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Interferon for postresection recurrence of hepatocellular carcinoma1
3200
World Literature Review
intrahepatic cholangiocarcinoma, whereas Whipple’s resection is the procedure of choice for operable extrahepatic cholangiocarcinoma. During more recent times, increasing use of these diagnostic tests as well as their improved accuracy might have resulted in: 1) an increase in the number of cholangiocarcinoma cases identified, thereby resulting in a fictitious increase in incidence; 2) reclassification or “diagnostic transfer” from extrahepatic biliary tumors, which have declined, to intrahepatic cholangiocarcinoma; and 3) misclassification of some cases of hepatocellular carcinoma, which is rising, as cholangiocarcinoma. However, hepatocellular carcinoma has characteristic gender distribution (2–3-fold higher in men compared with women) and ethnic differences (2–3-fold higher in blacks compared with whites), which were not observed for cholangiocarcinoma (3). Therefore, this type of misclassification is unlikely to have affected the temporal trends of cholangiocarcinoma. Several risk factors for intrahepatic cholangiocarcinoma have been well studied. These include sclerosing cholangitis related to inflammatory bowel disease, developmental abnormalities of the biliary tract (e.g., choledochal cysts), and hepatolithiasis (4). None of these conditions are increasing. Higher incidence of cholangiocarcinoma in certain areas of southeast and eastern Asia are associated with infestation by liver flukes Clonorchis sinensis and Opisthorchis Viverrini; these infections are rare in the United States and United Kingdom. Chemical exposures, including nitroamines, dioxin, asbestos, and polychlorinated biphenyls, have been associated with the development of cholangiocarcinoma (5). It is possible, but unproven, that greater occupational exposure to these toxins over the past 30 yr might have played a role in the observed increase in the incidence of cholangiocarcinoma. Preliminary evidence suggests a potential role for alcohol and hepatitis C virus (HCV) infection in cholangiocarcinoma. In one case-control study, patients with primary sclerosing cholangitis with past or current alcohol use were almost three times as likely to have cholangiocarcinoma than those who did not consume any alcohol (6). It has been proposed that HCV infection results in chronic biliary tract inflammation, which is associated with the development of cholangiocarcinoma. One cohort study of 600 HCV-infected patients conducted in Japan found that the 5- and 10-yr incidence rates of primary cholangiocellular carcinoma, a variant of cholangiocarcinoma, in patients with HCV-related cirrhosis were 1,000 times higher than those observed in the general population (7). Another cohort study (n ⫽ 11,605) reported that excess risk for all types of liver cancer is more pronounced for patients with cirrhosis, regardless of the underlying cause of cirrhosis (8). In summary, although issues related to the diagnosis and classification of intrahepatic cholangiocarcinoma could have impacted the reported incidence and mortality rates, the evidence suggests that an increase in intrahepatic cholangiocarcinoma has occurred. Although many risk factors are suspected to contribute to the observed increase of this
AJG – Vol. 97, No. 12, 2002
disease, further research is needed to determine the magnitude of effect of these exposures. Jessica A. Davila, Ph.D. Hashem B. El-Serag, M.D., M.P.H. The Houston Veterans Affairs Medical Center Baylor College of Medicine Houston, Texas
REFERENCES 1. Suh KS, Roh HR, Koh YT, et al. Clinicopathologic features of the intraductal growth type of peripheral cholangiocarcinoma. Hepatology 2000;31:12–7. 2. Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: A case-control study. Hepatology 1998;27:311– 6. 3. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745– 50. 4. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999;341:1368 –78. 5. Pitt HA, Dooley WC, Yeo CJ, Cameron JL. Malignancies of the biliary tree. Curr Probl Surg 1995;32:1–90. 6. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: A multicenter case-control study. Hepatology 2000;31:7–11. 7. Kobayashi M, Ikeda K, Saitoh S, et al. Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis. Cancer 2000;88: 2471–7. 8. Sorenson HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: A nationwide cohort study in Denmark. Hepatology 1998;28:921–5.
