The effect of prehabilitation on long-term survival and hospital admissions in older patients undergoing elective colorectal cancer surgery.

INTRODUCTION: There is a growing body of evidence for a beneficial effect of prehabilitation on short-term outcomes after colorectal cancer (CRC) surgery in older patients. However, long-term effects on survival or hospital admissions have not been investigated. This study reports these long-term outcomes from a previously published observational cohort study. METHODS: We compared patients ≥75 years who received elective CRC surgery in Reinier de Graaf Hospital before (2010-2013: standard care) and after implementation of a multimodal prehabilitation program (2014-2015; prehabilitation). With a six-year follow-up period, we analyzed survival using the Kaplan-Meier method and the occurrence of one or more hospital admissions using logistic regression analyses. RESULTS: Overall, 137 patients were included in the standard care group and 86 patients in the prehabilitation group. There were no differences in patients, tumor and treatment characteristics. After six years, 51.1% in the standard care group and 59.3% in the prehabilitation group (p = 0.167) were still alive. When corrected for confounders in the prehabilitation group less patients had one or more hospital admissions during follow-up (odds ratio (OR) 0.43 (95% CI 0.24-0.77). CONCLUSIONS: Unfortunately these limited historical cohorts did not allow for strong conclusions concerning long-time survival. However, after prehabilitation less patients had hospital admissions during follow up. Hopefully, this first study into the long-term effects of multimodal prehabilitation will trigger more future research.

Recognition of cognitive dysfunction in hospitalised older patients: a flash mob study.

BACKGROUND: It is important that healthcare professionals recognise cognitive dysfunction in hospitalised older patients in order to address associated care needs, such as enhanced involvement of relatives and extra cognitive and functional support. However, studies analysing medical records suggest that healthcare professionals have low awareness of cognitive dysfunction in hospitalised older patients. In this study, we investigated the prevalence of cognitive dysfunction in hospitalised older patients, the percentage of patients in which cognitive dysfunction was recognised by healthcare professionals, and which variables were associated with recognition. METHODS: A multicentre, nationwide, cross-sectional observational study was conducted on a single day using a flash mob study design in thirteen university and general hospitals in the Netherlands. Cognitive function was assessed in hospitalised patients aged ≥ 65 years old, who were admitted to medical and surgical wards. A Mini-Cog score of < 3 out of 5 indicated cognitive dysfunction. The attending nurses and physicians were asked whether they suspected cognitive dysfunction in their patient. Variables associated with recognition of cognitive dysfunction were assessed using multilevel and multivariable logistic regression analyses. RESULTS: 347 of 757 enrolled patients (46%) showed cognitive dysfunction. Cognitive dysfunction was recognised by attending nurses in 137 of 323 patients (42%) and by physicians in 156 patients (48%). In 135 patients (42%), cognitive dysfunction was not recognised by either the attending nurse or physician. Recognition of cognitive dysfunction was better at a lower Mini-Cog score, with the best recognition in patients with the lowest scores. Patients with a Mini-Cog score < 3 were best recognised in the geriatric department (69% by nurses and 72% by physicians). CONCLUSION: Cognitive dysfunction is common in hospitalised older patients and is poorly recognised by healthcare professionals. This study highlights the need to improve recognition of cognitive dysfunction in hospitalised older patients, particularly in individuals with less apparent cognitive dysfunction. The high proportion of older patients with cognitive dysfunction suggests that it may be beneficial to provide care tailored to cognitive dysfunction for all hospitalised older patients.

Delirium in older patients with COVID-19: Prevalence, risk factors and clinical outcomes across the first three waves of the pandemic.

