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Background: Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer (ABC) non-responsive to hormone therapy and without visceral crisis. This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC., Methods: Eligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80 mg/m 2 (first cycle at 60 mg/m 2 , escalated to 80 mg/m 2 in the absence of grade 3/4 toxicity) or intravenous paclitaxel 80 mg/m 2 on days 1, 8, and 15 every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR; confirmed complete or partial response, or stable disease for ≥6 weeks)., Results: The 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6-85.5%) with vinorelbine and 75.4% (63.1-85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes., Conclusion: Oral vinorelbine and paclitaxel demonstrated similar DCRs (∼75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors arising in the gastrointestinal tract. Second primary tumors (SPTs) have been reported frequently, either synchronously or during follow-up, in patients diagnosed with GISTs., Methods: We carried out an electronic search of PubMed, SCOPUS, Web of Science, EMBASE, and the Cochrane Library seeking articles investigating the incidence of SPTs in patients with concomitant GIST. All studies were evaluated for heterogeneity before meta-analysis and for publication bias. Pooled incidence rate was estimated using fixed- and random-effects models. Subsite of SPTs was also investigated., Results: A total of 32 studies met the inclusion criteria, for a total of 19,627 patients with a diagnosis of GIST. The pooled prevalence of SPTs was 20%, with 14% and 3% being synchronous and metachronous tumors, respectively. We found a risk for several specific cancer sites, in particular gastrointestinal (5%) and genitourinary tract cancers (3%). The most frequently associated malignancies were: colorectal (17%), prostate (14%), gastric (9%), esophageal (5.5%), lung (5.4%), hepato-biliopancreatic (4.7%), breast (4.6%), lymphoma (4.4%), kidney (4.35%), and sarcomas (3.3%). Regression analyses revealed a significant positive association for all SPTs with follow-up and Miettinen risk., Conclusions: Our results indicate that 20% of patients with GIST experienced a SPT, primarily synchronously with a diagnosis of GIST. In particular, we observed an excess of incident gastrointestinal tumors. These findings have important implications for both pathologists, who should perform extensive molecular analysis of surgical non-GIST specimens in resected patients, and for oncologists, who should continue to follow up GIST patients., (Copyright © 2019. Published by Elsevier Ltd.)

Gemcitabine and nab-paclitaxel (GEM-NAB) and the combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) are valid first-line options for advanced or metastatic pancreatic cancer (mPC). However, no randomized trials comparing the two schemes have been performed. This meta-analysis aims to compare GEM-NAB and FOLFIRINOX in terms of safety and effectiveness, taking into account data from real-life studies on mPC. We systematically searched PubMed, EMBASE and Cochrane library up to November 2018 to identify retrospective or cohort studies on mPC comparing GEM-NAB and FOLFIRINOX. We included 16 retrospective studies, including 3813 patients (2123 treated with GEM-NAB and 1690 treated with FOLFIRINOX). Despite a median weighted overall survival (OS) difference in favor of FOLFIRINOX (mean difference: 1.15, 95% confidence interval CI 0.08⁻2.22, p = 0.03), in whole population OS was similar (hazard ratio (HR = 0.99, 95% CI 0.84⁻1.16; p = 0.9). PFS was also not different between the two arms (HR = 0.88, 95% CI 0.71⁻1.1; p = 0.26). The overall response rate was similar (25 vs. 24% with GEM-NAB and FOLFIRINOX). Among grade 3⁻4 toxicities, neutropenia, febrile neutropenia, and nausea were lower with GEM-NAB, while neurotoxicity and anemia were lower with FOLFIRINOX. In conclusion, despite a numerically longer median OS with FOLFIRINOX as compared to GEM-NAB, the overall risk of death and progression were similar. Their toxicity was different with less nausea, neutropenia, and febrile neutropenia with GEM-NAB, as compared to less neurotoxicity and anemia with FOLFIRINOX. Therefore, analysis of non-randomized "real world" studies to date has not provided evidence of a major benefit of one regimen over the other.

Background: Even when resectable pancreatic cancer (PC) is associated with a dismal prognosis. Initial presentation varies according with primary tumor location. Aim of this systematic review and meta-analysis was to evaluate the prognosis associated with site (head versus body/tail) in patients with PC., Methods: We searched PubMed, Cochrane Library, SCOPUS, Web of Science, EMBASE, Google Scholar, LILACS, and CINAHL databases from inception to March 2018. Studies reporting information on the independent prognostic role of site in PC and comparing overall survival (OS) in head versus body/tail tumors were selected. Data were aggregated using hazard ratios (HRs) for OS of head versus body/tail PC according to fixed- or random-effect model., Results: A total of 93 studies including 254,429 patients were identified. Long-term prognosis of head was better than body/tail cancers (HR =0.96, 95% CI: 0.92-0.99; P=0.02). A pooled HR of 0.95 (95% CI: 0.92-0.99, P=0.02) from multivariate analysis only (n=77 publications) showed that head site was an independent prognostic factor for survival., Conclusions: Primary tumor location in the head of the pancreas at the time of diagnosis is a predictor of better survival. Such indicator should be acknowledged when designing future studies, in particular in the operable and neoadjuvant setting., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objective: The preferred neoadjuvant treatment for gastroesophageal junction (GEJ) adenocarcinoma is still matter of debate. We conducted a meta-analysis to assess the different impact of neoadjuvant combined chemotherapy and radiotherapy (CTRT) versus chemotherapy (CT) alone., Methods: A comprehensive search was performed in EMBASE, PubMed, and Cochrane Library databases from inception to 30th June 2018. Studies comparing survival of patients who underwent CTRT or CT alone before surgery for GEJ adenocarcinoma were included. Hazard ratio (HR) for overall survival (OS) was extracted, and a random-effects model was used for pooled analysis. Median OS, 5-year OS, complete pathologic response (pCR), locoregional and distant failure rates were also calculated., Results: 22 studies including 18,260 patients were considered for the final analysis. The pooled results demonstrated that combined CTRT do not significantly reduce the risk of death (HR 0.95, 95% CI 0.84-1.07; P = 0.41) but has a positive impact on the risk of relapse (HR 0.85, 95% CI 0.75-0.97; P = 0.01) compared to CT alone. Addition of RT to CT alone significantly increased the odds of pCR by 2.8 (95% CI 2.27-3.47; P < 0.001) and reduced the risk of locoregional failure (OR 0.6, 95% CI 0.39-0.91; P = 0.01) but not the risk of distant metastases (OR 0.81, 95% CI 0.59-1.11; P = 0.19)., Conclusions: In this systematic review and meta-analysis comparing neoadjuvant CTRT with CT for adenocarcinoma of GEJ, we found no difference in terms of median OS, despite a higher pCR rate and a reduced risk of locoregional recurrences for the combined approach. Further studies, preferably large randomized clinical trials, are needed to confirm these results.

Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.

Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogene and proto-oncogene transcripts involved in cancer code for RTKs. Consequently, these receptors are broadly studied as targets in the treatment of different tumours, and a large variety of small-molecule tyrosine kinase inhibitors (TKIs) are approved for therapy. In most cases, patients develop resistance to the TKIs within a short time. MicroRNAs are short (18-22 nucleotides) non-protein-coding RNAs that fine-tune cell homeostasis by controlling gene expression at the post-transcriptional level. Deregulation of microRNAs is common in many cancers, and increasing evidence exists for an important role of microRNAs in the development of resistance to therapies, including TKIs. In this review we focus on the role of microRNAs in mediating resistance to small-molecule TKIs in solid tumours.

Clinicopathologic and molecular characteristics of non-small-cell lung cancers (NSCLCs) associated with a strong expression of programmed death ligand 1 (PD-L1 + in > 5% of cells) have not been well elucidated. Expression of PD-L1 is a poor prognostic factor, but NSCLCs with higher levels of PD-L1 have greater benefit when treated with immunotherapy. We have performed a systematic review to synthesize the available evidence regarding clinicopathologic and molecular variables associated with PD-L1 expression in NSCLC. PubMed, EMBASE, SCOPUS, Web of Science and Cochrane Library databases were searched for relevant articles assessing predictors of PD-L1 expression in > 5% cells. Data were reported as odds ratio (OR) of events. Fifty-two studies (for a total of 5066 PD-L1 + out of 13,279 NSCLC patients) were included in this meta-analysis. Factors associated with PD-L1 expression were: smoking status (OR 5.48; 95% confidence interval (CI) 2.8-10.4; P < .001), male gender (OR 4.8; 95% CI 3.2-7.2; P < .001), adenocarcinoma histology (OR 2.75; 95% CI, 1.5-4.8; P < .001), Epidermal growth factor receptor (EGFR) wild type (OR 4.83; 95% CI, 2.1-11.1; P < .001), ALK mutation negative (OR 388.6; 95% CI, 222.5-678.7; P < .001), ROS mutation negative (OR 1904.8; 95% CI, 630-5757; P < .001), and KRAS wild type (OR 19.8; 95% CI, 7.6-51.6; P < .001). Conversely higher pT stages (OR 0.16; 95% CI, 0.04-0.7; P = .01), pN+ stages (OR 0.29; 95% CI, 0.17-0.5; P < .001) are inversely associated with PD-L1 expression in > 5% cells. Expression of PD-L1 is more common in male smokers, with adenocarcinoma histology and not carriers of EGFR/ALK/ROS/KRAS mutations. These data could be useful to screening of PD-L1 expression and to select patients for immunotherapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

CDX2 is a homeobox gene encoding transcriptional factors for intestinal organogenesis and represents a specific marker of colorectal adenocarcinoma (CRC) differentiation. We have evaluated if CDX2 expression is associated with better overall and disease-free survival (OS and DFS) in patients with CRC. PubMed, SCOPUS, EMBASE, The Cochrane Library, and Web of Science (from inception to July 2017) were systematically reviewed for relevant studies on adult patients with CRC where OS and DFS were calculated according to CDX2 expression in uni- or multivariate analysis were included. Hazard ratio (HR) for mortality and/or disease progression was calculated. The search produced 16 studies suitable for inclusion (6291 individual patients). The meta-analysis showed a reduced risk of death for patients with CDX2-positive CRC in 14 studies (HR, 0.5; 95% confidence interval [CI], 0.38-0.66; P < .001 according to random effect model). In 6 studies where only DFS data was available, CDX2 expression led to a 52% lower risk of relapse or death (HR, 0.48; 95% CI, 0.39-0.59; P < .001 according to random effect model). The results did not change as a function of ethnicity, type of study, CDX2 detection modality, or stage. Interestingly, in stages II to III, CDX2 expression was associated with a 70% lower risk of death (HR, 0.3; 95% CI, 0.12-0.77; P = .01). CDX2 expression confirms to be a strong prognostic factor in stage II and III CRC. In this setting, along with other clinical and pathologic factors, the lack of expression of CDX2 may be considered an important variable when deciding for adjuvant chemotherapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the Original Publication of the article, In Introduction part, 7th line, the value "5-100nM" has been published incorrectly. The correct value should read as "Plasma concentration of 50-100ng/ml". In the Original Publication of the article, page 591, Table 2 has been published incorrectly. The corrected table is shown in the following page.

Background: Survival for patients with advanced gastroesophageal cancer (AGC) using standard treatment regimens is poor. EGFR overexpression is common in AGC and associated with poor prognosis. We hypothesized that increasing the dose intensity of chemotherapy and adding panitumumab could improve efficacy., Methods: HER2 negative, PS 0-1 patients, received up to 4 cycles of panitumumab 6 mg/kg d 1, docetaxel 60 mg/m2 d 1, cisplatin 50 mg/m2 d 1, l-folinic acid 100 mg/m2 d 1-2, followed by 5-FU 400 mg/m2 bolus d 1-2, and then 600 mg/m2 as a 22 h c.i. on d 1-2, q15 d, plus pegfilgrastim 6 mg on d 3. Patients with disease control after 4 cycles received panitumumab until progression., Results: From 05/2010 to 01/2014, 52 patients (75% male; median age 64.5 y; metastatic 90%, locally advanced 10%; 96% adenocarcinoma; 25% GEJ) were recruited. Three CR, 29 PR, 10 SD and 8 PD were observed, for an ORR by ITT (primary endpoint) of 62% (95% CI, 48%-75%) and a DCR of 81%. Median TTP was 4.9 months (95% CI, 4.2-7.0) and mOS 10 months (95% CI, 8.2- 13.5). Most frequent G3-4 toxicities: leucopenia (29%), asthenia (27%), skin rash (25%), neutropenia (19%), anorexia (17%), febrile neutropenia (13%), and diarrhea (15%). EGFR expression tested both with dd-PCR and FISH was not associated with any significant clinical benefit from treatment., Conclusions: Dose-dense DCF plus panitumumab is an active regimen. However, the toxicity profile of this limits further development. Further research on predictive biomarkers for treatment efficacy in AGC is required.Clinical trial information: 2009-016962-10., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflict of interest.

