Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E.

BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.

Muscle and Adipose Wasting despite Disease Control: Unaddressed Side Effects of Palliative Chemotherapy for Pancreatic Cancer.

Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of all patients treated for aPC from 2013-2019 in Alberta, Canada (n = 504), computed-tomography (CT)-defined muscle and adipose tissue index changes (∆SMI, ∆ATI, cm2/m2) were measured for patients with CT images available both prior to and 12 ± 4 weeks after chemotherapy initiation (n = 210). Contributions of regimen and tumour response to tissue change were assessed with multivariable linear regression. Survival impacts were assessed with multivariable Cox's proportional hazards models. Tissue changes varied widely (∆SMI: -17.8 to +7.3 cm2/m2, ∆ATI: -106.1 to +37.7 cm2/m2) over 116 (27) days. Tumour progression contributed to both muscle and adipose loss (-3.2 cm2/m2, p < 0.001; -12.4 cm2/m2, p = 0.001). FOLFIRINOX was associated with greater muscle loss (-1.6 cm2/m2, p = 0.013) and GEM/NAB with greater adipose loss (-11.2 cm2/m2, p = 0.002). The greatest muscle and adipose losses were independently associated with reduced survival (muscle: HR 1.72, p = 0.007; adipose: HR 1.73, p = 0.012; tertile 1 versus tertile 3). Muscle and adipose losses are adverse effects of chemotherapy and may require regimen-specific management strategies.

Total energy expenditure assessed by 24-h whole-room indirect calorimeter in patients with colorectal cancer: baseline findings from the PRIMe study.

BACKGROUND: Total energy expenditure (TEE) determines energy requirements, but objective data in patients with cancer are limited. OBJECTIVES: We aimed to characterize TEE, investigate its predictors, and compare TEE with cancer-specific predicted energy requirements. METHODS: This cross-sectional analysis included patients with stages II-IV colorectal cancer from the Protein Recommendation to Increase Muscle (PRIMe) trial. TEE was assessed by 24-h stay in a whole-room indirect calorimeter before dietary intervention and compared with cancer-specific predicted energy requirements (25-30 kcal/kg). Generalized linear models, paired-samples t tests, and Pearson correlation were applied. RESULTS: Thirty-one patients (56 ± 10 y; body mass index [BMI]: 27.9 ± 5.5 kg/m2; 68% male) were included. Absolute TEE was higher in males (mean difference: 391 kcal/d; 95% CI: 167, 616 kcal/d; P < 0.001), patients with colon cancer (mean difference: 279 kcal/d; 95% CI: 73, 485 kcal/d; P = 0.010), and patients with obesity (mean difference: 393 kcal/d; 95% CI: 182, 604 kcal/d; P < 0.001). Appendicular lean soft tissue (ß: 46.72; 95% CI: 34.27, 59.17; P < 0.001) and tumor location (colon-ß: 139.69; 95% CI: 19.44, 259.95; P = 0.023) independently predicted TEE when adjusted for sex. Error between measured TEE and energy requirements predicted by 25 kcal/kg (mean difference: 241 kcal/d; 95% CI: 76, 405 kcal/d; P = 0.010) or 30 kcal/kg (mean difference: 367 kcal/d; 95% CI: 163, 571 kcal/d; P < 0.001) was higher for patients with obesity, and proportional error was observed (25 kcal/kg: r = -0.587; P < 0.001; and 30 kcal/kg: r = -0.751; P < 0.001). TEE (mean difference: 25 kcal/kg; 95% CI: 24, 27 kcal/kg) was below predicted requirements using 30 kcal/kg (-430 ± 322 kcal/d; P < 0.001). CONCLUSIONS: This is the largest study to assess TEE of patients with cancer using whole-room indirect calorimeter and highlights the need for improved assessment of energy requirements in this population. Energy requirements predicted using 30 kcal/kg overestimated TEE by 1.44 times in a controlled sedentary environment and TEE was outside of the predicted requirement range for most. Special considerations are warranted when determining TEE of patients with colorectal cancer, such as BMI, body composition, and tumor location. This is a baseline cross-sectional analysis from a clinical trial registered at clinicaltrials.gov as NCT02788955 (https://clinicaltrials.gov/ct2/show/NCT02788955).

Prediction of whole body composition utilizing cross-sectional abdominal imaging in pediatrics.

