Longitudinal patient-reported outcomes on genotype-guided irinotecan dosing: feasibility and clinical relevance.

INTRODUCTION: Standard investigator-based adverse events (AE) assessment is via CTCAE for clinical trials. However, including the patient perspective through PRO (patient-reported outcomes) enhances clinicians' understanding of patient toxicity and fosters early detection of AEs. We assessed longitudinal integration of PRO-CTCAE within clinical workflow in a phase II trial. MATERIALS AND METHODS: As a sub-study in a phase II trial of genotype-directed irinotecan dosing evaluating efficacy in patients with metastatic colorectal cancer receiving FOLFIRI and bevacizumab, patients reported on 13 AEs generating a PRO-CTCAE form. The primary objective was to estimate forms completed by patients and clinicians at least 80% of time. Secondary objectives were estimating concordance and time to first score of specific symptoms between patient and clinician pairs. RESULTS: Feasibility of longitudinal PRO-CTCAE integration was met as 96% of patients and clinician-patient pairs completed at least 80% of PRO-CTCAE forms available to them with 79% achieving 100% completion. Concordance between patient and clinician reporting a severe symptom was 73% with 24 disconcordant pairs, 21 involved patients who reported a severe symptom that the clinician did not. Although protocol-mandated dose reductions were guided by CTCAE not PRO-CTCAE responses, the median time to dose reduction of 2.53 months, and the time-to-event curve closely approximated time to patient-reported toxicity. CONCLUSION: Longitudinal integration of PRO-CTCAE paired CTCAE proved feasible. Compared to clinicians, patients reported severe symptoms more frequently and earlier. Patient-reported toxicity more closely aligned with dose decreases indicating incorporation into routine clinical practice may enhance early detection of toxicity improving patient safety and quality of life.

A phase II trial of UGT1A1 genotype-guided FOLFIRI plus bevacizumab as first-line therapy for advanced, unresectable colorectal cancer.

BACKGROUND: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. METHODS: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). RESULTS: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. CONCLUSIONS: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.

Statewide Survey of Primary Care and Subspecialty Providers on Hepatocellular Carcinoma Risk-Stratification and Surveillance Practices.

BACKGROUND: Hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis is associated with improved survival. Provision of HCC surveillance is low in the US, particularly in primary care settings. AIMS: To evaluate current hepatitis C virus (HCV) and HCC surveillance practices and physician attitudes regarding HCC risk-stratification among primary care and subspecialty providers. METHODS: Using the Tailored Design Method, we delivered a 34-item online survey to 7654 North Carolina-licensed internal/family medicine or gastroenterology/hepatology physicians and advanced practice providers in 2022. We included the domains of HCV treatment, cirrhosis diagnosis, HCC surveillance practices, barriers to surveillance, and interest in risk-stratification tools. We performed descriptive analyses to summarize responses. Tabulations were weighted based on sampling weights accounting for non-response and inter-specialty comparisons were made using chi-squared or t test statistics. RESULTS: After exclusions, 266 responses were included in the final sample (response rate 3.8%). Most respondents (78%) diagnosed cirrhosis using imaging and a minority used non-invasive tests that were blood-based (~ 15%) or transient elastography (31%). Compared to primary care providers, subspecialists were more likely to perform HCC surveillance every 6-months (vs annual) (98% vs 35%, p < 0.0001). Most respondents (80%) believed there were strong data to support HCC surveillance, but primary care providers did not know which liver disease patients needed surveillance. Most providers (> 70%) expressed interest in potential solutions to improve HCC risk-stratification. CONCLUSIONS: In this statewide survey, there were great knowledge gaps in HCC surveillance among PCPs and most respondents expressed interest in strategies to increase appropriate HCC surveillance.

Future direction of total neoadjuvant therapy for locally advanced rectal cancer.

Despite therapeutic advancements, disease-free survival and overall survival of patients with locally advanced rectal cancer have not improved in most trials as a result of distant metastases. For treatment decision-making, both long-term oncologic outcomes and impact on quality-of-life indices should be considered (for example, bowel function). Total neoadjuvant therapy (TNT), comprised of chemotherapy and radiotherapy or chemoradiotherapy, is now a standard treatment approach in patients with features of high-risk disease to prevent local recurrence and distant metastases. In selected patients who have a clinical complete response, subsequent surgery might be avoided through non-operative management, but patients who do not respond to TNT have a poor prognosis. Refined molecular characterization might help to predict which patients would benefit from TNT and non-operative management. Specifically, integrated analysis of spatiotemporal multi-omics using artificial intelligence and machine learning is promising. Three prospective trials of TNT and non-operative management in Japan, the USA and Germany are collaborating to better understand drivers of response to TNT. Here, we address the future direction for TNT.

