Photodynamic therapy and photodiagnosis for Barrett's oesophagus and early oesophageal carcinoma

Photodiagnosis and Photodynamic Therapy (2004) 1, 319—334

REVIEW

Photodynamic therapy and photodiagnosis for Barrett’s oesophagus and early oesophageal carcinoma D. Mitton, P. Claydon, R. Ackroyd MD (Dist), FRCS ∗ Department of Surgery, K-floor, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK Available online 16 March 2005 KEYWORDS Photodynamic therapy; Photodiagnosis; Barrett’s oesophagus; Oesophageal carcinoma

Summary Over the last few decades the there has been a huge increase in the incidence of oesophageal adenocarcinoma, surpassing that of any other solid tumour. Barrett’s oesophagus is recognised as a pre-malignant cursor. Surveillance programmes have evolved to monitor Barrett’s oesophagus, with the intention to detect early malignant transformation. Using photosensitive agents photodiagnosis is developing to detect this transformation before it is visible endoscopically to allow early treatment. Photodynamic therapy is a non-thermal endoscopic ablative technique, which incorporates the same photosensitive agents to treat Barrett’s oesophagus as well as malignant disease. In this article we review the present status of photodiagnosis and photodynamic therapy in the management of Barrett’s oesophagus and early oesophageal carcinoma. © 2005 Elsevier B.V. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Light sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Light delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Light dosimetery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photodiagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photosensitisers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HpD/Photofrin® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-Aminolaevulinic acid (ALA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . m-Tetrahydroxyphenyl chlorin (m-THPC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PDT combined with endoscopic mucosal resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

320 320 321 321 322 322 322 325 327 329 329 331

Abbreviations: ALA, 5-aminolaevulinic acid; BE, Barrett’s oesophagus; CR, complete response; CiS, carcinoma in situ; EC, early carcinoma; HpD, haematoporphyrin derivative; HGD, high-grade dysplasia; IM, intestinal metaplasia; LGD, low-grade dysplasia; m-THPC, m-tetrahydroxyphenyl chlorin; ND, non-dysplastic; NS, not stated ∗ Corresponding author. Tel.: +44 114 2261398; fax: +44 114 2261398. E-mail address: [email protected] (R. Ackroyd) 1572-1000/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(05)00009-8

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Introduction In 1950 Norman Barrett, a London surgeon, described a case of a congenitally short oesophagus lined with columnar epithelium [1]. He believed that the columnar change was caused by the oesophagus pulling the stomach up into the thoracic cavity [2]. Over the ensuing years there has been much debate over the definition of Barrett’s oesophagus. Presently it is regarded as replacement of the normal squamous epithelium of the lower oesophagus by columnar epithelium with intestinal metaplasia [3]. Duodeno-gastro-oesophageal reflux provides the environment in which intestinal metaplasia can develop [4]. This metaplastic epithelium can progress through low-grade dysplasia (LGD) and high-grade dysplasia (HGD) to frank malignancy [5—7]. Barrett’s oesophagus is the major risk factor for development of oesophageal adenocarcinoma. Barrett’s oesophagus has been estimated to occur in about 1 in 100 people [7,8]. The estimated incidence of carcinoma developing in a patient with Barrett’s is 1 in 150 patient years, with a 30—125 fold increase of cancer over the general population [9,10]. The risk of carcinoma rises significantly with severity of dysplasia and the length of the Barrett’s segment [10—13]. Oesophageal carcinoma is increasing in incidence more rapidly than any other cancer in the Western World [14,15]. It is a disease that has a depressing prognosis, with a 5-year patient survival rate of 5—10% [16]. Oesophagectomy traditionally offers the only prospect of cure, although other endoscopic techniques may now also achieve the same result. Over the last four decades the operative mortality has progressively declined from 29 to 6.7% [16—18]. One of the reasons for this decline is probably better patient selection [18]. Unfortunately many patients whose tumours could be potentially resected are declined operative intervention on account of advanced age or significant co-morbid disease, occasionally the patient may not wish to undergo such major surgery. Both medical and surgical strategies are used to control symptoms of gastro-oesophageal reflux and attempt to reduce the extent of Barrett’s mucosa [19—24]. However, their results in this respect are controversial, with no evidence that they cause its regression with resultant reduction in malignant potential [25]. Injury to the metaplastic epithelium can result in its healing with normal squamous epithelium when in an acid normalised environment [26]. Many modalities are available to induce this damage including argon plasma coagulation (APC),