BACKGROUND: Although body composition is an important determinant of pediatric health outcomes, we lack tools to routinely assess it in clinical practice. We define models to predict whole-body skeletal muscle and fat composition, as measured by dual X-ray absorptiometry (DXA) or whole-body magnetic resonance imaging (MRI), in pediatric oncology and healthy pediatric cohorts, respectively. METHODS: Pediatric oncology patients (≥5 to ≤18 years) undergoing an abdominal CT were prospectively recruited for a concurrent study DXA scan. Cross-sectional areas of skeletal muscle and total adipose tissue at each lumbar vertebral level (L1-L5) were quantified and optimal linear regression models were defined. Whole body and cross-sectional MRI data from a previously recruited cohort of healthy children (≥5 to ≤18 years) was analyzed separately. RESULTS: Eighty pediatric oncology patients (57% male; age range 5.1-18.4 y) were included. Cross-sectional areas of skeletal muscle and total adipose tissue at lumbar vertebral levels (L1-L5) were correlated with whole-body lean soft tissue mass (LSTM) (R2 = 0.896-0.940) and fat mass (FM) (R2 = 0.874-0.936) (p < 0.001). Linear regression models were improved by the addition of height for prediction of LSTM (adjusted R2 = 0.946-0.971; p < 0.001) and by the addition of height and sex (adjusted R2 = 0.930-0.953) (p < 0.001)) for prediction of whole body FM. High correlation between lumbar cross-sectional tissue areas and whole-body volumes of skeletal muscle and fat, as measured by whole-body MRI, was confirmed in an independent cohort of 73 healthy children. CONCLUSION: Regression models can predict whole-body skeletal muscle and fat in pediatric patients utilizing cross-sectional abdominal images.

Drivers of Dietary Choice After a Diagnosis of Colorectal Cancer: A Qualitative Study.

BACKGROUND: Dietary changes often accompany management of a cancer diagnosis, but how and why patients with colorectal cancer (CRC) make dietary decisions requires further investigation. OBJECTIVE: To learn about patients' food-related beliefs and understand whether and why dietary changes were made by patients starting chemotherapy after a CRC diagnosis. DESIGN: A qualitative semi-structured interview study was conducted as a secondary analysis among a subset of patients with stages II-IV CRC enrolled at baseline in a randomized controlled trial. PARTICIPANTS/SETTING: Twenty-nine patients participated in the interview. Data were collected at the University of Alberta (Edmonton, Alberta, Canada) from 2016-2019 before any trial intervention. QUALITATIVE DATA ANALYSIS: Audio-recorded interviews were transcribed verbatim then coded inductively by two research team members. Qualitative content analysis was applied to capture emergent themes. RESULTS: Patients reported varied degrees of dietary change that stemmed from internal and external influences. Four main themes emerged to describe patients' dietary decisions after a CRC diagnosis: 1) Medical Influences: eating to live; 2) Health Beliefs: connecting lived experiences with new realities; 3) Static Diets: no changes postdiagnosis; and 4) Navigating External Influences: confluence of personal agency and social constraints. CONCLUSION: The extent to which patients altered their dietary choices depended on perspectives and beliefs. These included the degree to which dietary decisions provided some agency (ie, feeling of control) for dealing with physical ramifications of cancer treatment, individuals' personal understandings of healthy foods, and the role of diet in managing their new physical reality postdiagnosis. This information provides registered dietitian nutritionists and health care providers with insight into dietary intentions of select patients being treated for CRC. These findings can guide future research focused on effective strategies for streamlined nutritional support that aligns with patient needs.

Changes in Survival Outcomes of Patients With Neuroendocrine Neoplasms Over the Past 15 Years: A Real-World Study.

BACKGROUND: The past 2 decades have observed a number of advances in therapeutic approaches to patients with neuroendocrine neoplasms (NENs). This study aims to assess whether survival outcomes have changed among patients with NENs over the past 15 years, in a real-world, population-based study. MATERIALS AND METHODS: We accessed administrative databases within the province of Alberta, Canada, and we reviewed patients with invasive NENs diagnosed 2004 to 2019. Patients were classified according to the year of diagnosis into 3 groups: 2004 to 2008; 2009 to 2013; and 2014 to 2019. Kaplan-Meier survival estimates were used to compare overall survival (OS) according to different baseline characteristics (including the year of diagnosis). Multivariable Cox regression modeling was used to examine factors associated with the risk of death in this cohort. RESULTS: We included a total of 3431 patients in the study cohort. Using multivariable Cox regression analysis, the following factors were associated with worse survival: older age at diagnosis (hazard ratio [HR]: 3.45; 95% CI [confidence interval]: 2.74-4.35), male sex (HR: 1.38; 95% CI: 1.21-1.56), lung primary site (HR for lung vs. appendicular primary: 1.39; 95% CI: 1.01-1.92), Stage 4 disease (HR: 2.80; 95% CI: 2.38-3.30), South zone of the province (HR for South zone vs. Calgary zone: 1.85; 95% CI: 1.49-2.30), and higher comorbidity index (HR for ≥3 vs. 0: 2.66; 95% CI: 2.19-3.24). Although Kaplan-Meier method showed significant difference in OS according to diagnosis period, multivariable regression model showed that the period of diagnosis did not appear to impact OS (HR for diagnosis period 2004 to 2009 vs. 2014 to 2019: 1.04; 95% CI: 0.89-1.22). CONCLUSIONS: Over the study period (2004 to 2019), patients diagnosed during later periods did not appear to experience better OS compared with patients diagnosed at an earlier time.

