Sequential Treatment of Sorafenib-Regorafenib Versus Sorafenib-Physician's Choice: A Propensity Score-Matched Analysis.

BACKGROUND: Regorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients. OBJECTIVE: We performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib-regorafenib compared with sorafenib and physician's choice in a real-life setting. PATIENTS AND METHODS: A propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S-R) and the arm treated with sorafenib and physician's choice (S-P). Survival analysis was conducted on the matched population. RESULTS: After the application of propensity score matching, we analysed 99 patients in the arm treated with S-R and 99 patients in the arm treated with S-P. For the S-R group, the median overall survival was 22.2 months (95% CI 17.1-27.4), compared to 17.9 months (95% CI 15.1-50.0) for the S-P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S-R (p = 0.0382) compared to patients treated with S-P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread. CONCLUSION: This study provides additional proof of the superiority of the S-R treatment over the S-P treatment approach in advanced HCC patients from a real-life setting.

Lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: An inverse probability of treatment weighting analysis.

PURPOSE: Data from common clinical practice were used to generate balanced cohorts of patients receiving either sorafenib or lenvatinib, for unresectable hepatocellular carcinoma, with the final aim to investigate their declared equivalence. METHODS: Clinical features of lenvatinib and sorafenib patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint and occurrence of adverse events was the secondary. RESULTS: The analysis included 385 patients who received lenvatinib, and 555 patients who received sorafenib. In the unadjusted cohort, lenvatinib did not show a survival advantage over sorafenib (HR: 0.85, 95% CI 0.70-1.02). After IPTW adjustment, lenvatinib still not returned a survival advantage over sorafenib (HR: 0.82, 95% CI: 0.62-1.07) even in presence of balanced baseline characteristics. Lenvatinib provided longer survival than sorafenib in patients previously submitted to TACE (HR: 0.69), with PS of 0 (HR: 0.73) or without extrahepatic disease (HR: 0.69). CONCLUSION: Present results confirmed randomized controlled trial in the real-life setting, but also suggests that in earlier stages some benefit can be expected.

Prognostic Role of Blood Eosinophil Count in Patients with Sorafenib-Treated Hepatocellular Carcinoma.

BACKGROUND: Inflammation is a long-established hallmark of liver fibrosis and carcinogenesis. Eosinophils are emerging as crucial components of the inflammatory process influencing cancer development. The role of blood eosinophils in patients with hepatocellular carcinoma receiving systemic treatment is an unexplored field. OBJECTIVE: The objective of this study was to analyse the prognostic role of the baseline eosinophil count in patients with sorafenib-treated hepatocellular carcinoma. PATIENTS AND METHODS: A training cohort of 92 patients with advanced- or intermediate-stage sorafenib-treated hepatocellular carcinoma and two validation cohorts of 65 and 180 patients were analysed. Overall survival and progression-free survival in relation to baseline eosinophil counts were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS: A negative prognostic impact of low baseline eosinophil counts (< 50*109/L) was demonstrated in all cohorts (training cohort: hazard ratio = 50.1, 95% confidence interval 11.6-216.5, p < 0.0001 for low vs high eosinophil counts; first validation cohort: hazard ratio = 4.55, 95% confidence interval 1.24-16.65, p = 0.022; second validation cohort: hazard ratio = 3.21, 95% confidence interval 1.83-5.64, p < 0.0001). Moreover, low eosinophil counts had a negative prognostic role in patients progressing on or intolerant to sorafenib who received second-line regorafenib, but not capecitabine or best supportive care. CONCLUSIONS: Our analysis identified baseline blood eosinophil counts as a new prognostic factor in patients with sorafenib-treated hepatocellular carcinoma. Concerning second-line therapies, eosinophil counts were associated with survival outcomes only in regorafenib-treated patients, suggesting a possible predictive role in this setting.

Utility of neutrophil-to-lymphocyte ratio to identify long-term survivors among HCC patients treated with sorafenib.

