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Objective Computerized tomography (CT) imaging is routine in oncologic care and can be used to measure muscle quantity and composition that may improve prognostic assessment of older patients. This study examines the association of single-slice CT-assessed muscle measurements with a frailty index in older adults with cancer. Materials and Methods Using the Carolina Senior Registry, we identified patients with CT imaging within 60days ± of geriatric assessment (GA). A 36-item Carolina Frailty Index was calculated. Cross-sectional skeletal muscle area (SMA) and Skeletal Muscle Density (SMD) were analyzed from CT scan L3 lumbar segments. SMA and patient height (m 2 ) were used to calculate skeletal muscle index (SMI). Skeletal Muscle Gauge (SMG) was calculated by multiplying SMI×SMD. Results Of the 162 patients, mean age 73, 53% were robust, 27% pre-frail, and 21% frail. Significant differences were found between robust and frail patients for SMD (29.4 vs 24.1 HU, p p =0.003), but not SMI (41.9 vs 39.5cm 2 /m 2 , p =0.29). After controlling for age and gender, for every 5 unit decrease in SMD, the prevalence ratio of frailty increased by 20% (PR=1.20 [1.09, 1.32]) while the prevalence of frailty did not differ based on SMI. Conclusions Muscle mass (measured as SMI) was poorly associated with a GA-based frailty index. Muscle density, which reflects muscle lipid content, was more associated with frailty. Although frailty and loss of muscle mass are both age-related conditions that are predictive of adverse outcomes, our results suggest they are separate entities.

42 Background: As value-based payment models for cancer care expand, the need for measures which reliably assess the quality of care provided increases. This is especially true for models like the Oncology Care Model (OCM) that rely on quality rankings to determine potential shared savings. Under models like these, unreliable measures may result in arbitrary application of value-based payments. The goal of this project is to evaluate the extent to which measures used within the OCM are reliable indicators of provider performance. Methods: Data for this project came from North Carolina Medicare claims from 2015-2017. Episodes were attributed to physician practices at the tax identification number (TIN) level, lasted 6 months, and were divided into two performance years beginning 1/1/2016 and 7/1/2016. TINs with fewer than 20 attributed patients were excluded. Three claims-based OCM measures were used in this evaluation: 1) proportion of episodes with all-cause hospital admissions; 2) proportion of episodes with all-cause emergency department (ED) visits or observation stays; and 3) proportion of patients that died who were admitted to hospice for 3 days or more. Risk adjustment followed the method described by measure specifications from the OCM. Reliability was calculated as the ratio of between practice variation (e.g. signal) to the sum of between practice variation and within practice variation (e.g. noise). Variance estimates were derived from hierarchical logistic regression models used for risk adjustment. Results: For the hospitalization and ED visit measures, episode counts for years 1 and 2 were 30,746 and 28,430 and TIN counts were 86 and 84, respectively. Hospice use measures had fewer episodes (2,677 and 2,428) and TINs (36 and 33). Across all measures, median reliability scores failed to achieve the recommended 0.7 threshold and only hospice had a median reliability score above 0.5 (Table). Conclusions: These findings suggest claims-based measures included in the OCM may produce imprecise estimates of provider performance and are vulnerable to random variation. Consideration should be given to developing alternative measures which may be more reliable estimates of provider performance and to increasing minimum denominator requirements for existing measures.[Table: see text]

139 Background: Adjustment for social determinants of health (SDOH) when assessing provider care quality remains limited. The Oncology Care Model (OCM), for example, includes low-income status/dual eligibility (LIS/DE) as a part of the risk adjustment model for some quality measures, but does not account for any social risk variables in the hospice measure. No measures within the OCM account for additional social risk factors beyond LIS/DE such as patients’ race, rurality, and social deprivation. Additional SDOH adjustment could increase the accuracy of provider quality rankings and better align performance-based payments with true provider quality. Methods: North Carolina Medicare claims from 2015-2017 comprised the data for this study. The year 2015 was used to establish baseline covariates. Episodes were attributed to physician practices’ Tax Identification Number (TIN), lasted 6 months, and were divided into performance years beginning 1/1/2016 and 7/1/2016. Three measures were used: 1) all-cause hospital admissions; 2) all-cause emergency department visits or observation stays; and 3) admission to hospice for 3 days or more among patients who died. SDOH included patient-level race as well as county-level rurality and social deprivation, measured using the social deprivation index (SDI). TIN-level scores with and without expanded SDOH variables were divided into quintiles and compared descriptively as well as using weighted kappa statistics. Results: No SDOH were significantly associated with the hospitalization outcome (P = 0.118-0.944). For the ED measure, Black patients and rural patients were significantly more likely to have an ED visit or observation stay during an episode than white patients and urban patients (P < 0.0001). For the hospice measure, greater SDI values were associated with less hospice use (P < 0.05). Accordingly, including SDOH variables for ED visit/observation stay and hospice measures had a greater impact on TIN rankings than for the hospitalization measure (Table). Conclusions: Because quintile rankings in determine potential shared savings under models like the OCM, differences in rankings due to additional SDOH variables could have a meaningful impact on TIN-level revenue. Additional work is needed to expand the scope of patient-level SDOH variables used for risk adjustment and to explore differences across TINs which contribute to SDOH-sensitive changes in rankings.[Table: see text]

The only US Food and Drug Administration (FDA)-approved first-line systemic therapy for hepatocellular carcinoma (HCC) is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) and GEMOX (gemcitabine-oxaliplatin). Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib.

Outcomes for metastatic colorectal cancer have improved progressively with the incorporation of new drugs into standard treatment regimens. Most recently, targeted therapies against VEGF and EGFR have improved upon the prior standard for first-line therapy with FOLFOX or FOLFIRI. As attempts to combine anti-VEGF and anti-EGFR drugs have been unsuccessful, it is necessary to choose between them when beginning first-line therapy. This review summarizes the existing literature to best inform this decision. To date, three head-to-head trials have compared anti-EGFR and anti-VEGF therapy in RAS wild-type patients: PEAK, FIRE-3, and CALGB/SWOG 80405. PEAK and FIRE-3 suggested a survival advantage for anti-EGFR therapy over anti-VEGF therapy, though CALGB/SWOG 80405 did not. Results have emerged recently to suggest that tumors arising from the right colon are resistant to anti-EGFR therapy, and that any advantage of anti-EGFR therapy over anti-VEGF therapy may be limited to left-sided tumors.

Background Pharmacist-led medication reconciliation (PMR) ensures adequate recording and use of medications by patients. PMR may be important for cancer patients initiating new therapies, as they have a high burden of medication use and are more susceptible to inadvertent medication discrepancies. To describe medication changes (additions, discontinuations, and modifications) made to the electronic health record during a PMR among cancer patients initiating chemotherapy. Methods From October 2011 to March 2012, 397 cancer patients initiating chemotherapy underwent a PMR at the University of North Carolina Cancer Hospital. Self-reported medications and those in the patients’ electronic health record were reviewed. Log-binomial regression models were used to estimate adjusted prevalence ratios and 95% confidence intervals for the associations between patient characteristics and medication changes made to the electronic health record. Results Mean age at time of the PMR was 58. Median number of medications taken prior to the PMR was 10 and median time to PMR completion was 11 min. Vitamins and herbal supplements accounted for the largest proportion of medication additions (38%) and modifications (20%). Antimicrobials accounted for the largest share of discontinuations (15%). After adjustment for all other covariates, patients aged 60–69 years were more likely to have additions than those aged 50 and under (aPR = 1.47, 95%CI: 1.10–1.97). Patients 70 years and over were more likely to have modifications (aPR = 1.74, 95%CI: 1.07–2.82). Conclusion Our results show that most cancer patients had a medication change in the electronic health record. A brief oncology PMR can accurately capture and improve medication safety by preventing prescribing and administration errors.

