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Abstract Background Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. Methods The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. Discussion From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. Trial registration ClinicalTrials.gov ID NCT05652673, registration date: 08–12-2022.

Abstract Background Polypharmacy is common among patients with a limited life expectancy, even shortly before death. This is partly inevitable, because these patients often have multiple symptoms which need to be alleviated. However, the use of potentially inappropriate medications (PIMs) in these patients is also common. Although patients and relatives are often willing to deprescribe medication, physicians are sometimes reluctant due to the lack of evidence on appropriate medication management for patients in the last phase of life. The aim of the AMUSE study is to investigate whether the use of CDSS-OPTIMED, a software program that gives weekly personalized medication recommendations to attending physicians of patients with a limited life expectancy, improves patients’ quality of life. Methods A multicentre stepped-wedge cluster randomized controlled trial will be conducted among patients with a life expectancy of three months or less. The stepped-wedge cluster design, where the clusters are the different study sites, involves sequential crossover of clusters from control to intervention until all clusters are exposed. In total, seven sites (4 hospitals, 2 general practices and 1 hospice from the Netherlands) will participate in this study. During the control period, patients will receive ‘care as usual’. During the intervention period, CDSS-OPTIMED will be activated. CDSS-OPTIMED is a validated software program that analyses the use of medication based on a specific set of clinical rules for patients with a limited life expectancy. The software program will provide the attending physicians with weekly personalized medication recommendations. The primary outcome of this study is patients’ quality of life two weeks after baseline assessment as measured by the EORTC QLQ-C15-PAL questionnaire, quality of life question. Discussion This will be the first study investigating the effect of weekly personalized medication recommendations to attending physicians on the quality of life of patients with a limited life expectancy. We hypothesize that the CDSS-OPTIMED intervention could lead to improved quality of life in patients with a life expectancy of three months or less. Trial registration This trial is registered at ClinicalTrials.gov (NCT05351281, Registration Date: April 11, 2022).

Abstract Background Chemoradiation with capecitabine followed by surgery is standard care for locally advanced rectal cancer (LARC). Severe diarrhea is considered a dose-limiting toxicity of adding capecitabine to radiation therapy. The aim of this study was to describe the risk factors and the impact of body composition on severe diarrhea in patients with LARC during preoperative chemoradiation with capecitabine. Methods A single centre retrospective cohort study was conducted in a tertiary referral centre. All patients treated with preoperative chemoradiation with capecitabine for LARC from 2009 to 2015 were included. Patients with locally recurrent rectal cancer who received chemoradiation for the first time were included as well. Logistic regression analyses were performed to identify risk factors for severe diarrhea. Results A total of 746 patients were included. Median age was 64 years (interquartile range 57–71) and 477 patients (64%) were male. All patients received a radiation dosage of 25 × 2 Gy during a period of five weeks with either concomitant capecitabine administered on radiation days or continuously during radiotherapy. In this cohort 70 patients (9%) developed severe diarrhea. In multivariable logistic regression analyses female sex (OR: 4.42, 95% CI 2.54–7.91) and age ≥ 65 (OR: 3.25, 95% CI 1.85–5.87) were the only risk factors for severe diarrhea. Conclusions Female patients and patients aged sixty-five or older had an increased risk of developing severe diarrhea during preoperative chemoradiation therapy with capecitabine. No relation was found between body composition and severe diarrhea.

Abstract Background The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response. Methods The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs. Discussion From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients. Trial registration The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

Abstract Background Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. Methods This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 μg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4–12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. Discussion If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. Trial registration The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493. Date of registration September 23, 2018.

