World J. Surg. 16, 300-307, 1992
World Journal of Surgery © 1992by the Soci~t~ lnternationa~e de Chirurgie
Maintenance Therapy: Is There Still a Place for Antireflux Surgery? David Armstrong, M . A . , M.R.C.P. (UK), Marcel Nicolet, M.D., Phillippe Monnier, M.D., Germain Chapuis, M.D., Marcel Savary, M.D., and Andr6 L. Blum, M.D. Division of Gastroenterology, Department of Otorhinolaryngology,and Department of Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Effective and safe maintenance medical therapy for uncomplicated reflux esophagitis is now feasible with omeprazole and it is likely that other H÷K+ATPase blockers, and possibly very high dose H z receptor antagonist regimens, will also be acceptable. In addition, many patients with ulceration, strictures, and Barrett's esophagus will respond to conservative medical therapy and a proportion of patients with erosive esophagitis may remain in remission with cisapride or with low dose H 2 receptor antagonists, if disease is less severe. Thus, there is now a medical "gold standard" against which surgical therapy for uncomplicated esophagitis must be judged and it is essential that all future studies be conducted with clearly defined criteria for the assessment of the symptoms and endoscopic signs of esophagitis and its complications. As ever, the patient's wishes are paramount, but he or she must be allowed to select his or her therapy on the basis of a balanced and fully informed assessment of the long-term and short-term risks of all therapeutic modalities. The burdensome prospect of lifelong tablet ingestion and its potential dangers must be weighed against the alternative, in up to 30% of cases, that surgery may produce dysphagia, gas bloat, or dumping with no guarantee of a long-term cure.
treatment. Unless future studies are able to furnish a standardized description of treatment outcome, it will be virtually impossible to compare objectively the risks and benefits of different treatment options. In discussing the place of maintenance therapy for gastro-esophageal reflux disease, this article will consider the following facets of the disease and its management: the need for an accurate assessment of the severity of gastro-esophage~d reflux disease; methods for assessing disease severity, including a proposed classification system for reflux esophagitis; the efficacy of maintenance medical therapy; the potential side effects of maintenance medical therapy; and the risks and benefits of antireflux surgery. These points will form the basis for evaluating the roles of medical and surgical therapy in the long-term management of gastro-esophageal reflux disease. The Need for an Accurate Assessment of Disease Severity
As a result of recent advances in the medical management of gastro-esophageal reflux disease, the physician can now, for the first time, both heal an acute episode of esophagitis and maintain remission medically. In consequence, one is now entitled to ask whether maintenance medical therapy is a legitimate alternative to surgery for the management of severe gastro-esophageal reflux disease. There is, however, no simple answer to this question since the likelihood that any given treatment, whether medical or surgical, will produce prolonged freedom from esophagitis must be weighed against the likelihood that the treatment will also produce unwanted side effects. Such an assessment is further complicated by the fact that the response to treatment depends, at least in part, on the severity of the disease and its complications at the time when treatment commences. Thus, a rational assessment of the relative merits of different treatment options requires an understanding of the natural history of gastro-esophageal reflux disease as well as generally accepted criteria for assessing the severity of gastroesophageal reflux disease, the severity of reflux-related symptoms, and the presence and severity of problems attributable to Reprint requests: David Armstrong, M.D., Division de Gastroenterologie, CHUV/PMU, CH-1011 Lausanne, Switzerland.
Studies of medical treatment have, in general, assessed the severity of mucosal disease endoscopically before and after treatment but, by including patients with equivocal disease (e.g., mucosat erythema) or potentially irreversible complications (e.g., Barrett's epithelium) who could not be expected to respond, they risk underestimating the efficacy of the treatment under investigation [1]. Furthermore, if the proportion of patients with mild or severe esophagitis differs between treatment groups, it may be very difficult to compare the efficacy of different treatments, even within a single study [2]. Assessment of treatment efficacy is also difficult if different treatment endpoints have been used. For example, studies which describe successful treatment in terms of an improvement in esophagitis grade, regardless of whether full healing is achieved, cannot be compared directly with studies which define successful treatment as complete re-epithelialization of all mucosal defects. Similarly, in long-term studies, whether medical or surgical, relapse of esophagitis after complete healing [3, 4] cannot be compared directly with an increase in disease severity in a patient whose initial esophagitis has not healed [5, 6]. The results of .medical and surgical therapy may also be difficult to compare since, particularly in earlier studies, surgery was performed for indications such as hiatal hernia or respira-
D. Armstrong et al.: Maintenance Therapy for Gastro-Esophageal Reflux Disease tory complications [7], thus precluding direct comparison with other studies designed specifically to assess the treatment of reflux esophagitis. Furthermore, few surgical studies describe the severity of mucosal disease pre-operatively and, in general, the outcome of treatment is assessed symptomatically. The importance of assessing esophageal mucosal disease is illustrated by a report showing that, although a modified Toupet procedure produced a good or excellent 5 year symptomatic OUtcome in 18 (95%) of 19 patients, 4 (21%) patients still had endoscopic evidence of esophagitis at 5 years [8]. Methods for Assessing the Severity of Gastro-Esophageai Reflux Disease Although o n e must consider potential complications of the disease or its treatment as well as the patient's general health and wishes, it is the severity of a patient's symptoms and the associated mucosal disease which are the prime determinants of the most appropriate treatment option. Unfortunately, a review of the published data on the efficacy of different treatment options reveals no general agreement as to the assessment of disease severity before and after a course of treatment. EndosCopy is now the method of choice for the diagnosis and classification of reflux esophagitis [9] but, in the absence of esophageal mucosal lesions, it is not easy to decide if the patient's symptoms are indeed attributable to gastro-esophageal reflux, particularly if there is evidence of a structural abnormality such as a hiatus hernia. If endoscopy reveals a normal esophagus, it may be advisable to perform a supplementary examination such as 24 hour, ambulatory esophageal pH-metry With an evaluation which includes an objective, statistical assessment of the relationship between the patient's symptoms and the contemporaneous esophageal pH [10-12] before proCeeding to further treatment since the finding of, for example, a Prolonged reflux time does not necessarily indicate that gastroesophageal reflux is the cause of the patient's symptoms. If endoscopy with mucosal biopsies, to exclude other causes of esol~hagitis, reveals that the patient does indeed have reflux eSophagitis, the next step is to determine the severity of the disease. To date, the most widely used classification of esophagitis has been that of Savary and Miller [13] which rightly Considers the erosion or "touche peptique" to be the fundamental lesion of reflux esophagitis [9]. In this system, grades 1 to 3 reflect increasing severity and extent of acute erosive lesions whereas grade 4 covers all complications including Ulceration, stricture formation, and Barrett's epithelium regardless of whether there are coexistent erosive lesions. A recently Proposed system [14], based on the Savary classification, classifies the distinct lesion types (columnar Metaplasia, UlCers, Strictures and Erosions) independently in 4 grades (0: absent, 1: mild, 2: moderate, 3: severe) such that most of the endoscopic appearances of reflux esophagitis can be described Using the mnemonic " M U S E " (Fig. 1). This mnemonic does not describe the progression of reflux esophagitis through different stages but rather provides a standardized description of the features of reflux esophagitis which can form a basis for Predicting the probable response of a particular patient to treatment [3, 4, 15, 16], the likelihood that complications such as hemorrhage or malignancy will supervene, and the need for
301
long-term surveillance. In particular, it facilitates the distinction between acute erosive lesions (E, to E3) which are almost invariably reversible, acute ulcerative lesions (U, to U 3) and strictures (S~ to $3) which are more chronic and are rarely reversible, and columnar metaplasia (M, to M3) which has, so far, proved irreversible. Studies which distinguish clearly between these different lesion types and their severity will be able to define more precisely the effect of the treatment under investigation. The adoption of a formal, standardized preoperative and postoperative protocol for assessing disease severity, including symptoms [17-19], mucosal damage, and the presence of complications, will then pave the way for rational comparisons of different treatment modalities. The Efficacy of Medical Treatment for Reflux Esophagitis
Short-Term Therapy of Acute Disease The apparent efficacy of reflux esophagitis therapy depends to some extent on the goal of treatment. The initial consideration, particularly from the patient's point of view, is to alleviate symptoms and, before the advent of H, receptor antagonists, this was achieved primarily by Phase I therapies including life-style alterations and the regular use of antacids [20]. This generally helped somewhat with symptoms but rarely produced any long-lasting improvement in the degree of esophagitis. Phase II therapy with H2 receptor antagonists to reduce acid secretion has proved more successful, particularly in symptom relief. However, at conventional doses, H z receptor antagonists still produce 6 week healing rates of no more than 50% to 75% and it is necessary to continue therapy for 3 to 6 months [21,22] or to give very high doses (e.g., ranitidine 300 mg qid) to achieve acceptable healing rates [23]. Alternative approaches which have attempted to increase lower esophageal sphincter resting tone, improve esophageal clearance, and accelerate gastric emptying with anticholinergics, metoclopramide or domperidone have been less successful. However, the newer prokinetic agent, cisapride, is probably at least as effective as H2 receptor antagonists [24-27] and comparable healing rates have also been reported with sucralfate [28-30]. None of these Phase It therapies has, however, proved as effective with respect either to symptoms or to mucosal lesions, as the recently introduced H+K+ATPase inhibitors such as omeprazole and lansoprazole. Omeprazole, at daily doses of 20 mg to 40 mg, has now been shown consistently to produce 4 week to 8 week healing rates of 75% to 95% [4, 15, 31-37]. It is also very effective in cases of esophagitis resistant to H~ receptor antagonist therapy [38, 39] although more severe disease may occasionally require daily doses of 60 mg to 80 rag.