Background: Standard treatment with sunitinib for patients with metastatic renal cancer provides an 'on-off' schedule (daily administration of a 50-mg capsule for 4 weeks, followed by a 2-week break; consecutive 6-week cycles). We developed an alternative intermittent schedule to reduce the toxicity and symptoms of tumor regrowth during the rest period and to allow prolonged continuation of therapy, maintaining dose intensity., Objective: The objective of this study was to provide a retrospective evaluation of the feasibility, safety, and efficacy of an alternative schedule of sunitinib in patients who did not tolerate classical treatment., Methods: Patients treated with the classical schedule with at least grade 2 toxicity or recurrence of symptoms during the rest period were switched to an alternative schedule (the same daily dose 5 consecutive days per week for 5 weeks and then the same daily dose on days 1, 3, and 5 in the sixth week; consecutive 6-week cycles)., Results: Twenty-five patients were enrolled. The median time from sunitinib initiation to schedule switch was 2.9 months. After the switch, the median therapy duration was 9.2 months. Rate of delay, corrected by cycle number, was 10% for both schedules. After the switch, 48.7% of patients obtained a toxicity reduction (hypertension -82%, stomatitis -71%, cutaneous toxicity -69%). A reduction in 'on-off symptoms' (-86%) was achieved. Overall response rate was 40% and the disease control rate was 80%. Median progression-free survival was 16.4 months and median overall survival was 41.3 months., Conclusions: Despite the small sample size and retrospective nature, we demonstrated the feasibility, safety, and efficacy of the alternative schedule, allowing prolonged treatment and better quality of life.

The future feasibility of decarbonized industrial chemical production based on the substitution of fossil feedstocks (FFs) with renewable energy (RE) sources is discussed. Indeed, the use of FFs as an energy source has the greatest impact on the greenhouse gas emissions of chemical production. This future scenario is indicated as "solar-driven" or "RE-driven" chemistry. Its possible implementation requires to go beyond the concept of solar fuels, in particular to address two key aspects: i) the use of RE-driven processes for the production of base raw materials, such as olefins, methanol, and ammonia, and ii) the development of novel RE-driven routes that simultaneously realize process and energy intensification, particularly in the direction of a significant reduction of the number of the process steps., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Adjuvant chemotherapy (CT) is the standard of care for patients with resected pancreatic cancer (PC). Overall survival (OS) has traditionally represented the primary endpoint in randomized trials assessing adjuvant therapies for PC. The aim of this study was to assess if disease-free survival (DFS) was an adequate surrogate endpoint for OS in randomized trials of adjuvant therapy in PC., Methods: A systematic literature search was conducted in PubMed, Web of Science, SCOPUS and Embase, Cochrane Library and the World Health Organization International Clinical Trials Registry Platform up to February 2nd, 2017. Surrogacy of DFS with OS was assessed between endpoints and OS through the Spearman rank correlation coefficient, and between the treatment effects on the endpoints using the squared correlation R 2 ., Results: A total of 12 eligible randomized trials that enrolled 4,888 patients where identified for the final analysis. Correlation of DFS with OS was weak at the individual level (Spearman rank correlation coefficient = 0.31) and moderate at the trial level (R 2  = 0.44)., Conclusions: DFS does not represent an appropriate surrogate for OS in randomized trials of adjuvant therapy for resected PC. Hence, OS should remain the primary endpoint of future trials evaluating new agents in postsurgical setting., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: HER2 gene is a member of the epidermal growth factor receptor (EGFR) family. Across different malignancies, aberrations of HER2 gene commonly correspond to gain-of-function alterations leading to increased receptor signaling., Methods: We have reviewed the literature currently available on HER2 mutations in human breast cancer (BC) evaluating type and frequency of such mutations. The primary objective was to determine the frequency and the number of patients with HER2-mut in the series analyzed. The secondary objectives were to assess characteristics of mutated cases (ER and HER2 status and stage of disease, type of mutations, and finally the clinical outcome if reported)., Results: We retrieved 31 published papers, and the pooled rate of HER2 mutations across 12,905 BC patients was calculated. Overall, the frequency of HER2 mutations was 2.7% with most involving the intracellular domain. About 4% of patients were finally mutated. The predictive role was not described. Only 30% of these patients were simultaneously HER2 positive and 63% were ER positive., Conclusion: We have found that the prevalence of HER2 mutations is about 3%. These genic alterations are independently associated with HER2 amplification status, occurring in both ER-positive/HER2-negative diseases or HER2-enriched cancers. Ongoing trials are investigating small molecules tyrosine kinase inhibitors in patients harboring these mutations.

Introduction: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. In the last 10 years, clinical trials have established multitargeted tyrosine kinase inhibitors (TKIs) as the standard first-line treatment in patients with metastatic disease. Multiple agents are now available for treatment in subsequent lines.The mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus alone or with lenvatinib) are among the most effective options. Areas covered: This paper provides a complete and updated overview on mTOR inhibitors for the treatment of advanced RCC. The authors revised the results of the most recent completed clinical trials and provided information about ongoing trials. Expert opinion: mTOR pathway still represents an important driver for RCC management. Combination of everolimus and lenvatinib is considered a category 1 choice with cabozantinib and nivolumab for subsequent therapy in metastatic RCC according to NCCN guidelines v2.2017. These three treatments (levantinib/everolimus, cabozantinib, and nivolumab) all resulted in a superior efficacy compared to everolimus alone. Moreover, mTOR inhibitors, and in particular temsirolimus for poor risk patients, are available choices for treatment in non-clear cell carcinomas together with TKIs.

Introduction: Our group previously demonstrated the feasibility of the HuCare Quality Improvement Strategy (HQIS), aimed at integrating into practice six psychosocial interventions recommended by international guidelines. This trial will assess whether the introduction of the strategy in oncology wards improves patient's health-related quality of life (HRQoL)., Methods and Analysis: Multicentre, incomplete stepped-wedge cluster randomised controlled trial, conducted in three clusters of five centres each, in three equally spaced time epochs. The study also includes an initial epoch when none of the centres are exposed to the intervention, and a final epoch when all centres will have implemented the strategy. The intervention is applied at a cluster level, and assessed at an individual level with cross-sectional model. A total of 720 patients who received a cancer diagnosis in the previous 2 months and about to start medical treatment will be enrolled. The primary aim is to evaluate the effectiveness of the HQIS versus standard care in terms of improvement of at least one of two domains (emotional and social functions) of HRQoL using the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items) questionnaire, at baseline and at 3 months. This outcome was chosen because patients with cancer generally exhibit low HRQoL, particularly at certain stages of care, and because it allows to assess the strategy's impact as perceived by patients themselves. The HQIS comprises three phases: (1) clinician training-to improve communication-relational skills and instruct on the project; (2) centre support-four on-site visits by experts of the project team, aimed to boost motivation, help with context analysis and identification of solutions; (3) implementation of Evidence-Based Medicine (EBM) recommendations at the centre., Ethics and Dissemination: Ethics committee review approval has been obtained from the Ethics Committee of Parma. Results will be disseminated at conferences, and in peer-reviewed and professional journals intended for policymakers and managers., Trial Registration Number: NCT03008993; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: The incidence of gastric cancer (GC) arising in the upper third of the stomach, including the cardia or gastroesophageal junction (GEJ), has increased in the last decades due to established etiological risk factors such as diet, obesity, and gastroesophageal reflux. We conducted a systematic review and meta-analysis to determine the prognostic role of site of origin in patients with proximal versus distal GC., Material and Methods: We conducted a search of the PubMed, Cochrane Library, SCOPUS, Web of Science, EMBASE, Google Scholar, LILACS, and CINAHL databases from inception to September 2016. Studies reporting data on the independent prognostic effect of site in GC and comparing overall survival (OS) in proximal versus distal tumors were eligible. Data were pooled using OS hazard ratios (HRs) of proximal versus distal GC according to fixed- or random-effect model., Results: Overall, 50 studies including 128,268 patients were identified. Cancers located in the upper third of the stomach were associated with a significantly increased risk of all-cause mortality (HR 1.31, 95% confidence interval [CI] 1.17-1.46, p < 0.001, I 2  = 91%). After exclusion of GEJ tumors, prognosis was worse for pure cardia location (HR 1.39, 95% CI 1.22-1.58, p < 0.001, I 2  = 61%) compared with proximal or upper-third GCs without a specific subsite definition (HR 1.18, 95% CI 1.01-1.37, p = 0.04, I 2  = 91%)., Conclusions: Location of the primary GC in the upper third of the stomach, particularly at the GEJ/cardia, should be acknowledged as an important prognostic factor. Based on these results, more effective treatment strategies for proximal GCs are needed.

