Physical decline, falls, and hospitalization among vulnerable older patients in the trajectory of colorectal cancer treatment.

INTRODUCTION: Resilience to anticancer treatment for colorectal cancer (CRC) among older patients varies. Many experience weight loss, physical decline, falls, and hospitalization during treatment, often leading to early discontinuation of otherwise effective chemotherapy. Screening for vulnerability might help to identify patients at risk of these adverse outcomes in older adults. MATERIALS AND METHODS: This is a secondary analysis from the GERICO trial. Patients aged ≥70 years assessed for chemotherapy for CRC were screened for eligibility for the GERICO trial with the geriatric-8 (G8) frailty screening tool. The present study population comprised patients who were (1) screened with G8 but for reasons not included in the GERICO study and (2) patients who were randomized to the GERICO control group. We evaluated whether patients identified as vulnerable with G8 (≤14/17) or retrospectively constructed mG8 (≥6/35) had higher risk of experiencing decline in performance status (PS), falls, and unplanned hospitalization during treatment. The association between frailty status and the adverse outcomes was analyzed with univariate and multivariate logistic regression. The discriminative ability of G8/mG8 to predict outcomes was analyzed using the area under the curve for receiver operating characteristics curves. RESULTS: In total, 238 patients (median age 74 years [range 70-91]) were included in this analysis. More vulnerable than fit patients experienced decline in PS (G8: 41% vs. 14%, p = 0.006 and mG8: 28% vs. 17%, p = 0.04) during treatment. Furthermore, more vulnerable than fit patients experienced falls (G8 14% vs. 6% p = 0.04) and unplanned hospitalization (G8: 31% vs. 14%, p = 0.009 and mG8: 34% vs. 13%, p < 0.001). Multivariate analyses showed an association between G8 vulnerability and decline in PS, falls, and hospitalization. DISCUSSION: Patients with G8 or mG8 vulnerability were more likely to experience decline in PS and unplanned hospitalization during chemotherapy for CRC than fit patients. More G8 vulnerable patients experienced falls compared with fit patients. Appropriate interventions should be offered to older patients with CRC assessed as vulnerable with G8 or mG8 to maintain PS during chemotherapy.

Nurse-Led Individualized Follow-Up Versus Regular Physician-Led Visits After Early Breast Cancer (MyHealth): A Phase III Randomized, Controlled Trial.

PURPOSE: Follow-up after breast cancer with regular visits has failed to detect recurrences, be cost-effective, and address patient needs. METHODS: MyHealth is a phase III randomized controlled trial (ClinicalTrials.gov identifier: NCT02949167). Patients, who recently completed primary treatment for stage I-II breast cancer, were randomly assigned in variable block sizes and stratified by age and human epidermal growth factor receptor 2 status to intervention or control follow-up. The nurse-led intervention comprised three to five individual self-management sessions, regular reporting of symptoms, and navigation to health care services. The control follow-up comprised regular outpatient visits with the physician. The primary outcome was breast cancer-specific quality of life (QoL) measured by the Trial Outcome Index-Physical/Functional/Breast summary score of the Functional Assessment of Cancer Therapy-Breast 2 years after random assignment. Secondary outcomes were fear of recurrence, anxiety, depression, and health care utilization. Analyses were intention-to-treat and P values were two-sided with 95% confidence level set at 0.005 because of multiple comparisons. RESULTS: Among 1,101 eligible patients, 875 were invited and 503 were randomly assigned to control (n = 252) or intervention (n = 251) follow-up. At 2 years, patients in the intervention group reported a significantly and clinically relevant higher QoL (mean, 75.69 [standard deviation [SD], 12.27]) than patients in the control group (71.26 [SD, 14.08]), with a mean difference of 5.05 (95% CI, 3.30 to 6.79; P < .001). The intervention group reported significantly less fear of recurrence, anxiety, and depression; they had fewer physician consultations but more nurse contacts and an unchanged diagnostic imaging pattern. The effect on all outcomes was stable through a 3-year follow-up. CONCLUSION: The MyHealth study suggested a new strategy for follow-up after early breast cancer as it provided significant improvements in QoL.

