Tas-102 for Refractory Metastatic Colorectal Cancer: A Multicenter Retrospective Cohort Study.

Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6-9), while the median progression-free survival (PFS) was 3 months (95% CI, 3-4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups' population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.

Tolerability of Eribulin and correlation between polymorphisms and neuropathy in an unselected population of female patients with metastatic breast cancer: results of the multicenter, single arm, phase IV PAINTER study.

BACKGROUND: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses on prolonging patients' (pts) overall survival (OS) and improving their quality of life. Eribulin is a microtubule inhibitor that increases OS in pre-treated MBC pts. The most common adverse events (AEs) are asthenia, neutropenia and peripheral neuropathy (PN). METHODS: PAINTER is a single arm, phase IV study, aimed at evaluating the tolerability of eribulin in MBC pts. Secondary objectives were the description of treatment efficacy and safety, the assessment of the incidence and severity of PN and its association with genetic polymorphisms. Genomic DNA was isolated from blood samples and 15 Single Nucleotide Polymorphisms (SNPs) were genotyped by Taqman specific assays. The association between PN and SNPs were evaluated by Fisher exact test. RESULTS: Starting from May 2014 until June 2018 180 pts were enrolled in this study by 20 Italian centers. 170 of these pts could be evaluated for efficacy and toxicity and 159 for polymorphisms analysis. The median age of pts was 60 years old and the biological subtypes were luminal type (64.7%), Her2 positive (18.3%) and triple negative (17%). Pts were pretreated with a median of 5 lines for MBC. The median follow up of this study was 15.4 months with a median number of 4.5 cycles administered (minimum-maximum 1-23). The median overall survival was 12 months. 48.8% of pts experienced a dose reduction, mainly for neutropenia (23.9%) and liver toxicity (12%). 65 pts (38.2%) reported at least one severe toxicity. Neutropenia and neurotoxicity were the most frequent severe AEs (15.3% and 14.7%, respectively); other reported toxicities were osteo-muscular, abdominal or tumor site pain (19.4%), liver toxicity (6.6%), pulmonary toxicity (6.5%) and dermatological toxicity (3.6%). Among the 15 evaluated SNPs, an association with PN was found for rs2233335 and rs7214723. CONCLUSIONS: Eribulin is a well-tolerated treatment option in MBC. Schedule and dosage modifications were common, but toxicity rarely led to treatment discontinuation. SNPs rs2233335 (G/T and T/T) in the NDRG1 gene and rs7214723 (CC and CT) in the CAMKK1 gene were associated with PN. These findings, if validated, could allow a tailored treatment with eribulin in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02864030.

Exploring clinical and gene expression markers of benefit from FOLFOXIRI/bevacizumab in patients with BRAF-mutated metastatic colorectal cancer: Subgroup analyses of the TRIBE2 study.

BACKGROUND: Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF-mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study. PATIENTS AND METHODS: Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy. RESULTS: Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001). CONCLUSIONS: Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment.

Gas Damping in Capacitive MEMS Transducers in the Free Molecular Flow Regime.

We present a novel analysis of gas damping in capacitive MEMS transducers that is based on a simple analytical model, assisted by Monte-Carlo simulations performed in Molflow+ to obtain an estimate for the geometry dependent gas diffusion time. This combination provides results with minimal computational expense and through freely available software, as well as insight into how the gas damping depends on the transducer geometry in the molecular flow regime. The results can be used to predict damping for arbitrary gas mixtures. The analysis was verified by experimental results for both air and helium atmospheres and matches these data to within 15% over a wide range of pressures.

Oral maintenance metronomic vinorelbine versus best supportive care in advanced non-small-cell lung cancer after platinum-based chemotherapy: The MA.NI.LA. multicenter, randomized, controlled, phase II trial.

