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Alessia E Russo,1 Domenico Priolo,1 Giovanna Antonelli,1 Massimo Libra,2 James A McCubrey,3 Francesco Ferraù1 1Medical Oncology Department, San Vincenzo Hospital, Taormina (Messina), Italy; 2Laboratory of Translational Oncology & Functional Genomics, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; 3Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA Abstract: Non-small-cell lung cancer (NSCLC) represents about 85% of all lung cancers, and more than half of NSCLCs are diagnosed at an advanced stage. Chemotherapy has reached a plateau in the overall survival curve of about 10 months. Therefore, in last decade novel targeted approaches have been developed to extend survival of these patients, including antiangiogenic treatment. Vascular endothelial growth factor (VEGF) signaling pathway plays a dominant role in stimulating angiogenesis, which is the main process promoting tumor growth and metastasis. Bevacizumab (bev; Avastin®) is a recombinant humanized monoclonal antibody that neutralizes VEGF’s biologic activity through a steric blocking of its binding with VEGF receptor. Currently, bev is the only antiangiogenic agent approved for the first-line treatment of advanced or recurrent nonsquamous NSCLC in “bev-eligible” patients. The ineligibility to receive bev is related to its toxicity. In the pivotal trials of bev in NSCLC, fatal bleeding events including pulmonary hemorrhage were observed with rates higher in the chemotherapy-plus-bev group. Therefore, in order to reduce the incidence of severe pulmonary hemorrhage, numerous exclusion criteria have been characteristically applied for bev such as central tumor localization or tumor cavitation, use of anticoagulant therapy, presence of brain metastases, age of patients (elderly). Subsequent studies designed to evaluate the safety of bev have demonstrated that this agent is safe and well tolerated even in those patients subpopulations excluded from pivotal trials. This review outlines the current state-of-the-art on bev use in advanced NSCLC. It also describes patient selection and future perspectives on this antiangiogenic agent. Keywords: bevacizumab, nonsquamous NSCLC, eligibility, safety, subpopulations

Michele La Greca,1 Giuseppe Grasso,2 Giovanna Antonelli,1 Alessia Erika Russo,1 Salvatore Bartolotta,3 Alessandro D’Angelo,1 Felice Vito Vitale,1 Francesco Ferraù1 1Medical Oncology Department, San Vincenzo Hospital, Taormina, Messina, Italy; 2Pathology Department, San Vincenzo Hospital, Taormina, Messina, Italy; 3Surgical Unit, Casa di Cura Gretter-Lucina, Catania, Catania, Italy Abstract: Neoadjuvant chemotherapy has been successfully tested in several bulky solid tumors, but it has not been utilized in advanced cutaneous melanoma, primarily because effective medical treatments for this disease have been lacking. However, with the development of new immunotherapies (monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 [anti-CTLA-4] and programmed death protein-1 [anti-PD1]) and small molecules interfering with intracellular pathways (anti-BRAF and mitogen-activated protein kinase kinase [anti- MEK]) the use of this approach is becoming a viable treatment strategy for locally advanced melanoma. The neoadjuvant setting provides a double opportunity for a better knowledge of these drugs: a short-term evaluation of their intrinsic activity, and a deeper analysis of their action and resistance-induction mechanisms. BRAF inhibitors seem to be ideal candidates for the neoadjuvant setting, because of their prompt, repeatedly confirmed response in V600E BRAF-mutant metastatic melanoma. In this report we summarize studies focused on the neoadjuvant use of traditional medical treatments in advanced melanoma and anecdotal cases of this approach with the use of biologic therapies. Moreover, we discuss our experience with neoadjuvant targeted therapy as a priming for radical surgery in a patient with BRAF V600E mutation-positive advanced melanoma. Keywords: neoadjuvant setting, biologic, targeted therapy, vemurafenib, advanced melanoma

