Modified cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability, and survival of initially unresectable hepatocellular carcinoma.

BACKGROUND: The purpose of this study was to evaluate the factors associated with response rate, resectability, and survival after cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) combination therapy in patients with initially unresectable hepatocellular carcinoma. METHODS: The study included 2 groups of patients treated with conventional high-dose PIAF (n = 84) between 1994 and 2003 and those without hepatitis or cirrhosis treated with modified PIAF (n = 33) between 2003 and 2012. Tolerance of chemotherapy, best radiographic response, rate of conversion to curative surgery, and overall survival were analyzed and compared between the 2 groups, and multivariate and logistic regression analyses were applied to identify predictors of response and survival. RESULTS: The modified PIAF group had a higher median number of PIAF cycles (4 versus 2, P = .049), higher objective response rate (36% versus 15%, P = .013), higher rate of conversion to curative surgery (33% versus 10%, P = .004), and longer median overall survival (21.3 versus 10.6 months, P = .002). Multivariate analyses confirmed that positive hepatitis B serology (hazard ratio [HR] = 1.68; 95% confidence interval [CI] = 1.08-2.59) and Eastern Cooperative Oncology Group performance status ≥ 2 (HR = 1.75; 95% CI = 1.04-2.93) were associated with worse survival whereas curative surgical resection after PIAF treatment (HR = 0.15; 95% CI = 0.07-0.35) was associated with improved survival. CONCLUSIONS: In patients with initially unresectable hepatocellular carcinoma, the modified PIAF regimen in patients with no hepatitis or cirrhosis is associated with improved response, resectability, and survival.

Defining the role of echinocandin catechol functional groups in the development of secondary hepatocellular carcinoma.

OBJECTIVES: To determine whether the catechol functional group on echinocandins decreases the catechol-O-methyltransferase (COMT) metabolism of catechol oestrogens (CEs) and the potential role of this functional group in the development of hepatocellular cancer. METHODS: Human COMT expression was measured by RT-PCR in a panel of selected human cancer cell lines and human hepatocytes. An ex vivo human hepatocyte model was employed to evaluate the metabolism of 17-ß-oestradiol to CEs in the presence of a catechol (B(0)C) versus a non-catechol echinocandin (B(0)) compound. COMT inhibition assays were conducted to evaluate the metabolism of CEs in the presence of B(0)C or B(0). Oestrogen receptor expression in human hepatic carcinoma cells was evaluated by RT-PCR and western blotting. Cell proliferation assays were used to evaluate the impact of B(0) or B(0)C on cancer cell growth. RESULTS: MCF-7 and Hep-G2 cells and human hepatocytes expressed variant Met/Met COMT. At clinically relevant concentrations, only B(0)C significantly increased CE levels in the COMT inhibition assays, to 90.0 µM compared with 79.8 µM in the untreated controls (P = 0.032). A high concentration (500 µg/mL) of B(0)C decreased COMT expression to 79%, 94% and 90% of untreated, baseline control levels in the three cell lines, respectively. B(0)C and B(0) did not increase cell growth in the cancer cell lines evaluated. CONCLUSIONS: At clinically achievable concentrations only B(0)C significantly inhibited COMT activity and increased CE concentrations. Short-term exposure did not alter the rate of cancer cell growth. Confirmation is needed to determine the clinical impact of long-term exposure to and the use of echinocandins with catechol functional groups.

Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States.

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3-6.3). Restricted analyses among hepatitis virus-negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7-32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3-153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6-5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC.

Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study.

The International Agency for Research on Cancer has declared smoking to be a risk factor for hepatocellular carcinoma (HCC). However, passive exposure to cigarette smoke and use of noncigarette tobacco products on the risk of HCC has not been examined. Therefore, we evaluated the independent effects of different types of smoking exposure along with multiple risk factors for HCC and determined whether the magnitude of smoking was modified by other risk factors in men and women. We conducted a case-control study at The University of Texas M. D. Anderson Cancer Center where 319 HCC patients and 1,061 healthy control subjects were personally interviewed for several HCC risk factors. Multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for each potential risk factor. Use of smokeless tobacco (chewing tobacco and snuff), cigars, pipes and passive smoking exposure were not related to HCC among noncigarette smokers. However, regular cigarette smoking was associated with HCC in men: AOR, 1.9 (95% CI, 1.1-3.1). Heavy alcohol consumption was associated with HCC in women: AOR, 7.7 (95% CI, 2.3-25.1). Cigarette smoking interacted synergistically with chronic infection of hepatitis C virus in men: AOR, 136.3 (95% CI, 43.2-429.6) and with heavy alcohol consumption in women: AOR, 13.7 (95% CI, 3.2-57.9). We conclude that sex differences were observed in HCC relationship with cigarette smoking and alcohol consumption. Controlling for smoking exposure might be a prudent approach to the prevention of HCC, especially in patients with chronic viral hepatitis infections.

Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma.

