Matteo Giaj Levra

Predictive value of a proteomic signature in patients with non-small-cell lung cancer treated with second-line erlotinib or chemotherapy (PROSE): a biomarker-stratified, randomised phase 3 trial.

BACKGROUND An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer. METHODS From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m(2), intravenously, every 21 days, or docetaxel 75 mg/m(2), intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690. FINDINGS 142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8-10·9) in the chemotherapy group and 7·7 months (5·9-10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction=0·017 when adjusted for stratification factors; pinteraction=0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08-2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77-1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [<1%] in the erlotinib group), whereas skin toxicity (one [<1%] vs 22 [16%]) was the most frequent in the erlotinib group. INTERPRETATION Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. FUNDING Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.

Malignant pleural mesothelioma: clinicopathologic and survival characteristics in a consecutive series of 394 patients

OBJECTIVE Treatment of malignant pleural mesothelioma (MPM) remains disappointing, although recent reports suggest that multimodality therapy including surgery may provide a significant survival benefit. The aims of this single institution study were: to investigate clinicopathologic characteristics and potential prognostic factors in MPM patients, and to ascertain whether surgery followed by adjuvant therapy had an independent prognostic role. METHODS Retrospective review of a prospectively compiled computerized database of all patients with MPM evaluated between 1989 and 2003. Kaplan-Meier method, log-rank test, and Cox model were used in the statistical analysis. RESULTS There were 394 patients: 270 men (68.5%), 124 women, median age 64 (range 28-93). Twenty-seven patients (6.8%) underwent surgical resection (extrapleural pneumonectomy 15, pleurectomy/decortication 12), followed by adjuvant therapy. As of March 2006, 381 patients (96.7%) had died (median survival, 11.7 months; range 0.03-117.9). Median follow-up of 13 surviving patients (3.3%) was 45.2 months (range 28.7-126.5). Overall survival at 2 years was 18.8%. Multimodality therapy including surgery yielded a median survival of 14.5 months and a 2-year survival rate of 29.6%. Using univariate analysis, age (p=0.009), chest pain (p=0.01), weight loss (p=0.001), performance status (p=0.0001), platelet count (p=0.008), histology (p=0.0001), macroscopic appearance of pleural surface (non-specific inflammation, tumor-like thickening, or nodules; p=0.0001), visceral pleura involvement (p=0.0001), degree of involvement of pleural cavity (less than or more than one third of the cavity; p=0.0001), and multimodality therapy (p<0.01) were found to be significant prognostic factors. At multivariate analysis, performance status, platelet count, histology, and degree of involvement of pleural cavity remained independently associated with survival, whereas multimodality therapy failed to enter the model. CONCLUSIONS Significant predictors of survival include performance status, platelet count, histology, and degree of involvement of pleural cavity. Within the confines of this retrospective study and the small number of patients undergoing multimodality therapy, the role of surgery in the treatment of MPM remains unclear. Further investigation is warranted to determine the optimal treatment strategy in this disease.

Extending Survival of Stage IV Non-Small Cell Lung Cancer☆

Most of patients with newly diagnosed non-small cell lung cancer (NSCLC) present with locally advanced or metastatic disease. In this setting the goal of treatment is to prolong survival and to control disease- and treatment-related symptoms. Currently systemic cytotoxic chemotherapy remains the first-line treatment for most patients with stage IV NSCLC, but preferred treatments are now defined by histology and based on the presence of specific molecular abnormalities. In first-line the combination of platinum plus pemetrexed with or without bevacizumab is a reasonable choice in patients with non-squamous NSCLC. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy are the recommended for patients with EGFR-sensitizing mutations. A small-molecule TKI of anaplastic lymphoma kinase (ALK), crizotinib, showed pronounced clinical activity in the treatment of patients with NSCLC positive for EML4-ALK and it has rapidly entered into daily clinical practice. Currently no agents are specifically approved for the treatment of squamous cell carcinoma of the lung. Second-line treatments include docetaxel, pemetrexed, or erlotinib as single agents. There is a growing evidence that cytotoxics are better than EGFR-TKIs in EGFR wild-type patients. In the setting of the third line, the only approved agent is erlotinib. In elderly patients with good performance status (PS), doublet chemotherapy including platinum should not be excluded, especially for those patients 70-75 years of age without comorbidities. The better selection of patients, the identification of specific predictive biomarkers, a reasonable sequencing of all active and available treatments, including targeted therapies and cytotoxic, may significantly contribute to extend the natural history of stage IV NSCLC.

