Eva E. Schaake

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.

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.

Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.

PURPOSE/OBJECTIVE In patients with locally advanced lung cancer, planning target volume margins for mediastinal lymph nodes and tumor after a correction protocol based on bony anatomy registration typically range from 1 to 1.5 cm. Detailed information about lymph node motion variability and differential motion with the primary tumor, however, is lacking from large series. In this study, lymph node and tumor position variability were analyzed in detail and correlated to the main carina to evaluate possible margin reduction. METHODS AND MATERIALS Small gold fiducial markers (0.35 × 5 mm) were placed in the mediastinal lymph nodes of 51 patients with non-small cell lung cancer during routine diagnostic esophageal or bronchial endoscopic ultrasonography. Four-dimensional (4D) planning computed tomographic (CT) and daily 4D cone beam (CB) CT scans were acquired before and during radical radiation therapy (66 Gy in 24 fractions). Each CBCT was registered in 3-dimensions (bony anatomy) and 4D (tumor, marker, and carina) to the planning CT scan. Subsequently, systematic and random residual misalignments of the time-averaged lymph node and tumor position relative to the bony anatomy and carina were determined. Additionally, tumor and lymph node respiratory amplitude variability was quantified. Finally, required margins were quantified by use of a recipe for dual targets. RESULTS Relative to the bony anatomy, systematic and random errors ranged from 0.16 to 0.32 cm for the markers and from 0.15 to 0.33 cm for the tumor, but despite similar ranges there was limited correlation (0.17-0.71) owing to differential motion. A large variability in lymph node amplitude between patients was observed, with an average motion of 0.56 cm in the cranial-caudal direction. Margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) for the lymph nodes and -2%, 15%, and 7% for the tumor if an online carina registration protocol replaced a protocol based on bony anatomy registration. CONCLUSIONS Detailed analysis revealed considerable lymph node position variability, differential motion, and respiratory motion. Planning target volume margins can be reduced up to 27% in lung cancer patients when the carina registration replaces bony anatomy registration.

Mediastinal lymph node position variability in non-small cell lung cancer patients treated with radical irradiation

BACKGROUND AND PURPOSE Detailed knowledge on mediastinal lymph nodes position variability is lacking. In this study we quantified the variability over the irradiation course in non-small cell lung cancer (NSCLC) patients. METHODS A 0.35×5 mm gold fiducial marker was inserted in mediastinal lymph nodes of 14 stage III NSCLC patients. A respiration correlated 4D-planning-CT (pCT) and daily 4D-Cone Beam (CB)CT-scans were acquired. To calculate the systematic and random baseline variations, and respiratory motion variability of the lymph nodes, all CBCT scans were registered to both the bony anatomy and marker in the pCT. Patient population statistics of the peak-to-peak amplitude and time averaged mean position relative to the bony anatomy were calculated. RESULTS The average peak-to-peak amplitude was 0.21 cm, 0.52 cm and 0.20 cm in the Left-Right, Cranial-Caudal and Anterior-Posterior direction respectively, while the amplitude variability was ≤0.1 cm in each direction. Inter-fraction lymph node baseline variation was 0.21/0.2 cm, 0.34/0.23 cm, and 0.17/0.15 cm systematic/random. PTV margins for these variations were 0.92 cm, 1.24 cm, 0.82 cm for an online bone match and could be reduced to 0.77 cm, 0.82 cm and 0.86 cm for an online carina match. CONCLUSIONS Substantial and anisotropic, systematic and random mediastinal lymph node baseline variations were found in NSCLC patients indicating that non-uniform margins could be beneficial.

Phase II trial of Uracil/Tegafur plus leucovorin and celecoxib combined with radiotherapy in locally advanced pancreatic cancer

BACKGROUND AND PURPOSE To investigate the efficacy and toxicity of a short intensive Uracil/Tegafur (UFT) based chemoradiotherapy scheme combined with celecoxib in locally advanced pancreatic cancer. MATERIAL AND METHODS The Academic Medical Centre, Amsterdam and the Erasmus Medical Centre, Rotterdam enrolled 83 eligible patients with unresectable pancreatic cancer in a prospective multicentre phase II study. Median age was 62 years, median tumour size 40 mm and the majority of the patients (85%) had pancreatic head cancers. Treatment consisted of 20×2.5 Gy radiotherapy combined with UFT 300 mg/m(2) per day, leucovorin (folinic acid) 30 mg and celecoxib 80 0mg for 28 days concomitant with radiotherapy. Four patients were lost to follow-up. RESULTS Full treatment compliance was achieved in 55% of patients, 80% received at least 3 weeks of treatment. No partial or complete response was observed. Median survival was 10.6 months and median time to progression 6.9 months. Toxicity was substantial with 28% grades III and IV gastro-intestinal toxicity and two early toxic deaths. CONCLUSIONS Based on the lack of response, the substantial toxicity of mainly gastro-intestinal origin and the reported mediocre overall and progression free survival, we cannot advise our short intensive chemoradiotherapy schedule combined with celecoxib as the standard treatment.

