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Maintenance therapy comes of age for non-small-cell lung cancer, but at what cost?

There is perhaps no other topic that has engendered such controversy and confusion than that of epidermal growth factor receptor (EGFR) therapy biomarkers. Candidate markers, all of which have supporters and detractors, include EGFR protein expression, EGFR gene copy number, and EGFR and KRAS mutation status. The first question that must be asked is: Why has this confusion arisen? There likely is no simple answer to this question, but there are several possibilities.

Some degree of misinterpretation of biomarker analyses from the initial trials of EGFR tyrosine kinase inhibitors (TKIs) may have arisen because these trials were small and without control arms; as such, they could only identify predictive markers of response and could not determine the prognostic effect of the markers, nor could they identify a differential survival benefit from treatment. Subsequently, the early randomized trials of EGFR TKIs did not mandate tissue collection for all patients; their biomarker studies were, therefore, underpowered, and most analyses were unplanned and retrospective. Despite these limitations, correlative studies from the two placebo-controlled third-line trials of EGFR TKIs, NCIC Clinical Trials Group Study BR.21 and Iressa Survival Evaluation in Lung Cancer (ISEL), clearly identified patients who derived greater or lesser benefit from therapy on the basis of EGFR protein assessed by immunohistochemistry (IHC), EGFR gene copy number, and both EGFR and KRAS mutation status.

The trends were the same for both studies, although not all markers had the power to demonstrate statistical significance. These trials also provided a pure evaluation of the effect of markers on overall survival (OS) because when they were conducted, both cross-over and subsequent systemic therapies were minimal...

Impact of tumor size and tracer uptake heterogeneity in (18)F-FDG PET and CT non-small cell lung cancer tumor delineation.

The objectives of this study were to investigate the relationship between CT- and (18)F-FDG PET-based tumor volumes in non-small cell lung cancer (NSCLC) and the impact of tumor size and uptake heterogeneity on various approaches to delineating uptake on PET images.

METHODS: Twenty-five NSCLC cancer patients with (18)F-FDG PET/CT were considered. Seventeen underwent surgical resection of their tumor, and the maximum diameter was measured. Two observers manually delineated the tumors on the CT images and the tumor uptake on the corresponding PET images, using a fixed threshold at 50% of the maximum (T(50)), an adaptive threshold methodology, and the fuzzy locally adaptive Bayesian (FLAB) algorithm. Maximum diameters of the delineated volumes were compared with the histopathology reference when available. The volumes of the tumors were compared, and correlations between the anatomic volume and PET uptake heterogeneity and the differences between delineations were investigated.

RESULTS: All maximum diameters measured on PET and CT images significantly correlated with the histopathology reference (r > 0.89, P < 0.0001). Significant differences were observed among the approaches: CT delineation resulted in large overestimation (+32% ± 37%), whereas all delineations on PET images resulted in underestimation (from -15% ± 17% for T(50) to -4% ± 8% for FLAB) except manual delineation (+8% ± 17%). Overall, CT volumes were significantly larger than PET volumes (55 ± 74 cm(3) for CT vs. from 18 ± 25 to 47 ± 76 cm(3) for PET). A significant correlation was found between anatomic tumor size and heterogeneity (larger lesions were more heterogeneous). Finally, the more heterogeneous the tumor uptake, the larger was the underestimation of PET volumes by threshold-based techniques.

CONCLUSION: Volumes based on CT images were larger than those based on PET images. Tumor size and tracer uptake heterogeneity have an impact on threshold-based methods, which should not be used for the delineation of cases of large heterogeneous NSCLC, as these methods tend to largely underestimate the spatial extent of the functional tumor in such cases. For an accurate delineation of PET volumes in NSCLC, advanced image segmentation algorithms able to deal with tracer uptake heterogeneity should be preferred.

Persistent N2 disease after neoadjuvant chemotherapy for non-small-cell lung cancer.

OBJECTIVES: Patients achieving a mediastinal pathologic complete response with neoadjuvant chemotherapy have improved outcomes compared with patients with persistent N2 disease. How to best manage this latter group of patients is unknown, prompting a review of our institutional experience.

METHODS: All patients who initiated neoadjuvant therapy for non-small-cell lung cancer from 1995 to 2008 were evaluated. The patients were excluded if they had received preoperative radiotherapy, had had a mediastinal pathologic complete response, or had evidence of disease progression after neoadjuvant chemotherapy. The clinical endpoints were calculated using the Kaplan-Meier product-limit method and compared using a log-rank test.

RESULTS: A total of 28 patients were identified. The median follow-up period was 24 months. Several neoadjuvant chemotherapy regimens were used, most commonly carboplatin with vinorelbine (36%) or paclitaxel (32%). A partial response to chemotherapy was noted in 23 (82%) and stable disease was noted in 5 (18%) on postchemotherapy imaging. Resection was performed in 22 of 28 patients, consisting of lobectomy in 14, pneumonectomy in 2, and wedge/segmentectomy in 6 (21/22 R0, 1/22 R1). There were no postoperative deaths. Postoperative therapy (radiotherapy and/or additional chemotherapy) was administered to 12 patients (55%). The remaining 6 patients generally received definitive radiotherapy with or without additional chemotherapy. The overall and disease-free survival rate at 1, 3, and 5 years was 75%, 37%, and 37% and 50%, 23%, and 19%, respectively. The survival rate at 5 years was similar between patients undergoing resection (34%) and those receiving definitive radiotherapy with or without chemotherapy (40%; P = .73).

CONCLUSIONS: Disease-free and overall survival was sufficiently high to warrant aggressive local therapy (surgery or radiotherapy) in patients with persistent N2 disease after neoadjuvant chemotherapy.

Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial.

Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC.

METHODS: 148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10(8) plaque forming units) plus cisplatin (75 mg/m(2) on day 1) and gemcitabine (1250 mg/m(2) on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818.

FINDINGS: 6-month PFS was 43·2% (32 of 74; 95% CI 33·4-53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9-45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%] vs 13 [18·1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4·1%] vs 10 [13·9%]) and pleural effusion (none vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event.

INTERPRETATION: This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated.
FUNDING: Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.

Evaluation and treatment of patients with non-small cell lung cancer.

Lung cancer is the most common cause of cancer-related death in the United States; however, recent clinical advances may change this outcome. New data on low-dose computed tomography for lung cancer screening, and technologic advances in surgery and radiation, have improved outcomes for those with early-stage disease. Identification of driver mutations in lung cancer has led to the development of molecular targeted therapy to improve survival of subsets of patients with metastatic disease.

These advances now allow for treatment of many patients with lung cancer with comorbidities or poor performance status who would have had limited options in the past.

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