Or is it just a little relaxation?
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fibrosis or cirrhosis. Of interest, a histological response wasalso seen in about 2635% of patients who did not have asustained virological response. Even in the cohort of pa-tients with a combination or poor prognostic factors (geno-type 1, high baseline viral load of .2.0 million copies/ml),10% of patients assigned to 180 mg of PEG IFN alfa-2a hada sustained virologic response.
Safety parameters were carefully evaluated, and the pro-portion of patients with a neutrophil count of ,500 ml3 atany time during the study was similar in the three groups(13%). No patient developed any serious infection or sep-sis secondary to the neutropenia, and no patient had todiscontinue treatment secondary to neutropenia. Eventhough a higher proportion of patients assigned to the higherdoses of PEG IFN had a decrease in the platelet counts to,50,000/ml3, none of the patients had clinically significantbleeding secondary to the thrombocytopenia. A higher pro-portion of the patients assigned to the 180 mg of PEG IFNalfa-2a had myalgia and inflammation at the injection site.Four deaths were reported: two from hepatic failure, onefrom hepatic neoplasm, and one from suspected methadoneoverdose. (Am J Gastroenterol 2001;96:16371638. 2001by Am. Coll. of Gastroenterology)
An estimated 4 million individuals in the United States arebelieved to be seropositive for hepatitis C (1), and globallyabout 170 million people (3%) are chronically infected. Theprevalence of hepatitis C infection in certain geographicareas of the world, such as Egypt, has been reported to be ashigh as 20%. HCV-related chronic liver disease is respon-sible for approximately 10,000 deaths annually in the US.Currently, hepatitis Crelated end stage liver disease is theleading indication for liver transplantation (2).
As we enter the new millennium, it has become very clearthat chronic hepatitis C infection and its sequelae will havea profound impact on the overall morbidity and mortalitydue to chronic liver disease and will consume a dispropor-tionate share of health care expenditures. The current arsenalin our armamentarium against hepatitis C is far from potent;even the combination of interferon with ribavirin achievessustained virologic response in only up to 40% of patients (3).
Better understanding of viral kinetics have made it pos-sible to make inroads into the development of more effectivedrugs. Since traditional interferon has a short half-life of 8 h,there likely is an intermittent increase in the viral load whenserum interferon levels are low during a regimen of thriceweekly administration. This prompted the development ofcovalently attached 40-kd branched chain polyethylene gly-col moiety to the standard interferon to create peginterferonalfa-2a. This has sustained absorption, slower clearance, anda longer half-life than conventional interferon. Another 12kd-pegylated interferon alfa-2a has also been developed andhas undergone extensive clinical trials.
The two studies published in the New England Journal of
Medicine address the issues of efficacy and safety in patientswith chronic hepatitis C and in those with bridging fibrosisand cirrhosis. There was sustained virologic response in39% of patients with chronic hepatitis C and 30% in thosewith cirrhosis/bridging fibrosis. Most of the patients toler-ated the therapy well, and discontinuation was required in,10% of the patients in both of the studies. No episodes ofneutropenia or thrombocytopenia were fatal, even in thecirrhotic cohort. Further in these studies, PEG IFN wassuperior to interferon alone and, particularly in the study byZeuzem et al., was comparable to the combination of inter-feron and ribavirin therapy. It is also anticipated that onceweekly administration of PEG IFN will enhance complianceand improve the quality of life in patients with chronichepatitis C.
In summary, peginterferon is here to stay as an alternativeto interferon-ribavirin combination therapy. In patients whoare intolerant or have a contraindication to ribavirin, PEGIFN monotherapy can be advocated with enthusiasm. Largescale, randomized trials of peginterferon-ribavirin combina-tion therapy are either close to completion or have beencompleted, and in the immediate future even better sus-tained virological response rates are expected. These twostudies have made us come closer to the ideal goal of findinga successful therapy for the majority of patients.
Umaprasanna S. Karnam, M.D.Ignacia Jaca, M.D.
K. Rajender Reddy, M.D., F.A.C.G.University of Miami School of Medicine
1. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalenceof hepatitis C virus infection in the United States, 1998 through1994. N Engl J Med 1999;341:55662.
2. Centers for Disease Control and Prevention. Recommendationsfor prevention and control of hepatitis C virus infection andHCV-related chronic disease. Morb Mortal Wkly Rep 1998;47(RR-19):139.
3. McHutchison JG, Gordon SC, Schiff ER, et al. Interferonalfa-2b alone or in combination with ribavirin as initial treat-ment for chronic hepatitis C. Hepatitis Interventional TherapyGroup. N Engl J Med 1998;339:148592.
