Long-term Outcome of Medical and Surgical Therapies for Gastroesophageal
Reflux Disease
Follow-up of a Randomized Controlled Trial
Author Information <http://jama.ama-assn.org/issues/v285n18/rfull/#aainfo>
Stuart Jon Spechler, MD; Edward Lee, MD; Dennis Ahnen, MD; Raj K. Goyal, MD;
Ikuo Hirano, MD; Francisco Ramirez, MD; Jean-Pierre Raufman, MD; Richard
Sampliner, MD; Thomas Schnell, MD; Stephen Sontag, MD; Z. Reno Vlahcevic,
MD; Renee Young, MD; William Williford, PhD
Context Severe gastroesophageal reflux disease (GERD) is a lifelong problem
that can be complicated by peptic esophageal stricture and adenocarcinoma of
the esophagus.
Objective To determine the long-term outcome of medical and surgical
therapies for GERD.
Design and Setting Follow-up study conducted from October 1997 through
October 1999 of a prospective randomized trial of medical and surgical
antireflux treatments in patients with complicated GERD. Mean (median)
duration of follow-up was 10.6 years (7.3 years) for medical patients and
9.1 years (6.3 years) for surgical patients.
Participants Two hundred thirty-nine (97%) of the original 247 study
patients were found (79 were confirmed dead). Among the 160 survivors (157
men and 3 women; mean [SD] age, 67 [12] years), 129 (91 in the medical
treatment group and 38 in the surgical treatment group) participated in the
follow-up.
Main Outcome Measures Use of antireflux medication, Gastroesophageal Reflux
Disease Activity Index (GRACI) scores, grade of esophagitis, frequency of
treatment of esophageal stricture, frequency of subsequent antireflux
operations, 36-item Short Form health survey (SF-36) scores, satisfaction
with antireflux therapy, survival, and incidence of esophageal
adenocarcinoma, compared between the medical antireflux therapy group and
the fundoplication surgery group. Information on cause of death was obtained
from autopsy results, hospital records, and death certificates.
Results Eighty-three (92%) of 90 medical patients and 23 (62%) of 37
surgical patients reported that they used antireflux medications regularly
(P<.001). During a 1-week period after discontinuation of medication, mean
(SD) GRACI symptom scores were significantly lower in the surgical treatment
group (82.6 [17.5] vs 96.7 [21.4] in the medical treatment group; P = .003).
However, no significant differences between the groups were found in grade
of esophagitis, frequency of treatment of esophageal stricture and
subsequent antireflux operations, SF-36 standardized physical and mental
component scale scores, and overall satisfaction with antireflux therapy.
Survival during a period of 140 months was decreased significantly in the
surgical vs the medical treatment group (relative risk of death in the
medical group, 1.57; 95% confidence interval, 1.01-2.46; P = .047), largely
because of excess deaths from heart disease. Patients with Barrett esophagus
at baseline developed esophageal adenocarcinomas at an annual rate of 0.4%,
whereas these cancers developed in patients without Barrett esophagus at an
annual rate of only 0.07%. There was no significant difference between
groups in incidence of esophageal cancer.
Conclusion This study suggests that antireflux surgery should not be
advised with the expectation that patients with GERD will no longer need to
take antisecretory medications or that the procedure will prevent esophageal
cancer among those with GERD and Barrett esophagus.
JAMA. 2001;285:2331-2338
JOC02260
Gastroesophageal reflux disease (GERD) is one of the most common chronic
disorders of the gastrointestinal tract. 1
<http://jama.ama-assn.org/issues/v285n18/rfull/#r1> , 2
<http://jama.ama-assn.org/issues/v285n18/rfull/#r2> Surveys have shown that
approximately 20% of US adults experience GERD symptoms such as heartburn
and acid regurgitation at least once per week. 3
<http://jama.ama-assn.org/issues/v285n18/rfull/#r3> , 4
<http://jama.ama-assn.org/issues/v285n18/rfull/#r4> GERD and its sequela,
Barrett esophagus, are strong risk factors for esophageal adenocarcinoma, 5
<http://jama.ama-assn.org/issues/v285n18/rfull/#r5> , 6
<http://jama.ama-assn.org/issues/v285n18/rfull/#r6> a malignancy that has
nearly quadrupled in frequency during the past 2 decades. 7
<http://jama.ama-assn.org/issues/v285n18/rfull/#r7> Medical treatment of
GERD involves long-term administration of antacids and antisecretory agents,
8 <http://jama.ama-assn.org/issues/v285n18/rfull/#r8> and patients in the
United States may spend as much as an estimated $5 billion annually on
antireflux medicines. 9 <http://jama.ama-assn.org/issues/v285n18/rfull/#r9>
Antireflux surgery (fundoplication) has become an increasingly popular form
of therapy for GERD since minimally invasive (laparoscopic) surgical
approaches have been developed. 10
<http://jama.ama-assn.org/issues/v285n18/rfull/#r10> , 11
<http://jama.ama-assn.org/issues/v285n18/rfull/#r11> It has been estimated
that 29 000 and 34 800 laparoscopic Nissen fundoplications were performed in
the United States in 1998 and 1999, respectively (Synergy, a division of
Quintiles Informatics, Waltham, Mass, unpublished data, March 2000).
