Altered splicing of ATG16-L1 mediates acquired resistance to tyrosine kinase inhibitors of EGFR by blocking autophagy in non-small cell lung cancer.

Despite the initial efficacy of using tyrosine kinase inhibitors of epidermal growth factor receptors (EGFR-TKIs) for treating patients with non-small cell lung cancer (NSCLC), resistance inevitably develops. Recent studies highlight a link between alternative splicing and cancer drug response. Therefore, we aimed to identify deregulated splicing events that play a role in resistance to EGFR-TKI. By using RNA sequencing, reverse-transcription PCR (RT-PCR), and RNA interference, we showed that overexpression of a splice variant of the autophagic gene ATG16-L1 that retains exon 8 and encodes the ß-isoform of autophagy-related protein 16-1 (ATG16-L1 ß) concurs acquired resistance to EGFR-TKI in NSCLC cells. Using matched biopsies, we found increased levels of ATG16-L1 ß at the time of progression in 3 of 11 NSCLC patients treated with EGFR-TKI. Mechanistically, gefitinib-induced autophagy was impaired in resistant cells that accumulated ATG16-L1 ß. Neutralization of ATG16-L1 ß restored autophagy in response to gefitinib, induced apoptosis, and inhibited the growth of in ovo tumor xenografts. Conversely, overexpression of ATG16-L1 ß in parental sensitive cells prevented gefitinib-induced autophagy and increased cell survival. These results support a role of defective autophagy in acquired resistance to EGFR-TKIs and identify splicing regulation of ATG16-L1 as a therapeutic vulnerability that could be explored for improving EGFR-targeted cancer therapy.

Survival of clinical stage III NSCLC according to therapeutic strategy: Relevance of the tumor board decision in the era of immunotherapy.

INTRODUCTION: Stage III NSCLC comprises a heterogeneous population. Different treatment strategies are available, including surgery, radiotherapy, and chemotherapy. The PACIFIC trial results represented a significant change and improvement in the therapeutic strategy for these patients. We aimed to compare the different treatment strategies employed in Stage III NSCLC patients within our institution. METHODS: All Stage III NSCLC patients discussed during the weekly thoracic oncology multidisciplinary team meetings at the University hospital Grenoble Alpes (France) between January 2010 and January 2017 were included. Patients' overall survival (OS) according to treatment strategies along with their respective changes were compared. RESULTS: Overall, 476 patients were identified. Among patients initially scheduled to receive neoadjuvant chemotherapy followed by surgery (n = 60), only 37 (62%) actually underwent surgery. Median OS of the cohort was 21.3 months [IQR 25%-75%: 9.6-48.3]. Patients who received neoadjuvant chemotherapy followed by surgery displayed better survival than those treated by CT-RT: 53.2 months [IQR 25%-75%: 16.1-87.3] versus 23.9 [IQR 25%-75%, 13.3-48.1]. Survival was slightly superior for patients treated by upfront CT-RT than for those planned for neoadjuvant chemotherapy followed by surgery who eventually converted to CT-RT (concurrent or sequential): 23.9 months [IQR 25%-75%: 13.3-48.1] versus 20.4 [IQR 25%-75%:10.8-36], respectively. CONCLUSION: While patients who underwent neoadjuvant chemotherapy followed by surgery displayed a better survival than those treated using CT-RT, switch from surgery to CT-RT actually shortened survival. These results stress the relevance of the tumor board in deciding which is the best therapeutic strategy for Stage III disease patients.

Discontinuation of immune checkpoint inhibitor (ICI) above 18 months of treatment in real-life patients with advanced non-small cell lung cancer (NSCLC): INTEPI, a multicentric retrospective study.

