Photodiagnosis and Photodynamic Therapy (2004) 1, 203—209

Barrett’s oesophagus and photodynamic therapy (PDT) Philippa Elizabeth Claydon, Roger Ackroyd, MD (Dist), FRCS∗ Department of Surgery, Royal Hallamshire Hospital, Sheffield S10 2JF, UK Available online 23 November 2004 KEYWORDS Barrett’s oesophagus; Photodynamic therapy

Summary Barrett’s oesophagus is a precursor of oesophageal adenocarcinoma. This cancer has the fastest growing incidence of any solid tumour in the Western world. Surveillance of Barrett’s oesophagus is routinely undertaken to detect early malignant transformation. However, ablative endoscopic treatments are available and these can obliterate the abnormal epithelium, allowing neosquamous re-growth. Photodynamic therapy (PDT) using haematoporphyrin derivative (HpD)/porfimer sodium (Photofrin® ), m-tetrahydroxyphenyl chlorin (mTHPC) and 5-aminolaevulinic acid (ALA) utilise such a technique. In this non-thermal method of ablation, the photosensitisers, together with light and oxygen, produce local tissue destruction. The use of PDT ablation of Barrett’s oesophagus is reviewed. © 2004 Elsevier B.V. All rights reserved.

Introduction In recent years there has been an unprecedented rise in oesophageal adenocarcinoma. One of the major risk factors for the disease is Barrett’s oesophagus. This pre-malignant, acquired condition due to duodeno-gastro-oesophageal reflux causes the normal squamous epithelium to be replaced by metaplastic columnar epithelium [1—5]. The disease itself has a spectrum, which encompasses non-dysplastic, low-grade dysplasia (LGD) and high-grade dysplasia (HGD); the latter carries a 40—50% risk of a carcinoma in situ being present [6,7]. It has been proposed that the incidence of Barrett’s oesophagus is approximately 4% in the

* Corresponding author. Tel.: +44 1142261398; fax: +44 1142261398. E-mail address: [email protected] (R. Ackroyd).

general population but this rises to 12% in patients with oesophagitis. The relative risk of Barrett’s oesophagus progressing to cancer has been reported as between 1 in 52 and 1 in 441 patient years [8,9]. At present treatment involves regular endoscopic surveillance with multiple random biopsies. All patients are also prescribed a proton pump inhibitor (PPI) which may cause minimal regression, but provides good symptomatic relief [10]. There is also evidence to suggest that a PPI may slow the progression to dysplasia [11]. If histology confirms HGD, then patients are offered surgical resection, but this is major surgery with a significant risk of morbidity and mortality [12]. The rapidly increasing incidence of Barrett’s oesophagus and oesophageal adenocarcinoma has led to the evolution of various ablative therapies, although these are still considered experimental for non-dysplastic Barrett’s and LGD in Barrett’s oesophagus.

1572-1000/$ — see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00062-6

204 Endoscopic ablation is a treatment modality, which has gained popularity. The rationale is to ‘‘injure’’ the metaplastic epithelium to allow neo-squamous re-growth. Various types of therapy are now available, including endoscopic mucosal resection (EMR), multipolar electrocoagulation (MPEC), argon plasma coagulation (APC), potassium-titanyl-phosphate (KTP) laser, neo-dynium-yttrium-aluminium-garnet (Nd:YAG) laser and photodynamic therapy (PDT). To date, three photosensitisers have been used for PDT ablation of Barrett’s oesophagus and include haematoporphyrin derivative (HpD)/porfimer sodium (Photofrin® ), m-tetrahydroxyphenyl chlorin (mTHPC) and 5-aminolaevulinic acid (ALA).

The evolution of PDT for Barrett’s oesophagus Throughout time light has been associated with the restoration of health. References of the use of light can be traced back through many ancient civilisations. PDT uses light to harness the chemical properties of a photosensitiser. Modern PDT was a serendipitous development, as certain chemicals were found to have an enhanced biological activity in the presence of light. Oscar Raab, a German medical student who was using acridine to kill paramecia performed the initial experiment that led to this discovery. His experiments had been more successful during a thunderstorm, which led him to the conclusion that it must have been due to the light, as all the other variables were constant. His supervisor Professor Herman von Tappeiner tested the hypothesis and went on to prove that oxygen was also required for the reaction to work. He coined the phrase ‘‘photodynamic action’’ in 1907 [13]. For PDT to be effective, three factors must be present: light, oxygen and a photosensitiser. The treatment involves the administration of a photosensitising drug, which is then activated by a nonthermal light directed at the tissues. This causes the molecule to be transferred to a higher energy state, from where it can excite oxygen molecules to form an oxygen singlet, which is a highly reactive and unstable species that causes local tissue damage [14]. PDT has been used for the treatment of both malignant and benign conditions. A variety of photosensitisers have also been used within the oesophagus again for both malignant and pre-malignant conditions such as Barrett’s oesophagus. The photosensitisers used to any degree in Barrett’s oesophagus have been haematoporphyrin derivative,

