Evaluation of the lung immune prognostic index in advanced non-small cell lung cancer patients under nivolumab monotherapy.

The lung immune prognostic index (LIPI) has been proposed as a new categorical blood-based biomarker to select advanced non-small cell lung cancer (NSCLC) patients for anti-programmed cell death-1 (PD-1) or programmed death ligand 1 (PD-L1) therapy. In this study, we investigate for the first time to the best of our knowledge the prognostic and predictive utility of the LIPI in a multicenter nivolumab monotherapy-based cohort. We retrospectively analyzed the influence of the baseline LIPI on overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and overall response rate (ORR) among 153 patients of a cohort of 188 advanced NSCLC patients treated with nivolumab in the second line of therapy or beyond. Worse LIPI was significantly associated with shorter OS in univariate [hazard ratio (HR) =3.12, 95% confidence interval (CI), 2.12-4.60; P<0.0001] and multivariate (HR =3.67, 95% CI, 1.96-6.86; P<0.0001) analyses. Worse LIPI was associated with shorter PFS (HR =1.45, 95% CI, 1.05-2.03; P=0.03), but this correlation did not reach statistical significance in multivariate analysis (HR =1.49, 95% CI, 0.94-2.38; P=0.09). Worse LIPI was associated with lower DCR in univariate [odds ratio (OR) =0.41, 95% CI, 0.24-0.70; P=0.001] and multivariate (OR =0.44, 95% CI, 0.25-0.78; P=0.005) analyses. This study confirms the utility of the LIPI in prognostication and disease control prediction in advanced NSCLC patients treated with nivolumab in the second line of therapy or beyond.

Alcohol consumption and lung cancer risk in never smokers: a pooled analysis of case-control studies.

Background: Lung cancer is the deadliest cancer in developed countries but the etiology of lung cancer risk in never smokers (LCRINS) is largely unknown. We aim to assess the effects of alcohol consumption, in its different forms, on LCRINS. Methods: We pooled six multi-center case-control studies developed in the northwest of Spain. Cases and controls groups were composed of never smokers. We selected incident cases with anatomopathologically confirmed lung cancer diagnoses. All participants were personally interviewed. We performed two groups of statistical models, applying unconditional logistic regression with generalized additive models. One considered the effect of alcohol type consumption and the other considered the quantity of each alcoholic beverage consumed. Results: A total of 438 cases and 863 controls were included. Median age was 71 and 66, years, respectively. Adenocarcinoma was the predominant histological type, comprising 66% of all cases. We found that any type of wine consumption posed an OR of 2.20 OR 95%CI 1.12-4.35), and spirits consumption had an OR of 1.90 (95%CI 1.13-3.23). Beer consumption had an OR of 1.33 (95%CI 0.82-2.14). These results were similar when women were analyzed separately, but for men there was no apparent risk for any alcoholic beverage. The dose-response analysis for each alcoholic beverage revealed no clear pattern. Conclusions: Wine and spirits consumption might increase the risk of LCRINSs, particularly in females. These results have to be taken with caution given the limitations of the present study.

Environmental tobacco smoke exposure and EGFR and ALK alterations in never smokers' lung cancer. Results from the LCRINS study.

Environmental tobacco smoke (ETS) exposure is a main risk factor of lung cancer in never smokers. Epidermal Growth Factor Receptor (EGFR) mutations and ALK translocations are more frequent in never smokers' lung cancer than in ever-smokers. We performed a multicenter case-control study to assess if ETS exposure is associated with the presence of EGFR mutations and its types and if ALK translocations were related with ETS exposure. All patients were never smokers and had confirmed lung cancer diagnosis. ETS exposure during childhood showed a negative association on the probability of EGRF mutation though not significant. Exposure during adulthood, at home or at workplace, did not show any association with EGFR mutation. The mutation type L858R seemed the most associated with a lower probability of EGFR alterations for ETS exposure at home in adult life. There is no apparent association between ETS exposure and ALK translocation. These results might suggest that ETS exposure during childhood or at home in adult life could influence the EGFR mutations profile in lung cancer in never smokers, reducing the probability of presenting EFGR mutation.

Small Cell Lung Cancer. Methodology and Preliminary Results of the SMALL CELL Study. / Cáncer de pulmón microcítico. Metodología y resultados preliminares del estudio SMALL CELL.