OBJECTIVES: Delirium is a serious condition, which poses treatment challenges during hospitalisation for COVID-19. Improvements in testing, vaccination and treatment might have changed patient characteristics and outcomes through the pandemic. We evaluated whether the prevalence and risk factors for delirium, and the association of delirium with in-hospital mortality changed through the pandemic. METHODS: This study was part of the COVID-OLD study in 19 Dutch hospitals including patients ≥70 years in the first (spring 2020), second (autumn 2020) and third wave (autumn 2021). Multivariable logistic regression models were used to study risk factors for delirium, and in-hospital mortality. Differences in effect sizes between waves were studied by including interaction terms between wave and risk factor in logistic regression models. RESULTS: 1540, 884 and 370 patients were included in the first, second and third wave, respectively. Prevalence of delirium in the third wave (12.7%) was significantly lower compared to the first (22.5%) and second wave (23.5%). In multivariable-adjusted analyses, pre-existing memory problems was a consistent risk factor for delirium across waves. Previous delirium was a risk factor for delirium in the first wave (OR 4.02), but not in the second (OR 1.61) and third wave (OR 2.59, p-value interaction-term 0.028). In multivariable-adjusted analyses, delirium was not associated with in-hospital mortality in all waves. CONCLUSION: Delirium prevalence declined in the third wave, which might be the result of vaccination and improved treatment strategies. Risk factors for delirium remained consistent across waves, although some attenuation was seen in the second wave.

Chemotherapy-Related Toxic Effects and Quality of Life and Physical Functioning in Older Patients.

Importance: Although older patients are at increased risk of developing grade 3 or higher chemotherapy-related toxic effects, no studies, to our knowledge, have focused on the association between toxic effects and quality of life (QOL) and physical functioning. Objective: To investigate the association between grade 3 or higher chemotherapy-related toxic effects and QOL and physical functioning over time in older patients. Design, Setting, and Participants: In this prospective, multicenter cohort study, patients aged 70 years or older who were scheduled to receive chemotherapy with curative or palliative intent and a geriatric assessment were included. Patients were treated with chemotherapy between December 2015 and December 2021. Quality of life and physical functioning were analyzed at baseline and after 6 months and 12 months. Exposures: Common Terminology Criteria for Adverse Events grade 3 or higher chemotherapy-related toxic effects. Main Outcomes and Measures: The main outcome was a composite end point, defined as a decline in QOL and/or physical functioning or mortality at 6 months and 12 months after chemotherapy initiation. Associations between toxic effects and the composite end point were analyzed with multivariable logistic regression models. Results: Of the 276 patients, the median age was 74 years (IQR, 72-77 years), 177 (64%) were male, 196 (71%) received chemotherapy with curative intent, and 157 (57%) had gastrointestinal cancers. Among the total patients, 145 (53%) had deficits in 2 or more of the 4 domains of the geriatric assessment and were classified as frail. Grade 3 or higher toxic effects were observed in 94 patients (65%) with frailty and 66 (50%) of those without frailty (P = .01). Decline in QOL and/or physical functioning or death was observed in 76% of patients with frailty and in 64% to 68% of those without frailty. Among patients with frailty, grade 3 or higher toxic effects were associated with the composite end point at 6 months (odds ratio [OR], 2.62; 95% CI, 1.14-6.05) but not at 12 months (OR, 1.09; 95% CI, 0.45-2.64) and were associated with mortality at 12 months (OR, 3.54; 95% CI, 1.50-8.33). Toxic effects were not associated with the composite end point in patients without frailty (6 months: OR, 0.76; 95% CI, 0.36-1.64; 12 months: OR, 1.06; 95% CI, 0.46-2.43). Conclusions and Relevance: In this prospective cohort study of 276 patients aged 70 or older who were treated with chemotherapy, patients with frailty had more grade 3 or higher toxic effects than those without frailty, and the occurrence of toxic effects was associated with a decline in QOL and/or physical functioning or mortality after 1 year. Toxic effects were not associated with poor outcomes in patients without frailty. Pretreatment frailty screening and individualized treatment adaptions could prevent a treatment-related decline of remaining health.

Atypical presentation of COVID-19 in older patients is associated with frailty but not with adverse outcomes.