Long-Term Maintenance Therapy The relapse rates for esophagitis, in the absence of active Phase It treatment after complete healing, vary from 45% to 90% at 6 months after cessation of medical therapy (Table 1). Relapse rates are particularly high after potent antisecretory therapy [4], probably because the study population then includes a higher proportion of patients with severe disease which would not otherwise have healed. Thus, short-term healing does not protect against subsequent relapse once medical therapy has
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World J. Surg. Vol. 16, No. 2, Mar./Apr. 1992
Ulcer
Degree of severity
~--1 Stricture~
[---1 ErosionS~
]. A b s e n t
I.Mild
2. M o d e r a t e
3. S e v e r e
circumferential (*Must be confirmedat X-ray)
Hiatushernia:
["] Absent 1-"] Present
(
cm)
Patient name: Date:
Fig. 1. An endoscopy report form based on a classification system in which the lesions of Metaplasia, Ulceration, Stricture formation and Erosions (MUSE) are assessed and graded independently according to their degree of severity: 0: absent, 1: mild, 2: moderate, 3: severe. For each lesion type, the appropriate box is ticked and, if relevant, the presence of a hiatus hernia or the extent of a lesion such as columnar metaplasia may be marked with reference to the diaphragmatic hiatus. Each diagram represents a single feature which may, however, co-exist with other lesion types. Thus, for example, St and $2 do not indicate "suspended" strictures with normal mucosa (Mo) distal to them; in fact, peptic strictures are almost invariablyjunctional and, if they are situated above the hiatus, they will necessarily be accompanied by circumferential metaplasia (M3). Examples of some MUSE classifications and the corresponding endoscopic appearances are: M3UoSIE3: Active peptic stricture, diameter > 9 mm, situated at the upper pole of a circumferential area of columnar metaplasia. MoUoS2E3: Active junctional stricture, diameter < 9 mm, situated at the level of the normal Z-line. M3U3SoEo: Circumferential columnar metaplasia (endobrachyesophagus) with a Barrett's ulcer and a junctional ulcer. MoUoSoEz: Multiple erosions, confluent, affected more than one longitudinal fold but non-circumferential. Reprinted with permission of publisher [t5].
stopped. However, treatment which heals acute episodes of reflux esophagitis is not necessarily effective as a long-term prophylactic treatment. Continuous maintenance therapy with low dose H 2 receptor antagonists has not produced relapse rates significantly lower than those seen with placebo (Table I). A more recent, multicenter trial of 185 patients showed no benefit from full dose H2 receptor antagonist maintenance treatment; again, 6 month relapse rates of 37.5% with ranitidine
150 mg bid and 41.0% with ranitidine 300 mg hs were not significantly different from the placebo relapse rate of 45.1% [41]. More encouragingly, a recent, double-blind, controlled trial [42] indicates that cisapride may provide effective prophylaxis. Significantly lower 12 month relapse rates were seen in patients who received cisapride 10 mg bid (27.5%) or cisapride 20 mg hs (28.4%) compared with those who received placebo (48.5%), although there was little difference between the two
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D. Armstrong et ai.: Maintenance Therapy for Gastro-Esophageal Reflux Disease Table 1. EndoscopicaUy-confirmed relapse rates for reflux esophagitis after documented healing.
Placebo Author (yr) [reference] Antonson (1990) [40] Armstrong (1989) [41] Bardhan (1990) [38] Behar (1975) [61] Berlin (1989) [63] Blum(1990)[42]
Duration (months)
6
Hz-receptor antagonist Relapse (%)
45
12-36 12-36 12
63b 27" 23
4 12
17 49
Dent (1990) [44] Festen (1980) [64] Hetzel (1988) [4] Isal (1990) [43]
6
Drug/dose (rag/day)
Duration (months)
Omeprazole Relapse (%)
R600/N600
1
79
R300
6
41/38"
C1600/3200
6 12 18
45 67 73
F20 F40
12 12
23 19
R300
12
75
C800
12
86
Dose (rag/d)
20 20,1
Duration (months)
12. 12
Koelz (1986) [3] Koop (1990) [55]
6
Lundell (1990) [66] Ottenjann (1986) [5] Sandmark (1985) [31] Sherbaniuk (1984) [6] Verlinden (1990)
0f
36
6
28
6 6
86" 89x'
C400
RI50
6
Relapse (%)
20 20
4 12
10/1 !" 28/28"
10
6
20
11 68
6
0r 20
6 12 18
17 26 28
20•40
3 6 12
29 32 26
42
R300
12
71
C400
6
25
6-12
0
R300/150 6
Duration (months)
21 54
10 6
Dose (rag/d)
82" 20 a
Kaul (1986) [65] Klinkenberg-Knol (1989) [39]
Cisapride Relapse (%)
20
39
[241 C = cimetidinei F = famotidine; N = nizatidine; R = ranitidine. "Divided daily dose, see text. bMedical therapy. "After surgery. '13 days per week, see text. "After curative omeprazole therapy. fMean esophagitis score before therapy was less than MUSE grade E t. ~After curative ranitidine therapy.
cisapride regimens apart from a tendency for fewer side effects in patients receiving once-daily rather than twice-daily treatment. As in short-term treatment, the most impressive improvements in long-term treatment have come with the use of omeprazole. In 84 patients with healed esophagitis, maintenance treatment with omeprazole 20 mg daily led to 6, 12 and 24 month relapse rates of 17%, 26% and 33%, respectively. Again full-dose omeprazole (40 mg to 60 mg per day) produced successful healing in those patients who relapsed during maintenance therapy [39]. The importance of continuous protection of the esophageal mucosa from acid exposure is illustrated by the finding that daily treatment with omeprazole 10 mg produced significantly lower 6 month relapse rates (21%) than did omeprazole 20 mg, 3 consecutive days per week (54%) [43].
Similarly, omeprazole 20 mg per day led to a 12 month relapse rate of 11% compared to relapse rates of 68% with omeprazole 20 mg, 3 consecutive days per week, and 75% with ranitidine 150 mg bid [44]. Thus, there is now good evidence that even previously refractory esophagitis will respond to full-dose omeprazole therapy and, furthermore, that very low 12 month relapse rates can be achieved with maintenance omeprazole therapy. Maintenance therapy with cisapride is also effective and although maintenance therapy with full-dose Hz receptor antagonists is ineffective in severe disease, it may nonetheless be more effective than placebo at preventing the relapse o f grade I ( E 0 esophagitis [41]. The main question which now remains regarding the efficacy of maintenance medical therapy is whether it will continue to
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prevent relapse over the l0 to 20 year periods which have been reported after surgical treatment.
no evidence of nodular hyperplasia, dysplasia, or neoplasia [57].
