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Background: Real-world data have suggested a detrimental effect of steroid use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immunotherapy. However, previous studies included heterogeneous cohorts of patients receiving different lines of treatment with several immuno-oncology agents and various combinations of chemotherapy and immuno-oncology agents., Patients and Methods: A comprehensive clinicopathologic database of patients with NSCLC and programmed cell death ligand 1 >50% treated with frontline pembrolizumab monotherapy was constructed in 14 centers in Italy, Spain, Greece, and Switzerland. A multivariate analysis adjusting for the established prognostic factors was performed using a Cox regression model., Results: For the 265 eligible patients, the median age at diagnosis was 67 years, 66% were male, 90% were current or former smokers, 18% had had an Eastern Cooperative Oncology Group performance status of 2 or 3. Of the NSCLC subtypes, 64% were adenocarcinoma and 25% were squamous cell. Of the patients, 18% had had brain metastases at diagnosis and 24% had received steroids before or during pembrolizumab treatment. The median time to progression was 4.4 months with and 13.7 months without steroid use (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.69-3.85; log-rank P < .001). The median survival was 22.5 months for the whole cohort, 7.7 months for the steroid group, and not reached for the non-steroid group (HR, 3.64; 95% CI, 2.34-5.68; log-rank P < .001). On multivariate analysis accounting for all established prognostic variables, steroid use was still independently associated with a high risk of progression (HR, 1.864; 95% CI, 1.179-2.949; P = .008) and death (HR, 2.292; 95% CI, 1.441-3.644; P < .001) CONCLUSIONS: In patients with advanced NSCLC and programmed cell death ligand 1 expression > 50% receiving frontline pembrolizumab monotherapy, any use of steroids before or during treatment was associated with an 86% increase in the risk of progression and a 2.3-fold increase in the risk of death, even accounting for palliative indication-related bias, including the presence of central nervous system metastasis. The use of steroids for palliative indications should be restricted to absolutely necessary for patients receiving immuno-oncology monotherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Molecular characterization of non-small-cell lung cancer (NSCLC), defined predictive and druggable mutations that greatly modified patient prognoses. The most frequent driver mutations detected in NSCLC are epidermal growth factor receptor (EGFR) mutations, accounting for approximately 90% of exon 19 deletions and exon 21 point mutations. The other EGFR mutations are classified as uncommon or nonclassical and include exon 18 point mutations, exon 20 insertions, and combined mutations, which present different sensitivity to tyrosine kinase inhibitor (TKI) targeting., Patients and Methods: We collected data from EGFR TKI-naive patients with metastatic NSCLC, harboring EGFR exon 18 mutations and EGFR combined mutations treated with first- or second-generation EGFR TKIs. Efficacy end points were evaluated considering the activity of EGFR TKIs in exon 18 versus double-mutation EGFR groups., Results: Eighty-eight patients harboring uncommon EGFR mutations were evaluated in our analysis, and subdivided into 2 group: complex mutations (cohort A = 46 patients) and double mutations in exon 18 (cohort B = 42 patients). The results showed a median progression-free survival of 8.3 versus 12.3 months (hazard ratio [HR], 0.65; P = .06) and a median overall survival of 17.0 versus 31.0 months (HR, 0.62, P = .04) favoring the EGFR combination group. Within the combination group, no detrimental effect was associated with exon 20 mutations., Conclusion: Our study confirmed that EGFR exon 18 and combination mutations might be considered potentially sensitive uncommon mutations, with a similar survival compared with the well known common EGFR mutations. Comparative analysis showed that patients with complex mutations achieved longer survival compared with the exon 18 group, without correlation with the presence of exon 20 mutations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The assessment of special categories of non-small-cell lung cancer (NSCLC) patients requires a comprehensive analysis of all factors potentially influencing the daily quality of life and the relative contribution of tumor-related symptoms on the overall patient health status. While for elderly patients prospective evidence and recommendations allow clinicians to better address their patients to a shared treatment, a paucity of reliable data refers to treatment opportunities for these patients, termed frail or unfit, who are not considered eligible for chemotherapy usually administered to adult patients. This consensus was inspired by the absence of clear criteria to define the category of unfit patients in the context of advanced NSCLC in order to share all the available tools for their classification and evaluation and to support decisions for clinical practice on a daily basis. After review of the literature and panelist consensus, a series of items was identified as relevant: age, performance status, renal function, heart failure, previous cerebrovascular events, uncontrolled hypertension, neuropathy, hearing loss, symptomatic brain metastases, severe psychiatric disorders, and absence of caregiver support. On the basis of these factors, a treatment algorithm for clinical practice to categorize unfit NSCLC patient into 3 major clinical scenarios was defined: (1) unfit for cisplatin-based chemotherapy, (2) unfit for carboplatin-based chemotherapy, and (3) unfit for single-agent chemotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Neoangiogenesis is particularly abundant in small-cell lung cancer (SCLC) and is associated with poor prognosis. As a result of the promising nature of phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line chemotherapy with cisplatin-etoposide for treatment of extensive disease SCLC. We present the treatment