Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program.

BACKGROUND: The treatment of metastatic non-small-cell lung cancer (mNSCLC) patients with EGFR/HER2 exon 20 insertion mutation (i-mut) remains an unmet clinical need. Poziotinib, a new generation tyrosine kinase inhibitor, is currently under investigation as a potential targeted therapy. This compassionate study of its use aims to describe the activity/toxicity of poziotinib in mNSCLC with EGFR/HER2-exon-20-i-mut. PATIENTS AND METHODS: NSCLC patients who were treated either with EGFR or HER2 exon 20-i-mut within an expanded access program were included in this study. Poziotinib (16 mg or less) was administrated orally quaque die (QD). The primary end-point was the overall response rate (ORR) assessed by central review using RECIST v1.1, and secondary end-points were median progression free survival (PFS), disease control rate (DCR), median overall survival (OS) and toxicity. RESULTS: The median age of all the 30 patients was 58 years (25-80 years), most of them were females (73%); ECOG 0-1 (83%), EGFR i-mut (73%) and pre-treated (83%). 73% started with poziotinib at a dose of 16 mg. At data cut-off, 22 of 33 patients (73%) experienced a progress in the disease and 12 of 30 (40%) died. Median PFS was 5.6 months (95% CI: 3.6-6.7 months) and the mOS 9.5 months (95% CI: 5.3 - not-reached months). The ORR was 30% (EGFR/HER2: 23/50%) and DCR 80%. G3 AEs were reported in 66% of the patients and were found with skin rash (50%), diarrhoea (17.6%), mucositis (7%) and paronychia (3%). G5, possibly associated with pneumonitis might also have occurred. CONCLUSIONS: Poziotinib exhibited effects in mNSCLC patients with EGFR/HER2-exon 20-i-mut. The toxicity rate was high leading to frequent dose interruption and reduction, thereby reducing mPFS in patients with good ORR/DCR. ZENITH20 trial is now being used to evaluate the low dose and new scheduled dose (e.g. bis in die (BID)).

Uncommon targets in non-small cell lung cancer: Everyone wants a slice of cake.

Target therapies completely changed the clinical approach in EGFR mutated and ALK rearranged non-small cell lung cancer, ensuring these patients exceptional outcomes with a better toxicity profile compared to conventional chemotherapy. In recent years, beyond EGFR and ALK alterations, new data are emerging about less common alterations, new drugs have been already approved and others agents have been recently investigated or are currently under investigation. In this review we will discuss some uncommon alterations in non-small cell lung cancer such as ROS1, BRAF, RET, HER2, NTRK, MET and other targets that are in an early evaluation phase. We will summarize the characteristics of patients harboring these alterations, the already approved or under investigation therapies and the related resistance mechanisms.

DiM: Prognostic Score for Second- or Further-line Immunotherapy in Advanced Non-Small-Cell Lung Cancer: An External Validation.

BACKGROUND: Other than the programmed cell death ligand 1 (PD-L1) value, oncologists have only the clinical characteristics of patients with advanced non-small-cell lung cancer (aNSCLC) to determine candidates for immunotherapy. A clinical prognostic score composed of the Eastern Cooperative Oncology Group performance status, sex, histologic type, stage, platinum-based first-line therapy, and response to first-line therapy has categorized 3 prognostic groups for patients undergoing second-line chemotherapy. We sought to validate the same score for patients with aNSCLC treated with second- or further-line immunotherapy. MATERIALS AND METHODS: We collected data from 2 Italian centers. A score was generated to divide patients into 3 prognostic groups: best, score < 5; intermediate, score 5 to 9; and worst, score > 9. Overall survival (OS) and progression-free survival (PFS) were the endpoints. RESULTS: A total of 347 patients were included for analysis. Their median age was 66 years (range, 30-88 years), most were aged < 70 years (67.5%), 70.7% were men, 79.5% were smokers, and 74.6% had had adenocarcinoma. The Eastern Cooperative Oncology Group performance status was 0 for 23%, 1 for 54.5%, and 2 for 22.5%. Of the 347 patients, 28% were in the best prognosis, 51% in the intermediate, and 21% in the worst prognosis group, respectively. The median OS was 18.0 months for the best, 8.5 months for the intermediate (hazard ratio [HR] vs. best, 1.83; 95% confidence interval [CI], 1.35-2.47; P < .001) and 2.6 months for worst (HR vs. best, 5.77; 95% CI, 3.99-8.33; P < .001) group. The median PFS was 3.4 months for the best, 3.7 months for the intermediate (HR vs. best, 1.35; 95% CI, 1.03-1.77; P = .032), and 1.9 months for the worst (HR vs. best, 2.51; 95% CI, 1.80-3.50; P < .001) group. CONCLUSIONS: The prognostic score was able to predict the outcomes of patients with aNSCLC who had received immunotherapy. The worst category showed a dismal life expectancy and probably would not benefit from active systemic therapy. Thus, for these patients, best supportive care could be the best choice.