Sorafenib is the first multikinase inhibitor demonstrating a survival benefit for patients suffering from advanced hepatocellular carcinoma (HCC). However, 1 issue remains open: what is the factor able to predict which patients will be long survivors?In the present study, we harnessed the potential of conditional survival, aiming at estimating the probability that a patient receiving sorafenib survives for more than 3 years.The present multicentric study was conducted on a cohort of 438 HCC patients. The primary end point was conditional overall survival. Kaplan-Meier survival analysis was used to calculate conditional overall survival probabilities at 3 years.The 3-year conditional survival of patients without disease progression highlights that NLR and ECOG are the factors that most accurately predict the probability of long survival. The 3-year conditional survival of patients with disease progression showed a medium effect size for HCV status, alpha-fetoprotein and NLR at all time-points. Macro-vascular portal vein invasion, extra hepatic disease, and BCLC we have a large effect size at 6 months and a medium effect size at 12 and 24 months.Our findings support the use of baseline NLR for the identification of patients with a higher probability of long-survival. NLR should be used as a stratification factor in the forthcoming clinical trials on the drugs for the advanced HCC now in pipeline.

The role of PNI to predict survival in advanced hepatocellular carcinoma treated with Sorafenib.

BACKGROUND AND AIMS: The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS: This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). RESULTS: A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. CONCLUSIONS: PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.

Angiogenesis Genotyping and Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib: The ALICE-2 Study.

BACKGROUND: Sorafenib represents one of the therapeutic strongholds for advanced hepatocellular carcinoma (HCC), but unfortunately, predictive factors are lacking. We previously reported that the VEGF single nucleotide polymorphisms (SNPs) rs2010963 and rs4604006 might correlate with clinical outcomes in sorafenib-treated HCC patients. OBJECTIVE: The objective of the ALICE-2 study is to define a prognostic angiogenesis profile to better identify HCC patients who are more likely to benefit from sorafenib treatment. PATIENTS AND METHODS: From 2008 to 2015, all consecutive HCC patients receiving sorafenib according to the Italian label were tested for specific HIF-1α, VEGF, and VEGFR SNPs. Results from angiogenesis genotyping were then correlated with clinical outcome parameters. RESULTS: Globally, a total of 210 patients were enrolled. At multivariate analysis rs12434438 of HIF1α, rs2010963 of VEGF-A, and rs4604006 of VEGF-C were confirmed as independent predictive factors. At the combined analysis of significant SNPs, the presence of two favourable alleles of rs2010963 and rs4604006 of VEGF compared to only one or to none favourable alleles, was able to identify three separate patients populations with different time-to-progression (TTP) (10.8 vs. 5.6 vs. 3.7 months, respectively; p < 0.0001) and overall survival (OS) (19.0 vs. 13.5 vs. 7.5 months, respectively; p < 0.0001). Furthermore, the presence of the GG genotype of rs12434438 (HIF-1α) seemed able to select a population with a particularly poor outcome, independently from the clinical effect of the two VEGF SNPs (TTP: 2.6 months, HR: 0.54, p = 0.0374; OS: 6.6 months, p = 0.0061, HR: 0.43). CONCLUSIONS: Our findings show that polymorphism analysis of HIF-1α, VEGF, and VEGFR genes may represent a prognostic panel to better identify HCC patients who are more likely to benefit from sorafenib treatment.

Second-line treatment efficacy and toxicity in older vs. non-older patients with advanced gastric cancer: A multicentre real-world study.

