Trials In Colorectal Cancer Research Articles

Abstract PO-071: Simulation of colorectal cancer clinical trials using real-world data and machine learning

Abstract Objectives To explore the feasibility of using real-world data (RWD) with machine learning methods to simulate colorectal cancer (CRC) trials (i.e., 6 Phase III randomized clinical trials comparing other treatment regimens with FOLFIRI—an FDA-approved standard of care first line chemotherapy treatment in patients with metastatic CRC). Methods We used RWD from the OneFlorida Clinical Research Consortium, a clinical research network contributing to the national PCORnet with longitudinal linked electronic health records of ~15 million Floridians. We used the study protocols in the original trials, including the eligibility criteria, to define the various study populations. We focused on patients’ safety outcomes in terms of the occurrence of severe adverse events (SAEs) after the treatments; calculated SAE prevalence, mean SAEs per patient, and SAE event rates for each category defined in the CTCAE v5.0. We considered two scenarios: (1) only simulating the control arm (CA) (i.e., the FOLFIRI arm), and (2) simulating both the CA and experimental arm (EA) (e.g., Panitumumab + FOLFIRI) and calculating the relative risk of SAE between the 2 arms. Two sampling strategies were used to simulate study population: random sampling and proportional sampling with gender and race. Among the 6 trials, only 2 had sufficient patients in OneFlorida for the two-arm simulations. We used propensity score matching (PSM) on baseline characteristics such as age, gender, race, and comorbidities to simulate the randomization process. In addition to the traditional logistic regression (LR) model, we considered machine learning (ML) models for PSM (such as neural networks) as LR-based PSM assumes linearity of the underlying variables. Each trial was simulated 1,000 times. Results Consistent with the existing literature, the mean SAE and SAE event rates were higher in all CAs simulated through RWD from OneFlorida. The proportional sampling strategy provided estimates of SAE prevalence more comparable to rates reported by the original trials. In the two-arm simulations, no significant differences were observed in the matched case-control samples using LR or ML methods. As expected with patients treated in real-world settings, larger mean SAEs and SAE event rates (but similar SAE prevalence ) were observed in the simulations compared with the original trials. The risk ratios of having SAE obtained from simulations comparing CA vs. EA were very close to the ratios calculated from the original trials. Conclusion Our study showed feasibility of simulating cancer trials using RWD and obtained comparable estimates to the original trial in terms of patient safety outcomes. Despite more SAEs in RWD, ratios between CAs and EAs were similar to the previously published rigorously conducted trials. Future in-depth investigations are warranted and shall consider state-of-the-art AI methods such as deep learning and causal AI methods to help tackle issues with using RWD for cancer trial simulation (e.g., data bias, high-dimensionality). Citation Format: Zhaoyi Chen, Hansi Zhang, Thomas George, Mattia Prosperi, Yi Guo, Dejana Braithwaite, Elizabeth Shenkman, Jonathan Licht, Jiang Bian. Simulation of colorectal cancer clinical trials using real-world data and machine learning [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-071.

Safety and activity of trifluridine/tipiracil and ramucirumab in previously treated advanced gastric cancer: an open-label, single-arm, phase 2 trial

Findings of preclinical and clinical trials in colorectal cancer have shown promising antitumour effects of the co-formulation trifluridine/tipiracil and VEGF inhibition. We aimed to investigate the safety and activity of trifluridine/tipiracil and ramucirumab for previously treated advanced gastric cancer. We did an open-label, single-arm, two-cohort, phase 2 study at eight centres in Japan. We enrolled patients with unresectable advanced gastric cancer or gastro-oesophageal junction adenocarcinoma. Cohort A included patients previously treated with one line of chemotherapy without ramucirumab and cohort B included patients previously treated with two to four lines of chemotherapy, including ramucirumab. Patients received trifluridine/tipiracil (35 mg/m2) orally twice daily on days 1-5 and days 8-12 of each 28-day treatment cycle, plus intravenous ramucirumab (8 mg/kg) on days 1 and 15. The primary endpoint was the disease control rate, assessed by investigators and defined as the proportion of patients with a confirmed best overall response, according to Response Evaluation Criteria in Solid Tumors version 1.1. This trial is registered on JapicCTI (JapicCTI-194596) and is ongoing but not recruiting. Between April 8 and Oct 11, 2019, 64 patients were enrolled and included in the safety and activity analyses, 33 in cohort A and 31 in cohort B. In cohort A, the disease control rate was 85% (95% CI 68-95; 28 of 33 patients) and in cohort B it was 77% (59-90; 24 of 31 patients). Common treatment-related adverse events of grade 3 or worse were neutrophil count decreased (27 [82%] in cohort A and 23 [74%] in cohort B), white blood cell count decreased (eight [24%] and seven [23%]), and platelet count decreased (eight [24%] and four [13%]). Serious treatment-related adverse events were recorded in three patients in cohort A (fatigue and neutrophil count decreased; large intestine perforation; and febrile neutropenia, platelet count decreased, and anaemia). No patients in cohort B had a serious treatment-related adverse event, and no treatment-related deaths were reported in either cohort. Trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure. Taiho Pharmaceutical and Eli Lilly.