PURPOSE: Because cirrhosis is extremely common in hepatocellular carcinoma (HCC) in the United States, and it precludes the use of several chemotherapy agents, this phase II trial of fluorouracil (FU) and recombinant interferon alfa-2b (rIFNalpha2b) in HCC was launched with the assumption that it could be tolerated by cirrhotics. PATIENTS AND METHODS: Forty-three patients with HCC (34), and fibrolamellar HCC (FLHCC; nine) were treated with continuous intravenous (IV) FU (200 mg/m2/d x 21 every 28 days) and subcutaneous (SC) rIFNalpha2b (4 million U/m2) three times weekly. Survival was determined in all 43 patients, and response could be assessed in 28 HCC and 8 FLHCC patients. RESULTS: The median ages of the patients were 63.5 and 19 years among HCC and FLHCC patients, respectively. Liver cirrhosis was present among 71% of HCC patients but among none of the FLHCC patients. Nine of 36 (25%; four of 28 [14%] HCC patients; five of eight [62.5%] FLHCC patients) patients in which a response could be assessed had a complete response (CR; one patient with FLHCC and no patients with HCC) or partial response (PR; eight patients [four HCC and four FLHCC patients]). Four HCC patients underwent resection, and two had a histologic CR; one HCC patient with a PR underwent orthotopic liver transplantation. One FLHCC patient also underwent resection without clear margins. Overall median survival was 19.5 months (95% confidence interval [CI], 11.2 to 27.8 months); median survival was 15.5 months (95% CI, 8.5 to 22.5 months) among HCC patients, and that of FLHCC patients was 23.1 months (95% CI, 10.3 to 35.9 months). Overall grade 3 or 4 toxicity included stomatitis (32.6%), fatigue (4.7%), and hematologic toxicity (9.3%). CONCLUSION: Continuous IV FU and thrice-weekly SC rIFNalpha2b are an effective treatment, especially for FLHCC, and may have a neoadjuvant role in this disease. This regimen has activity in HCC and can be tolerated even by cirrhotic patients.

Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma.

BACKGROUND: Despite the observed association between diabetes mellitus and hepatocellular carcinoma (HCC), little is known about the effect of diabetes duration before HCC diagnosis and whether some diabetes medications reduced the risk of HCC development. This objective of the current study was to determine the association between HCC risk and diabetes duration and type of diabetes treatment. METHODS: A total of 420 patients with HCC and 1104 healthy controls were enrolled in an ongoing hospital-based case-control study. Multivariate logistic regression models were used to adjust for HCC risk factors. RESULTS: The prevalence of diabetes mellitus was 33.3% in patients with HCC and 10.4% in the control group, yielding an adjusted odds ratio (AOR) of 4.2 (95% confidence interval [95% CI], 3.0-5.9). In 87% of cases, diabetes was present before the diagnosis of HCC, yielding an AOR of 4.4 (95% CI, 3.0-6.3). Compared with patients with a diabetes duration of 2 to 5 years, the estimated AORs for those with a diabetes duration of 6 to 10 years and those with a diabetes duration >10 years were 1.8 (95% CI, 0.8-4.1) and 2.2 (95% CI, 1.2-4.8), respectively. With respect to diabetes treatment, the AORs were 0.3 (95% CI, 0.2-0.6), 0.3 (95% CI, 0.1-0.7), 7.1 (95% CI, 2.9-16.9), 1.9 (95% CI, 0.8-4.6), and 7.8 (95% CI, 1.5-40.0) for those treated with biguanides, thiazolidinediones, sulfonylureas, insulin, and dietary control, respectively. CONCLUSIONS: Diabetes appears to increase the risk of HCC, and such risk is correlated with a long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin were found to confer the highest magnitude of HCC risk, whereas treatment with biguanides or thiazolidinediones was associated with a 70% HCC risk reduction among diabetics.

The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States.

BACKGROUND/AIMS: The study aimed at addressing the connection between positive family history of liver cancer and hepatocellular carcinoma (HCC) development in the USA. METHODS: At The University of Texas M.D. Anderson Cancer Center, 347 patients with pathologically confirmed HCC and 1075 healthy controls were studied. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the individual's relationship with the relative, and the age at which the relative was diagnosed. RESULTS: Independently of hepatitis B virus (HBV) and hepatitis C virus (HCV), a history of liver cancer in first degree relatives was significantly associated with HCC development (AOR=4.1 [95% CI, 1.3-12.9]). Multiple relatives with liver cancer were only observed among HCC patients with chronic HBV/HCV infection. Affected siblings with liver cancer is significantly associated with HCC development with and without HBV/HCV infection; (AOR=5.7 [95% CI, 1.2-27.3]) and (AOR=4.3 [95% CI, 1.01-20.9]), respectively. Individuals with HBV/HCV and a family history of liver cancer were at higher risk for HCC (AOR=61.9 [95% CI, 6.6-579.7]). CONCLUSIONS: First degree family history of liver cancer is associated with HCC development in the USA. Further research exploring the genetic-environment interactions associated with risk of HCC is warranted.

Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial.

