Photodynamic Therapy for Esophageal Cancer and High Grade Dysplasia

Drew B. Schembre, M.D.

Keywords

Esophageal cancer. high grade dysplasia (HGD), photodynamic therapy (PDT).

Disclosure

Limited support has been received from Axcan Scandipharm Inc. for speaking engagements.

Introduction

The incidence of adenocarcinoma of the esophagus in the United States is rising faster than any other cancer (1). The vast majority of these cancers arise within Barrett’s esophagus. Most of these tumors present at advanced stages and are often inoperable. A variety of non-surgical therapies have been developed to palliate dysphagia associated with these tumors. Photodynamic therapy (PDT) is a photochemical ablative treatment for re-establishing esophageal patency when tumor occludes the esophagus. PDT has also been used to ablate high-grade dysplasia and intra-mucosal carcinoma in the setting of Barrett’s esophagus to reduce the chance of progression to invasive cancer.

Esophageal Cancer

Photodynamic therapy utilizes non-thermal laser light to produce a photochemical reaction in tumor tissue (Figures 1 and 2). The reaction produces high local concentrations of singlet oxygen (free radicals), which binds to cell membranes, mitochondria and endothelial lining of vessels. This leads to direct cell death and microvascular thrombosis, which in turn leads to tumor necrosis and tissue sloughing (Figure 3).

Figure 1	Figure 2	Figure 3

In contrast to thermal methods (Neodymium:yttrium-aluminum-garnet laser, heater probe, argon plasma coagulation), where tumor ablation depends upon multiple focal applications of intense heat, PDT ablates a broad area—up to several centimeters—with one treatment. This tends to produce a more uniform effect and decreases the risk of over-treating a particular area, which may lead to perforation. The area of treatment depends upon the length of the light-diffusing, fiber optic probe used and its placement (Figure 4). Depth of treatment depends upon light frequency, intensity and duration of treatment. Different photosensitizers can be used with different light frequencies, although only one, porfimer sodium (Figure 5), is currently approved in the United States by the Federal Drug Administration for treating esophageal cancer. Porfimer sodium can be activated by several different light frequencies, but 630 nanometers is generally used because it penetrates tissue more deeply than other active wavelengths. Unlike thermal methods, where tissue effect is immediate, the effect of PDT is not apparent until several hours after treatment and improvement in dysphagia may take several days.

Figure 4	Figure 5

PDT has been shown to be as effective as Nd:YAG laser treatment for esophageal cancers but requires fewer treatments and is associated with fewer serious complications (2). The ability of PDT to palliate malignant dysphagia is variable and depends on many factors, including extent of tumor growth, and extraluminal tumor extension. The real advantage of PDT may be that it is faster and technically easier to perform than other ablative therapies. PDT and expandable stent placement have been found to be equally effective and durable for relief of malignant dysphagia. Quality of life measurements appear to be better after PDT than stent placement, however total cost of treatment may be up to three times higher (3). Unlike radiation therapy, PDT can be repeated, as there is no cumulative maximum dose.

An endoscopic ultrasound examination is essential before PDT in order to determine the depth of tumor involvement. PDT can be dangerous in patients with tumor extension into bronchi or major vessels, as extensive tumor necrosis may lead to life-threatening fistulae (Figure 6A). PDT will generally not penetrate deeply enough to affect malignant tissue in adjacent lymph nodes (Figure 6B) or strictures resulting from extra-luminal compression by tumor as tumor-killing effect penetrates only to about 5 mm. These tumors may be better treated with expandable stents. Circumferential, exophytic and shorter tumors tend to respond well to PDT.

Figure 6A	Figure 6B

Endoscopy can be performed with a standard gastroscope or with an ultra-thin gastroscope, if tight stricture is encountered. Because the light-diffusing probe is less than 2 mm in diameter, extensive pretreatment dilation is usually not necessary. Since no significant heat is generated, heavy sedation is also usually not necessary.

PDT can be used for obstructing tumors, either by passing a wire through the mass and advancing the probe along side it, or simply placing a short probe directly into the tumor mass. This procedure can be repeated every two days until a lumen is established. Because of the long half-life of porfimer sodium, this can be continued for up to two weeks.

Transient chest pain is common, as are radiographic plural effusions, which are rarely clinically significant. Some patients will experience increase in dysphagia for a few days as treated tissue becomes edematous before sloughing. Chest pain and odynophagia may persist for several days, especially if uninvolved esophageal tissue is included in the treatment field. However, most patients can remain at home with oral hydration and analgesia. The potentially serious side effect of photosensitivity underscores the need for absolute sunlight avoidance for 4-6 weeks after infusion. Extensive PDT of the normal esophagus can lead to stricture formation (4).