Background: Addition of deep hyperthermia to radiotherapy results in improved local control (LC) and overall survival compared to radiotherapy alone in cervical carcinoma patients. Based on preclinical data, the time interval between radiotherapy, and hyperthermia is expected to influence treatment outcome. Clinical studies addressing the effect of time interval are sparse. The repercussions for clinical applications are substantial, as the time between radiotherapy and hyperthermia should be kept as short as possible. In this study, we therefore investigated the effect of the time interval between radiotherapy and hyperthermia on treatment outcome.Methods: We analyzed all primary cervical carcinoma patients treated between 1996 and 2016 with thermoradiotherapy at our institute. Data on patients, tumors and treatments were collected, including the thermal dose parameters TRISE and CEM43T90. Follow-up data on tumor status and survival as well as late toxicity were collected. Data was analyzed using Cox proportional hazards analysis and Kaplan Meier analysis.Results: 400 patients were included. Kaplan Meier and univariate Cox analysis showed no effect of the time interval (range 30–230 min) on any clinical outcome measure. Besides known prognostic factors, thermal dose parameters TRISE and CEM43T90 had a significant effect on LC. In multivariate analysis, the thermal dose parameter TRISE (HR 0.649; 95% CI 0.501–0.840) and the use of image guided brachytherapy (HR 0.432; 95% CI 0.214–0.972), but not the time interval, were significant predictors of LC and disease specific survival.Conclusions: The time interval between radiotherapy and hyperthermia, up to 4 h, has no effect on clinical outcome. These results are re-ensuring for our current practice of delivering hyperthermia within maximal 4 h after radiotherapy.

BackgroundCisplatin (cDDP) has regained interest for metastatic breast cancer (MBC) patients, given the platinum sensitivity in subtypes and better manageable toxicity. Here, the primary aim was to determine whether molecular characteristics of circulating tumor cells (CTCs) could identify patients responding to cDDP and to describe the outcomes to cDDP monotherapy in a large group of MBC patients pretreated with anthracycline- and taxane-based treatments.MethodsBased on cell line data, a CTC-cDDP-sensitivity profile was generated. Applying an A’Herns single-stage phase II design, further investigation was considered worthwhile if 5/10 patients with a favorable profile responded to cDDP. Patients received 70mg/m2 cDDP every three weeks, CTCs were enumerated and the CTC-cDDP-sensitivity profile was determined. In total, 65 heavily pretreated MBC patients (77% received ≥2 lines of previous chemotherapy for MBC) were eligible for the per-protocol analysis. Primary endpoint was response rate, secondary endpoints included best observed response, progression-free survival (PFS) and overall survival (OS).ResultsThe best observed response during cDDP therapy was a partial response in 7% and stable disease in 56% of the patients. None of the patients with a favorable CTC-cDDP-sensitivity profile had a response. The median baseline CTC count was 8 (range 0-3254). Patients with

Background: Data on exposure-response or exposure-toxicity relationships of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are limited and inconclusive. We aimed to investigate whether there is an association between palbociclib exposure and progression-free survival (PFS), adverse events (AEs) and dose reductions., Materials and Methods: Data were retrieved from the prospective, multicentre SONIA trial in which patients with advanced estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer were randomised to receive CDK4/6i treatment in first versus second line. Blood for pharmacokinetics (PK) was taken at day 15 of cycles 1 and 2 during CDK4/6i treatment. Individual trough concentrations and plasma area under the curves of palbociclib were constructed using a population PK model. Associations with palbociclib exposure were tested using Cox regression for PFS and chi-square tests for AEs or dose reductions., Results: PK data were available for 344 patients. No association between palbociclib exposure and PFS was found. Although patients with higher palbociclib exposure had more dose reductions during their entire CDK4/6i treatment course, this was not reflected by a higher incidence of grade 3-4 AEs in the first 3 months., Conclusion: The absence of an association between palbociclib exposure and PFS and the presence of the association between palbociclib exposure and dose reductions suggest that dose reductions may safely be carried out in case of palbociclib-related toxicity., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Appropriate communication between healthcare providers and patients and their families is an essential part of good (palliative) care. We investigated whether implementation of a standardised palliative care pathway (PCP) facilitated communication, that is, aspects of shared decision-making (SDM), including advance care planning (ACP) conversations and satisfaction with care as experienced by bereaved relatives of patients with advanced cancer., Methods: We conducted a prospective preintervention and postintervention study in a hospital. Questionnaires were sent to relatives of patients who died between February 2014 and February 2015 (pre-PCP period) or between November 2015 and November 2016 (post-PCP period). Relatives' perceptions on communication and satisfaction with care were assessed using parts of the Views of Informal Carers-Evaluation of Services and IN-PATSAT32 Questionnaires., Results: 195 (46%) and 180 (42%) bereaved relatives completed the questionnaire in the pre-PCP and post-PCP period, respectively. The majority of all patients in both the pre-PCP period and the post-PCP period had been told they had an incurable illness (92% and 89%, respectively, p=0.544), mostly in the presence of a relative (88% and 85%, respectively, p=0.865) and had discussed their preferences for end-of-life (EOL) treatment (82% and 76%, respectively, p=0.426). Bereaved relatives were reasonably satisfied with the received hospital care in both groups., Conclusions: We found no overall effect of the PCP on the communication process and satisfaction with EOL care of bereaved relatives. Before the use of the PCP bereaved relatives already reported favourably about the EOL care provided., Competing Interests: Competing interests: CCDvdR received consulting fees from Lilly Nederland BV (via her institution) and (grants from the Netherlands Organization for Health Research and Development and from the Dutch Cancer Society for work outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ Group.)

