Endoscopic Therapies for Thoracic Diseases

Curative Intent

Photodynamic therapy has been used in an investigational setting for the treatment of lung cancer since 1980. It is currently approved as a treatment option for centrally located early stage 0 (TisN0M0) and stage 1 ( T1N0M0 ) lung cancer. These small central tumors are rare, although some centers with active early screening programs, such as sputum cytology or light-induced fluorescence bronchoscopy, encounter these tumors more frequently. The results of PDT for these small lesions should be compared with the results of surgical resection. The central location of these tumors may necessitate complex airway reconstructions. PDT may be a suitable alternative to resection in patients who are not surgical candidates or as an adjunct in decreasing tumor burden prior to surgical resection. There are few central airway tumors that are discovered at a curable stage, because most of these early-stage, centrally located endobronchial lesions often go undetected by radiologic studies. In addition, only about 10% of all non–small cell lung cancer tumors occur in a central location. Superficially spreading tumors (<3 cm ² ) and small endobronchial tumors (<1 cm ² ) are reasonable targets for PDT. Initial complete response can be expected in 65% (<3 cm ² ) to 85% (<1 cm ² ) of superficial cancers and in 30% (>0.5 cm nodule) to 92% (<0.5 cm nodule) of nodular cancers. Long-term response rates (i.e., >1 year) vary between 30% and 80%. At 5 years of follow-up, complete response rates of up to 29% to 66% have been reported depending upon the exact size, location, and stage of the lesion.

In a study of 21 operative candidates treated initially with two courses of PDT, 52% (11 of 21) were free of tumor at 1 year. Curative PDT failed in the remaining 48% (10 of 21), and they were offered surgery; 8 consented. Of the 11 responders, 9 (9 of 21; 43%) did not require surgery (mean follow-up, 68 months), and 2 were operated on for a second primary lung cancer. It is noteworthy that of the patients who eventually underwent resection, 30% were found to have N1 disease, supporting the role of resection when possible. Our policy has been to reserve curative PDT for patients with significant comorbid factors or those who refuse pulmonary resection. In this group of patients, PDT is an excellent option, with an expected 1-year survival of up to 80%. In our initial experience of treating 10 superficial cancers, a complete response was seen in 70% at a follow-up of 30 months. In other prospective series, 80% to 93% of nonsurgical candidates were alive at 5 years of follow-up.

Palliative Intent

Resection should continue to be the main therapy for early-stage non–small cell lung cancer, because only a relatively small number of patients will have curable central tumors that are suitable for PDT with curative intent. A much larger group of patients with advanced, inoperable, or obstructive central lung cancers may benefit from palliative PDT. In this situation, the therapeutic goal should be symptomatic relief and preservation of quality of life and functional status. Patients most notably find improvement in obstructive symptoms, such as dyspnea or hemoptysis, yet the need for strict photosensitivity precautions should be considered in patients with limited survival.

A cohort of 175 patients with endobronchial non–small cell lung cancer treated with PDT was observed prospectively for a period of 14 years. Most patients had squamous cell carcinoma (89.3%), and treatment by conventional modalities, including chemotherapy, radiotherapy, laser ablation, and surgery, had failed in 73.1%. The mean number of treatments was 2.8 per patient. After multivariate analysis, stage was found to have the most significant effect on survival. Poor performance status (i.e., Karnofsky performance status < 50) negatively affected outcome in advanced-stage tumors (IIIa-IV). However, patients with a low Karnofsky performance status (<50) secondary to pulmonary symptoms still derived benefit from PDT. Prolonged survival (12 to 37 months) was observed in 66% of stage IIIa-IV patients with poor performance. The median survival for the entire group was 7 months. Of the 44 patients with stage IV disease, 21% survived 12 months or longer.

Our initial experience with palliative PDT involved 44 patients with lung cancer and symptoms related to obstruction and hemoptysis. Thirteen patients required a second treatment course at a mean of 2.3 months for recurrent symptoms. There were no fatalities, and 82% of treatments were performed without complications. Hemoptysis was effectively palliated in 90% of treatment courses. Obstruction was successfully palliated in 59% of treatments. Median survival was 2.3 months. PDT has also been shown to be effective in palliating hemoptysis and dyspnea in patients with endobronchial metastases from malignant neoplasms of nonpulmonary etiology. An example of a patient who was treated for a complete lobar obstruction is demonstrated in Figures 6-2 through 6-6 . In general, we have not used PDT for massive hemoptysis for practical reasons; those best suited have subacute but persistent hemoptysis of low volume and have visible endoluminal granular rumor with a bleeding surface area.

