Ghassan K. Abou-Alfa

Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial.

CONTEXT In a randomized phase 3 trial, 400 mg of sorafenib twice daily prolonged overall survival of patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh A disease. In a phase 1 study, sorafenib combined with doxorubicin, 60 mg/m(2), was well tolerated by patients with refractory solid tumors. The combination of sorafenib and doxorubicin in patients with advanced HCC has not been evaluated in a phase 2 or 3 trial. OBJECTIVE To evaluate the efficacy and safety of doxorubicin plus sorafenib compared with doxorubicin alone in patients with advanced HCC and Child-Pugh A disease. DESIGN, SETTING, AND PATIENTS In a double-blind phase 2 multinational study, conducted from April 2005 to October 2006, 96 patients (76% male; median age, 65 years [range, 38-82 years]) with advanced HCC, Eastern Cooperative Oncology Group performance status 0 to 2, Child-Pugh A status, and no prior systemic therapy were randomly assigned to receive 60 mg/m(2) of doxorubicin intravenously every 21 days plus either 400 mg of sorafenib or placebo orally twice a day. The date of the last patients follow-up was April 2008. MAIN OUTCOME MEASURE Time to progression as determined by independent review. RESULTS Following complete accrual, an unplanned early analysis for efficacy was performed by the independent data monitoring committee, so the trial was halted. The 2 patients remaining in the placebo group at that time were offered sorafenib. Based on 51 progressions, 63 deaths, and 70 events for progression-free survival, median time to progression was 6.4 months in the sorafenib-doxorubicin group (95% confidence interval [CI], 4.8-9.2), and 2.8 months (95% CI, 1.6-5) in the doxorubicin-placebo monotherapy group (P = .02). Median overall survival was 13.7 months (95% CI, 8.9--not reached) and 6.5 months (95% CI, 4.5-9.9; P = .006), and progression-free survival was 6.0 months (95% CI, 4.6-8.6) and 2.7 months (95% CI, 1.4-2.8) in these groups, respectively (P = .006). Toxicity profiles were similar to those for the single agents. CONCLUSIONS Among patients with advanced HCC, treatment with sorafenib plus doxorubicin compared with doxorubicin monotherapy resulted in greater median time to progression, overall survival, and progression-free survival. The degree to which this improvement may represent synergism between sorafenib and doxorubicin remains to be defined. The combination of sorafenib and doxorubicin is not yet indicated for routine clinical use. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00108953.

Randomized Phase III Study of Exatecan and Gemcitabine Compared With Gemcitabine Alone in Untreated Advanced Pancreatic Cancer

PURPOSE Exatecan mesylate is a hexacyclic, water-soluble, topoisomerase-1 inhibitor. Exatecan has single-agent and combination activity with gemcitabine in advanced pancreatic cancer. A multicenter, randomized, phase III trial comparing exatecan plus gemcitabine versus gemcitabine alone in advanced pancreatic cancer was conducted. PATIENTS AND METHODS Eligibility criteria included Karnofsky performance status > or = 60%, locally advanced or metastatic pancreatic adenocarcinoma, and no prior chemotherapy. Radiation alone for locally advanced disease was permitted. Patients were randomly assigned on a 1:1 basis. For the exatecan plus gemcitabine arm, exatecan 2.0 mg/m2 and gemcitabine 1,000 mg/m2 were administered on days 1 and 8, every 3 weeks. Gemcitabine alone was dosed at 1,000 mg/m2 up to 7 weeks in the first cycle, then once a week for the first 3 weeks of a 4-week cycle. Tumor assessment was performed every 6 weeks. The primary end point was overall survival. An intent-to-treat analysis was used. RESULTS From August 2001 to January 2003, 349 patients were randomly assigned, 175 to exatecan plus gemcitabine and 174 to gemcitabine alone. Twenty-four patients (6.9%) were not treated. The median survival time was 6.7 months for exatecan plus gemcitabine and 6.2 months for gemcitabine alone (P = .52). One complete response (CR; < 1%) and 11 partial responses (PRs; 6.3%) were observed in the exatecan plus gemcitabine treatment group, and one CR (< 1%) and eight PRs (4.6%) were observed in the gemcitabine-alone group. Grade 3 and 4 toxicities were higher for the exatecan plus gemcitabine arm versus the gemcitabine alone arm; neutropenia (30% v 15%) and thrombocytopenia (15% v 4%). CONCLUSION Exatecan plus gemcitabine was not superior to gemcitabine alone with respect to overall survival in the first-line treatment of advanced pancreatic cancer.

Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC)

The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10‐year period.

Phase I and Pharmacokinetic Study of Sorafenib in Patients With Hepatic or Renal Dysfunction: CALGB 60301

PURPOSE We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction. PATIENTS AND METHODS Patients were assigned to one of nine cohorts: cohort 1, bilirubin < or = upper limit of normal (ULN) and AST < or = ULN and creatinine clearance (CC) > or = 60 mL/min; cohort 2, bilirubin more than ULN but < or = 1.5x ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5x ULN to < or = 3x ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3x ULN to 10x ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8. RESULTS Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found. CONCLUSION We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.

