Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.

AIMS: The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. METHODS: Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. RESULTS: Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4 nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. CONCLUSION: This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

Relationship Between Cetuximab Target-Mediated Pharmacokinetics and Progression-Free Survival in Metastatic Colorectal Cancer Patients.

BACKGROUND AND OBJECTIVE: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal immunoglobulin (Ig)G1 antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The influence of target-antigen on cetuximab pharmacokinetics has never been investigated using target-mediated drug disposition (TMDD) modelling. This study aimed to investigate the relationship between cetuximab concentrations, target kinetics and progression-free survival (PFS). METHODS: In this ancillary study (NCT00559741), 91 patients with mCRC treated with cetuximab were assessed. Influence of target levels on cetuximab pharmacokinetics was described using TMDD modelling. The relationship between cetuximab concentrations, target kinetics and time-to-progression (TTP) was described using a joint pharmacokinetic-TTP model, where unbound target levels were assumed to influence hazard of progression by an Emax model. Mitigation strategies of concentration-response relationship, i.e., time-varying endogenous clearance and mutual influences of clearance and time-to-progression were investigated. RESULTS: Cetuximab concentration-time data were satisfactorily described using the TMDD model with quasi-steady-state approximation and time-varying endogenous clearance. Estimated target parameters were baseline target levels (R0 = 43 nM), and complex elimination rate constant (kint = 0.95 day-1). Estimated time-varying clearance parameters were time-invariant component of CL (CL0= 0.38 L/day-1), time-variant component of CL (CL1= 0.058 L/day-1) and first-order rate of CL1 decreasing over time (kdes = 0.049 day-1). Part of concentration-TTP was TTP-driven, where clearance and TTP were inversely correlated. In addition, increased target occupancy was associated with increased TTP. CONCLUSION: This is the first study describing the complex relationship between cetuximab target-mediated pharmacokinetics and PFS in mCRC patients using a joint PK-time-to-progression model. Further studies are needed to provide a more in-depth description of this relationship.

Pectoralis major muscle atrophy is associated with mitochondrial energy wasting in cachectic patients with gastrointestinal cancer.

BACKGROUND: Cancer cachexia is a multifactorial syndrome characterized by involuntary and pathological weight loss, mainly due to skeletal muscle wasting, resulting in a decrease in patients' quality of life, response to cancer treatments, and survival. Our objective was to investigate skeletal muscle alterations in cachectic cancer patients. METHODS: This is a prospective study of patients managed for pancreatic or colorectal cancer with an indication for systemic chemotherapy (METERMUCADIG - NCT02573974). One lumbar CT image was used to determine body composition. Patients were divided into three groups [8 noncachectic (NC), 18 with mild cachexia (MC), and 19 with severe cachexia (SC)] based on the severity of weight loss and muscle mass. For each patient, a pectoralis major muscle biopsy was collected at the time of implantable chamber placement. We used high-resolution oxygraphy to measure mitochondrial muscle oxygen consumption on permeabilized muscle fibres. We also performed optical and electron microscopy analyses, as well as gene and protein expression analyses. RESULTS: Forty-five patients were included. Patients were 67% male, aged 67 years (interquartile range, 59-77). Twenty-three (51%) and 22 (49%) patients were managed for pancreatic and colorectal cancer, respectively. Our results show a positive correlation between median myofibres area and skeletal muscle index (P = 0.0007). Cancer cachexia was associated with a decrease in MAFbx protein expression (P < 0.01), a marker of proteolysis through the ubiquitin-proteasome pathway. Mitochondrial oxygen consumption related to energy wasting was significantly increased (SC vs. NC, P = 0.028) and mitochondrial area tended to increase (SC vs. MC, P = 0.056) in SC patients. On the contrary, mitochondria content and networks remain unaltered in cachectic cancer patients. Finally, our results show no dysfunction in lipid storage and endoplasmic reticulum homeostasis. CONCLUSIONS: This clinical protocol brings unique data that provide new insight to mechanisms underlying muscle wasting in cancer cachexia. We report for the first time an increase in mitochondrial energy wasting in the skeletal muscle of severe cachectic cancer patients. Additional clinical studies are essential to further the exploring and understanding of these alterations.

Cross-Cultural Adaptation and Psychometric Validation of the French Version of the FAMCARE-Patient (FFP-16) Questionnaire for Outpatients With Advanced-Stage Cancer.

