Background:the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher... Show moreBackground:the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients.Methods:In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (Cmin,ss) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first Cmin,ss. The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups.Results:A total of 542 patients were included in the different K.I. groups. A high Cmin,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a Cmin,ss >= 490, >= 870, >= 405, >= 150, and >= 25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group (P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups.Conclusions:For alectinib, high Cmin,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib. Show less
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large... Show moreCytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment. Show less
Simple Summary: Docetaxel has been approved as an anti-cancer agent in 1995. High rates of hypersensitivity reactions (HSR) and fluid retention were observed when this agent was first introduced.... Show moreSimple Summary: Docetaxel has been approved as an anti-cancer agent in 1995. High rates of hypersensitivity reactions (HSR) and fluid retention were observed when this agent was first introduced. The use of high dose systemic corticosteroids around docetaxel infusion appeared to decrease the incidence of HSR and fluid retention and has been applied in daily practice ever since. However, there is little evidence that supports this high dose of dexamethasone. Furthermore, the application of high-dosed corticosteroids can lead to undesirable adverse effects. In this phase 1 study, we aim to evaluate the impact of reducing the dose of dexamethasone as an adjunct to docetaxel on the incidence of HSR and fluid retention in patients with prostate or breast cancer. Background: There is little evidence that supports the registered high dose of dexamethasone used around docetaxel. However, this high dose is associated with considerable side effects. This study evaluates the feasibility of reducing the prophylactic oral dosage of dexamethasone around docetaxel infusion. Patients and methods: Eligible patients had a histologically confirmed diagnosis of prostate or breast cancer and had received at least three cycles of docetaxel as monotherapy or combination therapy. Prophylactic dexamethasone around docetaxel infusion was administered in a de-escalating order per cohort of patients. Primary endpoint was the occurrence of grade III/IV fluid retention and hypersensitivity reactions (HSRs). Results: Of the 46 enrolled patients, 39 were evaluable (prostate cancer (n = 25), breast cancer (n = 14). In patients with prostate cancer, the dosage of dexamethasone was reduced to a single dose of 4 mg; in patients with breast cancer, the dosage was reduced to a 3-day schedule of 4 mg-8 mg-4 mg once daily, after which no further reduction has been tested. None of the 39 patients developed grade III/IV fluid retention or HSR. One patient (2.6%) had a grade 1 HSR, and there were six patients (15.4%) with grade I or II edema. There were no differences in quality of life (QoL) between cohorts. Conclusions: It seems that the prophylactic dose of dexamethasone around docetaxel infusion can be safely reduced with respect to the occurrence of grade III/IV HSRs or the fluid retention syndrome. Show less
Goyenvalle, A.; Jimenez-Mallebrera, C.; Roon, W. van; Sewing, S.; Krieg, A.M.; Arechavala-Gomeza, V.; Andersson, P. 2022
The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even... Show moreThe nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network "DARTER," a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity in vitro or ex vivo to filter out potential toxic candidates before moving to in vivo phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human in vitro systems. Yet, small preliminary in vivo studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments. Show less
Bernsen, E.C.; Hanff, L.M.; Haveman, L.M.; Tops, B.B.J.; Lee, M. van der; Swen, J.J.; ... ; Diekstra, M.H.M. 2022
Paediatric oncology patients who develop severe chemotherapy-induced toxicity that requires dose reduction, delay or termination of treatment are at risk of decreased treatment efficacy. Previous... Show morePaediatric oncology patients who develop severe chemotherapy-induced toxicity that requires dose reduction, delay or termination of treatment are at risk of decreased treatment efficacy. Previous research has provided evidence that genetic variants in TPMT, NUDT15, UGT1A1 and DPYD are associated with toxicity of anticancer drugs. This led to pharmacogenetic guidelines that are integrated into clinical practice in paediatric oncology. Recently, novel genetic variants have been associated with a higher risk of developing chemotherapy-induced toxicity. In this case series, we selected 21 novel variants and genotyped these in nine patients with excessive chemotherapy-induced toxicity using whole exome sequencing or micro-array data. We observed that six out of nine patients carried at least one variant that, according to recent studies, potentially increased the risk of developing methotrexate- or vincristine-induced toxicity. As patient-derived genetic data are becoming widely accessible in paediatric oncology, these variants could potentially enter clinical practice to mitigate chemotherapy-induced toxicity. Show less