D. Mitton et al. neodymium—yttrium—aluminium—garnet (Nd-YAG) laser and electro-coagulation, all of which act by causing thermal injury to the epithelium. These treatments have been employed in treating Barrett’s and early carcinoma in patients unsuitable for surgery. Photodynamic therapy (PDT) is an alternative to the above techniques. It relies on activation of a previously administered photosensitive drug by non-thermal, visible light of the appropriate wavelength. The excited photosensitiser liberates its energy to molecular oxygen producing singlet oxygen, a highly reactive and cytotoxic species, which causes tissue injury and necrosis [27]. PDT has been used to treat Barrett’s as well as early and advanced oesophageal malignancy. As more mucosal and superficial lesions are discovered, endoscopic therapy incorporating PDT and/or endoscopic mucosal resection (EMR) will equal surgery with less morbidity and equal cure [28]. When used in early cancer with curative intent, PDT has been advocated for T1a lesions or less, as the risk of carcinoma spreading to the regional lymph nodes is proportional to disease stage. The risk is minimal with high-grade dysplasia or Tis [29,30]. This risk increases to 5—8% with T1a but rises significantly to 22—56% with T1b lesions [31]. As a treatment PDT has increased in popularity over the last 5 years, often being performed on an outpatient basis [32].

Light sources Lasers are an ideal source of light for use in PDT, producing monochromatic light, of a known wavelength, which is coherent and allows the power output to be adjusted for accurate light dosimetery. The light produced is easily coupled into a laser fibre, to be delivered endoscopically, to the target site within the oesophagus. Early lasers were expensive systems that required a large space for their installation, a separate power source and external water-cooling, as well as a lot of maintenance, as they were often unreliable. Two of the most commonly used systems were the argon-dye and KTP-dye lasers, whose wavelengths can be adjusted for use with different photosensitisers. Technological advances have resulted in small solid-state semiconductor diode lasers, with none of the drawbacks or their predecessors. However, they produce less power and the wavelength cannot be adjusted, such that they are very specific for the photosensitiser used.

Photodynamic therapy and photodiagnosis for Barrett’s oesophagus

Light delivery Initially fibres were straight tipped and the light was either illuminated on to the surface of the tumour or embedded within it to allow interstitial therapy [33—35]. These have been superseded with diffuser fibres that permit circumferential illumination of the oesophagus, over a large area, allowing homogeneous light distribution [36,37]. Diffuser fibres are placed adjacent to the lesion to be treated, so that adjacent healthy oesophageal mucosa remains unaffected. They come in a variety of lengths but in the case of extensive lesions sequential treatments can be performed [36,37]. When placed within the oesophageal lumen, the fibre may be positioned eccentrically, allowing non-uniform light delivery, producing unpredictable dosimetry and complications. A centring device overcomes this problem and facilitates homogenous light distribution [38]. Centering balloons are ideal for circumferential and multifocal lesions. Panjehpour et al. used a polyurethane centring balloon to treat patients with Barrett’s oesophagus and consequently in patients with dysplasia within a segment of Barrett’s and or early oesophageal carcinoma [39,40]. It is positioned over a previously placed guide wire. Balloon position is monitored by hand control and measured distance. Gossner et al. has developed a through the scope balloon to make the positioning easier [41]. When inflated, the centring balloons are approximately the same diameter of the oesophageal lumen and flatten oesophageal mucosal folds, eliminating the so-called ‘hill and valley’ phenomenon, which can cause incomplete light delivery. Care needs to be taken not to over-inflate the balloon as this can impair oesophageal blood flow, reducing oxygen delivery to the target site prejudicing the PDT process [42,43]. Balloon pressures of 20—25 mmHg allow uniform mucosal injury to occur [44]. Circumferential healing after PDT of the oesophagus can result in stricture formation, which may be difficult to treat necessitating multiple dilatations. Windowed balloons allow ‘targeted’ light delivery to be carried out [39]. Using 180◦ or 240◦ windows the incidence of stricture formation is reduced as any resultant scaring is not circumferential [45,46]. Steroids administered at the time of PDT do not reduce their formation [47]. One of the drawbacks of using a centring Balloon is that endoscopic visualisation during PDT is restricted, oesophageal movement can occur and overlapping treatments may result in stricture development. To overcome this Nakamura has developed a transparent hood that attaches to the tip of the endoscope [48]. Using Photofrin® he treated

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seven patients with 15 lesions (nine early SCC/six HGD) using this transparent hood. He visualized the lesion en face and then immobilized it within the hood before and during irradiation. All lesions were eradicated with one to two PDT sessions. No recurrences have developed during follow-up (4—51 months). It would appear that this hood is suitable for small superficial lesions, requiring good endoscopic technique to hold the lesion in place. Monitoring of position necessitates turning off the laser to make sure there isn’t slippage of the lesion. However, this technique needs further evaluation.

