Tolerance to anticancer drugs is determined by drug exposure and drug interactions, but also by side effects and the harm of interventions to prevent or reduce side ef- fects. The studies in this thesis are aimed at understanding and reducing the negative consequences of anticancer treatment. In Chapter 1, an introduction is given to side effects and factors that may influence the treatment with the chemotherapeutic agents capecitabine and paclitaxel, and with targeted therapies such as sorafenib. Additionally, an overview is given of the specific objectives of this thesis.
PART I: CHEMOTHERAPY
In Part I (Chapters 2-7), side effects and factors that may influence treatment with the chemotherapeutic drugs capecitabine and paclitaxel were investigated. The research in Chapter 2 describes a prospective investigation on hand-foot syndrome (HFS) and loss of fingerprints during treatment with capecitabine or tyrosine kinase inhibitors (TKIs) in a cohort of 112 patients. Within 8 weeks of treatment with capecitabine, severe finger- print loss was noted in 9 patients (14%). Only 4 of these 9 patients had HFS, while HFS was seen in 70% of the complete study population. There was no association between HFS and loss of fingerprints. Grades of HFS during capecitabine treatment were neither associated with the incidence of severe fingerprint loss. Newer drugs such as TKIs are known to develop hand-foot skin reaction (HFSR); a clinically and histopathological variant of HFS.1 2 In our study, fingerprint loss was infrequent during TKI treatment (n=1) and did not seem associated with HFSR. As this study had an explorative design, the mechanism of fingerprint loss could not be investigated. To date, there is no study with a plausible explanation for the mechanism underlying loss of fingerprints during capecitabine treatment.3 Although the loss of fingerprints can be considered a low-risk side effect, and with fingerprints returning within 2 to 4 weeks after cessation of treat- ment, our findings help to better inform patients about this side effect and to alert them to identification problems in daily life.4
Regarding the efficacy of capecitabine treatment, retrospective research pointed out a possible interaction of capecitabine and proton pump inhibitors (PPIs), potentially resulting in a reduced efficacy of capecitabine.5,6 In Chapter 3, we investigated the ef- fects of PPIs on capecitabine absorption in a randomized crossover study in 22 patients. Capecitabine pharmacokinetics were measured in 3 phases: A: with administration of the PPI esomeprazole three hours before capecitabine, B: with capecitabine alone, and C: with cola and esomeprazole administration. When esomeprazole was co-adminis- tered with capecitabine, there was an unexpected trend towards a 19% higher mean AUC0-inf of capecitabine (95%CL, -10% to 57%, P = 0.36) than when capecitabine was administered alone. As expected, concomitant cola did not reverse the effects observed after esomeprazole. This data illustrates that capecitabine exposure is not negatively influenced by esomeprazole co-treatment and therefore, altered capecitabine pharma- cokinetics do not explain the worse clinical outcome of PPI-co-treated cancer patients, which has been observed in previous retrospective cohort analyses. This is in line with other pharmacokinetic interaction studies, in which reduced capecitabine absorption was neither observed after Maalox 7 and rabeprazole 8 administration, nor in patients whom underwent gastrectomy.9 Hence, no hard conclusions can be drawn on the exis- tence of a true interaction between capecitabine and PPIs. Further prospective research is warranted to validate the presence of a pharmacodynamic drug-drug interaction between capecitabine and PPIs and, if present, to elucidate the mechanisms behind this interaction. Based on our results, we cannot conclude that there is a need to refrain from prescribing PPIs during capecitabine treatment. However, given the overuse of PPIs in cancer patients 10 it is prudent to routinely evaluate whether PPIs are needed during capecitabine treatment and, if possible, consider deprescribing.

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