P.E. Claydon, R. Ackroyd Photofrin® (porfimer sodium), 5-aminolaevulinic acid and meso-tetra (hydroxyphenyl) porphyrins (mTHPP). PDT was initially used for the treatment of oesophageal cancer with the defining trial for oesophageal PDT by Lightdale et al. [15]; prior to this there were case series only in this area. Lightdale et al., in a prospective multicentre randomised trial, treated patients with either porfimer sodium induced-PDT or Nd:YAG laser therapy. Two hundred and eighteen patients were treated for palliation of dysphagia from oesophageal carcinoma (PDT 110 and Nd:YAG 108). Tumour response objectively was equivalent at 1 week between the two groups, but at 1 month this was 32% in the PDT group and 20% in the Nd:YAG group. Perforations following treatment or following dilatation for treatment-induced strictures occurred in 7% after Nd:YAG and only 1% following PDT treatment. The authors concluded that PDT had an overall efficacy that was equal to that of Nd:YAG treatment and that a better objective tumour response with fewer perforations was seen in the PDT group [15]. Following this the FDA approved Photofrin® for the palliation of advanced oesophageal tumours. However, observations within these studies also showed regression of Barrett’s epithelium, which led to the next wave of PDT research into the treatment of dysplastic and non-dysplastic treatment of Barrett’s oesophagus. Laukka and Wang [16] reported a small pilot study using HpD-PDT (1.5—2.0 mg/kg) in five patients. The histological grade was improved and 13% had complete eradication of their Barrett’s oesophagus at 12 months. A number of smaller series continued to publish but the largest series by Overholt et al. [17] gave encouraging results. In this series the results were improved with 43% of patients having complete eradication. Dysplasia was also eliminated in 90% of patients, although two patients developed HGD under the neo-squamous epithelium. There were also a significant number of strictures, 34%, which required formal dilatation. MTHPC has been used in a few case series to treat Barrett’s oesophagus with HGD or adenocarcinoma arising in Barrett’s epithelium. Javaid et al. treated seven patients, six patients with HGD and one with adenocarcinoma. The results proved promising once again with 71% of patients reported as having no dysplasia. Of the two patients with continued dysplasia this had, however, been down regulated to mild dysplasia. Interestingly the patient with carcinoma had complete squamous reepithelialisation and remained disease free at 27 months follow-up. There was stricture formation in 29% of patients who required multiple dilatations to improve their dysphagia [18]. HpD and Photofrin are associated with a number of unwanted side effects,

Barrett’s oesophagus PDT which have made them less attractive in terms of PDT therapy for patients without frank malignancy. They have prolonged periods of cutaneous photosensitisation and can persist in body tissues for up to 3 months [14]. This, in conjunction with the high incidence of strictures, heightened the search for another suitable photosensitiser to be used in PDT for Barrett’s oesophagus. ALA is an attractive alternative and appears to have fewer complications. It has, therefore, been the photosensitiser of choice for the most recent studies into PDT ablation of Barrett’s oesophagus. This endogenous photosensitiser is part of the haem biosynthetic pathway. It is not ALA per se that is photosensitive, but rather its precursor, protoporphyrin IX (PpIX), which when combined with iron by ferrochelatase produces haem. The interesting anomaly is that in Barrett’s oesophagus there is an imbalance between porphobilinogen deaminase (PBG-D) activity and that of ferrochelatse (FC), which leads to a greater levels of PpIX [19]. ALA accumulates preferentially in the mucosa [20] and sets it apart from the other photosensitisers, HpD/Photofrin® and MTHPC, which also accumulate within the submucosa and muscularis mucosa. This means that the stricture and perforation rate are both reduced, as tissue penetration is less, thus making ALA a more suitable photosensitiser for nondysplastic and LGD Barrett’s epithelium. The depth of Barrett’s oesophagus has been delineated as being marginally more than that of normal squamous epithelium. It has a mean depth of 0.50 mm compared to 0.49 mm of normal squamous epithelium [21]. This depth is well within the treatment penetration of ALA-PDT [22]. Photodynamic therapy with ALA has been proven to be effective when using low doses of ALA (30 mg/kg) and at this level the number of side effects are also reduced [23]. In the first prospective randomised controlled trial, 36 patients with dysplastic Barrett’s oesophagus were randomised to receive either 30 mg/kg ALA or placebo followed 4 h later by laser endoscopy. The other significant difference with this trial was the use of green light (514 nm). Of the 18 patients treated with ALA, 89% showed macroscopic evidence of regression with a median reduction in area of 30%. Of the 18 patients who had placebo, 11% showed minimal macroscopic regression, but the median response was only 0%. In 33% of patients given ALA there was no evidence of residual LGD [24]. Following the success of this trial a greater number of patients were treated. Forty patients with LGD, including the 18 patients in the treatment group of the previous trial, were given 30 mg/kg ALA, followed by laser endoscopy 4 h later. The

