PDT with Ps

Ps first received approval in the Unites States in 1995 for palliation of patients with advanced esophageal carcinoma. This approval was on the basis of a multicenter randomized controlled trial comparing PDT with neodymium:yttrium-aluminum-garnet (Nd:YAG) laser therapy. The study involved 218 patients and it showed both treatments were equally effective in improving dysphagia, but there were fewer complications in the group treated with PDT. It was evident from the initial studies of esophageal cancer that treatment with PDT resulted in eradication of the segment of BE. This finding led to a number of studies using Ps-PDT for treatment of dysplastic Barrett’s mucosa. Overholt and colleagues reported their experience treating 100 patients with Ps-PDT, including 73 patients with BE-HGD, 14 patients with BE-LGD, and 13 patients with T1 to T2 adenocarcinoma. Patients were maintained on omeprazole and followed for a mean of 19 months. Small residual areas of Barrett’s mucosa were treated with Nd:YAG laser. Seventy-three patients received one PDT treatment, twenty-two received two treatments, and five patients received three treatments. The authors found that 77% of cancers, 88% of BE-HGD, and 92% of BE-LGD were eradicated by PDT and focal thermal ablation. In 43% of patients, there was complete elimination of all Barrett’s mucosa. The most common complication reported was stricture development in 34% of patients.

Wolfsen and colleagues retrospectively reviewed their experience with 48 patients (34 patients with BE-HGD and 14 patients with T1 cancers). All patients underwent only one course of Ps-PDT, and any residual Barrett’s tissue was subsequently treated with argon plasma coagulator (APC). Complete, successful ablation of all BE-HGD and cancer was documented in 47 of 48 patients. One patient with persistent cancer underwent curative esophagectomy. Most frequent complications included strictures in 11 patients (23%); photosensitivity in 7 patients (15%); and esophageal perforation in 1 patient (2%), which resolved with supportive care.

Multiple other studies confirmed the benefits of Ps-PDT and this led to the first randomized controlled treatment trial in BE with HGD. The study included 30 sites and used a centralized expert pathology laboratory. A total of 208 patients were entered into the study and randomized in a 2:1 ratio to omeprazole plus Ps-PDT (138 patients) versus omeprazole alone (70 patients). Patients could receive up to three courses of PDT. Balloon diffusing fibers were used for the study, at a lower light dose of 130 J/cm. Follow-up consisted of endoscopy and four-quadrant biopsies every 2 cm performed every 3 months until four consecutive quarterly biopsies were negative for HGD, then every 6 months thereafter. The mean follow-up was 24 months. The primary outcome measure was complete ablation of HGD being noted at any time during the study period. Complete ablation of HGD was achieved in 77% (106 of 138) of patients in the omeprazole plus Ps-PDT group compared with 39% (27 of 70) in the omeprazole alone group ( P < .0001). Complete eradication of all BE and dysplasia was seen in 52% of patients in the Ps-PDT group compared with 7% in the omeprazole group ( P < .0001). There was also a significant difference in progression to cancer, with 13% of patients (N = 18) in the Ps-PDT group developing cancer compared with 28% (N = 20) in the omeprazole group. The most common Ps-PDT–related events were photosensitivity reactions (69%), esophageal strictures (36%), vomiting (32%), noncardiac chest pain (20%), pyrexia (20%), and dysphagia (19%). The authors concluded that Ps-PDT was an effective therapy for ablating BE-HGD and reducing the incidence of esophageal adenocarcinoma. The results of this study led the Food and Drug Administration to approve the use of Ps-PDT for the treatment of BE-HGD.

A 5-year follow-up of the original study demonstrated the persistent superiority of Ps-PDT in eliminating HGD long-term (77% in the treatment group vs 39% in the omeprazole group). However, of the 102 patients eligible for long-term follow-up, only 61 patients (48 in the omeprazole plus Ps-PDT group and 13 in the omeprazole group) were enrolled in the long-term follow-up phase. The secondary outcome of progression to cancer remained significantly lower in the Ps-PDT group (15%) compared with 29% in the omeprazole group ( P = .027). There was also a significantly longer time to progression to cancer favoring Ps-PDT ( P = .004).