Modern medical and surgical antireflux therapies are highly effective in
controlling GERD symptoms, 8
<http://jama.ama-assn.org/issues/v285n18/rfull/#r8> but few published data
support the efficacy of any treatment in preventing GERD complications such
as adenocarcinoma. 12 <http://jama.ama-assn.org/issues/v285n18/rfull/#r12>
Some reports have suggested that fundoplication (which creates a barrier to
reflux of all gastric contents) might be more effective than medical therapy
(which is directed primarily at decreasing gastric acid secretion) for
preventing both peptic and neoplastic complications of GERD. 13-16
<http://jama.ama-assn.org/issues/v285n18/rfull/#r13> Two small studies(that
had methodological limitations) involving patients with Barrett esophagus
who received medical and surgical therapies for GERD have provided weak
support for this contention by reporting fewer cases of dysplasia and cancer
among surgically treated patients. 17
<http://jama.ama-assn.org/issues/v285n18/rfull/#r17> , 18
<http://jama.ama-assn.org/issues/v285n18/rfull/#r18> Some have proposed
that medical treatment of GERD with antisecretory agents might predispose to
cancer, perhaps by promoting reflux of deconjugated bile acids, 19
<http://jama.ama-assn.org/issues/v285n18/rfull/#r19> , 20
<http://jama.ama-assn.org/issues/v285n18/rfull/#r20> and that increasing
use of these drugs may be contributing to the increasing frequency of
esophageal adenocarcinoma. 21
<http://jama.ama-assn.org/issues/v285n18/rfull/#r21> However, the limited
studies that have addressed this issue directly have found no significant
association between esophageal adenocarcinoma and use of antisecretory
agents per se. 22 <http://jama.ama-assn.org/issues/v285n18/rfull/#r22> , 23
<http://jama.ama-assn.org/issues/v285n18/rfull/#r23>
Although severe GERD is judged to be a lifelong problem, few data are
available on the long-term outcome of any antireflux therapy. One study of
patients with severe GERD treated with omeprazole for a mean of 6.5 years
found that relapses occurred frequently and that patients often required
increasing dosages of omeprazole (up to 120 mg/d). 24
<http://jama.ama-assn.org/issues/v285n18/rfull/#r24> Such observations have
raised questions regarding the long-term utility and cost of medical therapy
for GERD. Successful antireflux surgery might obviate the inconvenience and
expense of lifelong medical treatment. Some investigators have reported
success rates that exceed 90% at 10 to 20 years after open fundoplication,
25 <http://jama.ama-assn.org/issues/v285n18/rfull/#r25> , 26
<http://jama.ama-assn.org/issues/v285n18/rfull/#r26> whereas others have
described return of reflux esophagitis in more than 50% of cases within 6
years. 27 <http://jama.ama-assn.org/issues/v285n18/rfull/#r27> However,
without additional meaningful, consistent, long-term data, it is difficult
to make a rational choice between medical and surgical therapy.
In the late 1980s, the Department of Veterans Affairs (VA) Cooperative
Studies Program conducted a randomized trial of medical and surgical
antireflux treatments for 247 patients with complicated GERD. 28
<http://jama.ama-assn.org/issues/v285n18/rfull/#r28> For the 2-year
duration of the study, surgery (open Nissen fundoplication) was found to be
significantly better than medical therapy (antacids, histamine2 receptor
blockers, metoclopramide, sucralfate) for controlling the symptoms and signs
of GERD. This study is one of the few randomized trials of medical and
surgical antireflux therapies ever reported. 29
<http://jama.ama-assn.org/issues/v285n18/rfull/#r29> , 30
<http://jama.ama-assn.org/issues/v285n18/rfull/#r30> To determine the
long-term outcome of GERD therapies, we conducted a follow-up study of this
well-defined cohort of patients.