Introduction: The use of adjuvant treatment (AT) in resected biliary tract cancers (BTC) is still controversial. No efficacy comparison has been performed between chemotherapy (CT) and chemoradiotherapy (CTRT). A systematic review of the available evidence regarding adjuvant chemotherapy (AC) in resected BTC was performed., Methods: PubMed, EMBASE, Web of Science, SCOPUS and The Cochrane Library databases were searched for relevant articles published. Only studies including at least 50 patients affected by tumors of gallbladder, intrahepatic, perihilar, and distal bile ducts were considered. Data were pooled using a random-effects model. The primary endpoint of the study was overall survival (OS)., Results: Thirty studies were analyzed with a total of 22,499 patients, 3967 of whom received AC. Eleven cohorts included Western patients and 19 were Asiatic. Surgeries were classified as R0 with negative margins, R1 with positive microscopic and R2 with positive macroscopic margins. Weighted mean OS difference among experimental (AC) and control arm was 4.3 months (95% CI 0.88-7.79, P = 0.014). AC reduced the risk of death by 41% (Hazard ratio [HR] = 0.59, 95% CI 0.49-0.71; P < 0.001)., Conclusions: AC administration gives an OS benefit in resected BTC. The results of prospective randomized studies are awaited in order to define the standard AT in BTC., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Vinflunine is the only chemotherapeutic agent shown to improve survival in platinum-refractory patients with metastatic transitional cell carcinoma of the urothelium (TCCU) in a phase III clinical trial, which led to product registration for this indication in Europe. The aim of this study was to assess the efficacy of vinflunine and to evaluate the prognostic significance of risk factors in a large, unselected cohort of patients with metastatic TCCU treated according to routine clinical practice., Methods: This was a retrospective multicenter study. Italian cancer centers were selected if, according to the Registry of the Italian Medicines Agency (AIFA), at least four patients had been treated with vinflunine between February 2011 and June 2014, after first- or second-line platinum-based chemotherapy. The primary objective was to test whether the efficacy measured by overall survival (OS) in the registration study could be confirmed in routine clinical practice. Multivariate analysis was carried out using Cox proportional hazard model., Results: A total of 217 patients were treated in 28 Italian centers. Median age was 69 years (IQR 62-76) and 84% were male; Eastern Cooperative Oncology Group performance status (ECOG PS) was ≥ 1 in 53% of patients. The median number of cycles was 4 (IQR 2-6); 29%, 35%, and 36% received an initial dose of 320 mg/m 2 , 280 mg/m 2 or a lower dose, respectively. Median progression-free survival (PFS) and OS for the entire population was 3.2 months (2.6-3.7) and 8.1 months (6.3-8.9). A complete response was observed in six patients, partial response in 21, stable disease in 60, progressive disease in 108, with a disease control rate of 40%. Multivariate analysis showed that ECOG PS, number of metastatic sites and liver involvement were unfavorable prognostic factors for OS. Toxicity was mild, and grade 3-4 adverse effects were mainly: neutropenia (9%), anemia (6%), asthenia/fatigue (7%) and constipation (5%)., Conclusions: In routine clinical practice the results obtained with VFL seem to be better than the results of the registration trial and reinforce evidence supporting its use after failure of a platinum-based chemotherapy.

Importance: The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial., Objective: To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions., Data Sources: A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer)., Study Selection: Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded., Data Extraction and Synthesis: Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial., Main Outcomes and Measures: Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions., Results: Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12)., Conclusions and Relevance: For patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.

Oligometastatic non-small cell lung cancer (NSCLC), defined as a disease with low metastatic burden and limited organ involvement, is conceived as an intermediate condition between a truly localised disease and a widely metastatic tumour. Traditionally, local ablative therapies (LATs), such as surgery and radiotherapy, have been limited to symptoms' palliation in advanced NSCLC. Several retrospective studies suggest that using local ablative therapy for oligometastatic disease could offer good local control of the disease and improvement in terms of progression-free survival. The first randomised study of local consolidative therapy versus maintenance therapy or observation in oligometastatic NSCLC has been recently published. The results of this phase II trial showed an impressive improvement in median progression-free survival with local therapy and a delay in the appearance of new lesions, suggesting a systemically extended benefit of consolidation therapies. Nevertheless, further confirmation of this evidence with additional future trials is needed to definitively consider the combination of local treatment techniques with novel systemic agents recently approved for NSCLC therapy, such as immune checkpoint inhibitors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Neoadjuvant chemoradiotherapy (CTRT) is the current standard of care for treatment of locally advanced cancer of the esophagus or gastroesophageal junction. Many efforts have been made over the last years to identify the best chemotherapy and radiotherapy combination regimen, but specific randomized trials addressing this issue are still lacking. Areas covered: A systematic review of the literature was performed searching in PubMed all published studies of combinations CTRT regimens for operable or unresectable esophageal cancer to describe activity and toxicity. Studies considered were prospective series or clinical phase II-III trials including at least 40 patients and published in English language. Expert commentary: Long-term results of CROSS trial have established RT combined with carboplatin plus paclitaxel chemotherapy as the preferred neoadjuvant treatment option for both squamous and adenocarcinoma of the esophagus. More effective multimodal treatment strategies integrating novel biological agents including immunotherapy and based on an extensive molecular tumor characterization are eagerly awaited.

