Continuous ambulatory peritoneal dialysis: pharmacokinetics and clinical outcome of paclitaxel and carboplatin treatment

Purpose: Administration of chemotherapy in patients with renal failure, treated with hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) is still a challenge and literature data is scarce. Here we present a case study of a patient on CAPD, treated with weekly and three-weekly paclitaxel/ carboplatin for recurrent ovarian cancer. Experimental: During the first, second and ninth cycle of treatment, blood, urine and CAPD samples were collected for pharmacokinetic analysis of paclitaxel and total and unbound carboplatin-derived platinum. Results: Treatment was well tolerated by the patient. No excessive toxicity was observed and at the e

Quantification of ribociclib in dried blood spots by LC–MS/MS: Method development and clinical validation

A reliable, specific, selective and robust liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for the determination of ribociclib in both dried blood spot (DBS) samples and potassium EDTA plasma. DBS samples were obtained simultaneously with a plasma sample in advanced breast cancer patients treated with ribociclib. A 6 mm disk from the central part of the dried blood spot sample was punched, followed by extraction of ribociclib using liquid-liquid extraction spiked with ribociclib-d6 as internal standard. Concentrations of ribociclib in DBS samples were correlated with corresponding plasma concentrations. From the blood sample also hematocrit was determined. The method was validated for selectivity, sensitivity, precision, lower limit of detection, linearity, stability and accuracy according to the food and drug administration (FDA) guideline. The within- and between-run precisions were ≤10.6 and ≤1.07 %, respectively; while the average accuracy ranged from 100 to 103 %. The influence of hematocrit on validation parameters was tested in the range of 0.20 – 0.40 L/L. No influence of hematocrit on validation parameters was observed. Regression analysis and a Bland-Altman plot indicated correlation between the results obtained from DBS and plasma samples. A strong correlation (R2 >0.97) between DBS samples and plasma concentration from 17 breast cancer patients was found. A number of 12 out of 17 processed DBS samples (71 %) fell inside the acceptable range of 20 % difference of simultaneously obtained plasma samples. The lower limit of quantification in DBS is 10.0 ng/mL and linearity was demonstrated up to 1000 ng/mL. In conclusion, the newly developed assay met the required standard for validation. The methods were used to study ribociclib disposition in patients with advanced breast cancer

Quantification of ribociclib in dried blood spots by LC–MS/MS

A reliable, specific, selective and robust liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for the determination of ribociclib in both dried blood spot (DBS) samples and potassium EDTA plasma. DBS samples were obtained simultaneously with a plasma sample in advanced breast cancer patients treated with ribociclib. A 6 mm disk from the central part of the dried blood spot sample was punched, followed by extraction of ribociclib using liquid-liquid extraction spiked with ribociclib-d6 as internal standard. Concentrations of ribociclib in DBS samples were correlated with corresponding plasma concentrations. From the blood sample also hematocrit was determined. The method was validated for selectivity, sensitivity, precision, lower limit of detection, linearity, stability and accuracy according to the food and drug administration (FDA) guideline. The within- and between-run precisions were ≤10.6 and ≤1.07 %, respectively; while the average accuracy ranged from 100 to 103 %. The influence of hematocrit on validation parameters was tested in the range of 0.20 – 0.40 L/L. No influence of hematocrit on validation parameters was observed. Regression analysis and a Bland-Altman plot indicated correlation between the results obtained from DBS and plasma samples. A strong correlation (R2 &gt;0.97) between DBS samples and plasma concentration from 17 breast cancer patients was found. A number of 12 out of 17 processed DBS samples (71 %) fell inside the acceptable range of 20 % difference of simultaneously obtained plasma samples. The lower limit of quantification in DBS is 10.0 ng/mL and linearity was demonstrated up to 1000 ng/mL. In conclusion, the newly developed assay met the required standard for validation. The methods were used to study ribociclib disposition in patients with advanced breast cancer.</p

Development of a Clinical Prediction Model for 1-Year Mortality in Patients With Advanced Cancer