The Potential Side Effects of Medical Treatment for Esophagitis
Effects due to Suboptimal Medical Therapy
All of the drugs which might be useful for long-term maintenance therapy have proved to be remarkably safe in short-term use. The potential dangers of long-term medical treatment may be grouped into 3 broad classes: 1. Side effects which are specific to the drug itself; 2. Side effects which are secondary to long-term suppression of acid secretion; and 3. Effects attributable to suboptimal treatment of the underlying gastro-esophageal reflux disease.
Drug-Specific Side Effects Cisapride occasionally produces intolerable diarrhea, necessitating cessation of therapy, but no other side effects have been reported and it has no appreciable interaction with other medications. The H z receptor antagonists also have a very good safety record, both in the short-term and the long-term. Of the 4 widely available compounds, only cimetidine, and to a much lesser extent ranitidine, induce cytochrome P450 enzyme activit}, and this has only very rarely been associated with any serious side effects or drug interactions. Omeprazole, too, has a very low incidence of side effects and although there have been studies purporting to show that it is genotoxic [45], the experimental techniques used to support this contention are open to criticism [46, 47]. Similarly, although omeprazole also induces human hepatic cytochrome P450 activity [48, 49], the implications of a report that it may increase the risk of carcinogen formation [50] are unclear. There is, for the present, no evidence that this effect is clinically relevant.
Effects Secondary to Reduced Acid Secretion Bacterial overgrowth in the stomach [51], nitrosamine formation [52], hypergastrinaemia, and enterochromaflin-like (ECL) cell formation are all potential dangers which may follow potent acid suppression, but there has been no indication that omeprazole or the H 2 receptor antagonists currently available have any serious long-term side effects. The introduction of omeprazole into clinical practice was delayed because of the discovery that it produced hypergastrinemia and also ECL cell hyperplasia in female rats, but these effects have now also been reported with high dose H2 receptor antagonist therapy [53, 54]. Furthermore, although omeprazole produces hypergastrinemia during maintenance treatment for esophagitis [55, 56], serum gastrin concentrations do not rise further after the first 4 weeks unless the patient also has evidence of pyloric obstruction (Walan, A., personal communication). In addition, follow-up of patients who have taken omeprazote for 5 years has shown a good correlation between serum fasting gastrin and mean argyrophil cell volume density. Mean serum gastrin levels did not rise further after the first 2 to 3 months of therapy and there was only a slight increase in the pre-existing argyrophil cell hyperplasia which remained constant after 8 months of therapy with
It has been postulated that long-term medical maintenance therapy may abolish symptoms without healing esophagitis, thus permitting the inexorable progression of asymptomatic esophageal lesions to the extent that radical salvage surgery becomes necessary to resolve complications such as stricture formation, short esophagus, or carcinoma development. There are, however, few data to support this hypothesis and persistent or progressive disease, even during maintenance therapy, is usually accompanied by persistent symptoms [58]. Estimates of the prevalence of asymptomatic disease progression require long-term follow-up of patients receiving effective maintenance medical therapy. For the moment, good symptom relief with potent antisecretory agents seems to be associated with resolution of esophageal lesions. Another potential danger of ineffective medical treatment is that it will permit the development of irreversible changes in esophageal motility which will then induce a vicious cycle such that esophageal clearance is further impaired and the reflux disease becomes still worse. There is, however, no consensus on the pathogenetic mechanisms underlying the progression of gastro-esophageal reflux disease and there is, moreover, evidence that observed esophageal motor abnormalities may precede rather than follow the development of mucosal lesions [59, 60]. In summary, the drugs currently available for maintenance treatment of reflux esophagitis have proven remarkably free of side effects in the short-term and the potential dangers associated with their long-term use remain unsubstantiated. It is, of course, impossible to know what may happen in patients who have received these medications for periods of 20 or more years, but this is a problem common to all long-term treatments, be they medical or surgical. It is only now, after 30 to 40 years, that the poterrtial long-term risks of gastric surgery are being recognized [52]. However, at the time, it was the only effective treatment for duodenal ulcer disease. Current maintenance medical treatment in hypertensive or diabetic patients is also potentially dangerous in both the short-term and long-term, but it is given in the knowledge that the sequelae of untreated disease are also dangerous. Thus, a final decision as to the most appropriate therapy must balance the potential risks and benefits of all possible treatment options in the light of current knowledge with re-evaluation as new options become available. Choice Between Medical and Surgical Treatment
There will probably continue to be a few patients who do not respond to medical treatment for a number of reasons: very severe gastro-esophageal reflux disease, alkaline reflux which cannot respond to acid inhibition, or the presence of severe complications or esophageal dysmotility (leading to impaired clearance) when the patient's disease is first diagnosed. Whatever the reasons, such patients will become rarer and more difficult to treat while surgeons with the expertise necessary to treat them adequately will also become rarer. This should not, however, be taken as a justification for continuing to recom-
D. Armstrong et al." Maintenance Therapy for Gastro-Esophageal Reflux Disease
mend surgical therapy. It is unacceptable that necessarily complex surgical antireflux procedures should be perpetuated in order that younger, less experienced surgeons can gain the expertise necessary to perform the operation in the future, should it be required. In the final analysis, a clear assessment of the role of surgery in relation to medical therapy can come only as a result of comparative studies in which entry and outcome criteria are strictly defined, study populations are sufficiently large, patients are followed for at least 5 to 10 years, surgery is performed by experts and only state of the art medical and surgical therapies are considered. This is a tall order but, for the moment, unequivocal recommendations are impossible since the only comparative studies on the outcome of medical and surgical treatment have been conducted with what is now known to be suboptimal medical therapy [2, 61, 62]. Surgery will continue to be indicated for intractable disease or complications but such cases will almost certainly become steadily rarer. Since the outcome of surgery is, to a great extent, operator-dependent, operations will have to be performed in specialized centers to optimize the results and minimize the risk of known complications. In contrast, medical therapy is much more widely available and its results more readily predictable since the outcome is virtually independent of the experience of the administering physician. Although the medications in current use have admirable short-term safety records, there remain the potential imponderable dangers of long-term medical therapy. However, in the absence of any convincing evidence that maintenance therapy is dangerous, it seems invidious to deny patients the potential benefits of an effective treatment for their disease. Pragmatically, medical maintenance therapy can always be changed if necessary in the light of advances in pharmaceutical or surgical techniques, whereas surgical procedures are difficult, if not impossible, to reverse. R~sum~ Le traitement m6dical de l'oesophagite peptique non compliqu6c est devenu possible de faqon efficace et sfire grace ~t l'om6prazole. II est probable que d'autres inhibiteurs de FATPase et m f m e des traitments h forte posologie d'anti H2 soient 6galement accceptables. De plus de nombreux patients pr6sentant une ulc6ration, une st6nose et un endobrachyoesophage sont susceptibles de r6pondre au traitement m6dical conservateur. D ' a u t r e s patients ayant une oesophagite 6rosive peuvent 6tre maintenus en r6mission par un traitement par cisapride ou de faibles posologies d'anti-H2 si la maladie est moins s6v6re. On poss6de ainsi un traitement " 6 t a l o n " (gold standard) avec lequel tout traitement chirurgical pour oesophagite peptique non compliqu6e doit 6tre compar6. I1 est capital que les 6tudes ult6rieures soient conduites ~. l'aide de crit6res pr6cis d6finissant les sympt6mes, les signes endoscopiques de I'oesophagite et ses complications. Comme toujours, les d6sirs du patient sont fondamentaux. II doit pouvoir choisir le type de traitement en fonction des informations prEcises sur les effets et les risques ~t court ou ~i long terme de toutes les modalit6s th6rapeutiques. Le risque de voir appara'itre une dysphagie, une impossibilit6 d'6ructation ou un syndrome de Dumping survenant dans pros de 30% des cas apr~s chirurgie, sans garantie de gu6rison ~ long