Purpose: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer., Materials and Methods: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters., Results: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64-0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor., Conclusions: The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies., Competing Interests: Conflict of Interest: Drs. Emig, Ferry, Chandrawansa, Hsu, Sashegyi, and Liepa are full-time employees and stockholders of Eli Lilly and Company. Dr. Ferry additionally received honoraria from Eli Lilly and Company, Sanofi, and Roche; he also held an advisory role for Eli Lilly and Company, Sanofi, and Roche; he received research funding from Eli Lilly and Company and Sanofi; he gave expert testimony for Eli Lilly and Company; he received travel support from Sanofi and Roche. Dr. Fuchs served as a consultant for Eli Lilly and Company, Pfizer, Entrinsic Health, Genentech, Merck, Gilead Sciences, Macrogenics, Sanofi, Dicerna, Frive Prime Therapeutics, Bristol Myers Squibb, Bayer, Merrimack, and Celgene. Dr. Muro received honoraria from Takeda, Chugai Pharma, Yakult Honsha, Merck Serono, and Taiho Pharmaceutical. Dr. Tomasek received honoraria from Roche, Bayer, Merck, Amgen, and Eli Lilly and Company; he served in an advisory role for Ipsen, Amgen, and Roche; he received research funding from Amgen, Novartis, and Eli Lilly and Company; and he received travel support from Pfizer, Eli Lily and Company, Novartis, and Roche. Dr. Van Cutsem received research support from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Merck Serono, Novartis, Roche, Sanofi, Celgene, and Ipsen. Dr. Chau would like to acknowledge United Kingdom National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. Dr. Shimada received research funding from Eli Lilly and Company, Taiho Pharmaceutical, and Chugai Pharma. Dr. Al-Batran received honoraria and served as an advisor for Eli Lilly and Company. Dr. Passalacqua received honoraria from Eli Lilly and Company, Roche, and Novartis; he served as an advisor for Eli Lilly and Company; he is on the Speakers' bureau for Astellas Pharma; and he receives research funding from Amgen. Dr. Ohtsu is related to an employee of Celgene and he receives research funding from Bristol-Myers Squibb. Dr. Wilke received honoraria from Eli Lilly and Company and served as an advisor for Eli Lilly and Company.

The aim of the study was to collect the available data on central nervous system (CNS) metastases from esophageal and gastric cancer. A PubMed, EMBASE, SCOPUS, Web of Science, LILACS, Ovid and Cochrane Library search was performed. Thirty-seven studies including 779 patients were considered. Among the data extracted, treatment of tumor and brain metastases (BMs), time to BMs development, number and subsite, extracerebral metastases rate, median overall survival (OS) and prognostic factors were included. For esophageal cancer, the median OS from diagnosis of BMs was 4.2 months. Prognostic factors for OS included: performance status, multimodal therapy, adjuvant chemotherapy, single BM, brain only disease and surgery. For gastric cancer, median OS was 2.4 months. Prognostic factors for OS included: recursive partitioning analysis class 2, stereotactic radiosurgery (SRT) and use of intrathecal therapy. HER2-positive gastric cancer was shown to be associated with a higher risk and shorter time to CNS relapse. Patients harboring BMs from gastric and esophageal tumors, except cases with single lesions that are treated aggressively, have a poor prognosis. SRT (plus or minus surgery and whole brain radiotherapy) seems to give better results in terms of longer OS after brain relapse.

Importance: Primary tumor location is emerging as an important prognostic factor owing to distinct biological features. However, the side of origin of colon cancer (CC) still does not represent a prognostic parameter when deciding for adjuvant or palliative chemotherapy., Objective: To determine the prognostic role of left vs right-sidedness of primary tumor location in patients with CC., Data Sources: We searched PubMed, EMBASE, The Cochrane Library, Web of Science, LILACS, CINAHL, and SCOPUS for prospective or retrospective studies reporting data on overall survival for left-sided colon cancer (LCC) compared with right-sided colon cancer (RCC)., Study Selection: Studies were selected if: (1) side of CC was reported among variables entered into survival analysis, (2) survival information was available (overall survival [OS] was reported in the article as hazard ratio (HR) according to multivariate analysis, (3) articles were published in the English language., Data Extraction and Synthesis: Data were pooled using HRs for OS of LCC vs RCC according to fixed or random-effects models. Subgroup analysis and multivariate random-effects model meta-regression was also implemented adjusting for stage distribution, sample size, race, year of publication, type and quality of studies, and adjuvant chemotherapy., Main Outcomes and Measures: HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. In this analysis, all HRs with 95% CIs were pooled to obtain prognostic information on the location of the primary tumor (left vs right location site of CC) independent of other common clinicopathological covariates., Results: An analysis was made from the 66 studies conducted. It included 1 437 846 patients with a median follow-up of 65 months. Left sided primary tumor location was associated with a significantly reduced risk of death (HR, 0.82; 95% CI, 0.79-0.84; P < .001) and this was independent of stage, race, adjuvant chemotherapy, year of study, number of participants, and quality of included studies., Conclusions and Relevance: Based on these results, CC side should be acknowledged as a criterion for establishing prognosis in all stages of disease. It should be considered when deciding treatment intensity in metastatic settings, and should represent a stratification factor for future adjuvant studies.

Combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) is an active but not well-tolerated regimen for advanced gastric cancer (GC) with standard 3-weekly doses. Several modified schedules (mDCFs) have been designed to reduce acute toxicities and improve feasibility as first-line therapy in patients with metastatic GC. The objective of this systematic review was to evaluate overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade (G) greater than or equal to 3 adverse event of mDCF chemotherapy in this setting. MEDLINE, SCOPUS, Embase, Web of Science, LILACS, CINAHL, Google Scholar, and the Cochrane Library were searched for studies with mDCF schedules in advanced GC. Pooled median OS, PFS, ORR (the primary endpoints), and G3 or G4 adverse events (secondary endpoints) were presented according to random effect model. Twenty-four studies were included for a total of 1311 patients, with weekly or biweekly (n=11) and reduced doses 3-weekly (n=13) schedules. The median pooled PFS and OS were 7.2 months [95% confidence interval (CI): 5.9-8.8] and 12.3 months (95% CI: 10.6-14.3), respectively. Among 23 studies with available data for ORR, the pooled result was 49% (95% CI: 43.4-54.4). The incidence of grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia, stomatitis, diarrhea, nausea+vomiting, and neurotoxicity were 29.1, 5.6, 8.9, 7.6, 6.6, 4.9, and 9.9%, respectively. mDCF chemotherapy with splitted weekly or biweekly schedules, or reduced 3-weekly doses, is a very effective and well-tolerated regimen in metastatic GC. By providing a 50% ORR, such regimens may be particularly indicated for younger and fit patients for cytoreductive purposes (conversion therapy) or in case of symptomatic tumor burden.

