Antireflux Surgery and the Risk of Esophageal Adenocarcinoma

An Antithetical View of the Data From Sweden

Steven R. DeMeester, MD

Disclosures

Annals of Surgery. 2013;257(4):583-585. 

In this issue of Annals of Surgery, Lofdahl and colleagues[1] from the Karolinska Institute in Sweden continue to explore the relationship between gastroesophageal reflux, antireflux surgery, and esophageal adenocarcinoma. The initial report by this group, published in 1999, was a population-based, case-control study in Sweden for the 3-year period (1995–1997) that showed that the risk of adenocarcinoma of the esophagus was almost 8 times higher in people with weekly heartburn and regurgitation than in those without these symptoms.[2] Furthermore, the frequency and duration of symptoms were directly related to the risk of adenocarcinoma. The authors noted an almost 3-fold increase in cancer risk in people who used medications for reflux. In contrast, in a small group of 14 cancer patients and 6 control subjects who had undergone antireflux surgery, the risk estimates were similar to the total group of patients with symptoms of reflux. Barrett's was found on endoscopic biopsy specimens or within the resection specimen in 62% of the patients with esophageal adenocarcinoma. From this study, the authors concluded that "Barrett's appears to be a common, but not necessary, step in the evolution of esophageal adenocarcinoma." Furthermore, they stated that they found "no indication that treatment of reflux reduced the risk of esophageal cancer. In fact, patients who received medical treatment had a higher risk than those who did not."[2 p 830]

The next study, published in 2001, specifically explored the relationship between antireflux surgery and esophageal adenocarcinoma.[3] Using the Swedish Inpatient Register, the authors identified 85,526 patients who were discharged with at least 1 in-hospital diagnosis of heartburn, hiatal hernia, or reflux esophagitis from 1965 to 1997. From these, 13,198 patients had at least 1 record indicating antireflux surgery. The standardized incidence ratio (SIR), estimated as the ratio of the observed to the expected number of cancers, was used to estimate relative risk for esophageal adenocarcinoma. The expected number of cancers was derived from the cancer incidence rates in the entire Swedish population multiplied by the person-years of follow-up. Compared with the general population, the SIR was 6.3 in males with reflux symptoms who did not have antireflux surgery. The risk increased with time, and the SIR was nearly 11 with 10 or more years of follow-up. Among men who had antireflux surgery, the SIR was also significantly increased (14.1) compared with the general population, but the risk did not increase with time. The SIR for patients with 10 or more years of follow-up after antireflux surgery was 7.7. The authors concluded that there was no evidence of a protective effect of antireflux surgery against esophageal adenocarcinoma because the risk remained elevated compared with the general population even 10 or more years after surgery. However, they conceded that they "may have overlooked a small long-term protective effect of the surgery since the excess risk of cancer remained stable after the surgery but increased substantially with time among reflux patients who did not have surgery."[3 p 1291]

Later, in 2007, Lagergren and Viklund[4] explored the issue of fundoplication status in relationship to the risk of cancer. For this study, the authors used the same 3-year population-based, case-control database from their 1999 publication.[2] During the study years (1995–1997), patients with newly diagnosed esophageal adenocarcinoma and control subjects from the population register were interviewed and asked detailed questions about reflux symptoms, exposure history, medication use, and current and past medical history. For this new study, patients who underwent antireflux surgery less than 5 years before the interview were excluded to minimize bias due to a prevalent cancer. Esophageal adenocarcinoma developed in 7 of 189 case patients and 8 of 820 controls who underwent antireflux surgery 5 or more years before the interview. Symptomatic reflux was present in 4 of the 7 case patients, and all 7 had Barrett's adjacent to the tumor. The prevalence of Barrett's was unknown for the control subjects. The authors concluded that patients who develop esophageal adenocarcinoma after antireflux surgery were statistically significantly more likely to have persistent or recurrent reflux, supporting the hypothesis that esophageal adenocarcinomas occurring late after antireflux surgery might partly be due to postoperative gastroesophageal reflux.

