What are the treatment options for high-grade dysplasia in Barrett's esophagus?

The management of patients who have high-grade dysplasia (severe, precancerous tissue changes) in Barrett's esophagus is controversial. This is because there is no firm evidence supporting one way to manage these patients, safely, over another. This has led experts in Barrett's esophagus to come to different conclusions about how patients who have high-grade dysplasia should be managed.

At the present time, options for the treatment of high-grade dysplasia are esophagectomy (surgical removal of the esophagus) and endoscopic therapies. A significant number of patients who have high-grade dysplasia do not develop cancer when followed for many years by endoscopic biopsy surveillance. Therefore, an option, other than treatment for these patients, is to remain in close endoscopic biopsy surveillance of high-grade dysplasia, reserving esophagectomy or endoscopic therapy for cancer if it develops.

The controversy in the management of patients who have high-grade dysplasia

High-grade dysplasia is not the same as cancer because the dysplastic Barrett's cells can not invade or grow into other tissues and they can not metastasize (spread) throughout the body. However, esophagectomy has been a standard recommended treatment for high-grade dysplasia in Barrett's esophagus for two main reasons. First, there are surgical studies reporting that a significant number of patients who were diagnosed with high-grade dysplasia and then had esophagectomy actually had cancer in their esophagus that was missed by upper endoscopy with biopsy. Second, esophageal cancer is highly curable with esophagectomy if detected early, but is much less curable if detected when it is deeper and larger. For these reasons, experts who are advocates of esophagectomy as a treatment for high-grade dysplasia argue that if the esophagus is not removed, the patient may already have a cancer that was missed by endoscopy and that cancer may become larger and incurable by the time it is finally diagnosed. Esophagectomy is the only treatment for high-grade dysplasia in which complete removal of the Barrett's lining can be confirmed with certainty by examination of the esophagus when it is out of the body. Because complete removal of the entire Barrett’s lining can be confirmed, advocates of esophagectomy argue that the risk of developing an incurable cancer is eliminated, along with the need for continued endoscopic biopsy surveillance.

The main problem with recommending esophagectomy for all patients who have high-grade dysplasia is that a significant number of these patients do NOT develop cancer. In one large study, patients who had a diagnosis of high-grade dysplasia had a 31% to 59% chance of developing cancer over a 5-year period. In a second large study, patients who had a diagnosis of high-grade dysplasia had only a 15% chance of developing cancer over an 8-year period, with 85% all patients remaining cancer free. In addition, the mortality associated with esophagectomy (risk of death) and the rate of significant complications are much greater as compared to most other gastrointestinal surgeries. These problems are magnified in centers performing low volumes of esophagectomies. Many patients are elderly and have other medical problems, which may further increase their risk of having significant surgical complications

Endoscopic therapies

Many Barrett’s experts are now recommending endoscopic therapies for patients who have high-grade dysplasia. All of these therapies involve destruction of the Barrett's lining or cutting out the portion of the Barrett's lining that has high-grade dysplasia. Following the treatment, gastroesophageal reflux is controlled, usually with medication, to encourage the normal squamous esophageal lining to grow into the esophagus, replacing the destroyed Barrett's lining. All of these procedures are performed through the endoscope. Advocates of these therapies argue that they may successfully rid the patient of the high-grade dysplasia and thus the risk of developing cancer, without removing the patient's esophagus. This allows the patient to avoid the risk of death or complications associated with esophagectomy.

One of these endoscopic therapies, porfimer sodium photodynamic therapy (PDT) is FDA approved for the treatment of high-grade dysplasia based on the results of a recently published multi-center study (follow link to endoscopic therapies for details of this study). This study reported that PDT caused high-grade dysplasia to regress or disappear in twice as many patients as compared to endoscopic biopsy surveillance without treatment and PDT treated patients had half the cancer rate compared to that of untreated patients. However, PDT did not eliminate the cancer risk

The main disadvantage of endoscopic therapy is that unlike surgery, in which complete removal of the Barrett’s lining can be confirmed by analysis of the entire surgically removed esophagus, some of the Barrett's lining can still be present even after several treatments. In some cases, the area of Barrett’s lining that remains after treatment is so small that it cannot be seen through the endoscope and it appears, endoscopically, that the esophagus is completely lined by the normal white lining. Because there is a possibility that very small areas of the Barrett’s lining remain after treatment, experts performing endoscopic therapies recommend that endoscopic biopsy surveillance be continued after treatment to periodically check the patient for recurrence of high-grade dysplasia and the development of cancer.