rationale and study design of GOIRC trial (FARM6PMFJM study), a multicenter randomized phase III study, supported by AIFA (Agenzia Italiana del Farmaco)., Patients and Methods: Patients are randomized to receive either cisplatin 25 mg/m(2) and etoposide 100 mg/m(2) intravenously on days 1 to 3 (control arm) or the same chemotherapy combined with bevacizumab 7.5 mg/kg intravenously on day 1 (experimental arm). Treatment is repeated every 3 weeks and for a maximum of 6 courses. Patients randomized to the experimental arm in the absence of disease progression after 6 cycles continue bevacizumab alone until progression or for a maximum of 18 courses. Tumor assessment is done every 3 cycles. Major eligibility criteria are: age ≥ 18 years; histologically or cytologically documented extensive disease SCLC; Eastern Cooperative Oncology Group performance status ≤ 2; adequate hematological, hepatic and renal functions; no history of grade 2 or higher hemoptysis; and no evidence of tumor cavitation. The primary end point of this study is overall survival. Secondary end points include response rate, time to progression, and toxicity., Conclusion: An interim futility analysis was performed by an Independent Data Monitoring Committee in September 2013 and the trial obtained approval to continue. As of July 31, 2014, 171 patients of 206 planned have been randomized., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: There are no data on the patterns of care and outcome of elderly patients with mRCC treated with sunitinib. In a retrospective study, we assessed the routine use of first-line sunitinib in mRCC patients aged ≥ 70 years., Patients and Methods: We reviewed the clinical files of 185 patients aged ≥ 70 years with mRCC treated with first-line sunitinib in 17 Italian oncology units from February 2006 to September 2011. One hundred twenty-three patients (66.5%) received a standard 50 mg/d for a 4 weeks on/2 weeks off regimen (SR), and 62 patients (33.5%) received an AR consisting of 37.5 mg/d for a 4 weeks on/2 weeks off in 67.7% of cases., Results: Median age was 74 years. Patients treated with an AR were older than those treated with the SR (P < .0001). In the overall population, the median progression-free survival (PFS) was 11 months, and the median overall survival (OS) was 25.5 months. Grade 3-4 toxicities occurred in 87 of 123 SR (70.7%) and 32 of 62 AR (51.6%), respectively; dose reductions were required in 82 SR (66.7%) and 26 AR (41.9%), respectively; discontinuations because of therapy-related adverse events occurred in 25 SR (20.3%) and 15 AR (24.2%), respectively. In multivariate analysis, only performance status and the Heng score were predictors of either PFS or OS., Conclusion: Sunitinib is active and feasible in elderly patients with mRCC. A sunitinib AR could be considered as an option in selected older mRCC patients. The optimal treatment of frail patients with mRCC remains to be established., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Lymphopenia is associated with toxicity and outcomes in several cancer types. We assessed the association between pre-treatment lymphopenia, toxicity, and clinical outcomes in elderly patients with metastatic renal cell cancer (mRCC) treated with first-line sunitinib. Prognostic factors in these patients were also evaluated., Patients and Methods: We reviewed the clinical records of 181 patients with mRCC aged ≥70 years treated with first-line sunitinib in 17 Italian Oncology Units from February 2006 to September 2011. Baseline lymphopenia was defined as lymphocyte counts <1000/μL., Results: Twenty-nine (16%) patients had a baseline lymphocyte count <1000/μL (group A) and 152 (84%) patients had a lymphocyte count ≥1000/μL (group B). Although no differences between the two groups were reported in terms of overall response rate (P = 0.207), dose reductions (P = 0.740), discontinuation due to adverse events (P = 0.175) or overall incidence of grade 3-4 toxicities (P = 0.112), more patients in the lymphopenia group had grade 3-4 neutropenia (P = 0.017), grade 3-4 thrombocytopenia (P = 0.017) and grade 3-4 diarrhea (P = 0.006). In multivariate analysis, performance status and Heng score were predictors of progression-free survival (P = 0.015 and P = 0.0006, respectively), while performance status, Heng score, and lymphopenia were found to be significantly associated with overall survival (P = 0.007, P < 0.0001 and P = 0.023, respectively)., Conclusions: Sunitinib appears to be safe and active in elderly patients with lymphopenia. Lymphocyte count is an independent prognostic factor for overall survival in elderly patients with mRCC treated with first-line sunitinib., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Dystroglycan (DG) is an adhesion molecule responsible for crucial interactions between extracellular matrix and cytoplasmic compartment. It is formed by two subunits, alpha-DG (extracellular) and beta-DG (transmembrane), that bind to laminin in the matrix and dystrophin in the cytoskeleton, respectively. In this study we evaluated by Western blot analysis the expression of DG in a series of human cancer cell lines of various histogenetic origin and in a series of human primary colon and breast cancers. Decreased expression of DG was observed in most of the cell lines and in both types of tumors and correlated with higher tumor grade and stage. Analysis of the mRNA levels suggested that expression of DG protein is likely regulated at a posttranscriptional level. Evaluation of alpha-DG expression by immunostaining in a series of archival cases of primary breast carcinomas confirmed that alpha-DG expression is lost in a significant fraction of tumors (66%). Loss of DG staining correlated with higher tumor stage (P = 0.022), positivity for p53 (P = 0.033), and high proliferation index (P = 0.045). A significant correlation was also observed between loss of alpha-DG and overall survival (P = 0.013 by log-rank test) in an univariate analysis. These data indicate that DG expression is frequently lost in human malignancies and suggest that this glycoprotein might play an important role in human tumor development and progression.