Early Response to Chemotherapy in Patients With Non–Small-Cell Lung Cancer Assessed by [18F]-Fluoro-Deoxy-D-Glucose Positron Emission Tomography and Computed Tomography

BACKGROUND This study aimed to demonstrate that patients who exhibit a tumor metabolic response to first-line chemotherapy seen on FDG-PET and computed tomography (CT) would survive longer than those who did not show such a response, comparing this evaluation with the morphologic response seen on CT. PATIENTS AND METHODS Images were acquired in 22 consecutive patients with advanced non-small-cell lung cancer (NSCLC) randomized to receive carboplatin/paclitaxel/sorafenib or placebo. FDG-PET was performed within 4 weeks before (PET1) and 2 weeks after starting treatment (PET2). Similarly, CT (CT1) was performed at baseline and then every 2 cycles (6 weeks) during treatment (CT2). Responders and nonresponders were identified with FDG-PET, and metabolic response was then compared with morphologic changes detected by spiral CT. RESULTS Twenty-one of 22 patients completed this study. In terms of progression-free survival (PFS) (45 vs. 22.2 weeks) and overall survival (OS) (77 vs. 47.7 weeks), we observed a trend that was not statistically significant for patients whose response after 2 weeks of treatment was seen on FDG-PET (P = .22 for PFS; P = .15 for OS). CONCLUSION Patients with advanced NSCLC who had a positive outcome, as evidenced by prolonged survival, were those who showed a tumor metabolic response seen on FDG-PET.

Pulmonary function and quality of life after VMAT-based stereotactic ablative radiotherapy for early stage inoperable NSCLC: a prospective study

OBJECTIVES To analyze changes in pulmonary function and quality of life (QoL) at different time points after Stereotactic Ablative Radiotherapy (SABR) for early stage inoperable lung cancer, and potential correlations between radiation dose-volume parameters and pulmonary toxicity or changes in pulmonary function tests (PFT) and QoL. MATERIALS AND METHODS From July 2012 to October 2013, 30 patients were enrolled in this prospective observational study. Complete PFT were performed and Lung Cancer Symptoms Scale (LCSS) questionnaire administered prior to SABR; all patients then underwent Computed Tomography (CT) scan and PFT at 45, 135, 225 and 315 days after SABR, together with LCSS questionnaire. Clinical lung toxicity and radiological toxicity (acute and late) were prospectively recorded by using the Radiation Therapy Oncology Group (RTOG) scoring system. RESULTS A decline in Slow Vital Capacity (SVC), Forced Expiratory Volume in 1s (FEV1), Single-breath lung diffusing capacity (DLCO) and blood partial pressure of oxygen (PaO2) was seen at 135 days post-SABR. PaO2 values rescued to normal levels at 315 days. None of the baseline PFT parameters resulted to be associated with the occurrence of pulmonary toxicity or with late radiological changes. Mean V5, V10, and V20 and MLD2Gy were higher in patients who developed radiation pneumonitis, even if not significantly associated at Cox regression analysis. LCSS QoL showed a significant worsening of the single item fatigue at 135 days after SABR. CONCLUSIONS A small (mean 10%) but significant decline in lung volumes and DLCO was recorded after SABR, with clinical impact of such change difficult to estimate in individual patients. Global QoL was not significantly impaired. Dose-volume parameters did not emerge as significantly predictive of any clinical, radiological or functional toxicity.

Toward therapies tailored to patient characteristics.