Background Academic physicians, such as those affiliated with National Cancer Institute (NCI)–designated Comprehensive Cancer Centers, may have different practice patterns regarding the use of high-cost cancer drugs than nonacademic physicians. Materials and Methods For this cohort study, we linked cancer registry, administrative, and demographic data for patients with newly diagnosed cancer in North Carolina from 2004 to 2011. We selected cancer types with multiple U.S. Food and Drug Administration–approved, National Comprehensive Cancer Network–recommended treatment options and large differences in reimbursement between higher-priced and lower-priced options (stage IV colorectal, stage IV lung, and stage II–IV head-and-neck cancers). We assessed whether provider's practice setting—NCI-designated Comprehensive Cancer Center (“NCI”) versus other location (“non-NCI”)—was associated with use of higher-cost treatment options. We used inverse probability of exposure weighting to control for patient characteristics. Results Of 800 eligible patients, 79.6% were treated in non-NCI settings. Patients treated in non-NCI settings were more likely to receive high-cost treatment than patients treated in NCI settings (36.0% vs. 23.2%), with an unadjusted prevalence difference of 12.7% (95% confidence interval [CI], 5.1%–20.0%). After controlling for potential confounding factors, non-NCI patients remained more likely to receive high-cost treatment, although the strength of association was attenuated (adjusted prevalence difference, 9.6%; 95% CI −0.1%–18.7%). Exploratory analyses suggested potential heterogeneity across cancer type and insurance status. Conclusion Use of higher-cost cancer treatments may be more common in non-NCI than NCI settings. This may reflect differential implementation of clinical evidence, local practice variation, or possibly a response to the reimbursement incentives presented by chemotherapy billing.

Background Multiple claims-based proxy measures of poor function have been developed to address confounding in observational studies of drug effects in older adults. We evaluated agreement between these measures and their associations with treatment receipt and mortality in a cohort of older colon cancer patients. Methods Medicare beneficiaries age 66+ diagnosed with stage II-III colon cancer were identified in the Surveillance, Epidemiology, and End Results-Medicare database (2004-2011). Poor function was operationalized by: (1) summing the total poor function indicators for each model; and (2) estimating predicted probabilities of poor function at diagnosis. Agreement was evaluated using Fleiss' κ and Spearman's correlation. Associations between proxy measures and: (1) laparoscopic versus open surgery; (2) chemotherapy versus none; (3) 5-fluorouracil (5FU)+oxaliplatin (FOLFOX) versus 5FU monotherapy; and (4) 1-year mortality were estimated using log-binomial regression, controlling for age, sex, stage, and comorbidity. Survival estimates were stratified by functional group, age, and comorbidity. Results Among 29,687 eligible colon cancer patients, 67% were 75+ years and 45% had stage III disease. Concordance across the poor function indicator counts was moderate (κ: 0.64) and correlation of predicted probability measures varied (ρ: 0.21-0.74). Worse function was associated with lower chemotherapy and FOLFOX receipt, and higher 1-year mortality. Within age and comorbidity strata, poor function remained associated with mortality. Conclusions While agreement varied across the claims-based proxy measures, each demonstrated anticipated associations with treatment receipt and mortality independent of comorbidity. Claims-based comparative effectiveness studies in older populations should consider applying one of these models to improve confounding control.

e18706 Background: Real-world patients often differ from trial participants in prognostic factors such as age, sex, and cancer substage. New methods combine covariate data from real-world patients (the “target population”) with outcome and covariate data from a trial to estimate treatment effects in the target population that take these differences into account. With some assumptions, these methods can also estimate outcomes under treatment regimens not studied in the trial such as “what if we only gave six cycles of chemotherapy?” or “what if patients all perfectly followed a protocol?” Methods: Data from the MOSAIC trial of 5-fluorouracil (5FU) vs oxaliplatin + 5FU (FOLFOX) were combined with covariate data from a target population of stage III colon cancer patients in the US Oncology Network meeting trial eligibility criteria. We used weighting and G-computation to estimate five-year mortality and treatment-related paresthesia risk in the target population for four regimens: treatment with up to 12 cycles of 5FU, if providers used their discretion on dose reductions and delays (5FU-MD); up to 12 cycles of FOLFOX with similar physician discretion (FOLFOX-MD); up to 6 cycles of FOLFOX, with providers perfectly following a strict and specific protocol of dose reductions and delays (6-cycle FOLFOX-P, “P” for “per protocol”); and up to 12 cycles of FOLFOX, following the same strict protocol (12-cycle FOLFOX-P). Results: Tablepresents five-year all-cause mortality and paresthesia risk under each regimen in the stage III target population estimated from the models built in trial participants. Paresthesia risk increased with cumulative oxaliplatin dose. Estimated 5-year mortality was lowest with 12-cycle FOLFOX-P. Conclusions: In a target population of US Oncology Network patients with stage III colon cancer, strict protocols of 12 cycles of FOLFOX were predicted to improve survival compared to strict 6-cycle FOLFOX regimens or less strict 12-cycle FOLFOX and 5FU regimens at the cost of substantial increases in side effects. While estimates of risk differences in 5-year mortality were imprecise, combining trial and real-world data and then using weights and G-computation allowed estimation of benefits and harms of multiple regimens in a clinically relevant patient population.[Table: see text]

TPS3618 Background: The superiority of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H over chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti- epithelial growth factor receptor (EGFr) antibodies in mCRC has been demonstrated in a phase III trial (N Engl J Med 2020; 383:2207). However, more patients had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% vs. 12.3%) with mean progression-free survival (PFS) of 13.7 months. Preclinical models have demonstrated synergistic interactions between FOLFOX, anti-VEGF, and anti-PD-1. We hypothesize that the dMMR/MSI-H mCRC patients may be more effectively treated by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Methods: Initially a three-arm study, the mFOLFOX6/bev arm was closed to new enrollment on 6-4-20 due to emerging data; the redesigned COMMIT trial was reactivated on 1/29/2021 as a prospective phase III open-label trial that randomizes (1:1) mCRC dMMR/MSI-H pts (N=211) to either atezo monotherapy or mFOLFOX6/bev+atezo combination. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is PFS as assessed by site investigator. Secondary endpoints include overall survival (OS), objective response rate (RECIST v1.1), safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Clinical trial: NCT02997228. Support: U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

1521 Background: Patterns of chemotherapy delivery are likely to differ between trial and real-world populations. Typical measures used to compare these patterns are calculated at treatment completion, potentially missing key differences in the timing and trajectory of delays and dose reductions. We used a new measure, longitudinal cumulative dose (LCD), to compare treatment delivery over time in trial and real-world populations. Methods: We compared chemotherapy delivery in patients with stage II-III colon cancer enrolled in the MOSAIC trial of 5-fluorouracil (5FU) vs oxaliplatin + 5FU (FOLFOX4) to patients treated from 2008-2019 in the US Oncology Network with FOLFOX4, FOLFOX6, or mFOLFOX6. For each patient, we computed oxaliplatin LCD as the cumulative oxaliplatin dose received at a given timepoint (t) divided by the final standard oxaliplatin dose. We then estimated the median and 25th and 75th percentiles for oxaliplatin LCD within each regimen at day 68 (before the standard timing of the 7th dose), 168 (two weeks after the standard end of treatment), and 250. Results: The table shows the number of patients receiving each treatment regimen and the median and interquartile range for oxaliplatin LCD at each time. Higher LCDs in the trial show delivery closer to standard treatment, meaning fewer delays, dose reductions, and discontinuations. Differences between the medians, 25th percentiles, and 75th percentiles of LCD in each regimen were small at day 68 but grew considerably by days 168 and 250. Conclusions: Divergence from the standard dosing schedule was larger in real-world versus trial settings and varied by oxaliplatin regimen. LCD, as a longitudinal measure, showed that differences in delivery between trial and real-world populations grew substantially over time (even after 168 days and the standard end of treatment) possibly as real-world patients experienced more side effects and barriers to treatment than trial participants. These discrepancies in LCD may cause poorer outcomes in real-world settings than expected based on randomized trials.[Table: see text]

Introduction: Hepatocellular carcinoma (HCC) is a poor-prognosis cancer with a high symptom burden. Multidisciplinary HCC care is complex and unique in cancer medicine. We sought to determine whether the distinct process affects hospice use and how hospice affects end-of-life acute care utilization. Patients and Methods: Patients dying after HCC diagnosed from 2004 to 2011 were identified within SEER-Medicare. Hospice use and associated factors were described using logistic regression. Coarse exact and propensity score matching created groups of hospice and nonhospice comparators balanced on clinical characteristics. Health care use from first hospice claim to death and the matched duration in the nonhospice group were compared. Results: Of 7,992 decedent patients with HCC, 63% used hospice before death, with a median duration of 18 days (interquartile range, 5-51 days). Initial treatment with surgery and ablation (odds ratio [OR], 0.63; 95% CI, 0.53 to 0.74) or chemoembolization/radioembolization (OR, 0.71; 95% CI, 0.62 to 0.80) was associated with decreased odds of subsequent hospice use compared with untreated patients. Hospice use was more likely in those consulting hematology/oncology (OR, 1.33; 95% CI, 1.13 to 1.56) but not in those consulting gastroenterology (OR, 0.79; 95% CI, 0.65 to 0.95). Hospice patients had lower rates of hospitalization (7.9% v 47.8%; risk ratio [RR], 0.16; 95% CI, 0.14 to 0.19), intensive care unit stay (2.8% v 25.3%; RR, 0.11; 95% CI, 0.09 to 0.14), and in-hospital death (3.5% v 58.4%; RR, 0.06; 95% CI, 0.05 to 0.07). Conclusion: Processes of care influence which patients with HCC are referred to hospice. Hospice use has a marked effect on acute care use at the end of life in patients with HCC. Efforts to incorporate cancer-focused palliative care might improve the quality of end-of-life care in HCC.