Purpose: To evaluate the efficacy and safety of dose-dense TCF in elderly (≥65 years) compared to younger patients., Methods: Safety and efficacy data relative to 119 consecutive patients with locally advanced or metastatic gastric cancer treated at our institution and enrolled in different phase II trials were retrospectively collected. All patients were treatment-naive and received docetaxel 70 mg/m2 day 1, cisplatin 60 mg/m2 day 1, l-folinic acid 100 mg/m2 days 1-2, followed by 5-fluorouracil 400 mg/m2 bolus days 1-2, and then 600 mg/m2 as a 22-hour continuous infusion days 1-2, every 14 days, plus pegfilgrastim 6 mg on day 3. Sixty patients (50%) aged ≥65 years received the same schedule with a dose reduction by 30%., Results: A total of 86% of patients were evaluable for response and all for toxicity. In patients aged ≥65 years, we observed an overall response rate of 51%. Median overall survival was 11.2 (95% confidence interval [CI] 7.3-15.1) and 11.8 months (95% CI 9.2-16.2) in elderly and younger patients, respectively. In the elderly patients, the most frequent grade 3-4 toxicities were neutropenia (13%), leukopenia (7%), thrombocytopenia (18%), anemia (3%), and febrile neutropenia (8%); in the younger patients, neutropenia (56%), leucopenia (31%), thrombocytopenia (22%), anemia (15%), and febrile neutropenia (15%)., Conclusions: Elderly patients can be safely treated with a dose-dense TCF regimen with a 30% dose reduction achieving similar efficacy results as younger patients with lesser toxicity.

Cancer care involves many ethical issues. The need for more patient-centered healthcare together with the improved empowerment of every person diagnosed with cancer have been transposed by the Italian Association of Medical Oncology (AIOM) and eventually translated in the Ragusa statement. This position paper describes the philosophy that lies beneath this document and its fundamental principles.

Background: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy., Methods: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher., Results: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease., Conclusions: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.

Purpose: This study examines the development and feasibility of a quality improvement strategy for the translation of evidence-based psychosocial care into clinical practice., Methods: The project involved all staff (oncologists, psychologists, and nurses) of the participating centers. Recommendations concerned: improvement of clinician communication skills; use of a patient question prompt list; assignment of a specialist nurse to each patient; screening for psychological distress and social needs; opportunity to attend a Point of Information and Support. The implementation strategy hinged on context analysis and problem solving. Four to six visits were held in each center by the project team to assist staff in identifying obstacles, finding solutions, and strengthening motivation. The primary variable was the adherence percentage to the recommendations (proportion of subjects receiving each intervention). The number of centers that failed to reach the objective was also reported (adherence percentage <75%)., Results: Twenty-seven of twenty-eight centers completed the study. Lack of resources was the most commonly perceived barrier preimplementation. Five-hundred-forty-five clinicians were actively involved in the project and completed training. The adherence percentage for each recommendation was greater than 85% except for the question prompt list (78%; 95% CI, 73-83%), where seven centers did not reach the objective., Conclusions: Our findings demonstrate that evidence-based interventions to improve the psychosocial care of people with cancer can be implemented in a diverse range of oncology wards. This requires the involvement and motivation of the entire staff of the ward, support by an expert team, and promotion by policymakers.

Background: Potentially myelosuppressive doublet and triplet chemotherapy combination regimens are considered the most active treatments in gastric cancer. This multicenter prospective observational study was designed to gain insight into the chemotherapy regimens being used in Europe and to evaluate neutropenia management in patients identified as at high risk for febrile neutropenia (FN)., Methods: Eligible patients had gastric cancer, were scheduled for ≥ 3 cycles of myelosuppressive chemotherapy, and had an investigator-assessed overall FN risk ≥ 20%. Data were collected for up to ten cycles. The primary endpoint was the proportion of patients who received granulocyte colony stimulating factor (G-CSF) primary prophylaxis (defined as G-CSF initiated on days 1-7 of cycle 1). Secondary endpoints included FN incidence, chemotherapy administration, and G-CSF use., Results: Of 199 patients who met the eligibility criteria and started at least one cycle of chemotherapy, mean age was 63 years, 76% were men, 83% had an ECOG score of 0 or 1, 54% had metastatic disease, and 24% had received prior chemotherapy. A total of 27 different backbone regimens were given; the most common regimen was modified docetaxel, cisplatin, and 5-fluorouracil (DCF). Despite all patients having been identified as having a ≥ 20% FN risk, only 70 (35%) received G-CSF primary prophylaxis. FN occurred in 14 patients overall (7%). Most FN events occurred in patients who received DCF/modified DCF (9/14 events, 64%)., Conclusions: The results of this study reveal a high use of myelotoxic treatment regimens in gastric cancer in Europe and low adherence to clinical practice guidelines for the use of primary and secondary G-CSF prophylaxis for FN.

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

Purpose: Guideline consistency in the prevention of chemotherapy-induced nausea and vomiting (CINV) remains low (29% in the Pan European Emesis Registry study) and very low (11%) in regimens with a high emetogenic risk. The aim of this study was to evaluate the guideline consistency of CINV prophylaxis for acute emesis in daily clinical practice in Italy., Methods: This was a prospective, observational, multicenter study. Patients scheduled to receive antitumor treatment on a single prespecified day were included. Data on patient characteristics (demographic and clinical), type of anticancer therapy, and type of antiemetic therapy prescribed for acute emesis were collected on electronic data capture forms. Chemotherapy regimens and antiemetic prophylaxis were categorized according to the MASCC 2011 guidelines. The study was approved by the local ethics committees., Results: From July 2013 to February 2014, a total of 502 patients were enrolled at 26 study sites. Median age was 62 years (range 27-87 years). Colorectal cancer and breast cancer were the most common malignancies. The emetogenic potential of the chemotherapy regimens used was high (HEC) (23.7%), moderate (MEC) (40.6%), low (31.3%) or minimal (4.4%). Overall, guideline consistency was 19.3%. Consistency reached 45% when the various 5HT3 receptor antagonists were considered equivalent and interchangeable in MEC regimens. Adherence to guidelines was lowest for MEC and Minimal risk groups. Ten percent of patients in HEC and MEC regimens did not receive any 5HT3 receptor antagonists. NK1 receptor antagonists were used in 8% of all regimens., Conclusions: Our study indicates that antiemetic guideline inconsistency remains an issue in daily clinical oncology practice in Italy.

There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL-2)+interferon-α (IFN-α) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-α or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12-151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 [95% confidence interval (CI), 0.54-1.31; P=0.44] and of 1.07 (95% CI, 0.64-1.79; P=0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of ≥ 2 of these factors, immunotherapy had a positive effect on RFS (HR=0.44; 95% CI, 0.24-0.82; P ≤ 0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR=2.27; 95% CI, 1.03-5.03 P=0.037). Toxicity of immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2+IFN-α showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating.