S Bordonaro,1 F Romano,1 E Lanteri,1 F Cappuccio,1 R Indorato,2 A Butera,2 A D’Angelo,3 F Ferraù,3 P Tralongo11Medical Oncology Unit, Umberto I Hospital, Rete Assistenza Oncologica, Siracusa, 2Medical Oncology Unit, S Giovanni di Dio Hospital, Agrigento, 3Medical Oncology Unit, S Vincenzo Hospital, Taormina, ItalyIntroduction: The advent of oral chemotherapy agents has had a strong impact on several aspects of the management of cancer patients, including survival rates, health-care expenditure, and health-related quality of life. However, access to care and adherence to oral chemotherapy are central to optimal outcomes.Patients and methods: In this multicenter observational study, we assessed the effect of the “Active Home Care” initiative – a structured, active, home-based cancer-treatment program – on quality of life, health-care utilization, and patient adherence and satisfaction using self-administered questionnaires. Sixty-two patients treated with oral chemotherapy (capecitabine, vinorelbine, imatinib, sunitinib, sorafenib, temozolomide, ibandronate) were enrolled in the program. Weekly home visits were scheduled, each one with a trained nurse who delivered the home-based chemotherapy and reviewed patients’ compliance and treatment toxicity. An oncologist evaluated patients and modified the dosage of oral chemotherapy based on toxicity reported during the previous cycle at bi-weekly visits.Results: A total of 460 home visits were performed between April 2012 and February 2013. The Active Home Care initiative was associated with significant improvements in physical functioning and symptoms, and reductions in the access to cancer facilities. Satisfaction with oral chemotherapy and care received was high. All patients reported having taken their medications according to their prescription, and no patient reported difficulties in managing the oral chemotherapy regimen. Conclusion: The Active Home Care program was associated with improvements in the quality of life of patients and caregivers, better adherence to treatment, and the effective management of therapy and cancer-related symptoms. Home-based cancer treatment may also optimize the utilization of health-care resources.Keywords: advanced cancer, home-based care, quality of life, adherence, patient satisfaction, effective therapy management

Paolo Tralongo1, Francesco Ferraù2, Nicolò Borsellino3, Francesco Verderame4, Michele Caruso5, Dario Giuffrida6, Alfredo Butera7, Vittorio Gebbia81Medical Oncology Unit, Azienda Sanitaria Provinciale, Siracusa; 2Medical Oncology Unit, Ospedale San Vincenzo, Taormina; 3Medical Oncology Unit, Ospedale Buccheri La Ferla, Palermo; 4Medical Oncology Unit, Ospedale Giovanni Paolo II, Sciacca; 5Medical Oncology Unit, Istituto Humanitas, Catania; 6Medical Oncology Unit, Istituto Oncologico del Mediterraneo, Catania; 7Medical Oncology Unit, Ospedale San Giovanni di Dio, Agrigento; 8Medical Oncology Unit, Dipartimento Oncologico, La Maddalena, Università degli Studi, Palermo, ItalyAbstract: Patient-centered home care is a new model of assistance, which may be integrated with more traditional hospital-centered care especially in selected groups of informed and trained patients. Patient-centered care is based on patients' needs rather than on prognosis, and takes into account the emotional and psychosocial aspects of the disease. This model may be applied to elderly patients, who present comorbid diseases, but it also fits with the needs of younger fit patients. A specialized multidisciplinary team coordinated by experienced medical oncologists and including pharmacists, psychologists, nurses, and social assistance providers should carry out home care. Other professional figures may be required depending on patients' needs. Every effort should be made to achieve optimal coordination between the health professionals and the reference hospital and to employ shared evidence-based guidelines, which in turn guarantee safety and efficacy. Comprehensive care has to be easily accessible and requires a high level of education and knowledge of the disease for both the patients and their caregivers. Patient-centered home care represents an important tool to improve quality of life and help cancer patients while also being cost effective.Keywords: cancer, home care, chemotherapy, biologic agents

Purpose: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. Methods: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). Results: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9–7.2) and 12.1 months (95% CI: 9.6–16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0–18.4), 6.1 months (95% CI: 4.0–8.9) for CTX-based and 5.3 months (95% CI: 4.1–9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3–16.7 and CTX-based ones (95%CI: 8.7–52.8). Tumour response, PFS and OS decreased proportionally in later lines. Conclusion: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation. [ABSTRACT FROM AUTHOR]

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3–10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8–11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3–15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients. • Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no drug-free breaks. • In 1st-line, the highest ORR was observed for VRL-based regimens, without any association between clinical or tumor characteristics and ORR. • Median TTF was 6.28 months (95% CI: 5.63 – 7.01), regardless of the drug used and median Survival-Post-Progression was 12.0 months (95% CI: 10.4 – 15.6). • The longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8-11.3, HR=0.72) and in CAPE-single agent (10.7, 95%CI 8.3-15.8, HR=0.70). [ABSTRACT FROM AUTHOR]

