Anne M. Covey

Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the few cancers in which a continued increase in incidence has been observed over several years. As such, there has been a focus on safe and accurate diagnosis and the development of treatment algorithms that take into consideration the unique complexities of this patient population. In the past decade, there have been improvements in nonsurgical treatment platforms and better standardization with respect to the diagnosis and patient eligibility for liver transplant. How to navigate patients through the challenges of treatment is difficult and depends on several factors: 1) patient‐related variables such as comorbid conditions that influence treatment eligibility; 2) liver‐related variables such as Child‐Pugh score; and 3) tumor‐related variables such as size, number, pattern of spread within the liver, and vascular involvement. The objectives of this review are to put into perspective the current treatment options for patients with HCC, the unique advantages and disadvantages of each treatment approach, and the evidence that supports the introduction of sorafenib into the multidisciplinary management of HCC. CA Cancer J Clin 2012;.

Combined Portal Vein Embolization and Neoadjuvant Chemotherapy As a Treatment Strategy for Resectable Hepatic Colorectal Metastases

Objectives:The objectives of this study are 1) to determine whether the future liver remnant will grow after portal vein embolization (PVE) in patients with colon cancer on concurrent chemotherapy and 2) to determine whether recovery after extended hepatectomy is improved after PVE. Purpose:Neoadjuvant chemotherapy followed by hepatic resection is an increasingly used therapeutic strategy for curative treatment for colorectal metastases. However, such chemotherapy may result in steatosis, liver damage, and compromised liver regeneration and recovery. This study aims to determine whether PVE can be used during neoadjuvant therapy to enhance growth of future residual liver and to improve postoperative recovery. Methods:From September 1999 to September 2004, 100 patients with colorectal metastases to the liver were subjected to PVE as preparation for extended hepatic resection, 43 of whom were embolized during neoadjuvant chemotherapy. Liver growth was examined by computed tomography volumetric analysis. Clinical outcomes of the 71 patients subsequently resected were compared with 100 consecutive patients subjected to extended resection without PVE (controls). Results:After a median wait of 30 ± 2 days after PVE, patients on neoadjuvant chemotherapy experienced a median contralateral (nonembolized) liver growth of 22% ± 3% compared with 26% ± 3% for those without chemotherapy (P = NS). The number of patients with <5% growth was also similar: 4 of 43 versus 6 of 57 (P = NS). Comparison of patients resected after PVE to a simultaneous cohort of 100 consecutive patients subjected to extended resection without prior PVE demonstrated a lower fresh frozen plasma requirement (P = 0.01), a lower peak bilirubin (P = 0.002), and a shorter length of stay (P = 0.03). Mortality was similar (0% vs. 2%). Conclusions:Liver growth occurs after PVE even when cytotoxic chemotherapy is administered. No major complications occurred with PVE. Patients requiring major hepatic resection should be considered for PVE during neoadjuvant chemotherapy to improve subsequent recovery after resection.

Management and Outcomes of Postpancreatectomy Fistula, Leak, and Abscess: Results of 908 Patients Resected at a Single Institution Between 2000 and 2005

BACKGROUND Anastomotic fistula, leak, and abscess are common complications of pancreatectomy. The goal of this study was to describe our current management and outcomes of clinically significant postpancreatectomy fistula, leak, and abscess. STUDY DESIGN Review of a prospectively maintained database identified 908 patients who underwent pancreatectomy between January 2000 and August 2005. Complication data were prospectively entered into a validated postoperative complication database. Patients were included if they were identified as having a clinically significant (>/=grade 2) pancreatic fistula, leak, or abscess. Multivariate analyses were performed to identify factors predictive of prolonged drainage (> 30 days). RESULTS Clinically significant postoperative fistula, leak, or abscess occurred in 158 of 908 resected patients (17%) and included 63 culture-positive pancreatic fistulas, 29 noninfected pancreatic fistulas, 42 abscesses, and 24 other collections (biliary fistula, culture-negative collection). Surgical drains were placed at the time of initial resection in 88 of these 158 patients (56%). Adequate drainage was obtained by prolonged use of surgical drains in 16 patients (16 of 88 [18%]). Reoperation was required in 26 of the 158 patients (16%). ICU admission was required in 22%. Within this group of 158 patients the mortality rate was 5% (8 of 158; 90 days). At the time of discharge a home health aide was required in 56% of patients, 8% were discharged to a rehabilitation facility, and readmission was required in 50% of patients. Mean drainage time was 38 days (range 3 to 228). Predictors of prolonged drainage included drain output > 200 mL during the first 48 hours (odds ratio = 2.88; p = 0.02) and distal (versus proximal) pancreatectomy (odds ratio = 4.29; p = 0.01). CONCLUSIONS Although mortality after pancreatectomy has decreased to approximately 2%, the morbidity associated with pancreatic fistula, leak, and abscess remains substantial.