Patient-centered communication (PCC) is an essential component of patient-centered care and contributes to patient satisfaction, health-related quality of life, and other important patient outcomes. The aim of this study was to develop and test survey questions to assess patients’ experiences with PCC in cancer care. We used a conceptual model developed by the National Cancer Institute as our framework. The survey questions align with the six core functions of PCC defined in the model: Exchanging Information, Managing Uncertainty, Enabling Patient Self-Management, Fostering Healing Relationships, Making Decisions, and Responding to Emotions. The study focused on colorectal cancer patients. We conducted two rounds of cognitive interviewing to evaluate patients’ ability to understand and provide valid answers to the PCC questions. Interviews were conducted in Maryland and North Carolina in 2014. We involved a patient advocacy group, Fight Colorectal Cancer, and a multidisciplinary panel of stakeholders throughout the measurement development process to ensure that the survey questions capture aspects of PCC that are important to patients and meet the needs of potential end users, including researchers, healthcare organizations, and health professionals. Patient and other stakeholder input informed revisions of draft survey questions, including changes to survey instructions, frame of reference for questions, response scales, and language. This study demonstrated the feasibility and value of engaging patients and other stakeholders in a measurement development study. The Patient-Centered Outcomes Research Institute (PCORI) conceptual model of patient-centered outcomes research provides a useful guide for patient engagement in research. Research funders should call for meaningful roles for patients and other stakeholders in health research, including in the development of patient-centered outcomes.

7 Background: Panitumumab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) and is a standard therapy in KRAS/NRAS/BRAF WT mCRC. Preclinical data shows that anti-EGFR therapy causes a tumor-specific adaptive immune response and immunogenic apoptosis, with functional adaptive immunity required to mediate efficacy. However, resistance to anti-EGFR antibody therapy inevitably develops and is associated with increased expression of CTLA-4 and PD-L1. We hypothesized that addition of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) to panitumumab will increase response rate in patients with KRAS/NRAS/BRAF WT MSS mCRC. Methods: LCCC1632 was a multicenter, single-arm, Simon’s two stage phase II clinical trial with a pre-specified safety run-in of panitumumab, ipilimumab, and nivolumab in KRAS/NRAS/BRAF WT, MSS mCRC (NCT03442569). Eligible patients must have received 1-2 prior lines of therapy and no prior anti-EGFR or immune checkpoint inhibitor therapy. Subjects received ipilimumab 1 mg/kg IV q6wk, nivolumab 240 mg IV q2wk, and panitumumab 6 mg/kg IV q2wk until progression, toxicity, or patient withdrawal. The primary endpoint was response rate at 12 weeks per RECIST 1.1, and key secondary endpoints included progression-free survival and duration of response. Results: A total of 56 subjects were enrolled 3/2018-6/2020. This included the 6-subject safety run-in, with 0/6 dose-limiting toxicities in first 12 weeks. The first stage of the Simon’s two-stage clinical trial (n=32) had sufficient response rate to merit full enrollment. There were 7 unevaluable subjects for the primary endpoint of 12-week response rate. Among 49 evaluable subjects, 12-week response rate was 35% (95% CI 21-48; n=17 responses). Twenty subjects had at least an unconfirmed response at any time. Median PFS was 5.7 months (95% CI 5.5-7.9). There was one treatment-related grade 5 adverse event of myocarditis. The most common treatment-related grade 3-4 AEs included lipase increased (9%), amylase increased (7%), ALT increased (5%), AST increased (5%), diarrhea (5%), hypophosphatemia (5%), and maculopapular rash (5%). Conclusions: The combination of panitumumab, ipilimumab, and nivolumab demonstrated evidence of activity and met its prespecified primary endpoint of 12-wk response rate criteria to merit further study. The PFS in this single-arm study compares favorably to expected PFS for anti-EGFR monotherapy in RAS wild-type patients, and results suggest activity of immune checkpoint inhibitors combined with anti-EGFR therapy in MSS mCRC. Clinical trial information: NCT03442569.

TPS232 Background: Despite the superiority in progression-free survival (PFS) of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H as compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFr) antibodies in mCRC, more pts had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% vs. 12.3%) with mean PFS of 13.7 months ( N Engl J Med 2020; 383:2207). We hypothesize that the dMMR/MSI-H mCRC pts may be more effectively treated by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF and between oxaliplatin/anti-PD-1 in murine CRC models and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Additionally, in other solid tumor malignancies, anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are standard first-line treatments. Methods: The redesigned COMMIT study was reactivated on 1/29/2021 as a two-arm prospective phase III open-label trial randomizing (1:1) mCRC dMMR/MSI-H (211 pts) to atezo monotherapy versus mFOLFOX6/bev+atezo combination. Assuming our control arm, atezo monotherapy, 48% PFS at 24 months, as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 months) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Enrollment actively continues to the target accrual of 211 patients randomized between the two immunotherapy arms. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

Context Many advanced patients with cancer have unrealistic prognostic expectations. Objectives We tested whether offering life expectancy (LE) statistics within palliative chemotherapy (PC) education promotes realistic expectations. Methods In this multicenter trial, patients with advanced colorectal and pancreatic cancers initiating first or second line PC were randomized to usual care versus a PC educational tool with optional LE information. Surveys at two weeks and three months assessed patients' review of the LE module and their reactions; at three months, patients estimated their LE and reported occurrence of prognosis and end-of-life (EOL) discussions. Wilcoxon tests and proportional odds models evaluated between-arm differences in LE self-estimates, and how realistic those estimates were (based on cancer type and line of treatment). Results From 2015 to 2017, 92 patients were randomized to the intervention and 94 to usual care. At baseline most patients (80.9%) wanted “a lot” or “as much information as possible” about the impact of chemotherapy on LE. Among patients randomized to the intervention, 52.0% reviewed the LE module by two weeks and 66.7% by three months—of whom 88.2% reported the information was important, 31.4% reported it was upsetting, and 3.9% regretted reviewing it. Overall, patients' LE self-estimates were very optimistic; 71.4% of patients with colorectal cancer estimated greater than five years; 50% pancreatic patients estimated greater than two years. The intervention had no effect on the length or realism of patients' LE self-estimates, or on the occurrence of prognostic or EOL discussions. Conclusions Offering LE information within a PC educational intervention had no effect on patients' prognostic expectations.