Prognostic Value of Pretreatment Plasma C-Reactive Protein in Patients with Early-Stage Breast Cancer.

BACKGROUND: Breast cancer incidence is now the highest among all cancers and accountable for 6.6% of all cancer-related deaths worldwide. Studies of the prognostic utility of plasma C-reactive protein (CRP) measurement in early-stage breast cancer have given discrepant results. METHODS: We identified 6,942 patients in the Danish Breast Cancer Cooperative Group database with early-stage breast cancer diagnosed between 2002 and 2016 who had a measure of pretreatment plasma CRP. Outcomes were recurrence-free interval and survival for a period up to 10 years. We analyzed associations with plasma CRP using Fine-Gray proportional subdistribution hazards model with recurrence-free interval. Data on plasma CRP were analyzed per doubling of concentration and in relation to CRP levels of <3 mg/L, 3 to 10 mg/L, and >10 mg/L and stratified according to standard clinical parameters in sensitivity analyses. RESULTS: A doubling of the plasma CRP concentration was associated with increased risk of recurrence (multivariate adjusted HR, 1.05; 95% CI, 1.01-1.08) and shorter survival (HR, 1.13; 95% CI, 1.09-1.16) in multivariate analyses. Survival was shorter in patients with plasma CRP levels of 3 to 10 and >10 mg/L versus <3 mg/L, with multivariate adjusted HRs of 1.30; 95% CI, 1.17-1.45 and 1.65; 95% CI, 1.39-1.95, respectively. CONCLUSIONS: Elevated plasma CRP measured before treatment in patients with early-stage breast cancer is an independent biomarker of increased risk of recurrence and early death. IMPACT: CRP measures before treatment might be used to individualize follow-up of patients with early-stage breast cancer.

Plasma YKL-40 is associated with prognosis in patients with metastatic pancreatic cancer receiving immune checkpoint inhibitors in combination with radiotherapy.

Background: YKL-40, also known as chitinase-3-like protein 1 (CHI3L1), is a secreted glycoprotein produced by various cell types including stromal, immune, and cancer cells. It contributes to cancer progression through tumor-promoting inflammation and has been shown to inhibit the cytotoxicity of T and NK lymphocytes. In vivo studies have demonstrated synergistic anti-cancer effects of blocking YKL-40 in combination with immune checkpoint inhibitors (ICIs). Biomarkers for the prediction of the response to ICIs are highly needed. We investigated the association between plasma YKL-40 and clinical benefit and survival in patients with metastatic pancreatic cancer (mPC) receiving ICIs and stereotactic body radiotherapy (SBRT). Methods: Blood samples were collected from 84 patients with mPC who participated in the randomized phase II CheckPAC study, in which patients received nivolumab with or without ipilimumab combined with a single fraction of SBRT. Plasma YKL-40 was measured using a commercial ELISA kit. Results: Elevated baseline plasma YKL-40 was an independent predictor of shorter overall survival (OS) (HR 2.19, 95% CI 1.21-3.95). A ≥ 40% decrease in plasma YKL-40 during treatment was associated with longer progression-free survival (p = 0.009) and OS (p = 0.0028). There was no correlation between plasma YKL-40 and the tumor burden marker CA19-9 at baseline or during treatment. Conclusion: This study contributes new knowledge regarding YKL-40 as a predictor of clinical benefit from ICIs and radiotherapy. These exploratory results warrant further investigation of YKL-40 as a biomarker for patients treated with immunotherapies. Clinical trial registration: Clinicaltrials.gov, identifier NCT02866383.

Pre-existing TGF-ß-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy.