Interferon for Postresection Recurrence of Hepatocellular Carcinoma Kubo S, Nishiguchi S, Hirohashi K, et al. Effects of Long-Term Postoperative Interferon-Alpha Therapy on Intrahepatic Recurrence After Resection of Hepatitis C VirusRelated Hepatocellular Carcinoma. A Randomized, Controlled Trial Ann Intern Med 2001;134:963–7
ABSTRACT In a randomized, controlled trial, 30 hepatitis C virus-infected men who underwent hepatic resection for hepatocellular carcinoma (HCC) were subsequently randomized to receive either interferon (INF)-alpha (n ⫽ 15) or no interferon (n ⫽ 15). Eighty percent of patients had hepatitis C virus genotype 1b, and 20% of patients had genotype 2a. Patients in the treatment group were given IFN-alpha, 6 M IU i.m. daily for 2 wk, then three times weekly for 14 wk, and finally twice weekly for 88 wk. The investigators were blinded to the treatment assignment. The median duration of follow-up was approximately 3 and 2.5 yr for the IFN and
AJG – December, 2002
control groups, respectively. Three patients (15%) did not complete IFN therapy as a result of side effects. In addition, four patients (20%) with recurrence of HCC had their IFN stopped before the end of the study to allow treatment of the tumor. In the IFN group, two patients had sustained viral response, and six had biochemical response. In a survival analysis that included all randomized patients, i.e., “intention to treat,” recurrent HCC was detected in five patients (30%) in the IFN-alpha group and in 12 control patients (80%) (p ⫽ 0.037). The difference in the rate of HCC between the groups became apparent only after the first 2 yr of follow-up. The authors concluded that IFN-alpha therapy appears to decrease the recurrence of HCC after resection in patients with chronic hepatitis C infection. (Am J Gastroenterol 2002;97:3200 –3202. © 2002 by Am. Coll. of Gastroenterology)
COMMENT Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is increasing in the United States, Japan, and some European countries (1). Survival after diagnosis remains dismal for most patients with HCC. Surgical resection of a small HCC (⬍5 cm) is potentially curative among patients with relatively preserved hepatic function. However, postsurgical recurrence of HCV-related HCC is common (up to 80% in 5 yr) because the residual liver continues to have inflammation, fibrosis, or cirrhosis caused by active HCV. There is growing interest in the use of antiviral treatment for the secondary prevention of HCC (patients with active HCV infection before developing HCC) as well as tertiary prevention (after surgical resection or transplantation for HCC). Interferon (IFN) has been the mainstay of HCV treatment regimens; in addition, it is an antiproliferating agent with postulated antitumor properties. Studies from Asia and Europe reported a decrease in the incidence of HCC in HCVinfected patients after IFN treatment (2–7). In a prospective, randomized, controlled trial, 90 patients with HCV-related compensated cirrhosis were randomly allocated to receive either IFN-alpha (45 patients) or no IFN treatment (45 controls) and were followed for 2–7 yr. Patients who received IFN-alpha had significant reduction in HCC incidence compared with the control group (4% vs 38%, p ⫽ 0.002) (2). In another study from Japan, 250 patients with chronic HCV were treated with INF and followed for 8 –11 yr post-therapy. The annual incidence of HCC was 0.37% in complete responders and 0.50% in biochemical responders, both of these rates being significantly lower than in nonresponders (p ⫽ 0.0001) (3). Furthermore, recent meta-analysis studies suggested that IFN treatment in patients with HCV-related cirrhosis was associated with a reduced risk of HCC (4, 5). The mechanism(s) by which IFN reduces the risk of HCC remain to be elucidated. These include but are not limited to virological clearance of HCV; other mechanisms may involve reduction of hepatic inflammation, or