Folate pathway gene expression in metastatic colorectal cancer patients treated with arfolitixorin/5-FU-based chemotherapy.

99 Background: Arfolitixorin is the natural, biologically active form of the marketed folates and is expected to be efficacious in a larger proportion of patients with less inter- and intra-individual variability compared with e.g. leucovorin. We have previously found a positive correlation between survival and expression of folate pathway genes in stage III/IV CRC treated with 5-fluorouracil/leucovorin (5-FU/LV). Low expression of folate-related genes may lead to poor response to 5-FU/LV-based treatment, since suboptimal transport and metabolization of LV yield insufficient active [6R]-5,10-methylenetetrahydrofolate and weak inhibition of the target enzyme thymidylate synthase (TYMS). The aim of the present study was to investigate possible confounders and biomarkers of arfolitixorin/5-FU-based treatment in relation to safety and response in a phase I/IIa metastatic colorectal cancer (mCRC) trial. Methods: ISO-CC-005 is a multi-center, phase I/IIa study in mCRC patients eligible for 5-FU/folate therapy alone or in combination with irinotecan or oxaliplatin ± bevacizumab. Patients were also treated with different doses of arfolitixorin as a single or double bolus. The study investigated safety and tolerability of arfolitixorin, and anti-tumor activity was evaluated by overall response rate (ORR) per RECIST v1.1 after 4 cycles of chemotherapy. RNA was prepared from FFPE tumor tissue, reverse transcribed and used for gene expression profiling. The following genes of interest were evaluated: ABCC3, MTHFD2, SLC46A1, SLC19A1, SLC25A32 and TYMS. An ANOVA test was used to rule out potential biases in the baseline expression levels of the genes and to assess the potential association with clinical response. Results: Eighty-one (77.1%) of 105 patients provided material for this analysis. A lower pre-treatment expression of TYMS was associated with clinical benefit (PR and SD; p = 0.021). No clear association was identified between the gene expression markers and the number of adverse events. Gender was not significantly associated with differences in gene expression. Conclusions: Low pre-treatment expression levels of TYMS were associated with clinical benefit (PR and SD) following treatment. Given the role of this gene in the folate metabolic pathways we plan to further assess its predictive potential on a larger cohort during our ongoing global phase III AGENT study. In parallel an assessment of the expression of the other candidate genes on specific patient sub-groups is currently ongoing. These studies will provide additional cues on the use of these genes as predictive markers for treatment outcome and their role in the mode of action of the drug. Clinical trial information: NCT02244632.

Selective Tumor Cell Apoptosis and Tumor Regression in CDH17-Positive Colorectal Cancer Models using BI 905711, a Novel Liver-Sparing TRAILR2 Agonist.

Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. TRAILR2 agonistic molecules have only had limited clinical success, to date, due either to lack of efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both TRAILR2 and CDH17 and represents a novel liver-sparing TRAILR2 agonist specifically designed to overcome the disadvantages of previous strategies. Here, we show that BI 905711 effectively triggered apoptosis in a broad panel of CDH17-positive colorectal cancer tumor cells in vitro. Efficient induction of apoptosis was dependent on the presence of CDH17, as exemplified by the greater than 1,000-fold drop in potency in CDH17-negative cells. BI 905711 demonstrated single-agent tumor regressions in CDH17-positive colorectal cancer xenografts, an effect that was further enhanced upon combination with irinotecan. Antitumor efficacy correlated with induction of caspase activation, as measured in both the tumor and plasma. Effective tumor growth inhibition was further demonstrated across a series of different colorectal cancer PDX models. BI 905711 induced apoptosis in both a cis (same cell) as well as trans (adjacent cell) fashion, translating into significant antitumor activity even in xenograft models with heterogeneous CDH17 expression. In summary, we demonstrate that BI 905711 has potent and selective antitumor activity in CDH17-positive colorectal cancer models both in vitro and in vivo. The high prevalence of over 95% CDH17-positive tumors in patients with colorectal cancer, the molecule preclinical efficacy together with its potential for a favorable safety profile, support the ongoing BI 905711 phase I trial in colorectal cancer and additional CDH17-positive cancer types (NCT04137289).

Phase III Radiation Oncology Clinical Trials: A Snapshot of the Last Two Decades

Modern radiation therapy is an integral modality in the treatment of cancer, yet data on the current state of Phase III radiation therapy trials remains scarce. We sought to characterize the landscape of radiation oncology phase III clinical trials in the last two decades. We searched ClinicalTrials.gov for phase III randomized controlled trials (RCTs) between 2003 and 2018. Randomized, multi-arm trials assessing a therapeutic intervention in adult cancer patients were included. Trials where radiation therapy was a main intervention were identified and grouped according to specific disease subsites and other trial information. Differences in trial factors between radiotherapy and other oncologic interventional trials were analyzed. Out of the 600 phase III RCTs identified, 15 trials were solely radiation therapy trials (2.5%). By disease subsite, we identified 3 (20%) breast cancer trials, 2 (13.3%) gastrointestinal cancer trials, 2 (13.3%) genitourinary cancer trials, 2 (13.3%) colorectal cancer trials, and 2 (13.3%) head and neck cancer trials. Radiation trials were less likely to be industry funded when compared to other oncological trials (20.0% vs 79.3% respectively, p<0.001). Furthermore, 73.3% of radiation trials had cooperative group sponsorship (vs 30.3% for other oncologic trials, p<0.001). Radiotherapy trials had less restrictions on including healthier patients (ECOG score 0 to 1) when compared to trials of systemic therapy (p<0.001). Even though radiation therapy is currently recognized as an integral modality in treating cancer patients, radiation therapy trials remain scarce and largely underfunded. Lastly, while cooperative groups seem to play an important role in radiation therapy trials, stakeholders are encouraged to assess and address ways to increase quality radiotherapy research.

Abstract 832: Construction and optimization of gene expression signatures for prediction of survival in two-arm clinical trials

Abstract Gene expression signatures for the prediction of differential survival of patients undergoing anti-cancer therapies are of great interest because they can be used to prospectively stratify patients entering new clinical trials, or to determine optimal treatment for patients in more routine clinical settings. Unlike prognostic signatures however, predictive signatures require training set data from clinical studies with at least two treatment arms, and the methodology for constructing and optimizing predictive signatures has been less prominently explored. Focusing on the “use case” of a two-arm clinical trial for metastatic colorectal cancer (CRC) patients treated with the anti-angiogenic molecule aflibercept, we present tools for the construction of signatures predictive of progression-free survival based on cross-validated multivariate Cox models. The work is organized around a specific approach called subtype correlation, which leverages a priori knowledge of molecular subtypes of tumors for a given indication. The tools and concepts presented here include the so-called differential log-hazard ratio, the survival scatter plot, the hazard ratio receiver operating characteristic, the area between curves and the patient selection matrix. In the CRC use case, the resulting signature stratifies the patient population into “sensitive” and “relatively-resistant” groups achieving a more than two-fold difference in the aflibercept-to-control hazard ratios across signature-defined patient groups. Through cross-validation and resampling the probability of generalization of the signature to similar CRC data sets is predicted to be high. The tools presented here should be of general use for building and using predictive multivariate signatures in oncology and in other therapeutic areas. Citation Format: Joachim Theilhaber, Marielle Chiron, Jennifer Dreymann, Donald Bergstrom, Jack Pollard. Construction and optimization of gene expression signatures for prediction of survival in two-arm clinical trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 832.

Bibliometric analysis of randomized controlled trials of colorectal cancer over the last decade.