205 patients received green light (514 nm) at a power density of 120 mW/cm2 . Each patient received two treatments only. At 1 month, a macroscopic response was observed in 33 out of 40 patients. This response ranged from 0 to 90% of the treated area. The median reduction in area was 30%. Biopsies from the area of re-epithelialisation confirmed that there was no evidence of buried glands. In those areas that had not shown regression there was, however, no evidence of dysplasia in 39 out of the 40 patients [25]. Gossner et al. treated a mixed cohort of 32 patients, 10 with HGD and 22 with mucosal cancer in Barrett’s oesophagus. All patients were either unfit or had declined surgical resection. Complete regression of dysplasia was seen in all the patients with HGD. Of those with mucosal cancer, 77% (17 out of 22) showed complete remission. In the five patients whose tumour thickness was greater than 2 mm at EUS, only partial remission was achieved. These five patients went on to further PDT treatment, but with mTHPC as the photosensitiser. Three of these patients then achieved complete remission. The remaining two patients underwent surgery despite the known risks and one patient died post-operatively with respiratory complications. Two patients were found to have specialised columnar epithelium under the neo-squamous epithelium, although this was without dysplasia. A further two patients with early carcinoma also required further PDT after local recurrence was detected [22]. Table 1 provides an overview of the clinical studies of PDT-induced ablation of Barrett’s oesophagus. An interesting combination of treatment, which may give improved long-term results, involves endoscopic mucosal resection followed by PDT. The results so far have been encouraging with several small studies now completed. Buttar et al. treated 17 patients with superficial cancers arising from Barrett’s epithelium. Seven patients had intramucosal disease whilst the remaining 10 patients had invasive adenocarcinoma. Photofrin® was the chosen photosensitiser for this study. The results are encouraging with 94% of patients remaining in remission at a median followup of 13 months (range: 3 months to 4 years). One patient was reported to have nodularity around a stricture 3 months after PDT. Biopsies from this area showed diffuse LGD but one sample had evidence to suggest adenocarcinoma. The patient underwent an oesophagectomy but interestingly the histology did not identify any residual cancer and there were no positive lymph nodes. Five patients developed strictures that required endoscopic dilatations. Phototoxicity was experienced in two patients, which

206

Table 1

Clinical studies of PDT-induced ablation of Barrett’s oesophagus.

Author

Light wavelength (nm)

Sensitiser dose (mg/kg)

Number of patients

Laukka and Wang [16]

630

15—20 HpD

55

Wang et al. [33]

630

3—4 HpD

11

Wang et al. [34]

630

1.75 HpD

29

Overholt et al. [17]

630

2 Porfimer sodium

Overholt and Bronner [32]

630

Lovat and Spencer [35] Javaid et al. [18]

Follow-up (month)

Results

9 HGD, 32 LGD, 23 IM 6 HGD, 5 Ca

25

Better histological grade 13% complete eradication 36% complete eradication 20% stricture IM most responsive all show regression 78% dysplasia eradication 34% strictures PDT vs. PPI ↓ in rate of cancer progression PDT 1 death, fistula 71% eradication HGD 100% eradication Ca 1 pt complete response, 2 pts partial response 100% down regulation of dysplasia 77% total or partial regression 100% and 77% eradication of HGD and Ca 16.7% total eradication CIS/in Ca no change, all HGD no dysplasia 100% eradication of LGD 40% eradication Median 60% reduction 98% local regression 50% eradication 1 death? arrhythmia 96% endoscopic reduction