BACKGROUND: The optimal treatment duration of ICIs for patients with advanced NSCLC remains uncertain. In phase 3 clinical trials, treatment continued for 2 years or until disease progression with similar long-term survival rates. Real-life data are missing. PATIENTS AND METHODS: This academic multicentric retrospective study aims at analyzing the characteristics of patients who discontinued treatment after at least 18 months of ICI monotherapy, in the setting of controlled disease. RESULTS: Of the 1127 patients treated with immunotherapy in the given period in six centers, 107 patients had their tumor controlled after at least 18 months of treatment and 54 (50%) of them had discontinued ICI. The median duration of treatment was 26 months. Treatment was stopped due to prescriber choice or toxicity in 46% and 22% of cases, respectively. After a median follow-up of 21 months from ICI discontinuation (95% CI 15.0-26.1 months), 18 (33%) patients experienced tumor progression after a median time of 10.0 months (range 2-33). From discontinuation, 12-month overall survival (OS) and progression-free survival (PFS) were 90% (95% CI 77.7-95.7) and 71% (95% CI 56.8-81.5), respectively; 24-month OS and PFS were 84% (95% CI 68.7-92.2) and 63% (95% CI 46.1-76.2), respectively. Duration of disease control after ICI discontinuation was correlated with tumor response at treatment discontinuation: PFS rate at 12 months was 76% after complete response (CR n = 11) or partial response (PR n = 37) and 22% after only stable disease (SD n = 6) as best response, p-value = 0.0002. PFS rate at 12 months was 80% for CR and/or complete metabolic response with 18F-FDG PET/CT (CMR) and 65% for others. Fourteen patients out of the 18 relapse patients received a subsequent treatment: seven with ICI rechallenge (best response 14% PR and 86% SD) and five with localized therapy with 60% CR. CONCLUSIONS: This real-life study provides new insight into long-term outcomes of patients with advanced NSCLC treated with ICI for at least 18 months before treatment discontinuation in the absence of PD. Tumor response and CMR with FDG PET just before therapy discontinuation may be a predictive factor of prolonged disease control upon discontinuation. These results call for caution in discontinuing treatment in patients with stable disease as the best response.

Factors associated with survival of patients with solid Cancer alive after intensive care unit discharge between 2005 and 2013.

BACKGROUND: At intensive care unit (ICU) admission, the issue about prognosis of critically ill cancer patients is of clinical interest, especially after ICU discharge. Our objective was to assess the factors associated with 3- and 6-month survival of ICU cancer survivors. METHODS: Based on the French OutcomeRea™ database, we included solid cancer patients discharged alive, between December 2005 and November 2013, from the medical ICU of the university hospital in Grenoble, France. Patient characteristics and outcome at 3 and 6 months following ICU discharge were extracted from available database. RESULTS: Of the 361 cancer patients with unscheduled admissions, 253 (70%) were discharged alive from ICU. The main primary cancer sites were digestive (31%) and thoracic (26%). The 3- and 6-month mortality rates were 33 and 41%, respectively. Factors independently associated with 6-month mortality included ECOG performance status (ECOG-PS) of 3-4 (OR,3.74; 95%CI: 1.67-8.37), metastatic disease (OR,2.56; 95%CI: 1.34-4.90), admission for cancer progression (OR,2.31; 95%CI: 1.14-4.68), SAPS II of 45 to 58 (OR,4.19; 95%CI: 1.76-9.97), and treatment limitation decision at ICU admission (OR,4.00; 95%CI: 1.64-9.77). Interestingly, previous cancer chemotherapy prior to ICU admission was independently associated with lower 3-month mortality (OR, 0.38; 95%CI: 0.19-0.75). Among patients with an ECOG-PS 0-1 at admission, 70% (n = 66) and 61% (n = 57) displayed an ECOG-PS 0-2 at 3- and 6-months, respectively. At 3 months, 74 (55%) patients received anticancer treatment, 13 (8%) were given exclusive palliative care. CONCLUSIONS: Factors associated with 6-month mortality are almost the same as those known to be associated with ICU mortality. We highlight that most patients recovered an ECOG-PS of 0-2 at 3 and 6 months, in particular those with a good ECOG-PS at ICU admission and could benefit from an anticancer treatment following ICU discharge.

Implementing ctDNA Analysis in the Clinic: Challenges and Opportunities in Non-Small Cell Lung Cancer.

