Caterina Vivaldi

FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO)

BACKGROUND The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12-13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies. PATIENTS AND METHODS We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², and folinate 200 mg/m² on day 1, followed by fluorouracil 3000 mg/m² as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12-13-61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m² after two of the first three patients reported grade 3-4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR). RESULTS Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7-12.9 months). After amendment, most common grade 3-4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered. CONCLUSIONS Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras-BRAF wild-type patients are promising.

Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer

Background:The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model.Methods:Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models.Results:The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215–0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370–0.891), progression-free survival after first-line CT ⩾6 months (P=0.027; HR, 0.633; 95% CI 0.422–0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392–0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001).Conclusions:Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.

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.

First‐line treatment with FOLFOXIRI for advanced pancreatic cancer in clinical practice: patients' outcome and analysis of prognostic factors

FOLFIRINOX is a standard first‐line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty‐seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19–9.81) and 12 months (95% CI 9.75–14.25), respectively. Response rate was 38.6%, while disease‐control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42–3.59) and neutrophil‐lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38–4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good‐risk (0 factors, 38 pts), intermediate‐risk (1 factor, 49 pts) and poor‐risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.

Bevacizumab in the pre-operative treatment of locally advanced rectal cancer: A systematic review

Despite advances in the management of patients with locally advanced, non-metastatic rectal adenocarcinoma (LARC), prognosis remains largely unsatisfactory due to a high rate of distant relapse. In fact, currently available neoadjuvant protocols, represented by fluoropyrimidine-based chemo-radiotherapy (CT-RT) or short-course RT, together with improved surgical techniques, have largely reduced the risk of local relapse, with limited impact on distant recurrence. Available results of phase III trials with additional cytotoxic agents combined with standard CT-RT are disappointing, as no significant reduction in the risk of recurrence has been demonstrated. In order to improve the control of micrometastatic disease, integrating targeted agents into neoadjuvant treatment protocols thus offers a rational approach. In particular, the antiangiogenic agent bevacizumab has demonstrated synergistic activity with both CT and RT in pre-clinical and clinical models, and thus may represent a suitable companion in the neoadjuvant treatment of LARC. Preliminary results of phase I-II clinical studies are promising and suggest potential clinical parameters and molecular predictive biomarkers useful for patient selection: treatment personalization is indeed the key in order to maximize the benefit while reducing the risk of more complex neoadjuvant treatment schedules.

Identification of Responders to Sorafenib in Hepatocellular Carcinoma: Is Tumor Volume Measurement the Way Forward?

Objectives: Early assessment of hepatocellular carcinoma (HCC) response during sorafenib (SO) treatment is challenging, since tumor necrosis, extension and radiological appearance can be inhomogeneous. We evaluated the predictive value of different imaging criteria - such as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, European Association for the Study of the Liver (EASL), modified RECIST (mRECIST), tumor density and volume variations - in the early follow-up of SO treatment. Methods: The study included 22 patients. CT images from baseline and 2 months were reviewed to assess response according to RECIST 1.1, mRECIST, EASL, Chois criteria (decreased tumor density by ≥15%) and arterial-enhancing tumor volume ratio; α-fetoprotein (AFP) variations were expressed as AFP ratio. Results: The response criteria and volume measurements were reproducible (k > 0.80). The overall disease control rate was 40.9% by EASL and mRECIST, and 27.3% by RECIST 1.1; a ≥15% decrease in tumor density was observed in 9 patients (40.9%). The mean volume ratio was 1.73 ± 2.12, the mean AFP ratio 14 ± 37. The 1-year survival rate was 65.9%. Volume ratio was the only predictive factor for survival, with 1-year cumulative survival rates of 90% for volume ratios ≤1.1 and of 45.4% for volume ratios >1.1 (p = 0.04). Conclusions: Tumor volume measurements are reproducible and might provide an early predictive marker of response in HCC patients treated with SO.

Dissecting signaling pathways in hepatocellular carcinoma: new perspectives in medical therapy

Prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor and is largely influenced by associated liver comorbidities. Moreover, effective treatment alternatives are limited; with the exception of the multitargeted inhibitor sorafenib, established options in the treatment of advanced HCC no longer amenable with ablative or locoregional procedures are lacking. In light of the limited efficacy of chemotherapy in this setting, great efforts have been made in the definition of targetable molecular pathways with a central role in the progression of HCC. Targeting angiogenesis, growth factor receptors, intracellular transduction pathways, or mechanisms of gene-expression regulation represents the main way to improve patient outcome. At the same time, identifying clinical and biological factors, which may help selecting patients with higher chances of benefit, is essential in order to hasten drug development and maximize treatment efficacy.