CONTEXT: Satisfaction is known to be correlated with the quality of care; it indicates the adequacy of the caregivers' responses in meeting the needs and expectations of patients. The FAMCARE-Patient questionnaire has been used to quantify satisfaction level in outpatients with advanced-stage cancers. OBJECTIVES: To translate and cross-culturally adapt the FAMCARE-Patient questionnaire for French patients and to evaluate the psychometric properties of this version. METHODS: The original questionnaire was translated into French and adapted to French cultural context by an expert committee. The French FAMCARE-Patient Version 16 (FFP-16) was then pilot tested among 51 patients. Subsequently, psychometric properties were evaluated in a cross-sectional study by administrating the new tool to 176 adult outpatients with advanced-stage cancer who underwent oncological care at our university hospital. RESULTS: We performed a confirmatory factor analysis and assessed the reliability and validity of the questionnaire. The one-factor structure was confirmed, and it had an acceptable fit with a comparative fit index and root mean square error of approximation of 0.93 and 0.07, respectively. Internal reliability was high as shown by Cronbach's alpha (α = 0.95). Reproducibility was very good (intraclass correlation coefficient 0.91). The FFP-16 score was independent of the Eastern Cooperative Oncology Group and the overall Edmonton Symptom Assessment Scale distress scores. It was significantly but weakly correlated with anxiety, well-being, and overall quality of life (Spearman's correlation coefficient = -0.18, -0.20, and 0.30, respectively; P < 0.05). CONCLUSION: We found the FFP-16 questionnaire to be a reliable and valid instrument for the assessment of satisfaction in French outpatients with advanced-stage cancer.

Usefulness of confocal laser endomicroscopy for predicting postoperative recurrence in patients with Crohn's disease: a pilot study.

BACKGROUND AND AIMS: Confocal laser endomicroscopy (CLE) has been shown to predict relapse in inflammatory bowel disease, but its value in the detection of postoperative recurrence in Crohn's disease (CD) is unknown. The aims of this pilot study performed in patients with CD after ileocolonic resection were to compare the macroscopic appearance of the neoterminal ileum, according to the endoscopic Rutgeerts score, with the microscopic findings provided by CLE 6 to 12 months after surgery and to assess the predictive values of CLE-generated parameters for predicting further recurrence in patients with postoperative endoscopic remission. METHODS: In 25 consecutive patients with CD within 6 to 12 months of surgery, the neoterminal ileum was examined by standard white-light endoscopy (Rutgeerts scale) followed by CLE (Watson grade). Only patients without endoscopic recurrence (Rutgeerts i0 and i1) were then followed endoscopically and clinically (median follow-up 38 months). RESULTS: At the time of the first postoperative colonoscopy, 18 patients (72%) were in endoscopic remission, and 7 (28%) experienced an endoscopic recurrence (Rutgeerts ≥i2). The Rutgeerts score was significantly correlated with the Watson score (ρ = 0 .73; P < .0001). The Watson scores at baseline were significantly higher in patients with further endoscopic recurrence (median 2.0; interquartile range [IQR] 1.5-2.0) than in those with endoscopic remission (median 1.0; IQR 1.0-1.0; P = .032) and were significantly higher in patients with clinical relapse (medium 2.0, IQR 2.0-2.0) compared with those in clinical remission (median 1.0; IQR 1.0-1.0; P = .036). CONCLUSIONS: CLE could be useful in monitoring patients with CD after intestinal resection. Further studies with a larger population are necessary to confirm these preliminary results.

A study of the association between UGT1A1*28 variant allele of UGT1A1 gene and colonic phenotype of sporadic colorectal cancer.

INTRODUCTION: The transcriptional activity of the UGT1A1 gene is modulated by a variable number of repetitions of the dinucleotide (TA) within its promoter region. By comparison to the most common allele (TA)6 (UGT1A1*1), decreased activity is observed with increasing TA repetitions. The aim of this study was to determine whether the presence of the variant allele UGT1A1*28, harbouring seven TA repetitions, (TA)7, in the homozygous state, is associated with precancerous colonic lesions and/or with specific colorectal cancer characteristics. MATERIAL AND METHODS: All patients treated for colorectal cancer in a tertiary care centre, between January 2009 and December 2013, who had routine UGT1A1 genotyping for irinotecan dose-adjustment were included. Data were retrospectively collected. RESULTS: 292 patients were enrolled, including 23 UGT1A1*28/*28 homozygous (7.9%), 137 wild type homozygous (46.9%) and 132 heterozygous (45.2%). There were no significant differences in phenotypic colonic characteristics between homozygous and heterozygous patients carrying the UGT1A1*28 allele as compared to *1/*1 homozygous. Patients treated with aspirin were significantly more common in the UGT1A1*28/*28 homozygous group than in the other groups (7/23 (30.4%) compared to 22/269 (8.2%), p = 0.001). CONCLUSION: Dinucleotide polymorphism in the promoter region of the UGT1A1 gene is not associated with a specific colonic phenotype in patients with sporadic colorectal cancer.