Skeletal muscle is prognostic in resected stage III malignant melanoma.

BACKGROUND: Sarcopenia (low skeletal muscle index, SMI) and myosteatosis (low skeletal muscle radiodensity, SMD) have been associated with worse survival in cancer. This study evaluated associations of body composition with survival in patients with resected stage III melanoma. METHODS: A retrospective review was performed of resected stage III melanoma patients in Alberta, Canada from 2007 to 2017. Preoperative CT scans were analyzed to determine SMI and SMD. Cohort-specific SMI and SMD cut-offs that optimally predicted overall survival (OS) were identified through stratification, in addition to testing cut-offs previously established in the literature. Overall (OS), melanoma-specific (MSS), and recurrence-free survival (RFS) were determined from date of surgery and analysed using multivariable Cox regressions with age, sex, BMI, stage subgroup, ECOG PS, and tumor location as covariates. RESULTS: We included 330 patients in the final analysis. Mean age was 56 years and 62.4% of patients were male. At time of censoring 150 patients (45.6%) had died. Sarcopenia based on literature cut-offs was associated with decreased OS (HR 1.55, 95% CI 1.00-2.21, p = 0.016). Using cohort-specific cut-offs, sarcopenic patients also had significantly decreased OS (HR 1.87, 95% CI 1.27-2.76, p = 0.002). Myosteatosis defined using cohort-specific cut-offs predicted worse OS (HR 2.15, 95% CI 1.42-3.25, p < 0.001), MSS (HR 2.29, 95% CI 1.40-3.75, p = 0.001) and RFS (HR 1.52, 95% CI 1.02-2.27, p = 0.041). Increased BMI ( ≥ 25) and visceral fat index were not significantly associated with survival. CONCLUSIONS: Sarcopenia and myosteatosis, defined using two sets of cut-offs, are associated with decreased OS and MSS in resected stage III melanoma.

Case report: Proton pump inhibitor drug-related problem in pancreatic cancer patient unmasks pancreatic enzyme insufficiency.

