The potential of PIVKA-II as a treatment response biomarker in hepatocellular carcinoma: a prospective United Kingdom cohort study.

Prothrombin induced by vitamin K absence II (PIVKA-II) has recently been validated internationally as a diagnostic biomarker for hepatocellular carcinoma (HCC), as part of the GALAD model. However, its role as a treatment response biomarker has been less well explored. We, therefore, undertook a prospective study at a tertiary centre in the UK to evaluate the role of PIVKA-II as a treatment response biomarker in patients with early, intermediate and advanced stage HCC. In a cohort of 141 patients, we found that PIVKA-II levels tracked concordantly with treatment response in the majority of patients, across a range of different treatment modalities. We also found that rises in PIVKA-II levels almost always predated radiological progression. Among AFP non-secretors, PIVKA-II was found to be informative in 60% of cases. In a small cohort of patients undergoing liver transplantation, pre-transplant PIVKA-II levels predicted for microvascular invasion and poorer differentiation. Our results demonstrate the potential utility of PIVKA-II as a treatment response biomarker and in predicting microvascular invasion, in a Western population. PIVKA-II demonstrated improved performance over AFP but, as a single biomarker, its performance was still limited. Further larger prospective studies are recommended to evaluate PIVKA-II as a treatment response biomarker, within the GALAD model.

Intention to treat outcomes among patients with pancreatic cancer treated using International Study Group on Pancreatic Surgery recommended pathways for resectable and borderline resectable disease.

BACKGROUND: The International Study Group on Pancreatic Surgery recommends upfront surgery for resectable pancreatic cancer or borderline resectable-venous (BR-V) disease and neoadjuvant therapy (NAT) among those with arterial involvement (BR-A or locally advanced, LA). Though neoadjuvant therapy (NAT) is a promising strategy, outcomes are rarely reported on intention-to-treat (ITT) basis. This study presents ITT outcomes where pathways to surgery were in line with International Study Group on Pancreatic Surgery guidelines. METHODS: Patients recommended for potentially curative treatment with PDAC between 2012 and 2017 (n = 345) were classified as resectable, BR-A/BR-V or LA, according to NCCN criteria. The primary outcome was overall survival. Secondary outcomes were resection rates, positive margins and toxicity among patients receiving NAT. RESULTS: At surgery, the resection rates were 78% (172/221), 65% (35/54) and 54% (21/39) for those with resectable, BR-V and BR-A/LA disease, respectively (P < 0.0001). The median survival of those resected in the BR-A/LA cohort was 31 months. However, on an ITT basis, there was no significant difference in survival between resectable, BR-V and BR-A/LA disease (median: 19 versus 15 versus 19 months; P = 0.585). On review, some 31 (44%) patients of the BR-A/LA cohort either did not receive or did not complete NAT. CONCLUSION: To realize benefits of NAT, more patients need to complete NAT and to undergo resection. Upfront resection for BR-V disease is associated with equivalent outcomes to upfront surgery for resectable disease or NAT for BR-A/LA disease. Strategies to increase the proportion of patients who complete NAT and undergo resection are needed.

The role of down staging treatment in the management of locally advanced intrahepatic cholangiocarcinoma: Review of literature and pooled analysis.

BACKGROUNDS/AIMS: Approximately 60-80% of patients with intrahepatic cholangiocarcinoma (iCCA) are not suitable for surgical resection due to advanced disease at presentation. This review assesses the role of surgical resection followed by down staging treatment in the management of patients with locally advanced iCCA. METHODS: A systematic review and pooled analysis were performed of the relevant published studies published between January 2000-December 2018. The primary outcome measure was overall survival. Secondary outcome measures were rates of clinical benefit, margin-negative (R0) resections, overall and surgery-specific complications, and post-operative mortality. RESULTS: Eighteen cohort studies with 1880 patients were included in the review. The median overall survival in all patients was 14 months (range, 7-18 months). Patients undergoing resection following down staging had significantly longer survival than those who did not (median: 29 vs. 12 months, p<0.001). The Clinical Benefit Rate with this strategy (complete response+partial response+stable disease) was 64% (244/383), ranging from 33-90%. Thirty-eight percent of the patients underwent resections with a 60% R0 resection rate and 6% postoperative mortality. CONCLUSIONS: Although the evidence to support the benefits of NAT for iCCA is limited, the review supports the use of down staging treatment and also surgical resection in the cohort with response to NAT in order to improve long-term survival in patients with locally advanced iCCA.

Development and validation of a risk score to predict the overall survival following surgical resection of hepatocellular carcinoma in non-cirrhotic liver.

