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Targeting EGFR in non-small-cell lung cancer: lessons, experiences, strategies.

Cancer is a genetic disease and this concept is now widely exploited by both scientists and clinicians to design new targeted molecules. Indeed many data have already allowed us to ameliorate not only our knowledge about cancer onset, but also about patients treatment.

Correlation between mutations in cancer alleles and drug response is a key point to identify drugs that match the genetic profile of each individual tumors. On the other hand, experience derived from inhibition of tyrosine kinase receptors has pointed out that targeted treatment is really successful only in a small subset of tumors. The latter are eventually addicted to those genetic alterations which are responsible for receptors activation and for the continued expression of their signalling. Overall these observations provide a strong rationale for a molecular-based diagnosis and patients selection for targeted therapies.

This review analyses the current state of the art of molecularly-tailored pharmacological approach to lung cancer, one of the biggest killers among human solid tumors. Main relevance is addressed to genetic lesions activating the EGFR pathway transducers, focusing on their role as markers of targeted drug response.

A novel detection method of non-small cell lung cancer using multiplexed bead-based serum biomarker profiling.

OBJECTIVES: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality. Development of an early diagnosis method may improve survivals. We aimed to develop a new diagnostic model for NSCLC using serum biomarkers.

METHODS: We set up a patient group diagnosed with NSCLC (n = 122) and a healthy control group (n = 225). Thirty serum analytes were selected on the basis of previous studies and a literature search. An antibody-bead array of 30 markers was constructed using the Luminex bead array platform (Luminex Inc, Austin, Tex) and was analyzed. Each marker was ranked by importance using the random forest method and then selected. Using selected markers, multivariate classification algorithms were constructed and were validated by application to independent validation cohort of 21 NSCLC and 28 control subjects.

RESULTS: There was no difference in demographics between patients and the control population except for age (64.8 ± 10.0 for patients vs 53.0 ± 7.6 years for the control group). Among the 30 serum proteins, 23 showed a difference between the 2 groups (12 increased and 11 decreased in the patient group). We found the highest accuracy of multivariate classification algorithms when using the 5 highest-ranked biomarkers (A1AT, CYFRA 21-1, IGF-1, RANTES, AFP). When we applied the algorithms on a validation cohort, each method recognized the patients from the controls with high accuracy (89.8% with random forest, 91.8% with support vector machine, 88.2% with linear discriminant analysis, and 90.5% with logistic regression).

CONCLUSIONS: We confirmed that a new diagnostic method using 5 serum biomarkers profiling constructed by multivariate classification algorithms could distinguish NSCLC from healthy controls with high accuracy.

Robotic lobectomy for non-small cell lung cancer (NSCLC): long-term oncologic results.

OBJECTIVE(S): We evaluated a large series of patients undergoing robotic lobectomy for the treatment of early-stage non-small cell lung cancer (NSCLC) to assess long-term oncologic efficacy.

METHODS: A multi-institutional retrospective review of patients undergoing robotic lobectomy for NSCLC was performed. Robotic lobectomy was performed in a manner consistent with the Cancer and Leukemia Group B (CALGB) consensus video-assisted thoracic surgery (VATS) lobectomy technique using a robotic surgical system. Perioperative outcomes and long-term follow-up were recorded prospectively, and survival was calculated from the date of surgery to last follow-up.

RESULTS: From November 2002 through May 2010, a total of 325 consecutive patients underwent robotic lobectomy for early-stage NSCLC at 3 institutions. The median age of patients was 66 years (range, 30-87 years), and 37% (120) were female. The majority were in clinical stage I (IA, 247; IB, 63). Conversion rate to thoracotomy was 8% (27/325). Overall morbidity rate was 25.2% (82/325), and major complication rate was 3.7% (12/325). There was 1 in-hospital death (0.3%), and the median length of stay was 5 days (range, 2-28 days). Pathologic stage distribution was 54% (176) IA, 22% (72) IB, 13% (41) IIA, 5% (15) IIB, and 6% (21) IIIA. With a median follow-up of 27 months, overall 5-year survival was 80% (95% confidence intervals [CI] = 73-88), and by pathologic stage, 91% (CI = 83-99) for stage IA, 88% (CI = 77-98) for stage IB, and 49% (CI = 24-74) for all patients with stage II disease. Overall 3-year survival for patients with stage IIIA disease was 43% (CI = 16-69).

