Tamoxifen pharmacokinetics and pharmacodynamics in older patients with non-metastatic breast cancer.

BACKGROUND: We aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer. METHODS: Data for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen. CYP2D6 and CYP3A4 phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS). RESULTS: 668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7, p all < 0.05), independently of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95, p < 0.001, R2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R2 = 0.007). Older patients had worse RFSt (5.8 versus 7.3 years, p = 0.01) and worse OS (7.8 years versus 8.7 years, p = 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96-1.04, p = 0.84) or CYP polymorphisms. CONCLUSION: Serum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent of CYP2D6 or CYP3A4 gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients.

The Prognostic Value of a Geriatric Risk Score for Older Patients with Colorectal Cancer.

INTRODUCTION: VMS is a Dutch risk assessment tool for hospitalized older adults that includes a short evaluation of four geriatric domains: risk for delirium, risk for undernutrition, risk for physical impairments, and fall risk. We investigated whether the information derived from this tool has prognostic value for outcomes of colorectal surgery. METHODS: All consecutive patients over age 70 years who underwent elective colorectal cancer surgery in three Dutch hospitals (2014-2016) were studied. The presence of risk was scored prior to surgery and per geriatric domain as either 0 (risk absent) or 1 (risk present). The total number of geriatric risk factors was summed. The primary outcome was long-term survival. Secondary outcomes were postoperative complications, including delirium. Cox proportional hazards models were used to evaluate the sumscore and risk factors associated with overall survival. RESULTS: Five hundred fifty patients were included. Median age was 76.5 years, and median follow-up was 870 days. Patients with intermediate (1-2) or high (3-4) sumscore were independently associated with lower overall survival, with hazard ratio (HR) of 1.9 [95% confidence interval (CI) 1.1-3.5; p = 0.03] and 8.7 (95% CI 4.0-19.2; p < 0.001), respectively. Sumscores were also associated with postoperative complications (intermediate sumscore OR 1.8; 95% CI 1.2-2.7; high sumscore OR 2.4; 95% CI 1.02-5.5). CONCLUSIONS: This easy-to-use geriatric sumscore has strong associations with long-term outcome and morbidity after colorectal cancer surgery. This information may be included in risk models for morbidity and mortality and can be used in shared decision-making.

The effect of a geriatric evaluation on treatment decisions for older patients with colorectal cancer.

BACKGROUND: Treating elderly colorectal cancer patients can be challenging. It is very important to carefully weigh the risks and benefits of potential treatments in individual patients. This treatment decision making can be guided by geriatric consultation. Our aim was to assess the effect of a geriatric evaluation on treatment decisions for older patients with colorectal cancer. METHODS: Colorectal cancer patients who were referred for a geriatric consultation between 2013 and 2015 in three Dutch teaching hospitals were included in a prospective database. The outcome of geriatric assessment, non-oncological interventions and geriatricians' treatment recommendations were evaluated. RESULTS: The total number of included referrals was 168. The median age was 81 years (range 60-94). Most patients (71%) had colon cancer and 49% had tumour stage III disease. The reason for geriatric consultation was uncertainty regarding the optimal oncologic treatment in 139 patients (83%). Overall 93% of patients suffered from geriatric impairments; non-oncological interventions that followed after geriatric consultation was mostly aimed at malnutrition. The geriatrician recommended the 'more intensive treatment' option in 69% and the 'less intensive treatment' option in 31% of which 63% 'supportive care only'. CONCLUSION: Geriatric consultation can be useful in treatment decision making in elderly patients with colorectal cancer. It may lead to changes in the treatment plan for individual cases and may result in an additional optimisation of patient's health status prior to treatment.

Predictive value of selected geriatric parameters for postoperative outcomes in older patients with rectal cancer - A multicenter cohort study.