PURPOSE: Older patients with COVID-19 can present with atypical complaints, such as falls or delirium. In other diseases, such an atypical presentation is associated with worse clinical outcomes. However, it is not known whether this extends to COVID-19. We aimed to study the association between atypical presentation of COVID-19, frailty and adverse outcomes, as well as the incidence of atypical presentation. METHODS: We conducted a retrospective observational multi-center cohort study in eight hospitals in the Netherlands. We included patients aged ≥ 70 years hospitalized with COVID-19 between February 2020 until May 2020. Atypical presentation of COVID-19 was defined as presentation without fever, cough and/or dyspnea. We collected data concerning symptoms on admission, demographics and frailty parameters [e.g., Charlson Comorbidity Index (CCI) and Clinical Frailty Scale (CFS)]. Outcome data included Intensive Care Unit (ICU) admission, discharge destination and 30-day mortality. RESULTS: We included 780 patients, 9.5% (n = 74) of those patients had an atypical presentation. Patients with an atypical presentation were older (80 years, IQR 76-86 years; versus 79 years, IQR 74-84, p = 0.044) and were more often classified as severely frail (CFS 6-9) compared to patients with a typical presentation (47.6% vs 28.7%, p = 0.004). Overall, there was no significant difference in 30-day mortality between the two groups in univariate analysis (32.4% vs 41.5%; p = 0.173) or in multivariate analysis [OR 0.59 (95% CI 0.34-1.0); p = 0.058]. CONCLUSIONS: In this study, patients with an atypical presentation of COVID-19 were more frail compared to patients with a typical presentation. Contrary to our expectations, an atypical presentation was not associated with worse outcomes.

Surgical and non-surgical complications after colorectal cancer surgery in older patients; time-trends and age-specific differences.

BACKGROUND: Trends of surgical and non-surgical complications among the old, older and oldest patients after colorectal cancer (CRC) surgery could help to identify the best target outcome to further improve postoperative outcome. MATERIALS AND METHODS: All consecutive patients ≥70 years receiving curative elective CRC resection between 2011 and 2019 in The Netherlands were included. Baseline variables and postoperative complications were prospectively collected by the Dutch ColoRectal audit (DCRA). We assessed surgical and non-surgical complications over time and within age categories (70-74, 75-79 and ≥ 80 years) and determined the impact of age on the risk of both types of complications by using multivariate logistic regression analyses. RESULTS: Overall, 38648 patients with a median age of 76 years were included. Between 2011 and 2019 the proportion of ASA score ≥3 and laparoscopic surgery increased. Non-surgical complications significantly improved between 2011 (21.8%) and 2019 (17.1%) and surgical complications remained constant (from 17.6% to 16.8%). Surgical complications were stable over time for each age group. Non-surgical complications improved in the oldest two age groups. Increasing age was only associated with non-surgical complications (75-79 years; OR 1.17 (95% CI 1.10-1.25), ≥80 years; OR 1.46 (95% CI 1.37-1.55) compared to 70-74 years), not with surgical complications. CONCLUSION: The reduction of postoperative complications in the older CRC population was predominantly driven by a decrease in non-surgical complications. Moreover, increasing age was only associated with non-surgical complications and not with surgical complications. Future care developments should focus on non-surgical complications, especially in patients ≥75 years.

Delirium in older COVID-19 patients: Evaluating risk factors and outcomes.

OBJECTIVES: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. METHODS: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. RESULTS: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3-33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1-22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40-1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71-4.72] p < 0.001), but not in multivariable analyses. CONCLUSIONS: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty.

Validation of the ACS NSQIP surgical risk calculator in older patients with colorectal cancer undergoing elective surgery.