Or Is It Just a Little Relaxation?Lagergren J, Bergstrom R, Adami H, et al.Association Between Medications That Relax the LowerEsophageal Sphincter and Risk for Esophageal AdenocarcinomaAnn Intern Med 2000;133:16575
ABSTRACTLagergren et al. performed a population-based, case-controlstudy to investigate the possible association between use oflower esophageal sphincter (LES)relaxing medications and
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risk for adenocarcinoma of the esophagus, squamous cellcancer of the esophagus, and adenocarcinoma of the gastriccardia. They used randomly selected population-based con-trols from their population registry. The authors identifiedfive groups of medications introduced before 1970 as LESrelaxing: nitroglycerin, anticholinergics, b-adrenergic ago-nists, aminophylline, and benzodiazepines. They demon-strated an association, which they felt was causal, betweenthe use of LES-relaxing medications and risk for adenocar-cinoma of the esophagus. Long term use of LES-relaxingdrugs correlated positively with the degree of esophagealadenocarcinoma risk, as demonstrated by an incidence rateratio of 3.8 for esophageal adenocarcinoma in patients whoused LES-relaxing drugs, particularly anticholinergics, dailyfor .5 yr. Importantly, they also found a higher prevalenceof reflux among users of LES-relaxing agents. Cardia ade-nocarcinoma and esophageal squamous cell carcinoma werein general not associated with the use of these drugs, thougha weaker association was noted with long term use ofnitroglycerin and adenocarcinoma of the gastric cardia. Noconsistent association between use of LES-relaxing drugsand risk for esophageal squamous cell carcinoma was found.(Am J Gastroenterol 2001;96:16381640. 2001 by Am.Coll. of Gastroenterology)
Adenocarcinoma of the esophagus is the fastest rising can-cer in the US, with a .3-fold in incidence since 1975 (1).This trend is continuing, particularly in white males (2). Asimilar trend has been noted in western Europe (3). Thoughthe reasons for this increase are unknown, the most acceptedrisk factor, Barretts esophagus, appears to be on the in-crease (4). Frequent and long duration heartburn (more thanthree times a week, for .20 yr), the most common symptomof gastroesophageal reflux disease (GERD), has recentlybeen substantiated by this same group as a strong risk factorfor this increasing incidence of esophageal adenocarcinoma(5).
Thus the postulate that pharmacological agents that de-crease lower esophageal sphincter (LES) pressure, particu-larly over long periods of time, might be independent riskfactors for development of this disease. The agents studiedby the authors are known to decrease lower sphincter pres-sure (in short term laboratory studies), though their effect ontransient relaxation of the LES (TLESR), the major mech-anism underlying reflux in most patients with reflux disease,is not clear. Although, the factors controlling the rate ofTLESR and the occurrence of reflux during TLESR are notwell understood, various endogenous (2, 6) and exogenousfactors including several of these pharmaceutical agentshave been implicated in causing TLESR (7). In support ofthis study, Wang et al. (8) suggested that the rising inci-dence rate of esophageal adenocarcinoma might be associ-ated with the use of four categories of pharmaceutical prod-uctsantihistamines, anticholinergics, bronchodilators, and
b-adreneric stimulant agentsafter they observed a sharpincrease in the incidence of esophageal adenocarcinoma afew decades after the introduction of these LES-relaxingagents.
Although Lagergren et al. used sound methodology inmaking their case, it must be emphasized that the smallincrease in the odds ratio of esophageal cancer disappearedafter adjustment for reflux symptoms. These findings con-firm, in our minds, that reflux is the cofactor in increasingrisk, as these authors have previously shown, and the drugsadd little or nothing to the risk. Further, the major increasein odds ratio was seen with a class of agents, anticholin-ergics, that are rarely used for long periods (except perhapsin irritable bowel syndrome). In fact, no increase in the riskof cancer has been seen in studies of patients using calciumchannel blockers, agents likely causing greater decreases inLES pressure than those studied (9, 10).
We should always consider the possibility that our ther-apies may contribute to other harmful conditions, especiallyin a chronic disease like GERD. Concern has been raisedthat long term use of histamine-2 receptor antagonists andproton pump inhibitors might account for the increasedincidence of adenocarcinoma. The former was not supportedby a case-control study of 196 patients with adenocarcinomaof the esophagus and gastric cardia (11), which showed noincrease in association relative to matched controls, and thelatter was not substantiated as a risk by the authors in aprevious publication (5).
This article supports the known link between GERD andadenocarcinoma of the esophagus, which, though increasingat a rapid rate, is still a relatively rare disease. It seemsoverdone to suggest that these LES-relaxing agents in anyway substantially increase that risk independent of GERD.We would not change clinical practice because of this study.
Yogesh K. Govil, M.D., M.R.C.P. (UK)Philip O. Katz, M.D., F.A.C.G.
Division of GastroenterologyGraduate Hospital
Department of MedicinePhiladelphia, Pennsylvania
1. Blot WJ, Devesa SS, Kneller RW, et al. Rising incidence ofadenocarcinoma of the esophagus and gastric cardia. JAMA1991;265:12879.
2. Devesa SS, Blot WJ, Fraumeni JF. Changing patterns in theincidence of esophageal and gastric carcinoma in the UnitedStates. Cancer 1998;83:204953.
3. Powell J, McConkey CC. Increasing incidence of adenocarci-noma of the gastric cardia and adjacent sites. Br J Cancer1990;62:4403.
4. Spechler SJ, Goyal RK. Barretts esophagus. N Engl J Med1986;315:36271.
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5. Lagergren J, Bergstrom R, Lindgren A. Symptomatic gastro-esophageal reflux as a risk factor for esophageal adenocarci-noma. N Engl J Med 1999;340:82531.
6. Castell DO. The lower esophageal sphincter. Physiologic andclinical aspects. Ann Intern Med 1975;83:390401.
7. Phillip RW, Wong RKH. Barretts esophagus. Natural history,incidence, etiology, and complications. Gastroenterol ClinNorth Am 1991;20:791816.
8. Wang HH, Hsiesh CC, Antonioli DA. Rising incidence rate ofesophageal adenocarcinoma and use of pharmaceutical agents
that relax the lower esophageal sphincter (United States).Cancer Causes Control 1994;5:5738.
9. Jick H, Jick S, Derby LE, et al. Calcium-channel blockers andrisk of cancer. Lancet 1997;349:5258.
10. Rosenberg L, Rao RS, Palmer JR, et al. Calcium channelblockers and the risk of cancer. JAMA 1998;279:10004.
11. Chow WH, Finkle WD, McLaughlin JK, et al. The relation ofgastroesophageal reflux disease and its treatment to adenocar-cinomas of the esophagus and gastric cardia. JAMA 1995;274:4747.
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