BACKGROUNDColorectal cancer is one of the most common cancers globally. In China, its prevalence ranks fourth and fifth among females and males, respectively. Presently, treatment of rectal cancer follows a multidisciplinary comprehensive treatment approach involving surgery, radiotherapy, chemotherapy, and targeted therapy. With deepening theoretical and molecular research on colorectal cancer, randomized controlled trials (RCTs) on colorectal cancer have made significant progress. However, many RCTs have shortfalls.AIMTo investigate the RCTs of global colorectal cancer spanning from 2008 to 2018. To provide suggestions for conducting Chinese RCTs of colorectal cancer.METHODSPubMed and Web of Science databases were searched to obtain RCTs of colorectal cancer carried out between January 1, 2008, and January 1, 2018. The bibliometric method was used for statistical analysis of the publication years, countries/regions, authors, institutions, source journals, quoted times, key words, and authors.RESULTSColorectal cancer RCTs showed an upward trend between 2008 to 2018; the top 10 research institutions in the included literature were from the United States, the United Kingdom, and other countries with a high incidence of colorectal cancer. Most of the related research journals are sponsored by European and American countries. The 15 most cited studies involved international multicenter clinical research, having few participants from Chinese research institutions. Network visualization using key words showed that RCTs on colorectal cancer focus on screening, disease-free survival, drug treatment, surgical methods, clinical trials, quality of life, and prognosis. The result of the coauthorship network analysis showed that Chinese researchers are less involved in international exchanges compared to those from leading publication countries.CONCLUSIONHigh-quality RCTs are increasingly favored by leading international journals. However, there is still a large gap in clinical research between China and leading countries. Researchers should implement standardized and accurate clinical trials, strengthen international multicenter cooperation, and emphasize quality control.

Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with panitumumab-based first-line treatment strategy: A pre-specified secondary analysis of the Valentino study

BackgroundQuality of life (QoL) patient-reported outcomes (PROs) data from pivotal first-line trials in metastatic colorectal cancer (mCRC) are poor. The Valentino study showed that de-escalation to single-agent panitumumab after 4-month induction with panitumumab-FOLFOX is inferior to panitumumab-5-FU/LV in patients with RAS wild-type mCRC, although slightly reducing toxicity. We report QoL, a secondary end-point. MethodsPROs were assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQ-C30), EORTC QLQ-CR29, EuroQol EQ-5D questionnaires, at baseline and every 8 weeks until disease progression. First two evaluations correspond to induction treatment (identical in both arms), while subsequent to maintenance. To describe QoL changes over time, mean changes from baseline at each time point were calculated in overall population. To compare maintenance between two arms, mean changes and proportion of improved/stable/worse patients versus baseline were compared for each item. ResultsIn arm A/B, 91.5%/92.0% of enrolled patients completed questionnaires at baseline. No significant differences in the two arms were reported in compliance, baseline scores and mean changes versus baseline for the three questionnaires during maintenance (24/32/40 weeks). Overall, mean changes versus baseline showed an early deterioration during induction with partial recovering during maintenance for global QoL, functional scales and several symptoms/items of QLQ-C30 (fatigue, nausea/vomiting, appetite loss, diarrhoea) and QLQ-CR29 (body image, dry mouth, hair loss, taste, faecal incontinence, sore skin), and EQ-5D Visual Analogue Scale (VAS) score. ConclusionIn patients with RAS wild-type mCRC, induction with oxaliplatin-containing chemotherapy plus anti-EGFRs induces a transient significant QoL deterioration. After induction phase, treatment deintensification determines an overall recovery of health-related QoL, besides the expected prevention of oxaliplatin-related neurotoxicity.

Evaluating Discrimination of a Lung Cancer Risk Prediction Model Using Partial Risk-Score in a Two-Phase Study.

