Phase I study of intraperitoneal irinotecan with systemic capecitabine and oxaliplatin for patients with gastric peritoneal metastases.

Background: Peritoneal metastases of gastric cancer are associated with a poor prognosis (median overall survival (OS) ∼9 months). Catheter-based intraperitoneal (CBIP) chemotherapy is a locoregional approach to deliver chemotherapy leading to higher intraperitoneal (IP) concentrations of cytotoxic drugs compared to intravenous administration.

Method: This multicenter, open-label 3 + 3 + 3 dose-escalation phase I trial evaluated 3-weekly IP irinotecan with oral capecitabine and intravenous oxaliplatin (CAPOX).

Mechanisms of anti-VEGF therapy-induced kidney injury: current insights and future perspectives in combination with immune checkpoint inhibitors.

The formation of new blood vessels is crucial for tumor and metastatic progression. Consequently, targeted therapies directed toward the vascular endothelial growth factor (VEGF) pathway have significantly improved treatment outcomes in several malignancies. These treatment modalities are frequently used in current oncologic practice, as monotherapy or in combination with other anticancer regimens such as immune checkpoint inhibitors (ICIs), to enhance the anticancer effects.

Impact of immune-related adverse events on quality of life and physical functioning in older patients with solid tumors treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) improved survival in solid tumors but can cause immune-related adverse events (irAEs) that may affect quality of life (QOL) and physical functioning. The impact of severe irAEs on these outcomes remains unclear, particularly in frail older patients. This study evaluated the association between grade ≥ 3 irAEs and QOL and/or physical functioning over time in frail versus non-frail older patients receiving ICI therapy.

Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study.

Background: DPYD-guided dosing enhances safety of fluoropyrimidine-based chemotherapy. However, approximately 23 % of patients still experience severe toxicity unexplained by the four commonly tested DPYD-variant alleles. Elevated pre-treatment uracil levels have been proposed as a surrogate marker for reduced DPD activity and an independent predictor of toxicity.

Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment.

Pemetrexed is a cornerstone in chemo(immunotherapy) of non-small cell lung cancer and mesothelioma; however, it is contraindicated in patients with renal impairment due to severe toxicity concerns. Therefore, a large proportion of patients is withheld from effective chemo(immunotherapy). We performed an intra-patient 3 + 3 dose escalation renal impairment study (eGFR < 45 mL/min).

A Clinical Pharmacological Perspective on Intraperitoneal Chemotherapy.

Peritoneal metastases (PM), frequently observed in malignancies such as ovarian, colorectal, pancreatic, and gastric cancers, present a significant therapeutic challenge due to poor prognosis and limited effectiveness to systemic chemotherapy. The peritoneal-plasma barrier reduces effective drug transfer from plasma to the peritoneal cavity, reducing cytotoxic effects on PM. Intraperitoneal (IP) chemotherapy offers a locoregional approach, enabling high local drug concentrations that can enhance therapeutic efficacy while limiting systemic toxicity.

Omission of dexamethasone in paclitaxel premedication regimens: protocol of the multicentre, randomised, non-inferiority DEXASTOP trial.

Introduction: Standard premedication for paclitaxel-based chemotherapy includes dexamethasone and an histamine 1-antagonist to prevent hypersensitivity reactions (HSRs). However, the pharmacological rationale for dexamethasone is limited, and its use is associated with adverse effects such as hyperglycaemia, insomnia and immunodeficiency, negatively impacting health-related quality of life (HRQoL). No clear link has been established between dexamethasone dose, administration route and HSR incidence.

Onset and progression of atherosclerosis in patients with melanoma treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) are effective anticancer agents but significantly increase cardiovascular risk. This could be due to its potential to induce or worsen atherosclerosis. We evaluated the onset and progression of atherosclerosis during ICI treatment in patients with melanoma and investigated risk factors for substantial (>10%/year) atherosclerotic plaque growth in five segments of the arterial tree.

Pharmacokinetic boosting of olaparib: Study protocol of a multicentre, open-label, randomised, non-inferiority trial (PROACTIVE-B).

Background: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of the anticancer drug olaparib, a CYP3A-substrate, has the potential to reduce PK variability, side effects and financial burden associated with this drug. After establishing adequate pharmacokinetic exposure with boosting in the PROACTIVE-A study, the PROACTIVE-B study is designed to evaluate non-inferiority for both efficacy and toxicity of the boosted therapy compared to the standard monotherapy of olaparib.