INTRODUCTION: Palliative care aims to improve the quality of life of patients with a life-limiting or life-threatening illness and is multifaceted involving comprehensive interdisciplinary assessments and interventions. Interdisciplinary palliative care in the setting of untreatable cancer diagnoses is of particular importance due to additional considerations that must be taken as patients are often undergoing palliative chemotherapy and/or radiation therapy. These patients' complexity warrants special considerations and attentiveness to drug-related problems. CASE REPORT: The purpose of this case report is to highlight the importance of both complete and comprehensive medication histories in cancer care and the impact of proton pump inhibitors on pancreatic enzyme insufficiencies secondary to pancreatic cancers. This case involves a drug-related problem involving three medications that are commonly used in pancreatic cancer patients: pancreatic enzyme replacement therapy, a proton pump inhibitor, and a fluoroquinolone antibiotic. The patient presented in this case report is an 80-year-old man diagnosed with unresectable pancreatic cancer with a history of symptomatic gastroesophageal reflux disease managed with a proton pump inhibitor, specifically tablets of the 40 mg strength of pantoprazole magnesium taken orally once daily. During the patient's first of five 28-day cycles of palliative-intent chemotherapy with gemcitabine and nab-paclitaxel, the patient presented to the emergency department due to fever and, although not severely neutropenic, was prescribed amoxicillin/clavulanate and ciprofloxacin due to his advanced age. After reading a patient advisory on a ciprofloxacin patient information sheet that advised avoidance of concomitant administration of ciprofloxacin and magnesium, the patient self-discontinued his pantoprazole as it was a magnesium salt formulation. This discontinuation was followed by two weeks of persistent foul-smelling diarrhea, flatulence, and abdominal pain. MANAGEMENT AND OUTCOME: The patient's healthcare team symptomatically managed the patient with oral and intravenous rehydration unaware of the cause of the symptoms. A trial of pancreatic enzyme replacement therapy was initiated; however, it was unsuccessful in resolving his symptoms. After further investigation and a more in-depth patient interview, it was discovered that the discontinued proton pump inhibitor was likely the cause of the patient's new symptoms and was subsequently re-initiated. Pancreatic enzyme replacement therapy in combination with re-initiation of pantoprazole therapy essentially resolved all symptoms. DISCUSSION: Before his diagnosis of unresectable pancreatic cancer, the patient had been on proton pump inhibitor therapy for nearly a decade. He had significant atrophy of the pancreas and an undoubtedly decreased pancreatic enzyme and bicarbonate production; however, he did not experience foul-smelling diarrhea indicative of pancreatic enzyme insufficiency while he was on his proton pump inhibitor. We believe that with his proton pump inhibitor therapy, he was unknowingly being partially treated for his worsening pancreatic enzyme insufficiency, specifically the component related to his lack of bicarbonate production and secretion. His discontinuation of his proton pump inhibitor led to a decrease in gastric acid, small bowel, and normal intraduodenal pH, which resulted in any remaining pancreatic enzyme reserve to become non-functional, unmasking his pancreatic enzyme insufficiency. An initial empiric trial of pancreatic enzyme replacement therapy failed in the absence of a proton pump inhibitor; however, within days of restarting his proton pump inhibitor along with pancreatic enzyme replacement therapy, his gastrointestinal symptoms completely resolved. This is due to the decrease of gastric and intraduodenal acidity, which better enabled the function of pancreatic enzymes present in pancreatic enzyme replacement therapy.

Use of nab-paclitaxel and gemcitabine in pancreatic cancer without granulocyte colony-stimulating factor: A multicenter real-world experience.

INTRODUCTION: The metastatic pancreatic adenocarcinoma clinical trial (MPACT) trial established gemcitabine (gem) and nab-paclitaxel (nab) as a standard treatment for pancreatic cancer utilizing granulocyte colony-stimulating factors to manage neutropenia. This was a challenge for jurisdictions that do not use granulocyte colony-stimulating factors in palliative settings. We developed dosage guidelines to dose modify gem and nab without granulocyte colony-stimulating factors. We undertook a retrospective review to determine the efficacy and safety of these dose adjustment guidelines in the real world. METHODS: A multi-centered, retrospective chart review was performed on pancreatic patients between December 1, 2014, and August 21, 2018. Provincial electronic medical health records were reviewed. Using Log-rank statistics we determined the patient's progression-free survival and overall survival. RESULTS: Of 248 patients, 209 met patient selection criteria. Patients were excluded if they were lost to follow-up, on gem alone prior to nab/gem combination therapy or did not receive nab or gem. Patients who received nab/gem as first-line therapy had a median progression-free survival of 6.3 months (95% CI, 5.1-7.4), and median overall survival of 11.1 months (95% CI, 9.5-12.8). Those who received gem/nab in the second line had a median progression-free survival of 4.6 months (95% CI, 2.8-6.5), and median overall survival of 19.3 months (95% CI, 12.6-26.0). CONCLUSIONS: The patient's progression-free survival and overall survival taking nab/gem using our dose modification algorithm were equivalent or superior to the MPACT trial's progression-free survival and overall survival. Gem/nab can be given by our dose modification scheme without granulocyte colony-stimulating factor.

CT-based assessment of body composition and skeletal muscle in melanoma: A systematic review.

BACKGROUND/OBJECTIVES: Sarcopenia (low skeletal muscle index) and myosteatosis (low skeletal radiodensity) have been associated with poor outcomes in melanoma. This systematic review was performed to summarize and critically evaluate current literature surrounding body composition in melanoma. METHODS: MEDLINE and Embase databases were searched for studies of melanoma patients with computed tomography (CT) based body composition analysis from 2000 to 2020. Outcomes of interest were survival, including overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS), as well as treatment-related adverse events (AEs). RESULTS: Nine studies of 914 patients were included in the final review. The majority of studies were of metastatic melanoma patients treated with immunotherapy. Studies demonstrated a variety of CT analysis techniques and cut-offs to define sarcopenia and myosteatosis. Associations of sarcopenia or myosteatosis with survival (OS, PFS, DFS) or risk of treatment-related AEs were conflicting. Multiple studies had low quality of evidence due to small sample sizes, use of non-validated CT measures, and lack of multivariable analyses. CONCLUSIONS: Due to methodologic heterogeneity and low quality of evidence, impacts of CT-derived body composition parameters on outcomes in melanoma are unclear. Further research should be conducted to elucidate impacts of body composition in melanoma.