Tumor genomic profiling has a dramatic impact on the selection of targeted treatment and for the identification of resistance mechanisms at the time of progression. Solid tissue biopsies are sometimes challenging, and liquid biopsies are used as a non-invasive alternative when tissue is limiting. The clinical relevance of tumor genotyping through analysis of ctDNA is now widely recognized at all steps of the clinical evaluation process in metastatic non-small cell lung cancer (NSCLC) patients. ctDNA analysis through liquid biopsy has recently gained increasing attention as well in the management of early and locally advanced, not oncogene-addicted, NSCLC. Its potential applications in early disease detection and the response evaluation to radical treatments are promising. The aim of this review is to summarize the landscape of liquid biopsies in clinical practice and also to provide an overview of the potential perspectives of development focusing on early detection and screening, the assessment of minimal residual disease, and its potential role in predicting response to immunotherapy. In addition to available studies demonstrating the clinical relevance of liquid biopsies, there is a need for standardization and well-designed clinical trials to demonstrate its clinical utility.

Literature meta-analysis about the efficacy of re-challenge with PD-1 and PD-L1 inhibitors in cancer patients.

INTRODUCTION: Immune checkpoint inhibitor (ICPis) re-challenge could be an attractive therapeutic option considering its good safety profile. However, little data is available regarding anti-PD-1/anti-PD-L1 retreatment. We conducted a meta-analysis focusing on outcomes of solid cancer patients performing this strategy. METHODS: Fourteen full papers involving 74 patients were included. Individual data about best response or progression-free survival (PFS) upon the first and second course of anti-PD-1/anti-PD-L1 were collected. RESULTS: Non-small-cell lung cancer (53%) and melanoma (34%) were the most represented cancers. Higher objective response (46% versus 24%, P=4.10-4) and disease control rates (73% versus 52%, P=7.10-3) were obtained upon the first ICPi course compared to re-challenge. No association between responses obtained with the two ICPis courses was found (P=3.10-1). The PFS upon the first ICPi (PFS1) was longer than after re-challenge (PFSR) (6.6 versus 2.8 months, hazard ratio (HR) 0.57, P=2.10-3). A longer PFSR was obtained in patients with a longer PFS1 (P=6.10-3), in those who discontinued the first ICPi due to toxicity or per protocol (8.8 versus 2.1 months if disease progression occurs, P=2.10-3), and in those not receiving intercalated treatment between the two ICPis (6.6 versus 2.1 months for the treated ones, P=1.10-3). DISCUSSION: Anti-PD-1/anti-PD-L1 re-challenge showed interesting clinical activity in selected patients, mainly in those achieving a long-term response upon the first ICPi course, that do not discontinue therapy because of disease progression, or that are able to keep a treatment-free period.

Immune Checkpoint Inhibitors Rechallenge Efficacy in Non-Small-Cell Lung Cancer Patients.

BACKGROUND: Immune checkpoint inhibitor (ICPi) rechallenge could represent an attractive option in non-small-cell lung cancer (NSCLC), yet no sufficient data supporting this strategy are available. This retrospective observational multicenter national study explored the efficacy of anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) rechallenge in advanced NSCLC patients, looking for potential clinical features associated with greater outcomes. PATIENTS AND METHODS: We retrospectively collected data from 144 advanced NSCLC patients whose disease was rechallenged with ICPis after ≥ 12 weeks of discontinuation. The progression-free survival (PFS) and overall survival (OS) were calculated from first or second ICPi initiation to disease progression (PFS1 and PFSR, respectively), death, or last follow-up (OS1, OSR), respectively. RESULTS: The median (interquartile range) age was 63 (58-70) years. Most patients were male (67%) and smokers (87%). Most had adenocarcinomas (62%) and/or stage IV disease at diagnosis (66%). The best response at rechallenge was not associated with that under the first ICPi (P = 1.10-1). The median (95% confidence interval) PFS1 and PFSR were 13 (10-16.5) and 4.4 (3-6.5) months, respectively. The median (95% confidence interval) OS1 and OSR were 3.3 (2.9-3.9) and 1.5 (1.0-2.1) years, respectively. Longer PFSR and OSR were found in patients discontinuing first ICPi because of toxicity or clinical decision, those not receiving systemic treatment between the two ICPis, and those with good Eastern Cooperative Oncology Group performance status at rechallenge. Only performance status proved to affect outcomes at multivariate analysis. CONCLUSION: Patients discontinuing first ICPi because of toxicity or clinical decision, those able to maintain a treatment-free period, and those with good performance status may be potential candidates for rechallenge.