BACKGROUND: For clinical decision making it is important to identify patients at risk for adverse outcomes after colorectal cancer (CRC) surgery, especially in the older population. Because the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) surgical risk calculator is potentially useful in clinical practice, we performed an external validation in a Dutch multicenter cohort of patients ≥70 years undergoing elective non-metastatic CRC surgery. METHODS: We compared the ACS NSQIP calculator mean predicted risk to the overall observed rate of anastomotic leakage, return to operation room, pneumonia, discharge not to home, and readmission in our cohort using a one-sample Z-test. Calibration plots and receiver operating characteristic (ROC) curves were used to determine the calculator's performance. RESULTS: Six hundred eighty-two patients were included. Median age was 76.2 years. The ACS NSQIP calculator accurately predicted the overall readmission rate (predicted: 8.6% vs. observed: 7.8%, p = 0.456), overestimated the rate of discharge not to home (predicted:11.2% vs. observed: 7.0% p = 0.005) and underestimated the observed rate of all other outcomes. The calibration plots showed poor calibration for all outcomes. The ROC-curve showed an area under the curve (AUC) of 0.75 (95% confidence interval [CI] 0.67-0.83) for pneumonia and 0.70 (0.62-0.78) for discharge not to home. The AUC for all other outcomes was poor. CONCLUSIONS: The ACS NSQIP surgical risk calculator had a poor individual risk prediction (calibration) for all outcomes and only a fair discriminative ability (discrimination) to predict pneumonia and discharge not to home. The calculator might be considered to identify patients at high risk of pneumonia and discharge not to home to initiate additional preoperative interventions.

Characteristics and outcomes of older patients hospitalised for COVID-19 in the first and second wave of the pandemic in The Netherlands: the COVID-OLD study.

BACKGROUND: as the coronavirus disease of 2019 (COVID-19) pandemic progressed diagnostics and treatment changed. OBJECTIVE: to investigate differences in characteristics, disease presentation and outcomes of older hospitalised COVID-19 patients between the first and second pandemic wave in The Netherlands. METHODS: this was a multicentre retrospective cohort study in 16 hospitals in The Netherlands including patients aged ≥ 70 years, hospitalised for COVID-19 in Spring 2020 (first wave) and Autumn 2020 (second wave). Data included Charlson comorbidity index (CCI), disease severity and Clinical Frailty Scale (CFS). Main outcome was in-hospital mortality. RESULTS: a total of 1,376 patients in the first wave (median age 78 years, 60% male) and 946 patients in the second wave (median age 79 years, 61% male) were included. There was no relevant difference in presence of comorbidity (median CCI 2) or frailty (median CFS 4). Patients in the second wave were admitted earlier in the disease course (median 6 versus 7 symptomatic days; P < 0.001). In-hospital mortality was lower in the second wave (38.1% first wave versus 27.0% second wave; P < 0.001). Mortality risk was 40% lower in the second wave compared with the first wave (95% confidence interval: 28-51%) after adjustment for differences in patient characteristics, comorbidity, symptomatic days until admission, disease severity and frailty. CONCLUSIONS: compared with older patients hospitalised in the first COVID-19 wave, patients in the second wave had lower in-hospital mortality, independent of risk factors for mortality.The better prognosis likely reflects earlier diagnosis, the effect of improvement in treatment and is relevant for future guidelines and treatment decisions.

Can physical prehabilitation prevent complications after colorectal cancer surgery in frail older patients?

