What are some investigational therapies for Barrett's esophagus?

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What are some investigational therapies for Barrett's esophagus?

Definition of "Dysplasia"

At the present time, ablation therapies (therapies that destroy the Barrett's lining) remain the most widely available investigational (experimental) therapies in the treatment of Barrett's high-grade dysplasia and early cancer, although other investigational therapies are being developed. There are three main types of ablation therapy used today in the treatment of Barrett's esophagus. These therapies are photodynamic therapy, thermal ablation and endoscopic mucosal resection.

Photodynamic Therapy (PDT)

Photodynamic therapy involves administering a light-sensitizing drug, called a photosensitizer, through the patient's vein or by mouth. The most widely used light-sensitizing drug makes all cells in the body hyper-sensitive to light exposure, including the Barrett's esophagus cells. The Barrett's cells are then destroyed using a modified laser in the esophagus which activates the photosensitizing agent. This activation results in destruction of the Barrett's lining so that the Barrett's cells die and fall off of the esophageal wall. Patients are given strong anti-acid medications called proton-pump inhibitors to control their gastroesophageal reflux disease (GERD) so that the normal squamous esophageal lining will grow back inside the esophagus, replacing the destroyed Barrett's lining.

After photodynamic therapy, patients usually have chest pain within 24 hours that can be severe and require narcotics (strong pain killers). Nausea is also very common. A stricture (narrowing of the esophagus due to scar tissue formation) can occur and requires dilation (stretching the esophagus) in around one-quarter to one-third of patients. These strictures can be severe and require many dilations. Other reported problems after photodynamic therapy include fluid surrounding the lungs, irregular heart rhythms, abnormal liver blood tests and severe skin burns from light exposure. With the most commonly used photosensitizer, skin sensitivity to light and the risk of burn may last 4-6 weeks or longer after treatment.  Sunscreen provides no protection so the patient must completely cover-up (including using a ski mask and gloves).

Most patients who are treated with photodynamic therapy have high-grade dysplasia or early cancer. Some early studies report that most of the patients treated had no high-grade dysplasia on follow-up endoscopy with biopsy. The treatment of very early cancers has also been reported to be successful in many patients, short-term. However, complete disappearance of the Barrett's lining occurs only in an estimated one-third of patients treated.

Most photodynamic therapy studies have also reported that some patients have a situation in which the Barrett's lining doesn't completely go away but is still there underneath the new normal appearing squamous lining. In other words, when their esophagus is examined with the endoscope, it looks like the Barrett's is completely gone but some biopsies (small pieces of tissue taken during endoscopy to look for Barrett's lining under the microscope) show that small areas of Barrett's lining are still there underneath the new squamous lining. Some patients have developed cancer under what appeared to be normal squamous lining after photodynamic therapy. Barrett's lining under what looks to be normal squamous lining is a potentially dangerous situation because if cancer develops in that Barrett's lining, it may be hidden from sight by the endoscope until it becomes large and deep and much less curable with surgery.

There are still unanswered questions in the use of photodynamic therapy in the treatment of Barrett's esophagus and there are no large controlled studies in which patients have been followed for many years, so the long-term results are still unknown. How many patients whose high-grade dysplasia appears to be gone after treatment will again develop high-grade dysplasia and some develop cancer? Is the normal appearing squamous lining actually normal or is it genetically the same as the Barrett's lining and can also develop into a cancer? How long should a patient who has undergone apparently successful photodynamic therapy remain in endoscopic biopsy surveillance before a "cure" is declared? If cancer does develop under what appears endoscopically to be normal squamous lining, can endoscopic biopsy surveillance consistently detect these cancers in time, before they become large and much less curable with surgery?

At the present time, no one knows the answer to these important questions. We do know that in some treated patients, Barrett's esophagus has grown back, high-grade dysplasia has grown back, cancer has developed and cancer has developed under what looked like normal squamous lining. One study reported genetic abnormalities in the Barrett's lining did not go away with the endoscopic ablation therapy and may be a risk factor for the development of high-grade dysplasia after what appears to be a successful treatment. However, no one knows long-term what the failure rate will be. If it is low-enough, then photodynamic therapy will offer patients with high-grade dysplasia another alternative to esophagectomy or endoscopic biopsy surveillance, or if they have an early cancer, an alternative to esophagectomy. A large multicenter trial has been completed in patients who have high-grade dysplasia and is awaiting a peer-reviewed published report. At the present time, photodynamic therapy is still considered an experimental therapy and best performed at a large center preferably as part of a study. Patients who have an EARLY cancer or high-grade dysplasia and who are not good surgical candidates due to their health may choose this therapy or another ablation therapy such as endoscopic mucosal resection as the most appropriate alternative to esophagectomy. This therapy is not appropriate for patients who have large cancers because it cannot treat deep cancers or lymph nodes.  

