Yehuda Z. Patt

OncoSurge: A Strategy for Improving Resectability With Curative Intent in Metastatic Colorectal Cancer

PURPOSEnMost patients with colorectal liver metastases present to general surgeons and oncologists without a specialist interest in their management. Since treatment strategy is frequently dependent on the response to earlier treatments, our aim was to create a therapeutic decision model identifying appropriate procedure sequences.nnnMETHODSnWe used the RAND Corporation/University of California, Los Angeles Appropriateness Method (RAM) assessing strategies of resection, local ablation and chemotherapy. After a comprehensive literature review, an expert panel rated appropriateness of each treatment option for a total of 1,872 ratings decisions in 252 cases. A decision model was constructed, consensus measured and results validated using 48 virtual cases, and 34 real cases with known outcomes.nnnRESULTSnConsensus was achieved with overall agreement rates of 93.4 to 99.1%. Absolute resection contraindications included unresectable extrahepatic disease, more than 70% liver involvement, liver failure, and being surgically unfit. Factors not influencing treatment strategy were age, primary tumor stage, timing of metastases detection, past blood transfusion, liver resection type, pre-resection carcinoembryonic antigen (CEA), and previous hepatectomy. Immediate resection was appropriate with adequate radiologically-defined resection margins and no portal adenopathy; other factors included presence of < or = 4 or > 4 metastases and unilobar or bilobar involvement. Resection was appropriate postchemotherapy, independent of tumor response in the case of < or = 4 metastases and unilobar liver involvement. Resection was appropriate only for > 4 metastases or bilobar liver involvement, after tumor shrinkage with chemotherapy. When possible, resection was preferred to local ablation.nnnCONCLUSIONnThe results were incorporated into a decision matrix, creating a computer program (OncoSurge). This model identifies individual patient resectability, recommending optimal treatment strategies. It may also be used for medical education.

Risk Factors for Intrahepatic and Extrahepatic Cholangiocarcinoma: A Hospital-Based Case–Control Study

BACKGROUND:The risk factors for cholangiocarcinoma are poorly defined in the United States. We evaluated hepatitis C virus (HCV), hepatitis B virus (HBV), and liver cirrhosis as risk factors for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC).METHODS:A case–control study in which cases were cholangiocarcinoma patients referred to the M.D. Anderson Cancer Center between 1992 and 2002 and controls were healthy individuals. Information about liver diseases, family history, diabetes, smoking, and alcohol consumption were collected on both groups. Blood from all participants was tested for HBV and HCV markers.RESULTS:We identified 246 cases (83 ICC and 163 ECC) and matched them to 236 controls. Compared with controls, ICC patients had a higher prevalence of anti-HCV antibodies (6.0% vs 0.8%, P = 0.01), anti-HBc (9.6% vs 0%, P < 0.0001), and heavy alcohol consumption (21.7% vs 3.8%, P < 0.0001). The adjusted odds ratio and 95% confidence interval (CI) were 7.9 (95% CI 1.3–84.5), 28.6 (95% CI 3.9–1,268.1), and 5.9 (95% CI 2.1–17.4), respectively. Only heavy alcohol consumption was higher in patients with ECC than in controls (17.8% vs 3.8%, P = 0.003). The prevalence of diabetes and smoking were not significantly different between cases (ICC or ECC) and controls. The prevalence of cirrhosis was higher in patients with ICC than those with ECC (24.1% vs 4.9%, P < 0.0001).CONCLUSIONS:Liver cirrhosis and chronic HCV infection are possible risk factors for ICC but not ECC. Heavy alcohol consumption is a risk factor for both ICC and ECC.

Rising prevalence of hepatitis C virus infection among patients recently diagnosed with hepatocellular carcinoma in the United States

Background The aim of this study was to determine whether hepatitis C virus (HCV) is an underlying cause of the increase in the incidence of hepatocellular carcinoma (HCC) in the United States. Study The medical records of all patients who had received a pathologic diagnosis of HCC at the University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A., during 1993 through 1998 were reviewed. Only patients residing in the United States were analyzed. All patients were tested for HCV and hepatitis B virus serologic markers. Results The number of patients with HCC referred to M.D. Anderson Cancer Center increased from 143 in 1993 through 1995 to 216 in 1996 through 1998. Twenty-six patients (18%) and 66 patients (31%) with anti-HCV antibodies were diagnosed with HCC from 1993 to 1995 and from 1996 to 1998, respectively, thus constituting a significant increase (p = 0.01). Although the age distribution of these patients did not differ significantly between 1993 to 1995 and 1996 to 1998, the increase in HCV-associated HCC was greatest among patients 40 to 49 years old. Hepatitis B surface antigens (HBsAg) or anti-hepatitis B core antigens were found in 37 patients (26%) with HCC during 1993 to 1995 and in 37 patients (17%) with HCC during 1996 to 1998 (p = 0.06). Moreover, a significant decrease in the prevalence of HBsAg from 1996 to 1998 (21 patients; 10%) compared with 1993 to 1995 (25 patients; 18%) was observed (p = 0.03). Conclusion Hepatitis C infection is the major viral factor contributing to the increase in HCC incidence observed in this large-scale, single-center United States-based experience.

