To prospectively evaluate diagnostic computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for identification of histopathologic response to neoadjuvant erlotinib, an epidermal growth factor receptor–tyrosine kinase inhibitor in patients with resectable non-small cell lung cancer (NSCLC).

Purpose To prospectively evaluate diagnostic computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for identification of histopathologic response to neoadjuvant erlotinib, an epidermal growth factor receptor–tyrosine kinase inhibitor in patients with resectable non-small cell lung cancer (NSCLC). Methods This study was designed as an open-label phase 2 trial, performed in four hospitals in the Netherlands. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. CT and FDG-PET/CT were performed at baseline and after 3 weeks of treatment. CT was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. FDG-PET/CT, tumor FDG uptake, and changes were measured by standardized uptake values (SUV). Radiologic and …

Correspondence: GJM Herder St Antonius Ziekenhuis, Postbus 2500, 3430 EM Nieuwegein, The Netherlands Tel +31 030 609 24 28 Fax +31 088 320 14 49 Email j.herder@antoniusziekenhuis.nl Introduction: Previous research showed that the addition of bevacizumab (a monoclonal antibody against vascular endothelial growth factor [VEGF]) to chemotherapy resulted in a significant efficacy benefit in the treatment of selected patients with advanced nonsquamous non–small cell lung cancer (NSCLC). However, the occurrence and management of adverse events (AEs) during long-term maintenance treatment with bevacizumab is not well known. Methods: This report presents a descriptive analysis, including the management of AEs, of four patients with advanced NSCLC, who received a relatively long period of bevacizumab maintenance treatment. Results: In patient 1, a 72-year-old retired man with stage cT2N2M1b NSCLC, the only AE related to bevacizumab was a grade 1 rhinorrhea. Treatment resulted in a stable disease, with duration of response of 38 months. Patient 2 had NSCLC stage cT4N3M1b and developed a cavitation and infection after the first cycle of chemotherapy and bevacizumab, which caused a temporary decrease of her quality of life. Bevacizumab therapy resulted in a partial response, with duration of response of 15 months. A 52-year-old female (patient 3) with stage T2bN2M1a NSCLC is currently under treatment and has so far received 42 cycles of maintenance bevacizumab, with stabilized response (duration of response of 29 months) and no noteworthy AEs. The last patient is a 74-year-old male farmer with NSCLC T1N0M1, whose response has lasted for more than 3 years, with until now, no AEs. Conclusion: Our retrospective findings of these four patients show the long-term efficacy and safety of bevacizumab treatment in a real-life setting.

INTRODUCTION:Previous research showed that the addition of bevacizumab (a monoclonal antibody against vascular endothelial growth factor [VEGF]) to chemotherapy resulted in a significant efficacy benefit in the treatment of selected patients with advanced nonsquamous non-small cell lung cancer (NSCLC). However, the occurrence and management of adverse events (AEs) during long-term maintenance treatment with bevacizumab is not well known.METHODS:This report presents a descriptive analysis, including the management of AEs, of four patients with advanced NSCLC, who received a relatively long period of bevacizumab maintenance treatment.RESULTS:In patient 1, a 72-year-old retired man with stage cT2N2M1b NSCLC, the only AE related to bevacizumab was a grade 1 rhinorrhea. Treatment resulted in a stable disease, with duration of response of 38 months. Patient 2 had NSCLC stage cT4N3M1b and developed a cavitation and infection after the first cycle of chemotherapy and bevacizumab, which caused a temporary decrease of her quality of life. Bevacizumab therapy resulted in a partial response, with duration of response of 15 months. A 52-year-old female (patient 3) with stage T2bN2M1a NSCLC is currently under treatment and has so far received 42 cycles of maintenance bevacizumab, with stabilized response (duration of response of 29 months) and no noteworthy AEs. The last patient is a 74-year-old male farmer with NSCLC T1N0M1, whose response has lasted for more than 3 years, with until now, no AEs.CONCLUSION:Our retrospective findings of these four patients show the long-term efficacy and safety of bevacizumab treatment in a real-life setting.

BACKGROUNDEpidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect.PATIENTS AND METHODSA randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS).RESULTSTwo hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58-1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49-0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively.CONCLUSIONSPFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology.STUDY REGISTRATION NUMBERNCT00835471.

ABSTRACT Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p  Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.

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 Simon's 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.

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.

This study compared the effects of early intervention with standard use of epoetin alfa on haemoglobin (Hb) levels and transfusion requirements in cancer patients receiving chemotherapy. Patients with Hb>10 and ⩽12g/dL were randomised 1:1 to epoetin alfa (40,000 IU, subcutaneously, once weekly), initiated within 7d of the start of the first on-study chemotherapy cycle (defined as early intervention) versus epoetin alfa when Hb⩽10g/dL (defined as standard therapy). Increases in Hb values were significantly higher with early intervention compared to standard therapy from week 6 to 10 (P⩽0.05) and approached significance at week 15/16 (P=0.0531). Although the percentage of patients receiving blood transfusions was similar in both groups, the amount of blood transfused was almost twice as high in the standard epoetin alfa group (n.s.). Early intervention with epoetin alfa was well tolerated and overall survival did not differ significantly between groups. Initiation of epoetin alfa at the onset of chemotherapy and Hb<12g/dL improves Hb levels significantly versus standard therapy.

Erlotinib as single agent is associated with objective response rates of about 12% in unselected patients with NSCLC stage IIIB/IV. Much higher response rates were observed in selected groups of patients selected on the basis of EGFR mutations. To investigate whether erlotinib is able to make an extra contribution to surgical treatment of early stage NSCLC, a phase II study was initiated in the Netherlands. This study is meant to provide a proof of principle if erlotinib is a worthwhile induction therapy option and if erlotinib may be advised as induction regimen for a selected group of patients. We report a remarkable response in one of our first patients. A 58-year old woman presenting with a clinical stage I adenocarcinoma in the right upper lobe was asked to participate in the study. After written informed consent, she received erlotinib for 3 weeks according to protocol and consecutively underwent surgical resection. Radiological and metabolic response was measured by [18F]-FDG-PET/CT after 3 and 21 days, and postoperatively the pathological response was assessed in the resection specimen. Our patient had developed grade 2 skin toxicity in the third week of erlotinib treatment. Evaluation after 3 days and 21 days with [18F]-FDG-PET showed no appreciable metabolic response and stable disease on CT. A lobectomy of the right upper lobe with lymph node dissection was carried out. Pathological evaluation showed strong fibrotic degeneration of the original tumor, with a vital rest of less than 10%. All lymph nodes were free of tumor. The low percentage of tumor cells did not allow for EGFR mutation analysis. There were no postoperative complications, and skin toxicity dissolved spontaneously after cessation of erlotinib. In this patient with stage I adenocarcinoma of the right lung, receiving 3 weeks of preoperative erlotinib resulted in near complete pathologic response. This result shows that erlotinib could be a potent agent in neoadjuvant and/or adjuvant setting in the treatment of non-small cell lung cancer.

BACKGROUND:The ability of conventional CT scans and fiberoptic bronchoscopy to localize and properly stage radiographically occult lung cancer (ROLC) in the major airways is limited. High-resolution CT (HRCT) scanning and autofluorescence bronchoscopy (AFB) may improve the assessment of ROLC before the most appropriate therapy can be considered.PATIENTS AND METHODS:We prospectively studied 23 patients with ROLC, who were referred for intraluminal bronchoscopic treatment (IBT) with curative intent. Additional staging with HRCT and AFB was performed prior to treatment. Twenty patients were men, 9 patients had first primary cancers, and 14 patients had second primary cancers or synchronous cancers.RESULTS:HRCT scanning showed that 19 patients (83%) had no visible tumor or enlarged lymph nodes. With AFB, only 6 of the 19 patients (32%) proved to have tumors < or = 1 cm(2) with visible distal margins. They were treated with IBT. In the remaining 13 patients, abnormal fluorescence indicated more extensive tumor infiltration than could be seen with conventional bronchoscopy alone. Six patients underwent radical surgery for stage T1-2N0 (n = 5) and stage T2N1 (n = 1) tumors. Specimens showed that tumors were indeed more invasive than initially expected. The remaining seven patients technically did not have operable conditions, so they were treated with external irradiation (n = 4) and IBT (n = 3). The range for the time of follow-up for all patients has been 4 to 58 months (median, 40 months). The follow-up data underscore the correlation between accurate tumor staging and survival.CONCLUSIONS:Our data showed that 70% of patients presenting with ROLC had a more advanced cancer than that initially diagnosed, which precludes IBT with curative intent. Additional staging with HRCT and AFB enabled better classification of true occult cancers. Our approach enabled the choice of the most appropriate therapy for each individual patient with ROLC.

The aim of the study was to evaluate activity, toxicity and health-related quality of life (HRQL) with gemcitabine as second-line treatment after previous chemo- or radiotherapy in non-small-cell lung cancer (NSCLC). Patients with previously treated NSCLC were treated with gemcitabine (1000 mg/m(2)) on days 1, 8 and 15 in a 28-day cycle. Eighty patients were included; median age was 57 years (range 38-77). Prior treatment consisted of platinum-containing chemotherapy in 29 patients and high-dose thoracic radiotherapy in 51 patients. Median number of cycles was three (range 1-6). Granulocytopenia CTC grade 3 and 4 occurred in 9% and thrombocytopenia CTC grade 3 and 4 in 9% of cycles. Non-haematological toxicity was mild. Tumour response was achieved in 13% of the patients (95% CI 7-20), median survival time was 26 weeks and 1-year survival was 22%. Tumour response to second-line gemcitabine could not be predicted from response to first-line therapy, first-line treatment modality or treatment interval. In a subset of 35 patients HRQL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-LC13 questionnaires and showed improvement or control of symptoms and functioning in approximately 30% of patients. We conclude that gemcitabine in second-line treatment has modest anti-tumour activity, is well tolerated, and may control tumour-related symptoms and improve HRQL in a significant minority of patients.