Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status.

OBJECTIVE: To test hypotheses that appendectomy history might lower long-term colorectal cancer risk and that the risk reduction might be strong for tumors enriched with Fusobacterium nucleatum, bacterial species implicated in colorectal carcinogenesis. BACKGROUND: The absence of the appendix, an immune system organ and a possible reservoir of certain pathogenic microbes, may affect the intestinal microbiome, thereby altering long-term colorectal cancer risk. METHODS: Utilizing databases of prospective cohort studies, namely the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of appendectomy history with colorectal cancer incidence overall and subclassified by the amount of tumor tissue Fusobacterium nucleatum​​ (Fusobacterium animalis). We used an inverse probability weighted multivariable-adjusted duplication-method Cox proportional hazards regression model. RESULTS: During the follow-up of 139,406 participants (2,894,060 person-years), we documented 2811 incident colorectal cancer cases, of which 1065 cases provided tissue F. nucleatum analysis data. The multivariable-adjusted hazard ratio of appendectomy for overall colorectal cancer incidence was 0.92 (95% CI, 0.84-1.01). Appendectomy was associated with lower F. nucleatum-positive cancer incidence (multivariable-adjusted hazard ratio, 0.53; 95% CI, 0.33-0.85; P=0.0079), but not F. nucleatum-negative cancer incidence (multivariable-adjusted hazard ratio, 0.98; 95% CI, 0.83-1.14), suggesting a differential association by F. nucleatum status (Pheterogeneity=0.015). This differential association appeared to persist in various participant/patient strata including tumor location and microsatellite instability status. CONCLUSIONS: Appendectomy likely lowers the future long-term incidence of F. nucleatum-positive (but not F. nucleatum-negative) colorectal cancer. Our findings do not support the existing hypothesis that appendectomy may increase colorectal cancer risk.

Identifying modifiable risk factors to prevent aggressive colorectal cancer.

It remains unclear if pre-diagnostic factors influence the developmental pathways of colorectal cancer (CRC) that could enhance tumor aggressiveness. This study used prospective data from 205,489 cancer-free US health professionals to investigate the associations of 31 known or putative risk factors with the risk of aggressive CRC. Tumor aggressiveness was characterized by three endpoints: aggressive CRC (cancer that causes death within 5 years of diagnosis), fatal CRC, and tumor stage at diagnosis. The data augmentation method was used to assess the difference in the associations between risk factors and endpoints. We documented 3201 CRC cases, of which 899 were aggressive. The protective associations of undergoing lower endoscopy (hazard ratios [HR] 0.43, 95% confidence interval (CI) 0.37, 0.49 for aggressive versus HR 0.61, 95% CI 0.56, 0.67 for non-aggressive) and regular use of aspirin (HR 0.70, 95% CI 0.61, 0.81 versus HR 0.84, 95% CI 0.77, 0.92) were stronger for aggressive than non-aggressive CRC (pHeterogeneity <0.05). Lower intake of whole grains or cereal fiber and greater dietary inflammatory potential were associated with a higher risk of aggressive but not non-aggressive CRC. The remaining risk factors showed comparable associations with aggressive CRC and non-aggressive CRC. Aggressive cases were more likely to have KRAS-mutated tumors but less likely to have distal or MSI-high tumors (p < .007). Similar results were observed for fatal CRC and advanced tumor stages at diagnosis. These findings provide initial evidence for the role of pre-diagnostic risk factors in the pathogenesis of aggressive CRC and suggest research priorities for preventive interventions.

Ultra-processed food consumption and mortality among patients with stages I-III colorectal cancer: a prospective cohort study.