Transcatheter Arterial Embolization with Only Particles for the Treatment of Unresectable Hepatocellular Carcinoma

PURPOSE To determine the survival of patients with hepatocellular carcinoma (HCC) treated with a standardized method of transcatheter arterial embolization (TAE) with small embolic particles intended to impart terminal vessel blockade, and to evaluate prognostic factors that impact overall survival. MATERIALS AND METHODS A total of 322 patients with HCC who underwent 766 embolizations from January 1997 to December 2004 were retrospectively reviewed. Selective embolization of vessels feeding individual tumors was performed with small (50 microm) polyvinyl alcohol or spherical embolic particles (40-120 microm) intended to cause terminal vessel blockade. Repeat embolization was performed in cases of evidence of persistent viable tumor or development of new lesions. Patient, tumor, and treatment characteristics were prospectively recorded and tested for prognostic significance by univariate and multivariate analysis. RESULTS The median survival time was 21 months, with 1-, 2-, and 3-year overall survival rates of 66%, 46%, and 33%, respectively. In patients without extrahepatic disease or portal vein involvement by tumor, the overall 1-, 2-, and 3-year survival rates increased to 84%, 66%, and 51%, respectively. Okuda stage, extrahepatic disease, diffuse disease (> or =5 tumors), and tumor size were independent predictors of survival on multivariate analysis. There were 90 complications (11.9%) in 75 patients, including eight deaths (2.5%), within 30 days of embolization. CONCLUSIONS Hepatic arterial embolization with small particles to cause terminal vessel blockade is an effective treatment method for patients with unresectable HCC. These data support our hypothesis that particles alone may be the critical component of catheter-directed embolotherapy.

Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-Eluting Microspheres Compared With Embolization With Microspheres Alone

PURPOSE Transarterial chemoembolization is accepted therapy for hepatocellular carcinoma (HCC). No randomized trial has demonstrated superiority of chemoembolization compared with embolization, and the role of chemotherapy remains unclear. This randomized trial compares the outcome of embolization using microspheres alone with chemoembolization using doxorubicin-eluting microspheres. MATERIALS AND METHODS At a single tertiary referral center, patients with HCC were randomly assigned to embolization with microspheres alone (Bead Block [BB]) or loaded with doxorubicin 150 mg (LC Bead [LCB]). Random assignment was stratified by number of embolizations to complete treatment, and assignments were generated by permuted blocks in the institutional database. The primary end point was response according to RECIST 1.0 (Response Evaluation Criteria in Solid Tumors) using multiphase computed tomography 2 to 3 weeks post-treatment and then at quarterly intervals, with the reviewer blinded to treatment allocation. Secondary objectives included safety and tolerability, time to progression, progression-free survival, and overall survival. This trial is currently closed to accrual. RESULTS Between December 2007 and April 2012, 101 patients were randomly assigned: 51 to BB and 50 to LCB. Demographics were comparable: median age, 67 years; 77% male; and 22% Barcelona Clinic Liver Cancer stage A and 78% stage B or C. Adverse events occurred with similar frequency in both groups: BB, 19 of 51 patients (38%); LCB, 20 of 50 patients (40%; P = .48), with no difference in RECIST response: BB, 5.9% versus LCB, 6.0% (difference, -0.1%; 95% CI, -9% to 9%). Median PFS was 6.2 versus 2.8 months (hazard ratio, 1.36; 95% CI, 0.91 to 2.05; P = .11), and overall survival, 19.6 versus 20.8 months (hazard ratio, 1.11; 95% CI, 0.71 to 1.76; P = .64) for BB and LCB, respectively. CONCLUSION There was no apparent difference between the treatment arms. These results challenge the use of doxorubicin-eluting beads for chemoembolization of HCC.

Percutaneous Radiofrequency Ablation of Colorectal Cancer Liver Metastases: Factors Affecting Outcomes—A 10-year Experience at a Single Center