INTRODUCTION: Small cell lung cancer (SCLC) is the most aggressive histologic type of lung cancer, and accounts for approximately 10%-15% of all cases. Few studies have analyzed the effect of residential radon. Our aim is to determine the risk factors of SCLC. METHODS: We designed a multicenter, hospital-based case-control study with the participation of 11 hospitals in 4 autonomous communities. RESULTS: Results of the first 113 cases have been analyzed, 63 of which included residential radon measurements. Median age at diagnosis was 63 years; 11% of cases were younger than 50 years of age; 22% were women; 57% had extended disease; and 95% were smokers or former smokers. Median residential radon concentration was 128Bq/m3. Concentrations higher than 400Bq/m3 were found in 8% of cases. The only remarkable difference by gender was the percentage of never smokers, which was higher in women compared to men (P<.001). Radon concentration was higher in patients with stageIV disease (non-significant difference) and in individuals diagnosed at 63 years of age or older (P=.032). CONCLUSIONS: A high percentage of SCLC cases are diagnosed early and there is a predominance of disseminated disease at diagnosis. Residential radon seems to play an important role on the onset of this disease, with some cases having very high indoor radon concentrations.

Residential radon, EGFR mutations and ALK alterations in never-smoking lung cancer cases.

The aim of this study was to assess if residential radon exposure might cause EGFR mutations or ALK rearrangements in never-smokers.We designed a multicentre case-control study in a radon-prone area (Galicia, Spain); only lung cancer cases were included in the study. We obtained residential radon measurements and clinical information for all the participants. We compared the median values of residential radon between patients with EGFR mutations or ALK rearrangements versus those without them.323 patients were included. Median age was 70 years and 19.5% were males. 42 and 15% of patients were EGFR- and ALK-positive, respectively. The most frequent EGFR alterations were exon 19 deletions and exon 21 (L858R) single-point substitution mutations. ALK-positive patients were 10 years younger than ALK-negative patients. Residential radon levels were two-fold higher in patients with exon 19 deletions compared with patients with exon 21 (L858R) single-point substitution mutations (216 versus 118 Bq·m-3; p=0.057). There were no differences in residential radon levels by EGFR mutation status. ALK-positive patients (n=12) essentially had two-fold residential radon levels compared with ALK-negative patients (290 versus 164 Bq·m-3, respectively).Residential radon may have a role in the molecular signature of lung cancer in never-smokers, although more studies with larger sample sizes are needed to support this hypothesis.

Fluorescence in situ hybridization analysis of the ALK gene in 2,045 non-small cell lung cancer patients from North-Western Spain (Galicia).

Identification of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is a standard diagnostic test in patients with advanced non-small cell lung cancer (NSCLC). The current study describes the experience of ALK rearrangement detection of a referral center in the public health care system of Galicia in North-Western Spain. The fluorescence in situ hybridization (FISH) patterns of the ALK gene and the clinical and pathological features of these patients are reported. This study is also of interest for comparative purposes due to the relative geographical isolation of the area, which could have contributed to particular genetic features. A total of 2,045 tissue samples from NSCLC patients were collected between October 2010 and July 2015 and tested for ALK rearrangements by FISH. Examination of 1,686 paraffin-embedded tissue specimens and 395 cytological samples (306 cell block preparations and 53 cytological smears) was conducted, and any associations between the FISH results and clinicopathological features were assessed. The rate of successful evaluation was marginally higher in tissue samples than in cytological samples (92.9% vs. 84.1%); this difference was not significant. ALK rearrangements were identified in 82 patients(4%): 65 (79.3%) in tissue specimens, 15 (18.3%) in cell block samples and 2 (2.4%) in cytological smears. This genetic translocation appeared to be associated with a non-smoking history, younger age, female gender, stage IV and adenocarcinoma histological type. The findings demonstrate that ALK evaluation by FISH is feasible in tissue and cytological samples. The clinical and pathological features of the ALK-positive series of patients are similar to those previously reported in the literature.

EGFR testing and clinical management of advanced NSCLC: a Galician Lung Cancer Group study (GGCP 048-10).