Background: Ultra-processed foods (UPFs) are emerging as a risk factor for colorectal cancer (CRC), yet how post-diagnostic UPF intake may impact CRC prognosis remains unexplored. Methods: Data collected from food frequency questionnaires were used to estimate intakes of total UPFs and UPF subgroups (serving/d) at least 6 months but less than 4 years post-diagnosis among 2498 patients diagnosed with stages I-III CRC within the Nurses' Health Study and Health Professionals Follow-up Study during 1980-2016. Hazard ratios (HR) and 95% confidence intervals (CIs) of all-cause, CRC- and cardiovascular disease (CVD)-specific mortality in association with UPF consumption were estimated using an inverse probability weighted multivariable Cox proportional hazards regression model, adjusted for confounders. Findings: The mean (SD) age of patients at diagnosis was 68.5 (9.4) years. A total of 1661 deaths were documented, including 321 from CRC and 335 from CVD. Compared to those in the lowest quintile (median = 3.6 servings/d), patients in the highest quintile (median = 10 servings/d) of post-diagnostic UPF intake had higher CVD mortality (HR = 1.65, 95% CI = 1.13-2.40) but not CRC or all-cause mortality. Among UPF subgroups, higher consumption of fats/condiments/sauces was associated with a higher risk of CVD-specific mortality (highest vs. lowest quintile of intake, HR = 1.96, 95% CI = 1.41-2.73), and higher intake of ice cream/sherbet was associated with an increased risk of CRC-specific mortality (highest vs. lowest quintile, HR = 1.86, 95% CI: 1.33-2.61). No statistically significant association was found between UPF subgroups and overall mortality. Interpretation: Higher post-diagnostic intake of total UPFs and fats/condiments/sauces in CRC survivors is associated with higher CVD mortality, and higher ice cream/sherbet intake is linked to higher CRC mortality. Funding: US National Institutes of Health and the American Cancer Society.

Oxaliplatin-Based Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 12 Trials.

PURPOSE: A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS: We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS: A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION: In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Radiation Therapy Quality Assurance Analysis of Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX Plus Hypofractionated Radiation Therapy for Borderline Resectable Adenocarcinoma of the Pancreas.

PURPOSE: Alliance A021501 is the first randomized trial to evaluate stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy. In this post hoc study, we reviewed the quality of radiation therapy (RT) delivered. METHODS AND MATERIALS: SBRT (6.6 Gy × 5) was intended but hypofractionated RT (5 Gy × 5) was permitted if SBRT specifications could not be met. Institutional credentialing through the National Cancer Institute-funded Imaging and Radiation Oncology Core (IROC) was required. Rigorous RT quality assurance (RT QA) was mandated, including pretreatment review by a radiation oncologist. Revisions were required for unacceptable deviations. Additionally, we performed a post hoc RT QA analysis in which contours and plans were reviewed by 3 radiation oncologists and assigned a score (1, 2, or 3) based on adequacy. A score of 1 indicated no deviation, 2 indicated minor deviation, and 3 indicated a major deviation that could be clinically significant. Clinical outcomes were compared by treatment modality and by case score. RESULTS: Forty patients were registered to receive RT (1 planned but not treated) at 27 centers (18 academic and 9 community). Twenty-three centers were appropriately credentialed for moving lung/liver targets and 4 for static head and neck only. Thirty-two of 39 patients (82.1%) were treated with SBRT and 7 (17.9%) with hypofractionated RT. Five cases (13%) required revision before treatment. On post hoc review, 23 patients (59.0%) were noted to have suboptimal contours or plan coverage, 12 (30.8%) were scored a 2, and 11 (28.2%) were scored a 3. There were no apparent differences in failure patterns or surgical outcomes based on treatment technique or post hoc case score. Details related to on-treatment imaging were not recorded. CONCLUSIONS: Despite rigorous QA, we encountered variability in simulation, contouring, plan coverage, and dose on trial. Although clinical outcomes did not appear to have been affected, findings from this analysis serve to inform subsequent PDAC SBRT trial designs and QA requirements.

Postoperative chemotherapy relative dose intensity and overall survival in patients with colon cancer.

PURPOSE: Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of potential clinical benefit. METHODS: This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR). RESULTS: Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death [HR: 1.20 (95% CI: 1.08, 1.52)], whereas an increase in RDI from 85 to 95% was not associated with the risk of death [HR: 1.06 (95% CI: 0.82, 1.38)]. CONCLUSION: If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population.

Metabolomic signatures of inflammation and metabolic dysregulation in relation to colorectal cancer risk.