BACKGROUND: The aim of this study was to develop and validate a risk score to predict overall survival (OS) in patients undergoing surgical resection for hepatocellular carcinoma in non-cirrhotic liver (NC-HCC). METHODS: Patients who underwent resection for NC-HCC between 2004 and 2013 were identified from the SEER database. A derivation set of 75% of this cohort was used to develop a risk score. This was then internally validated on the remaining patients, and externally validated using a cohort of patients from The HPB Unit, Birmingham, UK. RESULTS: A total of 3897 patients were included from the SEER database, with a median post-diagnosis survival of 59 months. In the derivation set, multivariable analyses identified male sex, increasing tumour size, the presence of multiple tumours, bilobar tumours and major vascular invasion as adverse prognostic factors. A risk score generated from these factors was significantly predictive of OS, and was used to classify patients into low, medium and high-risk groups. These groups had a five-year OS of 69%, 51% and 19% in the internal, and 73%, 50% and 45% in the external validation sets. CONCLUSION: The proposed risk score is useful in the selection, pre-operative consenting and counselling of patients for surgery and to allow patients to make an informed decision regarding treatment.

Observational Study to Assess Quality of Life in Patients with Pancreatic Neuroendocrine Tumors Receiving Treatment with Everolimus: The OBLIQUE Study (UK Phase IV Trial).

BACKGROUND/AIMS: To assess health-related quality of life (HRQoL), treatment patterns, and clinical outcomes of adult (≥18 years) patients with advanced (unresectable or metastatic) pancreatic neuroendocrine neoplasms (PanNENs) treated with everolimus in routine clinical practice. METHODS: In a prospective, non-interventional, multi-center study patients administered at least one 10 mg dose of everolimus were evaluated for change in HRQoL (EORTC QLQ-C30 Global Health Status scale) from baseline after 6 months treatment (primary endpoint). Secondary endpoints included disease-specific HRQoL measures (EORTC QLQ-G.I.NET21), clinical outcomes, everolimus treatment patterns, and safety. RESULTS: Forty-eight patients were recruited (between August 2013 and March 2015); the median treatment duration was 27.8 months. EORTC QLQ-C30 Global Health score was not significantly different from baseline after 6 months of treatment (mean difference -1.9 points, p = 0.660, n = 30). In pairwise analyses, the only significant changes in HRQoL from baseline were for EORTC QLQ-C30 physical functioning score at month 3 (adjusted mean difference -8.8 points, p = 0.002, n = 36) and the EORTC QLQ-G.I.NET21 disease-related worries scores at months 1 and 2 (adjusted mean differences: -11.5 points [p = 0.001, n = 44] and -8.8 points [p = 0.017, n = 43], respectively). Disease progression or death was recorded in 44.4% (n = 20/45) patients during follow-up; median progression-free survival was 25.1 months and the cumulative survival rate at 3 years was 71%. No new safety signals were detected. CONCLUSIONS: The OBLIQUE study demonstrates that HRQoL is maintained in patients with PanNENs during treatment with everolimus in a UK real-world setting. This study adds to the limited HRQoL data available in this patient group.

Gemcitabine-Induced Cardiotoxicity in Patients Receiving Adjuvant Chemotherapy for Pancreatic Cancer: A Case Series.

Gemcitabine is not considered a cardiotoxic agent generally; so far only very few case reports have been reported in the literature on different aspects of cardiac side effects. Here we report a case series of 3 patients who developed congestive cardiac failure, when treated with gemcitabine monotherapy in the adjuvant setting for pancreatic cancers. Adjuvant chemotherapy with gemcitabine has been the standard of care for pancreatic cancer patients after successful surgery since the results of the CONKO-001 and ESPAC3 study were published. Gemcitabine was administered on days 1, 8, and 15 of a 28-day cycle at 1,000 mg/m2. All 3 patients developed symptoms suggestive of cardiac failure with a drop in ejection fraction on echocardiography, and responded to conservative treatment for heart failure after withdrawal of gemcitabine therapy. Early withdrawal of gemcitabine chemotherapy is recommended in addition to a need for studies required to evaluate the mechanism of cardiotoxicity. As per available literature, patients with diabetes and having received a total dose greater than 15,000 mg/m2 are generally at a higher risk and require close surveillance.

Non-secretion of AFP and neutrophil lymphocyte ratio as predictors for survival in hepatocellular carcinoma patients treated with sorafenib: a large UK cohort.