INTRODUCTION: Older patients have a higher risk for complications after rectal cancer surgery. Although screening for geriatric impairments may improve risk prediction in this group, it has not been studied previously. METHODS: We retrospectively investigated patients ≥70 years with elective surgery for non-metastatic rectal cancer between 2014 and 2018 in nine Dutch hospitals. The predictive value of six geriatric parameters in combination with standard preoperative predictors was studied for postoperative complications, delirium, and length of stay (LOS) using logistic regression analyses. The geriatric parameters included the four VMS-questionnaire items pertaining to functional impairment, fall risk, delirium risk, and malnutrition, as well as mobility problems and polypharmacy. Standard predictors included age, sex, body mass index, American Society of Anesthesiologists (ASA)-classification, comorbidities, tumor stage, and neoadjuvant therapy. Changes in model performance were evaluated by comparing Area Under the Curve (AUC) of the regression models with and without geriatric parameters. RESULTS: We included 575 patients (median age 75 years; 32% female). None of the geriatric parameters improved risk prediction for complications or LOS. The addition of delirium risk to the standard preoperative prediction model improved model performance for predicting postoperative delirium (AUC 0.75 vs 0.65, p = 0.03). CONCLUSIONS: Geriatric parameters did not improve risk prediction for postoperative complications or LOS in older patients with rectal cancer. Delirium risk screening using the VMS-questionnaire improved risk prediction for delirium. Older patients undergoing rectal cancer surgery are a pre-selected group with few impairments. Geriatric screening may have additional value earlier in the care pathway before treatment decisions are made.

Prognostic value of screening instrument based on the Dutch national VMS guidelines for older patients in the emergency department.

PURPOSE: It is important to identify which older patients attending the emergency department are at risk of adverse outcomes to introduce preventive interventions. This study aimed to assess the prognostic value of a shortened screening instrument based on the Dutch national Safety Management System [Veiligheidsmanagementsysteem (VMS)] guidelines for adverse outcomes in older emergency department patients. METHODS: A cohort study was performed including patients aged 70 years or older who visited the emergency department. Adverse outcomes included hospital admission, return emergency department visits within 30 days, and 90-day mortality. The prognostic value of the VMS-score was assessed for these adverse events and, in addition, a prediction model was developed for 90-day mortality. RESULTS: A high VMS-score was independently associated with an increased risk of hospital admission [OR 2.26 (95% CI 1.32-3.86)] and 90-day mortality [HR 2.48 (95% CI 1.31-4.71)]. The individual VMS-questions regarding history of delirium and help in activities of daily living were associated with these outcomes as well. A prediction model for 90-day mortality was developed and showed satisfactory calibration and good discrimination [AUC 0.80 (95% CI 0.72-0.87)]. A cut-off point that selected 30% of patients at the highest risk yielded a sensitivity of 67.4%, a specificity of 75.3%, a positive predictive value of 28.5%, and a negative predictive value of 94.1%. CONCLUSION: The shortened VMS-based screening instrument showed to be of good prognostic value for hospitalization and 90-day mortality. The prediction model for mortality showed promising results and will be further validated and optimized.

Comprehensive multidisciplinary care program for elderly colorectal cancer patients: "From prehabilitation to independence".

BACKGROUND: We implemented a multidisciplinary pre- and rehabilitation program for elderly patients (≥75 years of age) in a single center consisting of prehabilitation, laparoscopic surgery and early rehabilitation with the intention to lower 1-year overall mortality. METHODS: In this study we compared all patients that underwent elective surgery for stage I-III colorectal cancer before and during development and after implementation of the program (2010-2011, 2012-2013 and 2014-2015). Primary endpoint was 1-year overall mortality, the secondary endpoint was 30-day postoperative outcome. RESULTS: Eighty-six consecutive patients were included in the study cohort and compared to 63 patients from 2010 to 2011 and 75 patients from 2012 to 2013. Patient characteristics were comparable; median age in the study cohort was 80.6. Seventy-three patients (85%) participated in the program, 54 (63%) of whom followed a prehabilitation program, 46 (53%) of whom were discharged to a rehabilitation center. Laparoscopic surgery increased over the years from 70% to 83% in the study cohort. There was a trend in lower 1-year overall mortality: 11% versus 3% (p=0.08). There was a significant reduction in cardiac complications and the number of patients with a prolonged length of stay (p < 0.01). CONCLUSIONS: Multidisciplinary care for elderly colorectal cancer patients that includes prehabilitation and rehabilitation is feasible and may contribute to lower complications and reduced length of stay. This study did not show a clear benefit of implementing a comprehensive care program including both prehabilitation and rehabilitation. Dedicated multidisciplinary care seems the key attributer to favorable outcomes of CRC surgery in elderly patients.