An exploratory study of body composition as a predictor of dose-limiting toxicity in metastatic pancreatic cancer treated with gemcitabine plus nab-paclitaxel.

BACKGROUND: Body composition is increasingly being studied as a method of predicting chemotherapy toxicity. Our study aimed to evaluate associations of body composition with treatment toxicity in a group of pancreatic cancer patients treated with gemcitabine plus nab-paclitaxel. METHODS: A retrospective review was performed for all patients who received first-line gemcitabine plus nab-paclitaxel for metastatic pancreatic cancer at a northern Alberta cancer institute (Canada) from 2014 to 2017. Total lean body mass (LBM) was derived from measurements of muscle surface area at L3 on baseline computed tomography (CT) scans. Optimal stratification, or minimal p-value analysis, was used to assess for a threshold of nab-paclitaxel dose per LBM (mg/kg) associated with a higher risk of dose-limiting toxicity (DLT). RESULTS: 152 patients were included in the study, of whom 62 (40.8%) experienced DLT. nab-Paclitaxel dose/LBM ranged from 0.98 to 8.76 mg/kg. A threshold for nab-paclitaxel dose/LBM that optimally predicted risk of DLT was identified at 5.83 mg/kg. Above this cut-off, 18/31 (58.1%) patients experienced DLT, compared to 44/121 (36.4%) patients below (p = 0.028). Patients above this cut-off had a higher incidence of peripheral neuropathy compared to those below, though this was not statistically significant based on an adjusted p-value threshold (48.4 vs. 29.8% respectively, p = 0.050). Body mass index, body surface area, and absolute initial doses of nab-paclitaxel or gemcitabine did not significantly impact likelihood of DLT. CONCLUSIONS: nab-Paclitaxel dose normalized to LBM, based on CT-derived measures of skeletal muscle, has potential to predict risk of chemotherapy toxicity. Chemotherapy dosing based on body composition, rather than conventional anthropometric measures, may be effective in reducing treatment toxicity.

Uridine Glucuronosyltransferase 2B7 Polymorphism-Based Pharmacogenetic Dosing of Epirubicin in FEC Chemotherapy for Early-Stage Breast Cancer.

BACKGROUND: Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). Patients homozygous for the minor allele (CC) in the UGT2B7 -161 promoter polymorphism have lower clearance and significantly higher rates of leukopenia compared to wild-type homozygote (TT) or heterozygote (CT) patients. This study was designed to determine if TT and CT genotype patients could tolerate a higher epirubicin dose compared to CC genotype patients. PATIENTS AND METHODS: We studied women with histologically confirmed non-metastatic, invasive breast cancer who were scheduled to receive at least three cycles of FE100C in the (neo)adjuvant setting. Patients received standard-dose FE100C during the first 21-day cycle. Based on genotype, the epirubicin dose was escalated in the second and third cycles to 115 and 130 mg/m2 or to 120 and 140 mg/m2 for CT and TT genotype patients, respectively. The main outcome measurements were myelosuppression and dose-limiting toxicity. These were analyzed for relationships with the three genotypes. RESULTS: Forty-five patients were enrolled (10 CC, 21 CT, and 14 TT genotypes) and received 100 mg/m2 of epirubicin in the first cycle. Twelve and 10 TT patients were dose escalated at the second and third cycles, respectively; 16 CT patients were dose escalated at the second and third cycles. Leukopenia, but not febrile neutropenia, was genotype and dose dependent and increased in patients with CT and TT genotypes as their dose was increased. However, the third-cycle leukopenia rates were comparable to patients with the CC genotype receiving standard-dose epirubicin. CONCLUSION: Pharmacogenetically guided epirubicin dosing is well tolerated and allowed dose escalation without increased toxicity.

Myosteatosis is prognostic in metastatic melanoma treated with nivolumab.

