J.N. Vauthey

Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications

Background Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. Methods We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. Results There were significant differences between intrahepatic (nu200a=u200a55) and extrahepatic CCA (nu200a=u200a20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (nu200a=u200a20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. Conclusion There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

Limitations of conventional doses of chemoradiation for unresectable biliary cancer.

Abstract Purpose: To determine, in a retrospective review, the limitations of definitive chemoradiation in the treatment of patients with unresectable extrahepatic cholangiocarcinoma and generate testable hypotheses for future prospective clinical trials. Methods and Materials: Between 1957 and 2000, 52 patients with localized, unresectable cholangiocarcinoma were treated with radiotherapy (RT) with or without concurrent chemotherapy. Unresectable disease was defined, by evidence on imaging studies or at surgical exploration, as localized tumor abutting or involving the main portal vein, tumor involvement of secondary biliary radicals, or evidence of nodal metastases. Patients were grouped according to the RT dose: 27 patients received a total dose of 30 Gy (Group 1), 14 patients received 36–50.4 Gy (Group 2), and 11 patients received 54–85 Gy (Group 3). 192 Ir intracavitary boosts (median 20 Gy) were delivered in 3 patients, and an intraoperative boost (20 Gy) was used in 1 patient. Of the 52 patients, 38 (73%) received concomitant protracted venous infusion of 5-fluorouracil (200–300 mg/m 2 daily, Monday through Friday). Kaplan-Meier analysis was used to calculate the actuarial 1-year and median overall survival (OS), radiographic local progression, symptomatic progression, and distant failure. Treatment-related variables and prognostic factors were evaluated using the log-rank test. Results: The first site of disease progression was local in 72% of cases. The actuarial local progression rate at 12 months for all patients was 59%. The median time to radiographic local progression was 9, 11, and 15 months in Groups 1, 2, and 3, respectively ( p = 0.48). Fifteen percent of all patients developed metastatic disease (1-year OS rate 18%). The median survival rate for all patients was 10 months (1-year OS rate 44%). The RT dose, use of concurrent chemotherapy, histologic grade, initial extent of liver involvement, and extent of vascular involvement had no influence on radiographic local progression or OS. Grade 3 or greater toxicity was similar in all dose groups (22% vs. 14% vs. 27%, p = 0.718). Conclusion: The primary limitation of definitive chemoradiation was local progression. Although the small patient numbers limited the statistical power of this study, a suggestion of improved local control was found with the use of higher RT doses. To address this pattern of failure, future prospective investigation using high-dose conformal RT with novel cytotoxic and/or biologic agents with radiosensitizing properties is warranted.

Meta‐analysis of KRAS mutations and survival after resection of colorectal liver metastases

In patients with advanced colorectal cancer, KRAS mutation status predicts response to treatment with monoclonal antibody targeting the epithelial growth factor receptor (EGFR). Recent reports have provided evidence that KRAS mutation status has prognostic value in patients with resectable colorectal liver metastases (CLM) irrespective of treatment with chemotherapy or anti‐EGFR therapy. A meta‐analysis was undertaken to clarify the impact of KRAS mutation on outcomes in patients with resectable CLM.

Prognostic factors after resection of colorectal liver metastases following preoperative second-line chemotherapy: Impact of RAS mutations.

BACKGROUNDnAfter resection of colorectal liver metastases (CLM), RAS mutations are associated with modest survival benefit and second-line chemotherapy confers limited hope for cure.nnnOBJECTIVEnTo evaluate the impact of RAS mutation after second-line chemotherapy for patients undergoing potentially curative liver resection for CLM.nnnMETHODSnAmong 1357 patients operated for CLM between January 2005 and November 2014, patients with known RAS mutational status were identified. Outcomes after second-line chemotherapy were analyzed by RAS status.nnnRESULTSnAmong 635 patients undergoing resection of CLM, 46 received second-line chemotherapy before resection, including 14 patients (30%) with RAS mutations. Patients who received second-line chemotherapy had significantly larger and greater number of liver metastases and were more likely to undergo major hepatectomy. Median overall (OS) and recurrence free survival (RFS) were significantly worse among patients requiring second-line chemotherapy (OS: 44.4 vs. 61.1 months, pxa0=xa00.021; RFS: 7.3 vs. 12.0 months, pxa0=xa00.001). Among patients undergoing liver resection after second-line chemotherapy, RAS mutations were associated with worse median OS and RFS (OS: 35.2 vs. 60.7 months, pxa0=xa00.038; RFS: 3.6 vs. 8.3 months, pxa0=xa00.015). RAS mutation was the only independent factor associated with OS and RFS. All patients with RAS mutations recurred within 18 months. Among patients with RAS wild-type tumors, the receipt of second-line chemotherapy did not affect OS (pxa0=xa00.493).nnnCONCLUSIONnAmong patients undergoing resection of CLM after second-line chemotherapy, RAS mutational status is an independent predictor of survival and outweighs other factors to select patients for liver resection.

