Evaluating Treatments of Barrett s Esophagus That Shows High-Grade Dysplasia

Transcription

1 ...PRESENTATIONS... Evaluating Treatments of Barrett s Esophagus That Shows High-Grade Dysplasia Based on a presentation by Bergein F. Overholt, MD Presentation Summary Thermal ablation and surgery are currently indicated for the treatment of Barrett s esophagus that shows high-grade dysplasia. Recent clinical thought is that photodynamic therapy (PDT), a nonsurgical ablative therapy, along with proton pump inhibitor therapy, may be able to eliminate Barrett s esophagus with less morbidity and mortality, and perhaps at a lower cost, than other current treatments. PDT is currently under investigation for this indication. The principles of ablative therapy, complications of PDT, treatment results, the best candidates for PDT, and the workup strategy are discussed. Surgical procedures or thermal ablation are still necessary treatments for particular patients. However, recent clinical extrapolations suggest that photodynamic therapy (PDT) offers a potential nonsurgical ablative therapy to eliminate Barrett s esophagus (BE) in some patients. It should be noted that PDT for Barrett s high-grade dysplasia is a research technique and is currently considered an off-label use. Although this indication is currently under investigation, Medicare and many insurance companies cover it. PDT is not yet approved by the Food and Drug Administration for treating Barrett s high-grade dysplasia, but a multicentered trial examining PDT and proton pump inhibitor therapy for high-grade dysplasia is under way. The multicenter clinical trial data that may support a formal recommendation of its use in highgrade dysplasia are not yet available. However, phase I and II trials strongly suggest that PDT may become the treatment of choice for BE that shows high-grade dysplasia. Results of a current study in patients with low-grade dysplasia suggest that PDT may also be used to treat low-grade dysplasia if a clinician chooses to treat this patient population. PDT Treatment PDT requires several components: a photosensitizing drug, a centering balloon, a diffuser, a dye laser, gastric ph determinations, and proton pump inhibitor therapy to affect ph control. Patients are treated in the outpatient setting; hospitalization is seldom required. VOL. 6, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S903

2 ... PRESENTATIONS... Centering balloons are 20 to 25 mm in diameter, with caps on both ends, and there are 3-, 5-, or 7-cm windows. The diffuser must be long enough for such balloons or long and flexible if the clinician is treating without the balloon. Examples of both Figure 1. The Balloon Diffuser System With PDT: Centering Balloons The centering balloons: 3, 5, and 7 cm (top to bottom). The centering balloon, which is 25 mm in diameter, is passed over a guidewire. The guidewire is removed when the balloon is in position, and the diffuser is positioned in the centering channel of the balloon. Figure 2. The Balloon Diffuser System With PDT: The Diffuser The diffuser, which is long and flexible, is placed in the center of this window so that the light distribution can be directed circumferentially up to a 7-cm segment of Barrett s mucosa. Currently, diffusers are 5, 7.5, and 9 cm in length. Their length and flexibility allow them to travel down the scope and around a curve. are shown in Figures 1 and 2. The treatment time with the balloon diffuser system is only 7.5 minutes; treatment time was much longer when shorter diffusers were used. The theory behind PDT and ph control is that after the Barrett s mucosa is destroyed, the remaining tissue should heal in a low-acid or acid-free environment. That will allow stem-cell regeneration with normal squamous epithelium growth. 1 Gastric ph measurements are acceptable because patients are extremely averse to ambulatory ph measurements. In some clinical settings, patients are given a proton pump inhibitor (omeprazole 20 mg bid) at least 3 days prior to PDT therapy. Their gastric ph is measured on the day of therapy. If the ph is less than 4, the dose is often doubled. If the ph is above 4, patients are maintained long term on 20 mg twice a day. Treating BE When treating BE that shows highgrade dysplasia, it is important to remember that nonnodular Barrett s mucosa is 1.5 mm thick according to high-frequency endoscopic ultrasound (EUS) findings and normal mucosa is approximately 0.7 mm. Thus, the therapy must penetrate deeply enough to eradicate completely 1.5-mm thick mucosa, and it should produce equal circumferential injury. Therapy must be aggressive to reach deep into the mucosa. Clinicians may not be achieving uniform depth of ablation, which results in incomplete eradication of Barrett s. 2-6 One problem with thermal ablation is that when the heat is applied to one spot at a time, it is extremely difficult to affect all Barrett s mucosa areas equally. With PDT, the diffuser and centering balloon facilitate equal penetration. There is a limit to the amount of tissue that can be treated per PDT session. When more than 7 cm of esophagus is treated, patients become quite S904 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2000