BACKGROUND: While immunotherapy agents have improved outcomes in metastatic melanoma (MM), predictive biomarkers in these patients are lacking. Parameters identified from body composition analysis, such as low SMD (also termed myosteatosis), may prognosticate MM patients on immunotherapy. METHODS: In this retrospective study, 44 MM patients received nivolumab, either as monotherapy or in combination with ipilimumab. Pre-treatment computed tomography (CT) scans were analyzed to determine skeletal muscle density (SMD) in Hounsfield units (HU) and muscle surface area (MSA) in cm2 at L3. MSA was used to determine nivolumab dosing in mg/cm2. RESULTS: Low SMD was associated with worse overall survival (OS) by log rank test (median 12.03 vs. 34.96 months, p = 0.001) and in multivariate analysis when accounting for age, sex, performance status, and number of prior lines of therapy (HR 4.40, 95% CI 1.44-13.42, p = 0.009). Lower nivolumab dosing by MSA was significantly associated with improved OS (median 42.9 vs. 12.3 months, p < 0.001). This association remained significant in multivariate analysis with age, sex, performance status, and number of prior lines of therapy (HR 0.05, 95% CI 0.01-0.30, p = 0.001). Neither SMD nor higher nivolumab dose per MSA were associated with increased incidence of treatment toxicity. CONCLUSIONS: Low SMD is prognostic in MM treated with nivolumab immunotherapy. Presence of myosteatosis or higher nivolumab dose based on body composition did not predict treatment toxicity.

Protein Recommendation to Increase Muscle (PRIMe): Study protocol for a randomized controlled pilot trial investigating the feasibility of a high protein diet to halt loss of muscle mass in patients with colorectal cancer.

BACKGROUND: Severe muscle mass (MM) loss is a defining feature of cancer observed across all types and stages of disease and is an independent predictor of poor clinical outcomes including higher incidences of chemotherapy toxicity and decreased survival. Protein is essential to build MM, yet the optimal amount for preventing or treating muscle loss in patients with cancer remains undefined. METHODS: The Protein Recommendation to Increase Muscle (PRIMe) study is a single-center, two-armed, parallel, randomized, controlled pilot trial that assesses the feasibility of utilizing a high protein (HP) diet to positively impact clinical outcomes in people undergoing chemotherapy to treat colorectal cancer. Forty patients with newly diagnosed stage II-IV colorectal cancer who are scheduled to receive chemotherapy will be included. Participants are randomly assigned to a HP or normal protein (NP) diet for twelve weeks. The HP and NP groups receive nutrition recommendations to achieve 2.0 g of protein per kilogram of body weight per day (g∙kg-1∙d-1) and 1.0 g⋅kg-1⋅d-1, respectively. These values refer to the upper and lower recommended range of protein intake for people with cancer. Energy recommendations are based on measured energy expenditure. Assessments are completed within two weeks of starting chemotherapy (baseline), at week 6, and at week 12. Changes to skeletal MM, physical function, anthropometrics, body composition, muscle strength, physical activity, energy metabolism, metabolic markers, nutritional status, quality of life, readiness to change and psychosocial determinants of behavioural change are assessed between the HP and NP groups. Feasibility of the nutritional intervention is assessed by change in MM as a surrogate marker. CONCLUSIONS: This evidence-based study investigates the feasibility of increasing protein intake following a diagnosis of cancer on clinical outcomes during treatment for colorectal cancer. This study will inform larger trials assessing the impact of increasing protein intake in cancer to determine their importance and integration into standard clinical care for people with cancer.

Tolerability of pemetrexed and oxaliplatin in the treatment of stage III colon cancer during raltitrexed shortage.

Colorectal cancer is one of the most common malignancies diagnosed in Canada. Currently, adjuvant colorectal cancer treatment primarily includes chemotherapeutic regimens such as FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin), as well as alternative regimens such as TOMOX (raltitrexed, oxaliplatin). However, the prevalence of drug shortages in today's society may make these preferred regimens inaccessible. The purpose of this case report is to highlight the tolerability of an alternative adjuvant regimen (pemetrexed plus oxaliplatin) that has undergone both phase I and II clinical trials for the treatment of colorectal cancer. The patient presented in this case report is a 57-year-old female diagnosed with Stage III colon cancer. This patient received seven cycles of pemetrexed plus oxaliplatin and experienced several adverse events, with the majority of them being mild in nature including fatigue and cold dysesthesia. However, the patient also experienced progressive neuropathy which required a dose reduction and subsequent discontinuation of oxaliplatin. Overall, pemetrexed and oxaliplatin's tolerability seems comparable to other regimens used to treat colorectal cancer and could potentially be an option to consider in the future for alternative treatment of colorectal cancer pending further trials.

