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hotodiagnosis and Photodynamic Therapy (2007) 4, 151—159

avai lab le at www.sc iencedi rec t .com

journa l homepage: www.e lsev ier .com/ locate /pdpdt

LINICAL REVIEW

he current role of photodynamic therapy inesophageal dysplasia and cancer

oanna Gray, Grant Fullarton MD, FRCS ∗

epartment of Gastrointestinal Surgery, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UKvailable online 16 July 2007

KEYWORDSPhotodynamictherapy;Oesophageal cancer;High grade dysplasia;Barrett’s epithelium

Summary Over the last 15 years photodynamic therapy (PDT) has become a viable treat-ment for pre-malignant and malignant disease of the oesophagus. Its initial use was in thepalliation of oesophageal malignant obstruction bringing improved swallowing hence increas-ing nutritional intake and improving general quality of life. As the therapeutic boundaries ofPDT have stretched, current studies look at the role of PDT in the treatment of pre-malignantdysplastic Barrett’s epithelium and early malignancy as a curative mucosal ablative technique.As a curative treatment in early oesophageal cancer, PDT provides an alternative treatment tooesophagectomy for those more elderly or less medically fit patients.

This paper reviews the uses of photodynamic therapy in oesophageal cancer with referenceto the available publications on its use in the palliation of oesophageal cancer and treatmentof early cancer and high grade dysplasia in Barrett’s mucosa.© 2007 Elsevier B.V. All rights reserved.

ontents

Introduction.............................................................................................................. 152Photosensitizers.......................................................................................................... 152Light dosimetry .......................................................................................................... 152Safety.................................................................................................................... 153Oesophageal cancer—–incidence and epidemiology ....................................................................... 153Barrett’s epithelium...................................................................................................... 153PDT in high grade dysplasia (HGD) in Barrett’s and early oesophageal carcinoma......................................... 153High grade dysplasia ..................................................................................................... 154Early oesophageal cancer ................................................................................................ 155

Palliation of advanced oesophageal carcinoma ........................................................................... 156Future directions for PDT ................................................................................................ 157Conclusion ............................................................................................................... 157

References ............................................................................................................. 157

∗ Corresponding author.E-mail addresses: jojo.gray@gmail.com (J. Gray), grant.fullarton@btinternet.com (G. Fullarton).

572-1000/$ — see front matter © 2007 Elsevier B.V. All rights reserved.oi:10.1016/j.pdpdt.2007.04.003

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ntroduction

hotodynamic therapy (PDT) has become an establishedreatment modality over the last 15 years for use in sev-ral different malignant and pre-malignant conditions whichncludes oesophageal, skin, lung, bladder, head and neck andnvasive intracranial tumours. It involves the administrationf a photosensitizing agent which is then activated using anxternal light source in the presence of oxygen. PDT was firstntroduced as a palliative treatment for oesophageal cancerut its role has now been extended as a first line treatmentn patients with early cancer of the oesophagus or high gradeysplasia within a Barrett’s segment not fit enough for stan-ard treatments. We present here an overview of PDT’s rolen the treatment of oesophageal cancer.

PDT has been used in the treatment of oesophageal can-er for the last 10 years as a non-thermal ablative technique.t requires three main non-toxic components: a photosensi-izer, light and oxygen. It is a two stage process whereby

chemical photosensitizer given systemically may selec-ively concentrate in the target tissue. It has been shownhat systemically injected porphyrin (haematoporphyrin)hen activated by red light causes complete eradicationf transplanted experimental tumours [1]. This study alsoemonstrated the preferential accumulation of the pho-osensitizer in malignant tissue [1]. The sensitized tissues then illuminated at a wavelength that will activate thearticular photosensitizer. After activation the photosensi-izer is elevated from ground state to a long lasting excitedriplet state. This excited molecule can then react with cellembranes to form radical ions which interact further with

xygen to produce cytotoxic oxygenated molecules. Alterna-ively the excited molecule can transfer the energy directlyo an oxygen molecule to generate a reactive oxygen speciesROS) which is also highly cytotoxic. Both these reactionsccur simultaneously.

