Clinical and pharmacogenetic factors associated with irinotecan toxicity

Irinotecan is a topo-isomerase-I inhibitor with broad antitumor activity in solid tumors. Its use may lead to severe toxicities, predominantly neutropenia and diarrhea which can be life-threatening. This review discusses clinical determinants and pharmacogenetic factors associated with irinotecan toxicity. Age, performance status, co-medication and elevated transaminases have been associated with increased risk of diarrhea or neutropenia. Also, elevated bilirubin levels, due to liver impairment, conjugation disorders or UGT1A1 *28 genotype, have been associated with increased incidence of grades 3 intestinal toxicity and neutropenia. UGT1A1 *28 homozygosity is strongly associated with irinotecan-induced neutropenia and polymorphisms in the transporting peptides ABCB1 and OATP1B1 have also been associated with gastrointestinal toxicity and irinotecan pharmacokinetics, respectively. In the irinotecan product label, it is advised to reduce the irinotecan starting dose for UGT1A1 *28 homozygotes. However, due to the lack of prospective data, it is yet unknown whether dose reduction leads to reduced toxicity or altered antitumor effect. Combined toxicity analysis reveals that most patients experiencing grade 3-4 diarrhea and/or neutropenia are not homozygous for UGT1A1 *28. Future studies should combine pharmacogenetics with clinical determinants such as performance status and co-medication as to predict irinotecan toxicity and to develop predefined dosing algorithms.     

Multiplex pyrosequencing of two polymorphisms in DNA repair gene XRCC1

DNA repair enzymes play a pivotal role in platinum-based chemotherapy. Within the gene encoding for the base excision repair enzyme XRCC1, several nonsynonymous polymorphisms have been identified. It has been shown that the Arg399Gln single-nucleotide polymorphism results in a polymorphic enzyme that is less capable of initiating DNA repair. We developed a multiplex pyrosequence assay to simultaneously detect two nonsynonymous polymorphisms within the XRCC1 gene. Both of these polymorphisms resulted in amino acid changes: G/A in codon 399 changes Arg into Gln, and deletion of A in the second position of codon 576 results in a stopcodon. We established the frequency of these mutations in 270 patients suffering from colorectal cancer. Allele frequencies of G in second position of codon 399 and A in the second position codon 576 are 61.1 and 99.6%, respectively, in these patients. This fast and reliable method allows for simultaneous detection of the infrequent mutant C or CT alleles instead of the A deletion at codon 576. The method may be used in pharmacogenetic studies of platinum-based chemotherapy.     

Glutathione-S-transferase pi (GSTP1) codon 105 polymorphism is not associated with oxaliplatin efficacy or toxicity in advanced colorectal cancer patients

PurposeOxaliplatin is detoxified by conjugation to glutathione via the enzyme Glutathione-S-transferase pi (GSTP1). The aim of this study is to investigate the association of GSTP1 Ile105Val genetic polymorphism with oxaliplatin efficacy and toxicity in advanced colorectal cancer (ACC) patients.Experimental designA total of 91 ACC patients received capecitabine and oxaliplatin (CAPOX) as a part of a multicentre phase-III study of the Dutch Colorectal Cancer Group. Tumour response was evaluated according to RECIST, toxicity was graded using CTC, and GSTP1 Ile105Val was determined by pyrosequencing.ResultsOverall survival after CAPOX was similar for patients with the Ile/Ile (11.5 mo), Ile/Val (11.6 mo) and Val/Val (12.6 mo) genotypes (p = 0.602). Likewise, there were no statistically significant differences in progression-free survival (p = 0.252). Overall grades 3–4 toxicity was not related to genotype (p = 0.313). There were no differences in any grade or grades 3–4 neurotoxicity amongst the patients who received ?500 mg/m² of oxaliplatin (p-values of 0.376 and 0.772, respectively).ConclusionsThe results of this study indicate that the GSTP1 genotype is not predictive for progression-free survival or overall survival in ACC patients treated with CAPOX. Moreover, overall neurotoxicity and neurotoxicity in patients receiving ?500 mg/m² of oxaliplatin was not associated with GSTP1 genotype.     