BACKGROUND: Inflammation and metabolic dysregulation are associated with increased risk of colorectal cancer (CRC); the underlying mechanisms are not fully understood. We characterized metabolomic signatures of inflammation and metabolic dysregulation and evaluated the association of the signatures and individual metabolites with CRC risk. METHODS: Among 684 incident CRC cases and 684 age-matched controls in the Nurses' Health Study (n = 818 women) and Health Professionals Follow-up Study (n = 550 men), we applied reduced rank and elastic net regression to 277 metabolites for markers of inflammation (CRP, IL6, TNFRSF1B, and GDF15) or metabolic dysregulation (body mass index, waist circumference, C-peptide, and adiponectin) to derive metabolomic signatures. We evaluated the association of the signatures and individual metabolites with CRC using multivariable conditional logistic regression. All statistical tests were 2-sided. RESULTS: We derived a signature of 100 metabolites that explained 24% of variation in markers of inflammation and a signature of 73 metabolites that explained 27% of variation in markers of metabolic dysregulation. Among men, both signatures were associated with CRC (odds ratio per 1-standard deviation increase, inflammation = 1.34, 95% confidence interval 1.07 to 1.68; metabolic dysregulation = 1.25, 1.00 to 1.55); neither signature was associated with CRC in women. Eleven metabolites were individually associated with CRC and biomarkers of inflammation or metabolic dysregulation among either men or women. CONCLUSION: We derived metabolomic signatures and identified individual metabolites associated with inflammation, metabolic dysregulation, and CRC, highlighting several metabolites as promising candidates involved in the inflammatory and metabolic dysregulation pathways for CRC incidence.

RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer.

PURPOSE: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known. EXPERIMENTAL DESIGN: Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts. RESULTS: ERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer. CONCLUSIONS: Co-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted.

Alliance for clinical trials in Oncology (Alliance) trial A022101/NRG-GI009: a pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).

BACKGROUND: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. METHODS: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. DISCUSSION: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05673148, registered December 21, 2022.

CALGB 80802 (Alliance): Impact of Sorafenib with and without Doxorubicin on Hepatitis C Infection in Patients with Advanced Hepatocellular Carcinoma.

Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf-mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS). Whether HCV viral load impacts therapy and whether any correlation between HCV titers and outcome based on HCV was studied. In patients with HCV, HCV titer levels were evaluated at baseline and at multiple postbaseline timepoints until disease progression or treatment discontinuation. HCV titer levels were evaluated in relation to OS and progression-free survival (PFS). Among 53 patients with baseline HCV data, 12 patients had undetectable HCV (HCV-UN). Postbaseline HCV titer levels did not significantly differ between treatment arms. One patient in each arm went from detectable to HCV-UN with greater than 2 log-fold titer levels reduction. Aside from these 2 HCV-UN patients, HCV titers remained stable on treatment. Patients who had HCV-UN at baseline were 3.5 times more likely to progress and/or die from HCC compared with HCV detectable (HR = 3.51; 95% confidence interval: 1.58-7.78; P = 0.002). HCV titer levels remained unchanged, negating any sorafenib impact onto HCV titer levels. Although an overall negative phase III study, patients treated with doxorubicin plus sorafenib and sorafenib only, on CALGB 80802 had worse PFS if HCV-UN. Higher levels of HCV titers at baseline were associated with significantly improved PFS. SIGNIFICANCE: Sorafenib therapy for HCC may impact HCV replication and viral gene expression. In HCV-positive patients accrued to CLAGB 80802 phase III study evaluating the addition of doxorubicin to sorafenib, HCV titer levels were evaluated at baseline and different timepoints. Sorafenib did not impact HCV titer levels. Despite an improved PFS in patients with detectable higher level HCV titers at baseline, no difference in OS was noted.

Post-diagnostic multivitamin supplement use and colorectal cancer survival: A prospective cohort study.

BACKGROUND: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. METHODS: Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements. RESULTS: During a median follow-up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-uses, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p = .005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p = .04; HR, 0.79; 95% CI, 0.70-0.88), p < .001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (pnonlinearity < .001) and all-cause mortality (pnonlinearity  = .004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p = .005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality. CONCLUSIONS: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality.

Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders.

BACKGROUND: Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed. METHODS: This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18). RESULTS: In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder's TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response. CONCLUSIONS: Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab.