BACKGROUND: Oral vinorelbine administered at the maximum tolerated dose has already showed activity and a good safety profile in advanced non-small-cell lung cancer (NSCLC). The MA.NI.LA study was a phase II, multicenter, randomized, controlled trial that aimed to assess the effects of a 'switched maintenance' regimen with oral metronomic vinorelbine (OMV) in patients with NSCLC who had not progressed after first-line platinum-based chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to either OMV (50 mg three-times weekly) as maintenance treatment or best supportive care (BSC). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective disease control rate (DCR, CR + PR + SD), safety and quality of life. RESULTS: In total, 61 and 59 patients were assigned to OMV and BSC, respectively. At a median follow-up of 23.9 (IQR 10.2-38.2) months, patients treated with OMV reported a significantly lower progression rate compared to patient in the BSC arm (89% [54/61] vs 96% [56/58]; HR 0.73; 90% CI 0.53-0.999, p = 0.049). Median PFS for patients treated with vinorelbine was 4.3 months (95% CI 2.8-5.6) vs 2.8 months (95% CI 1.9-4.5) for patients receiving BSC. This benefit was specifically evident in patients aged ≥70 years, in current smokers, and in those who reported disease stabilization as best response to induction chemotherapy. OS and response rate and quality of life were similar in the two arms. Drop-out rate for major toxicity with OMV was unexpectedly high (25%, 14/61) mainly due to grade 3-4 neutropenia (11%, 7/61). Conclusions In patients with unselected NSCLC achieving disease control after platinum-based chemotherapy switch maintenance therapy with OMV prolonged PFS compared to BSC; however, the optimal dose of OMV requires further investigation.

Assessment of Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers: the ARMANI phase III trial.

BACKGROUND: Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4-6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment. METHODS: This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression. TRIAL REGISTRATION: ARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016-001783-12, April 202,016).

CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.

Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non-small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non-small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.

Ramucirumab as Second-Line Therapy in Metastatic Gastric Cancer: Real-World Data from the RAMoss Study.

BACKGROUND: Ramucirumab-alone or combined with paclitaxel-represents one of the main options for patients failing first-line treatment for advanced gastric cancer. OBJECTIVE: The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the "real-life setting". PATIENTS AND METHODS: Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m2 i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1-17 months). Global incidence of grade (G) 3-4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1-2 fatigue (27.5%), G1-2 neuropathy (26.3%), and G1-2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1-4.7), whereas median OS was 8.0 months (95% CI: 7.09-8.9). In a multivariate analysis, ECOG performance status <1 or ≥1 (HR 1.13, 95% CI 1.0-1.27, p = 0.04) and the presence versus absence of peritoneal metastases (HR 1.57, 95% CI 1.63-2.39, p = 0.03) were independent poor prognostic factors. CONCLUSIONS: These "real-life" efficacy data on ramucirumab treatment are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice.

EAGLES study: First-line Bevacizumab in Combination with Chemotherapy in Elderly Patients with Advanced, Metastatic, Non-squamous Non-small Cell Lung Cancer.

BACKGROUND/AIM: The management of elderly patients with advanced non-squamous NSCLC includes several strategies. PATIENTS AND METHODS: Patients (≥70 years) were randomly assigned to bevacizumab (7.5 mg/kg i.v. on day 1) plus gemcitabine (1,200 mg/m2 i.v. on days 1-8) (arm A) or bevacizumab (7.5 mg/kg i.v.) and cisplatin (60 mg/m2 i.v.) plus gemcitabine (1,000 mg/m2 i.v. on days 1-8) (arm B), to independently evaluate treatments. The primary endpoint was progression-free rate at 6 months; secondary endpoints included progression-free survival (PFS) and safety profiles. RESULTS: At 6 months, 5 (11.6%) patients in arm A and 5 patients (12.5%) in arm B were found to be progression-free. Median PFS was 4.8 months in arm A and 6.5 months in arm B, respectively. CONCLUSION: In our experience, combination of bevacizumab and chemotherapy had encouraging anti-tumor efficacy as first-line therapy in elderly patients with non-squamous NSCLC.

Characterization of the room temperature payload prototype for the cryogenic interferometric gravitational wave detector KAGRA.

KAGRA is a cryogenic interferometric gravitational wave detector currently under construction in the Kamioka mine in Japan. Besides the cryogenic test masses, KAGRA will also rely on room temperature optics which will hang at the bottom of vibration isolation chains. The payload of each chain comprises an optic, a system to align it, and an active feedback system to damp the resonant motion of the suspension itself. This article describes the performance of a payload prototype that was assembled and tested in vacuum at the TAMA300 site at the NAOJ in Mitaka, Tokyo. We describe the mechanical components of the payload prototype and their functionality. A description of the active components of the feedback system and their capabilities is also given. The performance of the active system is illustrated by measuring the quality factors of some of the resonances of the suspension. Finally, the alignment capabilities offered by the payload are reported.