Independent validation of risk prediction models in prospective cohorts is required for risk-stratified cancer prevention. Such studies often have a two-phase design, where information on expensive biomarkers are ascertained in a nested substudy of the original cohort. We propose a simple approach for evaluating model discrimination that accounts for incomplete follow-up and gains efficiency by using data from all individuals in the cohort irrespective of whether they were sampled in the substudy. For evaluating the AUC, we estimated probabilities of risk-scores for cases being larger than those in controls conditional on partial risk-scores, computed using partial covariate information. The proposed method was compared with an inverse probability weighted (IPW) approach that used information only from the subjects in the substudy. We evaluated age-stratified AUC of a model including questionnaire-based risk factors and inflammation biomarkers to predict 10-year risk of lung cancer using data from the Prostate, Lung, Colorectal, and Ovarian Cancer (1993-2009) trial (30,297 ever-smokers, 1,253 patients with lung cancer). For estimating age-stratified AUC of the combined lung cancer risk model, the proposed method was 3.8 to 5.3 times more efficient compared with the IPW approach across the different age groups. Extensive simulation studies also demonstrated substantial efficiency gain compared with the IPW approach. Incorporating information from all individuals in a two-phase cohort study can substantially improve precision of discrimination measures of lung cancer risk models. Novel, simple, and practically useful methods are proposed for evaluating risk models, a critical step toward risk-stratified cancer prevention.

Quality of adverse event reporting in phase III randomized controlled trials of breast and colorectal cancer: A systematic review.

BackgroundClinical trial reports often emphasize efficacy over harms, leading to misinterpretation of the risk‐to‐benefit ratio of new therapies. Clear and sufficiently detailed reporting of methods and results is especially important in the abstracts of trial reports, as readers often base their assessment of a trial on such information. In this study, we evaluated the quality of adverse event (AE) reporting and abstract quality in phase III randomized controlled trials (RCTs) of systemic therapies in breast and colorectal cancer.MethodsMedline, EMBASE, Cochrane Database of RCTs, and Cochrane Database of Systematic Reviews were searched from November 2005 to September 2018. Phase III RCTs evaluating systemic therapies in breast or colorectal cancer were included. Each article was independently reviewed by two investigators using a standardized data extraction form based on guidelines developed by the Consolidated Standards of Reporting Trials (CONSORT) group. Descriptive statistics, bivariate analysis, and multivariable linear regression were used to analyze data. All statistical tests were two‐sided.ResultsOf 166 RCTs identified, 99.4% reported harms in the manuscript body, and 59.6% reported harms in the abstract. Reporting was restricted to severe harms in 15.6% of RCTs. Statistical comparison of AE rates went unreported in 59.0% of studies. Information regarding AEs leading to dose reductions, treatment discontinuations, or study withdrawals went unreported in 59.3%, 18.7%, and 86.8% of studies, respectively. Recently published RCTs (P = .009) and those sponsored at least partially by for‐profit companies (P = .003) had higher abstract quality scores.ConclusionsBreast and colorectal cancer phase III RCTs inadequately report CONSORT‐compliant AE data. Improved guideline adherence and abstract reporting is required to properly weigh benefits and harms of new oncologic therapies.Systematic Review Registration NumberCRD42019140673.

A Bayesian approach for analyzing partly interval-censored data under the proportional hazards model.

Partly interval-censored time-to-event data often occur in biomedical studies of diseases where periodic medical examinations for symptoms of interest are necessary. Recent decades have seen blooming methods and R packages for interval-censored data; however, the research effort for partly interval-censored data is limited. We propose an efficient and easy-to-implement Bayesian semiparametric method for analyzing partly interval-censored data under the proportional hazards model. Two simulation studies are conducted to compare the performance of the proposed method with two main Bayesian methods currently available in the literature and the classic Cox proportional hazards model. The proposed method is applied to a partly interval-censored progression-free survival data from a metastatic colorectal cancer trial.

The landscape of gastrointestinal oncologic phase III clinical trials in the last two decades.