Importance: To optimize palliative care in patients with cancer who are in their last year of life, timely and accurate prognostication is needed. However, available instruments for prognostication, such as the surprise question ("Would I be surprised if this patient died in the next year?") and various prediction models using clinical variables, are not well validated or lack discriminative ability. Objective: To develop and validate a prediction model to calculate the 1-year risk of death among patients with advanced cancer. Design, Setting, and Participants: This multicenter prospective prognostic study was performed in the general oncology inpatient and outpatient clinics of 6 hospitals in the Netherlands. A total of 867 patients were enrolled between June 2 and November 22, 2017, and followed up for 1 year. The primary analyses were performed from October 9 to 25, 2019, with the most recent analyses performed from June 19 to 22, 2022. Cox proportional hazards regression analysis was used to develop a prediction model including 3 categories of candidate predictors: clinician responses to the surprise question, patient clinical characteristics, and patient laboratory values. Data on race and ethnicity were not collected because most patients were expected to be of White race and Dutch ethnicity, and race and ethnicity were not considered as prognostic factors. The models' discriminative ability was assessed using internal-external validation by study hospital and measured using the C statistic. Patients 18 years and older with locally advanced or metastatic cancer were eligible. Patients with hematologic cancer were excluded. Main Outcomes and Measures: The risk of death by 1 year. Results: Among 867 patients, the median age was 66 years (IQR, 56-72 years), and 411 individuals (47.4%) were male. The 1-year mortality rate was 41.6% (361 patients). Three prediction models with increasing complexity were developed: (1) a simple model including the surprise question, (2) a clinical model including the surprise question and clinical characteristics (age, cancer type prognosis, visceral metastases, brain metastases, Eastern Cooperative Oncology Group performance status, weight loss, pain, and dyspnea), and (3) an extended model including the surprise question, clinical characteristics, and laboratory values (hemoglobin, C-reactive protein, and serum albumin). The pooled C statistic was 0.69 (95% CI, 0.67-0.71) for the simple model, 0.76 (95% CI, 0.73-0.78) for the clinical model, and 0.78 (95% CI, 0.76-0.80) for the extended model. A nomogram and web-based calculator were developed to support clinicians in adequately caring for patients with advanced cancer. Conclusions and Relevance: In this study, a prediction model including the surprise question, clinical characteristics, and laboratory values had better discriminative ability in predicting death among patients with advanced cancer than models including the surprise question, clinical characteristics, or laboratory values alone. The nomogram and web-based calculator developed for this study can be used by clinicians to identify patients who may benefit from palliative care and advance care planning. Further exploration of the feasibility and external validity of the model is needed

Body composition is associated with risk of toxicity-induced modifications of treatment in women with stage I–IIIB breast cancer receiving chemotherapy

Purpose: Initial dose of chemotherapy is planned based on body surface area, which does not take body composition into account. We studied the association between fat mass (kg and relative to total body weight) as well as lean mass (kg and relative to total body weight) and toxicity-induced modifications of treatment in breast cancer patients receiving chemotherapy. Methods: In an observational study among 172 breast cancer patients (stage I–IIIB) in the Netherlands, we assessed body composition using dual-energy X-ray scans. Information on toxicity-induced modifications of treatment, defined as dose reductions, cycle delays, regimen switches, or premature termination of chemotherapy, was abstracted from medical records. Adjusted hazard ratios and 95% confidence intervals (95% CI) were calculated to assess associations between body composition and the risk of toxicity-induced modifications of treatment. Results: In total, 95 out of 172 (55%) patients experienced toxicity-induced modifications of treatment. Higher absolute and relative fat mass were associated with higher risk of these modifications (HR 1.14 per 5 kg; 95% CI 1.04–1.25 and HR 1.21 per 5%; 95% CI 1.05–1.38, respectively). A higher relative lean mass was associated with a lower risk of modifications (HR 0.83 per 5%; 95% CI 0.72–0.96). There was no association between absolute lean mass and risk of toxicity-induced modifications of treatment. Conclusions: A higher absolute and a higher relative fat mass was associated with an increased risk of toxicity-induced modifications of treatment. Absolute lean mass was not associated with risk of these treatment modifications, while higher relative lean mass associated with lower risk of modifications. These data suggest that total fat mass importantly determines the risk of toxicities during chemotherapy in breast cancer patients.</p

Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01)

The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis. During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032). Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. ClinicalTrials.gov NCT01099436 . Registered April 6, 201

Trastuzumab Resistance in Patients With HER2-Positive Advanced Breast Cancer:Results From the SONABRE Registry

BACKGROUND: This study aims to explore whether first-line pertuzumab use modifies the effect of prior use of (neo-) adjuvant trastuzumab on the PFS of first-line HER2-targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). METHODS: Patients diagnosed with HER2-positive ABC in 2008 to 2018 in 9 Dutch hospitals were derived from the SONABRE Registry (NCT03577197). Patients diagnosed with de novo metastatic breast cancer were excluded. Patients receiving first-line trastuzumab-based therapy for ABC were selected and divided into trastuzumab naïve (n = 113) and trastuzumab pretreated (n = 112). Progression-free survival (PFS) was compared using multivariable Cox proportional hazard models. The interaction effect of first-line pertuzumab was tested using the likelihood-ratio test. RESULTS: The median follow-up time was 47 months (95% confidence interval [CI]: 42-52). When comparing trastuzumab pretreated with trastuzumab naïve patients, the hazard ratio for first-line progression was 2.07 (CI:1.47-2.92). For trastuzumab pretreated patients who received first-line trastuzumab without pertuzumab, the hazard ratio for progression was 2.60 (95% CI:1.72-3.93), whereas for those who received first-line trastuzumab with pertuzumab the hazard ratio was 1.43 (95% CI: 0.81-2.52) (P interaction = .10). CONCLUSIONS: Prior use of trastuzumab as (neo-)adjuvant treatment had a negative impact on PFS of first-line HER2-targeted therapy outcomes. Adding pertuzumab to first-line trastuzumab-based therapy decreased the negative impact of prior (neo-)adjuvant trastuzumab use on first-line PFS. Further studies are needed to assess the effect of prior (neo-)adjuvant pertuzumab use on the outcomes of first-line pertuzumab-based therapy