Background: Black patients with cancer report worse symptom burden and management relative to Whites. Use of electronic patient-reported outcomes (ePROs) have been linked to improved cancer-related symptom management, with potential to address inequities in symptom management. Visualization of ePRO symptom data is a critical component of ePRO development; however, engagement of diverse patient and family stakeholders in the visualization of ePRO data has been limited. As part of the Symptom and Healthcare Access Reporting and Evaluation (SHARE) study, we engaged diverse stakeholders in the development of an ePRO tool. Herein, we describe our stakeholder engagement process, as well as feedback and recommendations for optimizing visualization of ePRO data with an equity prioritization lens. Methods: We leveraged a multi-step, mixed-methods, community-engaged research approach to solicit input from diverse patients in active treatment (n= 30 Black; n=49 White) and members of cancer-focused community advisory boards (n=1 Asian; n=8 White). Stakeholders provided feedback on two versions of the ePRO symptom report (Prototype 1[original version] and Prototype 2 [modified version based on initial stakeholder feedback]) through an iterative process. Feedback was obtained via surveys, individual interviews, and group meetings. Results: Compared with White patients, Blacks reported more challenges in using and understanding Prototype 1 of the symptom report. Community advisory board members shared similar concerns regarding ease of use of Prototype 1. In particular, patients and members noted that graphical legends and axes were difficult to interpret, making it difficult to identify which symptoms were worsening or improving. Prototype 2 of the ePRO symptom report incorporated feedback, such as increasing font and graph sizes, combining related symptoms (e.g., nausea and vomiting) into a single graph, and inclusion of color-graded graph schemes corresponding to symptom severity (e.g., green=no symptom; orange=moderate severity), which facilitated ease of use for patients with limited graphical literacy. In comparing Prototype 1 to Prototype 2, community advisory board members reported that Prototype 2 was more visually appealing and easier to use and understand. Conclusions: Overall, feedback from diverse patients and community stakeholder groups resulted in the development of a more usable and patient-centered ePRO symptom summary report. Our work highlights the importance and value of engaging diverse stakeholders in the development of ePRO systems, including the visualization of ePRO data, in order to optimize the in the use of ePRO tools for everyone. Citation Format: Wendi L. Elkins, Neda R. Padilla, Dani Cutts, Mattias Jonsson, Michelle Johnson, Giselle Corbie-Smith, Samuel Cykert, Bryce B. Reeve, Antonia V. Bennett, Donald L. Rosenstein, Hanna Sanoff, Cleo A. Samuel. Engaging diverse patients and families in the visualization of cancer-related patient-reported outcomes [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-042.

INTRODUCTION: Liver cancer–secreted serine protease inhibitor Kazal (LC-SPIK) is a protein that is specifically elevated in cases of hepatocellular carcinoma (HCC). We assessed the performance of LC-SPIK in detecting HCC, including its early stages, in patients with cirrhosis, hepatitis B virus (HBV), and hepatitis C virus (HCV). METHODS: We enrolled 488 patients, including 164 HCC patients (81 early HCC) and 324 controls in a blinded, prospective, case–control study. Serum LC-SPIK levels were determined by an enzyme-linked immunosorbent assay-based assay. The performance of serum LC-SPIK and α-fetoprotein (AFP), including area under the curve (AUC), sensitivity, and specificity, are compared. The performance of LC-SPIK was evaluated in an independent validation cohort with 102 patients. RESULTS: In distinguishing all HCC patients from those with cirrhosis and chronic HBV/HCV, LC-SPIK had an AUC of 0.87, with 80% sensitivity and 90% specificity using a cutoff of 21.5 ng/mL. This is significantly higher than AFP, which had an AUC of 0.70 and 52% sensitivity and 86% specificity using a standard cutoff value of 20.0 ng/mL. For early-stage HCC (Barcelona Clinic Liver Cancer stage 0 and A), LC-SPIK had an AUC of 0.85, with 72% sensitivity and 90% specificity, compared with AFP, which had an AUC of 0.61, with 42% sensitivity and 86% specificity. In addition, LC-SPIK accurately detected the presence of HCC in more than 70% of HCC patients with false-negative AFP results. DISCUSSION: The study provided strong evidence that LC-SPIK detects HCC, including early-stage HCC, with high sensitivity and specificity, and might be useful for surveillance in cirrhotic and chronic HBV/HCV patients, who are at an elevated risk of developing HCC.

211 Background: Cancer patients have many medical and psychosocial needs, which may increase during the coronavirus pandemic and may be difficult to identify or address in the absence of in-person patient visits. We sought to (1) risk stratify hematology/oncology patients using general medicine and cancer-specific methods to identify those at high risk for acute care utilization, (2) measure the correlation between risk-stratification methods, and (3) perform a phone-based needs assessment with intervention for these patients. Methods: Patients were risk-stratified using a general medical health composite score (HCS) embedded in the electronic medical record, and a cancer-specific risk (CSR) stratification based on disease and treatment characteristics. The correlation between HCS and CSR was measured using Spearman’s correlation. A multi-disciplinary team developed a focused needs assessment script with recommended interventions for patients categorized as high-risk by either method. The number of patient needs identified and referrals for services made in the first month of outreach are reported. Results: 1,421 patients were risk stratified, with 15% high-risk using HCS and 21.2% high-risk using CSR. Overall correlation between HCS and CSR was modest (r = 0.39). During the first month of the pilot, 287 patients were called for outreach with 245 contacted (85%). Commonly identified needs were financial difficulties (17%), uncontrolled symptoms (15%), and interest in advance care planning (13%), resulting in referral for supportive services for 33% of patients. Conclusions: There is a high burden of unmet medical and psychosocial needs in hematology/oncology patients during the coronavirus pandemic. A phone-based outreach program results in identification of and intervention for these needs, however additional cancer-specific risk models are needed to improve targeting to high-risk patients. This process can serve as a framework for other institutions wishing to implement similar outreach programs during this pandemic. [Table: see text]

Importance Despite requirements of informed consent, patients with advanced cancer often receive palliative chemotherapy (PC) without understanding that the likelihood of cure is remote. Objective To determine whether a PC educational video and booklet at treatment initiation could improve patients’ understanding of its benefits and risks. Interventions Regimen-specific PC videos and booklets presenting information about logistics, potential benefits, life expectancy (optional), adverse effects, and alternatives. Videos featured authentic patients sharing diverse experiences. After receiving treatment recommendations, research assistants distributed materials to patients for independent review. Design, Setting, and Participants Multicenter randomized clinical trial of patients with advanced colorectal or pancreatic cancer starting first-line or second-line PC in 5 US cancer centers with enrollment from June 2015 to September 2017 and follow-up to December 2019. Main Outcomes and Measures The primary outcome was accurate expectations of chemotherapy benefits at 3 months, defined as responding “not at all likely” to “What is your understanding of how likely the chemotherapy is to cure your cancer?” (from the Cancer Care Outcomes Research and Surveillance study). Secondary outcomes included understanding of adverse effects, decisional conflict (SURE test), regret (Decisional Regret Scale), and distress (Functional Assessment of Cancer Therapy–General emotional well-being subscale). Results Among 186 patients with advanced colorectal or pancreatic cancer who were starting first-line or second-line PC (94 randomized to usual care, 92 to intervention; mean [SD] age, 59.3 [12.6] [range, 28-86] years; 107 [58%] male; 118 [63.4%] colorectal and 68 [36.6%] pancreatic cancer), most patients wanted “a lot” of information or “as much information as possible” about adverse effects (149, 80.1%), likelihood of cure (148, 79.6%), and prognosis (148, 79.6%). Among the intervention arm, 59 (78%) reviewed the booklet and 30 (40%) reviewed the video within 2 weeks. The primary outcome did not differ between intervention and control arms (52.6%; 95% CI, 40.3%-65.0%; vs 55.5%; 95% CI, 45.1%-66.0%). Accurate adverse effect understanding was more common among intervention than control patients (56.0%; 95% CI, 44.3%-67.7%; vs 40.2%; 95% CI, 29.5%-50.9%;P = .05), although this did not meet the threshold for statistical significance. The intervention did not increase distress, despite frank prognostic information. Other secondary outcomes were similar. Conclusions and Relevance Provision of an educational video and booklet did not alter patients’ expectation of cure from PC. Alternative delivery strategies, such as integration with nurse teaching, could be explored in future studies. Trial Registration ClinicalTrials.gov Identifier:NCT02282722

7067 Background: Treatment effects may differ between trials and community settings, in part due to underrepresentation of certain patient subgroups in trials. We used a hybrid approach combining clinical trial and real-world data to compare the effectiveness of adjuvant FOLFOX vs 5FU for stage II-III colon cancer in community oncology practice. Methods: We used Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) combined with patients who met trial eligibility criteria within US Oncology from 1/1/2008-5/31/2019. In the combined data, we used logistic regression to estimate the probability of trial enrollment as a function of age, sex, substage, body mass index (BMI), and performance status. We estimated inverse odds of sampling weights and weighted MOSAIC participants to reflect three US Oncology populations: 1) patients meeting trial eligibility, 2) stage III patients, and 3) stage III patients initiating FOLFOX. Within the weighted trial populations, we estimated mortality hazard ratios (HRs) and bootstrapped 95% confidence intervals (CIs) comparing FOLFOX with 5FU. Results: There were 2246 MOSAIC participants and 9335 US Oncology patients. MOSAIC participants were younger, had more stage II cancer, lower BMI, and worse performance status compared with US Oncology patients. After weighting MOSAIC participants to reflect the US Oncology populations, the HRs were attenuated (Table) compared with the original MOSAIC estimate (HR = 0.84; 0.71,1.00). Conclusions: When differences between trial and clinical populations exist and response to therapy varies across subgroups, treatment efficacy can differ from clinical effectiveness. Compared with trial results, we found that effectiveness of FOLFOX versus 5FU was attenuated in community oncology practice. [Table: see text]