BACKGROUND: Circulating transforming growth factor-ß (TGF-ß)-specific T cells that recognize TGF-ß-expressing immune regulatory cells have been described in patients with cancer. TGF-ß-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-ß-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-ß-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC). METHODS: Immune responses to a TGF-ß-derived epitope entitled TGF-ß-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-É£ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-ß-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry. RESULTS: PBMCs from 32 patients were analyzed for immune responses to the TGF-ß-derived epitope entitled TGF-ß-15. Patients with a strong TGF-ß-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-ß-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-ß-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-ß-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-ß-15 vaccination, we showed that repeated stimulations with the TGF-ß-15 epitope in vitro enhanced the immune response to TGF-ß-15. CONCLUSION: A strong TGF-ß-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-ß-specific T cells in some patients was not caused by a general immune dysfunction. TGF-ß-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-ß-based vaccination with ICI/radiotherapy will be beneficial for patients with PC.

Therapy with pembrolizumab in treatment-naïve patients with nonmetastatic, mismatch repair deficient colorectal cancer.

Therapy with immune checkpoint inhibitors (ICI) is effective in patients with metastatic mismatch-repair deficient (dMMR) colorectal cancer (CRC); however, data on treatment with neoadjuvant ICI in patients with locally advanced CRC are limited. From March 2019 to June 2020, five Danish oncological centers treated 10 patients with a treatment-naïve dMMR CRC with preoperative pembrolizumab, 9 with a nonmetastatic, unresectable colon cancer and 1 with a locally advanced rectum cancer. All 10 patients were evaluated regularly at a multidisciplinary team (MDT) meeting, and they all had a radical resection after a median of 8 cycles (range 2-13) of pembrolizumab. A microscopic evaluation of the resected tumors revealed no remaining tumor cells in five patients, while five still had tumor cells present. The patients were given no additional therapy. No recurrences were reported after a median follow-up of 26 months (range 23-38.5 months). Biopsies from Danish patients with CRC are routinely screened for dMMR proteins. In 2017, data from the Danish Colorectal Cancer Group showed that 19% (565/3000) of the patients with colon cancer and 1.5% (19/1279) of those with rectum cancer had an dMMR tumor. Among the patients with MMR determination, 26% (99/384) patients had a T4 dMMR colon cancer; thus, the 10 patients treated with neoadjuvant pembrolizumab comprised about 9% of the patients with a T4 dMMR colon cancer (9/99) and 5% of patients with dMMR rectal cancer (1/19). Therapy with pembrolizumab was feasible and effective. Larger prospective trials are needed to confirm our findings.

Development and validation of circulating protein signatures as diagnostic biomarkers for biliary tract cancer.

Background & Aims: Biliary tract cancer (BTC) is associated with a dismal prognosis, partly because it is typically diagnosed late, highlighting the need for diagnostic biomarkers. The purpose of this project was to identify and validate multiprotein signatures that could differentiate patients with BTC from non-cancer controls. Methods: In this study, we included treatment-naïve patients with BTC, healthy controls, and patients with benign conditions including benign biliary tract disease. Participants were divided into three non-overlapping cohorts: a case-control-based discovery cohort (BTC = 186, controls = 249); a case-control-based validation cohort (validation cohort 1: BTC = 113, controls = 241); and a cohort study-based validation cohort including participants (BTC = 8, controls = 132) referred for diagnostic work-up for suspected cancer (validation cohort 2). Immuno-Oncology (I-O)-related proteins were measured in serum and plasma using a proximity extension assay (Olink Proteomics). Lasso and Ridge regressions were used to generate protein signatures of I-O-related proteins and carbohydrate antigen 19-9 (CA19-9) in the discovery cohort. Results: Sixteen protein signatures, including 2 to 82 proteins, were generated. All signatures included CA19-9 and chemokine C-C motif ligand 20. Signatures discriminated between patients with BTC vs. controls, with AUCs ranging from 0.95 to 0.99 in the discovery cohort and 0.94 to 0.97 in validation cohort 1. In validation cohort 2, AUCs ranged from 0.84 to 0.94. Nine signatures achieved a specificity of 82% to 84% while keeping a sensitivity of 100% in validation cohort 2. All signatures performed better than CA19-9, and signatures including >15 proteins showed the best performance. Conclusion: The study demonstrated that it is possible to generate protein signatures that can successfully differentiate patients with BTC from non-cancer controls. Impact and implications: We attempted to find blood sample-based protein profiles that could differentiate patients with biliary tract cancer from those without cancer. Several profiles were found and tested in different groups of patients. The profiles were successful at identifying most patients with biliary tract cancer, pointing towards the utility of multiprotein signatures in this context.

