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Are there any non-surgical treatments for high-grade dysplasia and cancer in Barrett's esophagus?

There are three main types of non-surgical  or endoscopic therapies used in the treatment of  Barrett's high-grade dysplasia and early cancer. These are photodynamic therapy, thermal ablation and endoscopic mucosal resection. Other non-surgical therapies are also being developed.

Porfimer sodium photodynamic therapy (PDT)

Porfimer sodium  photodynamic therapy (PDT) has been approved by the US Food and Drug Administration (FDA) for treatment of high-grade dysplasia in Barrett's esophagus. Porfimer sodium PDT is performed by first injecting a drug called porfimer sodium, (Photofrin®) intravenously (into a vein). This drug makes all the tissues in the body, including the Barrett's esophagus tissue, light sensitive. About 48 hours after the porfimer sodium is given, the patient returns for upper endoscopy. During the endoscopy, a red, non-heat producing laser light is passed through the endoscope and directed onto the Barrett's esophagus. The laser light activates the porfimer sodium in the Barrett's tissue which causes the Barrett's tissue to be destroyed by a photochemical reaction. Patients are also given strong anti-acid medications called proton-pump inhibitors to control their gastroesophageal reflux disease (GERD) so that the normal white squamous esophageal lining is encouraged to grow back inside the esophagus, replacing the destroyed red Barrett's lining. 

There have been single center studies reporting the effectiveness of porfimer sodium PDT in the treatment of high-grade dysplasia as well as early cancer in Barrett's esophagus. One single center study by Overholt, et al, reported the results of treatment of 103 patients who had dysplasia or early stage cancer with porfimer sodium PDT combined with Nd:Yag laser therapy to get rid of small areas of Barrett's esophagus that remained after treatment with PDT. These patients were followed an average of 4.2 years. In this study,  77.5% of patients who had high-grade dysplasia were successfully treated (did not have high-grade dysplasia detected in biopsies after treatment) and 44.4% of patients who had early stage cancer were successfully treated (did not have cancer detected in biopsies after treatment).

Porfimer sodium PDT was approved by the FDA for the treatment of high-grade dysplasia in Barrett's esophagus in 2003, based on the results of a recently published multi-center clinical trial in patients who had high-grade dypslasia . In this trial, one group of patients with high-grade dysplasia was treated with PDT and compared to a control group who did not have PDT . Both groups were given a proton pump inhibitor (omeprazole) and followed with endoscopic biopsy surveillance for 24 months.

In this trial, patients with Barrett's high-grade dysplasia, from 30 international centers, were randomly assigned in a 2:1 fashion to the PDT treatment group (138 patients) or to the omeprazole only group (70 patients). The primary goal of this trial was to determine whether PDT could cause more regression or disappearance of high-grade dysplasia compared to patients who had not received PDT. This study differed from previous single center studies in its use of a balloon system  to help smooth out the folds of the esophagus as well as its use of a significantly lower light dose.

The results were that significantly more patients who were treated with PDT (77%) had complete disappearance of their high-grade dysplasia as compared to those patients who were in endoscopic biopsy surveillance on omeprazole alone (39%).  Although not a primary goal of the study, cancer developed in 13% who had PDT as compared to 28% of those who were on omeprazole alone. This means that there was a 50% reduction in the development of cancer in those who received PDT. The majority of patients treated with PDT required more than one treatment.

This study is a very important one because it is the first prospective randomized multi-center clinical trial testing the effectiveness of endoscopic ablation therapy in the treatment of high-grade dysplasia. During the study follow-up period, investigators demonstrated complete regression of high-grade dysplasia in almost twice as many PDT treated patients as compared to those not treated with PDT and the reduction of cancer development in PDT treated patients to half that of patients who were not treated with PDT.

This multi-center clinical trial is also important because it underscores three other important points. First, of the 435 patients who referred to the study because of a diagnosis of high-grade dysplasia, less than half (208) actually had high-grade dysplasia based on the opinion of an EXPERT gastrointestinal pathologist. Second, untreated patients on proton pump inhibitors alone can have regression of their high-grade dysplasia (39%) or remain stable without progressing to cancer (72%), at least during a relatively short, 24 month, follow-up period. Third, patients who have had PDT need to continue endoscopic biopsy surveillance after treatment, even those patients who have achieved complete regression or disappearance of their high grade dysplasia. In the PDT multi-center trial, 48% of patients who received PDT still had Barrett's esophagus after treatment, 23% still had high-grade dysplasia after treatment, around 35% of patients who had complete disappearance of their high-grade dysplasia after PDT re-developed high-grade dysplasia by one year after treatment, and 50% re-developed high-grade dysplasia by 2.7 years after PDT treatment. Finally, 13% of patients treated with porfimer sodium PDT developed cancer during the study follow-up period. Although PDT significantly reduced the rate of re-development of high-grade dysplasia and the development of cancer as compared to omeprazole alone, in this trial, the risk of cancer was not  eliminated by profimer sodium PDT.