EPSILoN: A Prognostic Score for Immunotherapy in Advanced Non-Small-Cell Lung Cancer: A Validation Cohort.

BACKGROUND: Beyond programmed death ligand 1 (PD-L1), no other biomarkers for immunotherapy are used in daily practice. We previously created EPSILoN (Eastern Cooperative Oncology Group performance status (ECOG PS), smoking, liver metastases, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR)) score, a clinical/biochemical prognostic score, in 154 patients treated with second/further-line immunotherapy. This study's aim was to validate EPSILoN score in a different population group. METHODS: 193 patients were included at National Cancer Institute of Milan (second-line immunotherapy, 61%; further-line immunotherapy, 39%). Clinical/laboratory parameters such as neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels were collected. Kaplan-Meier and Cox hazard methods were used for survival analysis. RESULTS: Overall median progression-free survival and median overall survival were 2.3 and 7.6 months, respectively. Multivariate analyses for Progression-Free Survival (PFS) identified heavy smokers (hazard ratio (HR) 0.71, p = 0.036) and baseline LDH < 400 mg/dL (HR 0.66, p = 0.026) as independent positive factors and liver metastases (HR 1.48, p = 0.04) and NLR ≥ 4 (HR 1.49, p = 0.029) as negative prognostic factors. These five factors were included in the EPSILoN score which was able to stratify patients in three different prognostic groups, high, intermediate and low, with PFS of 6.0, 3.8 and 1.9 months, respectively (HR 1.94, p < 0.001); high, intermediate and low prognostic groups had overall survival (OS) of 24.5, 8.9 and 3.4 months, respectively (HR 2.40, p < 0.001). CONCLUSIONS: EPSILoN, combining five baseline clinical/blood parameters (ECOG PS, smoking, liver metastases, LDH, NLR), may help to identify advanced non-small-cell lung cancer (aNSCLC) patients who most likely benefit from immune checkpoint inhibitors (ICIs).

Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer.

OBJECTIVES: Most trials with Immune Checkpoint Inhibitors (ICIs) for Non-Small Cell Lung Cancer (NSCLC) included only small subgroups of patients aged ≥65. As NSCLC is often diagnosed in patients aged ≥70, real-world data about efficacy and safety of immunotherapy (IO) in elderly patients are essential. MATERIALS AND METHODS: We retrospectively collected data about all patients with advanced NSCLC treated with IO at our Institution between April 2013 and March 2019. The patients were stratified for age as follows: <70 year-old, 70-79 year-old, ≥80 year-old. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox model. RESULTS: We reviewed 290 cases, with a median age of 67 (range: 29-89). Patients aged<70, 70-79 and ≥80 year-old were 180, 94 and 16, respectively. Clinical/pathological variables were uniformly distributed across age classes, except for a higher rate of males (p 0.0228) and squamous histology (p 0.0071) in the intermediate class. Response Rate (RR) was similar across age groups (p 0.9470). Median Progression Free Survival (PFS) and Overall Survival (OS) did not differ according to age (p 0.2020 and 0.9144, respectively). Toxicity was comparable across subgroups (p 0.6493). The only variables influencing outcome were performance status (PS) (p < 0.0001 for PFS, p 0.0192 for OS), number of metastatic sites (p 0.0842 for PFS, p 0.0235 for OS) and IO line (p < 0.0001 for both PFS and OS). CONCLUSION: Advanced age was not associated to a reduced efficacy of IO in our case series. Furthermore, no toxicity concern emerged even among the eldest pts. To our opinion, ICIs should be considered irrespective of age, provided an optimal PS at baseline. Of note, IO is often the only therapeutic option applicable to these cases considering the toxicity of chemotherapy.

Characterization of patients with metastatic non-small-cell lung cancer obtaining long-term benefit from immunotherapy.

Aim: A minority of patients gains advantage from immunotherapy (IO). Predictive variables of long-term benefit (LTB) are incompletely understood. Materials & methods: We retrospectively collected data about metastatic non-small-cell lung cancer patients treated with IO from April 2013 to July 2017. We defined LTB to IO as complete response (CR), partial response (PR) or disease stability as best response and maintaining it for ≥12 months. Results: Thirty-five of the 147 patients had LTB. More LTB patients than controls showed CR/PR as first and best response to IO. Only CR/PR as best response to IO retained association to LTB at multivariate analyses. Conclusion: Objective response appears as a central factor for LTB from IO.

Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: Steroids are frequently used in patients with metastatic non-small cell lung cancer (mNSCLC), but they could be detrimental for patients treated with immune checkpoint inhibitors (ICIs). Here, we assessed the association between early use of steroids, clinical outcomes and peripheral immune blood cells modulation in patients with mNSCLC treated with ICIs. METHODS: We reviewed patients with mNSCLC treated at our institution between April 2013 and December 2017. Early use of steroids was defined as the use of a daily prednisone-equivalent dose ≥10 mg for at least 1 day within 28 days after ICI initiation. Peripheral immune blood cell counts were retrieved at baseline and at 4 and 6 weeks after ICI initiation. RESULTS: Out of 151 patients included, 35 (23%) made early use of steroids that was associated with poor disease control (OR 0.32, p=0.006), progression-free survival (HR 1.80, p=0.003) and overall survival (HR 2.60, p<0.001). Early use of steroids significantly correlated with higher median absolute neutrophil count, neutrophil to lymphocyte ratio (NLR) and derived NLR, and lower median absolute and relative eosinophil count, both at 4 and 6 weeks after ICI initiation. CONCLUSIONS: In patients with mNSCLC treated with ICIs, early use of steroids was associated with worse clinical outcomes and remarkable modulation of peripheral blood immune cells, which could contribute to restraining the activation of antitumour immunity. If confirmed in prospective studies, these findings would highlight the importance of carefully evaluating and, whenever possible, avoiding steroids during early phases of ICI treatment.

Lung Cancer App (LuCApp) study protocol: a randomised controlled trial to evaluate a mobile supportive care app for patients with metastatic lung cancer.

INTRODUCTION: Mobile health technologies may enhance patient empowerment and data integration along the whole care continuum. However, these interventions pose relatively new regulatory, organisational and technological challenges that limit appropriate evaluation. Lung Cancer App (LuCApp) is a mobile application developed by researchers and clinicians to promote real-time monitoring and management of patients' symptoms. This protocol illustrates a clinical trial designed to evaluate the usability, effectiveness and cost-effectiveness of LuCApp versus standard of care. METHODS AND ANALYSIS: This is a 24-week two-arm non-blinded multicentre parallel randomised controlled trial. A total of 120 adult patients diagnosed with small or non-small cell lung cancer and eligible for pharmaceutical treatments will be allocated 1:1 to receiving either standard care or LuCApp in addition to standard care at three oncology sites in Northern Italy. During the treatment period, LuCApp allows daily monitoring and grading of a list of symptoms, which trigger alerts to the physicians in case predefined severity thresholds are met. Patients will complete a baseline assessment and a set of valid and reliable patient-reported outcome measures every 3±1 weeks, and up to 24 weeks. The primary outcome is the change in the score of the Trial Outcome Index in the Functional Assessment of Cancer Therapy (Lung) questionnaire from baseline to 12 weeks. Secondary outcomes are the Lung Cancer Subscale, the EuroQoL 5D-5L questionnaire, the Hospital Anxiety and Depression Scale, the Supportive Care Needs Survey Short Form, the app usability questionnaire and the Zarit Burden Interview for the main caregiver. ETHICS AND DISSEMINATION: The trial received ethical approval from the three clinical sites. Trial results will be disseminated through peer-reviewed publications and conference presentations. CONCLUSIONS: This trial makes a timely contribution to test a mobile application designed to improve the quality of life and delivery of care for patients with lung cancer. TRIAL REGISTRATION NUMBER: NCT03512015; Pre-results.

Low Baseline Serum Sodium Concentration Is Associated with Poor Clinical Outcomes in Metastatic Non-Small Cell Lung Cancer Patients Treated with Immunotherapy.