Objectives: We conducted a multicenter phase II study to evaluate the clinical efficacy, toxicity, and dose intensity of a new weekly schedule of docetaxel and gemcitabine as first-line treatment of metastatic breast cancer patients. Methods: We enrolled 58 patients, 52% of whom had received a previous anthracycline-containing chemotherapy. The treatment schedule was: docetaxel 35 mg/m2 and gemcitabine 800 mg/m2 i.v. on days 1, 8, 15 every 28 days. Results: All patients were assessable for toxicity and 56 for efficacy. Overall response rate was 64.3% with 16.1% of complete responses and 48.2% of partial responses. Median survival was 22.10 months (95% CI: 15.53–28.67) and median time to tumor progression was 13.6 months (95% CI: 10.71–16.49). The most common hematological toxicity was neutropenia (no febrile neutropenia), which occurred in 28 patients (48.3%) but grade 3–4 in only 8 patients (14%). Alopecia, the most common nonhematological toxicity, occurred in 20 (34.5%) patients, but only 5 patients (8.6%) experienced grade 3 alopecia. Conclusion: The activity of docetaxel and gemcitabine in metastatic breast cancer is confirmed. The promising results of the employed schedule, in agreement with other published studies, need to be further confirmed within a phase III study. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The sequential doxorubicin --> CMF (CMF=cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF x 6 cycles (CMF); (b) doxorubicin x 4 cycles followed by CMF x 6 cycles (A --> CMF); (c) CMF x 6 cycles followed by goserelin plus tamoxifen x 2 years (CMF --> GT); and (d) doxorubicin x 4 cycles followed by CMF x 6 cycles followed by goserelin plus tamoxifen x 2 years (A --> CMF --> GT). The study used a 2 x 2 factorial experimental design to assess: (1) the effect of the chemotherapy regimens (CMF vs A --> CMF or arms a+c vs b+d) and (2) the effect of adding GT after chemotherapy (arms a+b vs c+d). At a median follow-up of 72 months, A --> CMF as compared to CMF significantly improved disease-free survival (DFS) with a multivariate hazard ratio (HR)=0.740 (95% confidence interval (CI): 0.556-0.986; P=0.040) and produced a nonsignificant improvement of overall survival (OS) (HR=0.764; 95% CI: 0.489-1.193). The addition of GT after chemotherapy significantly improved DFS (HR=0.74; 95% CI: 0.555-0.987; P=0.040), with a nonsignificant improvement of OS (HR=0.84; 95% CI: 0.54-1.32). A --> CMF is superior to CMF. Adding GT after chemotherapy is beneficial for premenopausal node-positive patients. [ABSTRACT FROM AUTHOR]

Pain is a highly distressing symptom for patients with advanced cancer. WHO analgesic ladder is widely accepted as a guideline for its treatment. Our aim was to describe pain prevalence among patients diagnosed with advanced non-small-cell lung cancer (NSCLC), impact of pain on quality of life (QoL) and adequacy of pain management. Data of 1021 Italian patients enrolled in three randomised trials of chemotherapy for NSCLC were pooled. QoL was assessed by EORTC QLQ-C30 and LC-13. Analgesic consumption during the 3 weeks following QoL assessment was recorded. Adequacy of pain management was evaluated by the Pain Management Index (PMI). Some pain was reported by 74% of patients (42% mild, 24% moderate and 7% severe); 50% stated pain was affecting daily activities (30% a little, 16% quite a bit, 3% very much). Bone metastases strongly affected presence of pain. Mean global QoL linearly decreased from 64.9 to 36.4 from patients without pain to those with severe pain (P<0.001). According to PMI, 616 out of 752 patients reporting pain (82%) received inadequate analgesic treatment. Bone metastases were associated with improved adequacy and worst pain with reduced adequacy at multivariate analysis. In conclusion, pain is common in patients with advanced NSCLC, significantly affects QoL, and is frequently undertreated. We recommend that: (i) pain self-assessment should be part of oncological clinical practice; (ii) pain control should be a primary goal in clinical practice and in clinical trials; (iii) physicians should receive more training in pain management; (iv) analgesic treatment deserves greater attention in protocols of anticancer treatment.British Journal of Cancer (2004) 90, 2288-2296. doi:10.1038/sj.bjc.6601810 www.bjcancer.com Published online 25 May 2004 [ABSTRACT FROM AUTHOR]