World Literature Review
3201
upregulating tumor-suppressor gene for HCC (6, 7). In the United States, long-term prospective studies of the effect of IFN on the prognosis of HCV-infected patients with advanced fibrosis or cirrhosis are underway. The present study by Kubo et al. represents the first prospective, randomized, investigator-blinded trial published to date to address the issue of “adjuvant” IFN therapy in HCC. One previous prospective trial evaluated 20 patients with HCV-related HCC who were treated with surgical resection or local ablation. These patients were randomized to receive either 6 MU of natural IFN-beta twice a week for 36 months (10 patients) or no IFN treatment (10 patients). None of the patients in either group lost HCV-RNA throughout the observation period (median 25 months). Nevertheless, 70% of patients in the nontreatment group had recurrent tumors versus only 10% in patients with IFN therapy (8). Similar results were suggested in retrospective studies (9, 10). For example, an analysis of 223 patients with HCV-related HCC, risk factors for postresection HCC recurrence included HCV viremia, severity of hepatitis, and lack of preoperative interferon therapy (9). Despite the small number of patients included in the present study and the relatively short follow-up period, the investigators showed significant reduction in HCC recurrence among patients who received IFN therapy than in those who did not. However, these results may not be reproducible in clinical practice, especially in the United States, given a different HCV genotype, the high dropout rate because of side effects, and the limited number of patients diagnosed with small resectable HCC and preserved hepatic function. Damien B. Mallat, M.D. Division of Gastroenterology Baylor College of Medicine Hashem B. El-Serag, M.D., M.P.H. The Houston Veterans Affairs Medical Center Houston, Texas
REFERENCES 1. El-Serag HB. Global epidemiology of hepatocellular carcinoma. Liver Clin N Am 2001;5:87–107. 2. Nishiguchi S, Kuroki T, Nakatani S, et al. Randomized trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346:1051–5. 3. Shindo M, Hamada K, Oda Y, et al. Long-term follow-up study of sustained biochemical responders with interferon therapy. Hepatology 2001;33:1299 –302. 4. Camma C, Giunta M, Andreone P, et al. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: An evidence-based approach. J Hepatol 2001;34:593– 602. 5. Papatheodoridis GV, Papadimitropoulos VC, Hadziyannis SJ. Effect of interferon therapy on the development of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: A meta-analysis. Aliment Pharmacol Ther 2001;15: 689 –98. 6. Merle P, Chevallier M, Levy R, et al. Preliminary results of
3202
7. 8.
9. 10.
World Literature Review
interferon-alpha therapy on woodchuck hepatitis virus-induced hepatocarcinogenesis: Possible benefit in female transgenic mice. J Hepatol 2001;34:562–9. Moriyama Y, Nishiguchi S, Tamori A, et al. Tumor-suppressor effect of interferon regulatory factor-1 in human hepatocellular carcinoma. Clin Cancer Res 2001;7:1293– 8. Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor—A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology 2000;32:436 – 8. Kubo S, Hirohashi K, Tanaka H, et al. Risk factors for recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. World J Surg 2000;24:1559 – 65. Oon CJ. Long-term survival following treatment of hepatocellular carcinoma in Singapore: Evaluation of Wellferon in the prophylaxis of high-risk pre-cancerous conditions. Cancer Chemother Pharmacol 1992;31(suppl):S137– 42.
