Citations

PURPOSE: In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. MATERIALS AND METHODS: Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. RESULTS: MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. CONCLUSION: Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

Abstract Background: Cetuximab, an EGFR inhibitor used to treat multiple cancer types, including colon cancer, causes severe skin toxicity in 5%–20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity. Methods: Our study included 1,209 patients with stage III colon cancer randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating approximately 10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade ≥ 3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as P < 5 × 10−8. Results: Participants were predominantly middle-aged white men; 20% (n = 243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity [OR, 3.93; 95% confidence interval (CI), 2.47–6.25; P < 7.8 × 10−9]. Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions. Conclusions: Identified variants could represent a potential target for risk stratification of patients with colon cancer receiving cetuximab. Impact: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.

Background Current adverse event reporting practices do not document longitudinal characteristics of adverse effects, and alternative methods are not easily interpretable and have not been employed by clinical trials. Introducing time parameters in the evaluation of safety that are comprehensive yet easily interpretable could allow for a better understanding of treatment quality. In this study, we developed and applied a novel adverse event reporting method based on longitudinal adverse event changes to aid describing, summarizing, and presenting adverse event profile. We termed it the “Adverse Event Load, Onset, and Maximum Grade” method. Methods We developed two adverse event summary metrics to complement the traditional maximum grade report. Onset time indicates the time period in which the maximum grade for a specific adverse event occurred and was defined as “early” (i.e. maximum grade happened for the first time before 6 weeks) or “late” (i.e. after the 6 th week). Adverse event load indicates the overall severity of a specific adverse event over the entire treatment. Higher adverse event load indicates a worse overall experience. These metrics can be calculated for adverse events with different maximum grades, in treatments with planned changes (e.g. dosage changes), using data sets with different number of adverse event data points between treatments (e.g. treatments with longer cycle lengths may have less adverse event data points) and on data sets with different adverse event data availability (e.g. cycle basis and patient-outcome reports). We tested the utility of this method using individual patient data from two major backbone therapies (“Irinotecan” and “Oxaliplatin”) from the N9741 trial available in the Fondation ARCAD database ( fondationarcad.org ). We investigated profiles of diarrhea, neutropenia/leukopenia, and nausea/vomiting. Results Our method provided additional information compared to traditional adverse event reports. For example, for nausea/vomiting, while patients in Irinotecan had a higher risk of experiencing maximum grade 3–4 (15.6% vs 7.6%, respectively; p < 0.001), patients in both groups experienced similar severity over time (adverse effect load = 0.102 and 0.096, respectively; p = 0.26), suggesting that patients in Oxaliplatin experienced a lower-grade but more persistent nausea/vomiting. For neutropenia/leukopenia, more patients in Irinotecan experienced their maximum grade for the first time early in the treatment compared to patients in Oxaliplatin (67.9% vs 41.7%; p < 0.001), regardless of maximum grade. Longitudinal information can help compare treatments or guide clinicians on choosing appropriate interventions for low-grade but persistent adverse event or early adverse event onset. Conclusion We developed an adverse event reporting method that provides clinically relevant information about treatment toxicity by incorporating two longitudinal adverse event metrics to the traditional maximum grade approach. Future research should establish clinical benchmarks for metrics included in this adverse event reporting method.

Abstract Background Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. Methods The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). Results Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P &lt; .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P &lt; .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P &lt; .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P &lt; .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P &lt; .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P &lt; .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P &lt; .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P &lt; .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P &lt; .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P &lt; .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P &lt; .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P &lt; .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P &lt; .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P &lt; .001]) were observed, with women being consistently at increased risk. Conclusions Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

AbstractBackgroundEnergy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.MethodsBaseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.ResultsMedian follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity &lt; .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend &lt; .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend &lt; .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03).ConclusionsAmong patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

AbstractThe WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system.

7009 Background: Survival outcomes of 2nd line mCRC therapy for OA are poorly understood. We evaluated the rates and survival outcomes of 2nd line therapy among OA age 70+ compared to younger adults (YA) age < 70 following progression on 1st line clinical trials. Methods: Associations between clinical characteristics of pts with available treatment data after progression on 10 of 23 1st line ARCAD trials, time to initial progression (TTiP) and 2nd line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA enrolled on 2nd line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: Sixteen percent of 1st line ARCAD trial participants were age 70+ (n = 870). Data for 2nd line therapy was available for 60.6% pts (3206/5289). Each additional decade of life was associated with 11% lower odds of receiving 2nd line therapy in multivariate analysis (p = 0.0117). OA participating in 2nd line trials (7.9% age 75+ of 7921) experience similar TTP and OS to YA (mTTP: 5.1 vs. 5.2mos; mOS 11.6 vs 12.4mos, respectively). Conclusions: We did not observe a statistical difference in survival outcomes by age following 2nd line mCRC therapy. Further study is needed to examine unmeasured comorbidity and use of geriatric assessment to select OA likely to benefit from 2nd line therapy. [Table: see text]

e16076 Background: Median overall survival (mOS) of patients (pt) with metastatic colorectal cancer (mCRC) has improved steadily over the past two decades. However, epidemiological data suggest that cancer outcomes for rural compared to urban dwelling pts are worse. In this study, we retrospectively compared progression free survival (PFS) and OS among mCRC pts residing in urban versus rural areas enrolled in N9741 (1997-2004) and CALGB 80405 (2005-2012) clinical trials. Methods: Zip code data from the Centers for Disease Control (CDC) were used to classify pts into rural or urban dwellers. Chi-square and Kruskal Wallis analyses were used to compare the groups. Survival outcomes were evaluated using Kaplan-Meier estimates, compared by stratified log rank and cox proportional hazards models. Results: In N9741 and 80405 respectively, 217 (35%) and 521 (21%) pts resided in rural areas. Median age of mCRC pts at diagnosis was 60.5 yrs. (rural) compared to 58.6 yrs. (urban) in 80405 (P < 0.01) and 59.6 yrs. to 60.2 yrs. in N9741 (P = 0.4). In 80405, pts in rural areas were less likely to be female (35% vs 43%, P < 0.01) black (6.6% vs 15.1%, P < 0.01), unmarried (51% vs 62%, P < 0.01), and to have private insurance (PI) (45% vs 50%, P = 0.03) when compared to pts in urban areas. In N9741, gender (P = 0.8) and PI (P = 0.3) distribution was similar; pts in rural areas were less likely to be black (1.4% vs 9.1%, P < 0.01). Rural vs urban pt PFS was no different in either trial. MOS was worse in pts in rural areas when compared to urban dwellers in 80405 (Table). OS outcomes stratified based on the use of cetuximab based regimen in 80405 showed worse outcomes for pts in rural compared to urban dwellers (21.9 vs 26.3 mo. HR: 1.22 (1.03-1.44), P = 0.02). Conclusions: MCRC pts from rural areas had a significantly worse mOS when compared to pts in urban areas in 80405. Furthermore, mOS with cetuximab based regimens was 4.4 months shorter in rural pts. The observed rural vs urban dweller mOS disparities in 80405 pts justifies additional research searching for causal factors and the necessity to identify actionable approaches in order to improve pt outcomes in rural areas. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA180830; Pfizer, Sanofi, BMS, Genentech, https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00003594, NCT00265850. [Table: see text]