305
terme dolt 6tre mis en balance avec la n6cessit6 de prendre des comprim6s A vie avec leurs possibles effets secondaires. Resumen
El mantenimiento de una terapia m6dica efectiva y segura en la esofagitis por reflujo no complicada es actualmente factible con omeprazol, y es probable que los bloqueadores de la ATPasa, y tal vez los regimenes a base de muy altas dosis de antagonistas de los receptores H2, tambi6n logren tasas de curaci6n aceptables. Adem~is, muchos pacientes con ulceraci6n, estrecheces y es6fago de Barrett respondent a la terapia m6dica conservadora y una proporci6n significativa de pacientes con esofagitiS erosiva puede permanecer en remisi6n con cisapride o con bajas dosis si la enfermedad es menos severa. Por consiguiente, exite a h o r a un "est~indar de o r o " , contra el cual la terapia quirt~rgica de la esofagitis no complicada debe set juzgada; es esencial que todos los futuros estudios sean ejecutados con criterios claramente definidos para la valoraci6n de sfntomas y de signos endosc6picos de esofagitis y sus complicaciones. Como siempre, los deseos del paciente son de enorme importancia, pero el paciente debe hacer la selecci6n de su terapia con base en una equilibrada y bien informada valoraci6n de los riesgos, a corto y largo plazo, de las diferentes modalidades terap6uticas. L a preocupante perspectiva de toda una vida de sometimiento a la ingesta de tabletas y de sus posibles peligros debe ser equiparada con la alternativa, que ocurre hasta en 30% de los casos, de que la cirugfa pueda producir disfagia, distensi6n gaseosa del est6mago o dumping, y sin garantla de curaci6n a largo plazo. La cirugfa seguir~i estando indicada para enfermedad intratable o complicaciones, pero tales casos ciertamente se harfin progresivamente m~is raros. Puesto que el resultado de la cirugfa est,'i, en gran parte, relacionado con la calidad y experiencia del operador, las operaciones deber~in ser realizadas en centros especializados con el fin de optimizar los resultados y minimizar el riesgo de complicaciones. En contraste, la terapia m6dica es m~s ampliamente asequible y sus resultados m~is predecibles, puesto que el resultado es virtualmente independiente de la experiencia de m6dico que prescribe. Aunque los medicamentos actualmente en uso tienen un admirable " r e c o r d " de seguridad a corto plazo, quedan todavia potenciales peligros imponderables en relaci6n con la terapia m6dica a largo plazo. Sin embargo, en ausencia de evidencia convincente de que la terapia de mantenimiento es peligrosa, parece ser inaceptable negar al paciente los beneficios potenciales de un tratamiento eficaz para su enfermedad. En forma pragm~itica, el tratamiento m6dico de mantenimiento siempre puede ser modificado, si es necesario, a la luz de avances en las t6cnicas farmac6uticas y quirt~rgicas, en tanto que los procedimientos quirtirgicos son diffciles, si no imposibles, de revertir. Acknowledgment This work was supported by Swiss National Foundation Grant: S N F 32-26369.89. Reproduction of Figure 1 was made possible by a grant from Astra Hfissle, MOlndal, Sweden.
306 References 1. Sontag, S.J.: The medical management of reflux esophagitis: Role of antacids and acid inhibition. Gastroenterol. Clin. North Am. •9:683, 1990 2. Johansson, K.E., Tibbling, L.: Maintenance treatment with ranitidine compared with fundoplication in gastro-esophageal reflux disease. Scand. J. Gastroenterol. 2•:779, 1986 3. Koelz, H.R., Birchler, R., Bretholz, A., Bron, B., Capitaine, Y., Delmore, G., Fehr, H.F., Fumagatti, I., Gehrig, J., Gonvers, J,J., Halter, F., Hammer, B., Kayasseh, L., Kobler, E., Miller, G., Mfinst, G., Pelloni, S., Realini, S., Schmid, P., Voirol, M., Blum, A.L,: Healing and relapse of reflux esophagitis during treatment with ranitidine. Gastroenterology 91:1198, 1986 4. Hetzel, D.J., Dent, J., Reed, W.D., Narielvala, F.M., Mackinnon, M., McCarthy, J.H., Mitchell, B., Beveridge, B.R., Laurence, B.H., Gibson, G.G., Grant, A.K., Shearman, D.J.C., Whitehead, R., Buckle, P.J.: Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 95:903, 1988 5. Ottenjann, R., Siewert, J.R., Heilman, K., Neiss, A., Drpfer, H.: Treatment of reflux esophagitis: Results of a multicenter study. In Diseases of the Esophagus, J.R. Siewert, A.H. HSlscher, editors, Berlin, Springer Verlag, 1988, pp. 1123-1129 6. Sherbaniuk, R., Wensel, R., Bailey, R., Trautman, A., Grace, M., Kirdeikis, P., Jewell, L., Pare, P., Levesque, D., Farley, A., Archambault, A., Thomson, A.B.R.: Ranitidine in the treatment of symptomatic gastro-esophageal reflux disease. J. Clin. Gastroenterol. 6:9, 1984 7. Launois, B., Paul, J.L., Teboul, F., Bourdonnec, P., Cardin, J.L., Campion, J.P., Meunier, B., de Chateaubriant, P.: Les rdsultats fonctionnels du traitement chirurgical du reflux gastro-oesophagien non compliqud: Analyse de 278 observations. Ann. Chir. 42:191, 1988 8. Thor, K.B.A., Silander, T.: A long-term randomized prospective trial of the Nissen procedure versus a modified Toupet technique. Ann. Surg. 210:7t9, 1989 9. Savary, M.: Les hernies hiatales non compliquds. Endoscopie. Maladie peptique oesophagienne et gastrites herniares. Mdd. et Hyg. 26:789, 1968 10. Erode, C., Armstrong, D., Blum, A.L.: Chest pain due to gastroesophageal reflux: Presentation of a mathematical procedure to assess its significance. J. Gastrointest. Motil. 2:140, 1990 11. Ghillibert, G., Janssens, J., Vantrappen, G., Nevens, F., Piessens, J.: Ambulatory 24 hour intraoesophageal pH and pressure recordings v provocation tests in the diagnosis of chest pain of oesophageal origin. Gut 3•:738, 1990 12. Wiener, G.J., Richter, J.E., Copper, J.B., Wu, W.C., Castell, D.O.: The symptom index: A clinically important parameter of ambulatory 24-hour esophageal pH monitoring. Am. J. Gastroenterol. 83:358, 1988 13. Savary, M., Miller, G.: L'oesophage: Manuel et atlas d'endoscopie, Soleure, Suisse, Verlag Gassamann, 1977 14. Armstrong, D., Monnier, Ph., Nicolet, M., Blum, A.L., Savary, M.: Endoscopic assessment of oesophagitis. Gullet. 1:63, 1991 15. Havelund, T., Laursen, L.S., Skoubo-Kristensen, E., Andersen, B.N., Pedersen, S.A., Jensen, K.B., Fenger, C., Hanberg-SOrensen, F., Lauritsen, K.: Omeprazole and ranitidine in treatment of reflux oesophagitis: Double blind comparative trial. Br. Med. J. 296:89, 1988 16. Tytgat, G.N.J., Nicolai, J.J., Reman, F.C.: Efficacy of different doses of cimetidine in the treatment of reflux esophagitis: A review of three large, double-blind, controlled trials. Gastroenterology 99:629, 1990 17. Spechler, S.J., Williford, W.O., Krol, W.F., the Veterans Administration Cooperative Study Group: Development and validation of a gastro-esophageal reflux disease activity index (GRACI). Gastroenterology 98:AI30, 1990 18. Lieberman, D.A.: Medical therapy for chronic reflux esophagitis. Arch. Intern. Med. 147:1717, 1987 19. Johnsson, H., Joelsson, B., Gudmundsson, K., Floren, C.H., Walther, B.: Effects of fundoplication on the antireflux mechanism. Br. J. Surg. 74:1111, 1987