Low-Dose Aspirin: Protection From the Panacea Lai KC, Lam SK, et al. Lansoprazole for the Prevention of Recurrences of Ulcer Complications From Long-Term Low-Dose Aspirin Use N Engl J Med 2002;346:2033– 8
ABSTRACT Lai et al. prospectively studied the role of gastric acid suppression in the prevention of recurrence of ulcer complications after eradication of Helicobacter pylori (H. pylori) infection in patients taking long-term low-dose aspirin. They enrolled 123 H. pylori-treated patients who had developed ulcer complications 1 month or longer after commencing low-dose aspirin treatment. The primary endpoints were clinical (recurrence of ulcer complications defined as bleeding, perforation, or obstruction). A total of 245 (243 with gastric outlet obstruction and two with upper GI bleeding) patients were screened. Of these, 171 were infected with H. pylori and 123 met the criteria for inclusion into the study. These patients were randomized to 100 mg of aspirin and 30 mg of lansoprazole (62 patients) or to 100 mg of aspirin and a matched placebo (61 patients). The mean duration of follow-up was 12 months. Fourteen upper GI events were reported to a blinded committee that confirmed 10 adverse outcomes. There was one (1.6%) episode of GI bleeding in the lansoprazole group compared with nine (14.8%) in the placebo group (adjusted hazards ratio ⫽ 9.6, 95% CI ⫽ 1.2–76.1). However, four of the nine patients in the placebo group had a recurrence of H. pylori, and two had taken nonsteroidal anti-inflammatory drugs. The authors concluded that in patients with ulcer complications related to the long-term use of low-dose aspirin, treatment with lansoprazole in addition to the eradication of H. pylori infection significantly reduce the rate of recurrence of ulcer complications. (Am J Gastroenterol 2002;97: 3202–3203. © 2002 by Am. Coll. of Gastroenterology)
AJG – Vol. 97, No. 12, 2002
COMMENT Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are among the most commonly prescribed drugs in the world. The prevalence of once-weekly or greater NSAID use among patients 65 yr or older has been reported to be as high as 70%. NSAIDs are a common cause of GI injury in the United States. Fifteen to 30% of patients taking NSAIDs have endoscopic evidence of ulceration, and half have erosions at endoscopy (1). Clinical GI events take place in 3–5% of patients taking NSAIDs, and serious GI complications occur in approximately 1.5% of patients (1). Several studies have shown that low-dose aspirin is a risk factor for GI bleeding (2, 3). Helicobacter pylori (H. pylori) infection has also been shown to increase the risk for bleeding in patients receiving low-dose aspirin (4). Screening and treatment for H. pylori infection has been shown to reduce the incidence of ulcers in patients commencing NSAID therapy (5). A recent study showed that in patients with H. pylori infection and a history of upper GI bleeding who were taking low-dose aspirin, eradication of H. pylori was equivalent to treatment with omeprazole in preventing recurrent bleeding. Omeprazole was superior to the eradication of H. pylori in preventing recurrent bleeding in patients who were taking other NSAIDs (6). The study by Lai et al. is important because it addresses an issue that has not been studied in randomized, controlled trials thus far: does proton pump inhibitor therapy after eradication of H. pylori infection continue to protect high-risk individuals from adverse upper GI events? Of the 123 patients participating in the study, 14 had adverse upper GI events. Four of these had dyspepsia with no endoscopically demonstrable lesion, which responded to antacid therapy. One patient in the lansoprazole group and nine in the placebo group developed ulcers, an estimated probability of ulcer recurrence of 1.6% in the lansoprazole group (95% CI ⫽ 0 –9) and 14.8% in the placebo group (95% CI ⫽ 7–26, p ⫽ 0.008). The calculated number of patients who need to be treated with proton pump inhibitors to prevent one adverse event is a modest eight patients. It is important to note however, that four of the nine patients in the placebo group who developed ulcers had a relapse of H. pylori infection, and two others had begun taking other NSAIDs (despite instructions to the contrary) in the preceding 4 wk of the index event. Because H. pylori infection and NSAID use are wellknown risk factors for ulcerogenesis, one may recalculate the data for those who truly had eradication and remained free of H. pylori and were taking only low-dose aspirin. The ulcer incidence would then drop to three of 55 patients (5%) in the placebo group, a relative risk reduction of 68%, an absolute risk reduction of 3.4%. With these criteria, the number of patients that would need to be treated would rise to 30 to prevent one adverse outcome. This is an important study because it demonstrates that high-risk patients taking low-dose aspirin can benefit from