Context: Subcutaneous (SC) administration of fentanyl allows for rapid dose titration to treat urgent cancer-related pain. After establishing the optimal fentanyl dose, patients typically rotate towards transdermal (TD) fentanyl patches. Continuing the SC fentanyl up to 12h after application of the patch led to elevated fentanyl concentrations and fentanyl-related toxicities. Based on these findings, and simulations using a pharmacokinetic (PK) model, SC fentanyl administration was discontinued immediately following the application of the patch., Objectives: To validate the fentanyl rotation schedule by assessing the PK equivalence in fentanyl exposure before and after rotation., Methods: PK samples and clinical data were prospectively collected from 12 hours prior to rotation until 12 hours after rotation in patients with cancer-related pain undergoing fentanyl rotation., Results: Between December 2021 and September 2023, 29 evaluable patients were enrolled in the study. The 90% confidence interval (CI) of the geometric mean ratio between the post- over pre-rotation area under the curve (AUC) fell within the prespecified 0.8-1.25 equivalence interval (90% CI 1.05-1.16). Patient-reported intensity of both nausea (P = 0.047) and transpiration (P = 0.034) decreased post-rotation. Pain intensity and other adverse events did not differ significantly pre and post-rotation. One patient needed adjustment of opioid therapy 40 hours after rotation due to fentanyl-related toxicities., Conclusion: The updated rotation scheme, implying a 1:1 dose conversion and discontinuation of SC fentanyl directly after rotation, resulted in equivalent fentanyl exposure pre and post-rotation. Moreover, the dosing regimen showed to be safe and efficacious during rotation. The new dosing regimen when rotating from SC to TD fentanyl can be effectively and safely implemented in routine palliative care., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Alectinib, a small-molecule kinase inhibitor, is used as first-line treatment for ALK-positive (ALK+) NSCLC. Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity., Methods: In this multicenter observational cohort study in patients with advanced ALK+ NSCLC receiving alectinib treatment, we investigated the association between toxicity, pharmacokinetics, and key genetic variants in ABCB1, CYP3A4, PPAR-α, POR, and CYP3A5. Data on demographics, adverse events, and alectinib trough levels were collected from five hospitals., Results: Among 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; p = 0.001) and had +35% higher alectinib trough levels (p < 0.001). Homozygous carriers of the PPAR-α 209G>A variant exhibited a higher incidence of grade greater than or equal to 3 toxicity (38%) compared with patients who carried at least one wild-type allele (11%) (p = 0.004). This remained significant after Bonferroni correction. Patients who experienced severe toxicity had +18.5% (95% confidence interval: 2.9%-36.6%; p = 0.019) higher trough levels., Conclusions: Female patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. PPAR-α 209G>A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pretreatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity., Competing Interests: Disclosure Dr. Muntinghe-Wagenaar reports receiving travel grants from Bristol-Myers Squibb. Dr. Bahce reports receiving research grants from AstraZeneca, Bristol-Myers Squibb, and Boehringer-Ingelheim and funds for advisory boards (all paid to institution) from AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Takeda, Pfizer, Merck Sharp & Dohme, and Regeneron. Dr. Hendriks reports receiving research funding (all paid to the institute) from Roche, GlaxoSmithKline, Novartis, Blueprint, Mirati, AbbVie, Merck Sharp & Dohme, Amgen, Genentech, AstraZeneca, Boehringer-Ingelheim, Takeda, Merck, Pfizer, Novartis, Janssen, Anheart Bayer, Lilly, and Gilead and was an invited speaker for AstraZeneca, Bayer, Lilly, Merck Sharp & Dohme, high5oncology, Takeda, Janssen, GlaxoSmithKline, Sanofi, and Pfizer (all paid to institution), and Medtalks, Benecke, VJOncology, and Medimix (paid to self). Dr. van der Wekken reports receiving consulting fees from AstraZeneca, Boehringer-Ingelheim, Janssen, Lilly, Merck KGaA, Darmstadt, Germany, Novartis, Roche, Pfizer, and