Light dosimetery Tumour response to PDT is influenced by many variables. One of the most critical is light dosimetry. If the fluence is too low, mucosal injury does not occur, if too high excessive damage results and is associated with a higher rate of complications. Thomas et al. subjected tumours to different light and power settings and assessed their response at endoscopy [49]. The degree of tumour necrosis was proportional to the dose of light delivered. Minimal necrosis was observed with doses less than 150 J/cm2 , but total endoscopic necrosis occurred with doses ∼200 J/cm2 . When the power setting was greater than 1.5 W most tumour slough occurred which was also associated with thermal injury and the most complications. Heier treated 10 patients with an initial light dose of 200 J/cm and a second light dose of 200—600 J/cm, 13 patients received 300 J/cm at the first and second light applications [50]. Endoscopy was performed 2—4 days after the second light application, at which time the depth of necrosis was determined by the post-debridement increase in luminal diameter. The log tissue dose of light correlated with the depth of tissue necrosis (r = 0.664, n = 368, p < 0.001). When the data was restricted to tumours with circumferential involvement, which were not dilated prior to treatment, to limit the consequences of tumour compression and increased tissue density on light penetration and necrosis measurements, this correlation was more apparent (r = 0.749, n = 183, p < 0.001). Overholt demonstrated that at 200 J/cm only mild oedema and mucosal injury occurred, at 250 J/cm circumferential mucosal injury results sufficient to destroy dysplastic mucosa [42]. These results support uniform light doses of 300 J/cm (400 mW/cm fibre for 750 s) to obtain clinically effective tumour necrosis, as recommended by the pharmaceutical company, Axcan Pharma.

322 The UK Clinical PDT study group recommend a total light dose of 200 J/cm (400 mW/cm for 500 S) [51].

Photodiagnosis To date there is no proven or reliable method to diagnose occult dysplasia other than by biopsy. Barrett’s surveillance programmes rely on quadrantic biopsies or biopsies of suspicious appearing areas to detect dysplastic or malignant transformation. Chromo-endoscopy using methylene blue can help direct the endoscopist to mucosa that may have highly dysplastic mucosa or malignant Barrett’s [52]. Fluorescence techniques have evolved to identify non-visible disease. The method relies on the incident light exciting tissue fluorophores with resultant fluorescence. Autofluorescence is dependant on endogenous fluorophores (co-enzymes of the respiratory chain) and exogenous fluorescence is dependant upon previously administered fluorophores that accumulate to a greater extent within dysplastic or malignant tissue. Autofluoresence has not been successful in Barrett’s because of high false positive rates [53]. 5-Aminolaevulinic acid (5-ALA), a haem precursor, has been used in photodiagnosis, although it does not have regulatory approval for this. Exogenously administered 5-ALA bypasses the inhibitory feedback mechanism within the haem biosynthetic pathway, with resultant accumulation of protoporphyrin IX (PpIX). Reduced ferrochelatase within dysplastic cells permits PpIX to accumulate to a greater extent, within dysplastic tissue than in surrounding normal tissues [54]. When illuminated at the correct wavelength abnormal tissues fluoresce to a greater extent allowing targeted biopsies to be taken with an increased diagnostic yield. At the end of the Nineties case reports demonstrated that this photodynamic diagnosis (PDD), using 5-ALA, could be successfully applied to dysplastic Barrett’s and oesophageal malignancy [55,56]. Endlicher et al. administered differing doses of 5-ALA both orally (5—30 mg/kg) and topically (500— 1000 mg) in 47 patients with Barrett’s, 10 with known dysplasia [57]. White light endoscopy was performed before switching to blue light (380—440 nm) endoscopy allowing fluorescence detection (EFD). Endoscopy was performed at 4—6 h after oral or 1—2 h after topical administration of 5-ALA. Areas with high PpIX concentrations demonstrated red fluorescence. Using EDF dysplasia and two carcinomas were detected which were not identified with white light endoscopy. Sensitivity after systemic administration did not improved at

D. Mitton et al. doses above 20 mg/kg, indeed false positive fluorescence occurred with doses above this. Following systemic administration light sensitivity occurred in all patients as well as nausea/vomiting in some. Specificity was improved with local application of 5-ALA, with no side effects being reported. Ortner et al. sprayed 5-ALA (500 mg) solution onto the mucosa during gastroscopy, 1—2 h before fluorescent guided gastroscopy was performed [58]. Areas that demonstrated high, medium and low PpIX fluorescence were biopsied. Dysplasia was observed by laser induced fluorescence spectroscopy (LIFS) in 14 of 53 patients (X4-HGD/X10LGD), whereas in only five of these patients had dysplasia been identified by conventional endoscopy, three early cancers were also detected with LIFS. The median normalised fluorescence intensity of dysplastic tissue was significantly higher than in nondysplastic Barrett’s mucosa. LGD could be discriminated from non-dysplastic Barrett’s mucosa with a sensitivity of 76% and specificity of 63%. Distinction between specialised intestinal metaplasia (SIM) and other types of columnar epithelium in short segment Barrett’s was also feasible.