Possible association of CAG repeat polymorphism in KCNN3 encoding the potassium channel SK3 with oxaliplatin-induced neurotoxicity.

INTRODUCTION: Data suggest a role of the potassium channel SK3 (KCNN3 gene) in oxaliplatin-induced neurotoxicity (OIN). Length variations in the polymorphic CAG repeat of the KCNN3 gene may be associated with the risk of OIN. MATERIALS AND METHODS: We performed patch-clamp experiments on HEK293 cell lines, expressing SK3 channel isoforms with short (11) or long (24) CAG repetitions, to measure intracellular calcium concentrations to test the effects of oxaliplatin on current density. A retrospective study was carried out on patients with colorectal cancer who had received oxaliplatin-based chemotherapy. DNA for KCNN3 genotyping was extracted from leukocytes. The region containing the CAG repeats was amplified by PCR and the products separated by capillary electrophoresis for length analysis. The patients were divided into three groups depending on whether they carried two short alleles, one short allele and one long allele, or two long alleles. The primary endpoint was the onset of grade 2 or 3 neuropathy to oxaliplatin. RESULTS: There was no difference in current density, but oxaliplatin induced a differential effect on apamin-sensitive current density between the two isoforms expressed in the HEK cell lines. There was a significant reduction of store-operated calcium entry into cells expressing the short and more active isoform only after high concentration of oxaliplatin exposition. Eighty-six patients were included in the clinical study. There was no significant association between OIN and KCNN3 polymorphism for the three groups. CONCLUSION: We observed a slight association between OIN and CAG repeat polymorphisms of the KCNN3 gene in a preclinical model, but not a clinical study.

Development and validation of an ELISA to study panitumumab pharmacokinetics.

AIM: Panitumumab is a monoclonal antibody directed against EGFR that is approved for the treatment of metastatic colorectal cancer. To investigate its pharmacokinetics and concentration-response relationship, a validated assay is required. RESULTS: An ELISA assay was developed and validated according to international recommendations. Six calibrators (ranging from 0.1 to 20 mg/l) plus one anchor point (50 mg/l) and three quality controls (0.45, 2 and 8 mg/l) were defined. The limit of detection, lower limit of quantification and upper limit of quantification were 0.033, 0.112 and 10 mg/l, respectively. CONCLUSION: This method is validated and can be used to study pharmacokinetics of panitumumab or to perform therapeutic drug monitoring.

Gemcitabine plus platinum-based chemotherapy for first-line treatment of hepatocholangiocarcinoma: an AGEO French multicentre retrospective study.

BACKGROUND: Hepatocholangiocarcinoma (cHCC-ICC) is a rare liver tumour for which no data on chemosensitivity exist. The aims of this multicentre study were to evaluate overall survival (OS), progression-free survival (PFS), and prognostic factors in cHCC-ICC treated by gemcitabine plus platinum as first-line. METHODS: Unresectable cHCC-ICC treated by gemcitabine plus platinum-based chemotherapy between 2008 and 2017 were retrospectively analysed. Diagnosis was based on histology or, in case of ICC or HCC histology, on discordant computerised tomography scan enhancement patterns associated with discordant serum tumour marker elevation suggesting the alternative tumour. OS and PFS were evaluated by Kaplan-Meier method and prognostic factors by Log-rank test and Cox model. RESULTS: Among 30 patients included, cHCC-ICC was histologically proven in 22 (73.3%). 18 (60%) received gemcitabine plus oxaliplatin (GEMOX), 9 (30%) GEMOX plus bevacizumab, and 3 (10%) gemcitabine plus cisplatin. RECIST criteria were reported in 28 patients: 8 (28.6%) showed partial response, 14 (50%) stable disease, and 6 (21.4%) tumour progression at first evaluation. Median PFS and OS were 9.0 and 16.2 months, respectively. Serum bilirubin ⩾30 µmol l-1 (P=0.001) and positive serology for HBV and/or HCV (P=0.014) were independent poor prognostic factors for OS. CONCLUSIONS: Gemcitabine plus platinum-based chemotherapy is effective as first-line for advanced cHCC-ICC.

