Worse capecitabine treatment outcome in patients with a low skeletal muscle mass is not explained by altered pharmacokinetics

Molenaar-Kuijsten, Laura; Jacobs, Bart; Kurk, Sophie A; May, Anne M.; Dorlo, Thomas P. C.; Beijnen, J. H.; Steeghs, Neeltje; Huitema, Alwin D. R.

doi:10.1002/cam4.4038

Cited by 7 publications

(13 citation statements)

References 32 publications

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Section: Discussionmentioning

confidence: 94%

“…In addition, patients with low SMM were generally more likely to receive a lower cumulative cisplatin and carboplatin dose compared with patients with intermediate or high SMM, which is a potential validation of the need for dose reduction or different treatment regimens in patients with low SMM compared with patients with intermediate/high SMM. In a recent study among 151 patients with solid tumours treated with capecitabine (a hydrophilic chemotherapeutic agent), no alterations in pharmacokinetics of capecitabine and the active and toxic metabolite 5‐FU were observed in patients with low SMM 29 . The previously identified increased toxicity and decreased survival in patients with low SMM could therefore not be explained by changes in pharmacokinetic characteristics of capecitabine and its metabolites 29 .…”

Section: Discussionmentioning

confidence: 96%

“…In a recent study among 151 patients with solid tumours treated with capecitabine (a hydrophilic chemotherapeutic agent), no alterations in pharmacokinetics of capecitabine and the active and toxic metabolite 5‐FU were observed in patients with low SMM 29 . The previously identified increased toxicity and decreased survival in patients with low SMM could therefore not be explained by changes in pharmacokinetic characteristics of capecitabine and its metabolites 29 . In addition, according to a pharmacokinetic study, in 184 oesophageal cancer patients treated with paclitaxel, skeletal muscle measures were not superior to BSA in predicting pharmacokinetics of paclitaxel and did not have any added value to BSA 30 …”

Section: Discussionmentioning

confidence: 99%

“…29 The previously identified increased toxicity and decreased survival in patients with low SMM could therefore not be explained by changes in pharmacokinetic characteristics of capecitabine and its metabolites. 29 In addition, according to a pharmacokinetic study, in 184 oesophageal cancer patients treated with paclitaxel, skeletal muscle measures were not superior to BSA in predicting pharmacokinetics of paclitaxel and did not have any added value to BSA. 30 An additional explanation for a higher incidence of chemotherapy-induced toxicity in patients with low SMM is the correlation between low SMM and frailty, which has been observed in multiple studies performed in patients with head and neck cancer.…”

Section: Main Findingsmentioning

confidence: 94%

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The association between skeletal muscle measures and chemotherapy‐induced toxicity in non‐small cell lung cancer patients

Jong

Chargi

Herder

et al. 2022

J cachexia sarcopenia muscle

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Background Chemotherapy‐induced toxicities frequently occur in non‐small cell lung cancer (NSCLC) patients treated with platinum‐based chemotherapy. Low skeletal muscle mass (SMM) has been associated with a higher incidence of toxicities for several types of cancers and cytostatics. The aim of this study was to evaluate the association between skeletal muscle measures and chemotherapy‐induced toxicity in a large cohort of NSCLC patients. Methods A multicentre prospective follow‐up study (PGxLUNG, NTR number NL5373610015) in NSCLC patients was conducted. Included were patients diagnosed with NSCLC (stage II–IV) treated with first‐line platinum‐based (cisplatin or carboplatin) chemotherapy of whom pretreatment imaging was available. Skeletal muscle area (SMA) segmentation was performed on abdominal imaging at the level of the third lumbar vertebra (L3). SMA at the level of L3 was corrected for squared height (m2) to yield the lumbar skeletal muscle mass index (LSMI). Skeletal muscle density (SMD) was calculated as the mean Hounsfield Unit (HU) of the segmented SMA. SMM and SMD were categorized as low, intermediate, and high, based on LSMI and mean HU tertiles, respectively. Chemotherapy‐induced toxicity was scored using CTCAE v4.03 and categorized into haematological (anaemia, leukocytopenia, neutropenia, and thrombocytopenia), non‐haematological (nephrotoxicity, neurotoxicity, and esophagitis), and dose‐limiting toxicity (DLT) (treatment switch, delay, de‐escalation, discontinuation, or hospitalization). The relationship between SMM, SMD, and toxicities was assessed with logistic regression modelling taking into account potential confounders like gender and body mass index (BMI). Results In total, 297 patients (male n = 167, median age 64 years) were included. Haematological toxicity grade 3/4 was experienced in 36.6% (n = 108) of the patients, 24.6% (n = 73) experienced any non‐haematological toxicity grade ≥2, and 55.6% (n = 165) any DLT. Multivariate logistic regression analysis showed that low SMM (ORadj 2.41, 95% CI 1.31–4.45, P = 0.005) and age at diagnosis >65 years (ORadj 1.76, 95% CI 1.07–2.90, P = 0.025) were statistically significantly associated with overall haematological toxicity grade 3/4. No statistically significant associations were found between low SMM or low SMD and non‐haematological toxicities. Low SMM (ORadj 2.23, 95% CI 1.23–4.04, P = 0.008) and high SMD (ORadj 0.41, 95% CI 0.23–0.74, P = 0.003) were statistically significantly associated with a higher respectively lower risk of DLT. Conclusions Non‐small cell lung cancer patients with pretreatment low SMM are at significant higher risk for haematological toxicities grade 3/4 and DLT. NSCLC patients with high SMD are at significant lower risk for DLT. Further studies should be aimed to investigate whether platinum dosing based on skeletal muscle measurements and/or improvement of pretreatment SMM/SMD could reduce the risk of toxicity without compromising efficacy.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Main Findingsmentioning

