Prevalence and follow-up of potentially inappropriate medication and potentially omitted medication in older patients with cancer - The PIM POM study

Objectives: To determine the prevalence of Potentially Inappropriate Medication (PIMs) and Potentially Omitted Medication (POMs) in older patients with cancer. Materials and Methods: In this prospective observational study (hospital) pharmacists conducted comprehensive medication reviews in older patients with cancer (aged >= 65 years) receiving parenteral chemotherapy and/or immunotherapy at the Deventer Hospital. PIMs and POMs were identified using the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP), the Screening Tool to Alert doctors to the Right Treatment (START), and pharmacists' expert opinion. Recommendations regarding PIMs and POMs were communicated to the patient's oncologist/haematologist and follow-up was measured. Associations between covariates and the prevalence of PIMs and POMs were statistically analysed. Results: For the 150 patients included, 180 PIMs and 86 POMs were identified with a prevalence of 78%. Using pharmacists' expert opinion in addition to only STOPP/START criteria contributed to 49% of the PIMs and 23% of the POMs. A follow-up action was required in 73% of the 266 PIMs and POMs. Number of medicines and Charlson Comorbidity Index score were both associated with having at least one PIM and/or POM (p = .031 and p = .016, respectively). Conclusion: The prevalence of PIMs and POMs and subsequent follow-up in older patients with cancer is high. A pharmacist-led comprehensive medication review is a good instrument to identify these PIMs and POMs and to optimize patients' treatment. A complete approach, including pharmacists' expert opinion, is recommended to identify all PIMs and POMs in clinical practice. (C) 2020 The Authors. Published by Elsevier Ltd

Tyrosine Kinase Inhibitors and Proton Pump Inhibitors:An Evaluation of Treatment Options

Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given

Digital image analysis of HER2 immunohistochemistry in gastric- and oesophageal adenocarcinoma:a validation study on biopsies and surgical specimens

AimsTo test the validity of diagnostics incorporating digital image analysis (DIA) for human epidermal growth factor 2 (HER2) immunohistochemistry (IHC) in gastro-oesophageal adenocarcinomas, as an alternative to current standard diagnostics using manual scoring. Methods and resultsWe included 319 consecutive gastro-oesophageal adenocarcinomas (232 biopsies and 87 surgical specimens). DIA was applied to determine HER2 IHC classification, using both standard breast cancer (BC) and modified gastro-oesophageal cancer (GEC) cut-offs. Consensus manual scores were established by four independent observers. Chromogenic in-situ hybridization (CISH) was performed on all 2+ cases by manual scoring, DIA or both. HER2 status was considered positive in 3+ and CISH-positive 2+ cases. Overall agreement between DIA and consensus manual scores was 76.5% (weighted = 0.66, BC cut-offs) and 85.6% (weighted = 0.80, GEC cut-offs). Agreement was similar for biopsies and surgical specimens. All disagreement occurred in the manual IHC equivocal cases. DIA resulted in a reduction of 2+ cases: 75.8% with BC cut-offs and 46.5% with GEC cut-offs. HER2 status was positive in 48 cases (15%) with standard diagnostics and DIA using GEC cut-offs, and 46 cases (14.4%) using BC cut-offs (all with CISH in 2+ cases). Considering standard diagnostics as a reference, DIA showed 93.8% sensitivity and 99.6% specificity (BC cut-offs) or 97.9% sensitivity and 99.6% specificity (GEC cut-offs). ConclusionsDIA is a reliable and feasible alternative to manual HER2 IHC scoring in gastro-oesophageal adenocarcinoma, both in biopsies and surgical specimens, leading to a reduction of 2+ cases for which subsequent ISH testing is required

Tyrosine Kinase Inhibitors and Proton Pump Inhibitors: An Evaluation of Treatment Options

Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment

Independent replication of polymorphisms predicting toxicity in breast cancer patients randomized between dose-dense and docetaxel-containing adjuvant chemotherapy

