Learning Objectives
After completing this course, the reader will be able to:
Describe the mechanisms of action of sorafenib.
Discuss the safety and toxicity data from phase I trials of sorafenib.
...Evaluate phase I and II trials of sorafenib with activity data.
Discuss future areas for research in the development of this drug.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single‐agent, dose‐escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum‐tolerated dose of 400 mg twice daily (bid). The most frequently reported drug‐related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand–foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal–related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non‐small cell lung cancer.
Disclosure of potential conflicts of interest is found at the end of this article.
We have investigated the subcellular localization, the domain topology, and the amino acid residues that are critical for the function of the presumptive Arabidopsis thaliana auxin influx carrier ...AUX1. Biochemical fractionation experiments and confocal studies using an N-terminal yellow fluorescent protein (YFP) fusion observed that AUX1 colocalized with plasma membrane (PM) markers. Because of its PM localization, we were able to take advantage of the steep pH gradient that exists across the plant cell PM to investigate AUX1 topology using YFP as a pH-sensitive probe. The YFP-coding sequence was inserted in selected AUX1 hydrophilic loops to orient surface domains on either apoplastic or cytoplasmic faces of the PM based on the absence or presence of YFP fluorescence, respectively. We were able to demonstrate in conjunction with helix prediction programs that AUX1 represents a polytopic membrane protein composed of 11 transmembrane spanning domains. In parallel, a large aux1 allelic series containing null, partial-loss-of-function, and conditional mutations was characterized to identify the functionally important domains and amino acid residues within the AUX1 polypeptide. Whereas almost all partial-loss-of-function and null alleles cluster in the core permease region, the sole conditional allele aux1-7 modifies the function of the external C-terminal domain.
Background The National Cancer Institute of Canada Clinical Trials Group CO.17 study showed that patients with advanced colorectal cancer had improved overall survival when cetuximab, an epidermal ...growth factor receptor–targeting antibody, was given in addition to best supportive care. We conducted a cost-effectiveness analysis using prospectively collected resource utilization and health utility data for patients in the CO.17 study who received cetuximab plus best supportive care (N = 283) or best supportive care alone (N = 274). Methods Direct medical resource utilization data were collected, including medications, physician visits, toxicity management, blood products, emergency department visits, and hospitalizations. Mean survival times for the study arms were calculated for the entire population and for the subset of patients with wild-type KRAS tumors over an 18- to 19-month period. All costs were presented in 2007 Canadian dollars. One-way and probabilistic sensitivity analysis was used to determine the robustness of the results. Cost-effectiveness acceptability curves were determined. The 95% confidence intervals (CIs) for the incremental cost-effectiveness ratios and the incremental cost–utility ratios were estimated by use of a nonparametric bootstrapping method (with 1000 iterations). Results For the entire study population, the mean improvement in overall and quality-adjusted survival with cetuximab was 0.12 years and 0.08 quality-adjusted life-years (QALYs), respectively. The incremental cost with cetuximab compared with best supportive care was $23 969. The incremental cost-effectiveness ratio was $199 742 per life-year gained (95% CI = $125 973 to $652 492 per life-year gained) and the incremental cost–utility ratio was $299 613 per QALY gained (95% CI = $187 440 to $898 201 per QALY gained). For patients with wild-type KRAS tumors, the incremental cost with cetuximab was $33 617 and mean gains in overall and quality-adjusted survival were 0.28 years and 0.18 QALYs, respectively. The incremental cost-effectiveness ratio was $120 061 per life-year gained (95% CI = $88 679 to $207 075 per life-year gained) and the incremental cost–utility ratio was $186 761 per QALY gained (95% CI = $130 326 to $334 940 per QALY gained). In a sensitivity analysis, cetuximab cost and patient survival were the only variables that influenced cost-effectiveness. Conclusions The incremental cost-effectiveness ratio of cetuximab over best supportive care alone in unselected advanced colorectal cancer patients is high and sensitive to drug cost. Incremental cost-effectiveness ratios were lower when the analysis was limited to patients with wild-type KRAS tumors.