PURPOSE To identify predictors of oncologic outcomes after percutaneous radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLMs) and to describe and evaluate a modified clinical risk score (CRS) adapted for ablation as a patient stratification and prognostic tool. MATERIALS AND METHODS This study consisted of a HIPAA-compliant institutional review board-approved retrospective review of data in 162 patients with 233 CLMs treated with percutaneous RFA between December 2002 and December 2012. Contrast material-enhanced CT was used to assess technique effectiveness 4-8 weeks after RFA. Patients were followed up with contrast-enhanced CT every 2-4 months. Overall survival (OS) and local tumor progression-free survival (LTPFS) were calculated from the time of RFA by using the Kaplan-Meier method. Log-rank tests and Cox regression models were used for univariate and multivariate analysis to identify predictors of outcomes. RESULTS Technique effectiveness was 94% (218 of 233). Median LTPFS was 26 months. At univariate analysis, predictors of shorter LTPFS were tumor size greater than 3 cm (P < .001), ablation margin size of 5 mm or less (P < .001), high modified CRS (P = .009), male sex (P = .03), and no history of prior hepatectomy (P = .04) or hepatic arterial infusion chemotherapy (P = .01). At multivariate analysis, only tumor size greater than 3 cm (P = .01) and margin size of 5 mm or less (P < .001) were independent predictors of shorter LTPFS. Median and 5-year OS were 36 months and 31%. At univariate analysis, predictors of shorter OS were tumor size larger than 3 cm (P = .005), carcinoembryonic antigen level greater than 30 ng/mL (P = .003), high modified CRS (P = .02), and extrahepatic disease (EHD) (P < .001). At multivariate analysis, tumor size greater than 3 cm (P = .006) and more than one site of EHD (P < .001) were independent predictors of shorter OS. CONCLUSION Tumor size of less than 3 cm and ablation margins greater than 5 mm are essential for satisfactory local tumor control. Tumor size of more than 3 cm and the presence of more than one site of EHD are associated with shorter OS.

Radiofrequency Ablation in the Management of Liver Metastases from Breast Cancer

OBJECTIVE Systemic chemotherapy remains the standard treatment for patients with breast cancer hepatic metastases. Resection of metastases has survival advantages in a small percentage of selected patients. Radiofrequency ablation has been used in small numbers of selected patients. This small series was undertaken to review our experience with radiofrequency ablation in the management of patients with breast cancer hepatic metastases. CONCLUSION Radiofrequency ablation of breast cancer hepatic metastases is safe and may be used to control hepatic deposits in patients with stable or no extrahepatic disease.

A Herpes Oncolytic Virus Can Be Delivered Via the Vasculature to Produce Biologic Changes in Human Colorectal Cancer

Genetically engineered herpes simplex viruses (HSVs) can selectively infect and replicate in cancer cells, and are candidates for use as oncolytic therapy. This long-term report of a phase I trial examines vascular administration of HSV as therapy for cancer. Twelve subjects with metastatic colorectal cancer within the liver failing first-line chemotherapy were treated in four cohorts with a single dose (3 x 10(6) to 1 x 10(8) particles) of NV1020, a multimutated, replication-competent HSV. After hepatic arterial administration, subjects were observed for 4 weeks before starting intra-arterial chemotherapy. All patients exhibited progression of disease before HSV injection. During observation, levels of the tumor marker carcinoembryonic antigen (CEA) decreased (median % drop = 24%; range 13-74%; P < 0.02). One of three individuals at the 10(8) level showed a 39% radiologic decrease in tumor size by cross-section and 75% by volume. HSV infection was documented from liver tumor biopsies. After beginning regional chemotherapy, all patients demonstrated a further decrease in CEA (median 96%; range 50-98%; P < 0.008) and a radiologic partial response. Median survival for this group was 25 months. During follow-up, no signs of virus reactivation were found. Multimutated HSV can be delivered safely into the human bloodstream to produce selective infection of tumor tissues and biologic effects.

Treatment of metastatic sarcoma to the liver with bland embolization

The authors evaluated the impact of bland particle embolization on survival in patients with metastatic sarcoma to the liver.

Safety and Efficacy of Preoperative Portal Vein Embolization with Polyvinyl Alcohol in 58 Patients with Liver Metastases

OBJECTIVE The objective of our study was to evaluate the safety and efficacy of transhepatic lobar portal vein embolization (PVE) using polyvinyl alcohol (PVA) particles to induce contralateral lobar hypertrophy in patients with liver-only metastases and normal underlying liver function. MATERIALS AND METHODS Fifty-eight consecutive patients with small predicted future liver remnants (FLRs) underwent PVE with PVA particles to induce hypertrophy of the contralateral hemi-liver before surgical resection of liver metastases. Total liver, right hemi-liver, and left hemi-liver volumes were calculated before and after embolization using a 3D workstation. RESULTS Eight patients underwent left PVE; 47, right PVE; and three, right and segment IV PVE. There were no major complications of the procedure. The mean increases in the ratio of the FLR to the total estimated liver volume after right, right and segment IV, and left PVE were 9%, 10%, and 3%, respectively; the corresponding mean hypertrophy ratios were 24.3%, 31.9%, and 1.5%, respectively. CONCLUSION Right PVE using PVA particles alone as the embolic agent is safe and effective in achieving left hemi-liver hypertrophy. In contrast, left PVE did not induce significant right hemi-liver hypertrophy in this patient population.