Drug release from docetaxel-entrapped core-crosslinked polymeric micelles: A population pharmacokinetic modelling approach based on clinical data.

CPC634 is a core-crosslinked polymeric micelle entrapping docetaxel (DTX) developed to improve tolerability and tumour drug accumulation compared to conventional DTX. A pH-responsive covalent sulfone ester linker allows for controlled native DTX release. Prior research has shown CPC634's dose-proportional clinical pharmacokinetics (PK) and enhanced tumour uptake.

The prognostic value of peritoneal metastases in patients with gastric cancer: a nationwide population-based study.

Background: The peritoneum is a common metastatic site in gastric cancer. The prognosis of synchronous peritoneal metastases compared to other metastatic sites in gastric cancer remains understudied. This study aims to evaluate the impact of peritoneal metastases on survival in patients with metastatic gastric cancer.

Trifluridine-tipiracil in previously treated patients with oestrogen receptor-positive, HER2-negative metastatic breast cancer (BOOG 2019-01 TIBET trial): a single-arm, multicentre, phase 2 trial.

Background: Effective later-line chemotherapy treatment options are scarce for patients with metastatic breast cancer (MBC). Trifluridine-tipiracil has shown survival benefit in heavily pre-treated patients with metastatic colorectal and in gastric cancer refractory to a fluoropyrimidine. This study aimed to investigate the efficacy of trifluridine-tipiracil in a Western population of previously treated patients with oestrogen receptor (ER+), HER2- MBC to facilitate further optimization of this treatment strategy.

Environmental Impact Assessment of Intravenous Versus Subcutaneous Monoclonal Antibodies: A Carbon Footprint Analysis.

Purpose: The development of subcutaneous (SC) formulations for monoclonal antibodies (mAbs), as an alternative to conventional intravenous (IV) infusion, represents a shift in health care delivery. The relative environmental impact of these two administration methods is not well understood. Minimizing the environmental footprint of health care is crucial due to its substantial contribution to greenhouse gas (GHG) emissions.

From Prospective Evaluation to Practice: Model-Informed Dose Optimization in Oncology.

One dose does not fit all, especially in oncolytic drugs, where side effects and therapy failures highlight the need for personalized dosing approaches. In recent years, the quest to apply model-informed precision dosing to oncology drugs has gained significant momentum, reflecting its potential to revolutionize patient care by tailoring treatments to individual pharmacokinetic profiles. Despite this progress, model-informed precision dosing has not (yet) become widely integrated into routine clinical care.

Pseudo acute kidney injury in patients receiving CDK4/6 inhibitors.

Introduction: CDK4/6 inhibitors (CDK4/6i) improve progression-free survival in patients with advanced oestrogen-receptor-positive breast cancer. However, all CDK4/6i may increase creatinine levels, which can indicate kidney injury. In vitro research has shown that CDK4/6i can also inhibit tubular secretion of creatinine, thereby causing the phenomenon 'pseudo-acute kidney injury (pseudo-AKI)'.

Implementation of model-informed precision dosing for tamoxifen therapy in patients with breast cancer: A prospective intervention study.

Tamoxifen is an estrogen-receptor (ER) antagonist, used as adjuvant treatment of ER-positive breast cancer. It is converted by CYP2D6 into endoxifen, its most active metabolite. Patients with endoxifen plasma concentrations <16 nM face a higher risk of recurrence.

New metabolic insights into the mechanism of ifosfamide encephalopathy.

Ifosfamide causes neurotoxicity, including sometimes fatal encephalopathy, in a small number of patients. Why and how this occurs is not fully understood. It is generally believed that N-dechloroethylation of ifosfamide to 2-chloroacetaldehyde is the cause.

Body Weight Gain Associated With Alectinib in Patients With ALK+ Non-Small Cell Lung Cancer: Pooled Analysis of Individual Patient Data From Four Prospective Clinical Trials.

Purpose: Weight gain is a known adverse event (AE) of alectinib. This study evaluates the progression of actual weight gain over time and explores its association with baseline characteristics.

Methods: A pooled analysis of individual patient data from four clinical trials (ALEX, J-ALEX, ALUR, and ML29453) was conducted.

Effects of tamoxifen on cognitive function in patients with primary breast cancer.

Introduction: Tamoxifen may adversely affect cognitive function by interfering with estrogen action in the brain. Despite growing evidence for a relationship between tamoxifen and cognitive problems, findings remain inconclusive. While some tamoxifen-related side effects seem exposure-dependent with concentrations of tamoxifen or its main metabolite, endoxifen, this has never been investigated for cognitive function.