BACKGROUND: A consistent percentage of patients with metastatic non-small cell lung cancer (NSCLC) derives no or only marginal benefit from immunotherapy (IO). OBJECTIVE: Since serum sodium has been linked to both prognosis in NSCLC and modulation of immune cells activity, we aimed to assess the association between low baseline serum sodium concentration (≤ 135 mEq/L) and clinical outcomes of patients with metastatic NSCLC treated with IO. PATIENTS AND METHODS: We included metastatic NSCLC patients treated with checkpoint inhibitors in our department from April 2013 to April 2018 with available baseline serum sodium concentration. Demographics, clinical and pathological characteristics were collected. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional-hazards model. RESULTS: Of 197 patients included, 26 (13%) presented low baseline serum sodium concentration. Patients in the low sodium cohort experienced a poorer disease control rate (OR 0.36; 95% CI, 0.15-0.86; Wald test P = .02), median overall survival (OS) (2.8 vs. 11.6 months; HR 3.00; 95% CI, 1.80-4.80; P < .001) and progression-free survival (PFS) (1.8 vs. 3.3 months; HR 2.60; 95% CI, 1.70-3.90; P < .001) compared to patients in the control cohort. At multivariate analyses, low baseline serum sodium concentration was independently associated with disease control and OS, but not with PFS. CONCLUSIONS: Our study showed for the first time that low baseline serum sodium concentration is associated with impaired clinical outcomes in patients with metastatic NSCLC treated with IO. The role of serum sodium concentration in this setting warrants further pre-clinical and clinical investigation.

Practical issues for the management of hyponatremia in oncology.

Hyponatremia is common in cancer patients and has a negative impact on outcomes and survival. Both the diagnosis and treatment of hyponatremia are challenging. Easy-to-use, practical guidelines are needed. The aim of this article is to discuss practical issues related to the diagnostic workup and management of hyponatremia, with particular attention to complex patients, such as those affected by neoplastic diseases. Admittedly, these patients may present several comorbidities, which may cause sodium alterations. In addition, multidrug therapy may precipitate serum sodium fall. An algorithm for the diagnosis and treatment of hyponatremia was also developed, based on the discussion of the results of a questionnaire completed by the authors and of the published recommendations/guidelines on hyponatremia. The goal was to produce an algorithm that was as simple as possible but still comprehensive, without compromising information completeness. Many explanatory notes were added with the aim of guiding clinicians throughout the management of complex patients with hyponatremia, such as those with cancer. The resulting algorithm and supporting literature are presented.

Uncommon mutations in epidermal growth factor receptor and response to first and second generation tyrosine kinase inhibitors: A case series and literature review.

Epidermal growth factor receptor (EGFR) is the most common driver gene involved in non small cell lung cancer (NSCLC) growth, being found in approximately 10-15% of Caucasian and 40% of Asian patients. A wide variety of pathogenic mutations, deletions, insertions and duplications have been described in EGFR exons 18-21. The presence of the most common among them (e.g. exon 21 L851R and exon 19 deletions) is associated to response to first and second generation EGFR tyrosine kinase inhibitors (TKIs), which have demonstrated clear superiority over chemotherapy in terms of both progression free survival (PFS) and overall survival (OS) in all treatment lines. However, scarcity of data exists in literature about the response of rarer EGFR alterations to first and second generation TKIs, most works consisting in sporadic case reports and small case series. In this review we aim to discuss the available evidence about this topic, in order to derive suggestions for clinical practice. Furthermore, we report seven cases of patients with lung tumors harboring uncommon EGFR mutations, treated in our Institution with first or second generation TKIs.

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.

Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases.

The discovery of EGFR mutations and EML4-ALK gene rearrangements has radically changed the therapeutic scenario for patients with advanced non-small cell lung cancer. ALK and EGFR tyrosine-kinase inhibitors showed better activity and efficacy than standard chemotherapy in the first and second line treatment settings, leading to a clear advantage in overall survival of advanced non-small cell lung cancer patients harboring these genetic alterations. Historically the coexistence of EGFR mutations and EML4-ALK rearrangements in the same tumor has been described as virtually impossible. Nevertheless many recent observations seem to show that it is not true in all cases. In this review we will discuss the available literature data regarding this rare group of patients in order to give some suggestions useful for their clinical management. Furthermore we report here two cases of concomitant presence of both alterations that will help us in the development of discussion.

Italian, Multicenter, Phase III, Randomized Study of Cisplatin Plus Etoposide With or Without Bevacizumab as First-Line Treatment in Extensive-Disease Small-Cell Lung Cancer: The GOIRC-AIFA FARM6PMFJM Trial.