Commercial Versus Medicaid Insurance and Use of High-Priced Anticancer Treatments.

BACKGROUND: Because the markups on cancer drugs vary by payor, providers' financial incentive to use high-price drugs is differential according to each patient's insurance type. We evaluated the association between patient insurer (commercial vs Medicaid) and the use of high-priced cancer treatments. MATERIALS AND METHODS: We linked cancer registry, administrative claims, and demographic data for individuals diagnosed with cancer in North Carolina from 2004 to 2011, with either commercial or Medicaid insurance. We selected cancers with multiple FDA-approved, guideline-recommended chemotherapy options and large price differences between treatment options: advanced colorectal, lung, and head and neck cancer. The outcome was a receipt of a higher-priced option, and the exposure was insurer: commercial versus Medicaid. We estimated risk ratios (RRs) for the association between insurer and higher-priced treatment using log-binomial models with inverse probability of exposure weights. RESULTS: Of 812 patients, 209 (26%) had Medicaid. The unadjusted risk of receiving higher-priced treatment was 36% (215/603) for commercially insured and 27% (57/209) for Medicaid insured (RR: 1.31, 95% CI: 1.02-1.67). After adjustment for confounders the association was attenuated (RR: 1.15, 95% CI: 0.81-1.65). Exploratory subgroup analysis suggested that commercial insurance was associated with increased receipt of higher-priced treatment among patients treated by non-NCI-designated providers (RR: 1.53, 95% CI: 1.14-2.04). CONCLUSIONS: Individuals with Medicaid and commercial insurance received high-priced treatments in similar proportion, after accounting for differences in case mix. However, modification by provider characteristics suggests that insurance type may influence treatment selection for some patient groups. Further work is needed to determine the relationship between insurance status and newer, high-price drugs such as immune-oncology agents.

Social Determinants of Health and the Link to Colorectal Cancer Outcomes.

OPINION  STATEMENT: Colorectal cancer (CRC) remains the second most deadly cancer in the United States, behind only lung cancer. Despite improvements in incidence due to screening and mortality in part due to better treatments, there are some groups that have not seen these promising changes. American Indian/Alaska Native and non-Hispanic Black individuals, certain geographic regions, and lower socioeconomic groups have all been shown to have worse CRC outcomes. A significant body of evidence has linked these disparities in outcomes to social determinants of health (SDH). SDH are defined by the WHO as "the non-medical factors that influence health outcomes." These factors include but are not limited to income, education, social support, neighborhood of residence, and access to healthcare. Individuals who are negatively impacted by SDH have been shown to have a higher incidence of CRC. These individuals are also less likely to receive adequate CRC screening, are less likely to receive appropriate treatment, and have increased CRC mortality. Interventions that target different SDH domains have been shown to lead to increased rates of CRC screening and receipt of appropriate treatment while simultaneously improving CRC mortality. The aim of this review is to highlight the connection between SDH and CRC outcomes while also exploring interventions that target SDH and thereby improve CRC outcomes.

Scoping review of values elicitation tools for treatment decisions in hepatocellular carcinoma.

BACKGROUND: Treatment choices in hepatocellular carcinoma (HCC) involve consideration of tradeoffs between the benefits, toxicities, inconvenience, and costs. Stated preference elicitation methods have been used in the medical field to help evaluate complex treatment decision-making. The aim of this study was to conduct a scoping review to assess the evidence base for the use of preference elicitation tools or willingness to pay/willingness to accept methods for HCC treatment decision-making from both the patient and provider perspective. METHODS: We performed a scoping review to identify abstracts or manuscripts focused on the role preference elicitation tools or willingness to pay/willingness to accept methods for HCC treatment options among patients, caregivers, and/or providers. Two researchers independently screened full-text references and resolved conflicts through discussion. We summarized key findings, including the type and setting of preference-elicitation tools used for HCC treatment decisions. RESULTS: Ten published abstracts or manuscripts evaluated the role of preference elicitation tools for HCC treatments. The studies revealed several attributes that are considered by patients and providers making HCC treatment decisions. Many of the studies reviewed suggested that while patients place the most value on extending their overall survival, they are willing to forgo overall survival to avoid risks of treatments and maintain quality of life. Studies of physicians and surgeons found that provider preferences are dependent on patient characteristics, provider specialty, and surgeon or hospital-related factors. CONCLUSION: This scoping review explored both patient and physician preferences towards treatment modalities in all stages of HCC. The studies revealed a large scope of potential attributes that may be important to patients and that many patients are willing to forgo survival to maintain quality of life. Further research should explore both preference elicitation of currently available and emerging therapies for HCC as well as the use of this data to develop patient-facing tools to assist in navigating treatment options.