3522 Background: Adjuvant chemotherapy regimens take months to complete. Despite this, trials and observational studies evaluate chemotherapy adherence via measures assessed at the end of treatment (e.g. number of patients missing any dose, relative dose intensity [RDI]). This approach misses information that impacts outcomes, like treatment delays. We propose longitudinal cumulative dose (LCD) as a way to integrate the impact of dose reductions, missed doses, and dose delays at each cycle over time. Methods: We obtained data from the 2,246 participants in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC). We evaluated proportions of patients stopping treatment early and reducing (based on protocol), missing, or delaying a dose in each arm for each chemo agent at each visit. We obtained LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each chemo agent. We compared LCD medians over time and at the end of a standard regimen (24 weeks) between treatment arms and by age and performance status. We assessed agreement between oxaliplatin LCD and RDI with Fleiss’ kappa (Table). Results: Participants randomized to FOLFOX were more likely than those randomized to 5FU to stop treatment, reduce doses, miss doses, or delay visits; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. Graphs of median LCD for 5FU showed a clear difference between arms (FOLFOX arm median LCD: 81%; 5FU arm median LCD, 96%). While 5FU LCD decreased with age in the FOLFOX arm (median LCD in those age

Upfront chemoradiation with omission of surgery (CR-only) is increasingly being used to treat rectal cancer. When CR-only is used with curative intent, intense surveillance is recommended. We hypothesized that in practice, few patients treated with CR-only receive intensive post-treatment surveillance.Using Surveillance, Epidemiology, and End Results (SEER)-Medicare, all nonmetastatic rectal cancer patients (≥66 years old) diagnosed from 2004 to 2012, who received upfront chemoradiation, were included. Patients who received CR-only were compared with patients receiving neoadjuvant therapy plus proctectomy. In the 24 months after treatment, markers of surveillance, including carcinoembryonic antigen testing (CEA), endoscopy, and imaging, were compared between groups.A total of 2,482 individuals met the inclusion criteria: 21% (n = 514) had CR-only and 79% had conventional treatment (ie chemoradiation plus proctectomy). Only 2.5% and 3.4% of those in the CR-only and conventional treatment groups, respectively, were in complete compliance with National Comprehensive Cancer Network surveillance guidelines during the first 2 years post-treatment (p0.01). The CR-only group was less likely than the conventional treatment group to receive: CEA (adjusted risk ratio [aRR] 0.57; 95% CI 0.50 to 0.65), endoscopy (aRR 0.76; 95% CI 0.66 to 0.87), and office visits (aRR 0.88; 95% CI 0.84 to 0.92), respectively. However, there were similar rates of cross-sectional imaging between groups (aRR 1.31; 95% CI 0.93 to 1.85).Adherence to guideline-recommended surveillance was poor for all Medicare patients with rectal cancer. Despite recommendations for closer follow-up, patients treated with CR-only were less likely to receive surveillance than those treated with conventional treatment. Efforts should be made to increase adherence to surveillance guidelines for all rectal cancer patients treated with curative intent, but particularly for those with higher risk of recurrence, such as those treated with CR-only.

Background: F. nucleatum is an oral anaerobe aberrantly found in up to 43% of CRCs. F. nucleatum presence is associated with additional known prognostic variables, including BRAF mutation and immune infiltration. In nonmetastatic CRC, F. nucleatum is associated with post-chemotherapy recurrence and inferior cancer-specific survival. However, the prognostic value of F. nucleatum in mCRC is not well described. We evaluated the association between F. nucleatum, integrated with other significant prognostic clinicopathologic factors, in a prospective clinical trial cohort of mCRC. Methods: LCCC1029 was a 2:1 randomized phase II trial of 2nd-line chemotherapy with 5-fluorouracil/irinotecan plus either regorafenib or placebo in mCRC. DNA and RNA were extracted from FFPE archival tumor samples, and quantitative PCR to measure F. nucleatum levels was successfully performed on 73 of those samples. We compared PFS and OS using Kaplan-Meier method and log-rank tests, and univariate and multivariate hazard ratios (HR) were estimated using Cox proportional hazards method. Results: Among the 73 mCRC patients with F. nucleatum quantitated, 20 (27%) had a high level and 53 (73%) had undetectable or low levels of F. nucleatum. On univariate analysis, F. nucleatum high level was not associated with PFS (HR 0.78, 95% CI 0.46-1.33; log-rank p=0.36) or OS (HR 0.83, 95% CI 0.46-1.51; log-rank p=0.54). However, the F. nucleatum positive subgroup trended toward higher rates of BRAF mutation (12%, vs 2% in F. nucleatum low/negative), KRAS/NRAS mutation (47% vs 27%), and MSI-High (12% vs 5%). We thus performed multivariate analyses of PFS and OS including F. nucleatum high level, BRAF mutation, KRAS/NRAS mutation, MSI, prior antiangiogenic therapy, and age on the subgroup of 58 patients who had results from all platforms. On multivariate analysis, high F. nucleatum expression trended toward association with improved PFS, with HR 0.57 (0.30-1.10, p=0.095). BRAF mutation, prior antiangiogenic therapy, and F. nucleatum were significantly associated with improved OS, with high F. nucleatum expression having adjusted HR 0.48 (0.23-0.99, p=0.048). Conclusions: Expression of F. nucleatum in the tumor of patients with mCRC was significantly associated with improved OS in mCRC. While results need to be validated, these findings suggest that F. nucleatum is associated with prognosis in a context-dependent fashion and may confer differential prognosis in nonmetastatic versus metastatic CRC patients. Citation Format: Michael S. Lee, Temitope O. Keku, Amber McCoy, Sara R. Selitsky, Joel Parker, Todd Auman, Kelli Hammond, Sushant A. Patil, Ganiraju Manyam, Scott Kopetz, Hanna K. Sanoff, Federico Innocenti. Association of Fusobacterium nucleatum (F. nucleatum) with progression-free survival (PFS) and overall survival (OS) with 2nd-line FOLFIRI +/- regorafenib in metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A03.

PURPOSE: In older women, breast cancer and its treatment can have profound impact on their physical, mental, and social health, especially in frail patients. This study evaluated the association between frailty and long-term health-related quality of life (HRQOL) in older women undergoing breast cancer treatment. METHODS: Using the Carolina Senior Registry (CSR), participants with breast cancer were contacted to complete a follow-up HRQOL questionnaire (median 4 years). Baseline Geriatric Assessment (GA) variables were used to calculate the Carolina Frailty Index (CFI) and categorize participants as robust, pre-frail, or frail. Outcomes included HRQOL domains of physical function, social roles, fatigue, depression, anxiety, pain, and sleep disturbance assessed using PROMIS(®) instruments. Regression modeling compared outcomes between frailty groups using adjusted mean differences (AMD). RESULTS: Of 190 eligible patients, 63 completed follow-up HRQOL survey. Mean age was 70 years (range 65–86) and 91% were white. Based on the CFI, 49 (78%) patients were robust, 11 (18%) pre-frail, and 3 (5%) frail. After controlling for age and cancer stage, patients identified as pre-frail/frail reported worse physical function (AMD −9.2, p

BACKGROUND Methods developed to estimate intervention effects in external target populations assume that all important effect measure modifiers have been identified and appropriately modeled. Propensity score-based diagnostics can be used to assess the plausibility of these assumptions for weighting methods. METHODS We demonstrate the use of these diagnostics when assessing the transportability of treatment effects from the standard of care for metastatic colorectal cancer control arm in a phase III trial (HORIZON III) to a target population of 1,942 Medicare beneficiaries age 65+ years. RESULTS In an unadjusted comparison, control arm participants had lower mortality compared with target population patients treated with the standard of care therapy (trial vs. target hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.58, 0.89). Applying inverse odds of sampling weights attenuated the trial versus target HR (weighted HR = 0.96, 95% CI = 0.73, 1.26). However, whether unadjusted or weighted, hazards did not appear proportional. At 6 months of follow-up, mortality was lower in the weighted trial population than the target population (weighted trial vs. target risk difference [RD] = -0.07, 95% CI = -0.13, -0.01), but not at 12 months (weighted RD = 0.00, 95% CI = -0.09, 0.09). CONCLUSION These diagnostics suggest that direct transport of treatment effects from HORIZON III to the Medicare population is not valid. However, the proposed sampling model might allow valid transport of the treatment effects on longer-term mortality from HORIZON III to the Medicare population treated in clinical practice. See video abstract at, http://links.lww.com/EDE/B435.