Addition of zoledronic acid to neoadjuvant chemotherapy is not beneficial in patients with HER2-negative stage II/III breast cancer: 5-year survival analysis of the NEOZOTAC trial (BOOG 2010-01)

Background: Adjuvant bisphosphonates are associated with improved breast cancer survival in postmenopausal patients. Addition of zoledronic acid (ZA) to neoadjuvant chemotherapy did not improve pathological complete response in the phase III NEOZOTAC trial. Here we report the results of the secondary endpoints, disease-free survival, (DFS) and overall survival (OS). Patients and methods: Patients with HER2-negative, stage II/III breast cancer were randomized to receive the standard 6 cycles of neoadjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy with or without 4 mg intravenous (IV) ZA administered within 24 h of chemotherapy. This was repeated every 21 days for 6 cycles. Cox regression models were used to evaluate the effect of ZA and covariates on DFS and OS. Regression models were used to examine the association between insulin, glucose, insulin growth factor-1 (IGF-1) levels, and IGF-1 receptor (IGF-1R) expression with survival outcomes. Results: Two hundred forty-six women were eligible for inclusion. After a median follow-up of 6.4 years, OS for all patients was significantly worse for those who received ZA (HR 0.468, 95% CI 0.226-0.967, P = 0.040). DFS was not significantly different between the treatment arms (HR 0.656, 95% CI 0.371-1.160, P = 0.147). In a subgroup analysis of postmenopausal women, no significant difference in DFS or OS was found for those who received ZA compared with the control group (HR 0.464, 95% CI 0.176-1.222, P = 0.120; HR 0.539, 95% CI 0.228-1.273, P = 0.159, respectively). The subgroup analysis of premenopausal patients was not significantly different for DFS and OS ((HR 0.798, 95% CI 0.369-1.725, P = 0.565; HR 0.456, 95% CI 0.156-1.336, P = 0.152, respectively). Baseline IGF-1R expression was not significantly associated with DFS or OS. In a predefined additional study, lower serum levels of insulin were associated with improved DFS (HR 1.025, 95% CI 1.005-1.045, P = 0.014). Conclusions: Our results suggest that ZA in combination with neoadjuvant chemotherapy was associated with a worse OS in breast cancer (both pre- and postmenopausal patients). However, in a subgroup analysis of postmenopausal patients, ZA treatment was not associated with DFS or OS. Also, DFS was not significantly different between both groups. IGF-1R expression in tumor tissue before and after neoadjuvant treatment did not predict survival

Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

Circulating tumor cells (CTC) are detected by the CellSearch System in 20% to 25% of patients with primary breast cancer (pBC). To improve CTC detection, we investigated melanoma cell adhesion molecule (MCAM) as enrichment marker next to epithelial cell adhesion molecule (EpCAM) and tested the clinical relevance of MCAM-positive CTCs in patients with HER2-negative stage II/III pBC starting neoadjuvant chemotherapy (NAC) in the NEOZOTAC trial. Using the CellSearch System, EpCAM-positive and MCAM-positive CTCs were separately enriched from 7.5 mL blood, at baseline and after the first NAC cycle. Circulating endothelial cells (CEC) were measured using flow cytometry. Primary objective was to improve the CTC detection rate to ≥ 40% combining EpCAM/MCAM. Correlations of CTC and CEC counts and pathologic complete response (pCR) were also explored. At baseline, we detected EpCAM-positive and MCAM-positive CTCs in 12 of 68 (18%) and 8 of 68 (12%) patients, respectively. After one cycle, this was 7 of 44 (16%) and 7 of 44 (16%) patients, respectively. The detection rate improved from 18% at baseline and 16% after one cycle with EpCAM to 25% (P = 0.08) and 30% (P = 0.02), respectively, with EpCAM/MCAM. No patients with MCAM-positive CTCs versus 23% of patients without MCAM-positive CTCs at baseline achieved pCR (P = 0.13). EpCAM-positive CTCs and CEC counts were not correlated to pCR. Combined EpCAM/MCAM CellSearch enrichment thus increased the CTC detection rate in stage II/III pBC. We found no associations of CTC and CEC counts with pCR to NAC. The clinical relevance of MCAM-positive CTCs deserves further stud