Advances in Adherence Reporting of Resistance Training in a Clinical Trial during Adjuvant Chemotherapy for Colon Cancer.

PURPOSE: Detailed reporting of individually tailored exercise prescriptions (ExRx) used in clinical trials is essential to describe feasibility, tolerability, and efficacy of the intervention and to inform translation to clinical care. This paper outlines the methodology used to develop a resistance training (RT) ExRx for people with colon cancer receiving chemotherapy and reports adherence to the randomized controlled trial testing the impact of RT on relative dose intensity of chemotherapy and patient-reported toxicities. METHODS: Participants randomized to the exercise arm (n = 90) were included. To promote muscle hypertrophy, the ExRx was twice-weekly, moderate to heavy loads (65-85% 1-RM), high sets (3-5), and intermediate repetitions (6-10) of five large multi-joint movements with adjustable dumbbells. Attendance (achieved frequency) and adherence (achieved volume) were calculated. Group-based trajectory modeling was used to identify clusters of individuals with similar adherence patterns and compared baseline characteristics across adherence groups. RESULTS: The median attendance was 69.1%. Adherence was 60.6%, but higher for those receiving 3 versus 6 months of chemotherapy (80.4 vs. 47.4%; p < 0.05). Participants engaged in a median of 1.4 days of RT each week, lifting 62% of the 1-RM load, for 3.0 sets and 7.5 repetitions per set. Three distinct adherence groups were identified: 13% "non-starter", 37% "tapered off", and 50% "consistent exercisers". Females were more likely to be in the "non-starter" and "tapered off" groups. CONCLUSIONS: This paper outlines suggested methods for reporting ExRx of RT in oncology clinical trials and provides insight into the tolerance of ExRx of RT during chemotherapy treatment for colon cancer. These findings aim to foster constructive dialogue, and offer a premise for designing future research to elucidate the benefits of exercise during chemotherapy.

Effect of home-based resistance training on chemotherapy relative dose intensity and tolerability in colon cancer: The FORCE randomized control trial.

BACKGROUND: Many patients with colon cancer cannot fully adhere to postoperative chemotherapy due to dose-limiting toxicities, resulting in lower relative dose intensity (RDI) and potentially compromising overall survival. This study examined whether home-based resistance training (RT) during adjuvant chemotherapy improves RDI and patient-reported toxicities versus usual care (UC) in colon cancer patients. METHODS: Multicenter, randomized control trial (RCT) conducted at community and academic practices. Enrollment of patients receiving postoperative chemotherapy for colon cancer occurred between February 23, 2018, and September 29, 2021; final follow-up was March 21, 2022. Participants were randomized to RT (n = 90) or UC (n = 91) for the duration of chemotherapy. Participants in the RT group engaged in twice weekly home-based progressive RT. At the end of the study, UC was given an online exercise program. RESULTS: Among 181 randomized patients (mean age, 55.2 [SD, 12.8] years, 95 [52.5%] were men), there were no differences in the mean RDI among those in RT (79% [SD, 19%]) and those in UC (82% [SD, 19%]); (mean difference -0.04 [95% confidence interval (CI), -0.09 to 0.02]). Assignment to RT did not significantly reduce the number of moderate/severe symptoms per week across follow-up (relative rate: 0.94 [95% CI, 0.72-1.22]). Additionally, time since randomization did not significantly modify the effect of RT on the overall number of symptoms (p = .06). CONCLUSIONS: Among patients with colon cancer, these results do not support home-based RT as an adjunct to chemotherapy specifically to improve planned treatment intensity.

Cancer Diagnoses After Recent Weight Loss.