e14087 Background: Gastrointestinal (GI) cancers are among the most common cancers in adult patients. The prognosis of GI cancers differs widely between specific subsites, with some cancers having excellent prognoses, and others (such as pancreatic and hepatobiliary cancers) having an extremely poor prognosis. We sought to characterize the landscape of GI oncologic clinical trials in the last two decades. Methods: We searched ClinicalTrials.gov for phase III RCTs between 2003 and 2018. Randomized multi-arm trials assessing a therapeutic intervention in adult cancer patients were included. GI cancer trials were identified and grouped into specific disease subsites. Differences in trial factors between GI and non-GI trials and between different GI subsites were analyzed. Results: Out of the 600 RCTs identified, 76 trials assessed gastrointestinal cancers (12.7%). By disease subsite, we identified 21 (27.6%) gastro-esophageal cancer trials, 12 (15.8%) pancreatic cancer trials, 11 (14.5%) hepatobiliary cancer trials, and 32 (42.1%) colorectal cancer trials. GI cancer trials were more likely to be industry funded when compared to non-GI cancer trials (88.2% vs 76.3% respectively, p = 0.02). Furthermore, only 18.4% of GI trials had cooperative group sponsorship (vs 33.3% for non-GI trials, p = 0.01). Most GI cancer trials assessed systemic therapy interventions (85.5%); only 6 trials (7.9%) addressed supportive care interventions (vs 20.2% for non-GI trials, p = 0.01). Around half of GI cancer trials (51.3%) met their primary endpoints, but only 8 trials (10.5%) led to subsequent FDA approval. All FDA approvals were for colorectal cancer treatments, and none for gastroesophageal, pancreatic or hepatobiliary cancers (p = 0.01). Most patients (97.1%) accrued on GI cancer trials had a good performance status (Eastern Cooperative Oncology Group of 0 to 1). Specifically, 95.9% of patients in pancreatic trials and 98.6% of patients in hepatobiliary trials had a good performance status. Conclusions: While many GI cancers have a poor prognosis, very few trials assess supportive care interventions in this populations. Moreover, most patients included in GI cancer trials have a good performance status. In that regard, future GI cancer trials addressing supportive care measures with a wider cancer population are still warranted.

Identification of 102 Correlations between Serum Metabolites and Habitual Diet in a Metabolomics Study of the Prostate, Lung, Colorectal, and Ovarian Cancer Trial

Metabolomics has proven useful for detecting objective biomarkers of diet that may help to improve dietary measurement. Studies to date, however, have focused on a relatively narrow set of lipid classes. The aim of this study was to uncover candidate dietary biomarkers by identifying serum metabolites correlated with self-reported diet, particularly metabolites in underinvestigated lipid classes, e.g. triglycerides and plasmalogens. We assessed dietary questionnaire data and serum metabolite correlations from 491 male and female participants aged 55-75 y in an exploratory cross-sectional study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Self-reported intake was categorized into 50 foods, food groups, beverages, and supplements. We examined 522 identified metabolites using 2 metabolomics platforms (Broad Institute and Massachusetts General Hospital). Correlations were identified using partial Pearson's correlations adjusted for age, sex, BMI, smoking status, study site, and total energy intake [Bonferroni-corrected level of 0.05/(50×522) = 1.9×10-6]. We assessed prediction of dietary intake by multiple-metabolite linear models with the use of 10-fold crossvalidation least absolute shrinkage and selection operator (LASSO) regression. Eighteen foods, beverages, and supplements were correlated with ≥1 serum metabolite at the Bonferroni-corrected significance threshold, for a total of 102 correlations. Of these, only 5 have been reported previously, to our knowledge. Our strongest correlations were between citrus and proline betaine (r=0.55), supplements and pantothenic acid (r=0.46), and fish and C40:9phosphatidylcholine (PC) (r=0.35). The multivariate analysis similarly found reasonably large correlations between metabolite profiles and citrus (r=0.59), supplements (r=0.57), and fish (r=0.44). Our study of PLCO participants identified many novel food-metabolite associations and replicated 5 previous associations. These candidate biomarkers of diet may help to complement measures of self-reported diet in nutritional epidemiology studies, though further validation work is still needed.

Developing an FHIR-Based Computational Pipeline for Automatic Population of Case Report Forms for Colorectal Cancer Clinical Trials Using Electronic Health Records.