Takeda; acted as invited speaker for Pfizer and AstraZeneca; and reports receiving research grants by AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, and Takeda. Dr. Dingemans reports receiving grants (all paid to the institution) from Amgen. Dr. Mathijssen reports receiving unrestricted grants for investigator-initiated trials (all paid to the institution) from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Deuter Oncology, Echo Pharmaceuticals, Nordic Pharma, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: A novel Cone-Beam Computed Tomography (CBCT) named HyperSight provides superior CBCT image quality compared to conventional ring gantry CBCT imaging, and it is suitable for dose calculations for prostate cancer, but it comes with considerable additional costs. The aim of this study was to determine the added value of HyperSight CBCT imaging compared to conventional CBCT imaging in terms of organ visibility in the male pelvic region., Materials and Methods: Twenty prostate cancer patients were included in this prospective clinical study. For each patient three CBCT pairs, consisting of HyperSight and conventional CBCT scans acquired on consecutive days, were included. CBCT scans were evaluated by four observers in terms of visibility of the prostate, bladder, rectum and seminal vesicles. Visibility was scored on a 1-to-5 scale and by annotating axial slices where the organs were hard to delineate. Lastly, observers indicated whether the CBCT scans were of sufficient quality for an online adaptive radiation therapy workflow., Results: All four organs were better visible on HyperSight CBCT scans compared to conventional CBCT scans. The mean visibility scores increased from 3.1 to 4.5 on a 1--5 scale of and the mean number of annotated slices reduced from 4.5 to 1.1. 99% Of the HyperSight CBCT scans were considered suitable for an online adaptive workflow vs 25-83% for the conventional CBCT scans., Conclusion: HyperSight CBCT scans yielded a visibility of prostate, bladder, rectum and seminal vesicles comparable to planning CT scans and, can replace a repeat planning CT scan in case of anatomical changes requiring a new treatment plan., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The department of radiotherapy has research collaborations with Elekta AB, Stockholm, Sweden, Accuray Inc., Sunnyvale, CA, USA and Varian, Palo Alto, CA, USA. The current research was not funded by Varian., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Premedication, including a histamine-1 receptor (H 1 ) antagonist, is recommended to all patients treated with paclitaxel chemotherapy to reduce the incidence of hypersensitivity reactions (HSRs). However, the scientific basis for this premedication is not robust, which provides opportunities for optimization. Substitution of intravenously administered first-generation H 1 antagonist for orally administered second-generation H 1 antagonist could reduce side effects, and improve efficiency and sustainability. This study investigates the efficacy and safety of substituting intravenous clemastine for oral cetirizine as prophylaxis for paclitaxel-induced HSRs., Methods: This single-center, prospective, noninferiority study compares a historic cohort receiving a premedication regimen with intravenous clemastine to a prospective cohort receiving oral cetirizine. Primary end point of the study is HSR grade ≥3. The difference in incidence was calculated together with the 90% CI. We determined that the two-sided 90% CI of HSR grade ≥3 incidence in the oral cetirizine cohort should not be more than 4% higher (ie, the noninferiority margin) compared with the intravenous clemastine cohort., Results: Two hundred and twelve patients were included in the oral cetirizine cohort (June 2022 and May 2023) and 183 in the intravenous clemastine cohort. HSR grade ≥3 incidence was 1.6% (n = 3) in the intravenous clemastine cohort and 0.5% (n = 1) in the oral cetirizine cohort, resulting in a difference of -1.2% (90% CI, -3.4 to 1.1)., Conclusion: Premedication containing oral cetirizine is as safe as premedication containing intravenous clemastine in preventing paclitaxel-induced HSR grade ≥3. These findings could contribute to optimization of care for patients and improve efficiency and sustainability.