OBJECTIVES: Although gastric cancer (GC) incidence rises with age, older patients are poorly represented in clinical trials, whose results are therefore difficult to translate into standard management of older patients. Purpose of this study was to compare clinico-pathological features and survival outcomes between older and non-older patients with advanced GC treated with at least two chemotherapy lines. MATERIALS AND METHODS: Clinico-pathological characteristics, basal values, and treatment data of older (≥70 years at second-line start) and non-older patients were compared using chi-square test or 2-tailed Fisher exact test. The Kaplan-Meier estimation was used to calculate progression-free survival (PFS) and overall survival (OS), which were examined by log-rank test. RESULTS: Older patients represented 31.8% of the population (N = 868). Intestinal type was more frequent in older patients (P = .02). Poorly differentiated tumours were more often observed in non-older patients (P = .009). At stage IV diagnosis, the rate of liver metastases was higher in older patients (P = .02), while peritoneal spread was more represented in non-older patients (P = .002). Although older patients were more often treated with monotherapy (P = .001), they had similar PFS (HR 0.86, 95%CI 0.71-1.03, P = .102) and OS (HR 0.82, 95%CI 0.65-1.02, P = .08) compared to the non-older counterpart. No statistical differences were observed in treatment-related adverse events, hospital admissions, or further treatment lines between age groups. CONCLUSION: In our large cohort study, despite some differences in tumour characteristics and treatment intensity, no survival difference was found between older and non-older patients with advanced GC treated with at least two chemotherapy lines. Incidence of adverse events was similar between age groups.

Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers?

Sorafenib has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma (HCC) since 2007 and numerous studies have investigated the role of markers involved in the angiogenesis process at both the expression and genetic level and clinical aspect. What results have ten years of research produced? Several clinical and biological markers are associated with prognosis. The most interesting clinical parameters are adverse events, Barcelona Clinic Liver Cancer stage, and macroscopic vascular invasion, while several single nucleotide polymorphisms and plasma angiopoietin-2 levels represent the most promising biological biomarkers. A recent pooled analysis of two phase III randomized trials showed that the neutrophil-to-lymphocyte ratio, etiology and extra-hepatic spread are predictive factors of response to sorafenib, but did not identify any predictive biological markers. After 10 years of research into sorafenib there are still no validated prognostic or predictive factors of response to the drug in HCC. The aim of the present review was to summarize 10 years of research into sorafenib, looking in particular at the potential of associated clinical and biological markers to predict its efficacy in patients with advanced HCC.

Multicenter prospective study of angiogenesis polymorphism validation in HCC patients treated with sorafenib. An INNOVATE study protocol.

INTRODUCTION: Although sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS) in multivariate analysis. The ALICE-1 study results were confirmed in the ALICE-2 study, in which VEGF and VEGFR SNPs were analyzed. In the ePHAS study we analyzed the SNPs of eNOS. In univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set. METHODS: This nonpharmacological, interventional, prospective multicenter study aims to determine whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, PFS, and OS of advanced HCC patients treated with sorafenib. The study will involve 160 advanced HCC patients with Child-Pugh class A disease. The primary aim is to validate the prognostic or predictive roles of eNOS, Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to the clinical outcome (PFS) of HCC patients treated with sorafenib. CONCLUSIONS: Overall, our data may suggest that polymorphism analysis of the VEGF, VEGFR-2, HIF and eNOS genes can identify HCC patients who are more likely to benefit from sorafenib.

FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial.

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale.

PURPOSE: In 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance. PATIENTS AND METHODS: We analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples. RESULTS: In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P < .0001). We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%, respectively) (P = .013). CONCLUSIONS: Our findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin.

Validation of a Simple Scoring System to Predict Sorafenib Effectiveness in Patients with Hepatocellular Carcinoma.