Tyrosine Kinase Inhibitors Reduce Glucose Uptake by Binding to an Exofacial Site on hGLUT-1: Influence on 18 F-FDG PET Uptake.

Positron emission tomography (PET) using 2-deoxy-2-[18 F]fluoro-d-glucose ([18 F]FDG), a marker of energy metabolism and cell proliferation, is routinely used in the clinic to assess patient response to chemotherapy and to monitor tumor growth. Treatment with some tyrosine kinase inhibitors (TKIs) causes changes in blood glucose levels in both nondiabetic and diabetic patients. We evaluated the interaction of several classes of TKIs with human glucose transporter-1 (hGLUT-1) in FaDu and GIST-1 cells by measuring [3 H]2-deoxy-d-glucose ([3 H]2-DG) and [3 H]FDG uptake. Uptake of both was inhibited to varying extents by the TKIs, and representative TKIs from each class showed competitive inhibition of [3 H]2-DG uptake. In GIST-1 cells, [3 H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible. Molecular modeling studies showed that TKIs form multiple hydrogen bonds with polar residues of the sugar binding site (i.e., Q161, Q282, Q283, N288, N317, and W388), and van der Waals interactions with the H-pocket site. Our results showed interaction of TKIs with amino acid residues at the glucose binding site to inhibit glucose uptake by hGLUT-1. We hypothesize that inhibition of hGLUT-1 by TKIs could alter glucose levels in patients treated with TKIs, leading to hypoglycemia and fatigue, although further studies are required to evaluate roles of other SLC2 and SLC5 members. In addition, TKIs could affect tumor [18 F]FDG uptake, increasingly used as a marker of tumor response. The hGLUT-1 inhibition by TKIs may have implications for routine [18 F]FDG-PET monitoring of tumor response in patients.

Plasma levels of platinum-induced fatty acid [16:4n-3] do not affect response to platinum-based chemotherapy: A pilot study in non-small cell lung cancer patients.

BACKGROUND & AIMS: Pre-clinical studies suggest that 16:4(n-3) in purified form or as a component of fish oil might induce platinum-based chemotherapy resistance. Our aim was to determine plasma total and free 16:4(n-3) before and during platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients supplemented with fish oil or provided standard care, and to explore relationships between plasma 16:4(n-3) levels and tumor response to treatment. METHODS: In a retrospective, secondary data analysis of a prior clinical trial, plasma from patients with NSCLC (n = 21) who underwent platinum-based chemotherapy and were assigned to 2.2 g/day of eicosapentaenoic (EPA) plus 1.1 g DHA/day as fish oil (FO; n = 12) or received no intervention (standard care; SC; n = 9). Plasma 16:4(n-3) was quantified as free and esterified (total) fatty acid using HPLC-MS/MS. Plasma 16:4(n-3) levels were evaluated over time in relation to fish oil supplementation and response to platinum-based therapy, and compared with a group of healthy subjects (REF; n = 11). RESULTS: Plasma 16:4(n-3) was detected in all samples. The percentage change/day in plasma esterified (total) 16:4(n-3) was higher for FO versus SC group (2.7 versus -1.8%/d, U = 20, p = 0.02), but change in plasma free 16:4(n-3) was not different between FO and SC. Median plasma free and esterified 16:4(n-3) were similar between responders and non-responders to platinum-based chemotherapy. Total and free plasma 16:4(n-3) fatty acids were similar between NSCLC patients and REF (NSCLC vs REF: total 16:4(n-3): 122.9 vs. 95.2 nM and free 16:4(n-3) 23.9 vs. 27.6 nM). CONCLUSIONS: This first of its kind study that evaluated plasma 16:4(n-3) in NSCLC patients showed that 16:4 (n-3) was elevated during FO supplementation, independent of fish oil supplementation or platinum-based chemotherapy.

Body composition is prognostic and predictive of ipilimumab activity in metastatic melanoma.