METHODS
From July 1986 through October 1988, the VA conducted a cooperative study of
medical and surgical therapies for GERD. Patients with complicated GERD (243
men and 4 women) were instructed to implement antireflux lifestyle
modifications, stratified into 1 of 5 risk groups ( Table 1
<http://jama.ama-assn.org/issues/v285n18/fig_tab/joc02260_t1.html> ), and
then randomly assigned by concealed allocation to 1 of 3 treatment groups:
(1) continuous medical therapy consisting of antacid (2 tablets 1 and 3
hours after meals) and ranitidine (150 mg twice daily) regardless of
symptoms, with metoclopramide (10 mg 4 times daily) and sucralfate (1 g
dissolved in 10 mL of warm water, after meals) added when necessary for
persistent symptoms; (2) symptomatic medical therapy consisting of the
medications described for the previous group but given only when necessary
to control symptoms; or (3) surgical therapy consisting of open Nissen
fundoplication. Treatments were continued for the duration of the study (12
to 28 months). On completion of the study, patients returned to their
primary care physicians for nonstandardized GERD management.
The present follow-up study was conducted from October 1997 through October
1999. Prior to enrolling patients, all investigators met as a group to
standardize procedures and evaluation methods. We determined the whereabouts
of the original study patients using the VA computer database and a
professional search agency (Business Information Systems, Smyrna, Ga). For
patients who had died, we obtained information regarding the cause of death
from all available autopsy results, hospital records, and death
certificates. Surviving patients were contacted and invited to participate
in the follow-up study.
GERD Symptom Scoring
The Gastroesophageal Reflux Disease Activity Index (GRACI) score used in the
original study was used to assess the severity of GERD symptoms in the
follow-up study. GRACI was developed in a prospective investigation that
used multiple regression analysis techniques to correlate clinical data with
an experienced physician's assessment of GERD activity. These were the same
methods used to develop the Crohn Disease Activity Index. Details regarding
development, validation, and use of the GRACI score have been published
elsewhere. 28 <http://jama.ama-assn.org/issues/v285n18/rfull/#r28> , 31
<http://jama.ama-assn.org/issues/v285n18/rfull/#r31> Briefly, patients
maintain a standardized diary of GERD symptoms every day for 1 week, and the
GRACI score is calculated by assigning weighted numerical values to certain
symptoms (eg, the percentage of each day that the patient had heartburn,
general severity of heartburn for that day, episodes of odynophagia,
episodes of coughing or wheezing that awakened the patient from sleep). The
GRACI score can range from 74 (no symptoms) to 172 (worst symptoms);
published mean scores for patients with mild, moderate, and severe symptoms
are 93, 110, and 125, respectively. 31
<http://jama.ama-assn.org/issues/v285n18/rfull/#r31>
Patients in this study had GRACI scores determined during 2 consecutive
weeks. For the first week, patients were instructed to continue, without
modification, whatever antireflux regimen they had been using on a regular
basis. No new antireflux therapies were started, and patients were
instructed not to alter their routine lifestyle practices. For the second
week, patients were instructed to discontinue all antireflux medications. No
new antireflux therapies were started, and patients were instructed not to
alter their routine lifestyle practices. Antacids were allowed for relief of
intolerable heartburn.
Endoscopic Examination
Patients were asked to discontinue all antireflux medications for 1 week
prior to the procedure. Endoscopic severity of esophagitis was graded using
the scale used in the original study (grade 1, no evidence of inflammation;
grade 2, erythema, friability, or both; grade 3, esophageal erosions; and
grade 4, esophageal ulcers). For patients with a columnar-lined esophagus,
esophageal biopsy specimens were obtained at 1-cm intervals from the
squamocolumnar junction (Z-line) to the gastroesophageal junction (the most
proximal level of the gastric folds). Biopsy specimens were evaluated by the
study pathologist (E.L.) for epithelial type and presence of neoplasia.
24-Hour Esophageal pH Monitoring
All antireflux medications were discontinued for 72 hours before the
monitoring period. The studies were performed according to standard
procedures for the monitoring systems used at each of the 8 participating
centers.