Early Esophageal Cancer and High-Grade Dysplasia

In 1993, Berensen et al. (5) showed that if Barrett’s mucosa is injured to the point of ulceration (initially achieved w/ KTP:YAG laser), and allowed to heal in an acid-free environment (bid omeprazole), normal squamous mucosa tends to re-grow in its place. This principle is the basis for PDT for Barrett’s with HGD, since the injury produced by PDT at 200 j/cm is more uniform and generally deeper than injury generated by thermal means (Figures 7A-7D). A high degree of acid suppression can be achieved with multiple dosing of any of the available proton-pump inhibiting drugs.

Figure 7A	Figure 7B	Figure 7C	Figure 7D

Figure 8

In the first major publication, Overholt et al. (4), prospectively followed 100 consecutive patients, 87 patients with HGD and 13 patients with early carcinoma. After a follow-up of 4-84 months, complete regression of Barrett’s esophagus occurred in 43 patients, partial regression in 57 patients, elimination of dysplasia in 78 patients, and ablation of 10 of 13 superficial malignancies. Other studies have shown similar results. Wang et al. (6), followed 105 patients treated with PDT, 13 patients for early carcinoma, 48 patients for HGD, and 34 patients for LGD, followed by omeprazole 20-60mg/d. At an average follow-up of 45 months, 42 patients (40%) demonstrated endoscopic clearance of all Barrett’s tissue, 43 patients (41%) showed residual Barrett’s mucosa with no dysplasia, 14 patients (13%) demonstrated low-grade dysplasia, and 2 patients (2%) showed persistent HGD. Barrett’s mucosa length decreased from an average of 7 cm to 2 cm. A total of four cancers developed from pre-cancerous lesions. Based on accepted estimates of progression of dysplasia to cancer (7), 20 new cancers would have been expected in the group over the same time period (p<0.01), strongly supporting PDT as a beneficial treatment for HGD or early cancer. Concern has been raised about the possibility of dysplastic glandular tissue persisting after PDT, especially if the tissue is hidden beneath a layer of new squamous epithelium (Figure 8). In Overholt’s series, two patients developed subsquamous cancers, and one ultimately died of it.

Wolfsen et al. (8) reported results on 48 patients with Barrett’s esophagus, with 34 patients having HGD and 14 patients having early cancers treated with porphyrin-based PDT. At 18.5 months median follow-up, complete ablation of cancer and HGD was noted in 47 patients (98%). They reported a 44% complication rate, most of which were minor (stricture 23%, sunburn 15%).

At our own institution, we have experienced similar results with porfimer-based PDT. We have now treated 38 patients with PDT for 39 lesions: 36 patients with Barrett's esopagus and 3 patients with squamous cell cancers. All patients have had at least six months follow-up. Of these, 20 patients initially showed HGD, while 12 patients showed intramucosal carcinoma and 7 patients demonstrated T1 carcinoma. At a median follow-up of 24 months, 18 of 20 patients (90%) have shown elimination of HGD, while all intramucosal cancers (100%) were eradicated, and 4 patients (57%) with T1 lesions have shown elimination of cancer. Visible Barrett's mucosa was completely eliminated in 19 of 36 individuals (53%), and average length of Barrett's mucosa decreased from 6 cm to 1 cm (83%). One individual with HGD progressed to T1 carcinoma and underwent successful esophagectomy. The expected progression to cancer in this group would have been five cases. This reduction of expected cancers is identical to Wang's experience. A list of studies using PDT to treat HGD is listed in Table 1 (8).
 
A large, multi-center study comparing PDT + high dose omeprazole to high dose omeprazole alone for Barrett's esophagus with HGD (PHO-BAR for "photodynamic therapy for Barrett's") was completed recently and has not yet been formally published.  However, preliminary review of data suggests PDT, without additional post-PDT ablative therapy, reduced progression to cancer by 50%.

Figure 9

Debate exists about the need for endoscopic ultrasound prior to PDT for Barrett’s esophagus with HGD, since it is very difficult to identify HGD or to differentiate HGD from intramucosal cancer with even high-resolution EUS probes. However, because of the insensitivity of biopsies alone identifying early invasive carcinoma in the setting of HGD, most patients anticipating PDT will undergo EUS in order to identify tumors extending deeply into the submucosa or muscularis propria (Figure 9) which would be unlikely to benefit from the treatment. Greater use of EUS prior to PDT, especially with the higher frequency (12-30 MHz) through-the-scope EUS catheter probes, has been shown to identify submucosal invasion as well as peri-esophageal adenopathy (10). This greatly aids in the selection of appropriate candidates for attempts at cure. While intramucosal cancers rarely metastasize to regional lymph nodes, involvement of the submucosa may be associated with up to a 40% lymphatic invasion and regional lymph node metastases.

