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National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC.

SUBMITTER: George TJ

PROVIDER: S-EPMC6663584 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

George Thomas J TJ Franke Aaron J AJ Chakravarthy A Bapsi AB Das Prajnan P Dasari Arvind A El-Rayes Bassel F BF Hong Theodore S TS Kinsella Timothy J TJ Landry Jerome C JC Lee James J JJ Monjazeb Arta M AM Jacobs Samuel A SA Raben David D Rahma Osama E OE Williams Terence M TM Wu Christina C Coleman C Norman CN Vikram Bhadrasain B Ahmed Mansoor M MM

Cancer 20190424 16

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and patholo ...[more]

PMID: 31017664

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Project description:PurposeTherapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols.Patients and methodsTumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared.ResultsMolecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so.ConclusionWe demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.

Project description:One of the underpinning elements to support evidence-based decision-making in food and nutrition is the usual dietary intake of a population. It represents the long-run average consumption of a particular dietary component (i.e., food or nutrient). Variations in individual eating habits are observed from day-to-day and between individuals. The National Cancer Institute (NCI) method uses statistical modeling to account for these variations in estimation of usual intakes. This method was originally developed for nutrition survey data in the United States. The main objective of this study was to apply the NCI method in the analysis of Canadian nutrition surveys. Data from two surveys, the 2004 and 2015 Canadian Community Health Survey-Nutrition were used to estimate usual dietary intake distributions from food sources using the NCI method. The effect of different statistical considerations such as choice of the model, covariates, stratification compared to pooling, and exclusion of outliers were assessed, along with the computational time to convergence. A flowchart to aid in model selection was developed. Different covariates (e.g., age/sex groups, cycle, weekday/weekend of the recall) were used to adjust the estimates of usual intakes. Moreover, larger differences in the ratio of within to between variation for a stratified analysis or a pooled analysis resulted in noticeable differences, particularly in the tails of the distribution of usual intake estimates. Outliers were subsequently removed when the ratio was larger than 10. For an individual age/sex group, the NCI method took 1 h-5 h to obtain results depending on the dietary component. Early experience in using the NCI method with Canadian nutrition surveys data led to the development of a flowchart to facilitate the choice of the NCI model to use. The ability of the NCI method to include covariates permits comparisons between both 2004 and 2015. This study shows that the improper application of pooling and stratification as well as the outlier detection can lead to biased results. This early experience can provide guidance to other researchers and ensures consistency in the analysis of usual dietary intake in the Canadian context.

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National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

Publications

National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

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