3 ... EVALUATING TREATMENTS OF BARRETT S ESOPHAGUS... sick. If the Barrett s mucosa is less than 6 cm, the effect of PDT will extend distally and proximally beyond those 6 cm so that all of the Barrett s mucosa is treated. If the mucosa measures 7 to 8 cm, clinicians should treat as much of it as possible, then use aggressive thermal ablation on any areas remaining. Coagulation is not sufficient with thermal ablation; the clinician must divot to remove the mucosal layer. If the Barrett s mucosa is longer than 8 cm, the area should be considered too long for a single PDT plus thermal ablation treatment. It will require 2 PDT sessions. Injury and Complications With PDT As shown in Figure 3, the injury with PDT is total circumferential mucosal destruction. Exudate and superficial erosions are present, along with significant edema. Small pleural effusions are common after PDT. Although the pain from PDT usually abates in about 5 days, stricture symptoms and dysphagia typically occur 3 weeks after PDT. In the studies performed to date with 300 patients, atrial fibrillation after PDT was observed in 1% of the patients; all of the cases were among the 50 patients observed in the first phase I trial. 7,8 A tracheoesophageal fistula occurred in 1 patient (0.3% incidence). Photosensitivity also occurs but is considered a temporary side effect, usually lasting 4 to 6 weeks. Strictures are the most common complication, occurring in 20% of patients treated with PDT. With the initial PDT treatment, about 18% of patients get strictures. With 2 treatments, because the balloon overlaps the previously treated tissue, 40% to 50% of patients get strictures. Some strictures are difficult to treat, requiring multiple dilations, but the organ is preserved and the patients are able to swallow normally, or almost normally, after they have been fully dilated. Because the injury is deep, strictures are thick and fibrotic. As a result, stricture management requires early and aggressive therapy. Approximately half of patients require 3 to 5 dilations per stricture and half require more; the average is 7.5 dilations per stricture. 8 Dilation is performed on an outpatient basis. Savary dilation is preferred to a balloon dilation because a Savary produces a linear tear as well as a lateral stretch. Fluoroscopy is not used. Patients are dilated twice a week with either a #45 or a #48 Savary, then once a week with a #48 Savary for 3 or 4 weeks. After that, the treatment intervals can be lengthened. Steroid injection is also used frequently (20 mg depomedrol injected at 4 sites, totaling 80 mg) in an attempt to reduce stricture recurrence. The injections are administered by a sclerotherapy needle, typically given alongside the tears that occur with dilation. Treatment Results With PDT In a study published in 1999, PDT was observed to produce 90% clearance of dysplasia, and after PDT, 90% to 100% of Barrett s mucosa was Figure 3. Strictures Injury With PDT VOL. 6, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S905

4 ... PRESENTATIONS... Table. Workup for Photodynamic Therapy replaced by squamous epithelium, although some subsquamous epithelium was observed. 8 Subsquamous Barrett s mucosa has been observed in 4% of the original 100 patients treated with PDT and thermal ablation. The long-term follow up is now approaching 5 years. In the above-mentioned study, 1 patient developed 2- to 3-mm subsquamous cancer 6 months after PDT. This was believed to be a result of incomplete initial treatment. Another patient developed a 1-mm subsquamous adenocarcinoma at the gastroesophageal junction 5 1 /2 years after PDT for high-grade dysplasia/early cancer in another site. Both patients were subsequently retreated with PDT and remain clear of cancer. For cancer that is intramucosal (T1 mucosal lesion on EUS), PDT can be effective. Mucosal carcinoma has a 5% to 10% incidence of lymph node spread. If PDT proves to be ineffective or partially effective, surgery can be considered the next option. Surgery or PDT To date, no mortality has been observed with PDT, but surgical treatment is associated with 3% to 10% operative mortality rates, and the morbidity of surgery is significant. In CT: Chest X ray, Chest, ECG, Lab tests EUS EMR ABD Flat BE + HGD + Nodular BE + HGD BE + Carcinoma + + +/- + ABD = abdomen; BE = Barrett s esophagus; CT = computerized tomography; ECG = electrocardiogram; EMR = endoscopic mucosal resection; EUS = endoscopic ultrasound; HGD = high-grade dysplasia. community hospitals that perform fewer than 6 esophagectomies per year, the mortality is 17%. In those that perform more than 6, the average mortality is 3.5%. After an esophagectomy, as many as two thirds of patients have strictures. Most of these strictures can be dilated easily in the majority. However, with surgery the organ is not preserved, so the patient s diet will be restricted for the rest of his or her life. Surgery generally requires 10 to 21 days in the hospital, although with some new procedures, the stay may be reduced to about 1 week. Surgery patients return to work in 2 to 4 months. PDT, on the other hand, is an outpatient procedure; recovery usually takes 3 weeks. Patients return to work in 2 to 3 weeks. Surgery costs $35,000 to $95,000; PDT costs approximately $20,000. If a patient has cancer of a T1 submucosal grade, the incidence of metastatic lymph nodes is already 30%. In such cases, surgery is the treatment of choice. Likewise, a deeper lesion, such as a T2 lesion, should be subjected to surgery. However, if the patient is a poor operative risk and EUS shows no abnormal lymph nodes, PDT is a potential option. Patient Selection for PDT The key to the success of PDT will be the correct identification of patients most likely to benefit from this treatment. Patients are selected for this therapy through both endoscopic findings and histology. The key endoscopic landmarks, including the exact location of the squamocolumnar junction (SCJ), must be accurately identified prior to treatment to measure the impact of therapy. The position of the first gastric fold must be recorded, because the distance between the SCJ and the gastric folds is the length of Barrett s mucosa. The distance from the gastric folds to the S906 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2000