Physical exercise program to older frail patients receiving chemotherapy for colorectal cancer - feasibility and experiences from the GERICO study.

INTRODUCTION: Older and frail patients with cancer are at high risk of physical and functional decline during chemotherapy. Exercise interventions can often counteract chemotherapy related toxicity and may help patients to improve or retain physical function and quality of life. Studies evaluating feasibility and the effect of exercise in older patients are lacking. The aim of this study was to investigate the feasibility and effect of an exercise intervention in older frail patients during chemotherapy for colorectal cancer (CRC). MATERIALS AND METHODS: This is a secondary analysis from the GERICO study investigating the effect of geriatric interventions in frail patients ≥70 years receiving chemotherapy for CRC. All patients in the present analysis were patients randomized to geriatric interventions and who were found physically frail (low handgrip strength or slow 10 m gait speed) and therefore offered referral to the exercise program for twelve weeks. We evaluated reasons for dropping out and feasibility of an individually tailored exercise program twice a week for twelve weeks. Each 60 min session comprised warm-up followed by progressive resistance training and cool-down followed by an oral protein supplement. Baseline characteristics and the effect of exercise for patients with high and low adherence (attendance of <50% of exercise sessions) were compared. RESULTS: Of 71 patients in the intervention group, 47 (66%) were found physically frail and were offered referral to the exercise program. Seven patients were referred to municipal physiotherapy before study start. In the remaining population (N = 40) 19 had exercise adherence >50% and 21 had no or low exercise adherence. Baseline characteristics were similar between patients with high and low/no adherence, except for sex (68% and 33% were men in high and low/ no adherence group, respectively). Patients with >50% attendance had significant improvements in physical tests after twelve weeks of exercise. DISCUSSION: Low adherence to the exercise program was seen due to lack of energy and/or treatment related adverse events. Patients with high adherence benefitted from exercise during chemotherapy but did not differ from patients with low adherence at baseline. Consequently, exercise should be offered to all older frail patients receiving chemotherapy for CRC.

Preoperative plasma vitamin D in patients with localized colorectal cancer: Age-dependent association with inflammation, postoperative complications, and survival.

INTRODUCTION: Aging is often associated with low-grade chronic inflammation and a senescent immune system. Vitamin D is a regulator of immune function, and low plasma vitamin D is associated with poor health. The association between plasma vitamin D and inflammatory biomarkers and risk of postoperative complications and survival in patients with colorectal cancer (CRC) is unknown. Our aim was to investigate these associations and how they are influenced by age. MATERIALS AND METHODS: Circulating vitamin D and the inflammatory biomarkers C-reactive protein (CRP), interleukin (IL)-6, and YKL-40 were measured in 398 patients with stage I-III CRC preoperatively. Older patients (≥70 years, n = 208) were compared to younger patients (<70 years, n = 190). The relation between vitamin D and complications and high inflammatory biomarker levels was presented by odds ratios ([OR], 95% confidence interval [CI]). Associations with survival were presented with hazard ratios ([HR], 95% CI). RESULTS: Plasma vitamin D was higher in older patients than in younger patients (75 vs. 67 nmol/L, P = 0.001). High vitamin D was associated with low plasma CRP in younger patients (OR = 0.35, 95% CI 0.17-0.76), but not in older patients (OR = 0.93, 0.49-1.76). High vitamin D in older patients with CRC was associated with reduced risk of major complications (OR = 0.52, 0.28-0.95). This was not found in younger patients (OR = 1.47, 0.70-3.11). Deficient vitamin D (<25 nmol/L) was associated with short overall survival compared to sufficient (>50 nmol/L) irrespective of age (HR = 3.39, 1.27-9.37, P = 0.02). CONCLUSION: For patients with localized CRC, high vitamin D levels before resection were associated with reduced risk of high inflammatory biomarkers for younger patients and reduced risk of major postoperative complications for older patients. Vitamin D deficiency was associated with reduced survival regardless of age.