BACKGROUND: The treatment of patients with hepatocellular carcinoma (HCC) presents a major challenge, because associated cirrhosis limits the choice of chemotherapeutic agents. However, the abundant vascularity of HCC presents an attractive target for antiangiogenic therapy that potentially may be tolerated by cirrhotic patients. The current study was conducted to assess the antitumor activity, treatment tolerance, treatment-related toxicity, and patient survival after the administration of thalidomide in a Phase II trial. METHODS: Thirty-seven HCC patients were accrued between March, 1999, and March, 2000. Initially, the dose of oral thalidomide was escalated from 400 mg per day during the first week to 1000 mg per day by the fifth week, delivering one-third of the dose in the morning and the remaining two-thirds of the dose in the evening prior to bedtime. Changes in the daily drug administration schedule were allowed based on tolerance. Response was assessed at 8-week intervals. RESULTS: Thirty-two of 37 registered patients were evaluable for response. One patient had a partial response (PR), 1 patient had a minor response (MR), 10 patients had stable disease (SD) (31%; 95% confidence interval [95%CI], 16-51%), and 20 patients) (61%; 95%CI, 42-78%) had disease progression. The most commonly encountered toxicity was somnolence, with Grade 3-4 somnolence (>or= 4 hours of sleep during normal waking hours) in 9 patients (35%) and Grade 2 somnolence (800 mg if it was delivered at bedtime. Grade 3-4 skin reactions were observed in 20% of patients, and exfoliative dermatitis was observed in 1 responding patient. The overall median survival was 6.8 months. CONCLUSIONS: With a 5% PR rate, a 5% MR rate, and a 31% SD rate, the results indicate that thalidomide mostly may offer HCC patients disease stabilization. It is possible that, at a different dosage, or combined with other chemotherapy agents, or with the use of a different thalidomide analogue, longer patient survival may be achieved. However, in view of the significant neurologic toxicity encountered among these commonly cirrhotic HCC patients, thalidomide monotherapy at the high doses studied cannot be recommended for the treatment of HCC.

Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma.

BACKGROUND: The goal of the current study was to evaluate the efficacy and toxicity of capecitabine in patients with nonresectable hepatobiliary carcinoma. METHODS: The authors performed a retrospective analysis of all patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), or gallbladder carcinoma (GBC) who were ever treated with oral capecitabine. The medical records of 116 patients with hepatobiliary carcinoma who were treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between July 1998 and March 1999 were reviewed. RESULTS: A total of 63 patients were treated with capecitabine (37 with HCC, 18 with CCA, 8 with GBC). Capecitabine 1000 mg/m(2) was administered twice daily for 14 days. Treatment was repeated every 21 days. Each patient received 1-15 treatment cycles. Nine patients (14%)-11% of patients with HCC, 6% of patients with CCA, and 50% of patients with GBC-had either a complete response (CR) or a partial response. A CR was radiologically confirmed in one patient with HCC and in two patients with GBC. The median survival times were 10.1 months (95% confidence interval [CI], 4.5-15.7 months) for patients with HCC, 8.1 months (95% CI, 7.4-8.9 months) for patients with CCA, and 9.9 months (95% CI, 4.4-15.4 months) for patients with GBC. The most common toxicity was hand-foot syndrome (37%). Grade 3 thrombocytopenia occurred in 8% of patients with HCC. No other significant toxicities were observed. For all patients, response to treatment was positively correlated with survival and decline in tumor markers. CONCLUSIONS: Capecitabine was found to be safe for patients with hepatobiliary carcinoma, including those with cirrhosis. The antitumor activity of single-agent capecitabine was most pronounced in patients with GBC, was modest in patients with HCC, and was poor in patients with CCA.

Feasibility of adjuvant hepatic arterial infusion of chemotherapy after radiofrequency ablation with or without resection in patients with hepatic metastases from colorectal cancer.

BACKGROUND: The safety of combined hepatic artery infusion chemotherapy (HAI) and radiofrequency ablation (RFA) for liver metastases has not been assessed. We conducted a study to determine the feasibility of using HAI after RFA for colorectal cancer (CRC) liver metastases. METHODS: Between 1996 and 2001, patients with hepatic metastases from CRC were enrolled onto a prospective study of RFA plus HAI consisting of continuous-infusion floxuridine and bolus fluorouracil. Surgical complications, treatment-related toxicities, and patient outcomes were recorded. RESULTS: Fifty patients were treated with RFA and HAI with or without resection. A median of two lesions per patient, with a median greatest diameter of 2.0 cm, were treated with RFA. Postoperative complications, including 1 death, occurred in 11 of 50 patients. Toxicity from HAI was relatively mild. At 20 months' median follow-up, 32% of patients remained disease free. Ten percent of patients had recurrences at the site of RFA, 30% developed new liver metastases, and 48% developed extrahepatic disease. CONCLUSIONS: RFA of CRC liver metastases followed by HAI is feasible and is associated with acceptable complication and toxicity rates. The high rate of disease recurrence in our patients indicates that novel combinations of regional and systemic therapies are needed to improve patient outcomes.