Antiangiogenic agents after first line and sorafenib plus chemoembolization: A systematic review

Transarterial chemoembolization (TACE) is the standard treatment for intermediate stage, although the combination of TACE with sorafenib may theoretically benefit HCC patients in intermediate stage. Owing to the significant antiangiogenic effect of sorafenib and the limitation of TACE, it is rational to combine them. Though the strategy of combining TACE and sorafenib has been increasingly used in patients with unresectable HCC but the current evidence is controversial and its clinical role has not been determined yet. In first-line therapy, patients receiving sorafenib had increased overall survival and progression free survival. Therefore several antiangiogenic agents have entered clinical studies on HCC, many with negative results. This review discusses the current drug development for patients with HCC and role of TACE plus sorafenib

Familial adenomatosis polyposis–related desmoid tumours treated with low-dose chemotherapy: results from an international, multi-institutional, retrospective analysis

[Introduction] Desmoid tumour (DT) is a locally aggressive fibroblastic proliferative disease representing the most common extraintestinal manifestation of familial adenomatosis polyposis (FAP). As data on the activity of chemotherapy in these patients are limited, we examined the outcomes of patients treated with low-dose methotrexate (MTX)+vinca alkaloids (vinorelbine or vinblastine).[Patients and methods] We retrospectively reviewed clinical and outcome data from all patients with confirmed FAP-associated DTs treated with weekly MTX+vinca alkaloids in seven European sarcoma reference centres between January 2000 and December 2018. Radiological responses were assessed using RECIST V.1.0 and V.1.1. The Kaplan-Meier method associated to the log-rank test was used to estimate and compare survival curves.[Results] We identified 37 patients (median age 29 years, range 7–44). According to RECIST, 20/37 (54.1%) patients achieved partial response (PR), 15/37 (40.5%) patients had stable disease and 2/37 (5.4%) had progressive disease as best response. Overall, the median progression-free survival (PFS) was 6.5 years (range, 0.3–12.1 years). In the subset of patients achieving PR as best response, the median PFS was not reached. In a subset of 11 patients with progressive disease offered MTX+vinca alkaloids rechallenge (after chemotherapy withdrawal following prolonged disease control), the disease control rate was 100%, resulting in a median PFS after rechallenge of 5.8 years.[Conclusions] This is the largest series on the activity of low-dose chemotherapy in patients with FAP-related DT. In this population, MTX+vinca alkaloids is an active combination, as already reported in patients with sporadic DT

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

Impact of metformin, statin, aspirin and insulin on the prognosis of uHCC patients receiving first line Lenvatinib or Atezolizumab plus Bevacizumab

: Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1-3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1-3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0-2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1-2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group

Adjuvant Imatinib in Patients with GIST Harboring Exon 9 KIT Mutations : Results from a Multi-institutional European Retrospective Study

Purpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopatho-logic variables with survival was evaluated in a large multi-institutional European cohort. Experimental Design: Data from 185 patients were retrospec-tively collected in 23 European GIST reference centers. Propen-sity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Uni-variate and multivariate unweighted and weighted Cox propor-tional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival. Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79- 2.28]. The variables consistently associated with worse survival out-comes were high mitotic index and nongastric tumor location. Conclusions: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.Peer reviewe

Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients

Introduction: The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab.Materials and methods: A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line.Results: 49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6 months) and atezolizumab plus bev-acizumab first-line (15.7 months; p = 0.12; hazard ratio [HR] = 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who under-went trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8 months, p < 0.01; HR = 0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0 months) and those who under-went TACE (15.9 months) had a significative longer OS than patients treated with sorafenib (14.2 months; respectively, p = 0.01; HR = 0.45, and p < 0.05; HR = 0.46).Conclusion: Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy

Emerging kinase inhibitors of the treatment of gastric cancer

Introduction: Gastric cancer (GC) is the fifth most common malignancy in theworld. In the last years, for the first time in literature, the addition of atargeted therapy to standard chemotherapy has proved to prolong medianoverall survival. In this scenario, kinase inhibitors (KIs), smaller intracellularagents, could be an interesting and novel type of targeted treatment ofmetastatic GC both in first and further lines of therapy.Areas covered: Several KI have been evaluated in the preclinical setting. Thisreview will underline the most relevant targeted pathways involved in GCtumorigenesis and disease progression including EGFR, VEGFR, c-MET,mTOR, fibroblast growth factor receptor, Src and Aurora kinases.Expert opinion: Despite the good results of TOGA, RAINBOW and REGARDtrials about the addition of monoclonal antibodies to standard of care inGC, the addition of KI seems not to achieve comparable interesting resultsin management of GC. However, an improved patient selection before andduring treatment according to molecular characteristics, as well as combinationstudies evaluating the synergistic effect of combination schedules ofdifferent KIs and standard chemotherapy, or KI plus KI or KI plus antibodiesbasedtherapy may reveal interesting results and lead to understandmechanisms of multi-drug resistance

New frontiers in the medical management of gastrointestinal stromal tumours

The tyrosine kinase inhibitor (TKI) imatinib has radically changed the natural history of KIT-driven gastrointestinal stromal tumours (GISTs). Approved second-line and third-line medical therapies are represented by the TKIs sunitinib and regorafenib, respectively. While imatinib remains the cardinal drug for patients with GISTs, novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatments with the approved TKI, or to treat subsets of GISTs driven by rarer molecular events. Here, we review the therapy of GISTs, with a particular focus on the newest drugs in advanced phases of clinical testing that might soon change the current therapeutic algorithm

Sorafenib and dacarbazine in soft tissue sarcoma: A single institution experience

Background: To report on the anti-tumour activity and toxicity of sorafenib combined with dacarbazine in patients with pre-treated advanced soft tissue sarcoma (STSs). Methods: From November 2009 to December 2010, 17 patients affected by STSs who had failed two or more regimen of chemotherapy, with a performance status <= 2 and measurable disease were consecutively enrolled in the present case series. Sorafenib was administered at 400 mg b.i.d. continuous dosing in combination with dacarbazine, 300 mg/m(2) for three consecutive days every 21 days until disease progression or intolerable toxicity. Results: Fourteen patients were evaluable for response. Three patients stopped treatment early and were not evaluable for response. One of them died for not disease-dependent reason, the other two went off-study due to rapid clinical worsening, without performing radiologic evaluation. No complete responses were registered. As by RECIST, partial responses (PR) were observed in three patients (21%), stable disease (SD) in six patients (43%) and progressive disease (PD) in five patients (36%), with a clinical benefit rate (RECIST PR+SD > 6months) of 64%. The median time of progression was 20 weeks (range: 9 - 34 weeks) and the median overall survival was 43 weeks (range: 17 - 65 weeks). The main toxi-cities were neutropenia (36%), thrombocytopenia (36%), hypertension (36%), fatigue (50%) and skin reactions (57%). Five patients required dose reductions (both dacarbazine and sorafenib) for toxicity and three patients required only sorafenib reduction for dermatologic reactions. One patient was taken off-study because of severe sorafenib-related dermatologic toxicity. Conclusions: Sorafenib and dacarbazine combination seems to be an active and safety regimen in pre-treated STSs. A Phase II trial is ongoing in patient affected by selected sarcoma subtypes