Determination of temporal reproducibility and variability of cancer biomarkers in serum and EDTA plasma samples using a proximity extension assay.

BACKGROUND: Proximity extension assay (PEA) is a novel antibody-based proteomic technology. Sparse data have been published concerning the matrix effect of serum vs. ethylenediamine tetraacetic acid (EDTA) plasma and the reproducibility of results obtained using PEA technology. METHODS: We analyzed samples with the PEA-based 92-plex Olink® immuno-oncology (I-O) assay. To estimate the matrix effect, we analyzed paired serum and EDTA plasma samples from 12 patients with biliary tract cancer. To evaluate the reproducibility, we used data from 7 studies, where 6-8 serum samples from patients with pancreatic cancer were used as bridging samples on 3 versions of the panel over a 2.5-years period. RESULTS: For the study of serum vs. plasma, 80 proteins were evaluable. The mean serum to EDTA plasma ratio ranged from 0.41-3.01. For 36 proteins, the serum and plasma values were not comparable due to high variability of the ratio, poor correlation, or possible concentration effect. For the bridging samples, the mean intra-study inter-assay coefficient of variation (CV) ranged from 11.3% to 26.1%. The mean inter-study CV was 42.0% before normalization and 26.2% after normalization. Inter-study results were well correlated (r ≥ 0.93), especially for studies using the same version of the panel (r ≥ 0.99). CONCLUSION: For 44 of 92 proteins included in the Olink® I-O panel, the variation between results obtained using serum and EDTA plasma was constant and results were well correlated. Furthermore, samples could be stored for several years and used on different versions of the same PEA panel without it effecting results.

Circulating Protein Biomarkers for Prognostic Use in Patients with Advanced Pancreatic Ductal Adenocarcinoma Undergoing Chemotherapy.

Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a dismal prognosis. We aimed to find a prognostic protein signature for overall survival (OS) in patients with advanced PDAC, and to explore whether early changes in circulating-protein levels could predict survival. We investigated 92 proteins using the Olink Immuno-Oncology panel in serum samples from 363 patients with advanced PDAC. Protein panels for several survival cut-offs were developed independently by two bioinformaticians using LASSO and Ridge regression models. Two panels of proteins discriminated patients with OS < 90 days from those with OS > 2 years. Index I (CSF-1, IL-6, PDCD1, TNFRSF12A, TRAIL, TWEAK, and CA19-9) had AUCs of 0.99 (95% CI: 0.98−1) (discovery cohort) and 0.89 (0.74−1) (replication cohort). For Index II (CXCL13, IL-6, PDCD1, and TNFRSF12A), the corresponding AUCs were 0.97 (0.93−1) and 0.82 (0.68−0.96). Four proteins (ANGPT2, IL-6, IL-10, and TNFRSF12A) were associated with survival across all treatment groups. Longitudinal samples revealed several changes, including four proteins that were also part of the prognostic signatures (CSF-1, CXCL13, IL-6, TNFRSF12A). This study identified two circulating-protein indices with the potential to identify patients with advanced PDAC with very short OS and with long OS.

Effects of a 12-Week Multimodal Exercise Intervention Among Older Patients with Advanced Cancer: Results from a Randomized Controlled Trial.

BACKGROUND: Older patients with cancer are at risk of physical decline and impaired quality of life during oncological treatment. Exercise training has the potential to reduce these challenges. The study aim was to investigate the feasibility and effect of a multimodal exercise intervention in older patients with advanced cancer (stages III/IV). PATIENTS AND METHODS: Eighty-four older adults (≥65 years) with advanced pancreatic, biliary tract, or non-small cell lung cancer who received systemic oncological treatment were randomized 1:1 to an intervention group or a control group. The intervention was a 12-week multimodal exercise-based program including supervised exercise twice weekly followed by a protein supplement, a home-based walking program, and nurse-led support and counseling. The primary endpoint was change in physical function (30-second chair stand test) at 13 weeks. RESULTS: Median age of the participants was 72 years (interquartile range [IQR] 68-75). Median adherence to the exercise sessions was 69% (IQR 21-88) and 75% (IQR 33-100) for the walking program. At 13 weeks, there was a significant difference in change scores of 2.4 repetitions in the chair stand test, favoring the intervention group (p < .0001). Furthermore, significant beneficial effects were seen for physical endurance (6-minute walk test), hand grip strength, physical activity, symptom burden, symptoms of depression and anxiety, global health status (quality of life), and lean body mass. No effects were seen for dose intensity, hospitalizations, or survival. CONCLUSION: A 12-week multimodal exercise intervention with targeted support proved effective in improving physical function in older patients with advanced cancer during oncological treatment.