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

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.

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. (HEPATOLOGY 2009;49:1563–1570.)

Association between hypothyroidism and hepatocellular carcinoma

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. (HEPATOLOGY 2009;49:1563–1570.)

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.

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

BACKGROUND/AIMSnThe study aimed at addressing the connection between positive family history of liver cancer and hepatocellular carcinoma (HCC) development in the USA.nnnMETHODSnAt 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 individuals relationship with the relative, and the age at which the relative was diagnosed.nnnRESULTSnIndependently 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]).nnnCONCLUSIONSnFirst 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.

Prognostic factors influencing survival of patients with advanced colorectal cancer: hepatic-artery infusion versus systemic intravenous chemotherapy for liver metastases.

In this study of 232 patients with histologically confirmed large bowel carcinoma, patient- and tumor-related characteristics were examined and their effect on prognosis was determined. Serum alkaline phosphatase and albumin concentrations, symptom duration prior to diagnosis of the primary tumor, and the status of the primary tumor showed the strongest relationship to survival after diagnosis of surgically noncurable disease. Patients who had normal serum alkaline phosphatase and albumin concentrations, patients whose symptoms lasted over 12 months before diagnosis, and patients whose primary tumor had been resected before diagnosis of noncurable disease had a good prognosis. Performance status, weight loss, sex, presence of liver metastasis, hemoglobin concentration, and absolute lymphocyte or monocyte counts in the peripheral blood, at time of diagnosis of surgically noncurable disease, were significant factors when examined individually. One hundred seventy-nine patients with metastatic colorectal cancer confined to the liver were selected from 601 patients who received chemotherapy for advanced colorectal cancer over 10-year periods to compare the efficacy of hepatic-artery infusion therapy with that of intravenous 5-fluoropyrimidine--containing chemotherapy. The two groups were similar with respect to prognostic factors. The hepatic-artery infusion chemotherapy produced a higher response rate than intravenous chemotherapy, but did not result in significant prolongation of survival.

Capecitabine plus 3-weekly irinotecan (XELIRI regimen) as first-line chemotherapy for metastatic colorectal cancer: Phase II trial results

Background:Capecitabine results in superior response rate, improved safety, and improved convenience compared with 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (MCRC). Irinotecan in combination with 5-FU/LV has been shown to improve efficacy compared with 5-FU/LV alone in MCRC. Therefore, we evaluated the efficacy and safety of capecitabine plus irinotecan every 3 weeks (XELIRI regimen) as first-line treatment. Methods:Patients with MCRC who were <65 years of age received irinotecan 250 mg/m2 i.v. on day 1 + capecitabine 1000 mg/m2 orally twice daily on days 1 to 14, every 3 weeks. Patients ≥65 years of age and those with impaired renal function or with a history of prior radiotherapy received lower doses of both agents (200 mg/m2 and 750 mg/m2 twice daily, respectively). Results:A total of 52 patients (29 men, 23 women) were enrolled between October 2001 and August 2003. Median age was 57.5 years (range, 30–79 years); median Karnofsky performance status was 90 (range, 70–100). Treatment led to a response rate of 50% (ITT population) and a disease control rate of 71%. With a median cohort follow-up of 30.5 months, median time to progression and overall survival are 7.8 months (95% confidence interval, 5.6–10.0) and 16.8 months (95% confidence, 11.9 to not reached), respectively. Most common treatment-related grade 3/4 adverse events were neutropenia (25%), diarrhea (20%), vomiting (16%), dehydration (10%), nausea (6%), abdominal pain (6%), and hand-foot syndrome (6%). Conclusion:XELIRI is an active first-line treatment of MCRC. Implementation of upfront dose reductions for both agents in patients with risk factors for toxicity appears to have produced a safer regimen compared with previous studies of XELIRI without such dose reductions.