Patients must not forget that, at the present time, although it is hoped that other alternatives to esophagectomy will be available to patients who have HGD or cancer in Barrett's esophagus, esophagectomy is still the only proven cure. Patients who have undergone photodynamic therapy should remain in endoscopic biopsy surveillance indefinitely until the long-term results of this therapy are known. Most gastrointestinal (GI) doctors agree with this recommendation. In a recent poll of GI doctors, only 9% thought that ablation therapy decreased the need for endoscopic biopsy surveillance.

Thermal ablation

Like photodynamic therapy, thermal ablation is performed with the goal of destroying  high-grade dysplasia, early cancer, or the Barrett's epithelium. This therapy uses heat (electrical probes, lasers, or an electrically conducting gas) to directly burn the Barrett's lining off. The re-growth of normal squamous lining is then encouraged by the use of proton-pump inhibitors to control reflux. Some of these therapies, based on the names of the more commonly used devices, are: multipolar electrocoagulation (MPEC); argon plasma coagulation (APC); and laser ablation (KTP:YAG laser, Nd:YAG laser, argon laser). There are advantages and disadvantages with each of these therapies.

MPEC studies are small, but report a high rate of complete disappearance of the Barrett's lining and no significant complications. The therapy is low-cost. However, multiple treatments are frequently required..

Many studies have reported the use of argon plasma coagulation (APC) in the treatment of Barrett's patients, including those who have high-grade dysplasia. There have been different success rates reported in different studies with Barrett's lining still detected in up to one-third of patients treated. In more recent studies, however, ablation of Barrett's esophagus with APC appears to be more successful using a higher energy setting and higher doses of proton pump inhibitors. As with other therapies, there have been complications including perforations (making a hole in the esophagus), bleeding, strictures, and a reported death.

Laser ablation therapies (KTP:YAG laser, Nd:YAG laser, argon laser) have various success rates in destroying the Barrett's lining. Laser ablation in combination with MPEC has been reported to be very successful in treating a small number of patients who had an early cancer (intramucosal carcinoma) in Barrett's esophagus.

For thermal ablation, like photodynamic therapy,  there are no long-term follow-up studies of large numbers of patients to know whether treated patients are safe from developing cancer. Like photodynamic therapy, Barrett's lining can be buried under what appears through the endoscope to be normal squamous lining. There are no clinical trials in which patients who have high-grade dysplasia are treated with thermal ablation therapy and then compared to patients who are untreated and remain in surveillance or who undergo esophagectomy. Most thermal ablation therapies have fewer side-effects as compared to photodynamic therapy, however, at least one patient death, as a direct result of APC therapy, has been reported. Thermal ablation therapies generally require more treatment sessions as compared to photodynamic therapy. Like photodynamic therapy, thermal ablation is experimental, and if undertaken, the patient must be followed in periodic endoscopic biopsy surveillance indefinitely.

Endoscopic Mucosal Resection (EMR)

Endoscopic Mucosal Resection (EMR) is an experimental therapy that is used most often to treat early cancer but can also be used in the treatment of high-grade dysplasia if the high-grade dysplasia involves only a small area of the esophagus. EMR can also be combined with photodynamic therapy in an attempt to get rid of a large area of high-grade dysplasia or to treat very early cancers and also try and rid the patient of the remaining high-grade dysplasia. It is performed through the endoscope and involves lifting up the Barrett's lining to be removed by injecting a solution under it or applying suction to it and then cutting it off, much like colon polyp removal. The lining containing the early cancer or high-grade dysplasia is taken out through the endoscope and sent for histologic analysis (analysis under the microscope) to check if the margins are free of cancer or high-grade dysplasia. This procedure, unlike surgery, cannot remove all of the Barrett's lining but can be used to remove a small cancer; or remove a localized area of high-grade dysplasia, especially in those patients who are not good surgical candidates.

If EMR is used to treat an early cancer, before the EMR procedure is performed another procedure, called endoscopic ultrasound, is performed to make certain that the cancer involves only the very top layer of cells and is therefore an intramucosal cancer. An average 3-year survival rate of more than 80% has been reported for intramucosal cancers treated by EMR. The rate of severe complications, (bleeding or perforation) as high as 6.8% have been reported. Other studies have reported no significant side-effects.

Like the other ablation therapies, EMR is unproven, but the short-term follow-up of patients who have early cancer looks promising. Patients who have early cancers and who are not good surgical candidates or who are very elderly may want to consider this therapy as potentially curative. Again, if this therapy is chosen instead of esophagectomy, the patient needs to remember that it is experimental and close endoscopic biopsy surveillance must be continued in order to have the opportunity to diagnose a cancer at an early stage if it develops. Cancers that are deeper than intramucosal (submucosal or deeper) are not as likely to cured with this treatment. 

Other investigational therapies

At the present time, ablation therapies remain the most widely available experimental therapies in the treatment of Barrett's high-grade dysplasia and early cancer. In the future, ablation therapies might include those that use sound waves (ultrasonic therapy) or freezing (cryotherapies) to destroy the Barrett's lining.. Other possible therapies that might prevent cancer in Barrett's esophagus, or treat cancers once they develop, include Cox-2 inhibitor therapies (new arthritis drugs) and gene therapies.

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