In a randomized prospective study, PDT was compared with standard laser techniques for inoperable non–small cell lung cancer. The bronchoscopic response rate (PDT, 38.5%; laser, 23.5%) and symptomatic improvement at 1 month were equivalent in each group. PDT provided significantly longer-lasting relief (50 days vs. 38 days) and improved median survival (265 days vs. 95 days) compared with laser resection. However, this finding may be explained in part by the lower proportion of advanced-stage tumors seen in the PDT group.

In general, PDT is well tolerated with minimal morbidity. All bright light and direct sunlight exposure must be avoided initially. Patients remain photosensitive for 4 to 8 weeks, after which they can be gradually reexposed to sunlight. Inadvertent direct sunlight exposure has been reported to cause first- and second-degree burns in up to 10% of patients. The restrictions imposed by photosensitivity and their potential impact on quality of life should be considered before treatment. Immediate postprocedure mortality for lung and esophageal PDT (30-day) ranges from 2.6% to 7.1%, but in large part is due to the comorbidities and advanced stage of many of the patients in these series.

Curative Intent

The management of high-grade dysplasia associated with Barrett esophagus is controversial. In the recent past, most surgeons advocated esophagectomy because of the associated risks of occult malignant disease and lymph node metastases. On the other hand, concerns related to the morbidity and mortality of esophagectomy have led some clinicians to advocate alternative approaches, such as surveillance, endoscopic mucosal resection, or mucosal ablation. In our experience, we have reported good results and a mortality of approximately 1% with a minimally invasive esophageal resection for patients with Barrett esophagus and high-grade dysplasia. Currently available mucosal ablative methods include endoscopic mucosal resection, PDT, laser ablation, argon plasma coagulation, and radiofrequency ablation. All these techniques attempt to resect or eradicate Barrett epithelium with the hope that it will be replaced by squamous epithelium. Unfortunately, in some instances, islands of columnar epithelium may recur under a normal-appearing squamous epithelial layer leading to difficult detection. This problem is addressed by other endoscopic techniques, such as initial endoscopic mucosal resection or endoscopic submucosal dissection, whereby the esophageal mucosa is actually resected piecemeal. An in-depth discussion of endoscopic resection techniques is beyond the scope of this chapter, but it should be noted that this approach has become the standard of care in many centers for properly selected patients.

PDT is arguably the most established of these ablative techniques. In a large single-institution study, PDT was combined with the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser to treat 73 patients with high-grade dysplasia and 14 patients with low-grade dysplasia. All patients were observed endoscopically for 12 months. Regression to low-grade dysplasia or no dysplasia was observed in 88% of high-grade dysplasia cases and in 93% of low-grade dysplasia cases. Complete eradication of Barrett epithelium occurred in only 9% of patients after PDT alone. In focusing on the PDT-treated area, a 49% eradication rate was reported. The addition of laser ablation to residual areas of Barrett epithelium increased the eradication rate to 87%. In a 5-year prospective randomized multicenter international trial, PDT with Photofrin plus omeprazole was compared with omeprazole only for the treatment of Barrett esophagus with high-grade dysplasia. Complete ablation of high-grade dysplasia was observed significantly more often in the Photofrin group compared with controls (77% vs. 39%). Progression to esophageal cancer was significantly decreased in the Photofrin group (13% vs. 28%). Treatment-related side-effects were more common in the Photofrin group (94% vs. 13%). Strictures developed in 36% of patients, with 98% resolving after dilation. Notably, the benefits on dysplasia resolution and cancer progression persisted at 5-year follow-up. At 5 years, the study demonstrated that the addition of PDT with Photofrin to proton pump inhibitor therapy resulted in a 38% increase in eradication of Barrett esophagus with high-grade dysplasia, a 14% decrease in the incidence of invasive carcinoma, and a longer time to progression to cancer.

PDT can also be used to treat early-stage esophageal tumors (T1-T2) in patients who are not candidates for surgical resection. In a group of patients that included mostly T1 tumors (12 of 13), regression to Barrett esophagus with low-grade dysplasia or without dysplasia was observed in 77% of patients (10 of 13). At our center, PDT with curative intent is reserved for patients with prohibitively high operative risk. All others undergo minimally invasive esophagectomy. We have reviewed our institutional experience, from 1997 to 2005, using PDT for patients with high-grade dysplasia or superficial esophageal cancer. A total of 50 patients, who either refused or were unfit for surgery, had PDT with curative intent. The majority of patients (70%) had high-grade dysplasia or small (≤T1) tumors. At a median follow-up of 28 months, 32% of patients were alive without recurrence, 30% were alive with recurrent disease, and 38% were deceased from cancer or other causes. The patients with recurrences were retreated with PDT. There was no procedure-related mortality, and the stricture rate was 42%, which were generally easily dilated. Although these results are clearly inferior to esophageal resection, endoscopic ablation appears to be a suitable treatment option for nonsurgical candidates. In another cohort of 28 patients with high-grade dysplasia treated with minimally invasive esophagectomy, 96% remained free of recurrence at 13 months. These results were corroborated by other investigators who have observed excellent long-term survival (100%) after esophagectomy for high-grade dysplasia.