INTRODUCTION: Frail patients with colorectal cancer (CRC) are at increased risk of complications after surgery. Prehabilitation seems promising to improve this outcome and therefore we evaluated the effect of physical prehabilitation on postoperative complications in a retrospective cohort of frail CRC patients. METHODS: The study consisted of all consecutive non-metastatic CRC patients ≥70 years who had elective surgery from 2014 to 2019 in a teaching hospital in the Netherlands, where a physical prehabilitation program was implemented from 2014 on. We performed both an intention-to-treat and per protocol analysis to evaluate postoperative complications in the physical prehabilitation (PhP) and non-prehabilitation (NP) group. RESULTS: Eventually, 334 elective patients were included. The 124 (37.1%) patients in the PhP-group presented with higher age, higher comorbidity scores and walking-aid use compared to the NP-group. Medical complications occurred in 26.6% of the PhP-group and in 20.5% of the NP-group (p = 0.20) and surgical complications in 19.4% and 14.3% (p = 0.22) respectively. In all frailty subgroups, the medical complications were lower in the PhP-group compared to the NP-group (35.9% vs. 45.5% for patients with ≥2 comorbidities, 36.2% vs. 39.1% for ASA score ≥ III, 29.2% vs. 45.8% for walking-aid use). Differences were not significant. CONCLUSIONS: In this study, patients selected for physical prehabilitation had a worse frailty profile and therefore a higher a priori risk of postoperative complications. However, the postoperative complication rate was not increased compared to patients who were less frail at baseline and without prehabilitation. Hence, physical prehabilitation may prevent postoperative complications in frail CRC patients ≥70 years.

Frailty is associated with in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands: the COVID-OLD study.

BACKGROUND: During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, older patients had an increased risk of hospitalisation and death. Reports on the association of frailty with poor outcome have been conflicting. OBJECTIVE: The aim of the present study was to investigate the independent association between frailty and in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands. METHODS: This was a multicentre retrospective cohort study in 15 hospitals in the Netherlands, including all patients aged ≥70 years, who were hospitalised with clinically confirmed COVID-19 between February and May 2020. Data were collected on demographics, co-morbidity, disease severity and Clinical Frailty Scale (CFS). Primary outcome was in-hospital mortality. RESULTS: A total of 1,376 patients were included (median age 78 years (interquartile range 74-84), 60% male). In total, 499 (38%) patients died during hospital admission. Parameters indicating presence of frailty (CFS 6-9) were associated with more co-morbidities, shorter symptom duration upon presentation (median 4 versus 7 days), lower oxygen demand and lower levels of C-reactive protein. In multivariable analyses, the CFS was independently associated with in-hospital mortality: compared with patients with CFS 1-3, patients with CFS 4-5 had a two times higher risk (odds ratio (OR) 2.0 (95% confidence interval (CI) 1.3-3.0)) and patients with CFS 6-9 had a three times higher risk of in-hospital mortality (OR 2.8 (95% CI 1.8-4.3)). CONCLUSIONS: The in-hospital mortality of older hospitalised COVID-19 patients in the Netherlands was 38%. Frailty was independently associated with higher in-hospital mortality, even though COVID-19 patients with frailty presented earlier to the hospital with less severe symptoms.

Design and rationale of a routine clinical care pathway and prospective cohort study in older patients needing intensive treatment.

BACKGROUND: Treatment decisions concerning older patients can be very challenging and individualised treatment plans are often required in this very heterogeneous group. In 2015 we have implemented a routine clinical care pathway for older patients in need of intensive treatment, including a comprehensive geriatric assessment (CGA) that was used to support clinical decision making. An ongoing prospective cohort study, the Triaging Elderly Needing Treatment (TENT) study, has also been initiated in 2016 for participants in this clinical care pathway, to study associations between geriatric characteristics and outcomes of treatment that are relevant to older patients. The aim of this paper is to describe the implementation and rationale of the routine clinical care pathway and design of the TENT study. METHODS: A routine clinical care pathway has been designed and implemented in multiple hospitals in the Netherlands. Patients aged ≥70 years who are candidates for intensive treatments, such as chemotherapy, (chemo-)radiation therapy or major surgery, undergo frailty screening based on the Geriatric 8 (G-8) questionnaire and the Six-Item Cognitive Impairment Test (6CIT). If screening reveals potential frailty, a CGA is performed. All patients are invited to participate in the TENT study. Clinical data and blood samples for biomarker studies are collected at baseline. During follow-up, information about treatment complications, hospitalisations, functional decline, quality of life and mortality is collected. The primary outcome is the composite endpoint of functional decline or mortality at 1 year. DISCUSSION: Implementation of a routine clinical care pathway for older patients in need of intensive treatment provides the opportunity to study associations between determinants of frailty and outcomes of treatment. Results of the TENT study will support individualised treatment for future patients. TRIAL REGISTRATION: The study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107 . Date of registration: 22-10-2019.