PDT has also been combined with endoscopic mucosal resection (EMR) for treatment of dysplasia and intramucosal cancers in BE. Seventeen patients with either T0 or T1 esophageal adenocarcinoma by EMR staging underwent PDT with Ps. At a median follow-up of 13 months, 16 patients (94%) remained in clinical and histologic remission. Three patients with positive mucosal resection margins remained cancer-free after PDT. Barrett’s epithelium was eradicated in nine (53%) patients. Complications included self-limited bleeding after EMR in one patient (6%), and strictures after PDT in five patients (30%). In a retrospective study of 24 patients who underwent EMR followed by PDT for early esophageal adenocarcinoma, 83% of patients (20 of 24) remained free of cancer at a mean follow-up of 1 year.

A retrospective cohort study from Mayo Clinic evaluated the overall and cancer-free survival of two groups of patients with T1a esophageal adenocarcinoma in BE: one group was treated endoscopically with either EMR or EMR followed by Ps-PDT. The second group was treated with esophagectomy. There were 132 patients in the endoscopy-treated group (75 with EMR alone and 57 with EMR plus Ps-PDT), and 46 in the surgically treated group. Patients treated endoscopically were older and had more medical comorbidities than those treated surgically. Remission was initially successful in 91% of patients treated with EMR plus Ps-PDT and in 96% of patients treated with EMR alone. Overall survival at 5 years was comparable in the endoscopy treated group (83%) and the surgical group (95%). Sixteen patients (12%) in the endoscopy group had recurrent carcinoma detected during follow-up, and all except one was managed by EMR. The presence of residual dysplastic BE was a significant factor predicting recurrent carcinoma on univariate analysis. The authors concluded that endoscopic therapy was a reasonable alternative to esophagectomy in patients with mucosal esophageal adenocarcinoma in BE.

There have been a few long-term studies evaluating predictors of response to Ps-PDT and risk factors for recurrence of dysplasia postablation. In one retrospective study of 116 patients with BE-HGD, and intramucosal and T1 adenocarcinoma treated with Ps-PDT, pretreatment length of BE was inversely correlated with successful ablation of all Barrett’s epithelium. The presence of intramucosal adenocarcinoma (IMA) or T1 cancer was not associated with higher likelihood of treatment failure. In another study evaluating 261 patients who underwent Ps-PDT with and without EMR, significant predictors of recurrence of dysplasia or neoplasia on multivariate analysis were older age, presence of residual nondysplastic BE, and history of smoking. Biomarkers have also been examined as potential predictors of response to PDT. Using fluorescence in situ hybridization, one group found that p16 allelic loss predicted decreased response to PDT.

A number of complications have been described with PDT ( Table 1 ). Chest pain, nausea, dysphagia, and odynophagia are commonly reported within hours after laser light application. These are commonly treated with analgesics, both topical and systemic. These symptoms usually resolve within 1 to 2 weeks after therapy. Dehydration from poor oral intake needs to be closely monitored and treated, particularly in the elderly.

Photosensitivity has been reported in as many as 69% of patients. Because of the half-life of Ps and its absorption in cutaneous tissues, phototoxicity may last anywhere from 4 to 8 weeks. Patients are sensitive not only to sunlight but also to strong indoor lighting. Symptoms may range from mild erythema to blistering and bullae formation. Patients need to be advised on strict light-protective measures when outdoors, including use of clothing to cover all skin, hands, nose, ears, face, and scalp. By far, the most significant long-term complication of PDT is stricture formation, reported in about one third of patients. The reason strictures form after PDT with Ps is not known. It is possible that the deep tissue injury achieved by Ps-PDT leads to an aggressive fibrotic response that produces stricturing. Risk factors for development of strictures include history of previous esophageal stricture, performance of EMR before PDT, and more than one PDT application in one treatment session. Another study identified the following independent predictors of stricture development: longer segment Barrett’s, multiple PDT treatments, and evidence of intramucosal carcinoma before PDT. The incidence of stricture formation can be decreased by using lower light doses (≤115 J/cm), but this is at the expense of higher frequency of residual dysplasia or cancer in the treated area. The use of centering balloons for laser light delivery or oral steroids does not seem to reduce stricture formation. Other less common complications include fever; vomiting; development of cardiac arrhythmias (particularly atrial fibrillation); and development of asymptomatic pleural effusions.