In the treatment of Barrett esophagus with high-grade dysplasia, PDT is well tolerated with usually transient side effects, such as nausea, regurgitation, constipation, odynophagia, dysphagia, weight loss (average of 6 kg), and noncardiac chest pain. Other complications include stricture, tumor growth below the PDT-induced scarring, and Barrett esophagus and tumor recurrence. In our experience, approximately 30% of patients with high-grade dysplasia undergoing PDT will develop an esophageal stricture. Stricture is minimized by decreasing the intensity of light therapy compared with doses used for larger tumors.

Another endoscopic treatment modality for patients with Barrett esophagus is radiofrequency (RF) ablation. The components of the system include a sizing balloon (18 to 34 mm), a 3-cm balloon-based bipolar RF electrode, and a dedicated RF generator. The sizing balloon is used to ensure proper contact between the balloon electrode and the esophageal mucosa. The RF mucosal ablation is achieved by using a power of 300 W to deliver 10 to 12 J/cm ² . The coagulum is then removed from the esophageal surface by irrigation and suction. The maximum ablation depth is 1 mm, which translates to a depth of injury that is superficial to the muscularis mucosa. The depth of injury is highly reproducible and has been confirmed in the human esophagus. In addition to the circumferential balloon electrode, the approval of an RF ablation device that can be attached to the end of a flexible esophagoscope can be used to ablate focal areas of esophageal mucosa. Encouraging results have been published showing complete eradication of Barrett mucosa and intramucosal carcinoma when RF ablation was used in combination with endoscopic mucosal resection.

With further analysis, it seems that patients with high-grade dysplasia without visible raised or nodular lesions are the optimal candidates for endoscopic management with RFA. The presence of visible lesions requires the addition of a mucosal resection technique to allow for adequate staging and treatment.

Visible lesions containing high-grade dysplasia or intramucosal carcinoma can be treated successfully with RFA, but only as an adjunct to a mucosal resectional technique such as endoscopic mucosal resection.

The Surveillance vs. Radiofrequency Ablation (SURF) trial was a randomized multicenter trial conducted in Europe that randomized patients with a confirmed histologic diagnosis of Barrett esophagus with low-grade dysplasia to treatment with either RFA or standard endoscopic surveillance (at 6, 12, 24, and 36 months). RFA was demonstrated to significantly reduce the risk of progression to high-grade dysplasia or esophageal adenocarcinoma compared with standard endoscopic surveillance (1.5% vs. 27%) while also reducing the risk of progression to esophageal adenocarcinoma (1.5% vs. 8.8%).

Palliative Intent

Stenting of the esophagus is often the most commonly used modality to palliate dysphagia ; however, PDT offers some advantages in certain clinical situations. In addition to relieving obstruction, PDT can often be used to control or prevent tumor bleeding. It can also prevent the globus sensation associated with stents in the proximal esophagus and the reflux symptoms observed with stents bridging the gastroesophageal junction. PDT is a potential alternative to stenting for endoluminal cancers in both of these locations.

PDT has been compared with laser ablation in a randomized trial. PDT was equivalent to laser ablation for malignant dysphagia and was associated with a lower rate of perforation (PDT, 1%; laser, 7%). We reviewed our experience with PDT in 215 patients suffering from obstructing esophageal cancer. The most common pathologic process was adenocarcinoma (83%). The distal esophagus was involved in 71% of cases. Dysphagia improved in 85% of patients, and bleeding was successfully controlled in 90%. Stenting was subsequently required in 24% of patients. As expected, median survival was poor at 4.9 months; however, effective palliation lasting 3 to 4 months was provided to many of these unfortunate patients. In another prospective series of 77 patients for whom conventional therapy had failed or who were deemed unfit for surgery, investigators reported a median survival of 6.3 months after PDT. The only significant predictor of mortality was clinical stage. Photosensitivity appears to be an acceptable tradeoff in these patients. In one study using satisfaction questionnaires, patients reported that the ability to swallow food was more important than the limitations of photosensitivity. In most cases, the potential benefits of PDT far outweigh the risk of complications.

In patients with obstructing aerodigestive tumors, PDT can result in adverse events. Esophageal strictures (4.8% to 5.2%), perforation (0% to 9.1%), and esophagorespiratory fistulas (0% to 5.2%) are among the most serious PDT-related complications. Esophageal perforation and fistula are probably best treated by esophageal stenting. Other factors contributing to the mortality rate and risk of esophageal perforation include the generally poor performance status of this particular group of patients with advanced tumors and the fact that some patients with obstructing tumors receive concurrent radiation therapy and chemotherapy.