Purpose Considering promising results in phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Treatment-naive patients with ED-SCLC were randomly assigned to receive either cisplatin plus etoposide (arm A) or the same regimen with bevacizumab (arm B) for a maximum of six courses. In the absence of progression, patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses. The primary end point was overall survival (OS). Results Two hundred four patients were randomly assigned and considered in intent-to-treat analyses (103 patients in arm A and 101 patients in arm B). At a median follow-up of 34.9 months in arm A and arm B, median OS times were 8.9 and 9.8 months, and 1-year survival rates were 25% and 37% (hazard ratio, 0.78; 95% CI, 0.58 to 1.06; P = .113), respectively. A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen (hazard ratio, 0.60; 95% CI, 0.40 to 0.91; P = .011). Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B, respectively ( P = .030). Regarding hematologic toxicity, no statistically significant differences were observed; for nonhematologic toxicity, only hypertension was more frequent in arm B (grade 3 or 4, 1.0% v 6.3% in arms A v B, respectively; P = .057). Conclusion The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival, which, however, did not translate into a statistically significant increase in OS. Further research with novel antiangiogenic agents, particularly in the maintenance setting, is warranted.

Small-Cell Lung Cancer: Clinical Management and Unmet Needs New Perspectives for an Old Problem.

Small cell lung cancer is a highly aggressive, difficult to treat neoplasm. Among all lung tumors, small cell lung cancers account for about 20%. Patients typically include heavy smokers in 70s age group, presenting with symptoms such as intrathoracic tumors growth, distant spread or paraneoplastic syndromes at the time of diagnosis. A useful and functional classification divides small cell lung cancers into limited disease and extensive disease. Concurrent chemo-radiotherapy is the standard treatment for limited disease, with improved survival when combined with prophylactic cranial irradiation. Platinum compounds (cisplatin/carboplatin) plus etoposide remain the cornerstone for extensive disease. Nevertheless, despite high chemo- and radio-sensitivity of this cancer, nearly all patients relapse within the first two years and the prognosis is extremely poor. A deeper understanding about small cell lung cancer carcinogenesis led to develop and test a considerable number of new and targeted agents but the results are currently weak or insufficient. To date, small cell lung cancer is still a challenge for researchers. In this review, key aspects of small cell lung cancer management and controversial points of standard and new treatments will be discussed.

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.

Treatment of lung large cell neuroendocrine carcinoma.

Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy?

Malignant pleural mesothelioma is a rare cancer with a cause-effect relationship to asbestos exposure. The prognosis is poor and chemotherapy seems the best treatment option. In the last two decades a deeper understanding of mesothelioma carcinogenesis and invasiveness mechanisms has prompted research efforts to test new agents in patients with malignant pleural mesothelioma, but the results have been modest. Attractive preclinical data disappointed in subsequent experimental phases. Other promising agents failed to improve patient outcomes due to high toxicity. Interesting suggestions have come from preliminary data on immunotherapy. Several trials are ongoing and the results are eagerly awaited. The aim of this review is to discuss the most recent news on systemic therapy for advanced malignant pleural mesothelioma.

Nausea and vomiting during the first 3 intercycle periods in chemo-naive cancer patients receiving moderately/highly emetogenic therapy.

AIMS AND BACKGROUND: There is a paucity of data regarding the incidence, intensity, and treatment of nausea and vomiting during the intercycle periods of chemotherapy (CHT). The aims of the study were to assess the incidence and intensity of intercycle nausea and vomiting, to assess the use of rescue antiemetic medications, and to define the more uncomfortable symptom between nausea and vomiting. METHODS: In a prospective study, 108 chemotherapy-naive patients treated with highly or moderately emetogenic CHT for different primary cancers were enrolled. All patients filled out the Edmonton Symptom Assessment System tool before the first cycle of CHT (T0) and on 14-16 days thereafter for the first 3 cycles of CHT (i.e., T1, T2, T3). RESULTS: Sixty-seven patients completed the study. During CHT administration, all patients received antiemetics according to international guidelines. During the intercycle periods, nausea was reported in 6.0% of patients at T0, 10.5% at T1, and 26.9% at T2 and T3, respectively. The intensity of nausea was mild for 6.0%, 21%, and 18% of patients at T1, T2, and T3, respectively; moderate for 1.5%, 3.0%, and 6.0% at T1 to T3; and severe in only 3.0% of patients at any time. Vomiting was present in 1.5% and 10.5% of patients at T2 and T3. Rescue antiemetic medication was required for 41.8% at T1, 53% at T2, and 47.8% at T3. At the end of the study, 70.1% of patients described nausea as the more uncomfortable symptom compared to vomiting. CONCLUSIONS: Nausea has a higher burden of impact over vomiting and should be assessed and treated separately throughout multiple cycles of CHT.

Italian multicenter phase III randomized study of cisplatin-etoposide with or without bevacizumab as first-line treatment in extensive stage small cell lung cancer: treatment rationale and protocol design of the GOIRC-AIFA FARM6PMFJM trial.

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.