One concern after PDT is the presence of buried intestinal metaplasia or malignancy underneath neosquamous epithelium. In a study of 33 patients with BE-HGD or intramucosal carcinoma who underwent treatment with Ps-PDT, total buried BE was observed in 9 patients (27.3%) in pre-PDT biopsies and in 17 patients (51.5%) in post-PDT biopsies. Buried dysplastic BE or carcinoma was observed in four patients in pre-PDT biopsies (12.1%) and in nine patients (27.3%) in post-PDT biopsies. In another study involving 52 patients, not a single case of buried nondysplastic BE was noted pre-PDT. After PDT, buried nondysplastic BE was diagnosed in 12 biopsy levels (3.6% of 338 levels) of nine patients (17.3%). There was one patient (2%) with completely buried BE-HGD pre-PDT. After PDT, buried HGD-carcinoma was noted in 19 levels from 13 patients (25%). The occurrence of buried HGD-carcinoma after PDT was neither associated with the length of BE, the diffuseness of neoplasms, nor the presence of buried lesions before treatment. In the largest study of squamous overgrowth and buried glands after Ps-PDT, Bronner and colleagues analyzed the histologic specimens of 33,658 biopsies from the only randomized multicenter study of Ps-PDT for BE-HGD. A total of 208 patients were randomly assigned (in a 2:1 ratio) to omeprazole plus Ps-PDT versus omeprazole alone. Patients underwent rigorous follow-up with four-quadrant jumbo esophageal biopsies every 2 cm throughout the pretreatment length of BE until four consecutive quarterly results were negative for HGD and then biannually up to 5 years or treatment failure. At baseline, squamous overgrowth was identified in 8 (5.8%) of 138 patients in the Ps-PDT group and 2 (2.9%) of 70 in the omeprazole group. After treatment, the percentage of biopsies with squamous overgrowth increased, but there was no significant difference between the Ps-PDT group (39 [30%] of 132) and the omeprazole group (22 [33%] of 67). On a per biopsy basis, squamous overgrowth was present in 114 (0.5%) of biopsies in the Ps-PDT group, and in 130 (1.3%) of biopsies in the omeprazole group, and this difference was not significant. The most advanced diagnosis was never concealed solely beneath squamous overgrowth (not even in a single patient), but it was always present in a surface biopsy taken according to protocol. The authors concluded that subsquamous overgrowth increased equally in the treatment group (omeprazole plus Ps-PDT) and control (omeprazole), and that previous studies using pretreatment biopsies as controls were inadequate in their design. When intensive biopsy surveillance is instituted, squamous overgrowth does not obscure the most advanced diagnosis. Treatment with Ps-PDT does not seem to present a long-term risk of failure to detect subsquamous dysplasia or carcinoma.

PDT with 5-ALA

The first study of ALA-PDT for BE-HGD treated five patients with a median length of Barrett’s segment of 5 cm. Patients were given 60 mg/kg 5-ALA, followed 4 hours later by 630 nm of laser light at a dose of 90 to 150 J/cm ² . HGD was eradicated in all patients at 26 to 44 months of follow-up. In two patients, nondysplastic BE was noted underneath normal squamous mucosa. Gossner and colleagues treated 32 patients (10 patients with BE-HGD and 22 patients with uT1N0M0 adenocarcinoma) with ALA-PDT at a dose of 60 mg/kg. Light was delivered at a wavelength of 635 nm with an energy dose of 150 J/cm ² . All patients were on 20 to 40 mg of omeprazole daily. HGD was eradicated in all patients (10 of 10) and mucosal cancer was eliminated in 17 (77%) of 22 patients at a mean follow-up of 9.9 months. All tumors less than or equal to 2 mm in thickness were completely ablated (17 of 17). Fifteen patients experienced nausea up to 6 hours after treatment. Mild increase in transaminase levels was documented in 21 of 32 patients; these values reached normal levels within a week.