Interventions to reduce household air pollution (HAP) are key to reducing associated morbidity and mortality in low‐ and middle‐ income countries (LMICs); especially among pregnant women and young ...children. This systematic review aims to determine the effectiveness of interventions aimed to reduce HAP exposure associated with domestic solid biomass fuel combustion, compared to usual cooking practices, for improving health outcomes in pregnant women and children under five in LMIC settings. A systematic review and meta‐analysis was undertaken with searches undertaken in MEDLINE, EMBASE, CENTRAL, GIM, ClinicalTrials.gov, and Greenfile in August 2020. Inclusion criteria were experimental, non‐experimental, or quasi‐experimental studies investigating the impact of interventions to reduce HAP exposure and improve associated health outcomes among pregnant women or children under 5 years. Study selection, data extraction, and quality assessment using the Effective Public Health Practice Project tool were undertaken independently by two reviewers. Seventeen out of 7293 retrieved articles (seven pregnancy, nine child health outcome; 13 studies) met the inclusion criteria. These assessed improved cookstoves (ICS; n = 10 studies), ethanol stoves (n = 1 study), and Liquefied Petroleum Gas (LPG; n = 2 studies) stoves interventions. Meta‐analysis showed no significant effect of ICS interventions compared to traditional cooking for risk of preterm birth (n = 2 studies), small for gestational age (n = 2 studies), and incidence of acute respiratory infections (n = 6 studies). Although an observed increase in mean birthweight was observed, this was not statistically significant (n = 4). However, ICS interventions reduced the incidence of childhood burns (n = 3; observations = 41 723; Rate Ratio: 0.66 95% CI: 0.45–0.96; I2: 46.7%) and risk of low birth weight (LBW; n = 4; observations = 3456; Odds Ratio: 0.73 95% CI: 0.61–0.87; I2: 21.1%). Although few studies reported health outcomes, the data indicate that ICS interventions were associated with reduced risk of childhood burns and LBW. The data highlight the need for the development and implementation of robust, well‐reported and monitored, community‐driven intervention trials with longer‐term participant follow‐up.
Metformin for pancreatic cancer Aung, Kyaw L; Moore, Malcolm J
The lancet oncology,
07/2015, Volume:
16, Issue:
7
Journal Article
Peer reviewed
The observation from retrospective studies1,2 that metformin might decrease the risk of cancer and mortality in patients with diabetes has prompted the initiation of numerous preclinical and clinical ...studies to investigate its anticancer activity. Metformin inhibits complex I in the mitochondria respiratory chain, thereby reducing oxidative phosphorylation and ATP production in cells.7 This inhibition creates energy stress and could potentially lead to cancer cell arrest or death, especially in cells dependent on oxidative phosphorylation to fulfill the energy requirement8 or under certain conditions such as kinase inhibition-induced reduction in glycolysis.9 However, whether metformin produces a cytostatic or cytotoxic response in cancer cells, or any response at all, is likely to be dependent on many factors, including how they derive energy, the state of their microenvironment, the interaction between glycolytic and oxidative phosphorylation pathways, and the intracellular concentration of metformin.
National Cancer Institute of Canada Clinical Trials Group CO.17 demonstrated the antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab improves overall and progression-free ...survival in patients with advanced, chemotherapy-refractory colorectal cancer (CRC), particularly in patients with wild-type KRAS tumors. This article reports the health-related quality-of-life (HRQL) outcomes from CO.17.
Patients (N = 572) with pretreated EGFR-detectable advanced CRC were randomly assigned to cetuximab and best supportive care (BSC) or to BSC alone. HRQL primary end points assessed by the EORTC QLQ-C30 were physical function (PF) and global health status (GHS); mean changes from baseline to 8 and 16 weeks were assessed. Post hoc analysis by KRAS mutation status was performed.
Questionnaire compliance was 94% at baseline, but it declined differentially (67% v 47% for cetuximab v BSC at 16 weeks). PF change scores were -3.9 for cetuximab and -8.6 for BSC (P = .046) at 8 weeks and were -5.9 and -12.5 for cetuximab and BSC, respectively, (P = .027) at 16 weeks. GHS change scores were -0.5 and -7.1 (P = .008) at 8 weeks and were -3.6 and -15.2 (P = .008) at 16 weeks for cetuximab and BSC, respectively. In patients who had tumors with wild-type KRAS status, cetuximab resulted in less PF deterioration at 8 weeks (-0.7 v -7.2; P = .11) and 16 weeks (-3.4 v -13.8; P = .008) compared with BSC. Patients with wild-type status who received cetuximab experienced improved GHS at 8 weeks, whereas patients who received BSC alone deteriorated (3.2 v -7.7; P = .002). Cetuximab preserved GHS at 16 weeks (-0.2 v -18.1; P < .001). No significant differences were noted between study arms for patients with mutated KRAS tumors.
Cetuximab offers important HRQL and survival benefits for pretreated patients with advanced, wild-type KRAS CRC.