In 2010, this group further explored the relationship between antireflux surgery and the risk of esophageal adenocarcinoma, this time using the entire Swedish population as a database.[5] The study included all patients who had antireflux surgery for gastroesophageal reflux disease from 1965 to 2006 as recorded in the Swedish Inpatient Register. Cancers were identified by linking the national registration number of each patient who had antireflux surgery to the Swedish Cancer Registry. The study cohort consisted of 14,102 patients who had undergone antireflux surgery. The incidence of cancer in this cohort was compared with that in the corresponding Swedish background population matched by age, sex, and calendar-year. This study showed that the risk of esophageal adenocarcinoma was increased 12-fold after antireflux surgery compared with the background population and the risk did not decrease with time. The authors concluded that antireflux surgery does not prevent the development of esophageal adenocarcinoma and should not be considered a cancer-preventive therapy.[5]

The focus of the current article in this issue of the Annals of Surgery is on the risk factors for esophageal adenocarcinoma after antireflux surgery.[1] In particular the aim of this study was to determine whether recurrent reflux or factors such as obesity or tobacco smoking are responsible for adenocarcinoma developing after antireflux surgery. The authors used the same antireflux cohort from their 2010 publication and compared patients who developed esophageal adenocarcinoma after antireflux surgery with controls who had antireflux surgery but did not developed cancer.[5] For each case patient, 5 controls were selected, matched by age, sex, and calendar-year of surgery. Comparing the 55 case patients with the 240 controls, the authors found that the case patients were 3 times more likely than controls to have recurrent reflux symptoms. There was also a lower risk for esophageal adenocarcinoma after a total fundoplication than after a partial fundoplication, but it did not reach statistical significance. There was no significant difference between cases and controls for body mass index or tobacco smoking. The incidence of Barrett's was not known in the groups. The authors concluded that recurrent reflux was significantly more common among patients who developed esophageal adenocarcinoma after antireflux surgery and that these results were in keeping with studies showing a strong dose-response pattern for the association between the severity and duration of reflux symptoms and esophageal cancer risk.[2] They offered that their findings might at least in part explain the lack of a cancer-preventive effect of antireflux surgery.[1]

So, what have we learned from the series of studies by Lagergren and colleagues? Importantly, the authors have shown that adenocarcinoma of the esophagus develops in the setting of gastroesophageal reflux and that the duration and severity of reflux disease are directly related to the risk of cancer.[2] Barrett's was present in most endoscopic biopsy or resection specimens from patients with cancer but not in every case. Their data also indicated that the risk of adenocarcinoma of the esophagus was increased in patients on medical therapy for reflux disease and that the risk continued to increase over time in these patients. In contrast, the risk of esophageal adenocarcinoma was stable over time after antireflux surgery.[2] Finally, they showed that patients who develop esophageal adenocarcinoma after a fundoplication were significantly more likely to have recurrent or persistent gastroesophageal reflux.[1,4] From these findings, the authors reached their conclusions that Barrett's was not necessary for cancer to develop and that there was no evidence of a protective effect for antireflux surgery against esophageal adenocarcinoma. Are these conclusions justified?

Barrett's is the single most significant risk factor for esophageal adenocarcinoma. Unfortunately, the prevalence of Barrett's was unknown in the studies by Lagergren and colleagues because it was not tracked in the Swedish databases used for their studies. This is a critical flaw because it is virtually a certainty that the prevalence of Barrett's was different in the antireflux surgery group, the medically treated group, and the general population in Sweden. The basis for this statement is as follows: Barrett's is known to develop in patients with long-standing, severe reflux disease, particularly men. The Swedish Inpatient Register used by the authors for their 2001 publication included patients from 1965 to 1997. For many of the early years of the study, proton-pump inhibitor medications were not yet available and patients with the most severe reflux were typically referred for antireflux surgery for symptom control. Later, in the era of proton-pump inhibitor medications, symptoms are usually controlled in most patients with once-or-twice-daily dosing of these medications, and again, it is often those patients with the most severe reflux disease whose symptoms are not well controlled who are referred for antireflux surgery. Consequently, there can be little doubt that the antireflux cohort used for these studies by Lagergren and colleagues was stacked with patients who had severe reflux disease. Furthermore, most patients who had antireflux surgery and were in the Swedish Inpatient Register were men.[3] It is these patients, men with severe, long-standing reflux, who are most likely to have Barrett's.[6] There is also evidence that in Sweden, patients with Barrett's were preferentially referred for antireflux surgery. Hakansson et al, from Lund University, one of the major centers that contributes patients to the database used by Lagergren and colleagues, stated in a publication that "the policy in our departments has been to do an antireflux procedure for young and middle-aged patients with Barrett's to prevent further reflux on to the Barrett's."[7]