BACKGROUND Surgical resection provides the only potentially curative treatment of pancreatic cancer. Neoadjuvant chemotherapy and/or radiation (NAT) is used to downstage patients with borderline resectable tumors. The objective of this study was to examine the postoperative morbidity and mortality of NAT after pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDA). METHODS Using the American College of Surgeons-National Surgical Quality Improvement Project Targeted Pancreatectomy data, we identified patients who underwent a PD for PDA from 2014 to 2015. Patients were grouped by receipt of NAT 90 days before PD. Bivariable and multivariable analyses was used to compare postoperative outcomes. RESULTS A total of 3748 patients with PDA underwent PD; 926 (24.7%) received NAT. Those in the NAT group had more major vein resections, and longer operating times (all P

Background Rectal cancer is a common cancer. Curative treatment frequently includes surgery, radiation, and chemotherapy, all of which can result in long-term adverse effects. Objectives This descriptive, hypothesis-generating study sought to obtain input from survivors of rectal cancer regarding key features of their long-term experience. Methods The authors administered a 12-question, Internet-based survey to self-identified rectal cancer survivors to assess (a) how neuropathy, fatigue, trouble with ostomy or bowel movements, and trouble with sexual function affect daily life and (b) whether knowing about these symptoms a priori would have changed their treatment decisions. Responses are presented descriptively. Qualitative analysis assessed themes reported in response to an open-ended question. Findings Responses from 116 survivors of rectal cancer, 55 of whom provided open-ended responses, were obtained. Respondents were predominantly young and several years from treatment. They reported that their lives were affected "a lot" by bowel or ostomy trouble, trouble with sexual function, fatigue, and nerve toxicity. Survivors reported that knowing whether symptoms would affect their lives "a lot" would have changed their treatment decisions with a priori knowledge of these lasting effects. Key qualitative themes were the lack of information about and support for negative effects.

Background Colorectal cancer (CRC) diagnosis and treatment can have substantial detrimental impacts on health related quality of life (HRQOL) and physical function. This is especially true for older CRC patients and is of paramount concern in chemotherapy treatment decision making; yet, few studies to date have focused on understanding and managing fatigue in older CRC patients. We present the design of a study to evaluate the feasibility and impact of a home-based, self-directed physical activity intervention on fatigue in older CRC patients receiving adjuvant chemotherapy treatment. Secondary aims pertain to intervention impact on HRQOL, physical function, and self-efficacy for managing fatigue. Methods/design Multi-site, randomized controlled trial of physical activity intervention compared to usual care in a sample of older adults undergoing adjuvant chemotherapy for CRC. Forty CRC patients will be recruited and study questionnaires/assessments will be performed at baseline, 3 months, and after completion of adjuvant chemotherapy. The primary outcome is a comparison of the change in fatigue from baseline to 3 months between Intervention and Control arms. We will also compare changes in engagement in physical activity, HRQOL, physical function, and self-efficacy. Exploratory analyses will compare Intervention and Control arms with regard to changes in muscle mass and a biomarker aging that is known to increase during chemotherapy (p16 INK4a ). Discussion If positive, findings from this pilot study would suggest the potential for improving the care of older persons with CRC undergoing adjuvant chemotherapy through a home-based physical activity intervention to manage fatigue, HRQOL, and physical function. Trial Registration : NCT02191969

MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS-mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program–approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib “run-in” to evaluate FZD2 biomarker upregulation and KRAS-WT and KRAS-MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. KRAS stratification did not identify any differences in response between KRAS-WT and KRAS-MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation. Significance: These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies. Cancer Res; 78(18); 5398–407. ©2018 AACR.

Background The decision whether to treat older adults with advanced cancer with standard therapy (ST) or reduced therapy (RT) is complicated by heterogeneity in aging. We assessed the potential utility of the chemotherapy toxicity risk score (CTRS) [J Clin Oncol 2011;29:3457–3465] for treatment decisions in older adults. Materials and Methods This was a prospective observational study of patients aged ≥65 years receiving first-line chemotherapy for advanced cancer for which combination chemotherapy is the standard of care. Patients were categorized as high risk (CTRS ≥10), for whom RT (dose-reduced combination or single-agent chemotherapy) is deemed appropriate, or nonhigh risk (CTRS Results Fifty-eight patients (median age, 71 years) were enrolled. Thirty-eight patients received ST (21 had CTRS Conclusion Older patients with cancer with a high CTRS who receive combination chemotherapy have an exceedingly high rate of severe toxicity and hospitalization. Implications for Practice The potential utility of the chemotherapy toxicity risk score (CTRS) in old adults with advanced solid tumors receiving first-line chemotherapy was assessed. Little agreement was found between chemotherapy treatment decisions based on the clinical impression versus what was recommended based on the CTRS. Among patients treated with standard-dose combination chemotherapy, patients with CTRS ≥10 had a very high incidence of grade 3–4 toxicities and hospitalization, which was significantly greater than that of patients with a low CTRS (

Purpose The primary objective of this study was to evaluate the relationship between exercise and sleep disturbance in a sample of individuals diagnosed with stage I, II, and III colorectal cancer (CRC) as patients transitioned off first-line treatment. We also sought to identify heterogeneity in the relationship between sleep disturbance and exercise. Methods Data were obtained from the MY-Health study, a community-based observational study of adults diagnosed with cancer. Patient-Reported Outcomes Measurement Information System�� (PROMIS) measures (e.g., PROMIS Sleep) were administered, and participants self-reported demographics, comorbidities, cancer treatment, and exercise. Regression mixture and multiple regression models were used to evaluate the relationship between sleep disturbance and exercise cross-sectionally at an average of 10 months after diagnosis, and the change in sleep disturbance over a 7-month period, from approximately 10 to 17 months post-diagnosis. Results Patients whose exercise was categorized as likely at or above American College of Sports Medicine���s guidelines did not report statistically better sleep quality compared to patients who were classified as not active. However, retirement (B = ��� 2.4), anxiety (B = 0.21), and fatigue (B = 0.24) had statistically significant relationships with sleep disturbance (p < 0.05). Increase in exercise was not significantly associated with a decrease in sleep disturbance. No statistical heterogeneity was revealed in the relationship between sleep and exercise. Conclusions Further prospective research using an objective measure of exercise is warranted to confirm or refute the nature of the relationship between exercise and sleep disturbance in individuals diagnosed with CRC transitioning off first-line treatment.

Purpose: Few treatment options are available for patients with advanced or metastatic hepatocellular carcinoma (HCC). Based on preclinical and early clinical efficacy signals and lack of overlapping toxicity, we undertook this multicenter phase II trial to estimate efficacy and safety of everolimus and pasireotide in advanced HCC. Methods: Patients with advanced HCC not amenable to locoregional therapy and Child-Pugh A cirrhosis received everolimus 7.5 mg PO daily and pasireotide LAR 60 mg IM every 28 days. The primary endpoint was time to progression (TTP), with 26 events needed to evaluate if everolimus + pasireotide improved TTP from 2.8 to 4.4 months, with 80 % power and an alpha of 0.05. Secondary endpoints included response as measured by RECIST modified for HCC, treatment-emergent adverse events, and overall survival. Results: After 24 patients were enrolled, results of a randomized trial showing no benefit of everolimus in HCC were released prompting an unplanned interim analysis that found the conditional probability of rejecting the null hypothesis based on events in those patients was 0.08. Therefore accrual was halted. Patients had a median age of 59 years, 21 (88 %) had BCLC stage C cancer, and 11 (46 %) metastatic disease. Median TTP was 3.5 months (95 % CI 2–5.8) and median survival 6.7 months (95 % CI 6-infinity). Best response was stable disease in ten patients. Grade 3 hyperglycemia occurred in 6 (25 %). There were no grade 4 treatment-emergent events. Conclusion: Despite promising early efficacy signals, we found no benefit for the combination of everolimus and pasireotide in HCC.