Schrier, R. van der; Velzen, M. van; Roozekrans, M.; Sarton, E.; Olofsen, E.; Niesters, M.; ... ; Dahan, A. 2022
Background: Due the increasing need for storage of carbon dioxide (CO2) more individuals are prone to be exposed to high concentrations of CO2 accidentally released into atmosphere, with... Show moreBackground: Due the increasing need for storage of carbon dioxide (CO2) more individuals are prone to be exposed to high concentrations of CO2 accidentally released into atmosphere, with deleterious consequences. Methods: We tested the effect of increasing CO2 concentrations in humans (6–12%) and rats (10–50%) at varying inhalation times (10–60 min). In humans, a continuous positive airway pressure helmet was used to deliver the gas mixture to the participants. Unrestrained rats were exposed to CO2 in a transparent chamber. In both species regular arterial blood gas samples were obtained. After the studies, the lungs of the animals were examined for macroscopic and microscopic abnormalities. Results: In humans, CO2 concentrations of 9% inhaled for >10 min, and higher concentrations inhaled for <10 min were poorly or not tolerated due to exhaustion, anxiety, dissociation or acidosis (pH < 7.2), despite intact oxygenation. In rats, concentrations of 30% and higher were associated with CO2 narcosis, epilepsy, poor oxygenation and, at 50% CO2, spontaneous death. Lung hemorrhage and edema were observed in the rats at inhaled concentrations of 30% and higher. Conclusion: This study provides essential insight into the occurrence of physiological changes in humans and fatalities in rats after acute exposure to high levels of CO2. Humans tolerate 9% CO2 and retain their ability to function coherently for up to 10 min. These data support reconsideration of the current CO2 levels (<7.5%) that pose a risk to exposed individuals (<7.5%) as determined by governmental agencies to ≤9%. Show less
Binsbergen, A.L. van; Haas, V. de; Velden, V.H.J. van der; Groot-Kruseman, H.A. de; Fiocco, M.F.; Pieters, R. 2021
Background: Children with acute lymphoblastic leukemia (ALL) and high-risk (HR) features have a poor outcome and are treated with HR blocks, often followed by allogenic stem cell transplantation ... Show moreBackground: Children with acute lymphoblastic leukemia (ALL) and high-risk (HR) features have a poor outcome and are treated with HR blocks, often followed by allogenic stem cell transplantation (SCT). Procedure: This article analyses the outcomes of children treated with HR blocks between 2004 and 2017 according to DCOG ALL10/11 protocols. 1297 patients with newly diagnosed ALL were consecutively enrolled, of which 107 met the HR criteria (no complete remission; minimal residual disease (MRD) > 10(-3) after consolidation; "MLL-AF4" translocation and in ALL-10 also poor prednisone response). Patients were treated with one induction and consolidation course followed by three HR chemotherapy blocks, after which they received either SCT or further chemotherapy. MRD levels were measured at end of induction, consolidation, and after each HR block. Results: At five years, the event-free survival was 72.8% (95% CI, 64.6-82.0), and the cumulative incidence of relapse was 13.0% (95% CI, 6.3-19.8). Patients with only negative or low-positive MRD levels during HR blocks had a significantly lower five-year cumulative incidence of relapse (CIR) of 2.2% (95% CI, 0-6.6) compared with patients with one or more high-positive MRD levels (CIR 15.4%; 95% CI, 3.9-26.9). During the entire treatment protocol, 11.2% of patients died due to toxicity. Conclusions: The high survival with HR blocks seems favorable compared with other studies. However, the limit of treatment intensification might have been reached as the number of patients dying from leukemia relapse is about equal as the number of patients dying from toxicity. Patients with negative or low MRD levels during HR blocks have lower relapse rates. Show less
Glas, N.A. de; Bastiaannet, E.; Bos, F. van den; Mooijaart, S.P.; Veldt, A.A.M. van der; Suijkerbuijk, K.P.M.; ... ; Kapiteijn, E.W. 2021
Simple Summary: Trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included in these trials.... Show moreSimple Summary: Trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included in these trials. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma. We included 2216 patients aged >= 65 years from the Dutch Melanoma Treatment Registry and described outcomes of immunotherapy. The study showed that responses and severe side effects did not differ from previously reported younger populations and randomized trials, even in the oldest patients and in patients with other diseases. However, patients aged >= 75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. We therefore conclude that immunotherapy seems to have similar effects in older patients compared to younger patients, but the impact of less severe toxicity on quality of life should be further studied as older patients are more likely to discontinue treatment.Background: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma and to identify predictors of outcome. Methods: We included patients aged >= 65 years with metastatic melanoma from the Dutch Melanoma Treatment Registry. We described the reasons for hospital admissions and treatment discontinuation. Additionally, we assessed predictors of toxicity and response using logistic regression models and survival using Cox regression models. Results: We included 2216 patients. Grade >= 3 toxicity was not associated with age, comorbidities or WHO status. Patients aged >= 75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. Response rates were similar to previous trials (40.3% and 43.6% in patients aged 65-75 and >= 75, respectively, for anti-PD1 treatment) and did not decrease with age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity. Conclusion: Response rates and toxicity outcomes of checkpoint inhibitors did not change with increasing age or comorbidity. However, the impact of grade I-II toxicity on quality of life deserves further study as older patients discontinue treatment more frequently. Show less
High-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify... Show moreHigh-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify determinants of methotrexate-induced toxicities in osteosarcoma patients by investigating the relation between drug plasma levels, methotrexate-induced toxicities, and germline variants in genes related to drug absorption, distribution, metabolism, and elimination. A cohort of 114 osteosarcoma patients was genotyped for 1,931 variants in 231 genes using the Drug Metabolism Enzymes and Transporters Plus array. Methotrexate plasma levels and laboratory measurements during and after high-dose methotrexate treatment concerning renal function, liver damage, and myelopoiesis to reflect toxicity outcomes were obtained. One hundred and thirteen patients and a subset of 545 variants in 176 genes passed quality control checks. Methotrexate plasma levels showed associations with creatinine, alanine aminotransferase, and hemoglobin. Genetic variant rs3736599 in the 5'-untranslated region ofSULT1E1 was associated with lower 48 hour methotrexate plasma levels [coef -0.313 (95% CI -0.459 - -0.167); p = 2.60 x 10(-5)]. Association with methotrexate-induced decreased thrombocyte counts was found for two intronic variants in CYP2B6{rs4803418 [coef -0.187 (95% CI -0.275 - -0.099); p = 3.04 x 10(-5)] and rs4803419 [coef -0.186 (95% CI -0.278 - -0.093); p = 8.80 x 10(-5)]}. An association with increased thrombocyte counts was identified for the intronic variant rs4808326 in CYP4F8 [coef 0.193 (95% CI 0.099 - 0.287); p = 6.02 x 10(-5)]. Moreover, a secondary analysis with a binary approach using CTCAE toxicity criteria resulted in a nominal significant associations (p < 0.05) for two out of three variants (rs4803418 and rs4808326). This is the first study to identify genetic variants inSULT1E1, CYP2B6, andCYP4F8to be associated with methotrexate pharmacokinetics and toxicities. Validation of these variants in an independent cohort and further functional investigation of variants in the identified genes is needed to determine if and how they affect methotrexate plasma levels and the development of methotrexate-induced toxicities. Show less
Zazuli, Z.; Kos, R.; Veltman, J.D.; Uyterlinde, W.; Longo, C.; Baas, P.; ... ; Zee, A.H.M. van der 2020
Aim Antineoplastic effect of cisplatin, the first line treatment in non-small cell lung cancer (NSCLC), is hindered by its nephrotoxicity and myelotoxicity. Both low-dose and high-dose regimens are... Show moreAim Antineoplastic effect of cisplatin, the first line treatment in non-small cell lung cancer (NSCLC), is hindered by its nephrotoxicity and myelotoxicity. Both low-dose and high-dose regimens are used in the management of NSCLC. The aim of this study is to assess the risk on myelotoxicity and nephrotoxicity from the daily low-dose cisplatin (DLD) treatment as compared to cyclic high-dose cisplatin (CHD). Methods A retrospective cohort study was conducted. NSCLC patients treated with cisplatin between 2011 and 2018 in the Amsterdam UMC or Antoni van Leeuwenhoek cancer hospital were studied. Myelotoxicity and nephrotoxicity were defined based on common terminology criteria (CTCAE v4.03) and categorized as >= grade 1 and >= grade 2. Modified Poisson regression and Cox proportional hazards model were used to estimate relative risks and cumulative hazard respectively. Results Of the 115 NSCLC patients receiving DLD (N=62) and CHD (N=53), 60% had >= grade 1 anemia, 33.9% leukopenia, 31.3% neutropenia, 27.8% thrombocytopenia, 32.2% acute nephrotoxicity with combined definition (Cr-electrolyte nephrotoxicity), and 58.3% chronic nephrotoxicity. The DLD group was older, had an earlier cancer stage, had more comorbidities, and had higher baseline albumin levels. In the DLD group less >= grade 2 toxicities were reported compared to the CHD group except for Cr-electrolyte nephrotoxicity. However, there was a stronger association in the DLD group with >= grade 1 leukopenia, thrombocytopenia, and