Photodynamic Therapy for Barrett?s Esophagus and Esophageal Cancer

PICHON-RIVIERE, A.; AUGUSTOVSKI, F. A.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 30

1668-2793

Barrett´s Esophagus (BE) is a condition characterized by replacement of the esophagus normal squamous epithelium with columnar epithelium, as a reaction to chronic gastroesophageal reflux. It favors dysplasias, which may progress into esophageal adenocarcinoma. Esophageal cancer is the eighth most common malignancy in the world with a prevalence of 0.6% to 1% of the patients who undergo upper digestive endoscopies. In Argentina, the incidence rate reported in 2008 is 4.4 every 100,000 inhabitants.Curative treatments used for esophageal cancer include surgery (esophagectomy), ablation by endoscopic techniques or combined procedures. In advance stage neoplasms, palliative surgery is proposed; also non-surgical treatments such as radiotherapy with or without chemotherapy or endoscopic techniques are also considered. Photodynamic therapy (PDT) is an endoscopic technique used both for BE and esophageal cancer (curative and palliative intent). It is proposed because it is easy to use, fewer sessions are needed when compared with other endoscopic techniques, and it has a low morbidity-mortality and cost.TechnologyThe technique is to first mark the pathological tissue with a photosensitizer and then to destroy the selectively marked tissue using an endoscopic light source of varying wavelengths (PDT red, PDT green). Sodium porfimer (Ps) and 5-aminolevulinic acid (ALA) are the most common photosensitizers.PurposeTo assess the available evidence on the efficacy, safety and coverage related aspects for the use of PDT in patients with BE and esophageal cancer.MethodsA bibliographic search was carried out on the main literature databases, in regulatory and coverage agency websites, in medical associations related with the subject, Vortal HTAi, Euroscan, INAHTA search engines, Internet generic search engines and others. Systematic reviews; meta-analyses, clinical trials, observational studies, health technology assessments, economic assessments, clinical practice guidelines, documents from regulatory agencies and coverage policies from other health systems were included.ResultsTwenty-five primary studies were selected, 12 were randomized controlled clinical trials and thirteen were non-randomized controlled trials. Additionally, 11 documents including health technology assessments, clinical practice guidelines and systematic reviews, and 6 economic assessments were selected.Barrett?s EsophagusEfficacyAmong the clinical trials carried out with Ps, one trial published in 2007 randomized 208 patients with BE and high-grade dysplasia (HGD) to PDT with PS (2 mg/kg) plus omeprazole (138 patients) or omeprazole alone (70 patients). The follow-up was 5 years. Complete ablation after 5 years was achieved in 106 patients in the group undergoing PDT+PPI (77%, 95% CI 0.70-0.84) and in 27 patients in the PPI group (39%, 95% CI 0.27-0.50). Mean complete response period in the PDT group was 44.8 months and 3.2 months in the omeprazole group. After 5 years, the rate of patients who progressed to cancer was 15% in the PDT+OM vs. 29% in the omeprazole group (p=0.03).Another RCT published in 2005 randomized 26 patients with BE and dysplasia to APC or PDT with Ps (2 mg/kg). All the regimens included PPI. Mean age was 60 years and mean follow-up was 12 months. All the patients showed reduction of the BE size. As regards dysplasia eradication, after one year, the rates were 67% and 77% respectively, with a statistically non-significant result. Other works with Ps are described in this publication.Among the clinical trials reviewed which used ALA, one RCT published in 2000 randomized 36 patients with BE and LGD to ALA (30 mg/kg) + PPI, or placebo + PPI. Although after one month, macroscopic evidence of BE reduction was 89% for PDT vs. 11% in placebo (p < 0.001), after two years, no results on the progression to cancer or survival were reported. In 2004, one RCT which randomized 68 patients with BE to PDT with ALA (30 mg/kg) or APC was published. Both regimens included PPI. The group mean age was 61 years and follow up was 12 months. Complete response in 50% of the PDT group and 97% of the APC group (P<0.01) was evidenced. Other studies using ALA are described in this publication.SafetyWith Ps-PDT, the most common major adverse effects were photosensitivity and esophageal stricture (intermittent or not, requiring dilatations or not) and pleural effusions. In ALA-PDT, the most commonly reported adverse effects were transitory chest pain and dysphagia, nausea and vomiting, transaminase increase, photosensitivity with mild erythema and fever.Early-Stage Esophageal CancerEfficacyIn 2003, one comparative non randomized clinical trial included 88 patients with early-stage esophageal adenocarcinoma. Two groups were evaluated: twenty-four patients who had received EMR + PDT with Ps (2 mg/kg); and 64 patients who