World Literature Review
intrahepatic cholangiocarcinoma, whereas Whipple’s resection is the procedure of choice for operable extrahepatic cholangiocarcinoma. During more recent times, increasing use of these diagnostic tests as well as their improved accuracy might have resulted in: 1) an increase in the number of cholangiocarcinoma cases identified, thereby resulting in a fictitious increase in incidence; 2) reclassification or “diagnostic transfer” from extrahepatic biliary tumors, which have declined, to intrahepatic cholangiocarcinoma; and 3) misclassification of some cases of hepatocellular carcinoma, which is rising, as cholangiocarcinoma. However, hepatocellular carcinoma has characteristic gender distribution (2–3-fold higher in men compared with women) and ethnic differences (2–3-fold higher in blacks compared with whites), which were not observed for cholangiocarcinoma (3). Therefore, this type of misclassification is unlikely to have affected the temporal trends of cholangiocarcinoma. Several risk factors for intrahepatic cholangiocarcinoma have been well studied. These include sclerosing cholangitis related to inflammatory bowel disease, developmental abnormalities of the biliary tract (e.g., choledochal cysts), and hepatolithiasis (4). None of these conditions are increasing. Higher incidence of cholangiocarcinoma in certain areas of southeast and eastern Asia are associated with infestation by liver flukes Clonorchis sinensis and Opisthorchis Viverrini; these infections are rare in the United States and United Kingdom. Chemical exposures, including nitroamines, dioxin, asbestos, and polychlorinated biphenyls, have been associated with the development of cholangiocarcinoma (5). It is possible, but unproven, that greater occupational exposure to these toxins over the past 30 yr might have played a role in the observed increase in the incidence of cholangiocarcinoma. Preliminary evidence suggests a potential role for alcohol and hepatitis C virus (HCV) infection in cholangiocarcinoma. In one case-control study, patients with primary sclerosing cholangitis with past or current alcohol use were almost three times as likely to have cholangiocarcinoma than those who did not consume any alcohol (6). It has been proposed that HCV infection results in chronic biliary tract inflammation, which is associated with the development of cholangiocarcinoma. One cohort study of 600 HCV-infected patients conducted in Japan found that the 5- and 10-yr incidence rates of primary cholangiocellular carcinoma, a variant of cholangiocarcinoma, in patients with HCV-related cirrhosis were 1,000 times higher than those observed in the general population (7). Another cohort study (n ⫽ 11,605) reported that excess risk for all types of liver cancer is more pronounced for patients with cirrhosis, regardless of the underlying cause of cirrhosis (8). In summary, although issues related to the diagnosis and classification of intrahepatic cholangiocarcinoma could have impacted the reported incidence and mortality rates, the evidence suggests that an increase in intrahepatic cholangiocarcinoma has occurred. Although many risk factors are suspected to contribute to the observed increase of this
AJG – Vol. 97, No. 12, 2002
disease, further research is needed to determine the magnitude of effect of these exposures. Jessica A. Davila, Ph.D. Hashem B. El-Serag, M.D., M.P.H. The Houston Veterans Affairs Medical Center Baylor College of Medicine Houston, Texas
REFERENCES 1. Suh KS, Roh HR, Koh YT, et al. Clinicopathologic features of the intraductal growth type of peripheral cholangiocarcinoma. Hepatology 2000;31:12–7. 2. Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: A case-control study. Hepatology 1998;27:311– 6. 3. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745– 50. 4. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999;341:1368 –78. 5. Pitt HA, Dooley WC, Yeo CJ, Cameron JL. Malignancies of the biliary tree. Curr Probl Surg 1995;32:1–90. 6. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: A multicenter case-control study. Hepatology 2000;31:7–11. 7. Kobayashi M, Ikeda K, Saitoh S, et al. Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis. Cancer 2000;88: 2471–7. 8. Sorenson HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: A nationwide cohort study in Denmark. Hepatology 1998;28:921–5.