Addition of endoscopic mucosal resection probably increases the cure rate of PDT in early esophageal cancer. A group from the Mayo Clinic studied the efficacy of photodynamic therapy in combination with EMR for a group of patients with superficial esophageal cancer within Barrett’s esophagus (11). They followed 17 consecutive patients, all but two of whom were uT1 or less by EUS staging. Three patients demonstrated positive margins after EMR, and five required more than one PDT treatment. At a median of 13 months follow-up, 16 patients remained in remission. The one patient with biopsies suggestive of invasive carcinoma at three months underwent esophagectomy, however histology of the resected esophagus and lymph nodes failed to confirm recurrent cancer. Further, no biopsies from this group demonstrated sub-squamous Barrett’s epithelium, a major concern after ablative therapy. Only minor side effects such as chest pain, stricture and photosensitivity were noted. EUS images and EMR technique of a T1 esophageal cancer are shown in Figures 10A-10F.

Figure 10A	Figure 10B	Figure 10C
Figure 10D	Figure 10E	Figure 10F

The use of delta-amino levulinic acid (_-ALA) as a sensitizer for PDT has theoretical advantages. It is inexpensive, has a short half-life, and can be given orally or topically. However, tissue damage remained too superficial and incomplete with _-ALA. Tissue injury depth may be as little as 2 mm and can lead to the persistence of a substantial amount of sub-squamous glandular tissue which is at risk for malignant progression. Whether PDT with shorter-acting drugs like _-ALA which produce more superficial tissue damage would be effective—and more cost-effective—in treating non-dysplastic Barrett’s esophagus or low-grade dysplasia has not been studied.

The use of PDT for early and pre-cancers is controversial since esophagectomy is usually curative in these settings. However, because of the potential morbidity and mortality of surgery, there has been increasing interest in endoscopic ablative therapies. Only long-term studies will determine if PDT will become a standard treatment for these conditions in otherwise healthy individuals.

REFERENCES

1. National Cancer Institute website: www.cancer.gov, 2003.

2. Lightdale C, Heier SK, Marcon NE et al. Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: a multicenter randomized trial. Gastrointest Endosc 1995, 42:507-12.

3. Canto MI, Smith C, McClelland L, et al. Randomized trial of PDT vs. Stent for palliation of malignant dysphagia: cost-effectiveness and quality of life. Gastrointest Endsoc 2002,55:AB100.

4. Overholt BF, Panjepour M, Haydek JM. Photodynamic therapy for Barrett's esophagus: follow-up in 100 patients. Gastrointest Endosc 1999;49:1-7.

5. Berenson MM, Johnson TD, Markowitz NR, Buchi KN, Samowitz WS. Restoration of squamous mucosa after ablation of Barrett's esophageal epithelium. Gastroenterology 1993;104:1686-91.

6. Wang K, Song L, Buttar N, et al. Long-term follow-up after photodynamic therapy (PDT) for Barrett’s esophagus. Gastrointest Endosc 2002,55:AB100.

7. Reid B, Levine D, Longton G, et al. Predictors of progression to cancer in Barrett’s esophagus: baseline histology and flow cytometry identify low and high risk patient subsets. Am J Gastroenterol 2000,95:1669-76.

8. Wolfsen H, Woodward T, Raimondo M. Photodynamic therapy for dysplastic Barrett esophagus and early esophageal adenocarcinoma. Mayo Clin Proc 2002,77:1176-81.

9. Schembre D. Photodynamic therapy for premalignant lesions of the esophagus: interim results of initial 26 cases. Gastrointest Endsoc 2002,55:AB207.

10. Scotiniotis IA, Kochman ML, Lewis JD, et al. Accuracy of EUS in the evaluation of Barrett’s esophagus and high-grade dysplasia or intramucosal carcinoma. Gastrointest Endosc 2001, 54:689-96.

11. Buttar NS, Wang KK, Lutzke LS, et al. Combined endoscopic mucosal resection and photodynamic therapy for esophageal neoplasia within Barrett’s esophagus. Gastrointest Endosc 2001, 54:682-8.

Editor:
John C. Deutsch, M.D.
Duluth, MN

Editorial Board:
Manoop S. Bhutani, M.D.
Galveston, TX
William R. Brugge, M.D.
Boston, MA
Peter R. McNally, D.O.
Denver, CO
Iqbal S. Sandhu, M.D.
Salt Lake City, UT
Thomas J. Savides, M.D.
San Diego, CA