Influence of smoking on the pharmacokinetics and toxicity profiles of taxane therapy.

PURPOSE: Cigarette smoke is known to interact with the metabolism of several anticancer drugs. It may also affect the incidence and severity of adverse events and efficacy of chemotherapy. The main objective of this study was to examine the effects of smoking on the pharmacokinetics and toxicities of patients treated with docetaxel or paclitaxel. EXPERIMENTAL DESIGN: Smoking status, toxicity profiles, and pharmacokinetic parameters (calculated by nonlinear mixed-effect modeling population analysis) were determined in 566 patients (429 nonsmokers and 137 smokers) treated with docetaxel or paclitaxel. RESULTS: Smokers treated with docetaxel showed less grade IV neutropenia (35% vs. 52%; P = 0.01) than nonsmokers. Smokers treated with paclitaxel had less grade III-IV leukopenia than nonsmokers (12% vs. 25%; P = 0.03), and the white blood cell (WBC) nadir was lower in nonsmokers (median, 2.7 × 10(9)/L; range, 0.05 × 10(9) to 11.6 × 10(9)/L) than in smokers (median, 3.3 × 10(9)/L; range 0.8 × 10(9) to 10.2 × 10(9)/L; P = 0.02). Of interest, significantly lower WBC counts and absolute neutrophil counts at baseline were seen in nonsmoking patients treated with paclitaxel (P = 0.0001). Pharmacokinetic parameters were similar in smokers and nonsmokers for both taxanes. CONCLUSION: Cigarette smoking does not alter the pharmacokinetic determinants of docetaxel and paclitaxel. Smokers treated with docetaxel and paclitaxel have less neutropenia and leukopenia, but further research is warranted to elucidate this potential protective effect.

Therapeutic drug monitoring for the individualization of docetaxel dosing: a randomized pharmacokinetic study.

PURPOSE: Docetaxel pharmacokinetic (PK) parameters, notably clearance and exposure (AUC), are characterized by large interindividual variability. The purpose of this study was to evaluate the effect of PK-guided [area under the plasma concentration versus time curve (AUC) targeted], individualized docetaxel dosing on interindividual variability in exposure. EXPERIMENTAL DESIGN: A limited sampling strategy in combination with a validated population PK model, Bayesian analysis, and a predefined target AUC was used. Fifteen patients were treated for at least 2 courses with body surface area-based docetaxel and 15 with at least 1 course of PK-guided docetaxel dosing. RESULTS: Interindividual variability (SD of ln AUC) was decreased by 35% (N = 15) after 1 PK-guided course; when all courses were evaluated, variability was decreased by 39% (P = 0.055). PK-guided dosing also decreased the interindividual variability of percentage decrease in white blood cell and absolute neutrophil counts by approximately 50%. CONCLUSIONS: Further research is required to determine whether the decrease in PK variability can contribute to a reduction in interindividual variability in efficacy and toxicity.

Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study.

BACKGROUND: Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan. METHODS: Fourteen patients were treated with single agent irinotecan (600mg i.v., 90min) followed 3weeks later by a second cycle with concurrent use of omeprazole 40mg once daily, which was started 2weeks prior to the second cycle. Plasma samples were obtained up to 55h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS. RESULTS: The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole. CONCLUSION: Omeprazole 40mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.

Effects of methimazole on the elimination of irinotecan.