Although considerable progress has been made in the diagnosis and treatment of non-small cell lung cancer (NSCLC) in recent years, this disease is still associated with a dismal prognosis. Some improvements have been reported recently after the implementation of third-generation drugs into the clinic. Realistically, we have probably reached a plateau in terms of clinical outcomes with the ways in which we are currently administering cytotoxic chemotherapy. Further steps could be the implementation of molecularly targeted therapies and pharmacogenomics into the therapeutic armamentarium. Pharmacogenomics is the branch of pharmaceutics that deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug’s efficacy or toxicity. In this way, pharmacogenomics aims to develop rational means of optimizing drug therapy with respect to the patient’s genotype, to ensure maximal efficacy with minimal adverse effects. Such approaches suggest the advent of “personalized medicine,” in which drugs and drug combinations are optimized for each individual’s unique genetic makeup. Pharmacogenomics, the whole genome application of pharmacogenetics that examines the single gene interactions with drugs, holds the promise that drugs might one day be tailored to the individual and adapted to each person’s genetic makeup. Environment, diet, age, lifestyle, and state of health can all influence a person’s response to medicines, but understanding an individual’s genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety. What Are the Anticipated Benefits of Pharmacogenomics? Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases. This will facilitate drug discovery and allow drug makers to produce a therapy more targeted to specific diseases. This accuracy will not only maximize therapeutic effects, but also decrease damage to nearby healthy cells. Instead of the standard trial-and-error method of matching patients with the right drugs, physicians will be able to analyze a patient’s genetic profile and prescribe the best available drug therapy from the very beginning. This will not only take the guesswork out of finding the right drug, but also speed up recovery time and increase safety as the likelihood of adverse reactions is eliminated. Pharmacogenomics has the potential to dramatically reduce the estimated 100,000 deaths and 2 million hospitalizations that occur each year in the United States as the result of adverse drug response. Current methods of dosing based on weight and age will be replaced with dosages based on a person’s genetics, which will maximize the value of the therapy and decrease the chance of overdose. The decrease in the number of adverse drug reactions, the number of failed drug trials, the time it takes to get a drug approved, the length of time patients receive medication, the number of medications patients must take to find an effective therapy, the effects of a disease on the body (through early detection), and an increase in the range of possible drug targets will promote a net decrease in the cost of health care.

Fetal Adenocarcinoma of the Lung in a 25-Year-Old Woman

We report the case of a 25-year-old woman with a chance detection at x-ray of a well-defined mass in the right upper lobe during a medical examination. The patient suffered from a modest flu syndrome, with cough and fever. She was a current smoker. CT scan showed a homogeneous well-defined perihilar mass without calcifications, located in the right upper lobe and fully surrounded by aerated parenchyma. A right upper lobectomy with mediastinal lymph node sampling was performed. A pathologic diagnosis of well-differentiated fetal adenocarcinoma of the lung was made and staged as T2N0. Few cases of this type of malignancy have been reported in literature.

C2-02: Factors effecting risk of pneumothorax (PNX) in CT-guided transthoracic needle biopsy of lung lesions: results of 708 consecutive procedures

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PARP Inhibitors: An Interesting Pathway also for Non-Small Cell Lung Cancer?

Treatment of lung cancer is improving, also based on the identification of molecular characteristics of the tumor, of which some already constitute promising targets. One of the molecular characteristics thought to play an important role in lung cancer is DNA repair dysfunctionality. Deregulated expression of DNA repair proteins, such as PARP, has been studied in lung cancer as a possible biomarker and clinically useful target, but the literature remains relatively poor. Pharmacological inactivation of PARP has allowed the identification of a synthetic lethality with a second DNA repair protein such as BRCA1, but has also shown the potential to sensitize tumors to commonly used cytotoxic agents. The current manuscript reviews data regarding PARP in the context of DNA repair and its different pathways, as well as the clinical data generated until now with PARP inhibitors. A deeper understanding of the DNA damage response in lung malignancies, and particularly a clarification of the crosstalk between DNA repair functionality and genetic stability, is the key to optimize the development of PARP inhibitors in the setting of NSCLC.

Nivolumab dans le traitement des CBNPC

TREATMENT OF NSCLC WITH NIVOLUMAB Chemotherapy with docetaxel has remained a cornerstone of second-line treatment for more than 15 years, but it is associated with an unfavorable safety profile. Recently, the results of 2 randomized phase III trials assessing nivolumab in lung cancer, Check-Mate-017 and Check- Mate-057, have deeply changed our current clinical practice and open the debate for further improvements in the clinical care of lung cancer. This paper explores the recent findings about nivolumab in the second-line setting and discusses future directions for nivolumab and other immune Oncology drugs.Resume La chimiotherapie de seconde ligne des carcinomes bronchiques non a petites cellules (CBNPC) par docetaxel est le principal standard therapeutique depuis plus de 15 ans mais est associee avec un profil de tolerance defavorable. Tres recemment les resultats de 2 etudes de phase III comparant nivolumab a docetaxel en seconde ligne des CBNPC (Check-Mate-017 et Check-Mate-057) ont transforme nos standards de soins. Cet article detaille ces 2 etudes et les positionne par rapport a d’autres molecules concurrentes et propose des pistes de developpement futures.