Photosensitisers The first photosensitiser to be used in clinical practice was haematoporphyrin derivate (HpD). This is a crude mixture of monomeric and oligomeric porphyrins. This preparation can be refined to give the oligmeric rich fraction, mostly dihaematoporphyrin ester and ether (DHE). These are the clinically active components that are available commercially as Photofrin® (Axcan Pharma Inc, Montreal, Canada). Unfortunately this is associated with prolonged photosensitivity for several weeks. This is because the drug is retained by skin macrophages for up to 3 months [59,60]. This has resulted in the development of the second-generation photosensitisers 5-aminolaevulinic acid (5-ALA) and mtetrahydroxyphenyl chlorin (m-THPC).

HpD/Photofrin® Tian et al., in 1985, first described the application of PDT in patients with early stage oesophageal carcinoma [61]. Thirteen patients all with squamous cell carcinoma (SCC) were treated, complete remission was observed in 12 patients during followup of 24.6 months (range 21—32 months). From this initial paper there has been several similar case

Author

PDT with HpD/Photofrin® . Patient number

Disease stage

Photosensitiser

Dose (mg/kg)

t-interval (h)

Wavelength (nm)

Energy

Power

Results

Comments

CR—X3

3 patients had oesophagectomy Tumour absent in 1 patient

Tajiri et al. [34]

6

EC

HpD

2.5—3

60—72

630

NS

300—500 mW/cm2

Jin et al. [91]

11

EC

HpD

5

48—72

630

240 J/cm2

200 mW/cm2

Calzavara et al. [92]

21

EC

Hp

5

24—48

NS

60—205 J/cm2

20—200 mW/cm2

HpD

2.5

Sibille et al. [63]

123

u T1 -X61

HpD

2.5—3

u T2 -X27

Photofrin®

2

NS-X35

CR not seen in any patient Partial response in 7 CR—X11

3 patients required 2nd course of PDT X10 CR with power <120 mW/cm2 and light dose <160 J/cm2 CR in a further 6 patients who had DXT, after PR to PDT

48—72

630

200 J/cm2

NS

CR—X99/114

9 patients lost to follow up All adenocarcinomas— –PDT alone 67 patients PDT combined with DXT Local recurrence responds to 2nd course PDT Stenosis in X43 patients needing dilatation (X5 multiple)

Photodynamic therapy and photodiagnosis for Barrett’s oesophagus

Table 1

323

324

Table 1 (Continued ) Author

Patient number

Spinelli et al. [64]

20

Hayata [93]

33

McCaughan et al. [94] Overholt et al. [44]

8

Disease stage

Photosensitiser

Dose (mg/kg)

t-interval (h)

Wavelength (nm)

Energy

Power

Results

Comments

EC-X22

HpD

3

48

630

30—200 J/cm2

NS

CR—X16

Photofrin®

2

Used balloon distal to a transparent tube to eliminate ‘Hill and valley’ effect, oesophageal movement and reflux X2 stenoses responding to dilatation

HpD

2—5

48—72

630

100—600 J/cm2

NS

CR—X32

Photofrin®

2

9 patients survived greater than 5 years

CR—X7

5 year survival was 62% if no previous treatment

EC

Stage I

HpD

>60 J/cm2 24—72

630

300 J/cm

500 mW/cm

48

630

100—250 J/cm

400 mW/cm

Photofrin® 100

LGDX14 HGDX73 T1 -X12 T2 -X1

Photofrin®

2

Centring balloon used

D. Mitton et al.

Uniform injury at 20—25 mmHg Dosimetery studies 175—200 J/cm 73 patients X1 PDT session The rest >1 session Reduction of Barrett’s size in all patients 75—80% mucosa replaced with squamous epithelium, including short segment Barretts X34 strictures—11 needing multiple dilatations Most patients had pleural effusions at 48-h—–X2 needing formal drainage