BACKGROUND: Sorafenib is the current standard of care for patients with advanced or metastatic hepatocellular carcinoma. Currently no universally agreed model exists correlating the Neutrophil Lymphocyte ratio (NLR) and non-secretion of AFP with the survival of HCC patients treated with sorafenib. PATIENTS AND METHODS: We retrospectively analysed patient records with a confirmed diagnosis of HCC treated with sorafenib between April 2009 and March 2014. Survival analysis was performed using the Kaplan-Meier method and Cox regression. RESULTS: Patients separated into groups based on NLR (≤3 or >3), or AFP secretion profile (<7 ng/ml or ≥7 ng/ml) derived diverging Kaplan-Meier curves for overall survival (OS). The median OS in those with NLR ≤3.0 was 9.0 months (95% CI: 7.7-11.1 months) and in those with NLR >3.0 it was 6.0 months (95% CI: 4.9-8.2 months) [HR 1.32 (95% CI: 0.96-1.80)]. The median overall survival post sorafenib was higher in the "non-secretor" AFP group. OS for AFP <7 ng/ml was 10.0 months (95% CI: 7.7-19.3 months) compared to AFP ≥7ng/ml: 6.6 months (95% CI: 5.3-8.4 months) [HR 1.64 (95% CI: 1.15-2.33)]. CONCLUSION: NLR and AFP non - secretion at diagnosis are potential significant prognosticators for overall survival from initiation of sorafenib.

Exceptional serological and radiological response to sorafenib in 2 patients with advanced hepatocellular carcinoma and chronic hepatitis C viral infection: case report and review of the literature.

BACKGROUND: In patients with advanced hepatocellular carcinoma (HCC), the multikinase inhibitor sorafenib is the only systemic treatment that has been shown to increase overall survival. However, similar to other tyrosine kinase inhibitors, most patients achieve disease stabilisation radiologically, and only 2-3% of patients achieve a partial response. Recent exploratory subgroup analyses of the large phase 3 trials have demonstrated that patients with chronic hepatitis C virus (HCV) infection associated HCC survive longer than those who are negative for HCV. The mechanism underlying this currently remains unknown. A small number of cases of complete response to sorafenib treatment have now been reported worldwide, however a prolonged response has only been reported in 2 cases, both of whom had HCV-related HCC. CASE PRESENTATION: A 55 year old gentleman was diagnosed with hepatocellular carcinoma and concomitant chronic hepatitis C viral infection. He progressed following transarterial chemoemoblisation treatment and was commenced on sorafenib treatment. His serum alphafetoprotein level normalised within 2 months of treatment and he achieved an almost complete radiological response. This response was maintained for 20 months before the patient progressed. A 75 year old lady was diagnosed with advanced hepatocellular carcinoma and concomitant chronic hepatitis C viral infection. She was commenced on sorafenib treatment but required early dose reductions due to palmar plantar erythrodysesthesia, and liver decompensation. Despite this she achieved an excellent serological and radiological response that was maintained for 24 months. CONCLUSIONS: Our two cases show that patients with HCV-associated HCC can attain excellent responses to sorafenib treatment that is durable. Furthermore, such exceptional responses can be achieved even with dose reductions and treatment breaks.

Biliary stenting in advanced malignancy: an analysis of predictive factors for survival.

PURPOSE: Stenting of the biliary tree is a common palliative procedure to relieve obstructive jaundice in advanced malignancy. Although effective in relief of biliary obstruction and palliation of symptoms, little information is available on predictive factors for survival post-procedure. This retrospective study sought to assess factors influencing post-procedure survival in cancer patients after biliary stenting. METHODS: Case notes of all patients from a regional academic cancer center, who underwent biliary stenting for obstructive jaundice related to malignancy during 2008 and 2009 were reviewed. We collected epidemiological, biochemical, treatment and survival data on all patients. We used Kaplan-Meyer analysis to assess survival from day of first biliary stenting (adjusted for cancer types), and the Cox proportional hazards model for univariate and multivariate analysis. RESULTS: One hundred and ninety-four patients were included in the final analysis. Most cases were related to pancreatic cancer or cholangiocarcinoma (89 and 46 cases respectively). Median survival for all patients was 143 days. In multivariate analysis serum albumin ≥34 g/L at the time of procedure (hazard ratio 0.573; 95% confidence interval 0.424-0.773, P<0.001) and chemotherapy post-stent (hazard ratio 0.636; 95% confidence interval 0.455-0.889, P=0.008) were two independent prognostic factors predicting a better survival post-stenting. The 30 day mortality post-procedure in the 194 patients was 12%. CONCLUSION: This study suggests that stenting of the biliary tree in cases of malignant obstruction allows durable palliation of symptoms even in cases where further active chemotherapy treatment is not possible. However, the better outcome observed in patients with albumin ≥34 g/L and those receiving chemotherapy post-stent requires further validation.