BACKGROUND: Body composition is minimally investigated in an immunotherapy era. Specific body composition signals such as myosteatosis may reflect aspects of patients' immunology and thereby their ability to respond to immunotherapies. Ipilimumab is a key checkpoint inhibitor in metastatic melanoma. As an antibody, it may also be more accurately dosed using body composition parameters rather than weight alone. This retrospective study aimed to investigate body composition-based dosing and outcomes. METHODS: Pretreatment computed tomography images from metastatic melanoma, ipilimumab-treated patients from 2009 to 2014 were used to measure myosteatosis [skeletal muscle radiographic density or SMD, in Hounsfield units (HU)] and surface area (cm2 ) as previously described. Cut point analysis determined whether a level of ipilimumab dose and myosteatosis demonstrated differences in progression-free (PFS) and overall survival (OS). Secondary endpoints included objective response rates and toxicities. RESULTS: Of 121 identified, 97 patients were evaluable. Baseline demographics included 56 years median age, 60% male participants, and 23.7% with BRAF mutations. SMD analysis identified cut-offs of SMD < 42 in those with BMI < 25 kg/m2 and <20 HU in those with BMI ≥ 25 kg/m2 , respectively. Low SMD patients had poorer median PFS [2.4 vs. 2.7 months, hazard ratio (HR) 1.76, P = 0.008] and OS (5.4 vs. 17.5 months, HR 2.47, P = 0.001), which remained significant in multivariate modelling. High SMD patients had more immune-related adverse events, better objective response rates (17.9 vs. 3.3%, P = 0.051), and lower baseline neutrophil-to-lymphocyte ratio (21 vs. 39%, P = 0.049). Separately, patients receiving <2.03 mg/cm2 had improved median PFS (3.0 vs. 2.6 months, HR 1.88, P = 0.02) and OS (14.9 vs. 5.7 months, HR 1.98, P = 0.01). CONCLUSIONS: Low SMD and receiving >2.03 mg/cm2 are prognostic of poorer melanoma outcomes post ipilimumab. SMD may identify patients with flawed immunology and predict who may better respond to such therapy. Ipilimumab dosing by skeletal muscle index stands in contrast to weight-based dosing and may demonstrate a more accurate method of antibody dosing.

First Case of Regression of Carcinoid Heart Disease on Serial Transthoracic Echocardiograms following Octreotide Monotherapy in a Patient with Metastatic Pancreatic Neuroendocrine Tumor.

Well-differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal (GI) tract and pancreas are relatively rare; however, the annual incidence has been increasing. Carcinoid syndrome (CS) is a constellation of symptoms that occur when a GI NET metastasizes to the liver and releases high levels of vasoactive substances into the systemic circulation. CS occurs in 19% of NETs patients at diagnosis and is associated with shorter survival. Carcinoid heart disease (CHD) occurs in over 50% of patients with CS and is associated with poor long-term prognosis. NET-induced valvular fibrosis is a significant cause of mortality and morbidity in these patients. Somatostatin analogs relieve CS symptoms, but they have never been shown to reverse CHD progression or improve overall survival. Surgical therapy for right-sided valve disease is associated with improved symptoms and quality of life and possibly improved survival, despite relatively high morbidity and mortality associated with cardiac intervention. A 65-year-old woman with a metastatic pancreatic NET had typical signs and symptoms of CS. She presented in congestive heart failure and was found to have severe tricuspid regurgitation with characteristic features of CHD on transthoracic echocardiogram (TTE). Following octreotide monotherapy, serial TTEs demonstrated regression of tricuspid valve involvement. The patient improved clinically and remained asymptomatic on subsequent visits. This is the first case of CHD regression with medical therapy supported by serial TTEs. Developing a deeper understanding of cases like this will help us unlock new intervention targets and strategies for treatments in the future.

Profiling Determinants of Resting Energy Expenditure in Colorectal Cancer.

Background: Understanding resting energy expenditure (REE) is important for determining energy requirements; REE might be altered in individuals with cancer. The objective of this study was to characterize determinants of REE in patients with stages II-IV colorectal cancer (CRC).Methods: REE was measured via indirect calorimetry in patients with newly diagnosed CRC. Computerized tomography images from medical records ascertained skeletal muscle and total adipose tissue cross-sectional areas, which were then transformed to lean soft tissue (LST) and fat mass (FM) values (in kg). Linear regression assessed determinants of REE.Results: 86 patients were included (n = 55, 64.0% male; 60 ± 12 years old; median body mass index: 27.6, interquartile range: 24.3-31.2 kg/m2), with most (n = 40) having stage III disease. Age, sex, and weight were significant predictors of REE [R2 = 0.829, standard error of the estimate (SEE): 128 kcal/day, P < 0.001]. Replacing weight with LST and FM yielded a similar model, with age, sex, LST, and FM predictive of REE (R2 = 0.820, SEE: 129 kcal/day, p < 0.001).Conclusion: Age, sex, weight, LST, and FM were the main contributors to REE. Further investigation of REE changes over time and its relationship to total energy expenditure, dietary intake, and clinical outcomes should be explored.