PURPOSE: To study the possible pharmacokinetic and pharmacodynamic interactions between irinotecan and methimazole. METHODS: A patient treated for colorectal cancer with single agent irinotecan received methimazole co-medication for Graves' disease. Irinotecan pharmacokinetics and side effects were followed during a total of four courses (two courses with and two courses without methimazole). RESULTS: Plasma concentrations of the active irinotecan metabolite SN-38 and its inactive metabolite SN-38-Glucuronide were both higher (a mean increase of 14 and 67%, respectively) with methimazole co-medication, compared to irinotecan monotherapy. As a result, the mean SN-38 glucuronidation rate increased with 47% during concurrent treatment. Other possible confounding factors did not change over time. Specific adverse events due to methimazole co-treatment were not seen. CONCLUSIONS: Additional in vitro experiments suggest that these results can be explained by induction of UGT1A1 by methimazole, leading to higher SN-38G concentrations. The prescribed combination of these drugs may lead to highly toxic intestinal SN-38 levels. We therefore advise physicians to be very careful in combining methimazole with regular irinotecan doses, especially in patients who are prone to irinotecan toxicity.

Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia.

OBJECTIVE: Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors. PATIENTS AND METHODS: Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (-550 H/L and -221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course. RESULTS: Of the 133 patients, 28% experienced severe neutropenia and 10% experienced febrile neutropenia. No associations were found between exon polymorphisms and febrile neutropenia. However, patients with the H/H promoter genotype, associated with high MBL levels, experienced significantly more febrile neutropenia than patients with the H/L and L/L genotypes (20% versus 13% versus 5%). Moreover, patients with the HYA haplotype encountered significantly more febrile neutropenia than patients without this high MBL-producing haplotype (16% versus 4%). In the subgroup with wild-type exon polymorphisms (A/A), patients with the high MBL promoter phenotype had the highest incidence of febrile neutropenia, regardless of known risk factors. CONCLUSION: Patients with high MBL2 promoter genotypes and haplotypes seem more at risk for developing febrile neutropenia. If confirmed, these preliminary findings may contribute to more individualized approaches of irinotecan treatment.

A CYP3A4 phenotype-based dosing algorithm for individualized treatment of irinotecan.

PURPOSE: Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test. EXPERIMENTAL DESIGN: Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m(2) (group A) or doses based on an equation consisting of midazolam clearance, gamma-glutamyl-transferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course. RESULTS: Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%). CONCLUSIONS: Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment.

Irinotecan chemotherapy during valproic acid treatment: pharmacokinetic interaction and hepatotoxicity.

PURPOSE: Because of its supposed inhibiting capacities of uridine-diphosphate glucuronosyltransferase 1A (UGT1A)-mediated glucuronidation in rats, the antiepileptic drug valproic acid has been investigated as modulator of irinotecan-induced delayed-type diarrhea in rats. Here, we report on the pharmacokinetic and pharmacodynamic effects of this combination in a cancer patient. EXPERIMENTAL DESIGN: A patient who used valproic acid was administered irinotecan (600 mg). To investigate dose-limiting hepatotoxicity encountered during the first course, which was clinically attributed to a supposed higher exposure to the active irinotecan metabolite SN-38, valproic acid was tapered off. Blood samples for pharmacokinetic purposes were drawn during a course with and a course without concomitant valproic acid. Plasma-levels of irinotecan, SN-38, and SN-38G were determined using HPLC-assays. RESULTS: When irinotecan was combined with valproic acid, the exposure to SN-38 was 41% lower. Additionally, reversible elevations of the liver enzyme tests were noted. In particular, seven days after irinotecan administration gammaGT and transaminase levels raised up to 5.3-11.3 times the ULN (CTCAE grade 3). CONCLUSIONS: Valproic acid-induced plasma protein binding displacement and/or metabolic modulation of enzymes and drug transporters involved in irinotecan disposition may explain the reduced exposure to SN-38 in the presence of valproic acid. Given the herewith-coupled potential undertreatment, patients should firstly switch to another antiepileptic drug not known to interfere with irinotecan treatment. Additionally, this particular combination should not be implemented in clinical studies without simultaneously adjusting the irinotecan dose, and the risk of (severe) hepatotoxicity should be considered when designing protocols studying valproic acid (as histone deacetylase-inhibitor) in combination with other (anticancer) drugs.