PURPOSEThe Fast Healthcare Interoperability Resources (FHIR) is emerging as a next-generation standards framework developed by HL7 for exchanging electronic health care data. The modeling capability of FHIR in standardizing cancer data has been gaining increasing attention by the cancer research informatics community. However, few studies have been conducted to examine the capability of FHIR in electronic data capture (EDC) applications for effective cancer clinical trials. The objective of this study was to design, develop, and evaluate an FHIR-based method that enables the automation of the case report forms (CRFs) population for cancer clinical trials using real-world electronic health records (EHRs).MATERIALS AND METHODSWe developed an FHIR-based computational pipeline of EDC with a case study for modeling colorectal cancer trials. We first leveraged an existing FHIR-based cancer profile to represent EHR data of patients with colorectal cancer, and then we used the FHIR Questionnaire and QuestionnaireResponse resources to represent the CRFs and their data population. To test the accuracy of and overall quality of the computational pipeline, we used synoptic reports of 287 Mayo Clinic patients with colorectal cancer from 2013 to 2019 with standard measures of precision, recall, and F1 score.RESULTSUsing the computational pipeline, a total of 1,037 synoptic reports were successfully converted as the instances of the FHIR-based cancer profile. The average accuracy for converting all data elements (excluding tumor perforation) of the cancer profile was 0.99, using 200 randomly selected records. The average F1 score for populating nine questions of the CRFs in a real-world colorectal cancer trial was 0.95, using 100 randomly selected records.CONCLUSIONWe demonstrated that it is feasible to populate CRFs with EHR data in an automated manner with satisfactory performance. The outcome of the study provides helpful insight into future directions in implementing FHIR-based EDC applications for modern cancer clinical trials.

Endogenous estradiol and inflammation biomarkers: potential interacting mechanisms of obesity-related disease.

Disentangling the effects of endogenous estrogens and inflammation on obesity-related diseases requires a clearer understanding of how the two biological mechanisms relate to each other. We studied 155 healthy postmenopausal women not taking menopausal hormone therapy enrolled in the Prostate Lung Colorectal and Ovarian (PLCO) screening cancer trial. From a baseline blood draw, we measured endogenous estradiol and 69 inflammation biomarkers: cytokines, chemokines, adipokines, angiogenic factors, growth factors, acute phase proteins, and soluble receptors. We evaluated the estradiol-inflammation relationship by assessing associations across different models (linear, ordinal logistic, and binary logistic) using a variety of estradiol classifications. We additionally investigated the estradiol-inflammation relationship stratified by baseline obesity status (BMI < 30 stratum and BMI > 30 stratum). Associations of estradiol with 7 inflammation biomarkers met p < 0.05 statistical significance in linear and ordinal models: C-reactive protein (CRP), adiponectin, chemokine (C-X-C motif) ligand-6, thymus activation-regulated chemokine, eosinophil chemotactic protein, plasminogen activator inhibitor-1, and serum amyloid A. The positive association between estradiol and CRP was robust to model changes. Each standard deviation increase in endogenous estradiol doubled a woman's odds of having CRP levels higher than the study median (odds ratio 2.29; 95% confidence interval 1.28, 4.09). Estradiol was consistently inversely associated with adiponectin. Other estradiol-inflammation biomarker associations were not robust to model changes. Endogenous estradiol appears to be associated with CRP and adiponectin; the evidence is limited for other inflammation biomarkers.

Prognostic and predictive impact of primary tumor sidedness in first-line trials for advanced colorectal cancer: An analysis of 7,828 patients in the ARCAD database.

188 Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the prognostic and predictive impact of PTS on outcomes. Methods: PTS data of 7,828 mCRC patients (pts) from 10 first-line randomized trials in the ARCAD database were pooled. PTS was defined as right-sided (RS) or left-sided (LS) if tumor arose from the cecum to the hepatic flexure or from the splenic flexure to the rectum, respectively; transverse colon cancers were not included. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status (PS), prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (anti-EGFR plus chemotherapy vs. chemotherapy alone). Results: Compared to RS pts (2407, 31%), LS pts (5421, 69%) had better OS (median: 21.6 v 16.8 mos; HRadj: 0.73, 95% CI 0.69-0.78, P &lt; .001) and PFS (median 8.4 v 7.2 mos; HRadj: 0.81, 95% CI 0.76-0.86, P &lt; .001). Results were consistent among subgroups defined by age, sex, PS, metastatic sites and chemo backbone (irinotecan- and oxaliplatin-based). Interaction between PTS and KRAS mutation was significant (Pinteraction&lt; .001): LS is associated with better prognosis only among KRAS wild-type (wt) (HRadj: OS 0.62, 95% CI, 0.55-0.70; PFS 0.71, 95% CI 0.63-0.80), but not among KRAS mutated pts. Among KRAS wt pts, survival benefit from anti-EGFR was observed for LS, but not for RS (table). Conclusions: The prognostic value of PTS is restricted to the KRAS wt population. PTS is predictive of anti-EGFR efficacy, with a significant improvement of survival for LS mCRC pts. These results suggest treatment stratification in mCRC studies by both PTS and KRAS status. [Table: see text]

Informing metastatic colorectal cancer patients by quantifying multiple scenarios for survival based on real-life data.