Completion of Follow-up Questionnaire and SF-36
Patients were questioned regarding the frequency with which they had used
medications specifically for treatment of GERD since completion of the
original study. We also obtained data regarding any subsequent antireflux
operations performed, symptoms of gas-bloat syndrome, satisfaction with
antireflux therapies, treatments for esophageal stricture, and development
of esophageal cancer.
The 36-item Short Form general health and well-being survey (SF-36) assesses
8 health issues: limitations in physical activities due to health problems,
limitations in usual role activities due to physical health problems, bodily
pain, general health perception, vitality, limitations in social activities
due to physical or emotional problems, limitations in usual role activities
due to emotional problems, and general mental health.
Statistical Analysis
At the time of randomization into the original study, there were no
significant differences among the 3 treatment groups in demographic or
functional status ( Table 1
<http://jama.ama-assn.org/issues/v285n18/fig_tab/joc02260_t1.html> ). The
committee that planned the original study thought that it would be unethical
to include a placebo treatment for patients with complicated GERD and,
instead, included a control group of patients who would be treated medically
only as necessary for relief of symptoms (the symptomatic medical treatment
group). Those patients quickly became symptomatic when medical therapy was
stopped and, consequently, the 2 medical groups received the same
medications in similar dosages for the 2-year duration of the original
study. The 2 medical treatment groups did not differ significantly in any
outcome measured in that study, and all patients received nonstandardized
GERD management after the study ended in 1988. Since the continuous and
symptomatic medical treatment groups were virtually identical in baseline
characteristics, study treatments, study outcomes, and subsequent
management, we have combined these 2 groups into 1 medical treatment group
to simplify analyses in the present follow-up study.
Primary statistical analyses in both the original and present studies were
based on the intention-to-treat principle. All tests of statistical
significance are 2-sided. A log-rank statistic was used to compare survival
distributions between the medical and surgical treatment groups.
Kaplan-Meier analysis was used to construct life-table plots.
The study was approved by the Human Rights Committee of the VA Cooperative
Studies Program Coordinating Center (Perry Point, Md) and the institutional
review boards at each of the 8 participating VA medical centers. Patients
who agreed to participate provided written informed consent.
RESULTS
We determined the whereabouts of 239 (97%) of 247 patients in the original
study. Seventy-nine patients were confirmed to be dead; the 160 remaining
patients (157 men and 3 women) were contacted and invited to participate in
the follow-up study. The mean (SD) age of surviving patients at the time of
contact was 67 (12) years. Thirty-one of the 160 patients (21 [19%] of 112
medical patients and 10 [21%] of 48 surgical patients) either refused or
were unable to participate in the follow-up study; 129 patients (91 medical
patients and 38 surgical patients) participated in at least some of the
follow-up procedures. Thus, specific follow-up data were obtained for 208
(84%; 129 survivors and 79 deaths) of the original 247 patients. Mean and
median durations of follow-up (from termination of the original study to
death or last contact) were 10.6 and 7.3 years, respectively, for medical
patients and 9.1 and 6.3 years, respectively, for surgical patients.
Survival
There were no surgery-related deaths in the original study. The 79 deaths
that occurred during follow-up involved 33 (40%) of the 82 patients
randomized to the surgical group and 46 (28%) of the 165 patients randomized
to receive medical treatment. In an intention-to-treat analysis, the Cox
proportional hazards model showed that survival during a period of 140
months was decreased significantly in the surgical group compared with the
medical group (relative risk of death in the medical group [RR], 1.57; 95%
confidence interval [CI], 1.01-2.46; P = .047) ( Figure 1
<http://jama.ama-assn.org/issues/v285n18/fig_tab/joc02260_f1.html> ). In the
original study, 24 of the 82 patients randomized to surgery and 16 of the
165 patients randomized to medical therapy refused to accept the treatments
to which they were assigned. When the survival analysis was limited to the
207 patients who actually received their assigned treatments, the observed
difference between the groups was greater (RR, 1.89; 95% CI, 1.14-3.13; P =
.01) ( Figure 1
<http://jama.ama-assn.org/issues/v285n18/fig_tab/joc02260_f1.html> ).