Circulating Protein Biomarkers for Use in Pancreatic Ductal Adenocarcinoma Identification.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Most patients are diagnosed at an advanced stage where curative surgery is not an option. The aim of this study was to identify a panel of circulating proteins that could distinguish patients with PDAC from non-PDAC individuals. EXPERIMENTAL DESIGN: We investigated 92 proteins known to be involved in inflammation, development, and progression of PDAC using the Olink immuno-oncology panel in serum samples from 701 patients with PDAC (stage I-IV), 102 patients with nonmalignant pancreatic diseases, and 180 healthy blood donors. Patients were included prospectively between 2008 and 2018. Plasma carbohydrate antigen 19-9 (CA19-9) was measured in all samples. The protein panels with the best diagnostic performances were developed by two bioinformaticians working independently, using LASSO and Ridge regression models. RESULTS: Two panels of proteins (index I, containing 9 proteins + CA19-9, and index II, containing 23 proteins + CA19-9) were identified. Index I was able to discriminate patients with PDAC from all patients with non-PDAC, with a ROC AUC value of 0.92 [95% confidence interval (CI), 0.89-0.96] in the discovery cohort and 0.92 (95% CI, 0.87-0.97) in the replication cohort. For index II, the AUC value was 0.96 (95% CI, 0.95-0.98) in the discovery cohort and 0.93 (95% CI, 0.90-0.96) in the replication cohort. All nine serum proteins of index I were found in index II. CONCLUSIONS: This study identified two circulating protein indices with the potential to discriminate between individuals with and without PDAC.

Cetuximab plus irinotecan administered biweekly with reduced infusion time to heavily pretreated patients with metastatic colorectal cancer and related RAS and BRAF mutation status.

Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third-line setting. The intention-to-treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next-generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAFV600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAFV600E genes. In patients with RAS-WT and RAS-MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy.

Myocardial Ischemia Induced by 5-Fluorouracil: A Prospective Electrocardiographic and Cardiac Biomarker Study.

BACKGROUND: Cardiotoxicity induced by 5-fluorouracil (5-FU) is well known but poorly understood. In this study, we undertook ECG recording (Holter) and analyses of the biomarkers troponin and copeptin in patients receiving 5-FU to increase our understanding of the cardiotoxicity. SUBJECTS, MATERIALS, AND METHODS: Patients with colorectal or anal cancer that received first-time treatment with 5-FU-based chemotherapy were prospectively included. Holter recording, clinical evaluation, 12-lead electrocardiogram, and assessment of plasma concentrations of troponin I and copeptin were performed before (control) and during 5-FU treatment (intervention). RESULTS: A total of 108 patients were included, 82 with colorectal and 26 with anal cancer. The proportion of patients with myocardial ischemia on Holter recording was significantly higher during the first 5-FU infusion (14.1%) than before (3.7%; p = .001). The ischemic burden per day (p = .001), the number of ST depression episodes per day (p = .003), and the total duration of ischemic episodes per day (p = .003) were higher during the first 5-FU infusion than before, as was plasma copeptin (p < .001), whereas plasma troponin I was similar (p > 0.999). Six patients (5.6%) developed acute coronary syndromes and two (1.8%) developed symptomatic arrhythmias during 5-FU treatment. CONCLUSION: 5-FU infusion is associated with an increase in the number of patients with myocardial ischemia on Holter recording. According to biomarker analyses, 5-FU is associated with an increase in copeptin, but rarely with increases in cardiac troponin I. However, 5%-6% of the patients developed acute coronary syndromes during treatment with 5-FU. IMPLICATIONS FOR PRACTICE: Symptomatic 5-fluorouracil (5-FU) cardiotoxicity occurs in 0.6%-19% of patients treated with this drug, but a small electrocardiographic (Holter) study has revealed silent myocardial ischemia in asymptomatic patients, suggesting a more prevalent subclinical cardiac influence. This study demonstrated a significant increase in the number of patients with myocardial ischemia on Holter recording during 5-FU treatment and an increase in ischemic burden. Cardiac biomarker analyses suggested that 5-FU infusion results in endogenous stress (increased copeptin) but rarely induces myocyte injury (no change in troponin). These findings suggest a more prevalent cardiac influence from 5-FU and that Holter recording is an important tool in the evaluation of patients with suspected cardiotoxicity from 5-FU.