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR).

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3'UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient's baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15-0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52-1.01, p = 0.056) in terms of PFS.

Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study.

AIM: To confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer (CRC) in Italy. METHODS: This multicentric, prospective, open-label study included patients with CRC previously untreated with chemotherapy. Patients were administered bevacizumab in combination with XELOX. The primary efficacy end-point was progression-free survival (PFS). Secondary end-points included time to overall response (TOR), duration of response (DOR), time to treatment failure (TTF) and overall survival (OS). The incidence and type of adverse events AEs and severe AEs were evaluated. Also, the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing, and quality of life (QoL) was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit. RESULTS: The intention-to-treat population included 197 patients (mean age: 62.3 ± 9.9 years, 56.4% males). At baseline, 16/34 evaluable subjects (47.1%) harbored a KRAS and/or a BRAF mutation; the mean QoL index was 80.2 ± 14.3. First-line therapy was given for 223.7 ± 175.9 d, and after a mean follow-up of 387.7 ± 238.8 d all patients discontinued from the study mainly for disease progression (PD, 45.4%) and AEs (25.4%). Median PFS was 9.7 mo (95%CI: 8.4-10.5) and the median values for secondary end-points were: TOR = 3.9 mo (95%CI: 2.6-4.7), DOR = 8.5 mo (95%CI: 7.3-10.3), TTF = 6.7 mo (95%CI: 6.0-7.7) and OS = 23.2 mo (95%CI: 20.1-27.2). Patients carrying at least one lesion had a lower overall response rate (66.7% vs 88.9%) and a lower probability of achieving complete or partial response than those without mutations, but the difference in relative risk was not statistically significant (P = 0.2). Mean EQ-5D-3L raw index score significantly decreased to 74.9 ± 19.1 at the last visit (signed-rank test, P = 0.0076), but in general the evaluation on QoL perceived by patients was good. CONCLUSION: The efficacy of bevacizumab in combination with XELOX in terms of PFS in patients with aCRC or mCRC in Italy was confirmed, with acceptable toxicity.

Capecitabine, oxaliplatin and irinotecan in combination, with bevacizumab (COI-B regimen) as first-line treatment of patients with advanced colorectal cancer. An Italian Trials of Medical Oncology phase II study.

BACKGROUND: A dose-finding phase I/II trial that evaluated the maximum tolerated doses of a combination of three drugs with irinotecan, oxaliplatin and capecitabine (COI regimen) has been conducted in patients with metastatic colorectal cancer (mCRC). In this study the safety and activity of the combination of COI regimen plus bevacizumab (COI-B) were assessed. METHODS: Patients judged to be unresectable for metastatic disease, were enrolled in a phase II, open-label study and treated with the combination of bevacizumab (5mg/kg on day 1) and COI regimen (irinotecan 180mg/mq on day 1, oxaliplatin 85mg/mq on day 2, capecitabine 2000mg d2-6; q14) as first-line treatment. Induction treatment was administered for a maximum of 8 cycles, followed by maintenance treatment with bevacizumab (7.5mg/kg on d1, q21) until progression. RESULTS: Fifty-one patients were enrolled in six Italian centres. The primary end-point of overall response rate was met, reaching the value of 62% in the per-protocol population and 57% in the intent-to-treat population, patients with stable disease were also taken into account, the clinical benefit rate was 94%. In the intention-to-treat population, median progression-free and overall survivals were 10.3 and 22 months, respectively. Toxicity was different from 5-fluorouracil-based triplet regimens, with 31% of severe diarrhoea, but a low incidence of grade 3/4 neutropenia (6%) and mucositis (4%). CONCLUSIONS: Our results show the feasibility and promising activity of the combination of capecitabine, oxaliplatin, irinotecan and bevacizumab.

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.

Natural history of malignant bone disease in gastric cancer: final results of a multicenter bone metastasis survey.