Long-term survival for adult patients with solid tumours continues to increase. For some cancers, the possibility of recurrence after a number of years is extremely low, and the risk of death becomes similar to that of the general population of the same sex and age. During the Fifth European Conference on Survivors and Chronic Cancer Patients held in Siracusa, Italy, June 2014, oncologists, general practitioners, epidemiologists, cancer patients and survivors, and patient advocates joined to discuss the possible use of the term "cured" in reference to some adult patients with solid tumours. The specific focus was the appropriateness of using the term in communicating with cancer patients, survivors, and their families. Initial results of the discussion, in concert with a review of the published literature on the subject, were later further discussed by all participants through electronic communication. The resulting final statement aims to suggest appropriate ways to use the word "cured" in the clinical and communicative setting, to highlight the potential impact of the word on patients, and to open a critical discussion concerning this timely and delicate matter. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that environmental contaminants can exert endocrine disruptors activities and that pollution exposition can have a role in tumorigenic processes. Several environmental pollutants have been shown to affect pituitary cells biology and function. The aryl hydrocarbon receptor (AHR) pathway is involved in xenobiotics' metabolism and in tumorigenesis. A deregulation of the AHR pathway could have a role in pituitary tumours' pathophysiology, especially in the GH secreting ones. AHR-interacting protein (AIP) is one of the key partners of AHR and is implicated in pituitary tumours' pathogenesis. Moreover, an increased prevalence of acromegaly has been reported in a highly polluted area of the province of Messina (Sicily, Italy). Nevertheless, at present, few data are available about the potential role of environmental factors in the pathogenesis and clinical expression of GH secreting pituitary tumours. This review is aimed at discussing the evidences on the potential links among environmental pollutants, the AHR pathway and the pathophysiology of GH-secreting pituitary adenomas. [ABSTRACT FROM AUTHOR]

Abstract: Background: More than 50% of brain metastases (BMs) occur in advanced non-small cell lung cancer (NSCLC) patients. Untreated patients with BMs have a poor prognosis with a median survival of 2 months. In most cases BMs are multiple and their optimal therapy is whole-brain radiation therapy (WBRT). The role of systemic therapies for these patients is still a matter for investigation due to concerns about the ability of these drugs to cross the blood–brain barrier (BBB). Cisplatin (CDDP) remains the backbone for medical treatment of NSCLC and fotemustine (FTM) is a nitrosurea able to cross the BBB. Methods: Patients with advanced NSCLC, ECOG performance status (PS) 0–1 and multiple BMs not amenable to surgery or stereotactic radiotherapy were treated with 2 cycles of FTM 80mg/m2 days 1, 8 and CDDP 80mg/m2 day 1, every 3 weeks followed by WBRT 30Gy (3Gy daily in 10 fractions). Radiological restaging was performed before WBRT to assess the role of chemotherapy both for cranial and extracranial disease. Patients with disease control (DC: complete response plus partial response) received 4 more cycles. To assess the basic activities of daily living (ADL), the Barthel ADL Index was used to score patients’ performance every 2 cycles. The trial design provides a two-step evaluation according to the optimal two-stage design of Simon. In the first phase 29 patients were enrolled in order to verify if this schedule showed more than 25% response rate both for cranial and extracranial disease. If so, enrolment added up to a total of 81 patients. Results: After the first evaluation 4 out of 29 patients were excluded from the study (3 untreated/1 not included for administrative reasons). At the time of the planned interim analysis patient''s characteristics were the following: median age 61 years (range 44–70), M/F=16/9, adenocarcinoma 11, squamous 5, large cell 2, undefined NSCLC 7; PS 0/1 in 11/14 cases, median Barthel Index score was 20 . Three (12%) partial responses were observed, 9 subjects (36%) with stable disease and 13 (52%) showing disease progression. These data did not satisfy the pre-planned hypothesis and the study was stopped. At the time of the first evaluation before WBRT 12/25 (48%) patients had a systemic DC in contrast with 15/25 (60%) patients with BMs DC. Chemotherapy was relatively well tolerated with a prevalence of asthenia as the most relevant specific toxicity while the haematological toxicity was mild. Conclusion: CDDP and FTM combined with WBRT do not represent a therapeutic option for patients with NSCLC. Therefore further studies to evaluate the combination of systemic treatments with WBRT are warranted. [Copyright &y& Elsevier]