[Immunotherapy of metastatic non-small cell lung cancer from first line to resistance and its management]. / Immunothérapie des cancers bronchiques non à petites cellules métastatiques, de la première ligne à la résistance et sa prise en charge.

Immunotherapy alone or in combination with chemotherapy is now an integral part of the treatment of metastatic NSCLC. This treatment is transforming the management of these cancers, with 20-30% of patients achieving long survival. However, disease progression under treatment is still the rule for the majority of patients, raising problems both in understanding its mechanisms and in subsequent appropriate management. This study examines current therapeutic options and proposes solutions to circumvent resistance to immunotherapy. The mechanisms of resistance to these treatments is also analysed.

Nivolumab treatment in advanced non-small cell lung cancer: real-world long-term outcomes within overall and special populations (the UNIVOC study).

OBJECTIVE: To describe long-term outcomes of patients treated with nivolumab for advanced non-small cell lung cancer (aNSCLC) in everyday clinical practice in France, with a focus on patients aged ⩾80 years, patients with renal impairment and patients with brain metastases. METHODS: The study included all patients with aNSCLC recorded in the French national hospital database, starting nivolumab in 2015-2016 and followed until December 2018. Patients were stratified by age, the presence of renal impairment and brain metastasis, as documented in the hospital discharge summaries. Information was retrieved on demographics, comorbidities and treatment history at baseline. Time to discontinuation of nivolumab treatment and overall survival were estimated using Kaplan-Meier survival analysis. RESULTS: Overall, 10,452 patients were included, of whom 514 were octogenarians, 479 had renal impairment and 1800 had brain metastases at baseline. Median duration of nivolumab treatment was 2.8 months in the overall population and in both the octogenarian and renally impaired subgroups, and 2.3 months in patients with brain metastases. Median overall survival in these patient groups was 11.7 months (95% confidence interval: 11.3-12.2), 11.7 months (11.3-12.1), 11.7 months (11.3-12.2) and 9.9 months (9.0-10.9) respectively. Three-year overall survival rates were 19.1% (18.1-20.2) in the overall population, 16.5% (11.6-23.4) in octogenarians, 15.9% (11.8-21.4) in patients with renal impairment and 21.7% (19.4-24.2) in those with brain metastases. CONCLUSION: This large nationwide retrospective real-life cohort provided narrow estimates of long-term overall survival, which reached 19% at 3 years, consistent with data from phase III trials of nivolumab. Survival rates were comparable in the three special populations of interest and the overall population.

Trends in response rate and survival in small-cell lung cancer patients between 1997 and 2017.

INTRODUCTION: Median survival of small-cell lung cancer (SCLC) patients is usually around 1 year. The advent of new drugs may have slightly improved their prognosis. We aimed to assess whether SCLC response to chemotherapy and survival had changed over time. METHODS: Consecutive SCLC patients were included at Grenoble University Hospital, France. We compared the patients' characteristics, response to chemotherapy and survival between 1997-2009 (period 1) and 2010-2017 (period 2). RESULTS: A total of 529 patients were identified, of whom 498 received a first line of chemotherapy and 279 a second line. The majority (n = 290, 58%) had extensive disease. The objective response rate (ORR) to first-line chemotherapy in metastatic patients was 63% in period 1 and 62% in period 2; the ORRs to second-line chemotherapy were 39% and 29%, respectively. Median overall survival from first-line chemotherapy was 13.2 months (interquartile range [IQR] 7.4-24.4) in period 1 and 11.2 months (IQR 7.1-21.2) in period 2. Mortality in these two periods did not differ significantly even after adjustment for prognostic factors (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.66-1.00). The factors independently associated with death were cardiovascular comorbidities (HR = 1.28 [95%CI 1.05-1.55]), liver comorbidities (HR = 1.31 [95%CI 1.03-1.65]), poor ECOG performance status (3-4vs. 0-1, HR = 2.45 [95%CI 1.83-3.30]) and extensive disease (HR = 2.69 [95%CI 2.18-3.33]). CONCLUSIONS: Since 1997, there has been no improvement in the survival or response rate to chemotherapy of SCLC patients. There is a desperate need for new approaches in this setting.