3

100

9 HGD, 10 LGD, 10 IM 87 D, 13 Ca

23—27 4—84

2 Photofrin®

138

138 HGD

12

652 652

0.15 mTHPC 0.15 mTHPC

3 7

3 Ca in BE 6 HGD, 1 Ca

12—24 27

Grosjean et al. [36]

652 or 514

0.15 mTHPC

27

8—26

Barr et al. [37]

630

60 ALA

5

3 Adeno Ca (mixed cohort) 5 HGD

26—44

Ortner [38] Gossner et al. [22]

632 635

14—16 ALA 60 ALA

14 32

7 LGD, 7 IM 10 HGD, 22 Ca

1—30

Tan et al. [39] Ackroyd et al. [29]

630 514 or 630

60—75 ALA 30 ALA

12 10

Ackroyd et al. [24,40] Jamieson [31] Kelty [41] May et al. [27] Kelty et al. [42] Hage et al. [43]

514 635 635 635 635 630

30 ALA 60 ALA 30—60 ALA 60 ALA 30 ALA 60 ALA

37 15 25 32 34 26

2 CIS, 10 Ca 3 LGD, 4 HGD, 1 CIS, 2 in Ca 37 LGD 11 HGD, 4 Ca 25 ND 20 EC/12HGD IM 32 IM, 8 LGD

Mean 16 28 18—54 2—29 1 34 ± 10 12 12

IM, intestinal metapalsia; ND, non-dysplastic; EC, early cancer; CIS, carcinoma in situ; Ca, carcinoma; in Ca, invasive carcinoma; D, dysplastic; BE, Barrett’s oesophagus.

P.E. Claydon, R. Ackroyd

Histological grade

Barrett’s oesophagus PDT resolved with conservative treatment. One patient also experienced bleeding after EMR but this was self-limiting [26]. May et al. treated 10 patients with early carcinoma with this combination. Treatment failed in one patient, who subsequently went on to an oesophagectomy. Of the remaining nine patients, eight responded and achieved complete local remission. However, during the follow-up period of 34 ± 10 months three patients developed a recurrence or metachronous tumour [27]. Pacifico et al. used retrospective data to assess patients that had undergone combined EMR and PDT against those that had had surgery for Barrett’s oesophageal adenocarcinoma. A total of 88 patients were studied, 64 of these had undergone surgery and 24 had undergone EMR and PDT. PDT was performed with porfimer sodium. The outcomes showed a significantly higher rate of procedure related morbidity in the surgery group compared with the EMR and PDT group. In 17%, residual adenocarcinoma was found in the EMR and PDT group. However, it in all these patients the residual adenocarcinoma was picked up on the first endoscopic follow-up examination. It was concluded that further treatment could be offered without a significant delay having occurred due to a trial of EMR and PDT. There was one surgically attributable death in the surgery group and no direct treatment related deaths in the EMR and PDT group. The follow-up of patients who were disease free is comparable between the two groups [28]. The

207 authors suggest that a randomised prospective trial into these two forms of treatment would be the next logical step. A number of abstracts have also been published with encouraging results for EMR and PDT ablation in patients with HGD and early carcinomas.

Conclusion PDT has been shown to be effective in the ablation of Barrett’s epithelium throughout its spectrum. However, to optimise the treatment it is necessary to match the degree of dysplasia to the type of photosensitiser. The main choices are between ALA and Photofrin® . Photofrin® has been granted a license in the UK for the treatment of HGD (March 2004) and advanced cancer in the palliative setting. ALA has been tried in the treatment of HGD and invasive carcinoma but the results are not as encouraging [29—31] as when used for LGD and non-dysplastic Barrett’s epithelium. Ackroyd et al. treated a mixed cohort of 10 patients with Barrett’s oesophagus (three with LGD, four with HGD, one with carcinoma in situ and two with invasive carcinoma) with ALA-induced PDT. In the three patients with in situ or invasive carcinoma no change was observed macroscopically or histologically, with persistent malignant cells found in all cases [29]. Photofrin® , with its deeper penetration, seems a more natural choice to treat HGD and invasive can-

Figure 1. Flowchart of treatment for Barrett’s oesophagus and carcinoma.

208 cers [17,32]. In summary, a suitable choice would be ALA for disease up to 2 mm and Photofrin® or mTHPC for disease greater than 2 mm based on the known penetration of the drugs. Fig. 1 shows the approach adopted by this unit. The treatment of Barrett’s oesophagus continues to be a complex issue. PDT offers a credible choice for all the spectra of Barrett’s oesophagus. Further randomised prospective trials are now required, together with the collection of long-term follow-up data for the patients already treated.

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