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prevent relapses of peptic esophagitis following therapy with a proton pump inhibitor. Gastroenterology 98:A16, 1990 Armstrong, D., Blum, A.L., the REZITIC Study Group: Full-dose H2-receptor antagonist prophylaxis does not prevent relapse of reflux oesophagitis. Gut 30:A1494, 1989 Blum, A.L., Verlinden, M., the EUROCIS trialists: Cisapride prevents the relapse of reflux esophagitis. Gastroenterology 98: A22, 1990 Isal, J.P., Zeitoun, P., Barbier, P., Cayphas, J.P., Carlsson, R.: Comparison of two dosage regimens of omeprazole--10 mg once daily and 20 mg weekends--as prophylaxis against recurrence of reflux esophagitis. Gastroenterology 98:A63, 1990 Dent, J., Mackinnon, M., Reed, W., Narielvala, F.M., Hetzel, D.J.: Omeprazole prevents relapse of peptic esophagitis. Presentation at the World Congresses of Gastroenterology. Sydney: Australia, 1990 Burlinson, B., Morris, S.H., Gatehouse, D.G., Tweats, D.J.: Genotoxicity studies of gastric acid inhibiting drugs. Lancet 335: 419, 1990 Helander, H,F., Larsson, H., Carlsson, E.: Omeprazole and genotoxicity. Lancet 335:910, 1990 Wright, N.A., Goodlad, R.A.: Omeprazole and genotoxicity. Lancet 335:909, 1990 Gugler, R., Jensen, J.C.: Omeprazole inhibits oxidative drug metabolism: Studies with diazepam and phehytoin in vivo and 7-ethoxycoumarin in vitro. Gastroenterology 89:1235, 1985 Henry, D.A., Somerville, K.W., Kitchingman, G., Langman, M.J.S.: Omeprazole: Effects on oxidative drug metabolism. Br. J. Clin. Pharmacol. 18:195, 1984 Diaz, D., Fabre, I., Daujat, M., Saint Aubert, B., Bories, P., Michel, H., Maurel, P.: Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 99:737, 1990 Colin-Jones, D.G.: Acid suppression: How much is needed'? Br. Med. J. 301:564, 1990 Hall, C.N., Darkin, D., Brimblecombe, R., Cook, A.J., Kirkham, J.S., Northfield, T.C.: Evaluation of the nitrosamine hypothesis of gastric carcinogenesis in precancerous conditions. Gut 27:49 I, 1986 Havu, N., Mattsson, H., Ekman, L., Carlsson, E.: Enterochromaffinlike cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine. Digestion 45:189, 1990 Wallmark, B., Sk~mberg, I., Mattsson, H., Andersson, K., Sundler, F., Hfikanson, R., Carlsson, E.: Effect of 20 weeks' ranitidine treatment on plasma gastrin levels and gastric enterochromaffin-like cell density in the rat. Digestion 45:181, 1990 Koop, H., Wachtman, H., Eissele, R., Arnold, R.: Efficacy and
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safety of long-term omeprazole maintenance therapy in H2blocker-resistant reflux esophagitis healed by omeprazole. Gastroenterology 98:A70, 1990 Jansen, J.B.M.J., Klinkenberg-Knol, E.C., Meuwissen, S.G.M., De Bruijne, J.W., Festen, H.O.M., Snel, P., L~ickers, A.E.G., Biemond, I., Lamers, C.B.H.W.: Effect of long-term treatment with omeprazole +on serum gastrin and serum Group A and C pepsinogens in patients with reflux esophagitis. Gastroenterology 99:621, 1990 Creutzfeldt, W., Lamberts, R.: Is hypergastrinaemia dangerous to man? Scand. J. Gastroenterol. Suppl. (in press) Gozzetti, G., Pilotti, V., Spangaro, M., Bassi, F., Grigioni, W., Carulli, N., Loria, P., Felice, V., Lerro, F., Mattioli, S.: Pathophysiology and natural history of acquired short esophagus. Surgery 102:507, 1987 Baldi, F., Ferrarini, F., Longanesi, A., Angeloni, M., Ragazzini, M., Miglioli, M., Barbara, L.: Oesophageal function before, during and after healing of erosive oesophagitis. Gut 29:157, 1988 Eriksen, C.A., Sadek, S.A., Cranford, C., Sutton, D., Kennedy, N., Cuschieri, A.; Reflux oesophagitis and oesophageal transit: Evidence for a primary oseophageal motor disorder. Gut 29:448, 1988 Behar, J., Sheahan, D.G., Biancani, P., Spiro, H.M., Storer, E.H.: Medical and surgical management of reflux esophagitis: A 38-month report on a prospective clinical trial. N. Engl. J. Med. 293:263, 1975 Spechler, S.J., Williford, W.O., the Veterans Administration Cooperative Study Group: A prospective randomized trial of medical and surgical therapies for gastroesophageal reflux disease (GERD). Gastroenterology 98:A129, 1990 Berlin, R., Ebel, D., Cook, T.: Famotidine (F) 20 HS & 40 HS vs placebo (P) in the maintenance therapy (MT) of reflux esophagitis (RE). Gastroenterology 96:A39, 1989 Festen, H.P.M., Driessen, W.M.M., Lamers, C.B.H.W., Van Tongeren, J. H. M.: Cimetidine in the treatment of severe ulcerative reflux esophagitis: Results of an 8-week double-blind study and of subsequent long-term maintenance treatment. Neth. J. Med. 23: 237, 1980 Kaul, B., Petersen, H., Erichsen, H., Myrvold, H.E., Grette, K,, Halvorsen, T., FjCsne, U.: Gastroesophageal reflux disease: Acute and maintenance treatments with cimetidine. Scand. J. Gastroenterol. 21:139, 1986 Lundell, L., Backman, L., Ektrbm, P., Enander, L.K., Fausa, O., Lind, T., Lbnroth, H., Sandmark, S., Sandz6n, B., Unge, P., Westin, I.H.: Prevention of relapse of esophagitis after endoscopic healing: The efficacy of omeprazole compared with ranitidine. Gastroenterology 98:A82, 1990
World Journal of Surgery © 1992by the Soci~t~ lnternationa~e de Chirurgie
Maintenance Therapy: Is There Still a Place for Antireflux Surgery? David Armstrong, M . A . , M.R.C.P. (UK), Marcel Nicolet, M.D., Phillippe Monnier, M.D., Germain Chapuis, M.D., Marcel Savary, M.D., and Andr6 L. Blum, M.D. Division of Gastroenterology, Department of Otorhinolaryngology,and Department of Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Effective and safe maintenance medical therapy for uncomplicated reflux esophagitis is now feasible with omeprazole and it is likely that other H÷K+ATPase blockers, and possibly very high dose H z receptor antagonist regimens, will also be acceptable. In addition, many patients with ulceration, strictures, and Barrett's esophagus will respond to conservative medical therapy and a proportion of patients with erosive esophagitis may remain in remission with cisapride or with low dose H 2 receptor antagonists, if disease is less severe. Thus, there is now a medical "gold standard" against which surgical therapy for uncomplicated esophagitis must be judged and it is essential that all future studies be conducted with clearly defined criteria for the assessment of the symptoms and endoscopic signs of esophagitis and its complications. As ever, the patient's wishes are paramount, but he or she must be allowed to select his or her therapy on the basis of a balanced and fully informed assessment of the long-term and short-term risks of all therapeutic modalities. The burdensome prospect of lifelong tablet ingestion and its potential dangers must be weighed against the alternative, in up to 30% of cases, that surgery may produce dysphagia, gas bloat, or dumping with no guarantee of a long-term cure.
treatment. Unless future studies are able to furnish a standardized description of treatment outcome, it will be virtually impossible to compare objectively the risks and benefits of different treatment options. In discussing the place of maintenance therapy for gastro-esophageal reflux disease, this article will consider the following facets of the disease and its management: the need for an accurate assessment of the severity of gastro-esophage~d reflux disease; methods for assessing disease severity, including a proposed classification system for reflux esophagitis; the efficacy of maintenance medical therapy; the potential side effects of maintenance medical therapy; and the risks and benefits of antireflux surgery. These points will form the basis for evaluating the roles of medical and surgical therapy in the long-term management of gastro-esophageal reflux disease. The Need for an Accurate Assessment of Disease Severity
As a result of recent advances in the medical management of gastro-esophageal reflux disease, the physician can now, for the first time, both heal an acute episode of esophagitis and maintain remission medically. In consequence, one is now entitled to ask whether maintenance medical therapy is a legitimate alternative to surgery for the management of severe gastro-esophageal reflux disease. There is, however, no simple answer to this question since the likelihood that any given treatment, whether medical or surgical, will produce prolonged freedom from esophagitis must be weighed against the likelihood that the treatment will also produce unwanted side effects. Such an assessment is further complicated by the fact that the response to treatment depends, at least in part, on the severity of the disease and its complications at the time when treatment commences. Thus, a rational assessment of the relative merits of different treatment options requires an understanding of the natural history of gastro-esophageal reflux disease as well as generally accepted criteria for assessing the severity of gastroesophageal reflux disease, the severity of reflux-related symptoms, and the presence and severity of problems attributable to Reprint requests: David Armstrong, M.D., Division de Gastroenterologie, CHUV/PMU, CH-1011 Lausanne, Switzerland.
