Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second-line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child-Pugh A, 83% performance status (PS) 1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3-4.9) months, resulting from 4.6 (3.3-5.7) months for 123 progressors, 7.3 (6.0-10.0) months in 77 with adverse effects, and 1.8 (1.6-2.4) months in 60 decompensated patients (P < 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second-line therapy had a PSS of 5.3 (4.6-7.1) months, which was dependent on reasons of discontinuation (P 5 0.004), PS (P < 0.001), macrovascular invasion (P < 0.001), and extrahepatic metastases (P < 0.002). Conclusion: Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second-line therapy. (HEPATOLOGY 2015;62:784-791)

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• DSM-TACE is safe and effective as second-line treatment in HCC patients dismissing or ineligible for sorafenib • DSM-TACE allows the temporary occlusion of the smaller arterial vessels, improving overall therapeutic effectiveness by reducing the immediate wash-out of the cytostatic agent • DSM-TACE also decreases the risk of systemic toxicity and post-embolic syndrome.

Alterations in the transcriptional factor c-MYC could be involved in the anti-EGFR resistance in metastatic colorectal cancer (mCRC). The c-MYC expression was evaluated in 121 RAS and BRAF wild-type mCRC before treatment with anti-EGFR+Folfiri therapy and in 33 subsequent metastases collected during target therapy (TT) or in TT resistance phase. We analyzed the expression and the functional role of some c-MYC linked miRNAs (miR-31-3p, miR-143 and miR-145) in our patient group and in two CRC cell lines, also performing a c-MYC target PCR array. Patients with higher c-MYC expression (HME) showed a significant lower PFS and OS when compared to those with low c-MYC expression (LME). HME pattern was significantly more frequent in the metastases after TT and significantly associated to anti-EGFR molecular resistance alterations. We also found a significant correlation between the expression of the above-mentioned c-MYC linked miRNAs, c-MYC level and anti-EGFR resistance. Moreover, expression gene profiling pointed out the pivotal role of c-MYC in CRC-related cell-cycle, apoptosis, signal transduction and cell-growth pathways. c-MYC expression might distinguish patients with a lower PFS and OS in anti-EGFR treated mCRC. The individuation of some miRNAs involved in the c-MYC pathway regulation and the downstream c-MYC effector genes could provide a new possible target to overcome the anti-EGFR resistance in mCRC.

Early recognition of sarcopenia is beneficial for prevention of cancer cachexia and detection of patients at potential risk of serious adverse events. Gefitinib dosage should be reduced and modulated in sarcopenic patients.

Background:Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent.Methods:This was a multicentre, phase 2 trial, planned according to a two-stage Simon’s optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150–200 mg m−2 per day on days 1–5 every 28 days.Results:From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively.Conclusions:Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

In our exploratory analysis GEM seems as effective as FOLFIRINOX in terms of survival with a better safety profile in hENT1 positive metastatic pancreatic cancer.