A Pilot Study of Pembrolizumab in Combination With Y90 Radioembolization in Subjects With Poor Prognosis Hepatocellular Carcinoma.

BACKGROUND: Combination checkpoint inhibition therapy with yttrium-90 (Y90) radioembolization represents an emerging area of interest in the treatment of advanced hepatocellular carcinoma (HCC). HCRN GI15-225 is an open-label, single-arm multicenter, pilot study (NCT03099564). METHODS: Eligible patients had poor prognosis, localized HCC defined as having portal vein thrombus, multifocal disease, and/or diffuse disease that were not eligible for liver transplant or surgical resection. Patients received pembrolizumab 200 mg intravenously every 3 weeks in conjunction with glass yttrium-90 (Y90) radioembolization TheraSphere. Primary endpoint was 6-month progression-free survival (PFS6) per RECIST 1.1. Secondary endpoints included time to progression (TTP), objective response rate (ORR), overall survival (OS), and safety/tolerability. RESULTS: Between October 23, 2017 and November 24, 2020, 29 patients were enrolled: 2 were excluded per protocol. Fifteen of the remaining 27 patients were free of progression at 6 months (55.6%; 95% CI, 35.3-74.5) with median PFS 9.95 months (95% CI, 4.14-15.24) and OS 27.30 months (95% CI, 10.15-39.52). One patient was not evaluable for response due to death; among the remaining 26 patients, ORR was 30.8% (95% CI, 14.3-51.8) and DCR was 84.6% (95% CI, 65.1-95.6). CONCLUSION: In patients with localized, poor prognosis HCC, pembrolizumab in addition to glass Y90 radioembolization demonstrated promising efficacy and safety consistent with prior observations (ClinicalTrials.gov Identifier: NCT03099564; IRB Approved: 16-3255 approved July 12, 2016).

Visualizing External Validity: Graphical Displays to Inform the Extension of Treatment Effects from Trials to Clinical Practice.

BACKGROUND: In the presence of effect measure modification, estimates of treatment effects from randomized controlled trials may not be valid in clinical practice settings. The development and application of quantitative approaches for extending treatment effects from trials to clinical practice settings is an active area of research. METHODS: In this article, we provide researchers with a practical roadmap and four visualizations to assist in variable selection for models to extend treatment effects observed in trials to clinical practice settings and to assess model specification and performance. We apply this roadmap and visualizations to an example extending the effects of adjuvant chemotherapy (5-fluorouracil vs. plus oxaliplatin) for colon cancer from a trial population to a population of individuals treated in community oncology practices in the United States. RESULTS: The first visualization screens for potential effect measure modifiers to include in models extending trial treatment effects to clinical practice populations. The second visualization displays a measure of covariate overlap between the clinical practice populations and the trial population. The third and fourth visualizations highlight considerations for model specification and influential observations. The conceptual roadmap describes how the output from the visualizations helps interrogate the assumptions required to extend treatment effects from trials to target populations. CONCLUSIONS: The roadmap and visualizations can inform practical decisions required for quantitatively extending treatment effects from trials to clinical practice settings.

Patient-reported symptoms and interest in symptom monitoring in HCC treated with locoregional therapies: A qualitative study.

