Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel.

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.

Management of patients with extensive small-cell lung cancer in the immunotherapy era: An Italian consensus through a Delphi approach.

BACKGROUND: Immunotherapy represented a turning point for treating extensive small-cell lung cancer (ES-SCLC). Although, many issues remain debated. METHODS: A group of Italian medical and radiation oncologists with expertise in managing patients with ES-SCLC developed a list of statements divided in six areas of interest. The Delphi method was used to assess the consensus on the defined list of statements. RESULTS: 32 statements were included in the final list to be voted by the Delphi panel, and 26 reached a consensus on the agreement. A prompt involvement of a multidisciplinary team is a priority to provide an integrated treatment strategy. First-line recommended treatment is immunotherapy in combination with platinum-based chemotherapy and etoposide for four cycles followed by maintenance immunotherapy. CONCLUSIONS: While awaiting new data from clinical trials and real-world studies, these recommendations can represent a useful tool to guide the management of ES-SCLC patients in daily practice.

Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study.

BACKGROUND: Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a "real-life" Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study. PATIENTS AND METHODS: Data of advanced NSCLC patients with uncommon EGFR mutations who received first-line first-generation EGFR-TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of EGFR-TKIs in NSCLC patients harboring uncommon EGFR mutations. RESULTS: Thirty-five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR-mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR-anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19. CONCLUSION: Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy.

BE-POSITIVE: Beyond progression after tyrosine kinase inhibitor in EGFR- positive non small cell lung cancer patients: Results from a multicenter Italian observational study.

OBJECTIVES: Non-small-cell-lung-cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations develop drug resistance after 9-12 months of EGFR tyrosine kinase inhibitors (TKIs) therapy pointing out the issue of the second-line treatment choice. MATERIALS AND METHODS: From June 2009 until May 2013 patients affected by advanced NSCLC harbouring EGFR mutations receiving first-line TKI were collected mainly retrospectively in 24 Italian Centers. Primary objective was to describe the percentage of EGFR mutated patients receiving second-line therapy after progression to first-line EGFR-TKIs assessing the type, the activity in terms of objective response rate (ORR), efficacy in terms of progression free survival (PFS) and overall survival (OS), and safety of second-line treatment. Secondary objective was to describe the efficacy of first-line EGFR-TKIs. RESULTS: 312 patients were included. Most of them were females (203, 65.1%), never smokers (200, 64.1%), with adenocarcinoma histology (290, 92.9%). The most common mutations were EGFR exon 19 deletion and L858R, detected in 186 and 97 cases (59.6% and 31.1%), respectively. At data cut-off, 274 patients (95.1%) received any second-line treatment (including best supportive care or local treatments only). A total of 163 patients received second-line systemic therapy with an ORR of 20.9% (95% CI:14.62-27.10), a median PFS and OS of 4.7 (95% CI:3.81-5.26) and 24.5 (95% CI:21.65-27.37) months, respectively. Grade 3-4 hematological and non-hematological toxicities were reported in 9% and 6.3% of 144 patients treated with chemotherapy while non-hematological toxicity was reported in 4 cases of the 17 patients receiving second-line target agents. CONCLUSIONS: BE-Positive is the first multicenter observational study reporting outcomes of therapies in a "real-life Caucasian EGFR-mutated population", highlighting the need of further researches about new treatment strategies in this setting.

Italian multicenter survey to evaluate the opinion of patients and their reference clinicians on the "tolerance" to targeted therapies already available for non-small cell lung cancer treatment in daily clinical practice.

INTRODUCTION: The introduction of targeted therapies in non-small cell lung cancer (NSCLC) treatment has led to emerging toxicities, whose management and impact on quality-of-life (QoL) is not clearly defined. Aim of this Italian multicenter survey was to highlight any discrepancy between patients' and clinicians' perception of such toxicities in order to improve their management. METHODS: From October 2013 to April 2014, 133 NSCLC advanced patients, treated with targeted therapies, were consecutively enrolled to assess toxicities and QoL with dedicated questionnaires. One hundred and sixteen patients were included in the final analysis, having attended three consecutive evaluations (T0, T1, T2), starting at least 15 days after the biological treatment. The survey required monthly compilation of both physicians and patients' questionnaires, basing adverse event evaluation on CTCAE version 4.0. RESULTS: Most of the patients received either an EGFR-TKI or an anaplastic lymphoma kinase (ALK) inhibitor as targeted therapy (84.5% and 13.8%, respectively). At every checkpoint (T0, T1, T2) a significant difference in terms of perception of targeted therapies-related toxicities of any type and grade was described (P value =0.0001 in all cases). This difference was more pronounced for skin toxicity, fatigue and diarrhea. Furthermore, also the assessment of QoL revealed contrasting data between patients and clinicians, mainly QoL reported as good by the majority of patients and daily activities considered as slightly influenced by targeted therapies. CONCLUSIONS: In our knowledge, this is the first prospective survey in patients and doctors specifically designed for targeted therapies in advanced NSCLC. The results show an underestimation of toxicities by clinicians when compared with patients, the difference being greater for adverse events more strongly associated with daily life and QoL. Further studies are needed to confirm our first results. The discrepancy in perception of targeted therapies-related toxicities should be a result from which to start thinking about a new approach in their management.

Granulocyte colony-stimulating factors used in clinical practice: PoloNord Registry-Based Cohort Italian Study.

AIMS AND BACKGROUND: Granulocyte colony-stimulating factors are widely used to reduce myelotoxicity of chemotherapy and to allow its regular administration. National and international guidelines regulate their use. The aim of the study was to evaluate the use of pegfilgrastim and filgrastim/lenograstim in clinical practice, adherence to ASCO and ESMO guidelines, chemotherapy-related complications and adverse reactions. MATERIALS AND METHODS: Data from 645 consecutive patients and 3,150 chemotherapy administrations, receiving granulocyte colony-stimulating factors, as primary/secondary prophylaxis or therapeutic use, for the first time during a line of chemotherapy, were recorded from 08/2008 to 08/2011, in 10 Lombardy Italian cancer centers. Patients and chemotherapy administrations data were examined in a multiple logistic regression analysis model. RESULTS: Adherence to guidelines: primary prophylaxis, pegfilgrastim and filgrastim/ lenograstim 66%/47% (P = 0.002); secondary prophylaxis, 19.0%/26.8%; but 56.8%/ 53.6% including patients at high risk of febrile neutropenia with grade 3-4 neutropenia. Correct timing start (administration 24-72 h after chemotherapy): pegfilgrastim and filgrastim/lenograstim, 93.2%/61.5% (P <0.0001). CONCLUSIONS: Results suggest the more correct administration of pegfilgrastim as primary prophylaxis and timing start, compared to filgrastim/lenograstim. In secondary prophylaxis, the use of granulocyte colony-stimulating factors is extended beyond guideline recommendations to support patients at high risk of febrile neutropenia and to guarantee dose intensity. These outcomes suggest both the need of educational activities and the development of predictive tools to better define high risk patients and the use of granulocyte colony-stimulating factors.