Causes of Death
Causes of death in the treatment groups are shown in Table 2
<http://jama.ama-assn.org/issues/v285n18/fig_tab/joc02260_t2.html> . Heart
disease was the cause of 20% and 48% of deaths in the medical and surgical
groups, respectively (P = .004). Although deaths due to all types of heart
disease were significantly more common in the surgical group, the groups did
not differ significantly in frequency of any individual cardiac cause of
death. Also, there were no significant differences between groups in the
frequency of deaths due to any other major category of disease, including
cancer of all types and esophageal cancer. There were only 2 deaths from
esophageal cancer in the entire study group.
Cigarette smoking is a major factor that could influence mortality from
heart disease. The observed excess mortality from heart disease was not
anticipated and, consequently, data on cigarette smoking were not collected
in the follow-up study. During the original study, however, there were no
significant differences between the groups in the frequency of cigarette
smoking (34% of the medical patients and 39% of the surgical patients were
smokers; P = .45).
Esophageal Cancer
Five patients (all white men; 4 medical patients and 1 surgical patient)
developed esophageal adenocarcinoma after a mean follow-up of 7.1 years
(range, 4-12 years). There was no significant difference in the rate of
esophageal cancer development between the medical and surgical groups (P =
1.0 by Fisher exact test). However, we calculated that a study designed to
demonstrate a 50% relative reduction in risk of esophageal cancer during
this period would have required a sample size of 460 patients in each
treatment group (assuming a baseline cancer incidence of 0.5% per year;
power = 80%; P = .05). Therefore, our study did not have sufficient
statistical power to detect potentially important differences between groups
in the rate of cancer development.
Four patients were known to have developed esophageal adenocarcinomas before
the follow-up study was initiated, and 1 asymptomatic patient had cancer
discovered when he underwent endoscopic evaluation as part of the follow-up
study. Four of the 5 patients who developed cancer had Barrett esophagus
with specialized intestinal metaplasia at baseline. One patient who died of
metastatic esophageal adenocarcinoma had no evidence of Barrett esophagus
either at baseline endoscopy or during 2 subsequent endoscopies performed at
weeks 6 and 52 of the original study. Thirteen months before death, this
patient's tumor was resected. We obtained the pathologic specimens from the
resection and reviewed the gross photographs and histologic slides. The
tumor was 8 cm in length and crossed the gastroesophageal junction, but the
bulk of the adenocarcinoma (>75%) was located in the distal esophagus.
Review of multiple sections revealed no specialized intestinal metaplasia in
the esophagus, but the large neoplasm conceivably may have obliterated any
such metaplasia. Our assessment was that the adenocarcinoma most likely
originated in the distal esophagus, but the possibility that the neoplasm
arose from the proximal stomach could not be excluded, as is the case for
virtually any adenocarcinoma that crosses the gastroesophageal junction. 32
<http://jama.ama-assn.org/issues/v285n18/rfull/#r32>
In the original study, 108 patients had Barrett esophagus with specialized
intestinal metaplasia at entry. These 108 patients were followed up for a
total of 1037 patient-years, and 4 developed adenocarcinoma of the
esophagus, for an incidence rate of 1 esophageal cancer per 259
patient-years of follow-up (0.4% per year). The 139 patients who had severe
GERD without apparent Barrett esophagus were followed up for a total of 1357
patient-years, and 1 developed adenocarcinoma, for an incidence rate of 1
esophageal cancer per 1357 patient-years of follow-up (0.07% per year).
Long-term Outcomes of GERD
Table 3 <http://jama.ama-assn.org/issues/v285n18/fig_tab/joc02260_t3.html>
summarizes the results of some long-term outcome measures of GERD. GRACI
symptom scores were significantly lower in the surgical treatment group
during the week when antireflux medications were discontinued. For
comparison, mean (SD) GRACI scores were 89 (2) for the medical treatment
group and 78 (2) for the surgical treatment group at the time of completion
of the original study (after 104 weeks of therapy). After 1 week without
antireflux medications, there was no significant difference in the
endoscopic grade of esophagitis between the medical and surgical treatment
groups.
The mean (SD) duration of acid reflux was greater in the medical treatment
group (while not receiving therapy) than in the surgical treatment group
(31.0% [61.6%] vs 17.1% [41.1%] of the 24-hour monitoring period), but the
difference was not statistically significant. These results are based on a
relatively small sample size (because most patients refused 24-hour
esophageal pH monitoring), and the SDs are large. Consequently, our data on
24-hour esophageal pH monitoring are inconclusive.