BACKGROUND: Patient-reported outcomes (PRO) measures relevant to domains most important to patients with HCC who received locoregional therapies are needed to advance patient-centered research. Furthermore, electronic PRO monitoring in clinical care has been shown to reduce hospitalizations and deaths in patients with other cancers. We conducted a qualitative study among patients with HCC who recently received locoregional therapies to (1) identify common and distressing posttreatment symptoms to prioritize PRO domain selection and (2) gauge interest in an electronic PRO symptom monitoring system. METHODS: We performed semi-structured telephone interviews among adult patients who received locoregional therapies (median of 26 days after treatment) for treatment-naïve HCC at a single tertiary care center. Interviews were conducted until thematic saturation was reached. Qualitative content analysis was conducted to identify emerging themes and sub-themes. RESULTS: Ten of 26 patients (38%) reported at least 1 symptom before treatment. In contrast, all participants (n = 26) with recently treated HCC reported at least 1 posttreatment physical symptom, with the most common being appetite loss (73%), fatigue (58%), abdominal pain (46%), and nausea (35%). Most participants (77%) stated they saw potential benefits in posttreatment ePRO symptom monitoring. CONCLUSIONS: Posttreatment symptoms after HCC locoregional therapies are common and often severe. These data can inform and prioritize PRO domain selection. Patients are interested in ePRO monitoring to monitor and proactively address posttreatment symptoms. Given the clinical benefits in patients with metastatic cancers, ePRO monitoring warrants investigation in patients with HCC.

Qualitative evaluation of barriers and facilitators to hepatocellular carcinoma care in North Carolina.

BACKGROUND: Many patients with hepatocellular carcinoma (HCC) never receive cancer-directed therapy. In order to tailor interventions to increase access to appropriate therapy, we sought to understand the barriers and facilitators to HCC care. METHODS: Patients with recently diagnosed HCC were identified through the University of North Carolina (UNC) HCC clinic or local hospital cancer registrars (rapid case ascertainment, RCA). Two qualitative researchers conducted in-depth, semi-structured interviews. Interviews were audiotaped, transcribed, and coded. RESULTS: Nineteen interviews were conducted (10 UNC, 9 RCA). Key facilitators of care were: physician knowledge; effective communication regarding test results, plan of care, and prognosis; social support; and financial support. Barriers included: lack of transportation; cost of care; provider lack of knowledge about HCC; delays in scheduling; or poor communication with the medical team. Participants suggested better coordination of appointments and having a primary contact within the healthcare team. LIMITATIONS: We primarily captured the perspectives of those HCC patients who, despite the challenges they describe, were ultimately able to receive HCC care. CONCLUSIONS: This study identifies key facilitators and barriers to accessing care for HCC in North Carolina. Use of the RCA system to identify patients from a variety of settings, treated and untreated, enabled us to capture a broad range of perspectives. Reducing barriers through improving communication and care coordination, assisting with out-of-pocket costs, and engaging caregivers and other medical providers may improve access. This study should serve as the basis for tailored interventions aimed at improving access to appropriate, life-prolonging care for patients with HCC.

Hepatocellular Carcinoma Surveillance among Individuals with Cirrhosis: Trends by Payer, Etiology, and Calendar Year, from a Statewide, Multi-Payer Dataset, 2010-2018.

BACKGROUND: Hepatocellular carcinoma (HCC) surveillance is underutilized, with <25% of individuals with cirrhosis receiving surveillance exams as recommended. The epidemiology of cirrhosis and HCC in the United States has also shifted in recent years, but little is known about recent trends in surveillance utilization. We characterized patterns of HCC surveillance by payer, cirrhosis etiology, and calendar year in insured individuals with cirrhosis. METHODS: We conducted a retrospective cohort study of individuals with cirrhosis using claims data from Medicare, Medicaid, and private insurance plans in North Carolina. We included individuals ≥ 18 years with a first occurrence of an ICD-9/10 code for cirrhosis between January 1, 2010, and June 30, 2018. The outcome was HCC surveillance by abdominal ultrasound, CT, or MRI. We estimated 1- and 2-year cumulative incidences for HCC surveillance and assessed longitudinal adherence to surveillance by computing the proportion of time covered (PTC). RESULTS: Among 46,052 individuals, 71% were enrolled through Medicare, 15% through Medicaid, and 14% through private insurance. The overall 1-year cumulative incidence of HCC surveillance was 49% and the 2-year cumulative incidence was 55%. For those with an initial screen in the first 6 months of their cirrhosis diagnosis, the median 2-year PTC was 67% (Q1, 38%; Q3, 100%). CONCLUSIONS: HCC surveillance initiation after cirrhosis diagnosis remains low, though it has improved slightly over time, particularly among individuals with Medicaid. IMPACT: This study provides insight into recent trends in HCC surveillance and highlights areas to target for future interventions, particularly among patients with nonviral etiologies.

