Paclitaxel is a cytotoxic agent with proven antitumour activity in metastatic breast cancer. Weekly administration of paclitaxel has demonstrated sustained efficacy together with a more favourable ...toxicity profile (e.g. less myelotoxicity) than the 3-weekly administration. This study evaluates the activity and toxicity of weekly paclitaxel (Taxol®) as first-line chemotherapy in elderly patients (>70 years of age) with hormone-refractory metastatic breast cancer. Patients with metastatic breast cancer received 80 mg/m2 paclitaxel administered weekly on days 1, 8 and 15 of a 28-day cycle. Additional cycles were given until disease progression, or unacceptable toxicity. A dose increase to 90 mg/m2 was allowed in the absence of toxicity. 26 Patients received a total of 101 cycles (median 4, range 1–11). 22 patients completed at least two cycles (six administrations). In 23 patients who were evaluable for response, there were 10 partial responses (38%), 9 patients with stable disease (35%), while 4 patients had disease progression (15%). The median duration of response was 194 days (>6 months). Overall treatment was relatively well tolerated, but 8 patients (32%) had to prematurely discontinue treatment because of fatigue. Neuropathy >grade 1 was noted only after five or more cycles in 4 patients. Weekly paclitaxel at this dose and schedule is an effective treatment regimen in the elderly patient with metastatic breast cancer, and is feasible, but yields relevant fatigue in a subset of patients.
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To prospectively study the pharmacokinetics and toxicity profile of docetaxel in elderly patients with cancer.
Docetaxel was administered at a dose 75 mg/m(2) once every 3 weeks to 25 elderly cancer ...patients aged >/= 65 years and 26 cancer patients aged younger than 65 years. Pharmacokinetic studies and toxicity assessments were performed during the first cycle of therapy.
Of 51 patients treated, 20 aged >/= 65 years (median, 71 years; range, 65 to 80 years) and 20 aged younger than 65 years (median, 53 years; range, 26 to 64 years) were assessable for pharmacokinetic studies, and 39 were assessable for toxicity. Patient characteristics were similar (P >/= .15) between the two cohorts. Mean docetaxel clearance was not altered in the elderly versus younger patients: 30.1 L/h (standard deviation SD 18.3 L/h) v 30.0 L/h (SD, 14.8 L/h; P = .98). The percentage of patients with grade 4 and febrile neutropenia was higher in the elderly (63% and 16%, respectively) versus younger (30% and 0%, respectively) cohort, although this observation did not reach a level of statistical significance (P = .056). From logistic regression analysis, the odds ratio for a patient aged 65 years was 1.98 for developing grade 4 neutropenia compared with a patient aged 50 years (P = .091).
Docetaxel plasma pharmacokinetics are unaltered in elderly patients. Patients aged >/= 65 years appear to be more sensitive to docetaxel-induced neutropenia.
Purpose: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer
patients
Experimental Design: A total of 134 patients (62 females; ...age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe
of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 ( CYP3A4*1B , CYP3A4*6 , CYP3A4*17 , and CYP3A4*18 ) and CYP3A5 ( CYP3A5*3C and CYP3A5*6 ).
Results: CYP3A activity ( AUC 0–40min ) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity ( P > 0.2954). CYP3A activity was reduced by ∼50% in patients with concurrent elevations in liver transaminases and alkaline
phosphatase or elevated total bilirubin ( P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures
( P > 0.05), but liver function combined with the concentration of the acute-phase reactant, α-1 acid glycoprotein, explained
∼18% of overall variation in CYP3A activity ( P < 0.001).
Conclusions: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic
CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive
protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory
and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.
Objective
In vitro studies indicate that the anticancer drug docetaxel is primarily eliminated by cytochrome P450 (CYP) 3A4–mediated metabolism. Coadministration of drugs that modulate the activity ...of CYP3A4 is, therefore, likely to have undesirable clinical consequences. We investigated the effects of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of docetaxel in patients with cancer.
Methods
Seven patients were treated in a randomized crossover design with docetaxel (100 mg/m2), followed 3 weeks later by docetaxel (10 mg/m2) given in combination with orally administered ketoconazole (200 mg once daily for 3 days), or the reverse sequence. Plasma concentration–time data were analyzed by noncompartmental analysis.
Results
Ketoconazole coadministration resulted in a 49% decrease in clearance of docetaxel (P = .018). The mean (±SD) clearance values were 35.0 ± 11.8 L/h (95% confidence interval, 24.1–45.9 L/h) for docetaxel alone and 18.2 L/h (95% confidence interval, 9.22–27.1 L/h) in the presence of ketoconazole, respectively. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the area under the curve of ketoconazole (R2 = 0.529, P = .064).