32 Background: Reported median overall survival (mOS) in trials of metastatic colorectal cancer (mCRC) patients receiving systemic therapy has increased to over 30 months. When informing patients, many clinicians quote the mOS reported in these trials. It is uncertain whether trial results translate to real-life populations. Moreover, patients prefer presentation of multiple survival scenarios over presentation of just mOS. Therefore, we quantified multiple scenarios for survival time of real-life mCRC patients. Methods: Nationwide population-based data of all stage IV CRC patients diagnosed between 2008 and 2016 were obtained from the Netherlands Cancer Registry. We calculated percentiles (scenarios) of OS per year of diagnosis for the total population, and for treatment subgroups: 10th (best-case), 25th (upper-typical), 50th (median), 75th (lower-typical), and 90th (worst-case). Results: The total study population comprised 27,275 patients. Twenty-five percent these patients did not receive any antitumor treatment. From 2008-2016, mOS of the total population remained unchanged at approximately 12 months. OS improved only for the upper-typical and best-case patients; by 4.2 to 29.1 months (p&lt;0.001), and by 6.0 months to 62.0 months (p&lt;0.001), respectively. No clinically relevant change was seen among patients who received systemic therapy, with mOS close to 15 months and best-case scenario approximately 40 months. mOS and worst-case scenario for survival were highest in patients who underwent both metastasectomy and systemic therapy: around 48 and 15 months, respectively. A clinically relevant improvement in survival over time was observed only in patients who initially received metastasectomy without systemic treatment. Conclusions: In contrast to the wide belief that mOS of mCRC patients receiving systemic therapy has improved substantially, improvement could not be demonstrated in our real-life population. Clinicians should consider quoting multiple scenarios for survival based on real-life data, instead of point estimates from clinical trials, when informing patients about their life expectancy.

Quality of life assessment and reporting in colorectal cancer: A systematic review of phase III trials published between 2012 and 2018.

In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials. We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals. Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints. QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.

Outcomes Among Minority Patients With Metastatic Colorectal Cancer in a Safety-net Health Care System

BackgroundMetastatic colorectal cancer (CRC) outcomes continue to improve, but they vary significantly by race and ethnicity. We hypothesize that these disparities arise from unequal access to care. Materials and MethodsThe Harris Health System (HHS) is an integrated health delivery network that provides medical care to the underserved, predominantly minority population of Harris County, Texas. As the largest HHS facility and an affiliate of Baylor College of Medicine’s Dan L. Duncan Comprehensive Cancer Center, Ben Taub Hospital (BTH) delivers cancer care through multidisciplinary subspecialty that prioritize access to care, adherence to evidence-based clinical pathways, integration of supportive services, and mitigation of financial toxicity. We performed a retrospective analysis of minority patients diagnosed with and treated for metastatic CRC at BTH between January 2010 and December 2012. Kaplan-Meier survival curves were compared with survival curves from randomized control trials reported during that time period. ResultsWe identified 103 patients; 40% were black, 49% were Hispanic, and 12% were Asian or Middle Eastern. Thirty-five percent reported a language other than English as their preferred language. Seventy-four percent of patients with documented coverage status were uninsured. Eighty-four percent of patients received standard chemotherapy with a clinician-reported response rate of 63%. Overall survival for BTH patients undergoing chemotherapy was superior to that of subjects enrolled in the CRYSTAL (Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial (median, 24.0 vs. 19.9 months; P = .014). ConclusionHHS provides a health delivery infrastructure through which minority patients with socioeconomic challenges experience clinical outcomes comparable with highly selected patients enrolled in randomized control trials. Efforts to resolve CRC disparities should focus on improving access of at-risk populations to high-quality comprehensive cancer care.

Methylomic Biomarkers for Magnesium Deficiency in the Personalized Prevention of Colorectal Cancer Trial

Methylomic Biomarkers for Magnesium Deficiency in the Personalized Prevention of Colorectal Cancer Trial