A possible association of baseline serum IL-17A concentrations with progression-free survival of metastatic colorectal cancer patients treated with a bevacizumab-based regimen.

BACKGROUND: Colorectal cancer is a major public health issue worldwide. Interleukin-17 (IL-17) and Th17 (T-helper cell type 17)-related molecules are involved in tumor development and in resistance to bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody used in association with chemotherapy in metastatic colorectal cancer. Some studies have previously shown that IL-17A and IL-17F polymorphisms, respectively rs2275913 and rs763780, are associated with gastric or colorectal cancer risk. Here we aimed at studying the influence of IL-17A-related individual factors on overall survival and progression-free survival in patients with metastatic colorectal cancer treated with a bevacizumab-based chemotherapy. METHODS: Pre-treatment serum biomarkers were retrospectively evaluated in 122 metastatic colorectal cancer patients treated by bevacizumab in combination with chemotherapy at 2-weeks intervals in a prospective cohort study (NCT00489697). The polymorphisms of IL-17A and IL-17F were analyzed by polymerase chain reaction - restriction fragment length polymorphism. Serum concentrations of Th17-related cytokines were measured by MultiPlex. The impact of individual parameters on overall survival and progression-free survival was assessed using multivariate Cox models. RESULTS: High baseline IL-17A serum concentrations were significantly associated with shorter progression-free survival [p = 0.043]. Other baseline serum Th17-related cytokines and polymorphisms of IL-17 were not associated with overall survival or progression-free survival. CONCLUSIONS: In this ancillary study, baseline serum IL-17A concentration is the only Th17/IL-17 related factor that was significantly associated with the response of patients with metastatic colorectal cancer to bevacizumab. But this main significant result is highly dependent on one case which, if left out, weakens the data. Other clinical studies are required to confirm this association. TRIAL REGISTRATION: NCT00489697 . June 20, 2007.

Clinical, histological, and molecular risk factors for cancer recurrence in patients with stage II colon cancer.

INTRODUCTION: The assessment of risk factors of cancer recurrence in patients with stage II colon cancer (CC) is crucial. Our aim was to study the clinical, histological, and molecular features associated with 3-year disease-free survival in a series of consecutive patients with stage II CC treated in three regional digestive oncology centers. METHODS: Clinical and histological data of all patients after curative surgery for stage II CC, treated from 2001 until 2009, were collected retrospectively. Histological samples were obtained and tested prospectively for microsatellite instability using fluorescent PCR amplification. Cox proportional hazards regression models were used to calculate P values, hazard ratios (HRs), and 95% confidence intervals (CIs). RESULTS: Among 195 patients studied, 22 (11%) had disease recurrence during the 3-year period following diagnosis. On multivariate analysis, only low number of lymph nodes (HR=3.81, 95% CI: 1.19-12.19, P=0.02) and T4 status (HR=5.49, 95% CI: 1.06-28.43, P=0.04) were associated significantly with an increased risk of relapse. CONCLUSION: In this series of stage II CC patients, only T4 status and low number of lymph nodes were independent risk factors for poor 3-year disease-free survival, suggesting that patients with these features should be considered for adjuvant chemotherapy.

Bevacizumab Pharmacokinetics Influence Overall and Progression-Free Survival in Metastatic Colorectal Cancer Patients.

OBJECTIVE: Clinical response to bevacizumab varies between patients treated for metastatic colorectal cancer (mCRC). The aim of this study was to quantify individual factors affecting bevacizumab pharmacokinetic variability and assess the relationship between bevacizumab concentrations and clinical outcomes. METHODS: Bevacizumab pharmacokinetics were assessed in 130 mCRC patients using a two-compartment pharmacokinetic population model. Overall and progression-free survival (PFS) were analyzed using Cox models. RESULTS: The bevacizumab volume of distribution increased with height (p = 10-10) and was higher in patients with a 3/3 variable number tandem repeat of the FCGRT (Fc fragment of IgG receptor and transporter) gene (p = 0.039). The elimination rate constant increased with baseline carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) concentrations, and was higher in patients with extra-hepatic metastases (p = 0.00029, 0.011, and 0.014). A bevacizumab trough concentration ≤15.5 mg/L was associated with both shorter overall survival and PFS (hazard ratio [95 % CI] 1.90 [1.20-2.99] and 1.76 [1.20-2.58], respectively). CONCLUSION: High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals.