A randomised controlled trial of ALA vs. Photofrin photodynamic therapy for high-grade dysplasia arising in Barrett’s oesophagus

Abstract

Photofrin photodynamic therapy (PDT) is a licenced treatment for Barrett's oesophagus (BE) with high-grade dysplasia (HGD) but causes strictures and photosensitivity and complete reversal of dysplasia (CR-HGD) by 50 % at 5 years. 5-Aminolaevulinic acid (ALA) is an alternative treatment with non-randomised data suggesting 85 % CR-HGD and a low risk of side effects. We aimed to compare efficacy and side effect profile between the drugs. A single-centre randomised controlled trial was conducted. Presence of HGD was confirmed on three occasions by two specialist GI pathologists. Stratification was by length of BE and extent of dysplasia. Standard protocols for ALA and Photofrin-PDT were followed. Endoscopic follow-up with 2-cm four-quadrant biopsy was at 6 weeks, 4 months, and then annually. All adverse event data were collected. Sixty four patients were randomised, 34 ALA and 30 Photofrin-PDT. Median follow-up is 24 months. On intention-to-treat analysis, CR-HGD was 16/34 (47 %) with ALA-PDT and 12/30 (40 %) with Photofrin-PDT. The overall cancer incidence was 14 % (9/64). On sub-group log-rank analysis, for BE ≤ 6 cm, CR-HGD was significantly higher with ALA-PDT than Photofrin-PDT (χ(2) =5.39, p=0.02). Strictures and skin photosensitivity were significantly more common after treatment with Photofrin-PDT than ALA-PDT (33 vs. 9 % and 43 vs. 6 %, respectively, p<0.05). The rate of buried glands with either drug was significantly higher post-PDT (48 % of patients) than pre-PDT (20 %). ALA-PDT has a better risk profile than Photofrin-PDT. In patients with BE length ≤ 6 cm, preliminary results show ALA-PDT is associated with significantly higher CR-HGD. In longer segments of BE, neither PDT drug is sufficiently efficacious to warrant routine use.

Ablative Endoscopic Therapies for Barrett’s-Esophagus-Related Neoplasia

“…ALA seems to have slightly lesser side effects compared with Ps owing to its shorter half-life and more superficial effect, as shown in a randomized comparative trial. 44 A large multicenter study comparing PDT to PPI showed that the rate of IM eradication was 52% vs 7%, rate of HGD eradication was 77% vs 39%, and rate of progression to cancer 13% vs 28%, respectively. 45 The same group showed the maintenance of these results after 5 years of follow-up.…”

Esophageal neoplasia arising from subsquamous buried glands after an apparently successful photodynamic therapy or radiofrequency ablation for Barrett’s associated neoplasia

“…The presence of buried glands beneath the neosquamous epithelium after a successful PDT or RFA treatment has been described in several studies [10,11]. Buried metaplasia is reported less frequently after RFA (1%) than after PDT (14%) [12], although for PDT, the risk is most likely less for patients treated under optimum conditions.…”

“…If a suspicious lesion was noted at the repeat endoscopy, an EMR was performed. Patients were enrolled either into studies of PDT or, later on, RFA [6,8,10,11].…”

Another modality to treat esophageal cancer?

“…Drugs with a shorter biological half-life would reduce the duration of skin photosensitivity and might also open the way to repeat treatments. Slower, more controlled, tissue destruction could permit preferential regeneration of normal tissues, thus lowering the risk of perforation, and, if the PDT drug is preferentially taken up in the mucosa, as ALA is, there may be fewer side effects [3]. But there are other benefits to be had.…”

“…In fact, the most important RCT was the one which showed the value of PDT using the first generation drug, porfimer sodium (Photofrin), to eradicate high grade dysplasia in Barrett's esophagus (BE), which was published in GIE [2]. Our group later compared porfimer sodium with the shorter acting 5-aminolevulinic acid (ALA) and although neither drug was particularly successful in our study, ALA did have fewer side effects [3]. PDT is no longer used but this work paved the way for the development of radiofrequency ablation of BE which has been very successful [4,5], although its utility in squamous dysplasia has not yet been proven.…”