Eventual role of EGFR-tyrosine kinase inhibitors in early-stage non-small-cell lung cancer.

Nonadvanced non-small-cell lung cancer (NSCLC) has a poor long-term survival from surgery or definitive radiation that is minimally improved with induction/adjuvant conventional chemotherapy. EGFR-tyrosine kinase inhibitors (TKIs), which provide a significant benefit for molecularly selected EGFR-mutant patients with advanced NSCLC, have been infrequently explored in nonadvanced NSCLC to date. Current published studies reported no significant benefit from adding EGFR-TKI to the induction/adjuvant setting. However, many of them present eventual biases such as unpowered statistics, lack of molecular selection, recruitment of low-risk NSCLC, low sample size or unsuitable control arms. Results, strengths and deficiencies of completed and ongoing trials were fully discussed. Similarly, the selection of patients and control arms, the duration and risks of EGFR-TKI therapies in early-stage NSCLC, the evaluation of response and the diagnosis of EGFR status were considered and analyzed.

Afatinib: a second-generation EGF receptor and ErbB tyrosine kinase inhibitor for the treatment of advanced non-small-cell lung cancer.

First-generation reversible EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) changed our understanding of advanced non-small-cell lung cancer biology and behavior. The presence of sensitizing EGFR mutations in advanced non-small-cell lung cancer defines a subset of patients with a better prognosis and sensitivity to EGFR-TKIs with a better response rate, progression-free survival, quality of life and symptom control than with chemotherapy in the first-line therapy setting. However, current EGFR-TKIs show minimal responses in EGFR wild-type patients or with acquired TKI resistance mediated through the EGFR T790M allele. Afatinib is an irreversible pan-ErbB-TKI, active against wild-type EGFR, sensitizing and T970M-mutant EGFR, ErbB2 and ErbB4 receptors, and represents a step change between reversible first-generation and future irreversible highly specific third-generation EGFR-TKIs. Here, we review the clinical development of afatinib through the LUX-Lung trials portfolio highlighting benefits and toxicities.

Recommendations of the Spanish Society of Thoracic Surgery for the management of malignant pleural effusion.

This article summarizes the clinical guidelines for the diagnosis and treatment of malignant pleural effusion (MPE) sponsored by the Spanish Society of Thoracic Surgery (SECT). Ten clinical controversies were elaborated under the methodology of PICO (Patient, Intervention, Comparison, Outcome) questions and the quality of the evidence and grading of the strength of the recommendations was based on the GRADE system. Immunocytochemical and molecular analyses of pleural fluid may avoid further invasive diagnostic procedures. Currently, the definitive control of MPE can be achieved either by pleurodesis (talc poudrage or slurry) or the insertion of a indwelling pleural catheter (IPC). It is likely that the combination of both techniques (i.e., thoracoscopy with talc poudrage and insertion of a IPC, or instillation of talc slurry through a IPC) will have a predominant role in the future therapeutic management.

PD-(L)1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer Patients with High PD-L1 Expression: A Network Meta-Analysis.

Programmed cell death-ligand 1 (PD-L1) has emerged as a potential biomarker for selection of patients more likely to respond to immunotherapy and as a prognostic factor in non-small cell lung cancer (NSCLC). In this network meta-analysis, we aimed to evaluate the efficacy of first-line anti-PD-(L)1 monotherapy in advanced NSCLC patients with high PD-L1 expression (≥50%) compared to platinum-based chemotherapy. We also evaluated efficacy outcomes according to tumor mutational burden (TMB). To that end, we conducted a systematic review. Six clinical trials with 2111 patients were included. In head-to-head comparisons, immunotherapy showed a significant improvement in progression-free survival (PFS: HRpooled = 0.69, 95% CI: 0.52-0.90, p = 0.007), overall survival (OS: HRpooled = 0.69, 95% CI: 0.61-0.78; p < 0.001) and overall response rate (ORR) (Risk ratio (RR)pooled = 1.354, 95% CI: 1.04-1.762, p = 0.024). In the assessment of relative efficacy for PFS through indirect comparisons, pembrolizumab (results from KEYNOTE-024) ranked highest followed by cemiplimab and atezolizumab, with statistical significance determined for some of the drugs. In terms of OS, cemiplimab ranked highest followed by atezolizumab and pembrolizumab, although non-significant OS was determined for these drugs. In conclusion, PD-(L)1 inhibitor monotherapy improves efficacy outcomes in the first line setting of advanced NSCLC patients with high PD-L1 expression. Evaluations with longer follow up are still needed to determine the superiority of any specific drug.