Biomarkers in colorectal liver metastases

Despite a 5‐year overall survival rate of 58 per cent after liver resection for colorectal liver metastases (CLMs), more than half of patients develop recurrence, highlighting the need for accurate risk stratification and prognostication. Traditional prognostic factors have been superseded by newer outcome predictors, including those defined by the molecular origin of the primary tumour.

Prognostic value of carbohydrate antigen 19-9 in patients undergoing resection of biliary tract cancer

The clinical significance of abnormally high levels of carbohydrate antigen (CA) 19‐9 after resection of biliary tract cancer (BTC) is not well established. The aim of this study was to determine the prognostic value of CA19‐9 normalization in patients undergoing resection of BTC with curative intent.

Biologic mesh spacer placement facilitates safe delivery of dose-intense radiation therapy: A novel treatment option for unresectable liver tumors

INTRODUCTIONnPatients with unresectable liver tumors who fail initial treatment modalities have a poor prognosis (<1xa0yr). Although effective, delivery of high dose radiation therapy to these tumors is limited by proximity of radiosensitive bowel. We have previously reported that placement of a biologic mesh spacer (BMS) can effectively displace the bowel allowing for dose-intense radiation to be delivered with low short-term toxicity. The purpose of this study was to assess and report the long-term safety and oncologic outcomes of this cohort.nnnMETHODSnFrom 2012 to 2014 seven patients with unresectable hepatic malignancy (6 IHCC, 1 CRLM) underwent BMS (acellular human dermis) placement (2 open, 5 MIS) prior to radiation therapy. Prospective registry data were reviewed for tumor and treatment details, progression, metastasis and survival. RTOG guidelines were used to define radiation toxicities.nnnRESULTSnMean patient age was 50.4 years (30-62 years) and 4 patients were male (57.1%). Prior to surgery, all patients had been treated for an average of 12.5 months with surgery, chemotherapy, radiation and/or TACE. After surgery, all patients recovered well and received a mean radiation dose of 76.1xa0Gy (58.1-100xa0Gy) over 13-25 fractions. 1 patient received SBRT; 4 fractions, 10xa0Gy each. Maximum dose delivered was 100xa0Gy (Biologic Equivalent Dose of 140xa0Gy, α/βxa0=xa010). Mean time to initiation of radiation therapy was 24 days (12-48 days) from surgery. No significant GI toxicity was recorded, and no GI bleeding or ulcers were observed. Mean follow-up after XRT was 18.2 months (5.5-31 months). Three patients had no loco-regional progression of disease. 2 patients had infield progression of liver disease and another had progressive lymphadenopathy. 3 patients developed pulmonary metastasis, at a mean time to distant failure of 3 months. There are 4 survivors over 2-years from surgery.nnnCONCLUSIONnFor patients with unresectable liver tumors, placement of a BMS enhances the safety and efficacy of high-dose radiotherapy, providing a survival benefit via delay in time to progression compared to traditional treatments with no significant short or long term GI toxicity.