In the only double-blind, randomized, placebo-controlled study reported of ALA-PDT, 36 patients with BE and LGD were randomized to receive oral ALA (30 mg/kg) or placebo. All patients were treated with green light (514 nm) at an energy density of 60 J/cm ² . Up to 6 cm of Barrett’s were treated according to protocol. All patients were maintained on omeprazole, 20 mg daily. A response was seen in 16 (89%) of 18 patients in the ALA-PDT group, with a median decrease in area in the treated region of 30% (range, 0%–60%). In the placebo group, a median area decrease of 0% was seen (range, 0%–10%). This difference was statistically significant. Furthermore, there was complete eradication of LGD in all 18 patients in the ALA-PDT group, compared with only 6 (33%) of 18 in the placebo group ( P < .001). The effects of treatment were maintained for up to 24 months.

The first long-term study of ALA-PDT in BE-HGD and T1a adenocarcinoma was reported by Pech and colleagues. A total of 66 patients (35 with BE-HGD and 31 with intramucosal cancer) were treated with ALA-PDT at a dose of 60 mg/kg. Light was delivered at a wavelength of 635 nm with an energy dose of 150 J/cm ² . Median follow-up was 37 months. Complete remission was achieved in 34 (97%) of 35 patients with BE-HGD. Six patients (6 [18%] of 34) developed a recurrence or a metachronous lesion, but five of these underwent successful repeat treatment. In the IMA group, complete remission was achieved in all patients (31 of 31), but nine patients had recurrence of metachronous carcinoma (9 [29%] of 31). One patient was found to have HGD. Seven patients were successfully treated with ALA-PDT, and one went to surgery. One patient was not a surgical candidate and received palliative treatment 2 years later. Seven patients died during follow-up but no deaths were tumor related. The calculated 5-year survival was 97% in the BE-HGD group and 80% in the carcinoma group.

Other studies of ALA-PDT have shown somewhat disappointing results. In a study from the Netherlands, the authors set out to evaluate the efficacy of ALA-PDT in the eradication of residual neoplasia after previous EMR, and to assess the recurrence rate of neoplasia during follow-up. Patients were separated into two groups. Group A (11 patients) consisted of patients with proved residual HGD or early carcinoma after EMR. Group B (nine patients) consisted of patients with possible residual HGD or early carcinoma after EMR (no HGD or cancer other than in the resected focal lesion). Patients were given 5-ALA at a dose of 40 mg/kg. Ninety minutes to 4 hours after ingestion, red light was delivered at a wavelength of 630 nm for a total light dosage of 100 J/cm ² . The overall success rate was 15 (75%) of 20. There was a significant difference in success rate between group A (55%) and group B (100%) ( P = .03). All patients had residual BE after PDT. The median regression percentage was 50%. Recurrence of HGD-carcinoma occurred in four patients (two in each group) after a median follow-up of 30 months. It is not clear as to what accounted for the low success rates reported in this study. A lower dose of oral 5-ALA (40 mg/kg) was used, compared with other studies that used 60 mg/kg. There was a shorter interval between 5-ALA administration and light delivery (90–240 minutes as opposed to 240–360 minutes used in other studies). Thirdly, the total light dose in the study (100 J/cm ² ) was lower than others have used. Still, the authors argued, and rightly so, that there is no consensus about the optimal setting for any of these parameters.

It is clear there is a wide range of results reported with ALA-PDT, and there is also a high-recurrence rate in patients with early cancer. This variability in results could be caused by multiple factors including 5-ALA dose; light dose; and type of light used (green vs red). In a nonrandomized light dose escalation study, 24 patients with BE-HGD received oral ALA at 60 mg/kg activated by different light doses. The light dose can be expressed as either joule per centimeter length of treated esophagus or joule per square centimeter of the surface of the balloon. Light was administered as 500 J/cm (low dose, equivalent to 100 J/cm ² ); 750 J/cm (medium dose, equivalent to 150 J/cm ² ); 1000 J/cm (high dose, equivalent to 200 J/cm ² ); or two 1000 J/cm treatments given 1 month apart (highest light dose, equivalent to 400 J/cm ² ). The study revealed the highest light dose was significantly better than low and medium light dose for the eradication of HGD in BE. Six (75%) out of eight patients treated with the highest light dose (400 J/cm ² ) compared with one (50%) out of two with a single high light dose treatment (200 J/cm ² ), two (22%) out of nine receiving medium light dose (150 J/cm ² ), and zero (0%) out of five receiving low light dose (100 J/cm ² ), had successful long-term eradication of HGD.

