Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival ...in cancer patients.
The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans.
Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013).
Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment.
Learning Objectives
After completing this course, the reader will be able to:
Describe the profile of severe toxicities in patients treated with sorafenib.
Summarize the pharmacokinetics of ...sorafenib‐induced toxicities.
Identify predictive factors for early and delayed toxicities in patients treated with sorafenib.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity.
Methods.
We analyzed the severity and kinetics of sorafenib‐induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography.
Results.
For 83 patients (median age, 62 years; range, 21–84 years), median sorafenib 12‐hour area under the curve (AUC0–12) was 52.8 mg · h/L (range: 11.8–199.6). A total of 51 patients (61%) experienced grade 3–4 toxicities, including hand‐foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC0–12 preceding grade 3–4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose‐normalized AUC0–12 on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand‐foot skin reactions significantly decreased over time.
Conclusion.
Sorafenib AUC0–12 decreases over time, similarly to the incidence of hypertension and hand‐foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression.
This study analyzes the severity and timing of sorafenib‐induced toxicities in a cohort of unselected consecutive patients with cancer to determine whether the pharmacokinetics of sorafenib influence its toxicity.
Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. ...Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients.
Gefitinib and erlotinib are two oral tyrosine kinase inhibitors (TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Published methods for simultaneous analysis of ...erlotinib and gefitinib in plasma are exclusively based on mass spectrometry. The purpose of this study was to develop a simple and sensitive HPLC-UV method to simultaneously quantify these two TKI in plasma. Following liquid–liquid extraction, gefitinib, erlotinib and sorafenib (internal standard), were separated with gradient elution (on a C8+ Satisfaction
® using a mobile phase of acetonitrile/20
mM ammonium acetate pH 4.5). Samples were eluted at a flow rate of 0.4
ml/min throughout the 15-min run. Dual UV wavelength mode was used, with gefitinib and erlotinib monitored at 331
nm, and sorafenib at 249
nm. The calibration was linear in the range 20–1000
ng/ml and 80–4000
ng/ml for gefitinib and erlotinib, respectively. Inter- and intra-day imprecision were less than 7.2% and 7.6% for gefitinib and erlotinib, respectively. This analytical method was successfully applied to assess the steady state plasma exposure to these TKI in NSCLC patients. This simple, sensitive, accurate and cost-effective method can be used in routine clinical practice to monitor gefitinib or erlotinib concentrations in plasma from NSCLC patients.
Background.
Hypertension is a common toxicity of bevacizumab, but the frequency of assessment of blood pressure and standardized grading remain to be defined. This study aimed to describe the ...incidence of bevacizumab‐induced hypertension and factors associated with its development, then to retrospectively assess its relation with activity.
Patients and methods.
One hundred nineteen patients with advanced or metastatic non‐small cell lung cancer, colorectal cancer, or ovarian cancer receiving bevacizumab (2.5 mg/kg per week) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines, and graded according to the National Cancer Institute Common Toxicity Criteria (NCI‐CTC), version 3.0, and the European Society of Hypertension (ESH) criteria.
Results.
Home‐based measurements detected significantly more cases of hypertension than in‐clinic measurements did, according to the ESH criteria (54.6% versus 24.4%; p < .001) or the NCI‐CTC (42.9% versus 22.7%; p = .0015). Very early hypertension (within 42 days, according to the ESH criteria) but not hypertension (occurring at any time during treatment period) was predictive of response (p = .0011 and p = .26, respectively).
Conclusions.
Our preliminary results indicate that home‐based measurement and grading according to the ESH criteria represents a reliable method to detect bevacizumab‐induced hypertension. Whether hypertension is a biomarker of bevacizumab activity remains to be determined in a prospective study.
摘要
背景. 高血压是贝伐珠单抗导致的常见毒性反应，血压监测频率及标准化分级还有待明确。本研究旨在描述贝伐珠单抗所致高血压的发生率及其发展相关因素，并回顾性评估高血压与贝伐珠单抗活性的关系。
患者与方法.119例接受贝伐珠单抗（每周2.5 mg/kg）和化疗的晚期或转移性非小细胞肺癌、结直肠癌及卵巢癌患者纳入本研究。按国际指南及国立癌症研究院常见毒性标准（NCI‐CTC）3.0版与欧洲高血压学会（ESH）标准，每天在家测两次血压。
结果.按ESH或NCI‐CTC标准，居家测量检出的高血压病例显著多于门诊测量（分别为54.6%#x0025;vs 24.4%#x0025;；p<0.001；42.9%#x0025;vs 22.7%#x0025;；p=0.0015）。极早期出现的高血压（42天内，按ESH标准）可预测疗效，而（治疗期间任何时间出现的）高血压无法预测（分别为p=0.0011和p=0.26）。
结论.本研究初步结果表明，居家测量及按ESH标准分级可有效检出贝伐珠单抗所致高血压。高血压能否作为贝伐珠单抗活性的生物标志物有待前瞻性研究的证实。
The incidence of bevacizumab‐induced hypertension and factors associated with its development are described, and its relation with activity is retrospectively assessed. A reliable method for the detection and grading of hypertension is determined and recommendations for further studies aiming to study hypertension as a biomarker for bevacizumab efficacy are established.