CONCLUSIONS: Robotic lobectomy for early-stage NSCLC can be performed with low morbidity and mortality. Long-term stage-specific survival is acceptable and consistent with prior results for VATS and thoracotomy.

Pulmonary Nodules: growth rate assessment in patients by using serial CT and three-dimensional volumetry.

To determine the precision of a three-dimensional (3D) method for measuring the growth rate of solid and subsolid nodules and its ability to detect abnormal growth rates.

MATERIALS AND METHODS: This study was approved by the Institutional Research Board and was HIPAA compliant. Informed consent was waived. The growth rates of 123 lung nodules in 59 patients who had undergone lung cancer screening computed tomography (CT) were measured by using a 3D semiautomated computer-assisted volume method. Clinical stability was established with long-term CT follow-up (mean, 6.4 years±1.9 [standard deviation]; range, 2.0-8.5 years). A mean of 4.1 CT examinations per patient±1.2 (range, two to seven CT examinations per patient) was analyzed during 2.4 years±0.5 after baseline CT. Nodule morphology, attenuation, and location were characterized. The analysis of standard deviation of growth rate in relation to time between scans yielded a normative model for detecting abnormal growth.

RESULTS: Growth rate precision increased with greater time between scans. Overall estimate for standard deviation of growth rate, on the basis of 939 growth rate determinations in clinically stable nodules, was 36.5% per year. Peripheral location (P=.01; 37.1% per year vs 25.6% per year) and adjacency to pleural surface (P=.05; 38.9% per year vs 34.0% per year) significantly increased standard deviation of growth rate. All eight malignant nodules had an abnormally high growth rate detected. By using 3D volumetry, growth rate-based diagnosis of malignancy was made at a mean of 183 days±158, compared with radiologic or clinical diagnosis at 344 days±284.

CONCLUSION: A normative model derived from the variability of growth rates of nodules that were stable for an average of 6.4 years may enable identification of lung cancer.

A comparison of surgical intervention and stereotactic body radiation therapy for stage I lung cancer in high-risk patients: a decision analysis.

OBJECTIVE: We sought to compare the relative cost-effectiveness of surgical intervention and stereotactic body radiation therapy in high risk patients with clinical stage I lung cancer (non-small cell lung cancer).

METHODS: We compared patients chosen for surgical intervention or SBRT for clinical stage I non-small cell lung cancer. Propensity score matching was used to adjust estimated treatment hazard ratios for the confounding effects of age, comorbidity index, and clinical stage. We assumed that Medicare-allowable charges were $15,034 for surgical intervention and $13,964 for stereotactic body radiation therapy. The incremental cost-effectiveness ratio was estimated as the cost per life year gained over the patient's remaining lifetime by using a decision model.

RESULTS: Fifty-seven patients in each arm were selected by means of propensity score matching. Median survival with surgical intervention was 4.1 years, and 4-year survival was 51.4%. With stereotactic body radiation therapy, median survival was 2.9 years, and 4-year survival was 30.1%. Cause-specific survival was identical between the 2 groups, and the difference in overall survival was not statistically significant. For decision modeling, stereotactic body radiation therapy was estimated to have a mean expected survival of 2.94 years at a cost of $14,153 and mean expected survival with surgical intervention was 3.39 years at a cost of $17,629, for an incremental cost-effectiveness ratio of $7753.

CONCLUSIONS: In our analysis stereotactic body radiation therapy appears to be less costly than surgical intervention in high-risk patients with early stage non-small cell lung cancer. However, surgical intervention appears to meet the standards for cost-effectiveness because of a longer expected overall survival. Should this advantage not be confirmed in other studies, the cost-effectiveness decision would be likely to change. Prospective randomized studies are necessary to strengthen confidence in these results.

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