Minor-but-complex liver resection: An alternative to major resections for colorectal liver metastases involving the hepato-caval confluence

Abstract Major hepatectomy (MH) is often considered the only possible approach for colorectal liver metastasis (CRLM) at the hepato-caval confluence (CC), but it is associated with high morbidity and mortality. With the aim to reduce MH, we developed the “minor-but-complex” (MbC) technique, which consists in the resection of less than 3 adjacent liver segments with exposure of the CC and preservation of hepatic outflow until spontaneous maturation of peripheral intrahepatic shunts between main hepatic veins. We have evaluated applicability and outcome of MbC resections for the treatment of CRLM involving the CC. In this retrospective cohort study, all consecutive liver resections (LR) performed for CRLM located in segments 1, 7, 8, or 4a were classified as MINOR – removal of <3 adjacent segments; MbC – removal of <3 adjacent segments with CC exposure; and MH – removal of ≥3 adjacent segments. The rate of avoided MH was obtained by the difference between the rate of potentially MH (PMH) plus potentially inoperable cases and the rate of the MH performed. Taking into account that postoperative mortality is mainly related to the amount of resected liver, MbC was compared with minor resections for safety, complexity, and outcome. Of the 59 LR analyzed, 29 (49.1%) were deemed PMH and 4 (6.8%) potentially inoperable. Eventually, MH was performed only in 8 (13.5%) with a decrease rate of 42.4%. Minor LR was performed in 23 (39.0%) and MbC LR in 28 (47.5%) patients. Among MbC cases, 32.1% had previous liver treatments, 39.3% required vascular reconstruction (no reconstructed vessel thrombosis occurred before maturation of peripheral intrahepatic shunts between main hepatic veins), and 7.1% had grade IIIb–IV complications, their median hospital stay was 9 days and 90-day mortality was 0%. After a median follow-up of 22.2 months, oncological results were comparable with those of minor resections. MbC hepatectomy lowers the need for MH and allows for the resection of potentially inoperable patients without negative impact on safety and survival.

Second-line therapy for advanced pancreatic cancer: Evaluation of prognostic factors and review of current literature

BACKGROUND FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC) and no accepted second-line regimen exists. MATERIAL & METHODS We enrolled 71 aPC patients progressed to modified FOLFIRINOX (mFOLFIRINOX) treated with second-line chemotherapy. RESULTS Five partial responses (7.1%) and 19 (27.1%) disease stabilizations were reported. After a median follow-up of 20.1 months, median progression-free survival was 2.5 months (95% CI: 2.1-2.9 months) and median overall survival was 6.2 months (95% CI: 5.3-7.1 months). At multivariate analysis, CA19.9 level ≥ 59 upper normal limit resulted associated with worse survival (hazard ratio: 2.32; 95% CI: 1.12-4.78; p = 0.023). CONCLUSION Salvage chemotherapy could be useful for a subgroup of aPC patients. Prognostic factors might be helpful to identify patients with greater benefit.

Molecular and pathological characterization of the EZH2 rs3757441 single nucleotide polymorphism in colorectal cancer

BackgroundThe enhancer of zeste-homolog 2 (EZH2) is involved in cancer development through gene silencing by trimethylation of lysine 27 of histone 3 (H3K27me3). The C/C genotype for the EZH2 rs3757441 single-nucleotide polymorphism (SNP) is linked with poor prognosis in metastatic colorectal cancer (CRC), but molecular and pathological characterization of this SNP is lacking.Methods119 primary CRCs were analyzed. SNP was evaluated by real-time PCR from colonic healthy tissue, while EZH2 and H3K27me3 expression were studied by immunohistochemistry. We primarily looked for correlation between EZH2 rs3757441 genotypes and EZH2/H3K27me3 expression. Potential associations between EZH2/H3K27me3 expression and clinico-pathological features or KRAS exon 2 and BRAF exon 15 mutations were secondary endpoints. Statistical analysis was performed by chi-square test, T-test or ANOVA.ResultsThe C/C genotype was significantly associated with higher EZH2 (100 vs. 44 %; P = 0.019) and H3K27me3 (100 vs. 38 %; P = 0.009) staining intensity compared with C/T and T/T. EZH2 3+ staining significantly correlated with stronger H3K27me3 expression (P = 0.039). KRAS and BRAF mutations were not associated with EZH2 or H3K27me3 expression.ConclusionEZH2 rs3757441 C/C genotype is associated with stronger EZH2 and H3K27me3 immunoreactivity in primary CRC: this SNP may serve as a promising biomarker for EZH2-targeting agents and may add independent information to KRAS and BRAF testing.