The inability to match cases and controls for the prevalence of Barrett's in studies on esophageal adenocarcinoma is like trying to study ovarian cancer without knowing the prevalence of women in the case and control groups. It is an insurmountable problem for interpretation of the findings in the series of studies by Lagergren and colleagues. However, if one assumes that the prevalence of Barrett's was higher in the group that had antireflux surgery, it is easy to understand why in 2001 the authors noted that the antireflux group had "an excess risk" of cancer compared with the patients with reflux who were treated medically.[3] The only other potential explanation is that antireflux surgery increases cancer risk, but if that was the case, then the risk should have increased further with time after the fundoplication. Instead, the risk was stable with time after antireflux surgery. In contrast, the cancer risk increased over time in the nonfundoplication patients with reflux, likely related to disease progression, development of Barrett's, and ultimately esophageal adenocarcinoma in some of these patients. The stable risk after antireflux surgery is actually evidence that antireflux surgery affects the natural history of gastroesophageal reflux disease. Otherwise, one would have expected to see a similar or even greater increase in the cancer risk in the fundoplication group, given the more severe reflux disease almost certainly present before surgery in these patients. Instead, the SIR in patients at 10 or more years after antireflux surgery (7.7) was lower than that in medically treated patients (11) at 10 or more years of follow-up. This concurs with the findings from their 1999 article that showed that cancer risk was increased in patients on medical therapy for reflux but was similar to the general population with reflux after antireflux surgery.[2]

The second major conclusion from the studies by these authors was that there was no evidence of a protective effect of antireflux surgery for esophageal adenocarcinoma. The logic for this conclusion is flawed. It makes sense that if severe, long-standing reflux is associated with esophageal adenocarcinoma, then elimination of reflux should affect the development of this cancer, similar to avoiding the sun should impact the risk of skin cancer. The finding in 2 studies by Lagergren and colleagues that recurrent or persistent reflux was associated with an increased risk for esophageal adenocarcinoma is clear evidence that a fundoplication alters the natural history of the disease, otherwise the functioning or nonfunctioning of the fundoplication would be irrelevant in terms of cancer risk.[1,4] A major basis for the authors' conclusion that a fundoplication has no protective cancer effect was from their 2001 and 2010 studies, in which they showed that compared with the corresponding Swedish population, the cancer risk remained elevated in patients after antireflux surgery.[3,5] The problem with these studies and the authors' conclusions is that the comparison group should not be the general population of Sweden. That is like looking at the risk of a myocardial infarction in patients with heart disease on statins and comparing it with the risk in the general population. Undoubtedly, the risk of myocardial infarction would be elevated in the statin group because this is the group with heart disease. To conclude that statins are not effective because there are more cases of myocardial infarction in the group taking them than in the general population is inappropriate. Similarly, Lagergren and colleagues' conclusions about antireflux surgery and cancer risk are inappropriate. There is no therapy that prevents disease 100% of the time and that is not the standard that is applied to medical or surgical interventions. Instead, the standard for acceptance of efficacy of a medical or surgical therapy is that it reduces the risk compared with an alternative (or no) therapy. Antireflux surgery will not prevent all esophageal adenocarcinomas from developing, but that is not the standard it needs to achieve. The appropriate question is "Does antireflux surgery reduce the risk of esophageal adenocarcinoma compared with alternative therapies?" The findings from this series of articles by Lagergren and colleagues, in combination with other studies showing regression of short segments of Barrett's, loss of dysplasia, and normalization or stabilization of biomarkers associated with Barrett's and adenocarcinoma after antireflux surgery, all point in the same direction—that antireflux surgery impacts the natural history of reflux disease.[1–5,8–13] Consequently, I believe that the aforementioned question is in fact answered, and the answer is, yes it does.

Certainly, there is more work to be done in this area and important questions remain unanswered. One such question is whether the cancer risk in a patient without Barrett's who has a functioning fundoplication is reduced down to the level of the population without reflux disease. The use of large population databases provides an opportunity to study disease processes that occur infrequently enough to make randomized studies nearly impossible, but they have limitations and the findings must be evaluated in light of these shortcomings. One message is clear to those of us who are surgeons performing antireflux surgery, it is of no benefit if the fundoplication breaks down and reflux recurs. The onus is upon us to select appropriate patients, do it well, and make it last.

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