Quantitative determination of erlotinib and O-desmethyl erlotinib in human EDTA plasma and lung tumor tissue.

BACKGROUND To increase knowledge about lung tumor tissue levels of erlotinib and its primary active metabolite, and about erlotinib plasma levels in intercalated dosing schedules, a sensitive and accurate method for determination of erlotinib and O-desmethyl erlotinib (OSI-420) in human plasma and lung tumor tissue has been developed. RESULTS A method with HPLC-MS/MS was validated over a linear range from 5 to 2500 ng/ml in plasma and from 5.0 to 500 ng/ml for lung tumor tissue homogenate (50-5000 ng/g for lung tumor). Calibration curves in plasma were used to quantify analytes in lung tumor tissue homogenate. Lung tumor tissue of 15 patients has been collected and analyzed with the presented method. CONCLUSION This method has been successfully validated and applied to determine plasma and lung tumor tissue concentrations of erlotinib and O-desmethyl erlotinib in patients with non-small-cell lung cancer.

Concentrations of Erlotinib in Tumor Tissue and Plasma in Non-Small-Cell Lung Cancer Patients After Neoadjuvant Therapy

INTRODUCTION Tumors might not optimally respond to systemic therapy if minimal effective levels are not reached within the tumor. Erlotinib has mainly been studied in the adjuvant or palliative setting and, therefore, little is known about erlotinib tumor penetration. The purpose of this exploratory study was to investigate lung tumor tissue erlotinib concentrations after neoadjuvant therapy for non-small-cell lung cancer. PATIENTS AND METHODS Patients were treated preoperatively with erlotinib (150 mg once daily for 3 weeks) up to 48 hours before surgery. Plasma samples were collected during treatment. Surgical resection involved radical resection of the lung tumor and tumor biopsies were frozen directly after surgery. Erlotinib and O-desmethyl erlotinib concentrations in lung tumor tissue and predose plasma were determined using high performance liquid chromatography coupled with tandem mass spectrometry. RESULTS Thirteen evaluable patients were included. The mean plasma and lung tumor tissue erlotinib levels were 1222 ng/mL (SD, 678) and 149 ng/g (SD, 153), respectively. In 2 individual patients, erlotinib and O-desmethyl erlotinib concentrations in lung tumor tissue were detectable up to 13 days and 7 days after erlotinib intake, respectively. Mean erlotinib tissue concentrations extrapolated to a time point directly after intake of erlotinib were approximated at > 200 ng/g tissue, which is greater than the reported half maximal inhibitory concentration (IC50) of wild type epidermal growth factor receptor (EGFR) (183 ng/mL). CONCLUSION No strong accumulation of erlotinib in lung tumor tissue was observed. Nevertheless, extrapolated intratumoral concentrations during erlotinib therapy were greater than the IC50 of wild type EGFR.

Abstract 4113: Kinase activity based biomarkers: Identification of prognostic and erlotinib response prediction markers in NSCLC patients

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Reliable diagnostic tests are needed to identify early stage non-small cell lung carcinoma (NSCLC) patients with poor prognosis. Concomitantly there is a clear need for tests that enable the selection of patients who will benefit from targeted therapy with kinase inhibitors. We evaluated kinase activity profiles in two groups of early stage NSCLC patients, either for prognosis of long- or short-term survival, or for predicting erlotinib drug response. Method: Retrospective studies were performed on fresh frozen resection material of two groups of early stage NSCLC patients. The first group consisted of 48 short- and long-term survivors who underwent a complete surgical resection (5+ years follow-up). The second group consisted of 14 NSCLC patients who received 3 weeks of neo-adjuvant treatment with erlotinib prior to complete surgical resection. Response evaluation to neo-adjuvant treatment was based on histopathological examination of the surgical specimens. For both studies, kinase activity profiles of lysed cryosections of tumour tissues were generated in the presence and absence of protein tyrosine kinase inhibitors on PamChip® peptide micro-arrays, comprising 144 tyrosine containing peptides, derived from known phosphorylation sites of human proteins. Partial least square discriminant analysis was used to construct prediction models. ClustalW alignment algorithms were used to investigate the most informative phosphorylation sites. Results: Kinase activity profiles obtained in the absence of inhibitor did not distinguish between subgroups (long- versus short-term survival, responder or non-responder to TKI), whereas ratios of inhibited versus non-inhibited signals resulted in distinct classifiers predicting survival for the first group, and response for the second group. Multivariate unsupervised analysis with leave-one-out cross-validation resulted in an error rate for survival prediction of 29%. In the drug response prediction 13 out of 14 patients were correctly classified. Conclusion: This is the first study to show that kinase activity profiles of tumour tissue exposed to a kinase inhibitor can be used to identify NSCLC patients likely to respond to erlotinib treatment. Furthermore, based on kinase activity profiles of early stage NSCLC tumours, a prognostic classifier, for a set of 48 patients, was obtained. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4113. doi:10.1158/1538-7445.AM2011-4113