Background: We previously studied a dose-dense TCF (TCF-dd) regimen demonstrating its feasibility and an activity comparable to epirubicin-based chemotherapy and TCF q3w in terms of overall survival and time to progression (TTP). We report here the final results of a phase II study of chemotherapy with a modified TCF-dd regimen in locally advanced or metastatic gastric cancer (MGC)., Methods and Study Design: Patients with histologically confirmed measurable MGC, not previously treated for advanced disease, received docetaxel 70 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, l-folinic acid 100 mg/m(2) days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/m(2) bolus days 1 and 2, and then 600 mg/m(2) as a 22-h continuous infusion days 1 and 2, every 14 days, plus pegfilgrastim 6 mg on day 3. Patients aged ≥65 years received the same schedule with a dose reduction of 30 %., Results: Study duration: December 2007-November 2010. Forty-six consecutive patients were enrolled (78 % male, 22 % female; median age, 66 years, range, 38-76 years; ECOG PS: 0, 48 %, 1, 46 %). Primary endpoint was overall response rate (ORR). A median of four cycles (range, one to six) was administered. Forty-three patients were evaluated for response (93.5 %) and all for toxicity: 3 complete response (CR), 25 partial response (PR), 10 stable disease (SD), and 5 progressive disease (PD) were observed, for an ORR by intention to treat (ITT) of 61 % (95 % CI 47-75). Median overall survival (OS) was 17.63 months (95 % CI, 13.67-20.67); median progression-free survival was 8.9 months (95 % CI, 6.5-13.4). Twenty-one patients (46.0 %) were treated at full doses without any delay, thus respecting the dose-dense criterion. Most frequent grade 3-4 toxicities were neutropenia (20 %), leukopenia (4 %), thrombocytopenia (2 %), anemia (2 %), febrile neutropenia (6 %), asthenia (22 %), diarrhea (4 %), nausea/vomiting (11 %), and hypokalemia (6 %). Overall, TCF-dd was shown to be safe., Conclusions: The TCF-dd regimen in locally advanced or MGC is confirmed to be feasible and very active and needs to be further tested in randomized studies.

The activation of lymphocytes by gefitinib treatment has been described. In this phase II pilot trial, we explored the possible synergism between IL-2 and gefitinib for non-small cell lung cancer (NSCLC) treatment. From September, 2003, to November, 2006, 70 consecutive patients with advanced, progressive NSCLC, previously treated with chemotherapy, received oral gefitinib 250 mg daily. The first 39 patients received gefitinib alone (G group). The other 31 also received subcutaneous IL-2 (GIL-2 group): 1 MIU/m2 (Million International Unit/m2)twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for four consecutive weeks with a four-week rest period. Median follow-up was 25.2 months. Grade 3-4 toxicity of gefitinib was represented by skin rash (7%), asthenia/anorexia (6%) and diarrhea (7%); patients treated with IL-2 showed grade 2-3 fever (46%), fatigue (21%) and arthralgia (13%). In the GIL-2 group and G-group, we respectively observed: an overall response rate of 16.1% (6.4% complete response) and 5.1% (only partial response); a disease control rate of 41.9% and 41%; a median time to progression of 3.5 (CI 95% = 3.2-3.8) and 4.1 (CI 95% = 2.6-5.7) months; a median overall survival of 20.1 (CI 95% = 5.1-35.1) and 6.9 (CI 95% = 4.9-8.9) months (p = 0.002); and an actuarial one-year survival rate of 54% and 30%. Skin toxicity (p < 0.001; HR = 0.29; CI 95% = 0.16-0.54) and use of IL-2 (p < 0.001; HR = 0.33; CI 95% = 0.18-0.60) were independently associated with improvement of survival. In this consecutive, non-randomized, series of advanced NSCLC patients, the use of IL-2 increased the efficacy of gefitinib.

Background: Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer., Methods: We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384., Findings: 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug., Interpretation: Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer., Funding: ImClone Systems., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Gastric cancer is a highly aggressive disease. In metastatic setting, median overall survival, even with modern chemotherapy regimens, generally does not exceed 1 year and toxicity is a major concern. Angiogenesis plays a crucial role in cancer development and progression, and VEGF is one of the most important mediators of this process. Ramucirumab, an anti-VEGFR-2 antibody, has been recently evaluated in the large Phase III REGARD trial, demonstrating a significant survival benefit in second-line treatment of patients with advanced gastric or gastro-eosophageal junction adenocarcinoma. Unlike traditional chemotherapy, treatment with ramucirumab was associated with very few toxic effects. This article will review the main findings of the REGARD trial and discuss their potential impact on future treatment of metastatic gastric cancer.

Pituitary metastases are unusual complications of malignancies. In about only 2% of patients they origin from colorectal cancer (CRC), with breast and lung as the most common primary tumors. Nevertheless, some authors reported a recent increase of the incidence of metastases in infrequent sites, such as brain or bone, arising from gastrointestinal cancers, probably due to the expanded treatment options and the resulting improved survival. Here, we report the case of a 54-year old woman diagnosed with lung metastases from rectal cancer, who, after several cycles of radio- and chemotherapy, presented symptoms and signs of pituitary disfunction (i.e. diabetes insipidus, hypothyroidism and diplopy). The diagnosis of pituitary metastasis from rectal cancer was histologically confirmed after surgery.

Thymic carcinoma (TC) is a rare intrathoracic malignancy that it can be invasive and refractory to conventional treatment. Comprehensive genomic analysis evidenced a molecularly distinct subset of thymic carcinoma with high prevalence of c-kit mutation, which may behave as a gastrointestinal stromal tumor (GIST). Here, we present a case report of TC with c-Kit mutation, who has relapsed after exposure to multiple lines of combination chemotherapy, but he has shown an impressive and long lasting response to sunitinib after imatinib failure., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS)., Results: From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039)., Conclusion: Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.