Overall, 92% of patients in the medical treatment group and 62% of those in
the surgical treatment group reported that they had used antireflux
medications regularly since completion of the original study (P<.001). Nine
medical patients (10%) and 6 surgical patients (16%) had had 1 or more
antireflux operations since the end of the original study (P = .38).
Esophageal strictures requiring treatment were reported by 8% and 14% of
patients in the medical and surgical treatment groups, respectively (P =
.46).
The majority of patients in both groups were either very satisfied (67% of
medical and 58% of surgical patients; P = .42) or satisfied (29% of medical
and 31% of surgical patients; P = .83) with the antireflux treatments they
had received since completion of the original study. When patients in the
surgical group were asked to rate their satisfaction specifically with the
results of the original operation, 72% said they were very satisfied, 14%
were satisfied, 10% were dissatisfied, and 3% were very dissatisfied. When
these same patients were asked if they would still have the operation if
they could do it over again, 89% answered yes.
Patients in both treatment groups were questioned regarding symptoms that
have been attributed to postfundoplication gas-bloat syndrome. There were no
significant differences between groups in the frequency of any of these
symptoms, including increased abdominal girth (36% of medical and 34% of
surgical patients), abdominal fullness (41% of medical and 42% of surgical
patients), inability to belch (20% of medical and 29% of surgical patients),
and inability to vomit (20% of medical and 32% of surgical patients).
SF-36 General Health and Well-being
There were no significant differences between groups for any profile on the
SF-36 except bodily pain, which was significantly better in surgical
patients (mean [SD] score, 51.7 [25.2] for medical patients vs 64.0 [28.9]
for surgical patients [P = .02]; a higher score in this profile represents
less bodily pain). No significant differences between groups were noted for
the overall physical and mental component scores.
COMMENT
This study is unique in providing data on the long-term outcome of a
well-defined cohort of patients who participated in a randomized trial of
medical and surgical treatments for GERD. Compared with the medical
treatment group, surgical patients exhibited a significant decrease in
survival during the 10- to 13-year follow-up. Surgery was not the direct
cause of death, and the excess late mortality resulted largely from a
significant increase in deaths due to heart disease. The shortened life
expectancy in surgical patients was an unexpected finding, and the study was
not designed to investigate mechanisms underlying a difference in mortality
rates. Consequently, the explanation for the observed excess mortality due
to heart disease after fundoplication is not clear. While this issue
requires further investigation, it seems prudent to advise patients who are
to undergo or who have had antireflux surgery to make extra efforts to
control their risk factors for cardiovascular disease.
GERD and Barrett esophagus are both risk factors for esophageal
adenocarcinoma. 5 <http://jama.ama-assn.org/issues/v285n18/rfull/#r5> , 6
<http://jama.ama-assn.org/issues/v285n18/rfull/#r6> In this study, patients
with Barrett esophagus developed adenocarcinoma at the rate of 1 esophageal
cancer per 259 patient-years (0.4% per year). The reported annual incidence
of cancer with Barrett esophagus has ranged from 0.2% to 1.9%, 33-36
<http://jama.ama-assn.org/issues/v285n18/rfull/#r33> and, by pooling data
from these studies, 1 widely quoted report has estimated the cancer risk in
patients with this condition at 1% per year. 33
<http://jama.ama-assn.org/issues/v285n18/rfull/#r33> However, a recent
report has suggested that the cancer risk associated with Barrett esophagus
has been overestimated because of publication bias. 37
<http://jama.ama-assn.org/issues/v285n18/rfull/#r37> The authors of that
report have estimated the annual risk of cancer in patients with Barrett
esophagus at approximately 0.5%, a rate close to the 0.4% annual incidence
observed in our study and in 2 recent, prospective US studies of Barrett
esophagus. 33 <http://jama.ama-assn.org/issues/v285n18/rfull/#r33> , 38
<http://jama.ama-assn.org/issues/v285n18/rfull/#r38> Acceptance of this low
rate of cancer incidence could have a profound influence on recommendations
regarding endoscopic surveillance for patients with Barrett esophagus.