Photodynamic therapy and photodiagnosis for Barrett’s oesophagus reports. However, the momentum for the use of PDT in oesophageal carcinoma occurred in 1995. This is generally acknowledged to be as a result of a highly influential paper by Lightdale et al. [62]. In this phase III, multi-centre, prospective study, 218 patients with advanced oesophageal malignancy were randomised to either Photofrin-induced PDT (110 patients) or thermal ablation using Nd:YAG laser (108 patients). Improvement in dysphagia was similar for each treatment. Tumour response was statistically higher for the PDT group (32%) than the Nd:YAG group (20%) at 4 weeks. Complete response was achieved in nine patients after PDT and two after Nd:YAG laser. Median survival was similar with both treatments, 123 days for PDT versus 140 days for Nd:YAG laser. Significantly more adverse events occurred in the PDT group (92%) than the Nd:YAG group (82%). However, the perforation rate was significantly higher after Nd:YAG laser therapy (7%) than with PDT (1%). It should be noted that 20 and 40% of patients, in the PDT group, were lost to follow-up at 1 and 4 weeks, respectively. It was as a result of this paper that the U.S. Food and Drug Administration (FDA) granted Photofrin® a licence for use in the palliation of oesophageal malignancy, allowing PDT to rapidly expand as a viable treatment option. Its application has now been expanded to include early carcinomas (Table 1). Sibille et al. carried out PDT in 123 patients to assess the feasibility of curative treatment in early disease [63]. PDT was used as the sole treatment modality in 56 patients (including all patients with adenocarcinoma) and as part of a multi-modal therapeutic approach in 67 patients. Complete response occurred in 87% of 114 patients at 6 months, local recurrence developing in 36% of these patients during follow-up (significantly more often in the adenocarcinoma group than the SCC groups; 75% versus 28.5%, respectively). Local recurrence responded well to a repeat treatment course of PDT. Survival was not influenced by tumour histology, multi-modal therapy or EUS stage. The 5-year survival for the 123 patients was 25 ± 6%, with a disease specific survival of 74 ± 5%. Spinelli et al. treated 20 patients with 22 early oesophageal carcinomas using either HpD or Photofrin® induced PDT [64]. A transparent overtube placed over the endoscope with distal end occluded by a balloon, to eliminate the ‘hill and valley’ effect, reduce oesophageal movement and prevent gastric reflux, was used in 14 patients. At 3 months complete response occurred in 73% of patients after one to two cycles of PDT. This occurred in 79% of patients, in whom the overtube was used, as compared to 62% in the group in which it was not used. Complete response was observed in 86%

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of lesions less that a centimetre in diameter, compared with 50% in lesions with a diameter greater than a centimetre. Three in three patients developed recurrent disease between 6 and 14 months. The actuarial survival was 95, 79 and 26% at 1, 3 and 5 years, respectively. Overholt et al. have reported long-term follow up in 82 patients with Barrett’s with dysplasia and/or early carcinoma, treated with Photofrin PDT [65]. Nd:YAG laser supplemented PDT to small areas of residual Barrett’s (<1.5 cm). Barrett’s mucosa was eliminated in 56 (68%) patients, with a mean reduction in length of 6.9 cm (range 1—22 cm). Buried glands were found in 5% of these patients. Dysplasia was eradicated in all 13 patients with LGD. In 65 patients with HGD, dysplasia was eradicated in 62 (95%). Three patients with HGD went on to develop subsquamous adenocarcinoma, 6—52 months after initial PDT, despite elimination of Barrett’s and dysplasia on previous biopsies. Two of these patients underwent a second PDT treatment, with apparent success. It should be noted, the apparent frequency of carcinoma in those patients with HGD in this study is 4.6%, which is much less than would be expected (25—50%). This needs to be addressed in further studies. Cancer was eliminated in four of the nine patients with early carcinoma. The remaining five patients have all died, only one death was disease related.

5-Aminolaevulinic acid (ALA) ALA has been the preferred photosensitiser of PDT ablation of Barrett’s oesophagus for most of the recent trials (Table 2). This endogenous photosensitiser is part of the haem biosynthetic pathway. ALA itself has no photosensitive properties but is converted into protoporphyrin IX (PpIX), the photosensitive component, which is further on in the pathway. However, in Barrett’s oesophagus there exists an interesting anomaly, which leads to the accumulation of PpIX, through the imbalance between porphobilinogen deaminase (PBG-D) activity with that of ferrochelatase (FC) [66]. The accumulation of the drug within the mucosa sets it apart from the other photosensitisers, Photofrin® and m-THPC, which both accumulate within the sub-mucosa and muscularis mucosa. With preferential uptake in the mucosa the drug has a reduced stricture and perforation rate owing to the reduced tissue penetration. The tissue penetration gained with ALA-induced ablation is ample to destroy Barrett’s epithelium, which has a mean depth of 0.5 mm [67,68]. Barr et al. reported the first clinical trial for ALA-PDT

326

Table 2

PDT with 5-aminolaevulinic acid.

Author

Patient number

Disease stage

Dose (mg/kg)

t-interval (h)

Wavelength (nm)

Energy

Power

Comments

5

X5-HGD

60

4

630

90—150 J/cm2

150 mW/cm2

HGD down-regulated in all patients

Ortner et al. [95]

14

X7-IM X7-LGD

14—16

1.5—2

632

180 J/cm2

NS

LGD eradicated in all patients IM persisted in 11 patients

Gossner et al. [67]

32

X10HGD X22-Ca

60

4—6

635

150 J/cm2

100 mW/cm2

HGD eradicated in all patients CR in 77% patients with carcinoma

Tan et al. [96]