Operation and Chemotherapy: Prognostic Factors for Lung Cancer With One Synchronous Metastasis.

BACKGROUND: Stage IV non-small cell lung cancer (NSCLC) is considered incurable; however, some patients with only few metastases may benefit from treatment with a curative intent. We aimed to identify the prognostic factors for stage IV NSCLC with synchronous solitary M1. METHODS: A database constructed from our weekly multidisciplinary thoracic oncology meetings was retrospectively screened from 1993 to 2012. Consecutive patients with NSCLC stages I to IV were included. RESULTS: Of the 6,760 patients found, 4,832 patients were studied. Among the 1,592 patients (33%) with stage IV NSCLC, 109 (7%) had a synchronous solitary M1. Metastasis involved the brain in 64% of patients. Median overall survival was significantly longer in synchronous solitary M1 than in other stage IV (18.9 months, interquartile range [IQR]: 9.9 to 34.6 months versus 6.1 months, IQR: 2.3 to 13.7 months], respectively, p < 10-4). Among patients with synchronous solitary M1, 90 (83%) received a local treatment with curative intent at the primary and metastatic sites. Factors independently associated with survival were age older than 63 years (hazard ratio [HR] 1.63, 95% confidence interval [CI]: 1.01 to 2.63), Performance status of 3 or 4 (HR 7.91, 95% CI: 2.23 to 28.03), use of chemotherapy (HR 0.38, 95% CI: 0.23 to 0.64), and operation conducted at both sites (HR 0.35, 95% CI: 0.19 to 0.65). CONCLUSIONS: Synchronous solitary M1 treated with chemotherapy and operation at both sites resulted in better survival. Survival of NSCLC with synchronous solitary M1 was more similar to stage III than other stage IV NSCLCs. The eighth TNM classification takes this into account by distinguishing between stages M1b and M1c.

[Not Available]. / 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.

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.

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.

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.

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.

Clinical meta-analyses of targeted therapies in adenocarcinoma.

Although the interpretation of the data reported in meta-analyses may hide several issues, it is undoubtable that this methodological approach may significantly contribute to implement the results of clinical trials, and represent a useful and practical tool for the evidence-based medicine process. Indeed, level-one recommendations should consider well-conducted meta-analyses as well as large and adequately powered randomized trials as the main contributors for the definition of guidelines for clinical practice. In addition, the role of meta-analyses for issues whereas conflicting data (and/or unpowered results) are provided, is well established. In the field of lung cancer, meta-analyses already participated to change the current standard, and are now facing the challenging issues of predictive biomarkers of prognosis and/or efficacy of targeted agents. With this aim, the meta-analytic approach helped in the recent years to implement the quantification of the magnitude of the benefit of targeted agents, and added new insights by interpreting the data coming from clinical trials by integrating them with biomarkers. The treatment-interaction analyses according to putative predictive factors of efficacy may clarify unknown issues and generate new hypotheses for future perspectives. The current review attempts to put in the context of the clinical data of targeted agents for lung cancer all the pros and cons of the meta-analytic process published to date, and critically analyze all the potential perspectives which this methodology may add for both current practice and forthcoming research.

Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas.

BACKGROUND: Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited. METHODS: Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed. RESULTS: Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS. CONCLUSIONS: First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS.

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.

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.