NCIC Clinical Trials Group PA.3 was a randomized control trial that demonstrated improved overall survival (OS) in patients receiving erlotinib in addition to gemcitabine for locally advanced or ...metastatic pancreatic cancer. Prior to therapy, patients had plasma samples drawn for future study. We sought to identify biomarkers within these samples.
Using the proximity ligation assay (PLA), a probe panel was built from commercially available antibodies for 35 key proteins selected from a global genetic analysis of pancreatic cancers, and used to quantify protein levels in 20 uL of patient plasma. To determine if any of these proteins levels independently associated with OS, univariate and mulitbaraible Cox models were used. In addition, we examined the associations between biomarker expression and disease stage at diagnosis using Fisher's exact test. The correlation between Erlotinib sensitivity and each biomarkers was assessed using a test of interaction between treatment and biomarker.
Of the 569 eligible patients, 480 had samples available for study. Samples were randomly allocated into training (251) and validation sets (229). Among all patients, elevated levels of interleukin-8 (IL-8), carcinoembryonic antigen (CEA), hypoxia-inducible factor 1-alpha (HIF-1 alpha), and interleukin-6 were independently associated with lower OS, while IL-8, CEA, platelet-derived growth factor receptor alpha and mucin-1 were associated with metastatic disease. Patients with elevated levels of receptor tyrosine-protein kinase erbB-2 (HER2) expression had improved OS when treated with erlotinib compared to placebo. In conclusion, PLA is a powerful tool for identifying biomarkers from archived, small volume serum samples. These data may be useful to stratify patient outcomes regardless of therapeutic intervention.
ClinicalTrials.gov NCT00040183.
Cisplatin-based chemotherapy, a mainstay of treatment for disseminated germ cell tumors (GCTs), is associated with venous thromboembolism (VTE). Many patients with disseminated GCTs have large ...retroperitoneal lymph node (RPLN) metastases that may cause venous stasis and increase the risk of VTE development. We hypothesized that there was an association between large RPLN and chemotherapy-associated VTE risk.
The training cohort was composed of patients with disseminated GCT receiving first-line chemotherapy at Princess Margaret Cancer Centre between January 2000 and December 2010. Large RPLN was defined as more than 5 cm in maximal axial diameter. The predictive and discriminatory accuracies of a model using large RPLN in predicting VTE were compared with high-risk Khorana score (≥ 3) using logistic regression and area under receiver operator characteristic curves (AUROCs). The model was externally validated in a cohort of patients treated at the London Health Sciences Centre.
The training cohort comprised 216 patients, 21 (10%) of whom developed VTE during chemotherapy. VTE was associated with large RPLN (odds ratio OR, 5.26; P = .001), high-risk Khorana score (OR, 11.8; P < .001), intermediate-/poor-risk disease (OR, 3.76; P = .005), and hospitalization during chemotherapy (OR, 4.24; P = .002). Large RPLN showed higher discriminatory accuracy than high-risk Khorana score (AUROC, 0.71 v 0.67, respectively). Superior discriminatory accuracy of large RPLN over high-risk Khorana score was validated in the London cohort (AUROC, 0.61 v 0.57, respectively).
Large RPLN is associated with VTE in patients with disseminated GCT and provides higher discriminatory accuracy than high-risk Khorana score. Results should be validated in larger, prospective studies. Prophylactic anticoagulation may be considered in high-risk patients.
One tenth of the lethal dose to 10% of mice is one of the conventional parameters used to derive a safe starting dose in phase I trials of cytotoxic agents. There is no consensus on which preclinical ...models and parameters should define the starting dose for molecularly targeted agents.
Reports of 81 first-in-human phase I trials evaluating 60 different molecularly targeted agents administered as monotherapy were reviewed. The maximum-tolerated dose (MTD) was defined as the highest safe dose administered to patients, whereas the maximum-administered dose (MAD) was recorded if the MTD was not reached.
Fifty-seven of the 81 trials specified the animal model used to determine the starting dose, with 29 (51%) of 57 based on rodent data and 28 (49%) of 57 based on non-rodent data. A wide range of toxicologic parameters was used to select the starting dose. The starting dose exceeded the human MTD in three (3.7%) of 81 trials, and in all three trials, nonhematologic toxicity was dose limiting. The median number of dose levels to reach MTD or MAD from starting dose was five (range, one to 14 dose levels), and the median ratio of MTD or MAD to starting dose was 12 (range, < 1 to 300). Hypothetical doubling of the starting dose appeared to be safe, whereas tripling of the starting dose was unsafe.
The derivation of starting dose for first-in-human phase I trials of molecularly targeted agents in patients with cancer is safe but is based on diverse practices using a variety of preclinical toxicologic parameters.
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