Conclusion
Inhibition of CYP3A4 by ketoconazole in vivo results in docetaxel clearance values that have previously been shown to be associated with a several‐fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dose reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4.
Clinical Pharmacology & Therapeutics (2004) 75, 448–454; doi: 10.1016/j.clpt.2004.01.001
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Introduction
Local treatment of metastases is frequently performed in patients with multiorgan metastatic colorectal carcinoma (mCRC) analogous to selected patients with oligometastatic disease for ...whom this is standard of care. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multiorgan mCRC. Here, we report the preplanned safety and feasibility evaluation after inclusion of the first 100 patients.
Methods
Patients were eligible if at least 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. In case of clinical benefit after three or four cycles of respectively 5‐fluorouracil/leucovorin or capecitabine and oxaliplatin ± bevacizumab patients were randomized to tumor debulking followed by chemotherapy in the intervention arm, or standard treatment with chemotherapy.
Results
Twelve patients dropped out prior to randomization for various reasons. Eighty‐eight patients were randomized to the standard (n = 43) or intervention arm (n = 45). No patients withdrew after randomization. Debulking was performed in 82% (n = 37). Two patients had no lesions left to treat, five had progressive disease, and one patient died prior to local treatment. In 15 patients (40%) 21 serious adverse events related to debulking were reported. Postoperative mortality was 2.7% (n = 1). After debulking chemotherapy was resumed in 89% of patients.
Conclusion
Tumor debulking is feasible and does not prohibit administration of palliative chemotherapy in the majority of patients with multiorgan mCRC, despite the occurrence of serious adverse events related to local treatment.
Implications for Practice
This first prospective randomized trial on tumor debulking in addition to chemotherapy shows that local treatment of metastases is feasible in patients with multiorgan metastatic colorectal cancer and does not prohibit administration of palliative systemic therapy, despite the occurrence of serious adverse events related to local treatment. The trial continues accrual, and overall survival (OS) data and quality of life assessment are collected to determine whether the primary aim of >6 months OS benefit with preserved quality of life will be met. This will support evidence‐based decision making in multidisciplinary colorectal cancer care and can be readily implemented in daily practice.
The ORCHESTRA trial was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multi‐organ metastatic colorectal cancer. This article reports the preplanned safety and feasibility evaluation after inclusion of the first 100 patients.
The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m2 was ...administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in LF tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 l/h) and more variable in patients with LF abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may lie in identifying safe docetaxel doses for patients with LF abnormalities.
Clinical Pharmacology & Therapeutics (2008); 84, 1, 111–118 doi:10.1038/sj.clpt.6100476
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Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly ...caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A rs3918290, c.1905+1G>A, IVS14+1G>A, c.2846A>T rs67376798, D949V, c.1679T>G rs55886062, DPYD*13, I560S, and c.1236G>A rs56038477, E412E, in haplotype B3) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care.
In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete.
Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 39% of 85 patients) than in wild-type patients (231 23% of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63–2·73) for genotype-guided dosing compared with 2·87 (2·14–3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10–8·80) in c.1679T>G carriers, 2·00 (1·19–3·34) compared with 3·11 (2·25–4·28) for c.2846A>T carriers, and 1·69 (1·18–2·42) compared with 1·72 (1·22–2·42) for c.1236G>A carriers.
Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care.
Dutch Cancer Society.
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Objective
Our objective was to evaluate the association between exposure to unbound docetaxel and neutropenia in patients with cancer and to identify factors influencing unbound docetaxel clearance.
...Methods
Docetaxel was administered once every 3 weeks at a dose of 75 mg/m2 to 49 patients with normal liver function (n = 40, group 1) or mild elevations in liver function test results (n = 9, group 2) or at a dose of 50 mg/m2 to patients with moderate elevations in liver function test results (n = 6, group 3). Pharmacokinetic studies and toxicity assessments were performed during the first cycle of therapy. Total docetaxel concentrations were determined by HPLC and tandem mass spectrometry, and unbound docetaxel fraction was determined by equilibrium dialysis.
Results
In patients with normal liver function, unbound docetaxel disposition was characterized by mean (±SD) maximum plasma concentration (Cmax), area under the curve (AUC), and clearance values of 233 ± 101 ng/mL, 32 ± 143 ng/mL · h, and 565 ± 329 L/h, respectively. Unbound clearance varied 8.5‐fold; polysorbate 80 exhibited mean (±SD) Cmax, AUC, and clearance values of 451 ± 221 μg/mL, 528 ± 217 μg/mL · h, and 8.18 ± 3.66 L/h, respectively; and clearance varied 6.7‐fold. Unbound docetaxel clearance was reduced in patients with moderate liver impairment (groups 1 and 2 versus group 3, P = .020). From multiple linear regression analysis, only polysorbate 80 AUC and liver impairment were significantly associated with unbound docetaxel clearance. Both unbound docetaxel AUC and total AUC were correlated with the percentage decrements in absolute neutrophil count (P = .002 and P = .029, respectively), as well as the worst grade of neutropenia (P = .013 and P = .220, respectively), where higher exposure was associated with worse hematologic toxicity.