Background Our ability to optimize the care of older adults with cancer and comorbid illnesses is insufficient because most clinical trials lack systematic measurement. The primary purpose of this study was to evaluate the association between patient-reported comorbidity and all-cause mortality using various comorbidity scoring algorithms. Materials and Methods The Carolina Senior Registry was linked with the North Carolina Central Cancer Registry to obtain mortality data. Comorbidity was assessed using the patient-reported Older Americans Resources and Services Questionnaire subscale that assesses 13 specific conditions and the degree to which each impairs activities. Multivariable Cox proportional hazard regression models were used to evaluate the association between comorbidities and all-cause mortality. Results The study sample included 539 patients; the median age was 72 years, 72% were female, and 47% had breast cancer. Overall, 92% reported ≥1 comorbid condition, with a mean of 2.7 conditions (range 0–10), with arthritis and hypertension the most common (52% and 50%, respectively). Approximately 60% reported a functional limitation related to comorbidity. After adjusting for time from diagnosis to geriatric assessment, age, cancer type, and stage, the risk of death increased by 5% for each unit increase in comorbidity burden score (adjusted hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.01–1.10) and 12% for each comorbid condition impacting function (HR = 1.12, 95% CI: 1.02–1.23). Conclusion Comorbid conditions in older adults with cancer are highly prevalent and associated with all-cause mortality, particularly those conditions that impair function. Routine comorbidity assessment should be included in clinical trials and can be measured via a simple one-page patient-reported questionnaire. Implications for Practice In order to optimize and personalize the care of older adults with cancer, systematic measurement of comorbidities is necessary in both clinical trials and routine practice. Patient-reported comorbid conditions in older adults with cancer are highly prevalent and are associated with increased risk of all-cause mortality, particularly for those conditions that impair function. Comorbidity can be systematically measured via a one-page patient-reported questionnaire and should be incorporated into future clinical trials and considered for use in oncology clinics to aid in assessing older adults with cancer.

Great heterogeneity exists in the ability of adults with cancer to tolerate chemotherapy. Variability in body composition may affect rates of metabolism of cytotoxic agents and contribute to the variable chemotherapy toxicity observed. The objective of this exploratory study was to examine the association of low skeletal muscle, commonly known as sarcopenia, on the pharmacokinetics (PKs) of 5-fluorouracil (5FU) in patients receiving FOLFOX for colorectal cancer. We performed a secondary analysis of a completed multicenter trial that investigated PK-guided 5FU dosing in patients receiving mFOLFOX6 +/− bevacizumab for colorectal cancer. Cycle 1 PK samples were obtained 2–44 h after the start of the 5FU infusion (steady state). No significant differences in first cycle 5FU area-under-the-concentration-time-curve (AUC) were found between sarcopenic and non-sarcopenic patients (17.3 vs. 19.3 AUC, p = 0.43). Patients with grade 3/4 toxicity had a higher dose of 5FU per kg lean body mass (LBM) (105 vs. 93 mg/kg, p = 0.06), most notably for hematological toxicities (110 vs. 94 mg/kg, p = 0.002); however, no correlation between the dose/LBM and 5FU AUC was found. Although our results did not confirm the impact of low skeletal muscle on PKs of 5FU, further research exploring the impact of body composition on chemotherapy PKs and related toxicities is warranted with the potential for alternative dosing strategies in sarcopenic patients to reduce unnecessary toxicities while maintaining efficacy.

This study traces the use of the anticancer drug capecitabine through its loss of patent protection to evaluate the effect of generic pricing on the cost of oral anticancer drugs.

A geriatric assessment (GA) assesses functional age of older patients with cancer and is a well-established tool predictive of toxicity and survival. The objective of this study was to investigate the prognostic value of individual GA items.546 patients with cancer ≥ 65 years completed GA from 2009 to 2014 and were followed for survival status for a median of 3.7 years. The GA consisted of function, nutrition, comorbidity, cognition, psychological state, and social activity/support domains. GA items with p 0.05 in univariable analyses for overall survival (OS) were entered into multivariable stepwise selection procedure using a Cox proportional hazards model. A prognostic scale was constructed with significant GA items retained in the final model.Median age was 72 years, 49% had breast cancer, and 42% had stage 3-4 cancer. Three GA items were significant prognostic factors, independent of traditional factors (cancer type, stage, age, and Karnofsky Performance Status): (1) "limitation in walking several blocks", (2) "limitation in shopping", and (3) "≥ 5% unintentional weight loss in 6 months". A three-item prognostic scale was constructed with these items. In comparison with score 0 (no positive items), hazard ratios for OS were 1.85 for score 1, 2.97 for score 2, and 8.67 for score 3. This translated to 2-year estimated survivals of 85%, 67%, 51% and 17% for scores of 0, 1, 2 and 3, respectively.This three-item scale was a strong independent predictor of survival. If externally validated, this could be a streamlined tool with broader applicability.

Background: Older adults are often exposed to multiple medications, some of which could be inappropriate or have the potential to interact with each other. Older cancer patients may be at increased risk for medication-related problems due to exposure to cancer-directed treatment. Methods: We described patterns of potentially inappropriate medication (PIM) use and potential drug–chemotherapy interactions among adults age 66+ years diagnosed with stage I–III breast, stage II–III colon, and stage I to II lung cancer. Within the Surveillance, Epidemiology, and End Results–Medicare database, patients had to have Medicare Part D coverage with 1+ prescription in the diagnosis month and Medicare Parts A/B coverage in the prior 12 months. We estimated monthly prevalence of any and cancer-related PIM from 6 months pre- to 23 months postcancer diagnosis and 12-month period prevalence of potential drug–chemotherapy interactions. Results: Overall, 19,318 breast, 7,283 colon, and 7,237 lung cancer patients were evaluated. Monthly PIM prevalence was stable prediagnosis (37%–40%), but increased in the year following a colon or lung cancer diagnosis, and decreased following a breast cancer diagnosis. Changes in PIM prevalence were driven primarily by cancer-related PIM in patients on chemotherapy. Potential drug–chemotherapy interactions were observed in all cohorts, with prevalent interactions involving hydrochlorothiazide, warfarin, and proton-pump inhibitors. Conclusions: There was a high burden of potential medication-related problems among older cancer patients; future research to evaluate outcomes of these exposures is warranted. Impact: Older adults diagnosed with cancer have unique medication management needs. Thus, pharmacy specialists should be integrated into multidisciplinary teams caring for these patients. Cancer Epidemiol Biomarkers Prev; 27(1); 41–49. ©2017 AACR.

OBJECTIVE To identify patient characteristics associated with sleep disturbance and worsening of sleep in individuals diagnosed with localized colorectal cancer and assess heterogeneity in these relationships. METHODS Data were from the MY-Health study, a community-based observational study of adults diagnosed with cancer. Patient-Reported Outcomes Measurement Information System® Sleep Disturbance, Anxiety, Depression, Fatigue, and Pain Interference measures were administered. Participants self-reported demographics, comorbidities, and treatment information. Regression mixture and multiple regression models were used to evaluate the relationship between sleep disturbance and patient characteristics cross-sectionally at an average of 10 months after diagnosis (n = 613) as well as change in sleep disturbance over a 6-month period (n = 361). RESULTS Pain, anxiety, fatigue, and the existence of multiple comorbid conditions had statistically significant relationships with sleep disturbance (B = 0.09, 0.22, 0.29, and 1.53, respectively; P

196 Background: LCCC1029 was a 2:1 randomized phase II trial of 2nd-line FOLFIRI plus either regorafenib or placebo in mCRC. The addition of regorafenib improved PFS (median PFS 6.1 vs 5.3 mo, HR 0.73, 95% CI 0.53-1.01). However, the effect of somatic mutations on regorafenib activity has not been tested. Methods: We performed whole exome sequencing on archival primary tumor tissue and paired normal tissue in 85 patients of LCCC1029. We compared PFS and OS using Kaplan-Meier method and log-rank tests, and hazard ratios (HR) were estimated using Cox proportional hazards method. Results: Among the 85 subjects, 54 (64%) had tumors wild-type (WT) for KRAS and BRAF, 26 (31%) had tumors with KRAS mutations in exons 2-4, and 5 (6%) had tumors with BRAF V600E. The addition of regorafenib to FOLFIRI improved PFS in the KRAS/ BRAF WT subgroup (median PFS 8.0 vs 4.9 mo, HR 0.68, 95% CI 0.48-0.97, log-rank p=0.028), but not in the KRAS mutant subgroup (median PFS 6.8 vs 5.5 mo, HR 0.90, 95% CI 0.61-1.35, log-rank p=0.617) or the BRAF mutant subgroup (log-rank p=0.156). In all of these subgroups, the addition of regorafenib was not associated with significant difference in OS. BRAF V600E was prognostic and associated with significantly worse OS (median OS 8.4 vs 18.0 mo, HR 2.59, 95% CI 1.01-6.66, log-rank p=0.04). Conclusions: The addition of regorafenib to FOLFIRI improves PFS among the subgroup of patients with KRAS and BRAF dual WT CRC, but not among the KRAS mutant subgroup. These results indicate that the addition of anti-angiogenic therapy to second-line chemotherapy backbones may be more effective in KRAS/ BRAF WT tumors in particular. More confirmatory studies are needed to corroborate this finding.