confidence: 94%

See 2 more Smart Citations

The association between skeletal muscle measures and chemotherapy‐induced toxicity in non‐small cell lung cancer patients

Jong

Chargi

Herder

et al. 2022

J cachexia sarcopenia muscle

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“…Nevertheless, no changes in the PK properties of CAP and 5-FU were observed in patients with a low SMM. Therefore, the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by alterations in PK characteristics of CAP and its metabolites [ 33 ]. Taken together, substantial evidence indicated that systemic exposure to CAP and its metabolites in plasma was poorly predictive of safety and efficacy, which seemed to defeat the value of therapeutic drug monitoring for dosage adjustment [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

In vitro co-culture systems of hepatic and intestinal cells for cellular pharmacokinetic and pharmacodynamic studies of capecitabine against colorectal cancer

Huang

Zhang

et al. 2023

Cancer Cell Int

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Background As a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs. Methods Co-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for cellular PK in co-culture models. Results CAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP. Conclusion The simple and cost‑effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.

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Influence of the skeletal muscle index on pharmacokinetics and toxicity of fluorouracil

et al. 2022

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Background The body composition of patients has been associated with tolerability and effectiveness of anticancer therapy. This study aimed to assess the influence of the skeletal muscle index (SMI) on the pharmacokinetics and toxicity of fluorouracil. Methods Patients treated in an oncological practice with fluorouracil‐based chemotherapy and undergoing therapeutic drug monitoring were retrospectively investigated. Computed tomography images were analyzed to measure abdominal skeletal muscle areas in Hounsfield units for the psoas major muscle, back and total skeletal muscle to determine the SMI. For the latter, an automated segmentation method was used additionally. SMI measures were tested as covariates on fluorouracil clearance in a population pharmacokinetic model. Furthermore, regression analyses were performed to analyze the influence of SMI measures on the probability of clinically relevant adverse events (CTCAE grades ≥ 2). Results Fluorouracil plasma concentrations of 111 patients were available. Covariate analyses showed significant improvements of the model fit by all SMI measures. However, interindividual variability of fluorouracil clearance was only slightly reduced, whereas the SMI of the back muscle showed the largest reduction (−1.1 percentage points). Lower SMI values of the back muscle increased the probability for polyneuropathy and lower SMI of the psoas increased the probability for fatigue. Conclusions Our results suggest that pharmacokinetics and toxicity of fluorouracil may be associated with specific SMI measures which deserve further investigation.

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Worse capecitabine treatment outcome in patients with a low skeletal muscle mass is not explained by altered pharmacokinetics

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 32 publications

The association between skeletal muscle measures and chemotherapy‐induced toxicity in non‐small cell lung cancer patients

The association between skeletal muscle measures and chemotherapy‐induced toxicity in non‐small cell lung cancer patients

In vitro co-culture systems of hepatic and intestinal cells for cellular pharmacokinetic and pharmacodynamic studies of capecitabine against colorectal cancer

Influence of the skeletal muscle index on pharmacokinetics and toxicity of fluorouracil

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