Current recommendations, based on an assumed annual cancer incidence of
approximately 1%, call for endoscopic surveillance at intervals of every 2
to 3 years. 39 <http://jama.ama-assn.org/issues/v285n18/rfull/#r39> A
recent study using a computer model to explore the value of different
surveillance strategies found that if the risk of cancer in patients with
Barrett esophagus is 0.4% annually, endoscopy every 5 years would be the
only reasonable surveillance strategy. 40
<http://jama.ama-assn.org/issues/v285n18/rfull/#r40>
The Practice Parameters Committee of the American College of
Gastroenterology has recommended endoscopic screening for Barrett esophagus
of older patients who have chronic GERD symptoms. 41
<http://jama.ama-assn.org/issues/v285n18/rfull/#r41> The purpose of such
screening is to reduce mortality from esophageal cancer. However, 1 of the 5
patients in our study who developed esophageal adenocarcinoma had no
evidence of Barrett esophagus on 3 earlier endoscopic examinations performed
by study endoscopists who were specifically seeking evidence of the
disorder. It is not clear whether short-segment Barrett esophagus was missed
on those examinations or whether the patient indeed developed esophageal
adenocarcinoma without Barrett esophagus. Nevertheless, if a substantial
proportion of patients who develop esophageal adenocarcinoma do so without
having endoscopically apparent Barrett esophagus, endoscopic screening
programs designed to look for Barrett esophagus will have limited impact in
decreasing mortality from esophageal cancer.
In our study, the cancer incidence among patients who had severe GERD
without Barrett esophagus was only 0.07% per year. Furthermore, except for 2
deaths from esophageal cancer, none of the deaths in the entire study
population appeared to be a direct consequence of GERD. Thus, we found GERD
to be an uncommon cause of mortality, even in our elderly population of
patients with severe reflux esophagitis. We found no significant differences
between treatment groups in incidence of esophageal adenocarcinoma but, with
such a low incidence of this neoplasm, our study did not have sufficient
statistical power to detect such differences. Even if antireflux surgery
could prevent esophageal adenocarcinoma for patients with GERD, however, its
use solely for this purpose cannot be sanctioned because the surgical
mortality rate (at least 0.2%) 10
<http://jama.ama-assn.org/issues/v285n18/rfull/#r10> exceeds the annual
incidence of cancer (0.07%).
We found that GERD symptoms were significantly less severe in the surgical
treatment group when drug therapy was discontinued but not when patients
were permitted to take antireflux medications in their usual fashion. There
was no significant difference in the mean endoscopic grade of esophagitis
between groups, and the mean grade was in the mild category for both medical
and surgical patients. However, patients had discontinued medications for
only 1 week before endoscopy, and this may have been an insufficient amount
of time for visible esophagitis to occur. The majority (92%) of patients in
the medical treatment group continued to take antireflux medications
regularly during the follow-up period, and regular use of these medications
was significantly less common in the surgical treatment group. Nevertheless,
62% of surgical patients were taking antireflux medications on a regular
basis. This suggests that antireflux surgery should not be advised with the
expectation that patients will no longer take antisecretory medications.
During the follow-up period, a substantial number of patients in both groups
had 1 or more antireflux operations (10% of medical patients and 16% of
surgical patients; P = .38) and had treatment for esophageal stricture (8%
of medical patients and 14% of surgical patients; P = .46). No significant
differences between the groups were noted for overall physical and mental
well-being as assessed by SF-36 scores. Most patients in both groups were
satisfied or very satisfied with their antireflux therapy (96% of medical
patients and 89% of surgical patients; P = .24).
The original VA Cooperative Study predated the widespread availability of
proton pump inhibitors (released for general use in the United States in
1989) and laparoscopic fundoplication (introduced in 1991). Nevertheless,
the results of this follow-up study are relevant for a number of reasons.
First, proton pump inhibitors were available to all patients and used by
most during the follow-up period, albeit in a nonstandardized fashion. Next,
open fundoplication remains the surgical standard by which laparoscopic
fundoplication is judged. Although the operative approaches differ, the
technique of laparoscopic Nissen fundoplication is virtually identical to
that of the open procedure. 42
<http://jama.ama-assn.org/issues/v285n18/rfull/#r42> The laparoscopic
approach has become popular not because it produces a better functional
result than the open procedure but because of proposed advantages in the
degree of postoperative discomfort, duration of hospital stay, and cosmetic
outcome. 43 <http://jama.ama-assn.org/issues/v285n18/rfull/#r43> Two recent
randomized trials of laparoscopic and open Nissen fundoplication found no
significant differences in the functional results of the 2 procedures (ie,
relief of GERD symptoms, reduction in esophageal acid exposure). 44
<http://jama.ama-assn.org/issues/v285n18/rfull/#r44> , 45
<http://jama.ama-assn.org/issues/v285n18/rfull/#r45> However, 1 of those
studies was terminated prematurely because an interim analysis showed an
excess of adverse outcomes (primarily postoperative dysphagia) in the
laparoscopically treated group. 45
<http://jama.ama-assn.org/issues/v285n18/rfull/#r45> Furthermore, at least
1 study has shown that the primary factor involved in overall patient
satisfaction with antireflux surgery is relief of GERD symptoms, not
operative approach. 46 <http://jama.ama-assn.org/issues/v285n18/rfull/#r46>
Therefore, our study on the long-term outcome of open fundoplication remains
highly relevant, even in this era of laparoscopic surgery.