Predicting Acute Care Events Among Patients Initiating Chemotherapy: A Practice-Based Validation and Adaptation of the PROACCT Model.

PURPOSE: Acute care events (ACEs), comprising emergency department visits and hospitalizations, are a priority area for reduction in oncology. Prognostic models are a compelling strategy to identify high-risk patients and target preventive services, but have yet to be broadly implemented, partly because of challenges with electronic health record (EHR) integration. To facilitate EHR integration, we adapted and validated the previously published PRediction Of Acute Care use during Cancer Treatment (PROACCT) model to identify patients at highest risk for ACEs after systemic anticancer treatment. METHODS: A retrospective cohort of adults with a cancer diagnosis starting systemic therapy at a single center between July and November 2021 was divided into development (70%) and validation (30%) sets. Clinical and demographic variables were extracted, limited to those in structured format in the EHR, including cancer diagnosis, age, drug category, and ACE in prior year. Three logistic regression models of increasing complexity were developed to predict risk of ACEs. RESULTS: Five thousand one hundred fifty-three patients were evaluated (3,603 development and 1,550 validation). Several factors were predictive of ACEs: age (in decades), receipt of cytotoxic chemotherapy or immunotherapy, thoracic, GI or hematologic malignancy, and ACE in the prior year. We defined high-risk as the top 10% of risk scores; this population had 33.6% ACE rate compared with 8.3% for the remaining 90% in the low-risk group. The simplest Adapted PROACCT model had a C-statistic of 0.79, sensitivity of 0.28, and specificity of 0.93. CONCLUSION: We present three models designed for EHR integration that effectively identify oncology patients at highest risk for ACE after initiation of systemic anticancer treatment. By limiting predictors to structured data fields and including all cancer types, these models offer broad applicability for cancer care organizations and may offer a safety net to identify and target resources to this high risk.

Identifying patient profiles of disparate care in resectable pancreas cancer using latent class analysis.

BACKGROUND AND OBJECTIVES: Disparities in pancreas cancer care are multifactorial, but factors are often examined in isolation. Research that integrates these factors in a single conceptual framework is lacking. We use latent class analysis (LCA) to evaluate the association between intersectionality and patterns of care and survival in patients with resectable pancreas cancer. METHODS: LCA was used to identify demographic profiles in resectable pancreas cancer (n = 140 344) diagnosed from 2004 to 2019 in the National Cancer Database (NCDB). LCA-derived patient profiles were used to identify differences in receipt of minimum expected treatment (definitive surgery), optimal treatment (definitive surgery and chemotherapy), time to treatment, and overall survival. RESULTS: Minimum expected treatment (hazard ratio [HR] 0.69, 95% confidence interval [CI]: 0.65, 0.75) and optimal treatment (HR 0.58, 95% CI: 0.55, 0.62) were associated with improved overall survival. Seven latent classes were identified based on age, race/ethnicity, and socioeconomic status (SES) attributes (zip code-linked education and income, insurance, geography). Compared to the referent group (≥65 years + White + med/high SES), the ≥65 years + Black profile had the longest time-to-treatment (24 days vs. 28 days) and lowest odds of receiving minimum (odds ratio [OR] 0.67, 95% CI: 0.64, 0.71) or optimal treatment (OR 0.76, 95% CI: 0.72, 0.81). The Hispanic patient profile had the lowest median overall survival-55.3 months versus 67.5 months. CONCLUSIONS: Accounting for intersectionality in the NCDB resectable pancreatic cancer patient cohort identifies subgroups at higher risk for inequities in care. LCA demonstrates that older Black patients and Hispanic patients are at particular risk for being underserved and should be prioritiz for directed interventions.

Effect of a MUC5AC Antibody (NPC-1C) Administered With Second-Line Gemcitabine and Nab-Paclitaxel on the Survival of Patients With Advanced Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial.

Importance: Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. Objective: To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC. Design, Setting, and Participants: This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022. Interventions: Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks. Main Outcomes and Measures: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis. Results: A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival. Conclusions and Relevance: In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. Trial Registration: ClinicalTrials.gov Identifier: NCT01834235.

Treatment of Metastatic Colorectal Cancer: ASCO Guideline.