Embryonic origin of primary colon cancer predicts survival in patients undergoing ablation for colorectal liver metastases

BACKGROUNDnIn patients with primary colorectal cancer (CRC) or unresectable metastatic CRC, midgut embryonic origin is associated with worse prognosis. The impact of embryonic origin on survival after ablation of colorectal liver metastases (CLM) is unclear.nnnMETHODSnWe identified 74 patients with CLM who underwent percutaneous ablation during 2004-2015. Survival and recurrence after ablation of CLM from midgut origin (n = 18) and hindgut origin (n = 56) were analyzed. Prognostic value of embryonic origin was evaluated.nnnRESULTSnRecurrence-free survival (RFS) and overall survival (OS) after percutaneous ablation were worse in patients from midgut origin (3-year RFS: 5.6% vs. 24%, P = 0.004; 3-year OS: 25% vs. 70%, P 0.001). In multivariable analysis, factors associated with worse OS were midgut origin (hazard ratio [HR] 4.87, 95% CI 2.14-10.9, P 0.001), multiple CLM (HR 2.35, 95% CI 1.02-5.39, P = 0.044), and RAS mutation (HR 2.78, 95% CI 1.25-6.36, P = 0.013). At a median follow-up of 25 months, 56 patients (76%) had developed recurrence, 16 (89%) with midgut origin and 40 (71%) with hindgut origin (P = 0.133). Recurrent disease was treated with local therapy in 20 patients (36%), 2 (13%) with midgut origin and 18 (45%) with hindgut origin (P = 0.022).nnnCONCLUSIONnCompared to CLM from hindgut origin tumors, CLM from midgut origin tumors were associated with worse survival after ablation, which was partly attributable to the fact that patients with hindgut origin were more frequently candidates for local therapy at recurrence.

The Addition of Bevacizumab to Oxaliplatin-Based Chemotherapy: Impact Upon Hepatic Sinusoidal Injury and Thrombocytopenia

BackgroundnOxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI), portal hypertension, and splenic sequestration of platelets. Evidence suggests that bevacizumab may protect against HSI.nnnMethodsnTwo cohorts of metastatic colorectal cancer (CRC) were analyzed: a nonrandomized exploratory cohort of 184 patients treated at a single institution from 2003 to 2010 and a confirmatory cohort of 200 patients from a multi-institutional randomized trial (NO16966). All patients were treated with frontline fluoropyrimidine and oxaliplatin with or without bevacizumab. Changes in splenic volumes and platelet counts were compared by treatment, two-sided log-rank test.nnnResultsnIn the exploratory cohort, the bevacizumab-treated patients (nu2009=u2009138) compared with the nonbevacizumab-treated patients (nu2009=u200946) demonstrated a longer median time to splenic enlargement (≥30%, P = .02) and reduced rate of thrombocytopenia (<150u2009000/mm3, P = .04). In the confirmatory cohort (106 bevacizumab arm and 94 placebo arm), the median time to a spleen enlargement of 30% or more was 7.6 vs 5.4 (P = .01), and six-month cumulative incidence of thrombocytopenia (platelets < 100u2009000/mm3) was 19% vs 51% (P < .001) for bevacizumab compared with placebo. The development of an increasing spleen size was associated with the risk of either grade 1 or grade 2 thrombocytopenia (P < .001). The cumulative rate of grade 1 or grade 2 thrombocytopenia was statistically less in the bevacizumab arm, with six-month grade 2 thrombocytopenia rates of 4% vs 23% (P < .001). Patients with a large spleen prior to chemotherapy initiation appeared to be at highest risk of this toxicity.nnnConclusionnIn metastatic CRC, the addition of bevacizumab to oxaliplatin-based chemotherapy reduces the frequency of splenic enlargement and the rate of thrombocytopenia.

Loss of muscle mass during preoperative chemotherapy predicts worse recurrence-free survival in patients with resectable colorectal liver metastases

MTA and 9.7% in the RFA group (p = 0.85). There was no mortality. Median hospital stay was 1 day for both groups. For the RFA vs MTA groups, local recurrence (LR) rate per lesion was 20.3% and 8.5%, respectively (p = 0.01). On Cox Proportion Hazards model, ablation modality was an independent predictor of LR following risk adjustment. Conclusion: To our knowledge, this is the first comparison of RFA and MTA in the treatment of CRLM. Our results demonstrates MTA achieves better local tumor control with shorter operative and ablation time.