PURPOSE: This study aimed to assess the incidence of mutations in the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients in the Galician region of Spain and the clinical management and outcome of patients carrying EGFR mutations. PATIENTS AND METHODS: All newly diagnosed advanced or metastatic NSCLC patients were screened for EGFR mutations in matched tumor samples (tissue or cytology specimens) and serum samples. RESULTS: Of 198 patients screened for EGFR mutations in tumor samples, 184 had evaluable data and, of these, 25 (13.6%) had EGFR mutations (84% sensitizing mutations). EGFR mutation was found in serum in 14 (8.1%) patients (of 174 evaluable). Compared to matched tumor tissue, serum EGFR mutation testing specificity and sensitivity were 99% and 52%, respectively. All but two patients received gefitinib. Median progression-free survival and overall survival were 10 (95% confidence interval: 4.8-15.3) months and 17.8 (95% confidence interval: 13.9-21.6) months, respectively, in patients carrying sensitizing mutations. CONCLUSION: The incidence of EGFR mutations in Galicia is consistent with previous data in Spain. Our results also support the feasibility of EGFR testing to guide treatment decision making using tumor tissue or cytology samples, or serum samples if tumor specimens are unavailable. These findings also confirm that first-line gefitinib is an active treatment option in Caucasians with EGFR mutation-positive NSCLC.

Choriocarcinoma syndrome.

OBJECTIVE: To explore the possibility of choriocarcinoma syndrome developing as a potentially fatal complication in patients with this pathology. METHOD: Choriocarcinoma syndrome consists of hemorrhagic manifestations of metastases in advanced germ cell cancer containing large elements of choriocarcinoma. It should be suspected in patients with high tumor mass, multiple metastases and elevated tumor markers characteristic of germ cell tumors. It usually occurs before and during the onset of systemic treatment with chemotherapy. Failure to diagnose it can lead to fatal consequences and may require aggressive diagnostic and therapeutic measures such as surgery. It can also be prevented by developing a good therapeutic strategy that includes an interdisciplinary team, raising the possibility of deferring testicular surgery and beginning chemotherapy beforehand. RESULTS: We report two cases of men with the diagnosis of choriocarcinoma syndrome on liver metastases. We provide ultrasound and CT images of the two cases of hemorrhage on liver metastases and radiological characteristics peculiar to each case that have never been published before. CONCLUSIONS: There should be a high index of suspicion of life-threatening complications in patients with germ cell tumors with a choriocarcinoma component, including the development of life-threatening choriocarcinoma syndrome.

Second-line treatment in advanced non-small-cell lung cancer in the epidermal growth factor receptor wild-type population: review of patient profile.

After progression during first-line treatment in advanced non-small-cell lung cancer (NSCLC), a large percentage of patients are candidates for second-line treatment. The majority do not have epidermal growth factor receptor-activating mutations (EGFRwt). This article reviews the treatment options available for this subpopulation of patients, which includes essentially docetaxel, pemetrexed and erlotinib. These drugs all have similar efficacy, both in terms of objective response rates and overall survival, although with different toxicity profiles. In view of the similar efficacy of the three agents (docetaxel, pemetrexed and erlotinib) in the second-line treatment of NSCLC in the EGFRwt population, and although there are no prospective studies on predictive variables or new molecular markers available, selection of the treatment will depend on the histological type (pemetrexed); patient preference (oral as opposed to intravenous formulation); the presence of comorbid conditions; quality of life; previous or residual toxicities; the risk of neutropenia; response to and the duration of the first-line chemotherapy; and history of smoking.

First-line bevacizumab, cisplatin and vinorelbine plus maintenance bevacizumab in advanced non-squamous non-small cell lung cancer chemo-naïve patients.

OBJECTIVE: The aim of this study was to evaluate efficacy and safety of first-line treatment with bevacizumab, cisplatin and vinorelbine and bevacizumab maintenance in non-squamous, non-small cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: Forty-nine patients with stage IIIB plus pleural effusion or stage IV NSCLC were included in a Phase II clinical trial. Treatment consisted of 3-week cycles of bevacizumab (15 mg/kg on day 1), cisplatin (80 mg/m(2) on day 1) and vinorelbine (25 mg/m(2) on days 1 and 8). After 6 cycles, non-progressing patients received bevacizumab maintenance therapy. The primary end point was progression-free survival (PFS), calculated using the Kaplan-Meier method. RESULTS: Thirteen (29%) of 45 evaluable patients presented a partial response. PFS and overall survival were 6.0 months (95% confidence interval (CI) 4.5 - 7.5) and 14.7 months (95% CI 8.4 - 21), respectively. Fourteen patients (28%) experienced grade 3 - 4 neutropenia and 7 (14%) experienced febrile neutropenia during the combination treatment. During the maintenance phase, the most frequent grade 3 - 4 adverse event was hypertension. Neither grade 3 - 4 thrombocytopenia nor toxic death was observed. CONCLUSIONS: The studied regimen achieved a similar efficacy to other regimens containing platinum doublets. The data provide further evidence that bevacizumab may be used in combination with multiple standard platinum-based doublets in this setting.