PURPOSE: To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC). METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria. RECOMMENDATIONS: Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti-vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti-epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive RAS wild-type mCRC; chemotherapy and anti-vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair RAS wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated BRAF V600E-mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Comparing Trial and Real-world Adjuvant Oxaliplatin Delivery in Patients With Stage III Colon Cancer Using a Longitudinal Cumulative Dose.

Importance: Delivery of adjuvant chemotherapy can differ substantially between trial and real-world populations. Adherence metrics like relative dose intensity (RDI) cannot capture the timing of modifications and mask differences in the total amount of chemotherapy received. Objective: To compare oxaliplatin delivery between MOSAIC trial participants and patients treated in the US Oncology Network with stage III colon cancer using a longitudinal cumulative dose (LCD). Design, Setting, and Participants: This cohort study used secondary data from the MOSAIC trial, an international randomized clinical trial (concluded in 2004), and electronic health records from US Oncology (2009-2018), a network of community oncology practices in the US. It included participants in MOSAIC with stage III colon cancer who were randomized to receive treatment with oxaliplatin and fluorouracil/leucovorin (n = 663) and US Oncology patients with stage III colon cancer who were treated with a modified FOLFOX-6 regimen (n = 2523). Exposures: Oxaliplatin and fluorouracil/leucovorin. Outcomes and Measures: We evaluated RDI and LCD over time and at the end of treatment in the MOSAIC and US Oncology populations. We used bootstrapping to estimate 95% confidence bands for LCD differences between the populations. Results: The 663 MOSAIC participants (296 women [44.7%]) and 2523 US Oncology patients (1245 women [49.4%]) were generally similar with respect to demographic characteristics. Median RDI was lower in US Oncology (80% in MOSAIC vs 70% in US Oncology). The LCD also suggested differences in the total amount of oxaliplatin received between populations; the final median LCD in US Oncology was 10.2% lower than in MOSAIC, equivalent to receiving 1.2 fewer treatment cycles less of oxaliplatin. This difference only began 133 days into treatment and persisted after accounting for covariates, likely in terms of more frequent oxaliplatin treatment discontinuation in US Oncology patients than their MOSAIC counterparts. Conclusions and Relevance: The study results suggest that real-world patients in community practice in the US treated with modified FOLFOX 6 received less oxaliplatin than their historical counterparts in the MOSAIC trial, with differences manifesting late in the treatment course. The LCD allowed us to identify the amount and extent of these differences, the timing of which was unclear when using RDI alone. Trial Registration: ClinicalTrials.gov identifier: NCT00275210.

Trimodality Therapy vs Definitive Chemoradiation in Older Adults With Locally Advanced Esophageal Cancer.

BACKGROUND: The comparative effectiveness of trimodality therapy vs definitive chemoradiation for treating locally advanced esophageal cancer in older adults is uncertain. Existing trials lack generalizability to older adults, a population with heightened frailty. We sought to emulate a hypothetical trial comparing these treatments using real-world data. METHODS: A cohort of adults aged 66-79 years diagnosed with locally advanced esophageal cancer between 2004 and 2017 was identified in the Surveillance Epidemiology and End Results-Medicare database. The clone-censor-weight method was leveraged to eliminate time-related biases when comparing outcomes between treatments. Outcomes included overall mortality, esophageal cancer-specific mortality, functional adverse events, and healthy days at home. RESULTS: A total of 1240 individuals with adenocarcinomas and 661 with squamous cell carcinomas were identified. For adenocarcinomas, the standardized 5-year risk of mortality was 73.4% for trimodality therapy and 83.8% for definitive chemoradiation (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.82 to 0.95). Trimodality therapy was associated with mortality risk reduction for squamous cell carcinomas (RR = 0.87, 95% CI = 0.70 to 1.01). The 1-year incidence of functional adverse events was higher in the trimodality group (adenocarcinomas RR = 1.40, 95% CI = 1.22 to 1.65; squamous cell carcinomas RR = 1.21, 95% CI = 1.00 to 1.49). Over 5 years, trimodality therapy was associated with 160 (95% CI = 67 to 229) and 177 (95% CI = 51 to 313) additional home days in individuals with adenocarcinomas and squamous cell carcinomas, respectively. CONCLUSIONS: Compared with definitive chemoradiation, trimodality therapy was associated with reduced mortality but increased risk of function-related adverse events. Discussing these tradeoffs may help optimize care plans.

Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer.

BACKGROUND: Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. METHODS: We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months. RESULTS: Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia. CONCLUSION: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157).