Importance: Weight loss is common in primary care. Among individuals with recent weight loss, the rates of cancer during the subsequent 12 months are unclear compared with those without recent weight loss. Objective: To determine the rates of subsequent cancer diagnoses over 12 months among health professionals with weight loss during the prior 2 years compared with those without recent weight loss. Design, Setting, and Participants: Prospective cohort analysis of females aged 40 years or older from the Nurses' Health Study who were followed up from June 1978 until June 30, 2016, and males aged 40 years or older from the Health Professionals Follow-Up Study who were followed up from January 1988 until January 31, 2016. Exposure: Recent weight change was calculated from the participant weights that were reported biennially. The intentionality of weight loss was categorized as high if both physical activity and diet quality increased, medium if only 1 increased, and low if neither increased. Main Outcome and Measures: Rates of cancer diagnosis during the 12 months after weight loss. Results: Among 157 474 participants (median age, 62 years [IQR, 54-70 years]; 111 912 were female [71.1%]; there were 2631 participants [1.7%] who self-identified as Asian, Native American, or Native Hawaiian; 2678 Black participants [1.7%]; and 149 903 White participants [95.2%]) and during 1.64 million person-years of follow-up, 15 809 incident cancer cases were identified (incident rate, 964 cases/100 000 person-years). During the 12 months after reported weight change, there were 1362 cancer cases/100 000 person-years among all participants with recent weight loss of greater than 10.0% of body weight compared with 869 cancer cases/100 000 person-years among those without recent weight loss (between-group difference, 493 cases/100 000 person-years [95% CI, 391-594 cases/100 000 person-years]; P < .001). Among participants categorized with low intentionality for weight loss, there were 2687 cancer cases/100 000 person-years for those with weight loss of greater than 10.0% of body weight compared with 1220 cancer cases/100 000 person-years for those without recent weight loss (between-group difference, 1467 cases/100 000 person-years [95% CI, 799-2135 cases/100 000 person-years]; P < .001). Cancer of the upper gastrointestinal tract (cancer of the esophagus, stomach, liver, biliary tract, or pancreas) was particularly common among participants with recent weight loss; there were 173 cancer cases/100 000 person-years for those with weight loss of greater than 10.0% of body weight compared with 36 cancer cases/100 000 person-years for those without recent weight loss (between-group difference, 137 cases/100 000 person-years [95% CI, 101-172 cases/100 000 person-years]; P < .001). Conclusions and Relevance: Health professionals with weight loss within the prior 2 years had a significantly higher risk of cancer during the subsequent 12 months compared with those without recent weight loss. Cancer of the upper gastrointestinal tract was particularly common among participants with recent weight loss compared with those without recent weight loss.

Alliance A151945: Accrual and characteristics of adolescent and young adult patients in Alliance trials from 2000 to 2017.

BACKGROUND: Identifying patient- and disease-specific characteristics associated with clinical trial enrollment of adolescents and young adults (AYAs) with cancer may target efforts to improve accrual. METHODS: Alliance for Clinical Trials in Oncology (Alliance) trials opened from January 1, 2000, and closed before January 1, 2018, for common AYA cancers were identified. Proportions of AYAs (aged 18-39 years old) versus non-AYAs (aged ≥40 years old) enrolled by cancer type were summarized by descriptive statistics. Among studies with ≥20 AYAs enrolled, demographic and disease characteristics of AYAs versus non-AYAs were compared with χ2 and Kruskal-Wallis tests. A qualitative review was also conducted of therapeutic trials included in analysis in PubMed through December 31, 2021, that reported AYA-specific survival. RESULTS: Among 188 trials enrolling 40,396 patients, AYAs represented 11% (4468 of 40,396) of accrual. AYA accrual varied by cancer type (leukemia, 23.6%; breast, 9.9%; lymphoma, 14.8%; colorectal, 6.2%; central nervous system, 8.1%; melanoma, 11.8%; sarcoma, 12%). Across ages, the proportion of Black and Hispanic patients enrolled was 1%-10%. Compared to non-AYAs, AYAs in breast and colorectal cancer trials were less likely to be White and more likely to be Hispanic. Disease characteristics differed by age for selected trials. Two trials reported AYA-specific survival, with no significant differences observed by age. CONCLUSIONS: AYA accrual to Alliance trials was comparable to or exceeded population-based, age-specific prevalence estimates for most cancer types. Greater proportional representation of Hispanic and non-White patients among AYAs reflects US demographic trends. The small number of minority patients enrolled across ages underscores the persistent challenge of ensuring equitable access to trials, including for AYAs.

The metabolic potential of inflammatory and insulinaemic dietary patterns and risk of type 2 diabetes.

