Henk Codrington

Is 18F-FDG PET/CT Useful for the Early Prediction of Histopathologic Response to Neoadjuvant Erlotinib in Patients with Non–Small Cell Lung Cancer?

Early prediction of treatment response is of value in avoiding the unnecessary toxicity of ineffective treatment. The objective of this study was to prospectively evaluate the role of integrated 18F-FDG PET/CT for the early identification of response to neoadjuvant erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. Methods: From October 2006 to March 2009, 23 patients with non–small cell lung cancer eligible for surgical resection were evaluated for this study. Patients received preoperative erlotinib (150 mg) once daily for 3 wk. 18F-FDG PET/CT was performed before and at 1 wk after the administration of erlotinib. Changes in tumor 18F-FDG uptake during treatment were measured by standardized uptake values and assessed prospectively according to the criteria of the European Organization for Research and Treatment of Cancer. Patients with a decrease in standardized uptake values of 25% or more after 1 wk were classified as “metabolic responders.” The metabolic response was compared with the pathologic response, obtained by histopathologic examination of the resected specimen. Results: Following the 18F-FDG PET/CT criteria of the European Organization for Research and Treatment of Cancer, 6 patients (26%) had a partial response within 1 wk, 16 patients (70%) had stable disease, and 1 patient (4%) had progressive disease. The median percentage of necrosis in the early metabolic responder group was 70% (interquartile range, 30%–91%), and the median percentage of necrosis in the nonresponder group was 40% (interquartile range, 20%–50%; P = 0.09). The κ-agreement between the metabolic and pathologic responders was 0.55 (P = 0.008). Conclusion: The results of this study suggest that early during the course of epidermal growth factor receptor tyrosine kinase inhibitor therapy, 18F-FDG PET/CT can predict response to erlotinib treatment in patients with non–small cell lung cancer.

Tumor Response and Toxicity of Neoadjuvant Erlotinib in Patients With Early-Stage Non–Small-Cell Lung Cancer

PURPOSE The development of targeted therapy has introduced new options to improve treatment outcome in selected patients. The objective of this prospective study was to investigate the safety of preoperative erlotinib treatment and the (in vivo) response in patients with early-stage resectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This study was designed as an open-label phase II trial, performed in four hospitals in the Netherlands, according to a Simons minimax two-stage procedure. Initially, operable patients with early-stage NSCLC (n = 15) were entered from an enriched population (never-smoker, female sex, nonsquamous histology, or Asian ethnicity); thereafter, unselected patients were included to a total of N = 60. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. Response to treatment was evaluated using [18F] fluorodeoxyglucose positron emission tomography (PET) and computed tomography (CT) scans during treatment and histologic examination of the resection specimen. Primary end points were toxicity and pathologic response. RESULTS Sixty patients were included. Seven patients stopped treatment prematurely (12%). Skin toxicity was present in 37 patients (62%), and diarrhea was present in 21 patients (35%). PET evaluation revealed metabolic response (> 25% standardized uptake value decrease) in 16 patients (27%); CT evaluation using Response Evaluation Criteria in Solid Tumors (RECIST) showed response in three patients (5%). At surgery, no unexpected complications occurred. Pathologic examination showed more than 50% necrosis in 14 patients (23%), of whom three (5%) had more than 95% tumor necrosis. The response rate in the enriched population was 34% (10 of 29 patients). CONCLUSION According to predefined criteria, neoadjuvant erlotinib has low toxicity and sufficient activity to deserve further testing in future studies in an enriched population.

Influence of the Acidic Beverage Cola on the Absorption of Erlotinib in Patients With Non-Small-Cell Lung Cancer

PURPOSE Erlotinib depends on stomach pH for its bioavailability. When erlotinib is taken concurrently with a proton pump inhibitor (PPI), stomach pH increases, which results in a clinically relevant decrease of erlotinib bioavailability. We hypothesized that this drug-drug interaction is reversed by taking erlotinib with the acidic beverage cola. The effects of cola on erlotinib bioavailability in patients not treated with a PPI were also studied. PATIENTS AND METHODS In this randomized, cross-over, pharmacokinetic study in patients with non-small-cell lung cancer, we studied intrapatient differences in absorption (area under the plasma concentration time curve [AUC0-12h]) after a 7-day period of concomitant treatment with erlotinib, with or without esomeprazole, with either cola or water. At the 7th and 14th day, patients were hospitalized for 1 day for pharmacokinetic sampling. RESULTS Twenty-eight evaluable patients were included in the analysis. In patients treated with erlotinib and esomeprazole with cola, the mean AUC0-12h increased 39% (range, -12% to 136%; P = .004), whereas in patients not treated with the PPI, the mean AUC0-12h was only slightly higher (9%; range, -10% to +30%; P = .03) after erlotinib intake with cola. CONCLUSION Cola intake led to a clinically relevant and statistically significant increase in the bioavailability of erlotinib during esomeprazole treatment. In patients not treated with the PPI, the effects of cola were marginal. These findings can be used to optimize the management of drug-drug interactions between PPIs and erlotinib.

Long-term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab

BACKGROUND AND PURPOSE Radiation dose escalation using hypofractionation might improve overall survival (OS). We investigated OS in a phase II multicenter study in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with hypofractionated concurrent chemoradiotherapy. MATERIALS AND METHODS A 2-armed phase II, multi-center study (NTR2230) was performed with the aim to assess the effect of cetuximab to concurrent chemoradiotherapy in LA-NSCLC patients (stage II/IIIA/B). Arm A received high dose radiotherapy (24 × 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m(2)). Arm B received an identical treatment regimen with additional weekly cetuximab. Kaplan-Meier survival curves and 1-, 2- and 5-year OS proportions were calculated. RESULTS Between February 2009 and May 2011, 102 patients were randomly allocated in two arms. Median OS was 31.5 months (range 12.8-52.3), not significantly different between arms A and B; 33.0 (range 17.0-57.0) and 30.0 (11.0-52.0) months. 1-, 2- and 5-year OS rates were 74.5%, 59.4% and 37.3%, respectively. In multivariate analyses, worse performance score, V35 of the esophagus and the existence of comorbidities were significantly (P-value<0.05) associated with a shorter OS. DISCUSSION In this phase II trial, the median OS for the entire group was remarkably high; 31.5 months. Furthermore, 5-year OS was still 37.3%. Hypofractionation might contribute to improved OS in LA-NSCLC patients.