Biweekly administration of docetaxel and vinorelbine as second-line chemotherapy for patients with stage IIIB and IV non-small cell lung cancer: a phase II study of the Galician Lung Cancer Group (GGCP 013-02).

The current report aims to evaluate the efficacy and safety profile of a biweekly administration of docetaxel and vinorelbine to patients with advanced non-small cell lung cancer, who had previously been treated for this disease. In a prospective, multicenter, open-label, phase II trial, patients received 40 mg/m of docetaxel and 20 mg/m of vinorelbine on days 1 and 15, every 28 days. Treatment continued for up to a maximum of six cycles, unless disease progression or unacceptable toxicity occurred, or consent was withdrawn. Fifty patients were enrolled in the study and they received 174 cycles of chemotherapy, with a median of three cycles per patient. All patients were evaluated for efficacy and toxicity in an intention-to-treat analysis. The overall response rate was 10% [95% confidence interval (CI): 1-19], including one complete response (2%) and four partial responses (8%). Previous chemotherapy of 80% of the responders included paclitaxel. Median time to disease progression was 2.7 months (95% CI: 2.2-4.3) and median overall survival was 6.5 months (95% CI: 2.5-9.2). The survival rates at 1 and 2 years were 18% (95% CI: 7-29) and 4% (95% CI: 0-10), respectively. The most frequent severe toxicities were neutropenia (20% of patients) and leukopenia (8% of patients). Other toxicities appeared in 4% or fewer of the patients. Biweekly administration of docetaxel and vinorelbine is feasible as a second-line treatment for non-small cell lung cancer patients, but its level of activity and toxicity does not suggest any advantage compared with the results obtained with single-agent docetaxel in the same setting.

Gemcitabine plus docetaxel as first-line chemotherapy in patients with advanced non-small cell lung cancer: a lung cancer Galician group phase II study.

BACKGROUND: Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer (NSCLC) than that of both agents in monotherapy. METHODS: This phase II study evaluated a 3-week based schedule of docetaxel 85 mg/m(2) (1-h i.v. infusion, d8) combined with gemcitabine 1,000 mg/m(2) (30-min i.v. infusion; d1,8) as first-line chemotherapy for patients with advanced NSCLC. RESULTS: Forty-one patients with non-resectable, stage IIIB/IV, and bidimensionally measurable disease were enrolled. A total of 182 chemotherapy cycles (median 6, range 1-6) was administered to 40 patients during the study; one patient did not receive chemotherapy due to a protocol deviation. Two patients were not evaluable for treatment efficacy. The overall response rate found was 44% (95% CI, 29-59%): three patients (7%) had a complete response and 15 patients (37%) had a partial response (median duration of response = 4.0 months). With a median follow-up of 8.7 months, the median time to disease progression was 4.4 months and the median overall survival was 7.3 months. The combined gemcitabine plus docetaxel chemotherapy was well tolerated except for pulmonary toxicity. The main grade 3-4 hematological toxicity was neutropenia (28% of patients, 9% of cycles). Two cases of febrile neutropenia were reported. The main grade 3-4 non-hematological toxicity was pulmonary toxicity (23% of patients, 6% of cycles). CONCLUSION: Gemcitabine 1,000 mg/m(2) on days 1 and 8 in combination with docetaxel 85 mg/m(2) on day 8 given in 3-week cycles is an active and well-tolerated first-line chemotherapeutic regimen for advanced NSCLC.

Docetaxel plus fractionated cisplatin is a safe and active schedule as first-line treatment of patients with advanced non-small cell lung cancer: results of a phase II study.