AIMS/HYPOTHESIS: Diets with higher inflammatory and insulinaemic potential have been associated with an increased risk of type 2 diabetes. However, it remains unknown whether plasma metabolomic profiles related to proinflammatory/hyperinsulinaemic diets and to inflammatory/insulin biomarkers are associated with type 2 diabetes risk. METHODS: We analysed 6840 participants from the Nurses' Health Study and Health Professionals Follow-up Study to identify the plasma metabolome related to empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH), four circulating inflammatory biomarkers and C-peptide. Dietary intakes were assessed using validated food frequency questionnaires. Plasma metabolomic profiling was conducted by LC-MS/MS. Metabolomic signatures were derived using elastic net regression. Multivariable Cox regression was used to examine associations of the metabolomic profiles with type 2 diabetes risk. RESULTS: We identified 27 metabolites commonly associated with both EDIP and inflammatory biomarker z score and 21 commonly associated with both EDIH and C-peptide. Higher metabolomic dietary inflammatory potential (MDIP), reflecting higher metabolic potential of both an inflammatory dietary pattern and circulating inflammatory biomarkers, was associated with higher type 2 diabetes risk. The HR comparing highest vs lowest quartiles of MDIP was 3.26 (95% CI 2.39, 4.44). We observed a strong positive association with type 2 diabetes risk for the metabolomic signature associated with EDIP-only (HR 3.75; 95% CI 2.71, 5.17) or inflammatory biomarkers-only (HR 4.07; 95% CI 2.91, 5.69). In addition, higher metabolomic dietary index for hyperinsulinaemia (MDIH), reflecting higher metabolic potential of both an insulinaemic dietary pattern and circulating C-peptide, was associated with greater type 2 diabetes risk (HR 3.00; 95% CI 2.22, 4.06); further associations with type 2 diabetes were HR 2.79 (95% CI 2.07, 3.76) for EDIH-only signature and HR 3.89 (95% CI 2.82, 5.35) for C-peptide-only signature. The diet scores were significantly associated with risk, although adjustment for the corresponding metabolomic signature scores attenuated the associations with type 2 diabetes, these remained significant. CONCLUSIONS/INTERPRETATION: The metabolomic signatures reflecting proinflammatory or hyperinsulinaemic diets and related biomarkers were positively associated with type 2 diabetes risk, supporting that these dietary patterns may influence type 2 diabetes risk via the regulation of metabolism.

The dose-response effect of aerobic exercise on inflammation in colon cancer survivors.

Background: Physical activity after surgical resection for colon cancer is associated with significantly longer disease-free survival. Inflammation is hypothesized to mediate the association between physical activity and disease-free survival in colon cancer. Methods: In this exploratory analysis of a randomized dose-response trial, 39 colon cancer survivors who completed standard therapy were stratified by cancer stage and randomized in a 1:1:1 ratio to one of three treatment groups for 24 weeks of usual-care control, 150 min/wk of moderate-intensity aerobic exercise (low-dose), or 300 min/wk of moderate-intensity aerobic exercise (high-dose). Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL6), and soluble tumor necrosis factor-alpha receptor 2 (sTNFαR2). Mixed models for repeated measures were used to test the hypothesis that exercise was associated with dose-response reductions in inflammation; exploratory analyses examined treatment effects by cancer stage. Results: In the overall population, aerobic exercise was not associated with dose-response reductions in hs-CRP, IL6, or sTNFαR2. Cancer stage modified the association between randomized group and hs-CRP (P=0.022) and IL6 (P<0.001) but not sTNFαR2 (P=0.39). In stage I-II disease, compared to control, exercise was not associated with inflammation outcomes. In stage III disease, compared to control, low-dose exercise reduced hs-CRP: -35.4% (95% CI: -70.1, -0.7) and IL6: -29.6% (95% CI: -58.4, -0.8) but not sTNFαR2: 2.7% (95% CI: sTNFαR2: -15.7, 21.1); high-dose exercise was not associated with inflammation outcomes in stage III disease. Conclusion: This exploratory analysis offers preliminary data to support the hypothesis that inflammation may mediate the association between physical activity and disease-free survival in colon cancer. Clinical trial registration: clinicaltrials.gov, identifier NCT02250053.