The side effects of porfimer sodium PDT reported in the multi-center PDT trial are very similar to those reported by single centers performing PDT. The side effects include 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. Strictures may occur more often at higher laser light doses and with multiple treatments. These strictures can be persistent and require many dilations. Rarely esophageal perforation (poking a hole in the esophagus) has occurred. Other reported problems after photodynamic therapy include fluid surrounding the lungs, irregular heart rhythms, and severe skin burns from light exposure. Porfimer sodium makes skin cells sensitive to light and 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). 

In Europe, there have been clinical trials of PDT using a different photosensitizing agent called 5-ALA. One recent study from Germany reported the results of a 3-year follow-up of patients who had high-grade dysplasia and early cancer and who were treated with 5 ALA. Thirty-five patients had high-grade dysplasia and 31 patients had early cancer. Almost all patients had a good initial response to treatment. During follow-up, 11% of patients whose high-grade dysplasia had been treated with 5-ALA PDT, redeveloped high-grade dysplasia or cancer ( 2 patients or 6% of those treated developed cancer). Of the 31 patients who underwent this treatment for cancer, and who had a good response to treatment,  32% re-developed cancer during follow-up. This drug is given orally and causes less problems with light sensitivity of the skin and fewer esophageal strictures. However, this drug can cause heart and commonly blood pressure problems during the procedure that can be significant.

Most photodynamic therapy studies have also reported that a few 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. Rarely,  patients have developed cancer under what appeared to be normal squamous lining after photodynamic therapy. However, in the porfimer sodium PDT multi-center trial , most cancers that developed in the PDT treatment group as well as the omeprazole only group, were detected at an early stage, suggesting, that an intensive and careful endoscopic biopsy surveillance program can detect cancers when they are early, whether or not the patient has received prior PDT. 

At the present time, we do not know who will have the best results with porfimer sodium PDT. We do know that in some PDT treated patients, Barrett's esophagus has grown back, high-grade dysplasia has developed and cancer has developed. Some studies have reported that genetic abnormalities in the Barrett's lining did not go away with the endoscopic ablation therapy and may be a risk factor for the re-development of high-grade dysplasia or the development of cancer after what appears to be a successful treatment.

Based on the positive results of the multi-center trial, porfimer sodium PDT offers patients who have high-grade dysplasia another viable alternative to esophagectomy or endoscopic biopsy surveillance alone. Although the long-term effectiveness of porfimer sodium PDT is not known at this point, for many patients, especially the elderly with multiple medical problems, even a significant delay in the development of cancer may allow these patients to keep their esophagus, avoiding esophagectomy for the remainder of their life-time. Patients who have an EARLY cancer, including those who are not good surgical candidates due to their health, may now choose PDT or another endoscopic therapy such as endoscopic mucosal resection as the most appropriate alternative to esophagectomy.

All patients who have high-grade dysplasia or cancer should receive in-depth counseling concerning the risks and benefits associated with all of their options for management of their condition.  At the present time, photodynamic therapy as well as endoscopic biopsy surveillance of patients who have high-grade dysplasia, is best performed at a large specialty center with expertise in performing PDT and in the endoscopic biopsy surveillance of these patients. PDT is not appropriate as an intended cure for patients who have large cancers because it cannot treat deep cancers or lymph nodes. However, it is FDA approved  to help patients who have large cancers get relief from their swallowing difficulties (palliative therapy).

Endoscopic Mucosal Resection (EMR)

Endoscopic mucosal resection (EMR) is an endoscopic procedure that is now used most often to remove an area of high grade dysplasia or a small, early cancer. The FDA has approved two devices for EMR; the Olympus EMR cap and the Wilson-Cook Duette.