BACKGROUND: Sorafenib is recommended for the treatment of advanced-stage hepatocellular carcinoma (HCC). Nonetheless, it is expensive, effective in few patients, and may cause significant adverse effects. Therefore, accurate selection of patients is needed. In a previous study, we constructed a simple scoring system to predict patients' outcomes based on the occurrence of sorafenib adverse effects. OBJECTIVE: The present study aimed to validate this scoring system in a real-life cohort of HCC patients. PATIENTS AND METHODS: Clinical records of 279 outpatients treated with sorafenib in eight Italian centers were retrospectively analyzed. Adverse effects considered to calculate the score were skin toxicity, diarrhea, and arterial hypertension, occurring during the first month of therapy. For each adverse effect, 1 point was assigned if present; and 0 points if absent (resulting in a total score between 0 and 3). RESULTS: Median overall survival (OS) was 10.8 months and median time to progression (TTP) was 5.1 months. At multivariate analysis, performance status, α-fetoprotein (AFP), and Child-Pugh score were independently associated with TTP and OS. A progressive increase of OS and TTP was observed in patients with scores from 0 to 3 (p < 0.001). Six-, 12-, and 24-month survival probabilities were 55.1, 24.5, and 7.9% in score 0 patients, and 100, 80.9, and 46.2% in score 3 patients, respectively. Complete response was observed in one patient (0.4%), partial responses in 41 (15.2%), and stable disease in 117 (43.5%). The disease control rate in patients with scores of 0, 1, 2, and 3 was 34.3, 51.6, 80.9, and 96.3%, respectively (p < 0.001). Complete or partial responses were not observed in score 0 patients. CONCLUSIONS: We have validated a useful scoring system to predict outcomes in sorafenib-treated HCC patients. This score is easy to calculate and suitable for implementation in daily clinical practice.

Mismatch repair deficiency may affect clinical outcome through immune response activation in metastatic gastric cancer patients receiving first-line chemotherapy.

INTRODUCTION: The microsatellite-instable gastric cancer subtype, because of its supposed high antigenic potential, is a promising candidate for immunotherapy. We analyzed if the presence of a defective mismatch repair (MMR) system is associated with other markers of immune response and their relationship with outcome in advanced gastric cancer patients. METHODS: We analyzed the relationship between clinical outcome and MMR status, the presence of tumor-infiltrating lymphocytes (TIL), lymphocytosis, and neutrophil-to-lymphocyte ratio (NLR) in metastatic gastric cancer patients treated with a chemotherapy doublet in the first-line setting. Other stratification factors were sex, age, Eastern Cooperative Oncology Group performance status, adjuvant/neoadjuvant chemotherapy, metastatic sites, and histotype. RESULTS: One hundred three patients were eligible for analysis. Defective MMR was found in 15 patients (14 %), TILs were found in 18 patients (17 %), lymphocytosis was found in 24 patients (23 %), and high NLR was found in 75 patients (72 %). Significant correlations were found between defective MMR and TIL positivity (p = 0.0004), between defective MMR and lymphocytosis (p = 0.0062), between defective MMR and low NLR (p = 0.000069), and between TIL positivity and lymphocytosis (p = 0.000147). All factors had a statistically significant impact on overall survival, although on multivariate analysis only defective MMR (p = 0.0001) and TIL positivity (p = 0.0192) maintained their independent prognostic role. Similar results were observed for progression-free survival, with defective MMR (p = 0.0001) and TIL positivity (p = 0.0195) maintaining their prognostic role on multivariate analysis. CONCLUSIONS: Our analysis confirms the favorable prognosis of metastatic gastric cancer patients with a defective MMR system and suggests that expression of TILs might also be linked to better outcome. Because of the correlation between defective MMR status and measures of immune system activity, this group of patients would be the best candidates for novel immunotherapy-based therapies.

Immune inflammation indicators and implication for immune modulation strategies in advanced hepatocellular carcinoma patients receiving sorafenib.

We evalueted a systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) with the aim to explored their prognostic value in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. 56 advanced HCC patients receiving sorafenib were available for our analysis. Lymphocyte, neutrophil and platelet were measured before beginning of treatment and after one month. Patient with SII ≥ 360 showed lower median PFS (2.6 vs. 3.9 months, P < 0.026) and OS (5.6 vs. 13.9 months, P = 0.027) with respect to patients with SII < 360.NLR ≥ 3 had a lower median PFS (2.6 vs. 3.3 months, P < 0.049) but not OS (5.6 vs. 13.9 months, P = 0.062) than those with NLR < 3. After adjusting for clinical covariates SII and NLR remained an independent prognostic factor for OS. The SII and NLR represent potential prognostic indicator in patients with advanced HCC treated with sorafenib.

eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study.

Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progression-free survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs.14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs.18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.

Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib.