In summary, during a follow-up period of 10 to 13 years, we found that
patients with complicated GERD who were treated with antireflux surgery were
significantly less likely to take antireflux medications regularly, and,
when those medicines were discontinued, their GERD symptoms were
significantly less severe than those of medically treated patients. However,
62% of surgical patients took antireflux medications on a regular basis, and
there were no significant differences between the medical and surgical
treatment groups in rates of neoplastic and peptic complications of GERD,
overall physical and mental well-being scores, and satisfaction with
antireflux therapy. Patients with Barrett esophagus developed esophageal
adenocarcinoma at an annual rate of 0.4%, whereas the annual rate for
patients who had severe GERD without Barrett esophagus was only 0.07%.
Furthermore, esophageal cancer was an uncommon cause of death.
Fundoplication unexpectedly was associated with a significant decrease in
long-term survival.
We conclude that antireflux surgery should not be advised with the
expectation that patients will no longer take antisecretory medications or
that it is clearly a cancer-preventing procedure for patients with GERD and
Barrett esophagus. The low rates of esophageal cancer development and
mortality due to GERD found in this prospective study call for a
reevaluation of current screening and surveillance guidelines for Barrett
esophagus. These findings also suggest that the first requisite for any
antireflux therapy must be safety.
Author/Article Information
Author Affiliations: Department of Veterans Affairs Medical Center, Dallas,
Tex (Drs Spechler and Lee); Department of Veterans Affairs Medical Center,
Denver, Colo (Dr Ahnen); Department of Veterans Affairs Medical Center, West
Roxbury, Mass (Drs Goyal and Hirano); Department of Veterans Affairs Medical
Center, Phoenix, Ariz (Dr Ramirez); Department of Veterans Affairs Medical
Center, Little Rock, Ark (Dr Raufman); Department of Veterans Affairs
Medical Center, Tucson, Ariz (Dr Sampliner); Department of Veterans Affairs
Medical Center, Hines, Ill (Drs Schnell and Sontag); Department of Veterans
Affairs Medical Center, Richmond, Va (Dr Vlahcevic); Department of Veterans
Affairs Medical Center, Omaha, Neb (Dr Young); and Department of Veterans
Affairs Medical Center, Perry Point, Md (Dr Williford). Dr Vlahcevic is
deceased.
Corresponding Author and Reprints: Stuart Jon Spechler, MD, Division of
Gastroenterology (111B1), Department of Veterans Affairs Medical Center,
4500 S Lancaster Rd, Dallas, TX 75216 (e-mail: [log in to unmask]
<mailto:[log in to unmask]> ).
Author Contributions: Study concept and design: Spechler, Ahnen, Goyal,
Hirano, Raufman, Vlahcevic.
Acquisition of data: Spechler, Ahnen, Hirano, Ramirez, Raufman, Sampliner,
Schnell, Sontag, Vlahcevic, Young, Williford.
Analysis and interpretation of data: Spechler, Lee, Ahnen, Goyal, Raufman,
Williford.
Drafting of the manuscript: Spechler, Sontag, Williford.
Critical revision of the manuscript for important intellectual content:
Spechler, Lee, Ahnen, Goyal, Hirano, Ramirez, Raufman, Sampliner, Schnell,
Young.
Statistical expertise: Williford.
Obtained funding: Spechler, Ahnen, Goyal.
Administrative, technical, or material support: Spechler, Goyal, Hirano,
Raufman, Schnell, Sontag, Young, Williford.
Study supervision: Spechler, Ahnen, Hirano, Raufman, Sampliner.
Funding/Support: This work was supported by grants from the Department of
Veterans Affairs Medical Research Service Cooperative Studies Program (CSP
277A), and Ethicon Endo-Surgery, Cincinnati, Ohio.
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.
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