1638 World Literature Review
5, 2001
fibrosis or cirrhosis. Of interest, a histological response was
also seen in about 26 –35% of patients who did not have a
sustained 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 ␮g of PEG IFN alfa-2a had
a sustained virologic response.
Safety parameters were carefully evaluated, and the pro-
portion of patients with a neutrophil count of ⬍500 ml3 at
any time during the study was similar in the three groups
(1–3%). No patient developed any serious infection or sep-
sis secondary to the neutropenia, and no patient had to
discontinue treatment secondary to neutropenia. Even
though a higher proportion of patients assigned to the higher
doses of PEG IFN had a decrease in the platelet counts to
⬍50,000/ml3, none of the patients had clinically significant
bleeding secondary to the thrombocytopenia. A higher pro-
portion of the patients assigned to the 180 ␮g of PEG IFN
alfa-2a had myalgia and inflammation at the injection site.
Four deaths were reported: two from hepatic failure, one
from hepatic neoplasm, and one from suspected methadone
overdose. (Am J Gastroenterol 2001;96:1637–1638. © 2001
by Am. Coll. of Gastroenterology)
COMMENT
An estimated 4 million individuals in the United States are
believed to be seropositive for hepatitis C (1), and globally
about 170 million people (3%) are chronically infected. The
prevalence of hepatitis C infection in certain geographic
areas of the world, such as Egypt, has been reported to be as
high as 20%. HCV-related chronic liver disease is respon-
sible for approximately 10,000 deaths annually in the US.
Currently, hepatitis C–related end stage liver disease is the
leading indication for liver transplantation (2).
As we enter the new millennium, it has become very clear
that chronic hepatitis C infection and its sequelae will have
a profound impact on the overall morbidity and mortality
due to chronic liver disease and will consume a dispropor-
tionate share of health care expenditures. The current arsenal
in our armamentarium against hepatitis C is far from potent;
even the combination of interferon with ribavirin achieves
sustained 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 effective
drugs. Since traditional interferon has a short half-life of 8 h,
there likely is an intermittent increase in the viral load when
serum interferon levels are low during a regimen of thrice
weekly administration. This prompted the development of
covalently attached 40-kd branched chain polyethylene gly-
col moiety to the standard interferon to create peginterferon
alfa-2a. This has sustained absorption, slower clearance, and
a longer half-life than conventional interferon. Another 12
kd-pegylated interferon alfa-2a has also been developed and
has undergone extensive clinical trials.
The two studies published in the New England Journal of
AJG – Vol. 96, No.
Medicine address the issues of efficacy and safety in patients
with chronic hepatitis C and in those with bridging fibrosis
and cirrhosis. There was sustained virologic response in
39% of patients with chronic hepatitis C and 30% in those
with 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 of
neutropenia or thrombocytopenia were fatal, even in the
cirrhotic cohort. Further in these studies, PEG IFN was
superior to interferon alone and, particularly in the study by
Zeuzem et al., was comparable to the combination of inter-
feron and ribavirin therapy. It is also anticipated that once
weekly administration of PEG IFN will enhance compliance
and improve the quality of life in patients with chronic
hepatitis C.
In summary, peginterferon is here to stay as an alternative
to interferon-ribavirin combination therapy. In patients who
are intolerant or have a contraindication to ribavirin, PEG
IFN monotherapy can be advocated with enthusiasm. Large
scale, randomized trials of peginterferon-ribavirin combina-
tion therapy are either close to completion or have been
completed, and in the immediate future even better sus-
tained virological response rates are expected. These two
studies have made us come closer to the ideal goal of finding
a 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
Miami, Florida
REFERENCES
1. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence
of hepatitis C virus infection in the United States, 1998 through
1994. N Engl J Med 1999;341:556 – 62.
2. Centers for Disease Control and Prevention. Recommendations
for prevention and control of hepatitis C virus infection and
HCV-related chronic disease. Morb Mortal Wkly Rep 1998;
47(RR-19):1–39.
3. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon
alfa-2b alone or in combination with ribavirin as initial treat-
ment for chronic hepatitis C. Hepatitis Interventional Therapy
Group. N Engl J Med 1998;339:1485–92.
Or Is It Just a Little Relaxation?
Lagergren J, Bergstrom R, Adami H, et al.
Association Between Medications That Relax the Lower
Esophageal Sphincter and Risk for Esophageal Adenocarcinoma
Ann Intern Med 2000;133:165–75
ABSTRACT
Lagergren et al. performed a population-based, case-control
study to investigate the possible association between use of
lower esophageal sphincter (LES)–relaxing medications and
AJG – May, 2001
risk for adenocarcinoma of the esophagus, squamous cell
cancer of the esophagus, and adenocarcinoma of the gastric
cardia. They used randomly selected population-based con-
trols from their population registry. The authors identified
five groups of medications introduced before 1970 as LES
relaxing: nitroglycerin, anticholinergics, ␤-adrenergic ago-
nists, aminophylline, and benzodiazepines. They demon-
strated an association, which they felt was causal, between
the use of LES-relaxing medications and risk for adenocar-
cinoma of the esophagus. Long term use of LES-relaxing
drugs correlated positively with the degree of esophageal
adenocarcinoma risk, as demonstrated by an incidence rate
ratio of 3.8 for esophageal adenocarcinoma in patients who
used LES-relaxing drugs, particularly anticholinergics, daily
for ⬎5 yr. Importantly, they also found a higher prevalence
of reflux among users of LES-relaxing agents. Cardia ade-
nocarcinoma and esophageal squamous cell carcinoma were
in general not associated with the use of these drugs, though
a weaker association was noted with long term use of
nitroglycerin and adenocarcinoma of the gastric cardia. No
consistent association between use of LES-relaxing drugs
and risk for esophageal squamous cell carcinoma was found.