Interferon for Postresection Recurrence of Hepatocellular Carcinoma Kubo S, Nishiguchi S, Hirohashi K, et al. Effects of Long-Term Postoperative Interferon-Alpha Therapy on Intrahepatic Recurrence After Resection of Hepatitis C VirusRelated Hepatocellular Carcinoma. A Randomized, Controlled Trial Ann Intern Med 2001;134:963–7
ABSTRACT In a randomized, controlled trial, 30 hepatitis C virus-infected men who underwent hepatic resection for hepatocellular carcinoma (HCC) were subsequently randomized to receive either interferon (INF)-alpha (n ⫽ 15) or no interferon (n ⫽ 15). Eighty percent of patients had hepatitis C virus genotype 1b, and 20% of patients had genotype 2a. Patients in the treatment group were given IFN-alpha, 6 M IU i.m. daily for 2 wk, then three times weekly for 14 wk, and finally twice weekly for 88 wk. The investigators were blinded to the treatment assignment. The median duration of follow-up was approximately 3 and 2.5 yr for the IFN and
AJG – December, 2002
control groups, respectively. Three patients (15%) did not complete IFN therapy as a result of side effects. In addition, four patients (20%) with recurrence of HCC had their IFN stopped before the end of the study to allow treatment of the tumor. In the IFN group, two patients had sustained viral response, and six had biochemical response. In a survival analysis that included all randomized patients, i.e., “intention to treat,” recurrent HCC was detected in five patients (30%) in the IFN-alpha group and in 12 control patients (80%) (p ⫽ 0.037). The difference in the rate of HCC between the groups became apparent only after the first 2 yr of follow-up. The authors concluded that IFN-alpha therapy appears to decrease the recurrence of HCC after resection in patients with chronic hepatitis C infection. (Am J Gastroenterol 2002;97:3200 –3202. © 2002 by Am. Coll. of Gastroenterology)
COMMENT Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is increasing in the United States, Japan, and some European countries (1). Survival after diagnosis remains dismal for most patients with HCC. Surgical resection of a small HCC (⬍5 cm) is potentially curative among patients with relatively preserved hepatic function. However, postsurgical recurrence of HCV-related HCC is common (up to 80% in 5 yr) because the residual liver continues to have inflammation, fibrosis, or cirrhosis caused by active HCV. There is growing interest in the use of antiviral treatment for the secondary prevention of HCC (patients with active HCV infection before developing HCC) as well as tertiary prevention (after surgical resection or transplantation for HCC). Interferon (IFN) has been the mainstay of HCV treatment regimens; in addition, it is an antiproliferating agent with postulated antitumor properties. Studies from Asia and Europe reported a decrease in the incidence of HCC in HCVinfected patients after IFN treatment (2–7). In a prospective, randomized, controlled trial, 90 patients with HCV-related compensated cirrhosis were randomly allocated to receive either IFN-alpha (45 patients) or no IFN treatment (45 controls) and were followed for 2–7 yr. Patients who received IFN-alpha had significant reduction in HCC incidence compared with the control group (4% vs 38%, p ⫽ 0.002) (2). In another study from Japan, 250 patients with chronic HCV were treated with INF and followed for 8 –11 yr post-therapy. The annual incidence of HCC was 0.37% in complete responders and 0.50% in biochemical responders, both of these rates being significantly lower than in nonresponders (p ⫽ 0.0001) (3). Furthermore, recent meta-analysis studies suggested that IFN treatment in patients with HCV-related cirrhosis was associated with a reduced risk of HCC (4, 5). The mechanism(s) by which IFN reduces the risk of HCC remain to be elucidated. These include but are not limited to virological clearance of HCV; other mechanisms may involve reduction of hepatic inflammation, or