Studies of medical treatment have, in general, assessed the severity of mucosal disease endoscopically before and after treatment but, by including patients with equivocal disease (e.g., mucosat erythema) or potentially irreversible complications (e.g., Barrett's epithelium) who could not be expected to respond, they risk underestimating the efficacy of the treatment under investigation [1]. Furthermore, if the proportion of patients with mild or severe esophagitis differs between treatment groups, it may be very difficult to compare the efficacy of different treatments, even within a single study [2]. Assessment of treatment efficacy is also difficult if different treatment endpoints have been used. For example, studies which describe successful treatment in terms of an improvement in esophagitis grade, regardless of whether full healing is achieved, cannot be compared directly with studies which define successful treatment as complete re-epithelialization of all mucosal defects. Similarly, in long-term studies, whether medical or surgical, relapse of esophagitis after complete healing [3, 4] cannot be compared directly with an increase in disease severity in a patient whose initial esophagitis has not healed [5, 6]. The results of .medical and surgical therapy may also be difficult to compare since, particularly in earlier studies, surgery was performed for indications such as hiatal hernia or respira-
D. Armstrong et al.: Maintenance Therapy for Gastro-Esophageal Reflux Disease tory complications [7], thus precluding direct comparison with other studies designed specifically to assess the treatment of reflux esophagitis. Furthermore, few surgical studies describe the severity of mucosal disease pre-operatively and, in general, the outcome of treatment is assessed symptomatically. The importance of assessing esophageal mucosal disease is illustrated by a report showing that, although a modified Toupet procedure produced a good or excellent 5 year symptomatic OUtcome in 18 (95%) of 19 patients, 4 (21%) patients still had endoscopic evidence of esophagitis at 5 years [8]. Methods for Assessing the Severity of Gastro-Esophageai Reflux Disease Although o n e must consider potential complications of the disease or its treatment as well as the patient's general health and wishes, it is the severity of a patient's symptoms and the associated mucosal disease which are the prime determinants of the most appropriate treatment option. Unfortunately, a review of the published data on the efficacy of different treatment options reveals no general agreement as to the assessment of disease severity before and after a course of treatment. EndosCopy is now the method of choice for the diagnosis and classification of reflux esophagitis [9] but, in the absence of esophageal mucosal lesions, it is not easy to decide if the patient's symptoms are indeed attributable to gastro-esophageal reflux, particularly if there is evidence of a structural abnormality such as a hiatus hernia. If endoscopy reveals a normal esophagus, it may be advisable to perform a supplementary examination such as 24 hour, ambulatory esophageal pH-metry With an evaluation which includes an objective, statistical assessment of the relationship between the patient's symptoms and the contemporaneous esophageal pH [10-12] before proCeeding to further treatment since the finding of, for example, a Prolonged reflux time does not necessarily indicate that gastroesophageal reflux is the cause of the patient's symptoms. If endoscopy with mucosal biopsies, to exclude other causes of esol~hagitis, reveals that the patient does indeed have reflux eSophagitis, the next step is to determine the severity of the disease. To date, the most widely used classification of esophagitis has been that of Savary and Miller [13] which rightly Considers the erosion or "touche peptique" to be the fundamental lesion of reflux esophagitis [9]. In this system, grades 1 to 3 reflect increasing severity and extent of acute erosive lesions whereas grade 4 covers all complications including Ulceration, stricture formation, and Barrett's epithelium regardless of whether there are coexistent erosive lesions. A recently Proposed system [14], based on the Savary classification, classifies the distinct lesion types (columnar Metaplasia, UlCers, Strictures and Erosions) independently in 4 grades (0: absent, 1: mild, 2: moderate, 3: severe) such that most of the endoscopic appearances of reflux esophagitis can be described Using the mnemonic " M U S E " (Fig. 1). This mnemonic does not describe the progression of reflux esophagitis through different stages but rather provides a standardized description of the features of reflux esophagitis which can form a basis for Predicting the probable response of a particular patient to treatment [3, 4, 15, 16], the likelihood that complications such as hemorrhage or malignancy will supervene, and the need for
301
long-term surveillance. In particular, it facilitates the distinction between acute erosive lesions (E, to E3) which are almost invariably reversible, acute ulcerative lesions (U, to U 3) and strictures (S~ to $3) which are more chronic and are rarely reversible, and columnar metaplasia (M, to M3) which has, so far, proved irreversible. Studies which distinguish clearly between these different lesion types and their severity will be able to define more precisely the effect of the treatment under investigation. The adoption of a formal, standardized preoperative and postoperative protocol for assessing disease severity, including symptoms [17-19], mucosal damage, and the presence of complications, will then pave the way for rational comparisons of different treatment modalities. The Efficacy of Medical Treatment for Reflux Esophagitis
Short-Term Therapy of Acute Disease The apparent efficacy of reflux esophagitis therapy depends to some extent on the goal of treatment. The initial consideration, particularly from the patient's point of view, is to alleviate symptoms and, before the advent of H, receptor antagonists, this was achieved primarily by Phase I therapies including life-style alterations and the regular use of antacids [20]. This generally helped somewhat with symptoms but rarely produced any long-lasting improvement in the degree of esophagitis. Phase II therapy with H2 receptor antagonists to reduce acid secretion has proved more successful, particularly in symptom relief. However, at conventional doses, H z receptor antagonists still produce 6 week healing rates of no more than 50% to 75% and it is necessary to continue therapy for 3 to 6 months [21,22] or to give very high doses (e.g., ranitidine 300 mg qid) to achieve acceptable healing rates [23]. Alternative approaches which have attempted to increase lower esophageal sphincter resting tone, improve esophageal clearance, and accelerate gastric emptying with anticholinergics, metoclopramide or domperidone have been less successful. However, the newer prokinetic agent, cisapride, is probably at least as effective as H2 receptor antagonists [24-27] and comparable healing rates have also been reported with sucralfate [28-30]. None of these Phase It therapies has, however, proved as effective with respect either to symptoms or to mucosal lesions, as the recently introduced H+K+ATPase inhibitors such as omeprazole and lansoprazole. Omeprazole, at daily doses of 20 mg to 40 mg, has now been shown consistently to produce 4 week to 8 week healing rates of 75% to 95% [4, 15, 31-37]. It is also very effective in cases of esophagitis resistant to H~ receptor antagonist therapy [38, 39] although more severe disease may occasionally require daily doses of 60 mg to 80 rag.
Long-Term Maintenance Therapy The relapse rates for esophagitis, in the absence of active Phase It treatment after complete healing, vary from 45% to 90% at 6 months after cessation of medical therapy (Table 1). Relapse rates are particularly high after potent antisecretory therapy [4], probably because the study population then includes a higher proportion of patients with severe disease which would not otherwise have healed. Thus, short-term healing does not protect against subsequent relapse once medical therapy has
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World J. Surg. Vol. 16, No. 2, Mar./Apr. 1992
Ulcer
Degree of severity
~--1 Stricture~
[---1 ErosionS~
]. A b s e n t
I.Mild
2. M o d e r a t e
3. S e v e r e
circumferential (*Must be confirmedat X-ray)
Hiatushernia:
["] Absent 1-"] Present
(
cm)
Patient name: Date:
Fig. 1. An endoscopy report form based on a classification system in which the lesions of Metaplasia, Ulceration, Stricture formation and Erosions (MUSE) are assessed and graded independently according to their degree of severity: 0: absent, 1: mild, 2: moderate, 3: severe. For each lesion type, the appropriate box is ticked and, if relevant, the presence of a hiatus hernia or the extent of a lesion such as columnar metaplasia may be marked with reference to the diaphragmatic hiatus. Each diagram represents a single feature which may, however, co-exist with other lesion types. Thus, for example, St and $2 do not indicate "suspended" strictures with normal mucosa (Mo) distal to them; in fact, peptic strictures are almost invariablyjunctional and, if they are situated above the hiatus, they will necessarily be accompanied by circumferential metaplasia (M3). Examples of some MUSE classifications and the corresponding endoscopic appearances are: M3UoSIE3: Active peptic stricture, diameter > 9 mm, situated at the upper pole of a circumferential area of columnar metaplasia. MoUoS2E3: Active junctional stricture, diameter < 9 mm, situated at the level of the normal Z-line. M3U3SoEo: Circumferential columnar metaplasia (endobrachyesophagus) with a Barrett's ulcer and a junctional ulcer. MoUoSoEz: Multiple erosions, confluent, affected more than one longitudinal fold but non-circumferential. Reprinted with permission of publisher [t5].