(Am J Gastroenterol 2001;96:1638 –1640. © 2001 by Am.
Coll. of Gastroenterology)
COMMENTS
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). A
similar trend has been noted in western Europe (3). Though
the reasons for this increase are unknown, the most accepted
risk factor, Barrett’s esophagus, appears to be on the in-
crease (4). Frequent and long duration heartburn (more than
three times a week, for ⬎20 yr), the most common symptom
of gastroesophageal reflux disease (GERD), has recently
been substantiated by this same group as a strong risk factor
for 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 risk
factors for development of this disease. The agents studied
by the authors are known to decrease lower sphincter pres-
sure (in short term laboratory studies), though their effect on
transient 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 of
TLESR and the occurrence of reflux during TLESR are not
well understood, various endogenous (2, 6) and exogenous
factors including several of these pharmaceutical agents
have been implicated in causing TLESR (7). In support of
this 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-
ucts—antihistamines, anticholinergics, bronchodilators, and
World Literature Review 1639
␤-adreneric stimulant agents—after they observed a sharp
increase in the incidence of esophageal adenocarcinoma a
few decades after the introduction of these LES-relaxing
agents.
Although Lagergren et al. used sound methodology in
making their case, it must be emphasized that the small
increase in the odds ratio of esophageal cancer disappeared
after adjustment for reflux symptoms. These findings con-
firm, in our minds, that reflux is the cofactor in increasing
risk, as these authors have previously shown, and the drugs
add little or nothing to the risk. Further, the major increase
in odds ratio was seen with a class of agents, anticholin-
ergics, that are rarely used for long periods (except perhaps
in irritable bowel syndrome). In fact, no increase in the risk
of cancer has been seen in studies of patients using calcium
channel blockers, agents likely causing greater decreases in
LES pressure than those studied (9, 10).
We should always consider the possibility that our ther-
apies may contribute to other harmful conditions, especially
in a chronic disease like GERD. Concern has been raised
that long term use of histamine-2 receptor antagonists and
proton pump inhibitors might account for the increased
incidence of adenocarcinoma. The former was not supported
by a case-control study of 196 patients with adenocarcinoma
of the esophagus and gastric cardia (11), which showed no
increase in association relative to matched controls, and the
latter was not substantiated as a risk by the authors in a
previous publication (5).
This article supports the known link between GERD and
adenocarcinoma of the esophagus, which, though increasing
at a rapid rate, is still a relatively rare disease. It seems
overdone to suggest that these LES-relaxing agents in any
way 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 Gastroenterology
Graduate Hospital
Department of Medicine
Philadelphia, Pennsylvania
REFERENCES
1. Blot WJ, Devesa SS, Kneller RW, et al. Rising incidence of
adenocarcinoma of the esophagus and gastric cardia. JAMA
1991;265:1287–9.
2. Devesa SS, Blot WJ, Fraumeni JF. Changing patterns in the
incidence of esophageal and gastric carcinoma in the United
States. Cancer 1998;83:2049 –53.
3. Powell J, McConkey CC. Increasing incidence of adenocarci-
noma of the gastric cardia and adjacent sites. Br J Cancer
1990;62:440 –3.
4. Spechler SJ, Goyal RK. Barrett’s esophagus. N Engl J Med
1986;315:362–71.
1640 World Literature Review
5. Lagergren J, Bergstrom R, Lindgren A. Symptomatic gastro-
esophageal reflux as a risk factor for esophageal adenocarci-
noma. N Engl J Med 1999;340:825–31.
6. Castell DO. The lower esophageal sphincter. Physiologic and
clinical aspects. Ann Intern Med 1975;83:390 – 401.
7. Phillip RW, Wong RKH. Barrett’s esophagus. Natural history,
incidence, etiology, and complications. Gastroenterol Clin
North Am 1991;20:791– 816.
8. Wang HH, Hsiesh CC, Antonioli DA. Rising incidence rate of
esophageal adenocarcinoma and use of pharmaceutical agents
AJG – Vol. 96, No. 5, 2001
that relax the lower esophageal sphincter (United States).
Cancer Causes Control 1994;5:573– 8.
9. Jick H, Jick S, Derby LE, et al. Calcium-channel blockers and
risk of cancer. Lancet 1997;349:525– 8.
10. Rosenberg L, Rao RS, Palmer JR, et al. Calcium channel
blockers and the risk of cancer. JAMA 1998;279:1000 – 4.
11. Chow WH, Finkle WD, McLaughlin JK, et al. The relation of
gastroesophageal reflux disease and its treatment to adenocar-
cinomas of the esophagus and gastric cardia. JAMA 1995;274:
474 –7.