BACKGROUND: Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature, few data on the natural history of bone disease in GC are available. PATIENTS AND METHODS: Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. RESULTS: Median time to bone metastasis was 8 months (CI 95%, 6.125-9.875 months) considering all included patients. Median number of SREs/patient was one. Less than half of the patients (31%) experienced at least one and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid before the first SRE, the median time to appearance of first SRE was significantly prolonged compared to control (7 months vs 4 months for control; P: 0.0005). CONCLUSIONS: To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Indeed, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis. Taken together, these data may support the beneficial effects of ZOL in GC patients.

Chemotherapy-induced anemia and oncologist perception on treatment: results of a web-based survey.

AIMS AND BACKGROUND: Anemia prevalence and incidence in chemotherapy-treated patients is high. Erythropoiesis-stimulating agents (ESAs) are frequently employed in the management of chemotherapy-induced anemia. However, other treatments such as red blood transfusion or iron supplementation are normally used. Recent international guidelines raised some concern about ESAs employment with a possible impact in chemotherapy-induced anemia management and changes in clinical practice behavior. METHODS: To evaluate opinions about chemotherapy-induced anemia clinical management preference, the Associazione Italiana Oncologia Medica (AIOM) Lombardy section coordinators sent via email a 12-item questionnaire about their knowledge on CIA and usual therapeutic strategies to manage this adverse event to AIOM Lombardy onco-hematologist members. RESULTS: From January 2011 to March 2011, 81 questionnaires were collected with an approximated share of 30%. The survey was completed mainly by oncologists (91%) aged 35-50 years (50%). Chemotherapy-induced anemia was considered to have clinical impact in changing cancer therapeutic strategy by nearly 60% of the respondents. ESAs were administered largely (80%) with concomitant iron supplementation in 52%; 38% jointly used blood transfusion as part of the therapy. Nearly 20% of those who replied correctly employed transferrin saturation levels as a marker to guide iron supplementation. Physician prescribers strictly followed the guidelines to start and stop ESAs even if 14% were negatively influenced by new ASCO recommendations. ESA biosimilars were considered future substitutes of originators in 45% of the cases. CONCLUSIONS: Chemotherapy-induced anemia was perceived as an adverse event with a mild impact on clinical practice. ESAs were largely employed, however the number of transfusions and lack of employment of markers of iron depletion suggested that adherence to guidelines could be theoretically met but with some discordances regarding the most appropriate strategies in daily clinical practice.

Rationale for treatment and study design of tailor: a randomized phase III trial of second-line erlotinib versus docetaxel in the treatment of patients affected by advanced non-small-cell lung cancer with the absence of epidermal growth factor receptor mutations.

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.

Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial.

PURPOSE: A phase III trial assessed the efficacy of palonosetron plus dexamethasone given once in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following a broad range of moderately emetogenic chemotherapy (MEC) regimens. METHODS: This multicentre, randomized, open-label, non-inferiority trial evaluated two different treatment groups. One group received palonosetron (0.25 mg intravenously) and dexamethasone (8 mg intravenously) before chemotherapy, while the other was administered the same regimen on day 1 followed by dexamethasone 8 mg orally on days 2 and 3. The primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medication) during the overall phase (days 1-5 after chemotherapy initiation). The non-inferiority margin was predefined as a 15% difference between groups in the primary endpoint. RESULTS: Of 332 chemotherapy-naïve patients included in the intention-to-treat analysis, 65.1% were female, and 35.2% received anthracycline plus cyclophosphamide (AC)-based regimens. Overall CR rates were 67.5% for those administered dexamethasone only on day 1 (n = 166), and 71.1% for those also administered dexamethasone on days 2 and 3 (n = 166; difference -3.6% (95% confidence interval, -13.5 to 6.3)). CR rates were not significantly different between groups during the acute (0-24 h post-chemotherapy; 88.6% versus 84.3%; P = 0.262) and delayed phases (days 2-5; 68.7% versus 77.7%; P = 0.116). CONCLUSIONS: Palonosetron plus single-dose dexamethasone administered before common MEC regimens provide protection against acute and delayed CINV which is non-inferior to that of palonosetron plus dexamethasone for 3 days. However, the major benefit of the single-day regimen occurs in patients receiving non-AC MEC regimens.