (74%) gave informed consent. A total of 55 were interviewed. Mean age was 61 years; 53% were female and 18% were non-white. Most were at least slightly religious (81%) or at least slightly spiritual (92%); 85% experienced at least 1 spiritual issue, and among these patients, a median of 3 spiritual issues was reported (Table 1). The majority (89% and 87%) believed it at least mildly important that oncology physicians and nurses, respectively, consider pati...

873 Background Male breast cancer accounts for 1% of all reported breast cancer cases. Due to its rarity, there are no large datasets examining the impact of adjuvant therapy. The purpose of this study is to assess survival in male patients with non-metastatic breast cancer who received surgery (S) with or without adjuvant therapy (Tamoxifen [T], chemotherapy [CT], and/or radiation [RT]). Methods A retrospective analysis of all male breast cancer patients receiving therapy at the Massachusetts General Hospital and Boston Medical Center between 1990 and 2003 was performed. Factors recorded included age, ER/PR status, tumor histology, stage (AJCC), and details of local and systemic treatment. Five and ten-year DFS and OS were calculated from the date of pathological diagnosis using the actuarial Kaplan-Meier method with comparisons made using the log-rank test. Results Forty-two men received treatment for localized breast cancer. Median age: 61 years (24–90). S: mastectomy in 34 and lumpectomy in 8. Thirty-...