Background and Objective: First-line bevacizumab-based therapy has been shown to improve outcomes in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The recent international phase IV SAiL study (a Study of Avastin [bevacizumab] in combination with platinum-containing chemotherapy in patients with advanced or recurrent non-squamous cell Lung cancer) evaluated the safety and efficacy of bevacizumab combined with standard chemotherapy regimens in routine clinical practice. Here we report the results of a subanalysis of baseline characteristics and efficacy data for Italian patients enrolled in SAiL., Methods: In the SAiL study, patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC received bevacizumab (7.5 or 15 mg/kg) every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Efficacy was assessed in terms of time to disease progression (TTP) and overall survival (OS)., Results: The Italian intent-to-treat population comprised 215 patients from a SAiL population of 2212 patients. At baseline, Italian patients tended to have less advanced disease than the overall population. Thus, the proportion of patients at enrollment with tumour stage IIIb and IV was 23.7 and 76.3 %, respectively, for the Italian population versus 19.7 and 80.3 % for the whole SAiL population. In addition, a higher proportion of Italian patients had an Eastern Cooperative Oncology Group performance status of 0 (72.6 vs. 37.2 %) and the prevalence of co-morbid conditions was lower in Italian patients (59.5 % of Italian patients reported a co-morbid condition and 60.0 % were receiving non-oncological treatment compared with 73.3 and 73.4 %, respectively, of SAiL patients overall). The mean exposures to bevacizumab and to chemotherapy were comparable between the Italian patient group and overall patient population, although cisplatin doublets were more commonly employed in Italian patients whereas carboplatin doublets were more commonly employed in the overall SAiL population. The median TTP and OS times for Italian and SAiL populations were comparable (TTP, 7.8 months vs. 7.8 months; OS, 14.8 months vs. 14.6 months)., Conclusion: The results of this subanalysis of the SAiL study of bevacizumab treatment in routine clinical practice suggest that Italian oncologists tend to prescribe bevacizumab to a selected population of patients with less advanced disease than is the case in the overall population. Nevertheless, the first-line use of bevacizumab in combination with chemotherapy offers clinical benefits to Italian patients with advanced or recurrent non-squamous NSCLC.

Background and Aim of the Work: Sunitinib 50 mg/day given for 4 weeks followed by 2 weeks off treatment (4+2 schedule) is a standard treatment for metastatic renal cell carcinoma, but several patients are forced to reduce the doses and/or had to discontinue therapy permanently due to toxicity. Recent data showed that increased exposure to sunitinib is associated with improved clinical outcome underlining the key role of dose-intensity in the efficacy/toxicity balance. We investigated the tolerability and efficacy of a modified schedule., Patients and Methods: This is a retrospective analysis which assessed consecutive non-progressive metastatic renal cell carcinoma patients admitted to our hospital who had at least a grade 2 toxicity during sunitinib therapy, and then switched to a modified schedule maintaining the same dose-intensity of 4+2 schedule: starting on Monday, 1 tablet/day for 5 consecutive days a week (days 6 and 7 off therapy) for 5 weeks and 1 tablet/day on days 1, 3 and 5 in the sixth week (days 2, 4, 6 and 7 off therapy) until disease progression. Primary end points were toxicity changes assessment and schedule feasibility., Results: Complete data from eight nephrectomized patients were collected: 6 males; median age 61; 3 pretreated patient. Median time from start therapy to switch was 7.4 months. After switch, treatment delays and dose reductions decreased from 50% to 25% and from 37% to 12% of patients respectively. Toxicity was reduced., Conclusions: Even though no conclusions can be drawn about the actual effectiveness and toxicity of our schedule compared to the standard dosing schedule, it seems to be well tolerated and able to maintain a high adherence to therapy, resulting in maintenance of antitumour activity. This new modified schedule requires and deserves further studies.(www.actabiomedica.it).

Aims and Background: The exact mechanism by which recombinant interleukine-2 and interferon-α modulate the immunological response, inducing long-term responses in metastatic renal cell carcinoma, is still not clear. The aim of the study was to analyze the modifications in peripheral blood lymphocytes during cycles of low-dose immunotherapy as a marker of the biological response to the treatment in 146 patients with renal cell carcinoma (advanced and localized disease)., Methods and Study Design: Peripheral blood lymphocytes were evaluated before and after every cycle of treatment., Results: We found a statistically significant overall difference between pre- and post-cycle values (mean increase of 39%). The differences between pre- and post-cycle lymphocyte counts for each cycle were significant. Also, the post-cycle lymphocyte count of each cycle remained higher than the baseline value. Furthermore, pre-cycle lymphocyte counts of each cycle were still higher than the baseline value, with no difference between a pre-cycle lymphocyte mean value and the other one (except that between the first and second cycle). From the end of each cycle, but before starting the next one, the absolute value of lymphocytes fell on the average by 15-30%, concurring with the fact that, even starting from pre-cycle values higher than baseline, the immune system remains sensitive to chronically repeated stimulation by immunotherapy. We also found that non-metastatic patients had a higher number of peripheral blood lymphocytes than metastatic patients, whereas the latter had a lower immune response to therapy., Conclusions: The results support the idea that "maintenance" immunotherapy may not develop resistance over time in terms of biological response and thus may have a role as chronic therapy in combination with other drugs such as target therapy. We suppose that the immune system of patients with metastases is in a state of relative impairment, resulting in less sensitivity to immunostimulating agents.

Background: The MINDACT (Microarray In Node-negative and 1-3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included., Methods: MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen→letrozole are offered., Results: During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7-11.8%; P<.0001). Compliance with the treatment decision was high (>92%)., Conclusions: The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses., (Copyright © 2011. Published by Elsevier Ltd.)

Purpose: To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer., Patients and Methods: Chemo-naïve patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85 mg/m(2) and cisplatin initially 75 mg/m(2) on day 1 [later modified due to toxicity: 70 and 60 mg/m(2) respectively], l-folinic acid 100 mg/m(2) on days 1 and 2, 5-fluorouracil 400 mg/m(2) bolus and then 600 mg/m(2) as a 22 h continuous infusion on day 1 and 2, every 14 days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85 mg/m(2), irinotecan 140 mg/m(2), l-folinic acid 200 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) on day 1 followed by 2,400 mg/m(2) as a 48 h continuous infusion, every 14 days). In both regimens pegfilgrastim 6 mg subcutaneously on day 3 was included., Results: Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40-70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45-75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3-4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3-4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively., Conclusions: A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients.

The aim of this study was to look for the maximum tolerated dose (MTD) of gemcitabine and 5-fluorouracil in a new regimen also containing the antiangiogenic bevacizumab and immunotherapy (IT) for the treatment of metastatic renal cell cancer. The primary objective of this multicenter dose-finding study was to establish the MTD of chemotherapy (CT) in combination with fixed doses of IT and bevacizumab. The secondary objective was to assess the combination's activity. Five escalated dose levels of CT with intravenous gemcitabine and 5-fluorouracil (days 1 and 8 every 28 d), were associated together with intravenous bevacizumab (10 mg/kg on days 1 and 15 every 28 d), subcutaneous interleukin-2 (1 MIU/m² bid on days 8, 9, 15, 16, and 1 MIU/m²/d on days 10-12 and 17-19), and interferon-α-2a (3 MIU on days 10, 12, 17, 19). Of the 27 enrolled patients, 59% had been pretreated. The MTD was not reached. The highest CT dose studied was gemcitabine 1000 mg/m² and 5-fluorouracil 600 mg/m². More frequent grade 3 to 4 toxicities included neutropenia (63%), thrombocytopenia (33%), and fever (26%). The response rate was 33% according to the Response Evaluation Criteria in Solid Tumors. This is the first study that explored the feasibility and safety of combined bevacizumab, IT, and CT in metastatic renal cell cancer. The activity of this regimen is interesting and its efficacy warrants further trials.