Curative Intent

PDT is approved for the treatment of small proximal endobronchial tumors. These small central tumors are rare, although some centers with active early screening programs, such as sputum cytology or light-induced fluorescence bronchoscopy, may encounter these more frequently.⁴ 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 candidates for surgery. In most cases, these small endobronchial tumors are occult to standard radiologic imaging, such as chest radiography, computed tomography, and positron emission tomography scanning. Assessment of response is difficult and requires bronchoscopic evaluation. It is unclear whether a complete response is the result of tumor eradication or merely reflects the limitations of surveillance techniques. Superficially spreading tumors (<3 cm²) and small endobronchial tumors (<1 cm²) are best suited for PDT. Initial complete response can be expected in 65% (<3 cm²) to 85% (<1 cm²) of superficial cancers and in 30% (>0.5 cm nodule) to 92% (<0.5 cm nodule) of nodular cancers.^5,6 Long-term response rates (i.e., >1 year) vary between 30% and 80%.^5–9 At 5 years of follow-up, complete response rates of up to 29% to 66% have been reported.^5,7

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.⁷ 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 PDT for patients with significant comorbid factors or those who refuse pulmonary resection. In this group of patients, PDT is an excellent modality with an expected 1-year survival of 80%.¹⁰ In our initial experience of treating 10 superficial cancers, a complete response was seen in 70% at a follow-up of 30 months.⁸ In other prospective series, 80% to 93% of nonsurgical candidates were alive at 5 years of follow-up.^5,11

Palliative Intent

Resection should continue to be the main therapy for early-stage non–small cell lung cancer. Only a relatively small number of patients will be candidates for PDT with curative intent. A much larger group of patients with advanced 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. Most of these patients will complain of dyspnea related to endobronchial obstruction or with hemoptysis.

A cohort of 175 patients with endobronchial non–small cell lung cancer treated with PDT was observed prospectively for a period of 14 years.¹¹ Most patients had squamous cell carcinoma (89.3%), and treatment by conventional modalities, such as chemotherapy, radiotherapy, laser ablation, and surgery, had failed in 73.1%. The mean number of treatments was 2.8 per patient. Stage had the most significant impact on survival after multivariate analysis. Poor performance status (i.e., Karnofsky performance status < 50) had a negative impact on outcome only 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 lung cancer patients with symptoms related to obstruction and hemoptysis.¹⁰ 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 is also effective in palliating hemoptysis and dyspnea in patients with endobronchial metastases from nonpulmonary malignant neoplasms.¹² An example of a patient who was treated for a complete lobar obstruction is demonstrated in Figures 6-2 through 6-6.

Figure 6–2 Radiographic picture of lung cancer obstructing the left main-stem bronchus before PDT.

Figure 6–3 Bronchoscopic picture before PDT.

Figure 6–4 Bronchoscopic picture during PDT.

Figure 6–5 Bronchoscopic picture after PDT.

Figure 6–6 Radiographic picture after PDT.

In a randomized prospective study, PDT was compared with standard laser techniques for inoperable non–small cell lung cancer.¹³ 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 versus 38 days) and improved median survival (265 days versus 95 days) compared with laser resection. However, this finding may be explained in part by the lower proportion of advanced-stage tumors in the PDT group.

In general, PDT is well tolerated with minimal morbidity. In the first 77 treatments that we performed for endobronchial disease, 82% were uneventful. Complications included respiratory failure (7.8%), pleural effusion (1.3%), and sunburn (5.2%). All bright light and sunlight exposure must be avoided initially. Patients remain photosensitive for a period of 4 to 8 weeks, after which they can be gradually reexposed to sunlight.^14,15 Inadvertent direct sunlight exposure has been reported to cause first- and second-degree burns in up to 10% of patients.³⁵ 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%.^11,13–15

Curative Intent

The management of high-grade dysplasia associated with Barrett’s esophagus is controversial. Most surgeons advocate esophagectomy because of the associated risks of occult malignant disease and lymph node metastases.¹⁶ On the other hand, concerns related to the morbidity and mortality of esophagectomy have led some clinicians to advocate alternative approaches, such as surveillance or mucosal ablation.¹⁷ In our experience, we have reported good results with a minimally invasive esophageal resection for patients with Barrett’s esophagus and high-grade dysplasia.^18,19 Mucosal ablative methods include laser ablation, argon plasma coagulation, radiofrequency ablation, and PDT.^20–23 All these techniques attempt to eradicate Barrett’s 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.²⁴ This problem is addressed by other endoscopic techniques, such as 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.

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 with low-grade dysplasia.²⁵ 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 93% of low-grade dysplasia cases. Complete eradication of Barrett’s 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’s epithelium increased the eradication rate to 87%. This group used a transparent centering balloon for PDT delivery, which is no longer available commercially. In a prospective randomized multicenter international trial, omeprazole (20 mg twice daily) was compared with omeprazole plus PDT for the treatment of Barrett’s esophagus with high-grade dysplasia.²⁶ The trial was initially planned for 2 years. However, at the end of 2 years, 65% of the omeprazole-alone group and 59% of the PDT group were enrolled in a long-term follow-up study. At 5 years, the addition of PDT with porfimer sodium to proton pump inhibitor therapy resulted in a 38% increase in Barrett’s high-grade dysplasia eradication rate, a 14% decrease in the incidence of invasive carcinoma, and a longer time to progression to cancer. PDT with a centering balloon was the only endoscopic modality used to ablate Barrett’s mucosa.