5 ... EVALUATING TREATMENTS OF BARRETT S ESOPHAGUS... diaphragmatic impression should also be noted. After the esophageal landmarks have been identified, 4-quadrant biopsies of the Barrett s mucosa should be taken at 2-cm intervals with jumbo biopsy forceps. Biopsy samples from each level should be placed in separate pathology bottles that are labeled with the location of origin so that any high-grade dysplasia fragment identified can be readily traced to its source. Workup for PDT. Once high-grade dysplasia has been diagnosed and PDT is under consideration, the workup strategy depends on the endoscopic findings (ie, the length of BE or the presence of nodules) and the histology (Table). For a patient with a flat BE and normal-looking mucosa, but high-grade dysplasia, the standard pretreatment workup (ie, a chest X ray, electrocardiogram, and laboratory tests) is appropriate. For a patient with nodular BE and high-grade dysplasia, the workup should include EUS to determine the depth of the nodule for staging purposes. This also helps to determine whether PDT is the appropriate therapy. PDT is effective for curing highgrade dysplasia and cancer graded as T1 mucosal, but submucosal cancer may be better treated with surgery. For nodular BE, current thought favors endoscopic mucosal resection (EMR) of the nodule followed by PDT treatment several months later. After dysplastic change occurs in one segment of the Barrett s mucosa, the rest of it is at great risk for developing highgrade dysplasia. Therefore, the goals of PDT in Barrett s dysplasia are first to eliminate the dysplasia and second to eliminate the Barrett s mucosa. If the EUS shows no invasion, even though the biopsy shows high-grade dysplasia, a computerized tomography (CT) scan is not required. If there is early carcinoma, the standard lab work and EUS are necessary to stage the cancer. If the carcinoma is nodular and appears to be superficial (eg, a T1 mucosal lesion), EMR is advisable. With a large piece of tissue from EMR, the pathologist can determine whether the margins are clear and whether the depth of invasion was sufficient. A CT scan is highly recommended if the diagnosis of cancer is made. The more severe the disease, the more extensive should be the investigation. Summary PDT, thermal ablation, and surgery each offer their own advantages and disadvantages. Thermal ablation does not produce a uniform effect across the surface area treated. PDT, although associated with some morbidity, is less expensive and better tolerated than surgery. Surgery may be the treatment of choice when cancer is a T1 submucosal grade. Whichever treatment is chosen, it must be sufficiently aggressive to penetrate to the submucosa. PDT currently remains under clinical investigation for highgrade dysplasia, but its role in managing BE is becoming clearer as more data are collected on the safety and efficacy of this technique.... REFERENCES Barham CP, Jones RL, Biddlestone LR, Hardwick RH, Shepherd NA, Barr H. Photothermal laser ablation of Barrett s oesophagus: Endoscopic and histological evidence of squamous re-epithelialisation. Gut 1997;41: Gossner L, May A, Stolte M, Seitz G, Hahn EG, Ell C. KTP laser destruction of dysplasia and early cancer in columnar-lined Barrett s esophagus. Gastrointest Endosc 1999;49: Sharma P, Bhattacharyya A, Garewal HS, Sampliner RE. Durability of new squamous epithelium after endoscopic reversal of Barrett s esophagus. Gastrointest Endosc 1999;50: Byrne JP, Armstrong GR, Attwood SEA. Restoration of the normal squamous lining in Barrett s esophagus by argon beam plasma VOL. 6, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S907

6 ... PRESENTATIONS... coagulation. Am J Gastroenterol 1998;93: Van Laethem JL, Cremer M, Peny MO, Delhaye M, Deviere J. Eradication of Barrett s mucosa with argon plasma coagulation and acid suppression: Immediate and mid term results. Gut 1998;43: Sampliner RE, Hixson LJ, Fennerty MB, Garewal HS. Regression of Barrett s esophagus by laser ablation in an anacid environment. Dig Dis Sci 1993;38: Overholt BF, Panjehpour M, Teffetellar E, Rose M. Photodynamic therapy for treatment of early adenocarcinoma in Barrett s esophagus. Gastrointest Endosc 1993;39: Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett s esophagus: Follow-up in 100 patients. Gastrointest Endosc 1999;49:1-7. S908 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2000