Endoscopic Mucosal Resection (EMR) 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 esophagectomy (surgical removal of the esophagus), usually does not remove all of the Barrett's lining but can be successful in removing a small cancer; or a localized area of high-grade dysplasia. A major advantage to endoscopic mucosal resection is the ability to remove a large piece of tissue and examined it for evidence of cancer or depth of cancer invasion which has previously not been available. Because it does not remove all of the Barrett's lining, the Barrett's lining left behind can develop other areas of high-grade dysplasia or cancer. EMR has been combined with photodynamic therapy in an attempt to get rid of remaining Barrett's tissue at risk for developing high-grade dysplasia or other cancers. More recently there are published reports of patients with high grade dysplasia or early stage cancer undergoing multiple endoscopic mucosal resections in an attempt to remove the entire Barrett's lining. A reasonable success rate in removing all of the Barrett's lining has been  reported but the length of time these patients have been followed after treatment is very short and the numbers of patients who have had this procedure are small. At the present time, it is unknown whether some patients will re-develop their Barrett's lining, high-grade dysplasia or cancer. More studies with longer patient follow-up are needed.

If EMR is used to treat an early cancer, before the EMR procedure is performed another procedure, called endoscopic ultrasound, is often 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. Bleeding can be controlled at the time of the procedure and rarely requires transfusion. Other studies have reported no significant side-effects.

EMR is unproven to have a long-term cure rate for early stage cancers 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 want to avoid esophagectomy may undergo this therapy as potentially curative. Again, if this therapy is chosen instead of esophagectomy, the patient needs to remember that close endoscopic biopsy surveillance must be continued in order to have the opportunity to diagnose a cancer at an early stage if it develops because cancers can develop in the Barrett's lining that remains after endoscopic mucosal resection. As with any endoscopic therapy, it should be performed at a specialty center with expertise in performing this procedure and, ideally, as part of a study. Cancers that are deeper than intramucosal (submucosal or deeper) are not as likely to be cured with this treatment.

Thermal ablation

Like photodynamic therapy, thermal ablation is performed with the goal of destroying the Barrett's lining. 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 gastroesophageal 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, but longer follow-up of these patients are needed.

For thermal ablation, there are no long-term follow-up studies of large numbers of patients to know whether treated patients are safe from developing cancer. Very few clinical trials have been performed. Like photodynamic therapy, Barrett's lining can be buried under what appears through the endoscope to be normal squamous lining and this appears likely to occur in certain forms of thermal therapy. Most thermal ablation therapies are reported to 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. Thermal ablation is experimental, and if undertaken, the patient must be followed in periodic endoscopic biopsy surveillance indefinitely at a specialty center experienced in the surveillance of patients who have undergone thermal ablation.

Other endoscopic therapies

At the present time, photodynamic therapy, thermal ablation therapy and endoscopic mucosal resection or a combination of these, remain the most widely available non-surgical, endoscopic  therapies in the treatment of Barrett's high-grade dysplasia and early cancer.  Recently, radiofrequency ablation therapies which are  those that use sound waves (ultrasonic therapy), such as the BarRX device has been developed. The BarRX uses a balloon device to apply radiofrequency energy to the Barrett's lining. The treatment can be used on up to three centimeteris of lining at a time. The radiofrequency device is designed to treat only the very superficial or top layers of the esophagus. Although this is a promising technology, studies have not yet been published demonstrating its efficacy. 

Freezing (cryotherapies) to destroy the Barrett's lining are also being tested for their effectiveness in getting rid of the Barrett's lining and dysplasia. Freezing therapies use devices that are like those used by dermatologists to treat skin growths, but instead, these esophageal cryotherapy devices help deliver liquid nitrogen onto the esophagus. 

It is also hoped that there will be drug therapies to prevent cancer from developing in Barrett's esophagus. One class of drugs that has received recent attention for its possible cancer prevention qualities are Cox  inhibitors (a class of arthritis drugs called NSAIDS). Recently, there have been concerns about the use of Cox 2 inhibitors and their effects on the cardiovascular system. One such drug, Vioxx was pulled from the drug market by its manufacturer after a study showed that it raised the risk of heart attacks and stroke. Based on the analysis of some population studies of aspirin and cancer prevention, there is evidence that aspirin, a Cox 1 and Cox 2 inhibitor may also be effective in reducing the rate of esophageal adenocarcinoma, but to date, there have been no published clinical trial results of  aspirin or other Cox inhibitors as esophageal cancer prevention agents.

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this site last reviewed and updated 9/11/2006