BACKGROUND AND OBJECTIVE: Several studies have reported an association between type 2 diabetes mellitus and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analyses have highlighted a reduction of about 50% in the risk of developing HCC in cirrhotic patients treated with metformin for diabetes. The aim of this study was to evaluate the different outcomes of patients who received or did not receive metformin during treatment with sorafenib. METHODS: We analyzed 93 patients consecutively treated with sorafenib. Forty-two (45.2%) patients were diabetic, of whom 31 were on metformin. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: The concomitant use of sorafenib and metformin was associated with a median PFS of 2.6 months (95% CI 1.9-3.3) compared to 5.0 months (95% CI 2.5-8.2) for patients receiving sorafenib alone (p = 0.029). The median OS of patients treated with the combination was 10.4 months (95% CI 3.9-14.4) compared to 15.1 months (95% CI 11.7-17.8) for those who were not given metformin (p = 0.014). CONCLUSIONS: Our findings could be the result of increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients.

The value of lactate dehydrogenase serum levels as a prognostic and predictive factor for advanced pancreatic cancer patients receiving sorafenib.

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

Hepatocellular carcinoma treatment over sorafenib: epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel?

INTRODUCTION: Sorafenib is currently the only approved therapy in hepatocellular carcinoma (HCC). Alternative first- and second-line treatments are a significant unmet medical need, and several biologic agents have been tested in recent years, with poor results. Therefore, angiogenic pathways and the cytokine cascade remain possible targets in HCC. Recent studies suggest a role of epigenetic processes, associated with the initiation and development of HCC. In this field, DNA methylation, micro-RNAs (miRNAs) and tumor microenvironment cells became a possible new target for HCC treatment. AREAS COVERED: This review explains the possible role of DNA methylation and histone deacetylase inhibitors as predictive biomarkers and target therapy, the extensive world of the promising miRNA blockade strategy, and the recent strong evidence of correlation between HCC tumors and peritumoral stroma cells. The literature and preclinic/clinic data were obtained through an electronic search. EXPERT OPINION: Future research should aim to understand how best to identify patient groups that would benefit most from the prescribed therapy. To overcome the 'therapeutic stranding' of HCC, a possible way out from the current therapeutic tunnel might be to evaluate the major epigenetic and genetic processes involved in HCC carcinogenesis, not underestimating the tumor microenvironment and its 'actors' (angiogenesis, immune system, platelets). We are only at the start of a long journey towards the elucidation of HCC molecular pathways as therapeutic targets. Yet, currently this path appears to be the only one to cast some light at the end of the tunnel.

Metronomic chemotherapy from rationale to clinical studies: a dream or reality?

Metronomic chemotherapy (MC) refers to the close administration of a chemotherapeutic drug for a long time with no extended drug-free breaks. It was developed to overcome drug resistance, partly by shifting the therapeutic target from tumor cells to the tumor vasculature, with less toxicity. Because of this peculiar way of administration, MC can be viewed as a form of long-term 'maintenance' treatment, and can be integrated with standard and conventional chemotherapy in a "chemo-switching" strategy. Additional mechanisms are involved in its antitumor activity, such as activation of immunity, induction of tumor dormancy, chemotherapy-driven dependency of cancer cells, and the '4D effect'. In this paper we report the most important studies that have analyzed these processes. In fact, a number of preclinical and clinical studies in solid tumors as well as in multiple myeloma, have been reported regarding several chemotherapy drugs which have been proposed with a metronomic schedule: vinorelbine, cyclophosphamide, capecitabine, methotrexate, bevacizumab, etoposide, gemcitabine, sorafenib, everolimus and temozolomide. The results of these studies have been sometimes conflicting, highlighting the need to develop reliable tools for patient selection and stratification. However, a more precise evaluation of MC strategies with the ongoing randomized phase II/III clinical is fundamental, because of the strict correlation of this approach with translational research and target therapy. Moreover, because of the low toxicity of MC, these studies will also help to better evaluate the clinical benefit of this treatment, with a special focus on elderly and low performance status patients.