Circulating tumor DNA (ctDNA) holds promise as a biomarker for guiding adjuvant treatment decisions in solid tumors. This review systematically assembles ongoing and published trials investigating ctDNA-directed adjuvant treatment strategies. A total of 57 phase II/III trials focusing on ctDNA in minimal residual disease (MRD) detection were identified, with a notable increase in initiation over recent years. Most trials target stage II or III colon/colorectal cancer, followed by breast cancer and non-small cell lung cancer. Trial methodologies vary, with some randomizing ctDNA-positive patients between standard-of-care (SoC) treatment and intensified regimens, while others aim to de-escalate therapy in ctDNA-negative patients. Challenges in trial design include the need for randomized controlled trials to establish clinical utility for ctDNA, ensuring adherence to standard treatment in control arms, and addressing the ethical dilemma of withholding treatment in high-risk ctDNA-positive patients. Longitudinal ctDNA surveillance emerges as a strategy to improve sensitivity for recurrence, particularly in less proliferative tumor types. However, ctDNA as longitudinal marker is often not validated yet. Ultimately, designing effective ctDNA interventional trials requires careful consideration of feasibility, meaningful outcomes, and potential impact on patient care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Palliative systemic treatment is currently standard of care for metastatic gastric cancer. However, patients with peritoneal metastases of gastric origin are often underrepresented in clinical studies due to unmeasurable radiologic disease. This study describes the systemic treatment strategies and outcomes in patients with peritoneal metastases in a nationwide real-world setting., Methods: Patients with gastric adenocarcinoma and synchronous peritoneal metastases (with or without other metastases) diagnosed in the Netherlands between 2015 and 2020 were identified from the nationwide Netherlands Cancer Registry. Median overall survival (OS) and time-to-treatment failure were determined and multivariable Cox regression analyses were used to compare treatment groups, corrected for relevant tumor and patient characteristics., Results: In total, 1,972 patients were included, of whom 842 (43%) were treated with palliative systemic therapy. The majority received capecitabine + oxaliplatin (CAPOX; 44%), followed by fluorouracil/leucovorin/oxaliplatin (FOLFOX; 19%), and epirubicin + capecitabine + oxaliplatin (EOX; 8%). Of the 99 (45%) patients who received second-line systemic treatment, ramucirumab + paclitaxel were administered most frequently (63%). After adjustment for sex, age, comorbidities, performance status, tumor location, Lauren classification, and the presence of metastases outside of the peritoneum, patients treated with a triplet containing docetaxel and those treated with a regimen containing trastuzumab had a significantly longer OS compared with patients treated with a doublet containing a fluoropyrimidine derivate + oxaliplatin (hazard ratio [HR], 0.69; 95% CI, 0.52-0.91, and HR, 0.68; 95% CI, 0.51-0.91, respectively). Monotherapy was associated with a shorter OS (HR, 2.08, 95% CI, 1.53-2.83)., Conclusions: There is substantial heterogeneity in systemic treatment choices in patients with gastric cancer and peritoneal metastases in the Netherlands. In this study, patients treated with triplets containing docetaxel and with trastuzumab-containing regimens survived longer than patients who received doublet therapy. Despite this, median OS for all treatment groups remained below one year.

Background and Objectives: Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug-drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine., Methods: In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction., Results: Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (- 12.6%; 97.5% confidence interval - 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil., Conclusions: Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure., Clinical Trial Registration: NL8067 (registered 04-10-2019)., (© 2024. The Author(s).)