TPS260 Background: Deficient DNA mismatch repair (dMMR) colorectal cancer (CRC) is highly immunogenic. Preclinical data showed synergistic interactions among FOLFOX, anti-VEGF, and programmed cell death-1 (PD-1) pathway blockade. Prior phase I study of mFOLFOX6/ bevacizumab (bev) + atezolizumab (atezo) was well tolerated and enhanced intratumoral infiltration of CD8+ T cells. We hypothesize that the dMMR subset of CRC may be effectively targeted with combination of PD-1 pathway blockade and mFOLFOX6/bev. Methods: This is a prospective randomized phase III open-label trial. Pts (N=347) with mCRC dMMR will be randomized to three trial arms (1:1:1): mFOLFOX6/bev; atezo monotherapy; or mFOLFOX6/bev + atezo. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is progression-free survival (PFS) assessed by study investigator of mFOLFOX6/bev/atezo and atezo monotherapy compared to mFOLFOX6/bev. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and PFS by retrospective central review. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2); availability of archived tumor tissue for central confirmation of dMMR status; and measurable disease per RECIST. Activated 11-7-17. As of 9-11-19, enrollment continues with 44/347 pts enrolled. Clinical trial: NCT02997228. Support:U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

BACKGROUND Data on health-related quality of life (HRQoL) changes among Americans aged ≥65 following colorectal cancer (CRC) diagnosis and treatment are limited. This study compared HRQoL changes among CRC patients across stages from before to after diagnosis with matched noncancer controls. METHODS This population-based study used the Surveillance, Epidemiology, and End Results Medicare Health Outcomes Survey (MHOS) data set (1998-2007). Medicare Advantage beneficiaries diagnosed with CRC between their baseline and follow-up MHOS (n = 349) were matched to noncancer controls (n = 1745) using propensity scores. Mixed-effects analysis of covariance models estimated changes in HRQoL (measured by the Medical Outcomes Study Short Form-36/Veterans RAND 12-item Survey) and the ability to perform 6 activities of daily living (ADLs) between baseline and follow-up. Logistic regression models estimated odds ratios for ADL impairments and major depressive disorder (MDD) risk. RESULTS Mean time between CRC diagnosis and follow-up MHOS was 12.3 ± 9.8 months. Compared with controls, CRC patients had significantly lower scores in all physical and mental health domains at follow-up. The greatest decrements were observed in physical health and were largely driven by declines in the 6 months postdiagnosis and in stage III and IV patients. At follow-up, CRC patients had greater overall ADL impairment and difficulty with dressing, eating, and getting in/out of chairs. CRC patients, particularly stage IV patients, had greater odds of being at risk for MDD relative to controls. CONCLUSIONS This study further underscores the adverse effects of CRC on physical health and the need to support older Americans' basic self-care needs, with attention to later-stage patients' increased debility. Cancer 2015;121:943–950. © 2014 American Cancer Society.

BACKGROUND African American (AA) patients with colon cancer (CC) experience worse outcomes than whites partly due to differential treatment. The National Cancer Institute's Community Clinical Oncology Program (CCOP), a provider-based research network, adopts and diffuses innovative CC treatments quickly. The authors hypothesized that CCOP participation would lessen racial differences in the receipt of oxaliplatin, an innovative treatment for CC, among patients with stage III CC in the community. METHODS Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, the authors performed a population-based retrospective cohort study of AA and white individuals aged ≥66 years who were diagnosed with AJCC stage III CC from 2003 through 2005. Generalized estimating equations were used to calculate the odds of receiving an oxaliplatin-containing regimen. Predicted probabilities of oxaliplatin receipt for race-CCOP combinations were calculated. The absolute difference in oxaliplatin receipt between races was estimated using the interaction contrast ratio. RESULTS Of 2971 included individuals, 36% received oxaliplatin, 29.5% were CCOP-affiliated, and 7.6% were AA. On multivariate analysis, early diffusion of oxaliplatin was not found to be associated with race or CCOP participation. The probability of receiving oxaliplatin for AAs participating in a CCOP (0.46) was nearly double that of AAs who were not participating in a CCOP (0.25; P

91 Background: Patients with advanced cancer who have minor children face unique challenges when coping with their life-limiting illness and the impact of their illness on their families. The goal of this study was to examine whether psychosocial functioning, treatment preferences, and treatment decisions in advanced cancer differ by parental status. Methods: A cohort of 60 parents with metastatic solid tumors age-matched with 60 non-parents (N = 120) participated in three structured interviews assessing treatment preferences and decisions over six months with complementary medical record review. Participants also completed validated measures of psychosocial functioning. Results: Seventy percent (n = 85) of the sample completed all study assessments. Mean age (45 years, SD 8), mean performance status score (ECOG = 1.2, SD 0.9), median duration of metastatic illness (19 months, range 1-115), gender ratio (66% female), and dropout rates were similar between groups. Parents and non-parents reported similar overall health-related quality of life, but parents were more likely to report poorer emotional well-being (p = 0.006) and more symptoms of depression (p = 0.04) and anxiety (p = 0.04) than non-parents. Parents and non-parents were equally likely to describe life-extension as their primary goal of anti-neoplastic treatment. Parents reported greater willingness to live in pain (48% “very willing” vs 27%, p = 0.007) and accept intubation/ventilation (40% vs 20%, p = 0.01) for life-extension. Compared to non-parents, parents were more likely to report their family members as the most influential factor in their decision-making (44% vs 12%) and less likely to cite their oncologist’s recommendation (25% vs 41%). There were no significant differences between groups for completion of a health care power of attorney or living will. Conclusions: Compared to similarly aged adults with metastatic cancer, parents experience greater psychological distress, are more willing to live in pain for life extension, and place greater importance on family-related factors in their cancer treatment decision-making.

116 Background: Patients with brain metastases (BMets) represent a subset of cancer patients who may experience high costs and frequent healthcare utilization. This study aims to assess whether patients with BMets have higher likelihood of healthcare utilization at the end of life (EOL) compared to other patients with metastatic cancer. Methods: Using the Cancer Information and Population Health Resource, linking North Carolina Medicare, Medicaid, and private payer claims with state cancer registry data, we conducted an observational cohort study of decedents with metastatic melanoma, renal cell carcinoma, breast cancer, or lung cancer (diagnosed 2003-2014) with or without BMets. Multivariate logistic regression, adjusting for demographics, cancer type, systemic treatment, comorbidity, frailty, and hospice use, was used to examine the impact of BMets on use of the emergency department (ED), hospital, and intensive care unit (ICU) in the 30 days prior to death. Results: Patients with BMets are hospitalized at EOL more often than patients without BMets (44% vs 38%, p < 0.001), but experience no difference in ED or ICU use. BMets patients receiving systemic treatment were particularly high risk for hospital and ICU use (odds ratios in Table). Black race and Charlson comorbidity score 3+ increased risk of hospitalization and ICU use. Utilization did not vary by cancer type. Hospice care significantly reduced all utilization. Conclusions: Patients with BMets are high risk for hospitalization at the end of life. Further study is needed to determine if targeted health system interventions can decrease hospitalizations in this patient group. [Table: see text]