12

X2-CiS

60—75

4—6

630

100—200 J/cm2

90—150 nW/cm2

16.7% total eradication X10-Ca

Ackroyd et al. [72,97]

36

30

4

514

60 J/cm2

120 mW/cm2

100% eradication of LGD

Ackroyd [98]

10

X36LGD X3-LGD X4-HGD X1-CiS X2-Ca

30

4

514 630

50—100 J/cm2

100 mW/cm2

100% eradication of LGD

Jamieson [99]

15

X11HGD X4-Ca

60

NS

635

NS

NS

40% eradication

Kelty [100]

25

X25-ND

30—60

4—6

635

85 J/cm2

68 J/cm2

635

2

2

Barr et al. [69]

Kelty et al. [101] Hage et al. [102]

34 26

X34-IM X32-IM

60

4—6 1—4

630

85 J/cm

68J/cm

100 mW/cm

50% local regression 2

96% endoscopic reduction in Barrett’s at 6 weeks 1 death—–possibly as a result of an arrhythmia

D. Mitton et al.

X8-LGD

30

Median 60% reduction

Photodynamic therapy and photodiagnosis for Barrett’s oesophagus in 1996 [69]. Five patients were treated with HGD and during follow-up of 26—44 months it was noted that no patients had residual HGD. Although the treatment had successfully down-regulated the dysplasia, residual buried glands were found. The authors concluded that ALA-PDT destroyed the superficial layers but was unable to penetrate deeply, thus allowing preservation of the pluripotential stem cells [70]. Gossner et al. achieved impressive results in a mixed cohort of 32 patients, 10 with HGD and 22 with mucosal cancer in Barrett’s oesophagus [71]. Complete regression was achieved in 100% of patients with HGD and 77% of patient with mucosal cancer. The five patients who showed partial regression all had tumours that were greater than 2 mm in depth on endoscopic ultrasonography (EUS). Buried glands were again noted but these showed no dysplasia. The majority of trials with ALA have used red light (630—635 nm), but Ackroyd et al. showed good results with green light (514 nm) in the first prospective, double blind, randomised placebo controlled trial [72]. In this study, 36 patients with LGD were treated with 30 mg/kg ALA or placebo. The results were encouraging in the ALA-PDT group with all showing eradication of the LGD and also with 88.8% showing a macroscopic reduction in length of the Barrett’s oesophagus. The placebo group showed only 11.1% reduction in length of the Barrett’s oesophagus and 66.6% of patients had persistent LGD.

m-Tetrahydroxyphenyl chlorin (m-THPC) m-Tetrahydroxyphenyl chlorin (m-THPC) or tempoporfin is a second-generation photosensitiser. It is a pure compound, which is 100 times more phototoxic at 652 nm and 10 times more phototoxic at 514 nm, when compared to haematoporphyrin derivative or Photofrin® [73]. This allows irradiation times to be reduced dramatically [73] (Table 3). The period of photosensitisation is reduced when compared with Photofrin® , to 4—6 weeks [73,74]. At 72—96 h, m-THPC uptake is selective for mucosa, but discrimination between healthy and early disease of the mucosa does not occur [75,76]. This permits selective destruction of mucosal disease or intra-epithelial neoplasia, with sparing of the deeper tissues [76]. At 96 h m-THPC levels are minimal within endothelial cells of blood vessels, such that non-selective necrosis induced by vascular shutdown is minimal [73,76].

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Fluorescence measurement, within the oral cavity, correlates well with oesophageal tissue levels of m-THPC, such that fluorescence measurement prior to PDT may allow for more accurate light dosimetery [77,78]. This potentially could prevent under treatment of lesions, as well as complications [79]. Unfortunately at this moment in time this is still in its infancy, and not yet in routine clinical practice. Scotia pharmaceuticals (Guildford, UK), the company producing m-THPC (Foscan® ), withdrew the product after failing to get its use approved within Europe. Biolitec Pharma Ltd (Edinburgh, UK) now produce Foscan® . Javaid et al. examined the effect of m-THPC in six patients with HGD and one patient with superficial oesophageal carcinoma [80]. A laser emitting red light (652 nm) was used in four patients with HGD and in the patient with carcinoma. Two patients with HGD were treated using light from a non-laser light source (Paterson lamp) emitting light at 562 ± 15 nm. The light dose delivered was 8—20 J/cm2 with power at the tip never exceeding 200 mW/cm. One patient in the laser group had their Barrett’s and HGD eradicated, two patients had complete eradication of HGD, with a reduction in the length of their Barrett’s segments by 95% and 40%. The fourth patient showed downgrading of HGD to LGD, but no macroscopic reduction in the length of Barrett’s. In the patient with tumour both the Barrett’s segment and tumour were eradicated, with no recurrence at 27 months follow-up. Two patients in this group developed strictures, requiring three to five dilatations to achieve for normal swallowing. In the two patients treated using the Paterson lamp, dysplasia was eradicated in one patient following two PDT sessions. HGD was downgraded in the second patient to LGD, with approximately 40% squamous re-epithelisation of the Barrett’s. m-THPC has been employed when 5-ALA induced PDT has failed. In Gossner’s study five patients with early adenocarcinoma (all greater than 2 mm in depth) that failed to response to ALA, were treated with m-THPC, three of which showed a complete response [67]. Savary et al. have compared the three photosensitisers m-THPC, HpD and Photofrin® in 24 patients with 31 early squamous cell carcinomas of the oesophagus [81]. Complete response was observed in 29 tumours at 3 months. Three tumour recurrences occurred over a period of 7—9 months, but recurrence was not observed in the remaining patients during follow-up (3 months to more than 8 years, mean 2 years). Response was similar with all three photosensitisers. Complications appear to occur more frequently when red light is employed. When Grosjean et al.

