BackgroundIn this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H)... Show moreBackgroundIn this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile.Patients and methodsPatients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses.ResultsTwenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB.ConclusionDurvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. 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
Introduction: To compare the real-world safety profile of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors between younger and older patients.Materials and... Show moreIntroduction: To compare the real-world safety profile of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors between younger and older patients.Materials and Methods: All patients receiving pembrolizumab, nivolumab, atezolizumab or durvalumab between September 2016 and September 2019 at Haga Teaching Hospital, The Hague, The Netherlands were included in this retrospective study. Immune-related adverse drug reactions (irADRs) were manually retrieved from the electronic patient files. The cumulative incidence of irADRs were compared between younger (<65 years) and older (>= 65 years) patients using a Pearsons Chi-square test.Results: We identified 217 patients who were treated with at least one dose of PD-(L)1 inhibitor. 58% were 65 years or older at the start of immunotherapy. 183 patients (84.3%) received monotherapy PD-(L)1 inhibitors and 34 (15.7%) received chemo-immunotherapy. A total of 278 irADRs were registered. Cutaneous irADRs (53.9%), thyroid gland disorders (20.3%), and non-infectious diarrhoea/colitis (17.5%) were the most frequently reported irADRs. The majority of the irADRs were mild to moderate and no fatal irADRs were observed. 61 (21.9%) of the irADRs needed systemic treatment, of which 19 (6.8%) required treatment with corticosteroids. 18 irADRs (6.5%) were severe and resulted in hospitalisation.The cumulative incidence of cutaneous irADRs was different between the age groups: 45.7% of the patients <65 years and in 60.0% of the patients >= 65 years (p = 0.036). No statistical difference was found in the cumulative incidence of other irADRs between the two age groups.Discussion: Advanced age is not associated with immune-related adverse drug reactions of PD-1 and PD-L1 inhibitors. Show less
Purpose: Scalp cooling can prevent chemotherapy-induced alopecia (CIA). Previously, the post-infusion cooling time (PICT) could be successfully reduced in docetaxel-treated patients from 90 to 45... Show morePurpose: Scalp cooling can prevent chemotherapy-induced alopecia (CIA). Previously, the post-infusion cooling time (PICT) could be successfully reduced in docetaxel-treated patients from 90 to 45 and 20 min. Therefore, it seems plausible that the PICT can be shortened for paclitaxel-treated patients as well. Methods: Patients treated with weekly paclitaxel were included in this multi-centre trial and randomly assigned to a PICT of 45 or 20 min. The results were compared to a standard PICT of 90 min, derived from prospective collected data from the Dutch Scalp Cooling Registry. The primary endpoint was the percentage of patients who decide to not wear a wig or head covering. Secondary endpoints were the degree of CIA assessed with the Dean scale for assessment of hair loss; alopecia graded according to NCI CTC toxicity version 4.03 (CTCAE4.03); tolerance of scalp cooling and perceived distress of CIA. Results: Ninety-one patients were enrolled in this study; 74 patients were evaluable for hair loss. Hair preservation was successful in 27 patients (75%) with a PICT of 45 min and in 31 patients (82%) with a PICT of 20 min. There was no difference in success rate with the standard PICT of 90 min (85%, p = 0.29). Similar success rates were seen when using the Dean scale and CTCAE assessment, with no differences between groups (p = 0.12 and p = 0.38). Conclusions: A 20 min PICT is as effective as 45 and 90 min to prevent weekly paclitaxel-induced alopecia and should be the new standard of care. Show less
Laar, S.A. van; Gombert-Handoko, K.B.; Groenwold, R.H.H.; Hulle, T. van der; Visser, L.E.; Houtsma, D.; ... ; Zwaveling, J. 2022
The number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in... Show moreThe number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in investigating mRCC treatment efficacy, their external validity can be limited. Therefore, the efficacy of the different treatment options should also be evaluated in clinical practice. We performed a chart review of electronic health records using text mining software to study the current treatment patterns and outcomes. mRCC patients from two large hospitals in the Netherlands, starting treatment between January 2015 and May 2020, were included. Data were collected from electronic health records using a validated text mining tool. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan-Meier method. Most frequent first-line treatments were pazopanib (n = 70), sunitinib (n = 34), and nivolumab with ipilimumab (n = 28). The overall median PFS values for first-line treatment were 15.7 months (95% confidence interval [95%CI], 8.8-20.7), 16.3 months (95%CI, 9.3-not estimable [NE]) for pazopanib, and 6.9 months (95% CI, 4.4-NE) for sunitinib. The overall median OS values were 33.4 months (95%CI, 28.1-50.9 months), 39.3 months (95%CI, 29.5-NE) for pazopanib, and 28.1 months (95%CI, 7.0-NE) for sunitinib. For nivolumab with ipilimumab, median PFS and median OS were not reached. Of the patients who finished first- and second-line treatments, 64 and 62% received follow-up treatments, respectively. With most patients starting on pazopanib and sunitinib, these real-world treatment outcomes were most likely better than in pivotal trials, which may be due to extensive follow-up treatments. Show less
Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study,... Show moreAim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd. Show less
Zanden, V. van der; Soolingen, N.J. van; Viddeleer, A.R.; Trum, J.W.; Amant, F.; Mourits, M.J.E.; ... ; Souwer, E.T.D. 2021
Objective. To determine the predictive value of lumbar skeletal muscle mass and density for postoperative outcomes in older women with advanced stage ovarian cancer.Methods. A multicenter,... Show moreObjective. To determine the predictive value of lumbar skeletal muscle mass and density for postoperative outcomes in older women with advanced stage ovarian cancer.Methods. A multicenter, retrospective cohort study was performed in women >= 70 years old receiving surgery for primary, advanced stage ovarian cancer. Skeletal muscle mass and density were assessed in axial CT slices on level L3. Low skeletal muscle mass was defined as skeletal muscle index < 38.50 cm(2)/m(2). Low skeletal muscle density was defined as one standard deviation below the mean (muscle attenuation < 22.55 Hounsfield Units). The primary outcome was any postoperative complication <-30 days after surgery. Secondary outcomes included severe complications, infections, delirium, prolonged hospital stay, discharge destination, discontinua-tion of adjuvant chemotherapy and mortality.Results. In analysis of 213 patients, preoperative low skeletal muscle density was associated with postopera-tive complications <-30 days after surgery (Odds Ratio (OR) 2.83; 95% Confidence Interval (CI) 1.41-5.67), severe complications (OR 3.01; 95%CI 1.09-8.33), infectious complications (OR 2.79; 95%CI 1.30-5.99) and discharge to a care facility (OR 3.04; 95%CI 1.16-7.93). Preoperative low skeletal muscle mass was only associated with infec-tious complications (OR 2.32; 95%CI 1.09-4.92). In a multivariable model, low skeletal muscle density was of added predictive value for postoperative complications (OR 2.57; 95%CI 1.21-5.45) to the strongest existing pre-dictor functional impairment (KATZ-ADL >= 2).Conclusion. Low skeletal muscle density, as a proxy of muscle quality, is associated with poor postoperative outcomes in older patients with advanced stage ovarian cancer. These findings can contribute to postoperative risk assessment and clinical decision making. (C) 2021 The Author(s). Published by Elsevier Inc. Show less
Houtsma, D.; Groot, S. de; Baak-Pablo, R.; Kranenbarg, E.M.K.; Seynaeve, C.M.; Velde, C.J.H. van de; ... ; Gelderblom, H. 2021
The PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early... Show moreThe PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early hormone-receptor positive breast cancer. However, it remains unclear whether this SNP is a predictive marker for tamoxifen efficacy or a prognostic marker for breast cancer outcome. The aim of this study was to examine the prognostic potential of this SNP in postmenopausal early breast cancer patients treated with adjuvant exemestane. Dutch postmenopausal patients randomised to 5 years of adjuvant exemestane of whom tissue was available (N=807) were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial database. The SNP rs2234693 in the ESR1 gene was genotyped on DNA from formalin-fixed paraffin embedded (FFPE) tumor tissue using Taqman assays and related to the primary endpoint disease-free survival (DFS) and secondary endpoint overall survival (OS). Survival analyses were performed using Cox regression analysis. In total 805 patients were included in the analyses (median follow up of 5.22 years) and genotypes were obtained in 97% of the samples. The variant T allele of PvuII in ESR1 (rs2234693) was associated with a better DFS (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.480-0.989, P=0.044) in univariate analysis only, and a better OS in both univariate (HR 0.616, 95%, CI 0.411-0.923, P=0.019) and multivariate analyses (HR 0.571, 95% CI 0.380-0.856, P=0.007), consistent with a prognostic rather than a predictive drug response effect. Variation of PvuII in the ESR1 gene is related to OS in postmenopausal, early HR+breast cancer patients treated with exemestane in the TEAM study. Variation in the ESR1 gene may therefore be a prognostic marker of early breast cancer survival, and warrants further research. Show less
Pharmacogenetics is a rapidly developing field, especially in oncology. In the most ideal situation pharmacogenetics will allow oncologists to individualize therapy based on patients' individual... Show morePharmacogenetics is a rapidly developing field, especially in oncology. In the most ideal situation pharmacogenetics will allow oncologists to individualize therapy based on patients' individual germline genetic test results. This can help to improve efficacy, reduce toxicity and predict non-responders in a way that alternative therapy can be chosen or individual dose adjustments can be made. Multiple pathways have been studied extensively of which a brief review is presented here. Increased 5FU toxicity is associated with variations in the DPYD gene, TYMS gene and MTHFR gene. Furthermore variations in the UGT1A gene and the ABCB1 gene influence irinotecan metabolism and disposition. Other genetic changes result in reduced DNA repair capacity related to platinum efficacy or reduced cytochrome P450 2D6 activity related to tamoxifen efficacy. Despite the extensive number of pharmacogenetic studies and promising results, it is still unclear when and how pretreatment genetic screening should be implemented in oncology. Future prospective studies should focus on the effect of pharmacogenetics on patient outcome and combine this with cost effectiveness evaluations. Thus supplying us with predictive models helping in deciding when pretreatment genetic screening is useful. Show less