stopped. However, treatment which heals acute episodes of reflux esophagitis is not necessarily effective as a long-term prophylactic treatment. Continuous maintenance therapy with low dose H 2 receptor antagonists has not produced relapse rates significantly lower than those seen with placebo (Table I). A more recent, multicenter trial of 185 patients showed no benefit from full dose H2 receptor antagonist maintenance treatment; again, 6 month relapse rates of 37.5% with ranitidine
150 mg bid and 41.0% with ranitidine 300 mg hs were not significantly different from the placebo relapse rate of 45.1% [41]. More encouragingly, a recent, double-blind, controlled trial [42] indicates that cisapride may provide effective prophylaxis. Significantly lower 12 month relapse rates were seen in patients who received cisapride 10 mg bid (27.5%) or cisapride 20 mg hs (28.4%) compared with those who received placebo (48.5%), although there was little difference between the two
303
D. Armstrong et ai.: Maintenance Therapy for Gastro-Esophageal Reflux Disease Table 1. EndoscopicaUy-confirmed relapse rates for reflux esophagitis after documented healing.
Placebo Author (yr) [reference] Antonson (1990) [40] Armstrong (1989) [41] Bardhan (1990) [38] Behar (1975) [61] Berlin (1989) [63] Blum(1990)[42]
Duration (months)
6
Hz-receptor antagonist Relapse (%)
45
12-36 12-36 12
63b 27" 23
4 12
17 49
Dent (1990) [44] Festen (1980) [64] Hetzel (1988) [4] Isal (1990) [43]
6
Drug/dose (rag/day)
Duration (months)
Omeprazole Relapse (%)
R600/N600
1
79
R300
6
41/38"
C1600/3200
6 12 18
45 67 73
F20 F40
12 12
23 19
R300
12
75
C800
12
86
Dose (rag/d)
20 20,1
Duration (months)
12. 12
Koelz (1986) [3] Koop (1990) [55]
6
Lundell (1990) [66] Ottenjann (1986) [5] Sandmark (1985) [31] Sherbaniuk (1984) [6] Verlinden (1990)
0f
36
6
28
6 6
86" 89x'
C400
RI50
6
Relapse (%)
20 20
4 12
10/1 !" 28/28"
10
6
20
11 68
6
0r 20
6 12 18
17 26 28
20•40
3 6 12
29 32 26
42
R300
12
71
C400
6
25
6-12
0
R300/150 6
Duration (months)
21 54
10 6
Dose (rag/d)
82" 20 a
Kaul (1986) [65] Klinkenberg-Knol (1989) [39]
Cisapride Relapse (%)
20
39
[241 C = cimetidinei F = famotidine; N = nizatidine; R = ranitidine. "Divided daily dose, see text. bMedical therapy. "After surgery. '13 days per week, see text. "After curative omeprazole therapy. fMean esophagitis score before therapy was less than MUSE grade E t. ~After curative ranitidine therapy.
cisapride regimens apart from a tendency for fewer side effects in patients receiving once-daily rather than twice-daily treatment. As in short-term treatment, the most impressive improvements in long-term treatment have come with the use of omeprazole. In 84 patients with healed esophagitis, maintenance treatment with omeprazole 20 mg daily led to 6, 12 and 24 month relapse rates of 17%, 26% and 33%, respectively. Again full-dose omeprazole (40 mg to 60 mg per day) produced successful healing in those patients who relapsed during maintenance therapy [39]. The importance of continuous protection of the esophageal mucosa from acid exposure is illustrated by the finding that daily treatment with omeprazole 10 mg produced significantly lower 6 month relapse rates (21%) than did omeprazole 20 mg, 3 consecutive days per week (54%) [43].
Similarly, omeprazole 20 mg per day led to a 12 month relapse rate of 11% compared to relapse rates of 68% with omeprazole 20 mg, 3 consecutive days per week, and 75% with ranitidine 150 mg bid [44]. Thus, there is now good evidence that even previously refractory esophagitis will respond to full-dose omeprazole therapy and, furthermore, that very low 12 month relapse rates can be achieved with maintenance omeprazole therapy. Maintenance therapy with cisapride is also effective and although maintenance therapy with full-dose Hz receptor antagonists is ineffective in severe disease, it may nonetheless be more effective than placebo at preventing the relapse o f grade I ( E 0 esophagitis [41]. The main question which now remains regarding the efficacy of maintenance medical therapy is whether it will continue to
304
World J. Surg. Vol. 16, No. 2, Mar./Apr. 1992
prevent relapse over the l0 to 20 year periods which have been reported after surgical treatment.
no evidence of nodular hyperplasia, dysplasia, or neoplasia [57].
The Potential Side Effects of Medical Treatment for Esophagitis
Effects due to Suboptimal Medical Therapy
All of the drugs which might be useful for long-term maintenance therapy have proved to be remarkably safe in short-term use. The potential dangers of long-term medical treatment may be grouped into 3 broad classes: 1. Side effects which are specific to the drug itself; 2. Side effects which are secondary to long-term suppression of acid secretion; and 3. Effects attributable to suboptimal treatment of the underlying gastro-esophageal reflux disease.
Drug-Specific Side Effects Cisapride occasionally produces intolerable diarrhea, necessitating cessation of therapy, but no other side effects have been reported and it has no appreciable interaction with other medications. The H z receptor antagonists also have a very good safety record, both in the short-term and the long-term. Of the 4 widely available compounds, only cimetidine, and to a much lesser extent ranitidine, induce cytochrome P450 enzyme activit}, and this has only very rarely been associated with any serious side effects or drug interactions. Omeprazole, too, has a very low incidence of side effects and although there have been studies purporting to show that it is genotoxic [45], the experimental techniques used to support this contention are open to criticism [46, 47]. Similarly, although omeprazole also induces human hepatic cytochrome P450 activity [48, 49], the implications of a report that it may increase the risk of carcinogen formation [50] are unclear. There is, for the present, no evidence that this effect is clinically relevant.