Endoscopic biopsy surveillance

A significant number of patients who have high-grade dysplasia, 40% to 85%, do not develop cancer during long-term follow-up. Furthermore, a significant number of these patients have regression or disappearance of their high-grade dysplasia without treatment. Barrett's experts who are advocates of endoscopic biopsy surveillance for patients who have high-grade dysplasia, argue that many patients who have high-grade dysplasia are unnecessarily subjected to treatments that can have severe complications, even cause unnecessary death and that for many patients, endoscopic biopsy surveillance, reserving esophagectomy or an endoscopic therapy as a treatment for cancer if it develops, is the best management strategy.

There are studies reporting that upper endoscopy with biopsy frequently misses cancers in patients who have been diagnosed with high-grade dysplasia because a large number of these patients had unsuspected cancer in their surgically removed esophagus. However, advocates of endoscopic biopsy surveillance argue that most of these studies failed to give details of what was seen through the endoscope, how the patients were biopsied or if a biopsy protocol was used, that only one endoscopy was performed prior to the esophagectomy. Therefore, cancer was missed in the majority of these cases because the patients were not screened carefully for co-existing cancer.

Some centers have reported that endoscopic biopsy surveillance of high-grade dysplasia is successful in detecting cancer when it is early and curable if a systematic biopsy protocol (consistent method of taking the biopsies) is used and the patient is seen back frequently to have the biopsies performed. There are two published studies reporting that using a more intensive biopsy protocol (taking more biopsies) combined with performing several closely spaced endoscopic biopsy procedures is highly successful in separating those patients who have early cancer from those patients who have only high-grade dysplasia, minimizing the risk that the patient already has an undiagnosed cancer.

Additional evidence that cancer can be detected early, when careful biopsy surveillance is performed, comes from the multi-center photodynamic therapy (PDT) trial. As part of this trial, a standard systematic biopsy protocol was performed in patients who had high-grade dysplasia, both in PDT treated and untreated patients, every three months for two years. This same protocol was performed in 30 different centers as part of this trial and reportedly the great majority of cancers were diagnosed at an early stage. Although not an endpoint of this study, it was the first study to demonstrate that a systematic biopsy protocol could be performed successfully across multiple centers in patients who had high-grade dysplasia, detecting cancer at an early stage in most patients.

Although there is evidence that the use of an intensive biopsy protocol and seeing the patient back frequently for endoscopic biopsy surveillance decreases the risk of missing a cancer, it doesn't eliminate the risk. The disadvantage of endoscopic biopsy surveillance for high-grade dysplasia remains that a cancer can be missed during surveillance and become incurable by the time it is finally detected.

Referral to specialty centers

Because high-grade dysplasia is uncommon in patients who have Barrett’s esophagus, most gastroenterologists and general surgeons do not have the opportunity to see many of these patients in their medical practice. Therefore, consideration should be given to referral of these patients to large volume specialty centers that have expert pathologists, esophageal surgeons and gastroenterologists who are experienced in the care and counseling of patients who have high-grade dysplasia. Because there are no clinical trials directly comparing esophagectomy, endoscopic therapies and surveillance in the prevention of death from esophageal cancer, management of the patient who has high-grade dysplasia should include in-depth patient counseling with regard to the risks and benefits of each option for management of their high-grade dysplasia. Ultimately, the management of the patient who has high-grade dysplasia should be individualized, based on the patient’s desire for a particular course of action as well as their medical fitness to undergo a particular procedure.