Tivantinib, a new option for second-line treatment of advanced hepatocellular carcinoma? The experience of Italian centers.

In the last decades the management of hepatocellular carcinoma (HCC) has undergone significant changes following the introduction of novel therapies such as sorafenib, which have improved patient survival. Nevertheless, HCC is still the third most common cause of cancer-related death worldwide. The evidence-based therapy for advanced HCC that is unsuitable for locoregional treatment is limited to sorafenib, with no second-line option available.

A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study.

Background: The management of biliary tract cancers (BTCs) is complex due to limited data on the optimal therapeutic approach. This phase II multicenter study evaluated the efficacy and tolerability of vandetanib monotherapy compared with vandetanib plus gemcitabine or gemcitabine plus placebo in patients with advanced BTC.

Patients And Methods: Patients were randomized in a 1 : 1 : 1 ratio to three treatment groups: vandetanib 300 mg monotherapy (V), vandetanib 100 mg plus gemcitabine (V/G), gemcitabine plus placebo (G/P).

Final results of a phase II trial for stereotactic body radiation therapy for patients with inoperable liver metastases from colorectal cancer.

Purpose: To evaluate the feasibility and efficacy of stereotactic body radiation therapy (SBRT) in the treatment of colorectal liver metastases.

Methods: Forty-two patients with inoperable colorectal liver metastases not amenable to radiofrequency ablation (RFA) were treated with SBRT for a total number of 52 lesions. All patients received a total dose of 75 Gy in 3 consecutive fractions.

Stereotactic Ablative Radiotherapy (SABR) in inoperable oligometastatic disease from colorectal cancer: a safe and effective approach.

Background: To assess the safety and efficacy of Stereotactic Ablative Radiotherapy (SABR) in oligometastatic patients from colorectal cancer.

Methods: 82 patients with 1-3 inoperable metastases confined to one organ (liver or lung), were treated with SABR for a total of 112 lesions in an observational study. Prescription dose ranged between 48 and 75 Gy in 3 or 4 consecutive fractions.

MicroRNA-425-3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma.

Background & Aims: Sorafenib is the standard of care in advanced hepatocellular carcinoma (HCC), however no criteria have been established to select patients likely to benefit from this therapy. In this study, we evaluated the predictive role of microRNAs (miRNAs) in this setting of patients.

Methods: We profiled 522 miRNA in a series of 26 HCC patients treated with sorafenib (training set) and validated the results in an independent series of 58 patients (validation set).

An exploratory biomarker study in metastatic tumors from colorectal cancer patients treated with bevacizumab.

Aims: Inhibition of angiogenesis is an effective treatment option for metastatic colorectal cancer. Predictive biomarkers to select patients who are most likely to benefit from this therapeutic strategy are lacking. We conducted a pilot, retrospective biomarker study in a cohort of metastatic colorectal cancer patients treated with bevacizumab.

Tivantinib in MET-high hepatocellular carcinoma patients and the ongoing Phase III clinical trial.

There is no available effective systemic treatment for patients with advanced hepatocellular carcinoma (HCC) who are intolerant of sorafenib or who have disease that has progressed on sorafenib. In Phase I and II studies, tivantinib (ARQ 197), an oral inhibitor of MET, demonstrated promising antitumor activity in patients with HCC, both as monotherapy and in combination with sorafenib. A randomized Phase II trial in second-line HCC showed improved overall survival (hazard ratio: 0.

Lack of KRAS, NRAS, BRAF and TP53 mutations improves outcome of elderly metastatic colorectal cancer patients treated with cetuximab, oxaliplatin and UFT.

There is conflicting evidence on the predictive role of KRAS status when cetuximab is added to oxaliplatin-based regimens. This study investigated the impact of KRAS, NRAS, BRAF, PI3KCA and TP53 status on outcome of elderly metastatic colorectal cancer patients enrolled in TEGAFOX-E (cetuximab, oxaliplatin and oral uracil/ftorafur--UFT) phase II study. Twenty-eight patients were enrolled and all were evaluable for safety and activity.

SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono-institutional experience.

Background: To assess the efficacy and safety of stereotactic body radiotherapy (SBRT) in patients with either unresectable locally advanced pancreatic adenocarcinoma or by locally recurrent disease after surgery.

Methods: Between January 2010 and October 2011, 30 patients with unresectable or recurrent pancreatic adenocarcinoma underwent exclusive SBRT. Twenty-one patients (70%) presented with unresectable locally advanced disease and 9 patients (30%) showed local recurrence after surgery.

A phase II randomized dose escalation trial of sorafenib in patients with advanced hepatocellular carcinoma.

Background: Sorafenib has proven survival benefits in patients with advanced hepatocellular carcinoma (HCC). The viability of continuing sorafenib at a higher dosage in patients who experienced radiologic disease progression was investigated.