Effects Secondary to Reduced Acid Secretion Bacterial overgrowth in the stomach [51], nitrosamine formation [52], hypergastrinaemia, and enterochromaflin-like (ECL) cell formation are all potential dangers which may follow potent acid suppression, but there has been no indication that omeprazole or the H 2 receptor antagonists currently available have any serious long-term side effects. The introduction of omeprazole into clinical practice was delayed because of the discovery that it produced hypergastrinemia and also ECL cell hyperplasia in female rats, but these effects have now also been reported with high dose H2 receptor antagonist therapy [53, 54]. Furthermore, although omeprazole produces hypergastrinemia during maintenance treatment for esophagitis [55, 56], serum gastrin concentrations do not rise further after the first 4 weeks unless the patient also has evidence of pyloric obstruction (Walan, A., personal communication). In addition, follow-up of patients who have taken omeprazote for 5 years has shown a good correlation between serum fasting gastrin and mean argyrophil cell volume density. Mean serum gastrin levels did not rise further after the first 2 to 3 months of therapy and there was only a slight increase in the pre-existing argyrophil cell hyperplasia which remained constant after 8 months of therapy with
It has been postulated that long-term medical maintenance therapy may abolish symptoms without healing esophagitis, thus permitting the inexorable progression of asymptomatic esophageal lesions to the extent that radical salvage surgery becomes necessary to resolve complications such as stricture formation, short esophagus, or carcinoma development. There are, however, few data to support this hypothesis and persistent or progressive disease, even during maintenance therapy, is usually accompanied by persistent symptoms [58]. Estimates of the prevalence of asymptomatic disease progression require long-term follow-up of patients receiving effective maintenance medical therapy. For the moment, good symptom relief with potent antisecretory agents seems to be associated with resolution of esophageal lesions. Another potential danger of ineffective medical treatment is that it will permit the development of irreversible changes in esophageal motility which will then induce a vicious cycle such that esophageal clearance is further impaired and the reflux disease becomes still worse. There is, however, no consensus on the pathogenetic mechanisms underlying the progression of gastro-esophageal reflux disease and there is, moreover, evidence that observed esophageal motor abnormalities may precede rather than follow the development of mucosal lesions [59, 60]. In summary, the drugs currently available for maintenance treatment of reflux esophagitis have proven remarkably free of side effects in the short-term and the potential dangers associated with their long-term use remain unsubstantiated. It is, of course, impossible to know what may happen in patients who have received these medications for periods of 20 or more years, but this is a problem common to all long-term treatments, be they medical or surgical. It is only now, after 30 to 40 years, that the poterrtial long-term risks of gastric surgery are being recognized [52]. However, at the time, it was the only effective treatment for duodenal ulcer disease. Current maintenance medical treatment in hypertensive or diabetic patients is also potentially dangerous in both the short-term and long-term, but it is given in the knowledge that the sequelae of untreated disease are also dangerous. Thus, a final decision as to the most appropriate therapy must balance the potential risks and benefits of all possible treatment options in the light of current knowledge with re-evaluation as new options become available. Choice Between Medical and Surgical Treatment
There will probably continue to be a few patients who do not respond to medical treatment for a number of reasons: very severe gastro-esophageal reflux disease, alkaline reflux which cannot respond to acid inhibition, or the presence of severe complications or esophageal dysmotility (leading to impaired clearance) when the patient's disease is first diagnosed. Whatever the reasons, such patients will become rarer and more difficult to treat while surgeons with the expertise necessary to treat them adequately will also become rarer. This should not, however, be taken as a justification for continuing to recom-
D. Armstrong et al." Maintenance Therapy for Gastro-Esophageal Reflux Disease
mend surgical therapy. It is unacceptable that necessarily complex surgical antireflux procedures should be perpetuated in order that younger, less experienced surgeons can gain the expertise necessary to perform the operation in the future, should it be required. In the final analysis, a clear assessment of the role of surgery in relation to medical therapy can come only as a result of comparative studies in which entry and outcome criteria are strictly defined, study populations are sufficiently large, patients are followed for at least 5 to 10 years, surgery is performed by experts and only state of the art medical and surgical therapies are considered. This is a tall order but, for the moment, unequivocal recommendations are impossible since the only comparative studies on the outcome of medical and surgical treatment have been conducted with what is now known to be suboptimal medical therapy [2, 61, 62]. Surgery will continue to be indicated for intractable disease or complications but such cases will almost certainly become steadily rarer. Since the outcome of surgery is, to a great extent, operator-dependent, operations will have to be performed in specialized centers to optimize the results and minimize the risk of known complications. In contrast, medical therapy is much more widely available and its results more readily predictable since the outcome is virtually independent of the experience of the administering physician. Although the medications in current use have admirable short-term safety records, there remain the potential imponderable dangers of long-term medical therapy. However, in the absence of any convincing evidence that maintenance therapy is dangerous, it seems invidious to deny patients the potential benefits of an effective treatment for their disease. Pragmatically, medical maintenance therapy can always be changed if necessary in the light of advances in pharmaceutical or surgical techniques, whereas surgical procedures are difficult, if not impossible, to reverse. R~sum~ Le traitement m6dical de l'oesophagite peptique non compliqu6c est devenu possible de faqon efficace et sfire grace ~t l'om6prazole. II est probable que d'autres inhibiteurs de FATPase et m f m e des traitments h forte posologie d'anti H2 soient 6galement accceptables. De plus de nombreux patients pr6sentant une ulc6ration, une st6nose et un endobrachyoesophage sont susceptibles de r6pondre au traitement m6dical conservateur. D ' a u t r e s patients ayant une oesophagite 6rosive peuvent 6tre maintenus en r6mission par un traitement par cisapride ou de faibles posologies d'anti-H2 si la maladie est moins s6v6re. On poss6de ainsi un traitement " 6 t a l o n " (gold standard) avec lequel tout traitement chirurgical pour oesophagite peptique non compliqu6e doit 6tre compar6. I1 est capital que les 6tudes ult6rieures soient conduites ~. l'aide de crit6res pr6cis d6finissant les sympt6mes, les signes endoscopiques de I'oesophagite et ses complications. Comme toujours, les d6sirs du patient sont fondamentaux. II doit pouvoir choisir le type de traitement en fonction des informations prEcises sur les effets et les risques ~t court ou ~i long terme de toutes les modalit6s th6rapeutiques. Le risque de voir appara'itre une dysphagie, une impossibilit6 d'6ructation ou un syndrome de Dumping survenant dans pros de 30% des cas apr~s chirurgie, sans garantie de gu6rison ~ long
305
terme dolt 6tre mis en balance avec la n6cessit6 de prendre des comprim6s A vie avec leurs possibles effets secondaires. Resumen
El mantenimiento de una terapia m6dica efectiva y segura en la esofagitis por reflujo no complicada es actualmente factible con omeprazol, y es probable que los bloqueadores de la ATPasa, y tal vez los regimenes a base de muy altas dosis de antagonistas de los receptores H2, tambi6n logren tasas de curaci6n aceptables. Adem~is, muchos pacientes con ulceraci6n, estrecheces y es6fago de Barrett respondent a la terapia m6dica conservadora y una proporci6n significativa de pacientes con esofagitiS erosiva puede permanecer en remisi6n con cisapride o con bajas dosis si la enfermedad es menos severa. Por consiguiente, exite a h o r a un "est~indar de o r o " , contra el cual la terapia quirt~rgica de la esofagitis no complicada debe set juzgada; es esencial que todos los futuros estudios sean ejecutados con criterios claramente definidos para la valoraci6n de sfntomas y de signos endosc6picos de esofagitis y sus complicaciones. Como siempre, los deseos del paciente son de enorme importancia, pero el paciente debe hacer la selecci6n de su terapia con base en una equilibrada y bien informada valoraci6n de los riesgos, a corto y largo plazo, de las diferentes modalidades terap6uticas. L a preocupante perspectiva de toda una vida de sometimiento a la ingesta de tabletas y de sus posibles peligros debe ser equiparada con la alternativa, que ocurre hasta en 30% de los casos, de que la cirugfa pueda producir disfagia, distensi6n gaseosa del est6mago o dumping, y sin garantla de curaci6n a largo plazo. La cirugfa seguir~i estando indicada para enfermedad intratable o complicaciones, pero tales casos ciertamente se harfin progresivamente m~is raros. Puesto que el resultado de la cirugfa est,'i, en gran parte, relacionado con la calidad y experiencia del operador, las operaciones deber~in ser realizadas en centros especializados con el fin de optimizar los resultados y minimizar el riesgo de complicaciones. En contraste, la terapia m6dica es m~s ampliamente asequible y sus resultados m~is predecibles, puesto que el resultado es virtualmente independiente de la experiencia de m6dico que prescribe. Aunque los medicamentos actualmente en uso tienen un admirable " r e c o r d " de seguridad a corto plazo, quedan todavia potenciales peligros imponderables en relaci6n con la terapia m6dica a largo plazo. Sin embargo, en ausencia de evidencia convincente de que la terapia de mantenimiento es peligrosa, parece ser inaceptable negar al paciente los beneficios potenciales de un tratamiento eficaz para su enfermedad. En forma pragm~itica, el tratamiento m6dico de mantenimiento siempre puede ser modificado, si es necesario, a la luz de avances en las t6cnicas farmac6uticas y quirt~rgicas, en tanto que los procedimientos quirtirgicos son diffciles, si no imposibles, de revertir. Acknowledgment This work was supported by Swiss National Foundation Grant: S N F 32-26369.89. Reproduction of Figure 1 was made possible by a grant from Astra Hfissle, MOlndal, Sweden.
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D. Armstrong et al.: Maintenance Therapy for Gastro-Esophageal Reflux Disease
41. 42. 43.
44.
45. 46. 47. 48. 49. 50.
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