Introduction: Although pharmacogenomics has evolved substantially, a predictive test for chemotherapy toxicity is still lacking. We compared the toxicity of adjuvant dose-dense doxorubicin-cyclophosphamide (ddAC) and docetaxel-doxorubicincyclophosphamide (TAC) in a randomized multicenter phase III trial and replicated previously reported associations between genotypes and toxicity. Results: 646 patients (97%) were evaluable for toxicity (grade 2 and higher). Whereas AN was more frequent after ddAC (P < 0.001), TAC treated patients more often had PNP (P < 0.001). We could replicate 2 previously reported associations: TECTA (rs1829; OR 4.18, 95% CI 1.84-9.51, P = 0.001) with PNP, and GSTP1 (rs1138272; OR 2.04, 95% CI 1.13-3.68, P = 0.018) with PNP. Materials and methods: Patients with pT1-3, pN0-3 breast cancer were randomized between six cycles A60C600 every 2 weeks or T75A50C500 every 3 weeks. Associations of 13 previously reported single nucleotide polymorphisms (SNPs) with the most frequent toxicities: anemia (AN), febrile neutropenia (FN) and peripheral neuropathy (PNP) were analyzed using logistic regression models. Conclusions: In this independent replication, we could replicate an association between 2 out of 13 SNPs and chemotherapy toxicities. These results warrant further validation in order to enable tailored treatment for breast cancer patients

Treatment with lenalidomide in myelodysplastic syndromes with deletion 5q:results from the Dutch named patient program

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Dihydropyrimidine Dehydrogenase Phenotyping Using Pretreatment Uracil: A Note of Caution Based on a Large Prospective Clinical Study

In clinical practice, 25–30% of the patients treated with fluoropyrimidines experience severe fluoropyrimidine-related toxicity. Extensively clinically validated DPYD genotyping tests are available to identify patients at risk of severe toxicity due to decreased activity of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in fluoropyrimidine metabolism. In April 2020, the European Medicines Agency recommended that, as an alternative for DPYD genotype-based testing for DPD deficiency, also phenotype testing based on pretreatment plasma uracil levels is a suitable method to identify patients with DPD deficiency. Although the evidence for genotype-directed dosing of fluoropyrimidines is substantial, the level of evidence supporting plasma uracil levels to predict DPD activity in clinical practice is limited. Notwithstanding this, uracil-based phenotyping is now used in clinical practice in various countries in Europe. We aimed to determine the value of pretreatment uracil levels in predicting DPD deficiency and severe treatment-related toxicity. To this end, we determined pretreatment uracil levels in 955 patients with cancer, and assessed the correlation with DPD activity in peripheral blood mononuclear cells (PBMCs) and fluoropyrimidine-related severe toxicity. We identified substantial issues concerning the use of pretreatment uracil in clinical practice, including large between-center study differences in measured pretreatment uracil levels, most likely as a result of pre-analytical factors. Importantly, we were not able to correlate pretreatment uracil levels with DPD activity nor were uracil levels predictive of severe treatment-related toxicity. We urge that robust clinical validation should first be performed before pretreatment plasma uracil levels are used in clinical practice as part of a dosing strategy for fluoropyrimidines

A randomized phase 2 study exploring the role of bevacizumab and a chemotherapy-free approach in HER2-positive metastatic breast cancer: The HAT study (BOOG 2008-2003), a Dutch Breast Cancer Research Group trial

BACKGROUND: To explore the role of bevacizumab and a chemotherapy-free approach, the authors evaluated the combination of bevacizumab, trastuzumab, and paclitaxel (HAT) and the regimen of trastuzumab and bevacizumab (HA) with the addition of paclitaxel after progression (HA-HAT) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. METHODS: In a noncomparative phase 2 trial, patients were randomized between HAT and HA-HAT. The primary endpoint was the progression-free rate at 1 year (1-year PFR). In the HA-HAT group, progression-free survival (PFS) was separately established for HA (PFS1) and HAT (PFS2). RESULTS: Eighty-four patients received HAT (n = 39) or HA-HAT (n = 45). The 1-year PFR was 74.4% (95% confidence interval [CI], 61.8%-89.4%) and 62.2% (95% CI, 49.6%-89.4%) in the HAT and HA-HAT arms, respectively. The median PFS was 19.8 months (95% CI, 14.9-25.6 months) in the HAT arm and 19.6 months (95% CI, 12.0-32.0 months) in the HA-HAT arm. In the HA-HAT arm, the median PFS1 was 10.4 months (95% CI, 6.2-15.0 months), and the median PFS2 was 8.2 months (95% CI, 7.0-12.6 months). The number and severity of adverse events were comparable between the arms. CONCLUSIONS: Both HAT and HA-HAT have promising activity in patients with HER2-positive metastatic breast cancer. In particular, starting with only targeted agents and delaying chemotherapy is worth further exploration

High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: the randomized phase III NeoTN trial

Abstract Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution (p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23–1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III (n = 35; HR 0.16; 95% CI 0.03–0.75), but not stage II (n = 86; HR 1.00; 95% CI 0.30–3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24–87%), 71% (95% CI 48–100%) and 88% (95% CI 74–100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069