World Literature Review
3201
upregulating tumor-suppressor gene for HCC (6, 7). In the United States, long-term prospective studies of the effect of IFN on the prognosis of HCV-infected patients with advanced fibrosis or cirrhosis are underway. The present study by Kubo et al. represents the first prospective, randomized, investigator-blinded trial published to date to address the issue of “adjuvant” IFN therapy in HCC. One previous prospective trial evaluated 20 patients with HCV-related HCC who were treated with surgical resection or local ablation. These patients were randomized to receive either 6 MU of natural IFN-beta twice a week for 36 months (10 patients) or no IFN treatment (10 patients). None of the patients in either group lost HCV-RNA throughout the observation period (median 25 months). Nevertheless, 70% of patients in the nontreatment group had recurrent tumors versus only 10% in patients with IFN therapy (8). Similar results were suggested in retrospective studies (9, 10). For example, an analysis of 223 patients with HCV-related HCC, risk factors for postresection HCC recurrence included HCV viremia, severity of hepatitis, and lack of preoperative interferon therapy (9). Despite the small number of patients included in the present study and the relatively short follow-up period, the investigators showed significant reduction in HCC recurrence among patients who received IFN therapy than in those who did not. However, these results may not be reproducible in clinical practice, especially in the United States, given a different HCV genotype, the high dropout rate because of side effects, and the limited number of patients diagnosed with small resectable HCC and preserved hepatic function. Damien B. Mallat, M.D. Division of Gastroenterology Baylor College of Medicine Hashem B. El-Serag, M.D., M.P.H. The Houston Veterans Affairs Medical Center Houston, Texas
REFERENCES 1. El-Serag HB. Global epidemiology of hepatocellular carcinoma. Liver Clin N Am 2001;5:87–107. 2. Nishiguchi S, Kuroki T, Nakatani S, et al. Randomized trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346:1051–5. 3. Shindo M, Hamada K, Oda Y, et al. Long-term follow-up study of sustained biochemical responders with interferon therapy. Hepatology 2001;33:1299 –302. 4. Camma C, Giunta M, Andreone P, et al. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: An evidence-based approach. J Hepatol 2001;34:593– 602. 5. Papatheodoridis GV, Papadimitropoulos VC, Hadziyannis SJ. Effect of interferon therapy on the development of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: A meta-analysis. Aliment Pharmacol Ther 2001;15: 689 –98. 6. Merle P, Chevallier M, Levy R, et al. Preliminary results of
3202
7. 8.
9. 10.
World Literature Review
interferon-alpha therapy on woodchuck hepatitis virus-induced hepatocarcinogenesis: Possible benefit in female transgenic mice. J Hepatol 2001;34:562–9. Moriyama Y, Nishiguchi S, Tamori A, et al. Tumor-suppressor effect of interferon regulatory factor-1 in human hepatocellular carcinoma. Clin Cancer Res 2001;7:1293– 8. Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor—A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology 2000;32:436 – 8. Kubo S, Hirohashi K, Tanaka H, et al. Risk factors for recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. World J Surg 2000;24:1559 – 65. Oon CJ. Long-term survival following treatment of hepatocellular carcinoma in Singapore: Evaluation of Wellferon in the prophylaxis of high-risk pre-cancerous conditions. Cancer Chemother Pharmacol 1992;31(suppl):S137– 42.