PDT can also be used to treat early-stage esophageal tumors (T1-T2) in patients who refuse or are not candidates for surgical resection. In a group of patients that included mostly T1 tumors (12 of 13), regression to Barrett’s esophagus with low-grade dysplasia or without dysplasia was observed in 77% of patients (10 of 13).²⁵ At our center, PDT with curative intent is reserved for patients with high operative risk. All others undergo minimally invasive esophagectomy.¹⁸ We have reviewed our institutional experience, from 1997 to 2005, using PDT for patients with high-grade dysplasia or superficial esophageal cancer.²⁷ 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 re-treated with PDT. There was no procedure-related mortality, and the stricture rate was 42%. 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.¹⁸ These results were corroborated by other investigators who have observed excellent long-term survival (100%) after esophagectomy for high-grade dysplasia.²⁸

In the treatment of Barrett’s 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.^29,30 Other complications include stricture, tumor growth below the PDT-induced scarring, and Barrett’s esophagus and tumor recurrence.³¹ In our experience, approximately 30% of patients with high-grade dysplasia undergoing PDT will develop an esophageal stricture.²⁷ Stricturing is minimized by decreasing the intensity of light therapy compared with doses used for larger tumors.

Another emerging endoscopic treatment modality for patients with Barrett’s 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 joules/cm². 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.³² The depth of injury is highly reproducible and has been confirmed in the human esophagus. In addition to the balloon electrode, there is an RF ablation device that can be attached to the end of a flexible esophagoscope and used to ablate focal areas of esophageal mucosa. Encouraging results have been published showing complete eradication of Barrett’s mucosa and intramucosal carcinoma when RF ablation was used in combination with endoscopic mucosal resection.³³ However, studies involving larger cohorts of patients with longer follow-up time have not yet been published.

Palliative Intent

Stenting of the esophagus is probably the most commonly used modality to palliate dysphagia.³⁴ However, PDT offers some advantages in certain clinical situations. In addition to relieving obstruction, PDT can control or prevent bleeding from the tumor. It may 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%).³⁵ We reviewed our experience with PDT in 215 patients suffering from obstructing esophageal cancer.³⁶ 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 was provided to 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.¹⁴ 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.²⁹ In most cases, the potential benefits of PDT far outweigh the risk of complications.

In patients with obstructing aerodigestive tumors, PDT may 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.^7,14,37–39 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 and the fact that some patients with obstructing tumors receive concurrent radiation therapy and chemotherapy.

Expandable Metal Stents

The procedure can be performed either under conscious sedation or under general anesthesia. The stricture is identified endoscopically and measured. Esophageal stents are available in a wide range of lengths (60 to 150 mm), but in contrast to airway stents, most have a similar maximal internal diameter (17 to 23 mm). If the opening of the stricture is too small to accept the endoscope, the lumen may require dilation and laser ablation before length can be assessed accurately. Fluoroscopy is then used to mark the location of the stricture on the patient’s skin. This is done by use of two radiopaque markers (e.g., small stylets, paper clips) that are aligned with the tip of the endoscope when the endoscope is positioned at the proximal and distal edges of the stricture. Alternatively, some clinicians prefer to inject the submucosa at the proximal and distal ends of the tumor with a radiopaque liquid (Conray). Once the measurement of the tumor length is completed, the proper stent is selected. In general, we use an 18- to 23-mm-diameter stent that is 1 to 2 cm longer than the stricture to avoid crimping and infolding of the ends. A guide wire is passed through the stricture, and the endoscope is withdrawn. Under fluoroscopic control, the delivery system is inserted over the guide wire through the stricture and aligned with the skin or mucosal markers. The stent is deployed and expands within the lumen. Proper positioning and deployment are confirmed fluoroscopically and endoscopically. A postprocedure chest radiograph (in all cases) and barium esophagogram (in esophageal cases) are obtained. Expandable metal stents are popular, as they are easier to insert and do not require expertise in rigid bronchoscopy. Silicone stents are more challenging to place but may be less problematic in the long term. They are preferable for patients with benign strictures.

Silicone-Based Stents

Unless the patient has a tracheal stoma, rigid bronchoscopy is needed to insert a silicone-based stent. A chest tube and the stent are passed over a rigid scope in sequence. The chest tube serves as a pusher to deliver the stent over the rigid scope. For Y-shaped stents, the right main-stem bronchus limb is invaginated and the rigid scope passed through the left main-stem bronchus limb. After it is positioned, the scope is pulled back within the tracheal limb, and biopsy forceps are used to push out the right-sided limb. An alternative technique is to guide the right-sided limb into the right main-stem bronchus by use of a Fogarty catheter while positioning the proximal portion of the stent endoscopically. A complete technical description of rigid endoscopic stent insertion has already been published.⁴² Table 6-1 compares some of the features of silicone and metal stents.

Table 6–1 Characteristics of Silicone and Expandable Metal Stents