Outcome of patients with fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FL‐HCC) is a rare variant of hepatocellular carcinoma, has distinct pathologic features, and typically occurs in young patients without underlying hepatitis or cirrhosis.

Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy and immunotherapy.

Conventional cytotoxic chemotherapy has not provided clinical benefit or prolonged survival for patients with advanced HCC. This review summarizes the results of prospective clinical trials of several categories of systemic therapy, with emphasis on the more promising results from recent trials of biologically targeted therapeutic agents in HCC.

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.

Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine.

Purpose: Codon 12 mutations of K-ras are frequent in pancreatic adenocarcinoma, and represent potential tumor-specific neoantigens. The objective of this study was to assess the safety and efficacy of immunizing patients with resected pancreatic cancer with a vaccine targeted against their tumor-specific K-ras mutation. Methods: Patients with resected pancreatic cancer, with K-ras mutations at codon 12, were vaccinated once monthly for 3 months with a 21-mer peptide vaccine containing the corresponding K-ras mutation of the patients tumor. About 200 &mgr;g of peptide vaccine was injected intradermally on day 7 of a 10-day course of intradermal granulocyte macrophage colony-stimulating factor. Toxicity was assessed by National Cancer Institute Common Toxicity Criteria v2.0. Immune responses were evaluated by delayed-type hypersensitivity (DTH) tests and the enzyme-linked immunosorbent spot assays. Results: Of 62 screened patients, 24 were vaccinated. There were no grade 3–5 vaccine-specific toxicities. The only National Cancer Institute grade 1 and 2 toxicity was erythema at the injection site (94%). Nine patients (25%) were evaluable for immunologic responses. One patient (11%) had a detectable immune response specific to the patients K-ras mutation, as assessed by DTH. Three patients (13%) displayed a DTH response that was not specific. Median recurrence free survival time was 8.6 months (95% confidence interval, 2.96–19.2) and median overall survival time was 20.3 months (95% confidence interval, 11.6–45.3). Conclusions: K-ras vaccination for patients with resectable pancreatic adenocarcinoma proved to be safe and tolerable with however no elicitable immunogenicity and unproven efficacy. Future development of adjuvant vaccine therapies should use more immunogenic vaccines.

A review and update of treatment options and controversies in the management of hepatocellular carcinoma

Objective:To review the current management, outline recent advances and address controversies in the management of hepatocellular carcinoma (HCC). Summary of Background data:The treatment of HCC is multidisciplinary involving hepatologists, surgeons, medical oncologists, radiation oncologists, radiologists, interventional radiologists, and other disciplines. Each of these disciplines brings its unique perspective and differing opinions that add to controversies in the management of HCC. Methods:A focused literature review was performed to identify recent studies on the management of HCC and thereby summarize relevant information on the various therapeutic modalities and controversies involved in the treatment of HCC. Results:The main treatment algorithms continue to rely on hepatic resection or transplantation with controversies involving patients harboring early stage disease and borderline hepatic function. The other treatment strategies include locoregional therapies, radiation, and systemic therapy used alone or in combination with other treatment modalities. Recent advances in locoregional therapies, radiation, and systemic therapies have provided better therapeutic options with curative intent potential for some locoregional therapies. Further refinements in combination therapies such as algorithms consisting of locoregional therapies and systemic or radiation therapies are likely to add additional options and improve survival. Conclusions:The management of HCC has witnessed significant strides with advances in existing options and introduction of several new treatment modalities of various combinations. Further refinements in these treatment options combined with enrollment in clinical trials are essential to improve the management and outcomes of patients with HCC.

A Cancer and Leukemia Group B Phase II Study of Sunitinib Malate in Patients with Previously Treated Metastatic Pancreatic Adenocarcinoma (CALGB 80603)

BACKGROUND The Cancer and Leukemia Group B (CALGB) conducted a phase II study evaluating sunitinib in patients with progressive metastatic pancreas adenocarcinoma following prior gemcitabine-based therapy (trial CALGB 80603; ClinicalTrials.gov identifier, NCT00397787). The primary endpoint was to determine the disease control rate (DCR) as measured by the Response Evaluation Criteria in Solid Tumors (complete response, partial response [PR], and stable disease) at 6 weeks. PATIENTS AND METHODS Patients aged ≥18 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 and with progressive pancreas adenocarcinoma following treatment with gemcitabine were eligible. Sunitinib was dosed at 50 mg orally days 1-28, every 42 days (1 cycle). The statistical plan called for a three-stage design. A DCR ≥15% was considered worthy of further study. RESULTS In total, 77 patients were enrolled. Forty-two (54.6%) enrollees were male. The median age was 65 years. The ECOG performance status score distribution was: 0, 39%; 1, 50%; 2, 11%. The DCR was 21.6%; one patient (1.4%) had a PR and 15 patients (20.3%) had stable disease as their best response. The progression-free survival time was 1.31 months (95% confidence interval [CI] 1.25-1.38 months) and overall survival time was 3.68 months (95% CI, 3.06-4.24 months). CONCLUSIONS The study met its primary endpoint; however sunitinib had minimal activity and moderate toxicity in a population of gemcitabine-refractory pancreas adenocarcinoma patients. For future studies, limiting enrollment to patients with an ECOG performance status score of 0-1 is recommended.