Cr-electrolyte nephrotoxicity. The DLD group developed significantly more >= grade 1 leukopenia [adjusted relative risk (adjRR)=1.83, 95% CI 1.02-3.27], thrombocytopenia (adjRR=3.43, 95% CI 1.64-7.15), and >= grade 2 Cr-electrolyte nephrotoxicity (adjRR=3.02, 95% CI 1.20-7.56). The DLD group had a lower adjusted cumulative hazard for developing >= grade 2 myelotoxicity and chronic nephrotoxicity but not for Cr-electrolyte nephrotoxicity [adjusted hazard ratio (adjHR)=3.90, 95% CI 1.35-11.23]. In contrast, DLD showed protective effect to >= grade 2 nephrotoxicity when definition was restricted to the traditional creatinine-based definition (adjRR=0.07, 95% CI 0.01-0.86; adjHR=0.05, 95% CI 0.01-0.56). Conclusions Overall, the DLD regimen was safer than the CHD regimen when assessing the risk of >= grade 2 myelotoxicity and nephrotoxicity. However, this might not be the case in patients with a higher risk of electrolyte abnormalities. Show less
Heukelom, J.; Navran, A.; Gouw, Z.A.R.; Tesselaar, M.E.; Zuur, C.L.; Werkhoven, E. van; ... ; Al-Mamgani, A. 2019
Objective The aim of the current study was to determine the incidence of organ function preservation failure (OFPF) in patients with head and neck squamous cell carcinoma (HNSCC) treated by (chemo... Show moreObjective The aim of the current study was to determine the incidence of organ function preservation failure (OFPF) in patients with head and neck squamous cell carcinoma (HNSCC) treated by (chemo)radiotherapy and to identify its risk factors. Study Design Retrospective cohort analysis. Setting Tertiary cancer care center. Subjects and Methods A single-center retrospective cohort analysis was done (n = 703) in which OFPF after (chemo)radiotherapy was assessed. OFPF was defined as local failure or pure functional failure in the absence of local failure because of major surgical intervention (total laryngectomy, commando resection, permanent tracheostomy) or feeding tube dependence >2 years. Results OFPF occurred in 153 patients (21.8%). Reasons for OFPF were local failure in 103 patients (14.6%) and functional failure in 50 patients (7.2%). Evidence of functional failure included need for total laryngectomy (n = 9, 1.3%), commando resection (n = 2, 0.3%), permanent tracheostomy (n = 16, 2.3%), and/or long-term feeding tube for functional reasons (n = 23, 3.3%). In a Cox proportional hazards model, OFPF was worse for patients with T4 tumors (hazard ratio [HR] <0.5 and P < .001 for all other stages), for laryngeal vs oropharyngeal cancer (HR, 1.83; 95% confidence interval [CI], 1.20-2.79, P = .005, hypopharyngeal not significant), and for smokers (HR, 1.68; 95% CI, 1.10-2.56, P = .015). Exploratory multivariate analysis by tumor site showed that T4 tumor and pretreatment tracheostomy were the strongest predictive factors for OFPF in laryngeal and hypopharyngeal carcinoma while T4 tumor and smoking were predictive for poor OFPF in oropharyngeal carcinoma. Conclusion This work shows a detrimental effect of smoking on functional outcomes after (chemo-)radiotherapy for HNSCC. Moreover, T4 tumor, laryngeal subsite, and pretreatment tracheostomy are strong predictors of OFPF. Show less
Objective: Hyperthermia therapy (HT), heating tumors to 40?45??C, is a known radiotherapy (RT) and chemotherapy sensitizer. The additional benefit of HT to RT for recurrent breast cancer has been... Show moreObjective: Hyperthermia therapy (HT), heating tumors to 40?45??C, is a known radiotherapy (RT) and chemotherapy sensitizer. The additional benefit of HT to RT for recurrent breast cancer has been proven in multiple randomized trials. However, published outcome after RT?+?HT varies widely. We performed a systematic review to investigate whether there is a relationship between achieved HT dose and clinical outcome and thermal toxicity for patients with recurrent breast cancer treated with RT?+?HT. Method: Four databases, EMBASE, PubMed, Cochrane library and clinicaltrials.gov, were searched with the terms breast, radiotherapy, hyperthermia therapy and their synonyms. Final search was performed on 3 April 2019. Twenty-two articles were included in the systematic review, reporting on 2330 patients with breast cancer treated with RT?+?HT. Results: Thirty-two HT parameters were tested for a relationship with clinical outcome. In studies reporting a relationship, the relationship was significant for complete response in 10/15 studies, in 10/13 studies for duration of local control, in 2/2 studies for overall survival and in 7/11 studies for thermal toxicity. Patients who received high thermal dose had on average 34% (range 27%?53%) more complete responses than patients who received low thermal dose. Patients who achieved higher HT parameters had increased odds/probability on improved clinical outcome and on thermal toxicity. Conclusion: Temperature and thermal dose during HT had significant influence on complete response, duration of local control, overall survival and thermal toxicity of patients with recurrent breast cancer treated with RT?+?HT. Higher temperature and thermal dose improved outcome, while higher maximum temperature increased incidence of thermal toxicity. Show less