D3-creatine dilution, computed tomography and dual-energy X-ray absorptiometry for assessing myopenia and physical function in colon cancer: A cross-sectional study.

BACKGROUND: Low skeletal muscle mass (myopenia) is common in cancer populations and is associated with functional decline and mortality, but prior oncology studies did not assess total body skeletal muscle mass. Instead, they measured surrogates such as cross-sectional area (CSA) of skeletal muscle at L3 from computed tomography (CT) or appendicular lean mass (ALM) from dual-energy X-ray absorptiometry (DXA). D3-creatine (D3Cr) dilution is a non-invasive method to assess total body skeletal muscle mass, which has been examined in a variety of populations but not in cancer. To compare the associations of D3Cr muscle mass, CT CSA, and DXA ALM with myopenia and physical function, we conducted a cross-sectional study among 119 patients with colon cancer (2018-2022). METHODS: For each technique (D3Cr, CT and DXA), myopenia was defined as the lowest sex-specific quartile of its measurement. Physical function was measured by the short physical performance battery and grip strength. We calculated Pearson correlations (r) among three techniques, computed Cohen's kappa coefficients (κ) to assess the agreement of myopenia, and estimated Pearson correlations (r) of three techniques with physical function. All analyses were sex-specific. RESULTS: Sixty-one (51.3%) participants were male, the mean (standard deviation) age was 56.6 (12.9) years, and most (68.9%) had high physical function (short physical performance battery: ≥11 points). Correlations and myopenia agreement among three techniques were greater in men than women; for example, regarding D3Cr muscle mass versus CT CSA, r was 0.73 (P < 0.001) for men versus 0.45 (P < 0.001) for women, and κ was 0.82 (95% CI: 0.65, 0.99) for men versus 0.24 (95% CI: -0.08, 0.52) for women. Among men, higher D3Cr muscle mass was significantly correlated with faster gait speed (r = 0.43, P < 0.01) and stronger grip strength (r = 0.32, P < 0.05); similar correlations were observed for CT CSA and DXA ALM. However, among women, no measure of muscle or lean mass was significantly associated with physical function. CONCLUSIONS: This is the first study using D3-creatine dilution method to assess muscle mass in a cancer population. Regardless of the techniques used for muscle or lean mass assessment, we observed stronger correlations, greater myopenia agreement, and more significant associations with physical function in men with colon cancer than women. D3Cr, CT and DXA are not interchangeable methods for assessing myopenia and physical function, especially in women with colon cancer. Future studies should consider relative advantages of these techniques and examine the D3-creatine dilution method in other cancer types.

Vitamin C intake and colorectal cancer survival according to KRAS and BRAF mutation: a prospective study in two US cohorts.

BACKGROUND: The associations of vitamin C intake with colorectal cancer (CRC) survival according to tumour KRAS or BRAF mutation status remain unclear. METHODS: We used the inverse probability weighted multivariable Cox proportional hazards regression model to calculate the hazard ratio (HR) of mortality, and spline analysis to evaluate the dose-response relationship in the Nurses' Health Study and Health Professionals Follow-up Study. We also assessed SLC2A1 mRNA expression according to KRAS or BRAF mutation in the TCGA database. RESULTS: During an average of 12.0 years of follow-up, we documented 2,096 CRC cases, of which 703 cases had KRAS and BRAF mutation data. The association between total vitamin C intake and CRC-specific mortality suggestively differed according to KRAS or BRAF mutation status (Pinteraction = 0.04), with the multivariable HR (95% CI) per 400 mg/day increase in vitamin C intake for CRC-specific mortality of 1.07 (0.87-1.32, Ptrend = 0.52) in cases with both wild type and 0.74 (0.55-1.00, Ptrend < 0.05) in cases with either KRAS or BRAF mutant type. TCGA analysis showed a higher mRNA SLC2A1 expression in KRAS or BRAF-mutated tumours than in wild-type tumours (P = 0.02). CONCLUSION: Our findings support the laboratory evidence for a potential benefit of vitamin C for CRC patients with KRAS or BRAF mutated tumours.