Conclusions
Exposure to unbound docetaxel is closely related to drug‐induced hematologic toxicity and should be considered in future pharmacologic investigations.
Clinical Pharmacology & Therapeutics (2005) 77, 43–53; doi: 10.1016/j.clpt.2004.09.005
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Abstract only
4006
Background: Local control in locally advanced rectal cancer (LARC) has improved. However, systemic relapses remain high even with postoperative chemotherapy, possibly due to low ...compliance. Short-course radiotherapy (SCRT) followed by delayed surgery with, in the waiting period, chemotherapy, may lead to better compliance, downstaging and fewer distant metastases. The main objective of the international multicenter phase III RAPIDO trial is to decrease Disease-related Treatment Failure (DrTF), defined as locoregional failure, distant metastasis, a new primary colon tumor or treatment-related death, by reducing the risk of systemic relapse without compromising local control. Methods: MRI-diagnosed LARC patients with either cT4a/b, extramural vascular invasion, cN2, involved mesorectal fascia or enlarged lateral lymph nodes considered to be metastatic were randomly assigned to SCRT (5x5 Gy) with subsequent six cycles of CAPOX or nine cycles of FOLFOX4 followed by total mesorectal excision (TME) (experimental arm) or, capecitabine-based chemoradiotherapy (25-28 x 2.0-1.8 Gy) followed by TME and optional, predefined by hospital policy, postoperative eight cycles of CAPOX or twelve cycles of FOLFOX4 (standard arm). Results: Between June 2011 and June 2016, 920 patients were randomized. Pathological complete response rates were 27.7% vs 13.8% (OR 2.40 1.70 – 3.39; p < 0.001) in the experimental and standard arms, respectively. At three years, cumulative probability of DrTF was 23.7% in the experimental arm and 30.4% in the standard arm (HR 0.76 0.60 – 0.96; p = 0.02). Probability at three years of distant metastasis and locoregional failure were, in the experimental and standard arms, 19.8% vs 26.6% (HR 0.69 0.53 – 0.89; p = 0.004) and 8.7% vs 6.0% (HR 1.45 0.93 – 2.25; p = 0.10), respectively. No differences in DrTF between hospitals with or without policy for postoperative chemotherapy were found (p = 0.37). Overall health ( p = 0.192), quality of life ( p = 0.125) and low anterior resection syndrome score ( p = 0.136) were comparable between the two treatment arms. Conclusions: A lower rate of DrTF, as a result of a lower rate of distant metastases, in high-risk LARC patients can be achieved with preoperative short-course radiotherapy, followed by chemotherapy and TME than by conventional chemoradiotherapy. In addition, the high pCR rate, achieved with the experimental treatment regimen can contribute to organ preservation. This treatment can be considered as a new standard of care. Clinical trial information: NCT01558921 .
Real-world data (RWD) sources are important to advance clinical oncology research and evaluate treatments in daily practice. Since 2013, the Prospective Dutch Colorectal Cancer (PLCRC) cohort, linked ...to the Netherlands Cancer Registry, serves as an infrastructure for scientific research collecting additional patient-reported outcomes (PRO) and biospecimens. Here we report on cohort developments and investigate to what extent PLCRC reflects the "real-world". Clinical and demographic characteristics of PLCRC participants were compared with the general Dutch CRC population (n = 74,692, Dutch-ref). To study representativeness, standardized differences between PLCRC and Dutch-ref were calculated, and logistic regression models were evaluated on their ability to distinguish cohort participants from the Dutch-ref (AU-ROC 0.5 = preferred, implying participation independent of patient characteristics). Stratified analyses by stage and time-period (2013-2016 and 2017-Aug 2019) were performed to study the evolution towards RWD. In August 2019, 5744 patients were enrolled. Enrollment increased steeply, from 129 participants (1 hospital) in 2013 to 2136 (50 of 75 Dutch hospitals) in 2018. Low AU-ROC (0.65, 95% CI: 0.64-0.65) indicates limited ability to distinguish cohort participants from the Dutch-ref. Characteristics that remained imbalanced in the period 2017-Aug'19 compared with the Dutch-ref were age (65.0 years in PLCRC, 69.3 in the Dutch-ref) and tumor stage (40% stage-III in PLCRC, 30% in the Dutch-ref). PLCRC approaches to represent the Dutch CRC population and will ultimately meet the current demand for high-quality RWD. Efforts are ongoing to improve multidisciplinary recruitment which will further enhance PLCRC's representativeness and its contribution to a learning healthcare system.
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