Low-Dose Aspirin: Protection From the Panacea Lai KC, Lam SK, et al. Lansoprazole for the Prevention of Recurrences of Ulcer Complications From Long-Term Low-Dose Aspirin Use N Engl J Med 2002;346:2033– 8
ABSTRACT Lai et al. prospectively studied the role of gastric acid suppression in the prevention of recurrence of ulcer complications after eradication of Helicobacter pylori (H. pylori) infection in patients taking long-term low-dose aspirin. They enrolled 123 H. pylori-treated patients who had developed ulcer complications 1 month or longer after commencing low-dose aspirin treatment. The primary endpoints were clinical (recurrence of ulcer complications defined as bleeding, perforation, or obstruction). A total of 245 (243 with gastric outlet obstruction and two with upper GI bleeding) patients were screened. Of these, 171 were infected with H. pylori and 123 met the criteria for inclusion into the study. These patients were randomized to 100 mg of aspirin and 30 mg of lansoprazole (62 patients) or to 100 mg of aspirin and a matched placebo (61 patients). The mean duration of follow-up was 12 months. Fourteen upper GI events were reported to a blinded committee that confirmed 10 adverse outcomes. There was one (1.6%) episode of GI bleeding in the lansoprazole group compared with nine (14.8%) in the placebo group (adjusted hazards ratio ⫽ 9.6, 95% CI ⫽ 1.2–76.1). However, four of the nine patients in the placebo group had a recurrence of H. pylori, and two had taken nonsteroidal anti-inflammatory drugs. The authors concluded that in patients with ulcer complications related to the long-term use of low-dose aspirin, treatment with lansoprazole in addition to the eradication of H. pylori infection significantly reduce the rate of recurrence of ulcer complications. (Am J Gastroenterol 2002;97: 3202–3203. © 2002 by Am. Coll. of Gastroenterology)
AJG – Vol. 97, No. 12, 2002
COMMENT Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are among the most commonly prescribed drugs in the world. The prevalence of once-weekly or greater NSAID use among patients 65 yr or older has been reported to be as high as 70%. NSAIDs are a common cause of GI injury in the United States. Fifteen to 30% of patients taking NSAIDs have endoscopic evidence of ulceration, and half have erosions at endoscopy (1). Clinical GI events take place in 3–5% of patients taking NSAIDs, and serious GI complications occur in approximately 1.5% of patients (1). Several studies have shown that low-dose aspirin is a risk factor for GI bleeding (2, 3). Helicobacter pylori (H. pylori) infection has also been shown to increase the risk for bleeding in patients receiving low-dose aspirin (4). Screening and treatment for H. pylori infection has been shown to reduce the incidence of ulcers in patients commencing NSAID therapy (5). A recent study showed that in patients with H. pylori infection and a history of upper GI bleeding who were taking low-dose aspirin, eradication of H. pylori was equivalent to treatment with omeprazole in preventing recurrent bleeding. Omeprazole was superior to the eradication of H. pylori in preventing recurrent bleeding in patients who were taking other NSAIDs (6). The study by Lai et al. is important because it addresses an issue that has not been studied in randomized, controlled trials thus far: does proton pump inhibitor therapy after eradication of H. pylori infection continue to protect high-risk individuals from adverse upper GI events? Of the 123 patients participating in the study, 14 had adverse upper GI events. Four of these had dyspepsia with no endoscopically demonstrable lesion, which responded to antacid therapy. One patient in the lansoprazole group and nine in the placebo group developed ulcers, an estimated probability of ulcer recurrence of 1.6% in the lansoprazole group (95% CI ⫽ 0 –9) and 14.8% in the placebo group (95% CI ⫽ 7–26, p ⫽ 0.008). The calculated number of patients who need to be treated with proton pump inhibitors to prevent one adverse event is a modest eight patients. It is important to note however, that four of the nine patients in the placebo group who developed ulcers had a relapse of H. pylori infection, and two others had begun taking other NSAIDs (despite instructions to the contrary) in the preceding 4 wk of the index event. Because H. pylori infection and NSAID use are wellknown risk factors for ulcerogenesis, one may recalculate the data for those who truly had eradication and remained free of H. pylori and were taking only low-dose aspirin. The ulcer incidence would then drop to three of 55 patients (5%) in the placebo group, a relative risk reduction of 68%, an absolute risk reduction of 3.4%. With these criteria, the number of patients that would need to be treated would rise to 30 to prevent one adverse outcome. This is an important study because it demonstrates that high-risk patients taking low-dose aspirin can benefit from