328

Table 3

PDT with m-tetrahydroxyphenyl chlorin (m-THPC).

Author

Patient number

Grosjean et al. [45] 17

Javaid et al. [80]

7

Disease stage

Dose

t-interval (h)

Wavelength (nm)

Energy

Power

Results

EC-X17

0.15 mg/kg

96

652

6—16 J/cm2

514

30—100 J/cm2

40—150 mW/cm2

CR-X13 1 fistula and 2 perforations with red light (652) All patients had early stage SCC/adenocarcinoma 2 failures in patients with T1b tumours

652

8—20 J/cm2

Less than 200 mW/cm

CR-X5

Non-laser light source (Paterson lamp) used for 2 patients with HGD Transparent acrylic Eder Puestow used to centre fibre 2 patients downgraded from high to mild dysplasia All patients had tumours >2 mm which had not responded to 5-ALA

HGD-X6

0.15 mg/kg

96

652 ± 15*

EC-X1

Gossner et al. [67]

Savary et al. [81]

Etienne et al. [83]

5

14

12

Comments

EC

NS

NS

NS

NS

NS

CR-X2

Tis -X6

0.15 mg/kg-X2

20

652

6/8 J/cm2

40 mW/cm2

T1a -X8

0.30 mg/kg-X1

20

514.5

30 J/cm2

50 mW/cm2

0.15 mg/kg-X11 20/96

514.5

75 J/cm2

90 mW/cm2

CR-X12 1 patient failed treatment/1 recurrence Fewer complications with green light Patients also treated with Photofrin® and HpD no difference was observed between the photosensitisers Similar recurrence rates for red and green light

0.15 mg/kg

514

75 J/cm2

100 mW/cm2

HGD-X7

CR-X14 Stricture formation in 1 patient Asymptomatic pleural effusion in 1 patient No buried glands

D. Mitton et al.

Tim -X7

96

Photodynamic therapy and photodiagnosis for Barrett’s oesophagus used red light, one patient developed a tracheooesophageal fistula and occult perforation occurred in two patients [45]. Savary reported two oesophageal stenoses and two tracheo-oesophageal fistulae (one further complicated by an oesophageal stenosis) after irradiation with red light [81]. Fewer complications occurred when green light was used. The depth of tissue penetration is greater with red (632 nm) light than with green (514 nm) light; 4.16 and 1.25 mm, respectively [82]. The depth of Barrett’s and dysplastic epithelium is approximately 0.5 mm [68]. Therefore, green light can be used safely in mucosal disease and the risk of transmural necrosis and subsequent perforation is diminished [73,81]. There is, in the sheep model, some evidence that transmural injury can occur with green light when light doses in excess of 100 J/cm2 are delivered [79]. Etienne et al. treated 14 lesions in 12 patients, using m-THPC activated by green light (514 nm) [83]. The response to PDT was 100%, with only one patient developing a stricture, which responded successfully to repeat dilatation. It should be noted that this patient had undergone mucosectomy on two previous occasions as well as thermal ablative treatment (APC) prior to PDT. The risk of stenosis is further reduced by using windowed (180◦ /240◦ ) cylindrical diffusers [73,79,81,83]. The risk of this potential complication may be further reduced if less penetrating blue light is employed [79].