Systemic therapy for pulmonary carcinoids.

Between 25 and 33% of neuroendocrine tumours arise in the lung as low-grade typical pulmonary carcinoids (TPC), intermediate-grade atypical pulmonary carcinoids (APC), and high-grade large cell neuroendocrine or small cell carcinomas. The relatively uncommon incidence and prevalence of PCs are progressively increasing. However, data regarding systemic treatment for PCs are limited, controversial and based on old reports with few randomized or placebo-controlled trials, small sample sizes, or including tumours with very different behaviours. Moreover, conclusions are generally extrapolated from the outcome of extra-pulmonary carcinoids, treatment arms are not well defined or mix different therapies, and the indolent nature of some PCs is not adequately considered in designing control arms. Here, we reviewed and discuss current recommendations regarding systemic treatments for PCs.

Little things make big things happen: angiolymphatic invasion and tumor necrosis prognosticate the outcome of locally advanced non-small cell lung cancer treated with a prior induction therapy.

OBJECTIVES: Size, invasion of thoracic structures, and ipsilateral mediastinal lymph node involvement (pN2) are well-known prognostic factors that configure the staging of resectable, locally advanced non-small cell lung cancer (LA-NSCLC). The prognostic impact of angiolymphatic invasion (ALI) and tumor necrosis (TN) has been barely explored in LA-NSCLC treated with prior induction therapies. METHODS: We retrospectively reviewed 47 resected LA-NSCLCs treated with a prior platin-based chemotherapy or chemoradiation. The impact of ALI, TN, and other pathologic features on survival was analyzed. RESULTS: ALI was presented in 23.4% of cases and TN in 29.8%. Disease-free and overall survival decreased when ALI, TN, or pN2 was present. The incidence of ALI was lower in LA-NSCLC with a good response to induction. CONCLUSION: Our series is the first to report the prognostic impact of ALI and TN in induction-treated LA-NSCLC. The presence of ALI and TN should be included in the pathologic reports.

Age does not worsen the efficacy nor tolerance to combined induction therapies in locally advanced non-small cell lung cancer.

BACKGROUND: One third of non-small cell lung cancer (NSCLC) affects elderly patients in a locally advanced (LA) stage. Induction therapy followed by a curative approach is becoming the standard-of-care for LA-NSCLC. PATIENTS AND METHODS: We compared the efficacy and tolerance to induction chemotherapy or chemo-radiation followed by surgery or definitive radiotherapy in patients younger (N=64) and older (N=44) than 70 years with LA-NSCLC. RESULTS: Elderly patients trended towards having a worse baseline performance status, and presented a higher percentage of IIIB, and squamous tumors. Nevertheless, no significant differences in response rate, operability, or disease-free and overall survival were found between age groups in the whole series, nor in the sub-group of resected patients. Grade 3-4 toxicity tended to be lower in elderly patients. CONCLUSION: Age by itself did not significantly worsen either the efficacy or tolerance to combined induction and definitive treatment in patients with LA-NSCLC and Eastern Cooperative Oncology Group performance status 0-2.

Human papillomavirus in non-small-cell lung cancer: the impact of EGFR mutations and the response to erlotinib.