Methods: Patients who experienced disease progression while on sorafenib 400 mg twice daily were randomized to sorafenib 600 mg twice daily (n = 49) or best supportive care (n = 52).

Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma.

Purpose: Preclinical studies show that sorafenib, a multitarget kinase inhibitor, displays anti-proliferative, anti-angiogenic, and pro-apoptotic properties in hepatocellular carcinoma (HCC). However, the determinants of sorafenib sensitivity in vivo remain largely unknown.

Methods: We assessed the expression of Mcl-1, activated/phosphorylated extracellular signal-regulated kinase (pERK) 1/2, and activated/phosphorylated AKT (pAKT) in pretreatment tumor specimens from 44 patients with advanced HCC who received sorafenib.

Tivantinib: a new promising mesenchymal-epithelial transition factor inhibitor in the treatment of hepatocellular carcinoma.

Tivantinib (ARQ 197) is an orally administered, selective small molecule that inhibits mesenchymal-epithelial transition factor (MET) via a novel, ATP-independent binding mechanism. Preclinical studies demonstrated that tivantinib has a broad-spectrum anti-tumor activity, especially in cells expressing high levels of MET. A randomized Phase II study in second-line hepatocellular carcinoma showed statistically significant improvement in time to progression with tivantinib compared to a placebo.

A Phase-1b study of tivantinib (ARQ 197) in adult patients with hepatocellular carcinoma and cirrhosis.

Background: The mesenchymal-epithelial transition factor (MET) receptor is dysregulated in hepatocellular carcinoma (HCC), and tivantinib (ARQ 197) is an oral, selective, MET inhibitor.

Methods: This Phase-1b study assessed tivantinib safety as primary objective in patients with previously treated HCC and Child-Pugh A or B liver cirrhosis. Patients received oral tivantinib 360 mg twice daily until disease progression or unacceptable toxicity.

Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study.

Background: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma.

Methods: In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy.

Phase I pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors.

Background: The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours.

Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

Background: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B.

Patients And Methods: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily.

The role of hepatic metastases and pulmonary tumor burden in predicting survival after complete pulmonary resection for colorectal cancer.

Objective: Our objective was to investigate the role of clinicopathologic factors as predictors of outcome after complete pulmonary resection for metastatic colorectal cancer.

Methods: Consecutive patients undergoing radical pulmonary resection for colorectal cancer at our institution were included in the study. Clinicopathologic variables including sex, age, site and stage of the primary tumor, disease-free interval, prior hepatic resection, timing of pulmonary metastases, preoperative chemotherapy, type of pulmonary resection, number, size, and location of pulmonary metastases, and thoracic lymph node involvement were retrospectively collected and investigated for prognostic significance.

Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma.

Background & Aims: Tumor shrinkage has been considered a fundamental surrogate efficacy measure for new cancer treatments. However, in patients treated with sorafenib for advanced hepatocellular carcinoma (HCC), tumor shrinkage rarely accompanies increased survival, thereby questioning the prognostic value of imaging-based Response Evaluation Criteria in Solid Tumors (RECIST). We investigated the prognostic usefulness of a decrease in serum alpha-fetoprotein (AFP) and compared it to RECIST.

Detection of somatostatin receptor subtypes 2 and 5 by somatostatin receptor scintigraphy and immunohistochemistry: clinical implications in the diagnostic and therapeutic management of gastroenteropancreatic neuroendocrine tumors.

Aims And Background: Somatostatin receptor scintigraphy (SRS) is the standard method for the detection of somatostatin receptors (SSTRs). It is commonly used in gastroenteropancreatic neuroendocrine tumor (GEP-NET) staging, and represents the criterion of choice for treatment with somatostatin (SST) analogs. Immunohistochemistry (IHC) was reported as a reliable method for the detection of SSTRs with theoretically superior sensitivity over SRS.

Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism.

Background And Objectives: Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. The growth factor, progranulin, is overexpressed in a number of tumours. The study aims were to assess the expression of progranulin in cholangiocarcinoma and to determine its effects on tumour growth.

Optimized management of advanced hepatocellular carcinoma: four long-lasting responses to sorafenib.

The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate. Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC. Nevertheless, in clinical practice, some patients are discontinuing this drug because of side effects, and misinterpretation of radiographic response may contribute to this.

Adrenal metastases from adenocarcinoma of the esophagogastric junction: adrenalectomy and long-term survival.

Treatment of adrenal metastases from cancer of the esophagogastric junction (EGJ) is not defined. The aim of the present work is to analyze retrospectively our experience in treating patients with adrenal metastases from EGJ adenocarcinoma. 102 patients with Siewert 1 or 2 EGJ adenocarcinoma underwent esophagectomy between May 2001 and Jan 2009.