PDT combined with endoscopic mucosal resection Japanese endoscopists pioneered the technique of endoscopic mucosal resection to deal with flat dysplastic/neoplastic lesions of the stomach. In most cases a small amount of fluid is injected into the submucosa elevating the mucosa, allowing it to be excised with a snare. EMR allows the resected tissue to undergo pathological examination [84]. The technique has been modified to deal with similar lesions within the oesophagus and has been used in conjunction with PDT [85—87] (Table 4). Buttar et al. examined the use of EMR followed by PDT to the tumour bed, to eliminate any occult lesions and any unstable mucosa, in 17 patients with early stage adenocarcinoma arising within a segment of Barrett’s [88]. Histological examination of the resected specimens (average size 1 cm2 ) showed that seven patients had stage T0 disease and 10 patients T1 . Resection margins were involved by tumour in three patients. HpD or Photofrin-induced PDT was carried out 4 weeks sub-

329

sequent to EMR. A single session of PDT was required for 12 patients; three patients required a second course of PDT within 24 h, for small nonnecrotic mucosal islands. Two patients required two and three sessions of PDT. Sixteen patients, including those with positive resection margins, had no evidence of recurrent disease during follow-up (3 months to 4 years, median 13 months). Barrett’s was eradicated in nine patients, with no evidence of buried neo-squamous epithelium. In five patients with residual Barrett’s there was no evidence of dysplasia. Invasive adenocarcinoma was evident in one patient during follow-up, and they went on to have an oesophagectomy. Histological examination did not reveal any residual cancer. May et al. used a combination of EMR and PDT in 10 patients with early carcinoma [89]. Lesions whose depth was greater than 2 mm were treated using m-THPC whereas those less than 2 mm were treated with 5-ALA. One patient failed endoscopic treatment, because of locally advanced disease, and went on to have an oesophagectomy. Complete remission was achieved in eight patients. Follow-up surveillance detected three recurrent/metachronous lesions, which responded to further endoscopic therapy. The mean number of sessions required for each patient was 3.8 ± 2.5. EMR combined with PDT is an attractive endoscopic treatment modality for patients that have HGD or early stage carcinoma, as it appears to offer disease cure. The combined application of EMR and PDT is increasing in popularity but this should only be offered within the context of a clinical trial, with intensive endoscopic surveillance [90].

Discussion Over the last decade photodynamic therapy has proven itself as a viable treatment in the management of Barrett’s oesophagus, early and advanced oesophageal malignancy. Knowledge of a photosensitisers properties and the disease process allows the photosensitiser to be matched to the stage of the disease. 5Aminolaevulinic acid is the ideal photosensitiser to be used in Barrett’s oesophagus, as it is a disease of the mucosa and the photosensitiser localises preferentially to the mucosa. ALA can be employed for non-dysplastic and low-grade dysplasia. At present there are no medical recommendations for PDT or any other modality in the ablation of non-dysplastic or low-grade dysplastic Barrett’s oesophagus, except within the confines of carefully regulated clinical trials.

330

Table 4

PDT combined with EMR.

Author

Patient Disease number stage

Photosensitiser

Dose

t-interval (h)

Wavelength (, nm)

Energy

Power (mW/cm)

Results

Comments

Buttar et al. [88]

17

T0 -X7

HpD

4 mg/kg

48

630

200 J/cm

400

CR-X16

T1 -X10

Photofrin

2 mg/kg

630

200 J/cm

200

1 patient underwent oesophagectomy—–no residual tumour X5 strictures—–responded to dilatation

EC-X10

5-ALA

NS

NS

NS

NS

NS

m-THPC

NS

NS

NS

NS

NS

May et al. [89]

10

CR-X8/9 Treatment failure in 1 patient who went on to have an oesophagectomy 5-ALA in lesions ≤2 mm m-THPC in lesions >2 mm

24

EC-X24 HpD Photofrin

4 mk/kg 2 mg/kg

48

630

300 J/cm

400

CR-X20

Rahmani et al.a [104]

88

BE-X63

Photofrin

NS

NS

630

NS

NS

CR-X85

HGD EC

5-ALA

40 mg/kg NS

NS

100 J/cm2 NS

CR-X26

HGDX11 T1m -X11

5-ALA

40 mg/kg NS

633

NS

CR-X18

T1 -X25

Peters et al.a [105]

28

Haringsma et al.a [106] 22

a

Abstracts at Digestive Diseases Week (2004).

NS

2 patients died of progressive disease 20 symptomatic strictures 10 cases of sunburn

D. Mitton et al.

Pacifico et al. [103]

Photodynamic therapy and photodiagnosis for Barrett’s oesophagus However, when the disease is likely to have breached the basement membrane of the mucosa to involve the sub-mucosa or deeper tissues, i.e. high-grade dysplasia or carcinoma, Photofrin® or m-THPC should be employed. It the case of early disease T1a or less, it can be used with the intention of cure. The results of combined treatment with endoscopic mucosal resection are encouraging and this combined treatment is likely to further evolve. Presently Photofrin® is the only photosensitiser licensed for use in high-grade dysplasia or carcinoma. ALA and m-THPC do not have regulatory approval and, therefore, are only to be used within the context of approved clinical trials. The debate to the use of red, green or even blue light will continue. Much research is still devoted to the development of new photosensitisers without the limitations of those already in use. The role of PDT in oesophageal disease is developing, but as further randomised controlled trials are published, its role will become clearer.

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