In another study, the same group studied the optimal conditions for successful ablation of BE-HGD with ALA-PDT. Initially, 16 patients were given 5-ALA at 30 mg/kg and randomized to either red (635 nm) or green light (512 nm) at a light dose of 200 J/cm ² . An interim analysis of the study revealed that HGD had been successfully eradicated in only four patients (25%). After discussion with the ethics committee, the trial was restarted using 5-ALA at a dose of 60 mg/kg. Eleven patients were recruited and randomized to receive red or green light. All patients in the red light group had successful eradication of HGD, as opposed to one (20%) of five in the green light group ( P = .01). After another ethics review, the study was extended to treat a further 21 patients with the most effective regimen of 60 mg/kg of 5-ALA, activated by red light at a light dose of 200 J/cm ² . At 36 months’ follow-up, the success rate for HGD eradication in the patients treated with the best regimen was 89%. One patient had mild skin photosensitivity and no patients developed esophageal strictures. Two patients had self-limiting gastrointestinal bleeds, one of which required a blood transfusion. Nausea and vomiting were reported in over half of the patients and all patients receiving the 60 mg/kg dose showed minor, self-limiting elevation in liver function tests. The authors concluded that the optimal regimen to treat BE-HGD was a 5-ALA dose of 60 mg/kg, activated by red light at a light dose of 200 J/cm ² .

In general, 5-ALA has an acceptable safety profile. The most common side effects reported include nausea, vomiting, transient rise in liver enzymes, mild transient photosensitivity, and hypotension.

PDT with mTHPC

There are a limited number of studies evaluating the effectiveness of mTHPC for the treatment of BE-HGD and early esophageal cancer. In a study by Etienne and colleagues, 12 patients with BE-HGD or IMA were enrolled to receive mTHPC-PDT. Four of the twelve patients had failed other therapies (including EMR, EMR plus APC, and Nd:YAG laser therapy). mTHPC was injected intravenously (0.15 mg/kg) 4 days before PDT with green light at 514 nm. The energy density administered was 75 J/cm ² . There were four visible lesions (one HGD, one IMA, and two HGD-IMA). There were 10 nonvisible lesions (six HGD, one IMA, and three HGD-IMA). Twenty PDT sessions were required to eradicate all lesions (nine lesions required only one treatment). The efficacy was 100%, with complete disappearance of HGD and IMA in all patients and the replacement of BE by squamous mucosa in the treated area. The mean follow-up was 34 months. Three patients died during the follow-up period of unrelated reasons. The most common adverse events reported included chest pain, fever, hiccups, asymptomatic bilateral pleural effusion, skin photosensitivity, phlebitis, and esophageal strictures.

In a pilot study, mTHPC was administered to 19 patients (7 HGD and 12 with early esophageal cancer). The mean length of follow-up was 24 months. Successful eradication was seen using red light (652 nm) by diffuser in four of six patients with cancer and three of four with HGD. Using red light (652 nm) and a bare-tipped fiber resulted in eradication of cancer in only one of six patients. One patient in this group developed a fatal aortoesophageal fistula 10 weeks after PDT treatment. Another patient developed a tracheoesophageal fistula, successfully treated with a covered esophageal stent. This particular patient had received treatment with Nd:YAG laser 3 weeks before PDT. Both patients may have had biopsies early after PDT that may have contributed to these complications. None of the three patients with HGD treated with green light delivered by diffuser device had long-term eradication. Two patients developed esophageal strictures.

This limited experience demonstrates that although mTHPC-PDT is a promising ablative therapy, optimal light and drug dosimetry are unknown. Further studies are needed to determine the ideal parameters for treatment under an accepted safety profile.