A close relationship between tumor angiogenesis, growth, and carcinomatosis has been observed. Netrin-4 (NT-4) has been shown to regulate angiogenic responses. We aimed to examine the effects of NT-4 ...on colon tumor angiogenesis, growth, and carcinomatosis. We showed that NT-4 was expressed in human colon cancer cells (LS174). A 20-fold increase in NT-4 expression was stably induced by NT-4 pcDNA in LS174 cells. In vivo , a Matrigel angiogenesis assay showed that NT-4 overexpression altered vascular endothelial growth factor (VEGF)/basic fibroblast growth factor–induced angiogenesis. In nude mice with LS174 xenografts, NT-4 overexpression inhibited tumor angiogenesis and growth. In addition, these NT-4-involved inhibitory effects were associated with decreased tumor cell proliferation and increased tumor cell apoptosis. Using an orthotopic peritoneal carcinomatosis model, we demonstrated that NT-4 overexpression decreased colorectal cancer carcinomatosis. Moreover, carcinomatosis-related ascites formation was significantly decreased in mice transplanted with NT-4 LS174 cells versus control LS174 cells. The antiangiogenic activity of NT-4 was probably mediated by binding to its receptor neogenin. Netrin-4 had a direct effect on neither in vitro apoptosis and proliferation of cultured LS174 cells nor the VEGF-induced acute increase in vascular permeability in vivo . We propose that NT-4 overexpression decreases tumor growth and carcinomatosis, probably via an antiangiogenic effect, underlying the potential therapeutic interest in NT-4 in the treatment of colorectal cancer growth and carcinomatosis.
Netrins are secreted molecules with roles in axon guidance and angiogenesis. We identified Netrin-4 as a gene specifically overexpressed in VEGF-stimulated endothelial cells (EC) in vitro as well as ...in vivo. Knockdown of Netrin-4 expression in EC increased their ability to form tubular structures on Matrigel. To identify which receptor is involved, we showed by quantitative RT-PCR that EC express three of the six Netrin-1 cognate receptors: neogenin, Unc5B, and Unc5C. In contrast to Netrin-1, Netrin-4 bound only to neogenin but not to Unc5B or Unc5C receptors. Neutralization of Netrin-4 binding to neogenin by blocking antibodies abolished the chemotactic effect of Netrin-4. Furthermore, the silencing of either neogenin or Unc5B abolished Netrin-4 inhibitory effect on EC migration, suggesting that both receptors are essential for its function in vitro. Coimmunoprecipitation experiments demonstrated that Netrin-4 increased the association between Unc5B and neogenin on VEGF- or FGF-2-stimulated EC. Finally, we showed that Netrin-4 significantly reduced pathological angiogenesis in Matrigel and laser-induced choroidal neovascularization models. Interestingly, Netrin-4, neogenin, and Unc5B receptor expression was up-regulated in choroidal neovessel EC after laser injury. Moreover, Netrin-4 overexpression delayed tumor angiogenesis in a model of s.c. xenograft. We propose that Netrin-4 acts as an antiangiogenic factor through binding to neogenin and recruitment of Unc5B.
Gemcitabine has shown clinical activity against angiosarcoma in small series, alone, or combined with taxanes. We aimed to evaluate its activity as a single‐agent in a larger series of patients with ...advanced angiosarcoma. We retrospectively reviewed the electronic medical records of consecutive adult patients with advanced angiosarcoma treated with single‐agent gemcitabine at our institutions from January 2010 to January 2021. Response was evaluated according to RECIST 1.1, and toxicity was graded according to NCI‐CTC v5.0. 42 patients were identified. 38 patients (90%) had received prior anthracyclines and weekly paclitaxel, and 9 (21%) had received pazopanib. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%). All 8 patients with cardiac angiosarcoma experienced a PR. Median PFS was 5.4 months (95%CI: 3.1–6.5), and median OS was 9.9 months (95%CI: 6.6–13.4). Single‐agent gemcitabine has clinically meaningful activity in advanced, heavily pre‐treated angiosarcoma.
We aimed to evaluate the activity of single‐agent gemcitabine in the largest series of 42 patients with advanced angiosarcoma. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%), median PFS was 5.4 months, and median OS was 9.9 months. Single‐agent gemcitabine has clinically meaningful activity in advanced, heavily pre‐treated angiosarcoma.
Sunitinib malate is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Only mass spectrometry detection is currently available to determine sunitinib ...in human plasma. The purpose of this study was to develop a simple and sensitive high-performance liquid chromatographic method with UV-Visible detection for quantification of sunitinib concentrations in human plasma.
After a liquid–liquid extraction with ethyl acetate, sunitinib and ranitidine (internal standard) are separated on cyanopropyl column using a simple binary mobile phase of ammonium acetate buffer (20 mM; pH 6.8):acetonitrile (55:45,v/v). Samples were eluted isocratically at a flow rate of 1 mL/min throughout the 10 min run. Dual wavelength mode was used, with ranitidine monitored at 255 nm, and sunitinib at 431 nm.
The calibration was linear in the range 20–200 ng/mL. Inter- and intra-day coefficients of variation were less than 7%. This method is sensitive, accurate and selective. It has been successfully implemented to monitor trough sunitinib concentrations in plasma samples (
n
=
39) from 14 unselected cancer patients treated with the recommended once daily dose of 50 mg or less.
This method can be used in routine clinical practice to monitor plasma sunitinib concentrations in cancer patients treated with once daily administration.
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