Effect of Exercise on Physical Function and Psychological Well-being in Older Patients With Colorectal Cancer Receiving Chemotherapy-A Systematic Review.

The incidence of colorectal cancer (CRC) increases with older age. Cancer and treatment-related side effects often lead to physical decline, poor treatment adherence, and a lower quality of life. The aim of the present systematic review and meta-analysis was to evaluate the effects of exercise reported by randomized controlled trials (RCTs) on physical function, physical fitness (ie, aerobic capacity, muscle strength) physical activity, and psychological well-being in older patients with CRC undergoing chemotherapy. Eight RCTs with 552 participants were included in the meta-analysis. The mean age across the RCTs was 58.5 years, and 2 RCTs excluded patients aged > 80 years. The meta-analyses showed a low level of evidence for a small beneficial effect of exercise on self-reported physical function (standardized mean difference [SMD], 0.26; 95% confidence interval [CI], 0.04-0.48) and global quality of life (SMD, 0.22; 95% CI, 0.02-0.43) and low level of evidence for a moderate effect of exercise reducing fatigue (SMD, -0.49; 95% CI, -0.79 to -0.19) for patients receiving chemotherapy for CRC. We found no evidence for a beneficial effect of exercise on physical fitness. No adverse events related to the exercise interventions were reported. The evidence for the effect of exercise on physical outcomes and psychological well-being during chemotherapy for patients with CRC and especially for older patients is sparse. However, exercise during chemotherapy for patients with CRC is feasible and safe. We found a moderate to high risk of bias in most of the included studies, small sample sizes, and a low number of included patients. Moreover, all studies had excluded patients with comorbidities or walking impairment, a group of patients who would probably benefit the most from exercise. This positive result requires verification in larger trials of older and frail patients receiving chemotherapy for CRC.

Cancer patients, physicians, and nurses differ in their attitudes toward the decisional role in do-not-resuscitate decision-making.

PURPOSE: Do-not-resuscitate (DNR) decision-making in severely ill patients presents many difficult medical, ethical, and legal challenges. The primary aim of this study was to explore cancer patients' and health care professionals' attitudes regarding DNR decision-making authority and timing of the decision. METHODS: This study was a questionnaire survey among Danish cancer patients and their attending physicians and nurses in an oncology outpatient setting. Potential differences between patients', physicians', and nurses' answers to the questionnaire were analyzed using Fisher's exact test. RESULTS: Responses from 904 patients, 59 physicians, and 160 nurses were analyzed. The majority in all three groups agreed that DNR decisions should be made in collaboration between physician and patient. However, one-third of the patients answered that the patient alone should make the decision regarding DNR, which contrasts with the physicians' and nurses' attitudes, 0% and 6% pointing to the patient as sole decision-maker, respectively. In case of disagreement between patient and physician, a majority of both patients (66%) and physicians (86%) suggested themselves as the ultimate decision-maker. Additionally, 43% of patients but only 19% of physicians preferred the DNR discussion being brought up early in the course of the disease. CONCLUSIONS: With regard to the decisional role of patient vs. physician and the timing of the DNR discussion, we found a substantial discrepancy between the attitudes of cancer patients and physicians. This discrepancy calls for a greater awareness and discussion of this sensitive topic among both health care professionals and the public.

Antitumour immunity invoked by hepatic arterial infusion of first-line oxaliplatin predicts durable colorectal cancer control after liver metastasis ablation: 8-12 years of follow-up.

In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.

Basal biomarkers nestin and INPP4B predict gemcitabine benefit in metastatic breast cancer: Samples from the phase III SBG0102 clinical trial.

In a formal prospective-retrospective analysis of the phase III SBG0102 clinical trial randomizing metastatic breast cancer patients to gemcitabine-docetaxel or to single agent docetaxel, patients with basal-like tumors by PAM50 gene expression had significantly better overall survival in the gemcitabine arm. By immunohistochemistry (IHC), triple negative status was not predictive, but more specific biomarkers have since become available defining basal-like by nestin positivity or loss of inositol-polyphosphate-4-phosphate (INPP4B). Here, we evaluate their capacity to identify which patients benefit from gemcitabine in the metastatic setting. Nestin and INPP4B staining and interpretation followed published methods. A prespecified statistical plan evaluated the primary hypothesis that patients with basal-like breast cancer, defined as "nestin+ or INPP4B-", would have superior overall survival on gemcitabine-docetaxel when compared to docetaxel. Interaction tests, Kaplan-Meier curves and forest plots were used to assess prognostic and predictive capacities of biomarkers relative to treatment. Among 239 cases evaluable for our study, 36 (15%) had been classified as basal-like by PAM50. "Nestin+ or INPP4B-" was observed in 41 (17%) of the total cases and was significantly associated with PAM50 basal-like subtype. Within an estimated median follow-up of 13 years, patients assigned as IHC basal "nestin+ or INPP4B-" had significantly better overall survival on gemcitabine-docetaxel versus docetaxel monotherapy (HR = 0.31, 95%CI: 0.16-0.60), whereas no differences were observed for other patients (HR = 0.99), p-interaction < 0.01. In the metastatic setting, women with IHC basal breast cancers defined as "nestin+ or INPP4B-" have superior overall survival when randomized to gemcitabine-containing chemotherapy compared to docetaxel alone. These findings need to be validated using larger prospective-retrospective phase III clinical trials series.

Age-dependent differences in first-line chemotherapy in patients with metastatic colorectal cancer: the DISCO study.

OBJECTIVES: First-line chemotherapy for metastatic colorectal cancer (mCRC) is effective and feasible in selected older patients. We investigated age-dependent differences in treatment and outcomes in patients with mCRC in clinical practice. MATERIAL AND METHODS: A retrospective study of 654 patients with mCRC referred to first-line chemotherapy in 2008-2014. Patients were divided into two age groups: 50-69 and ≥70 (older patients). Binary outcomes were analyzed by logistic regression. Progression-free survival (PFS) and overall survival (OS) were analyzed by Cox proportional hazards regression, CRC-specific and other-cause mortality with Fine and Gray proportional hazard model for the sub-distribution of a competing risk. RESULTS: After adjusting for performance status (PS) and comorbidity, older patients were more likely to receive monotherapy (adjusted odds ratio (aOR) = 9.00, 95% confidence interval (CI) 4.52-17.91), lower doses, and no additional targeted therapy (aOR = 1.89, 95% CI 1.28-2.78) than younger patients. Yet, older patients experienced more toxicity and hospitalizations (aOR = 1.53, 95% CI 1.08-2.17). Among those treated, older patients had shorter PFS (hazard ratio (HR) = 1.32, 95% CI 1.11-1.57), but after adjusting for PS and comorbidity, PFS was similar. No significant difference was found in CRC mortality (HR = 1.15, 95% CI 0.95-1.40) between age groups. Poor PS was associated with shorter OS and PFS and higher CRC mortality. CONCLUSIONS: In the DISCO study, older patients with mCRC received less aggressive first-line chemotherapy. Yet, they experienced more toxicity. Younger and older patients had similar CRC mortality. Shorter PFS and higher CRC mortality were observed in patients with poor PS.