had undergone esophageal surgery (esophagectomy). Follow up was 12 months for the first group and 19 months for the second one. The rate of disease-free patients after one year was 83% for patients in the PDT group and 100% for patients in the surgery group. Patients who underwent esophagectomy had a significantly higher rate of complications than those who underwent to EMR+PDT (P<0.01). Other observational studies are also described in this publication.SafetyAdverse effects such as stenosis or constrictive esophageal fibrosis have been reported in 8 to 42%, photosensitivity and skin reactions in 8 to 13%, esophageal-tracheal fistulae in 8% of the patients, and nausea, vomiting, fever and chest pain.Late-Stage Esophageal CancerEfficacyAmong studies with curative intent, one RCT was published in 1995 as a congress abstract; it randomized 218 patients with dysphagia due to esophageal cancer to PDT with PS (2 mg/kg) or laser thermal ablation. Mean age was 70 years old. Complete response was achieved in 8% (9/110) of the PDT group and in 2% (2/108) of the laser group. There were no significant differences between the groups as regards improvement of the dysphagia score. The follow up period was not reported. In 2002, one RCT that randomized 56 patients with advanced and non-surgical esophageal cancer to PDT (DHP 1.7-4 mg/kg or PS 2 mg/kg) or stent placement was published. There were no significant differences in survival for both groups. Seventeen percent of the patients responded to PDT and were crossed over to stent placement. The text describes other studies.As regards studies with palliative intent, two RCTs compared PDT vs. Nd;Yag Laser. The first study used Ps (n=236) and the second one used a hematoporfirine derivative (HpD) (n=42). Both reported that no clinically or statistically significant clinical differences were found in mean survival between both techniques.As for PDT vs. radiotherapy, one RCT reported PDT with HpD + radiotherapy vs. radiotherapy alone. Survival rates after 5 years were reported to be higher for PDT + radiotherapy than radiotherapy alone (29.9% vs. 16.7%, p = 0.05), and survival after 10 years was reported to be higher (16.7% vs. 10.0%, respectively p < 0.05).Another study from 2011 randomized 93 subjects to three therapy arms with palliative intent in patients with malignant obstruction; APC with brachytherapy, APC with PDT and APC alone. APC+PDT and APC + Brachytherapy were significantly better than APC alone in terms of dysphagia. There were not differences in overall survival in any of the arms. Experiences with PDT + chemotherapy and PDT + oxygen hyperbaric therapy are also described.SafetyIn the group of patients, the most commonly reported adverse effects include chest pain, esophageal stricture, fistulae and photosensitivity.Coverage PoliciesSeveral coverage policies from U.S. private health insurance companies have been identified. Most of them agree on covering photodynamic therapy for the palliative treatment of obstructive cancer and to treat dysplasias in patients with non-resectable BE. No coverage policies were identified in relation to early-stage cancer.ConclusionsIn general, evidence of variable methodological quality was identified in relation to the effectiveness and safety of the technology for BE and esophageal cancer. This evidence consists in RCTs, one cohort study and several non-randomized controlled studies.In BE, the evidence suggests that PDT plus PPI would be more efficacious than PPI in achieving long-term ablation of HGD and to slow down progression to cancer. Due to methodological limitations, the RCTs which compared PDT to APC do not allow to conclude if PDT is better, equal or worse than APC.To assess PDT in patients with early-stage esophageal cancer, observational studies were found which included different populations and sensitizer type. It is not possible to draw conclusions on the effectiveness of the technology in this subgroup of patients.In advanced and obstructive esophageal cancer, in terms of treatment with curative intent, one RCT suggesting that PDT was more efficacious than the Nd:YAG laser therapy was found. No significant differences were found between Stents or PDT. Brachytherapy with PDT seems to be more efficacious than brachytherapy alone. Small RCTs with palliative intent suggest that the addition of PDT to radiotherapy might be beneficial. Nd:YAG Laser and PDT might not differ in terms of mortality. There is no consensus on the optimal scheme in terms of right choice of photosensitizer, wavelength and length of exposure. As regards safety, the most common adverse effects of PDT were esophageal strictures and skin manifestations due to photosensitivity.To conclude, the current evidence suggests a defined role in non-surgical patients with BE and late-stage esophageal cancer, especially with palliative intent. PDT has not been compared in the literature yet against emerging techniques with a better safety profile and growing use, as radiofrequency ablation.