This phase II trial evaluated the efficacy and safety of docetaxel 85 mg/m(2) (day 1) and cisplatin 80 mg/m(2) (administered as 40 mg/m(2) doses each on days 1 and 2) every 3 weeks as first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Forty-two NSCLC patients were enrolled, most of them with stage IV disease (74%). A total of 195 chemotherapy cycles were administered (median 6, range 1-6). All patients were considered evaluable for efficacy and toxicity in an intention-to-treat (ITT) analysis. The overall response rate was 48% (95% CI, 33-64), including one CR (3%) and 19 PRs (45%). Stable disease was found in 6 patients (14%). The median time to disease progression was 4.9 months (95% CI, 4.0-5.7) and the median overall survival was 10.5 months (95% CI, 5.1-16.0). The survival rates at 1 and 2 years were 36.0% (95% CI, 19.9-52.0) and 18.0% (95% CI, 3.9-32.1), respectively. Overall, the combination showed an excellent safety profile. Severe hematological toxicities were uncommon: neutropenia (5% of patients, 1% of cycles) and febrile neutropenia (2% of patients, 0.5% of cycles). Asthenia (12%) was the only grade 3/4 non-hematological toxicity that affected more than 10% of patients. There were no toxic deaths. In conclusion, docetaxel plus fractionated cisplatin as first-line treatment of advanced NSCLC patients showed similar efficacy as the same combination with higher doses of docetaxel but where cisplatin was administered in a single dose. This new schedule shows promise in its excellent hematological and non-hematological toxicity profile. A randomized phase III trial is needed to confirm these results.

Multicenter randomized trial comparing sequential with concomitant administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a Spanish Breast Cancer Research Group (GEICAM-9903) phase III study.

PURPOSE: This randomized, multicenter, phase III trial evaluated whether sequential doxorubicin and docetaxel (A-->T) reduced hematological toxicity, especially febrile neutropenia, compared with concomitant (AT) administration as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: One hundred forty-four patients were randomly assigned to receive three cycles of doxorubicin 75 mg/m(2) every 21 days followed by three cycles of docetaxel 100 mg/m(2), every 21 days (A-->T) or six cycles of the combination doxorubicin 50 mg/m(2) and docetaxel 75 mg/m(2) (AT) every 21 days. Patients previously treated with anthracyclines received two cycles of doxorubicin followed by four cycles of docetaxel (A-->T), or three cycles of AT followed by three cycles of docetaxel 100 mg/m(2) every 21 days. RESULTS: Febrile neutropenia was less common in the A-->T arm (29.3% of patients, 6.9% of cycles) compared with the AT arm (47.8% of patients, 14.8% of cycles; P =.02 and P =.0004, respectively). Asthenia, diarrhea, and fever occurred more frequently in the AT arm. The overall responses rates were 61% in the A-->T arm (95% CI, 50% to 72%) and 51% in the AT arm (95% CI, 39% to 63%). The median duration of response was 8.7 months (A-->T) and 7.6 months (AT); the median time to progression was 10.5 months (A-->T) and 9.2 months (AT); the median overall survival was 22.3 months (A-->T) and 21.8 months (AT); and no significant differences were found. CONCLUSION: A-->T significantly reduced febrile neutropenia compared with AT in MBC patients and maintains comparable antitumoral efficacy. A-->T represents a valid option for the treatment of MBC.

Biweekly docetaxel as second-line chemotherapy of patients with advanced non-small cell lung cancer: a phase II study of the Galician Lung Cancer Group (GGCP 006-00).

This phase II trial assessed the antitumoral activity and toxicity of docetaxel 50 mg/m (1-h i.v. infusion) administered every 2 weeks as second-line treatment in 45 patients with advanced non-small cell lung cancer (NSCLC). A total of 251 infusions (median 4 per patient) were administered. The actual and relative median dose intensity values were 24.2 mg/m/week and 0.97, respectively. Thirty-seven patients were evaluable for tumor response. The overall response rate was 20% [95% confidence interval (CI) 8-32%] and included one complete response (2%) and eight partial responses (18%). Stable disease was found in seven patients (16%). With a median follow-up of 4 months, the median time to disease progression was 2.8 months (95% CI 1.9-3.7), the median overall survival was 4.0 months (95% CI 3.4-4.6) and the 1-year survival rate was 23% (95% CI 9-37). The every-2-weeks docetaxel schedule was well tolerated. Grade 3/4 non-hematological toxicities showed rates of 5% or less of patients and 2% or less of cycles. The main grade 3/4 hematological toxicity was neutropenia (16% of patients and 8% of cycles). No febrile neutropenia was found. Nevertheless, one toxic death was reported. We conclude that the biweekly docetaxel schedule showed an antitumoral activity similar to that found with the every-3-weeks or weekly docetaxel schedule in a second-line setting for advanced NSCLC. This antitumoral effect was associated with a marked reduction in hematological toxicity, therefore suggesting that this new docetaxel schedule might be useful in the design of combined second-line schedules for treating NSCLC.