‘Twin2twin’ an innovative method of empowering midwives to strengthen their professional midwifery organisations

Background

midwives need professional support from a national midwifery organisation to be able to provide the services that are by regulatory mechanisms and accreditation expected of them. Not all midwives in the world are united in a professional organisation. The aim of this project was to strengthen the midwifery organisations of Sierra Leone and the Netherlands. During the process of the project it was realised that the development of a platform of exchange at organisational level would be enhanced by introducing personal exchange between individual midwives. In response to this new insight the original project plan was adjusted by incorporating the twin2twin method.

Method

twin2twin is a feminist methodology of mutual exchange between twenty pairs of midwives from different organisations (in this case Sierra Leone and the Netherlands). The method can be distinguished by 10 specific steps. It was developed, used and (re)evaluated through focus group discussions, storytelling and written evaluations.

Findings

twinning of organisations was strengthened by adding a human component to the process. With the use of the ‘twin2twin’ method, midwives were encouraged to invested in a professional and personal bond with their ‘twin sister’. This bond was independent and went beyond the relatively short four year project period. Through personal engagement and mutual exchange of knowledge and skills, midwives empowered each other to build and strengthen their midwifery organisations both in Sierra Leone and the Netherlands. (Empowerment refers to the expansion in people's ability to make strategic life choices in a context where this ability was previously denied to them ( Narayan, 2005); organisational empowerment includes processes and structures that enhance members' skills and provides them with the mutual support necessary to effect community level change ( Zimmerman, 1995).).

Conclusion and implications for practice

despite challenges we are convinced that twin2twin can be of additional benefit for the success of other projects involved in strengthening midwifery organisations in the long term. It can be used independently or alongside other forms of (co)development not only in midwifery but also in other professions.     

Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array

Purpose:

To identify new polymorphisms (single nucleotide polymorphisms, SNPs) in DNA repair pathways that are associated with efficacy and toxicity in patients receiving oxaliplatin and capecitabine for advanced colorectal cancer (ACC).

Methods:

We studied progression-free survival (PFS) in 91 ACC patients, of whom germ-line DNA was isolated and genotyped using an Asper Biotech array. Overall survival (OS) and toxicity were studied as secondary end points. A step-wise selection of SNPs was performed, involving univariate and multivariate log-rank tests and Cox regression analysis, with age and performance status as covariates.

Results:

A total of 81 SNPs in 46 genes on the array were selected for further analysis, based on genotyping success rates and minor allele frequencies. After step-wise selection, we found that homozygosity for the ataxia telangiectasia mutated gene (ATM) rs1801516 or excision repair cross-complementing gene (ERCC5) rs1047768 SNPs was associated with shorter PFS; however there were no significant associations (P>0.01) with OS or toxicity.

Discussion:

This is the first study describing the pathway gene approach for the selection of new candidate genes involved in oxaliplatin efficacy and toxicity. The results suggest that the ATM and ERCC5 genes may be associated with oxaliplatin efficacy in ACC.     

UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study

The aim of the study was to investigate the associations between UGT1A1(*)28 genotype and (1) response rates, (2) febrile neutropenia and (3) dose intensity in patients with metastatic colorectal cancer treated with irinotecan. UGT1A1(*)28 genotype was determined in 218 patients receiving irinotecan (either first-line therapy with capecitabine or second-line as monotherapy) for metastatic colorectal cancer. TA(7) homozygotes receiving irinotecan combination therapy had a higher incidence of febrile neutropenia (18.2%) compared to the other genotypes (TA(6)/TA(6) : 1.5%; TA(6)/TA(7) : 6.5%, P=0.031). TA(7) heterozygotes receiving irinotecan monotherapy also suffered more febrile neutropenia (19.4%) compared to TA(6)/TA(6) genotype (2.2%; P=0.015). Response rates among genotypes were not different for both regimens: combination regimen, P=0.537; single-agent, P=0.595. TA(7) homozygotes did not receive a lower median irinotecan dose, number of cycles (P-values >or=0.25) or more frequent dose reductions compared to the other genotypes (P-values for trend; combination therapy: 0.62 and single-agent: 0.45). Reductions were mainly (>80%) owing to grade >or=3 diarrhoea, not (febrile) neutropenia. TA(7)/TA(7) patients have a higher incidence of febrile neutropenia upon irinotecan treatment, but were able to receive similar dose and number of cycles compared to other genotypes. Response rates were not significantly different.