Colorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of... Show moreColorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of quality of life, treatment discontinuation and sometimes even death. Moreover, chances for curation in the metastatic setting are low. Therefore, a large window of opportunity to improve both safety as well as efficacy of chemotherapeutic treatment for the individual patient exists. A possible approach to improve chemotherapeutic treatment for CRC patients could be the discovery, validation and implementation of new genetic biomarkers. The use of genetic biomarkers allows to identify patients that are at higher risk for severe adverse drug events and to select patients which will benefit the most from chemotherapy. The aim of this thesis was therefore to improve the safety and efficacy of chemotherapeutic drugs in patients with colorectal cancer by individualising drug dosing and choice of drug based on germline genetic biomarkers. The described studies in this thesis brought us a few steps closer to safe and effective use of chemotherapeutic drugs in the individual colorectal cancer patient. Irinotecan should no longer be administered without a UGT1A1 genotype test and a start has been made towards personalised medicine for colorectal cancer patients with peritoneal metastases. Show less
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes... Show moreThe Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of the anti-cancer drug irinotecan to decrease the risk of severe toxicity, such as (febrile) neutropenia or diarrhoea. Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1 encoded by the UGT1A1 gene) enzyme deficiency increases risk of irinotecan-induced toxicity. Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity. Homozygous or compound heterozygous carriers of these allele variants are defined as UGT1A1 poor metabolisers (PM). DPWG recommends a 70% starting dose in PM patients and no dose reduction in IM patients who start treatment with irinotecan. Based on the DPWG clinical implication score, UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment. Show less
Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study,... Show moreAim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd. Show less
Hulshof, E.C.; Deenen, M.J.; Guchelaar, H.J.; Gelderblom, H. 2020
Background: Pre-therapeutic UGT1A1 genotyping is not yet routinely performed in most hospitals in patients starting irinotecan chemotherapy. The aim of this position paper was to evaluate the... Show moreBackground: Pre-therapeutic UGT1A1 genotyping is not yet routinely performed in most hospitals in patients starting irinotecan chemotherapy. The aim of this position paper was to evaluate the available evidence and to assess the potential value of genotyping of UGT1A1*28 and UGT1A1*6 in patients before starting treatment with irinotecan to reduce the risk of severe toxicity.Methods: The literature was selected and assessed based on five pre-specified criteria: 1) the level of evidence for associations between UGT1A1 polymorphisms and irinotecan-induced severe toxicity, 2) clinical validity and utility of pre-therapeutic genotyping of UGT1A1, 3) safety and tolerability of irinotecan in carriers of UGT1A1 polymorphisms, 4) availability of specific dose recommendations for irinotecan in carriers of UGT1A1 polymorphisms, 5) evidence of cost benefits of pre-therapeutic genotyping of UGT1A1.Results: On all five criteria, study results were favourable for pre-therapeutic genotyping of UGT1A1. A high level of evidence (level I) was found for a higher incidence of irinotecan-induced severe toxicity in homozygous carriers of UGT1A1*28 or UGT1A1*6. The clinical validity and utility of this genetic test proved to be acceptable. Dose-finding studies showed a lower maximum tolerated dose in homozygous variant allele carriers, and most of the drug labels and guidelines recommend a dose reduction of 25-30% in these patients. In addition, pre-therapeutic genotyping of UGT1A1 is likely to save costs.Conclusion: Pre-therapeutic genotyping of UGT1A1 in patients initiating treatment with irinotecan improves patient safety, is likely to be cost-saving, and should, therefore, become standard of care. (C) 2020 The Author(s). Published by Elsevier Ltd. Show less
Background The introduction of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with either oxaliplatin or mitomycin C for patients with colorectal... Show moreBackground The introduction of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with either oxaliplatin or mitomycin C for patients with colorectal peritoneal metastasis (CPM) has resulted in a major increase in overall survival. Nonetheless, despite critical patient selection, the majority of patients will develop recurrent disease within one year following CRS + HIPEC. Therefore, improvement of patient and treatment selection is needed and may be achieved by the incorporation of genetic biomarkers. This systematic review aims to provide an overview of genetic biomarkers in the DNA repair pathway that are potentially predictive for treatment outcome of patients with colorectal peritoneal metastases treated with CRS + HIPEC with oxaliplatin or mitomycin C. Methods A systematic review was conducted according to the PRISMA guidelines. Given the limited number of genetic association studies of intraperitoneal mitomycin C and oxaliplatin in patients with CPM, we expanded the review and extrapolated the data from biomarker studies conducted in colorectal cancer patients treated with systemic mitomycin C- and oxaliplatin-based chemotherapy. Results In total, 43 papers were included in this review. No study reported potential pharmacogenomic biomarkers in patients with colorectal cancer undergoing mitomycin C-based chemotherapy. For oxaliplatin-based chemotherapy, a total of 26 genetic biomarkers within 14 genes were identified that were signi?cantly associated with treatment outcome. The most promising genetic biomarkers wereERCC1rs11615,XPCrs1043953,XPDrs13181,XPGrs17655,MNATrs3783819/rs973063/rs4151330, MMR status, ATM protein expression,HIC1tandem repeat D17S5, andPIN1rs2233678. Conclusion Several genetic biomarkers have proven predictive value for the treatment outcome of systemically administered oxaliplatin. By extrapolation, these genetic biomarkers may also be predictive for the efficacy of intraperitoneal oxaliplatin. This should be the subject of further investigation. Show less
Introduction: Mitomycin C (MMC) is commonly used in patients with colorectal peritoneal metastases (CPM) treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS +... Show moreIntroduction: Mitomycin C (MMC) is commonly used in patients with colorectal peritoneal metastases (CPM) treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). MMC requires metabolic activation prior to exert its cytotoxic effect of which the main activating enzymes are NQO1 and POR. However, not all patients are able to activate MMC for example due to polymorphisms in the genes encoding these enzymes. The aim of this study was to investigate the association of NQO1*2, NQO1*3, and POR*28 with the efficacy of CRS + HIPEC with MMC in patients with CPM.Method: A retrospective follow-up design was used to study genetic association in patients with histologically proven CPM treated with CRS + HIPEC with MMC with respect to peritoneal recurrence rate after 3 months (primary endpoint), after 6 months, disease-free survival and overall survival. Genetic polymorphisms NQO1*2, NQO1*3, and POR*28 were tested for association.Results: A total of 253 patients were included. In NQO1*3 carriers the peritoneal recurrence rate 3 and 6 months after HIPEC was significantly higher than in wild type patients, respectively 30.0% vs 3.8% (p = 0.009) and 40.0% vs 12.1% (p = 0.031). In line with these results, NQO1*3 was associated with a shorter disease-free survival (HR 2.04, 95% CI [1.03-4.03]). There was no significant association with overall survival (HR 1.42, 95% CI [0.66-3.07]).Conclusion: Carriership of the NQO1*3 allele is associated with worse peritoneal recurrence rate and disease-free survival. These results suggest that individualization of patients treated with CRS + HIPEC based upon pharmacogenetics may be beneficial. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