It has been suggested that human papillomavirus (HPV) could participate in the development of non-small-cell lung cancer (NSCLC). A higher HPV infection rate has been reported in the NSCLC samples from Asian non-smoker patients, with adenocarcinomas or responders to EGFR tyrosine kinase inhibitors (EGFR-TKI). We explored a potential relationship between EGFR mutation, response to EGFR-TKI and HPV infection in Western NSCLC patients. We retrospectively analyzed 40 NSCLC samples and the impact of age, gender, histology, tobacco habit and sample type. HPV infection rate was 2.5% and it was not statistically modified by any analyzed variable, although the limited sample size did not provide definitive conclusions. The rate of HPV infection in NSCLC should be studied in patients with EGFR mutations or a tendency towards presenting them.

Phase II study of pemetrexed and cisplatin plus cetuximab followed by pemetrexed and cetuximab maintenance therapy in patients with advanced nonsquamous non-small cell lung cancer.

OBJECTIVES: The aim was to determine if combined pemetrexed, cisplatin, and cetuximab was efficacious and safe as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this single-arm, multicenter clinical trial, patients with Stage IIIB/IV nonsquamous NSCLC received first-line therapy consisting of pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on Day 1 (21-day cycles) plus weekly cetuximab (400 mg/m(2) loading dose, then 250 mg/m(2)) for 4-6 cycles. Non-progressing patients received maintenance therapy consisting of pemetrexed and cetuximab as above until disease progression. All patients received vitamin supplementation, dexamethasone, and antihistamine prophylaxis. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), 1-year survival rate, translational research (TR) and safety. RESULTS: Of the 113 patients receiving study drug, 109 were protocol-qualified. All patients completed ≥1 cycle of induction, and 51 (45%) and 49 (43%) patients completed ≥1 cycle of maintenance with pemetrexed and cetuximab, respectively. The ORR (n = 109) was 38.5% (80% confidence interval [CI], 32.3-45.1%), all partial responses. Median PFS was 5.8 (80% CI, 4.4-6.7) months. One-year survival rate was 45% (80% CI, 39-51%). In exploratory analyses, there was some preliminary evidence of potential prognostic relationships with efficacy outcomes for epidermal growth factor receptor and thyroid transcription factor-1 protein expression, but not for KRAS mutation or for thymidylate synthase or folate receptor-alpha protein expression. Seventy-three (64.6%) patients had study drug-related Grade 3/4 adverse events (AEs). Drug-related serious AEs were reported in 31 (27.4%) patients. There were 3 (2.7%) potentially drug-related deaths on-study or within 30 days of follow up. CONCLUSION: Pemetrexed, cisplatin, and cetuximab appeared efficacious and tolerable in advanced nonsquamous NSCLC patients. The TR outcomes are hypothesis-generating given the study's size and nonrandomized nature.

Role of gamma-delta T-cells in cancer: another opening door to immunotherapy.

The gamma-delta (γδ) T-cells are a subset of T-lymphocytes characterized by the presence of a surface antigen recognition complex type 2. Those γδ T-cells represent 2-5 % of peripheral T-cells only, but they are common in organs and mucosae, acting as a first defense system in the entries to the organism. The γδ T-cells take part on immune response by direct cytolysis, development of memory phenotypes, and modulation of immune cells, and they have been implied in autoimmune disorders, immune deficiencies, infections, and tumor diseases. We reported the role of γδ T-cells in oncology, focusing in their potential applications for cancer treatment. Experimental designs and clinical trials in the treatment of solid malignancies are extensively reviewed.

Pleural epithelioid hemangioendothelioma in an elderly patient. A case report and review of the literature.

Pleural epithelioid hemangioendothelioma is a really rare tumor of vascular origin and potentially aggressive behavior. We report the case of an 85 years old male patient diagnosed of pleural epithelioid hemangioendothelioma, taking advantage to review exhaustively literature and therapy for the disease.