The photosensitizer accumulates in the mitochondriahere it is synthesized [2] more so in tumour cells thanormal tissue at a ratio of 2:1. This most likely due to theumour tissue’s high vascular permeability, lack of lymphrainage and greater affinity for proliferating endothelium.he photosensitizer aggregates are relatively large and so

revents rapid clearance from tumour interstitial fluid andence uptake in lipophylic components of the cell [3].umour destruction then occurs by direct killing by ROSnd damage to tumour vasculature hence tumour infarc-ion. Studies have also suggested that there is activation

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Table 1 Photosensitizers

Route ofadministration

Dose(mg/kg)

Porfirmer sodium (Photofrin,Axcan, UK)

IV 2

m-Tetrahydroxyphenylchlorin(mTHPC) (Foscan, BiolitecPharma, Ireland)

IV 0.15

5 Aminolevulinic acid (5ALA)(Medac, Germany)

PO [13] 60

J. Gray, G. Fullarton

f an immune response against tumour cells. This may bey the photosensitizer aggregates causing phagocytosis byeticuloendothelial cells [3]. One study by Gollnick et al.4] examined the immunogenicity of PDT-generated murineumour cell lysates in a preclinical vaccine model comparedith other modes of creating whole tumour vaccines such asV or ionizing radiation. This showed PDT to be more effec-ive, tumour specific and appeared to induce a cytotoxic-cell response. Both the UV and PDT generated tumour cellysates were able to induce phenotypic dendritic cell (DC)aturation, only the PDT generated lysates could activateCs to express IL-12 which is critical to cellular immuneesponse development. This shows that the direct tumourffects of PDT play an important role in enhancing the hostntitumour immune response. A further literature review byan Duijnhoven et al. [5] also concludes that PDT destroyshe structure of the tumour thereby enabling the immuneells in the tumour stroma (that are separated from tumourells by extracellular matrix and cellular membrane struc-ures) to directly interact with the tumour cells resulting insystemic anti-tumour immune response.

hotosensitizers

he photosensitizers that have been used in oesophagealancer are porfimer sodium (Photofrin, Axcan UK),

second generation synthetic photosensitizer meta-etrahydroxyphenylchlorine (mTHPC) (Temoporfin, Foscan,iolitec Pharma, Ireland) and 5 aminolevulinic acid (5ALA) inarly oesophageal cancer [6]. Photofrin and Foscan are bothiven intravenously and 5ALA is given orally. We summariseheir properties and safety profile in Table 1.

ight dosimetry

he light dosimetry required to try to produce adequateumour necrosis with minimal normal tissue damage haseen assessed in previous studies. Hier et al. [16] in 1995erformed a preliminary trial using various doses of 630 nmight on 10 of 32 patients in a randomised trial compar-ng PDT and Nd:YAG for palliative treatment for malignant

bstruction using photofrin. This showed light dosimetryorrelated with depth of tumour necrosis (p < 0.001) with00 J/cm being recommended as the optimal light doseequired for effective and safe range of tumour necrosis foralliation of oesophageal carcinomas.

Time to peakconcentration (h)

Lightactivation

Depth ofnecrosis (mm)

48 [7,8] Red 630 nm 6—7 [9]

96 Red 652 nm,Green 514 nm[12]

5—10 [10,11]

6—8 Red 635 nm 2 [14,15]

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Photodynamic therapy in oesophageal dysplasia and cancer

Ten years later PDT is now being used for early cancerand ablation of high grade dysplasia in Barrett’s epithe-lium [17]. This requires a lesser depth of necrosis otherwisethere is high incidence of stricture formation. Panjeh-pour et al. [18] carried out a non randomised unblendeddose de-escalation study in consecutive patients to deter-mine the lowest dose effective for HGD/T1 cancer ablationwhile reducing stricture incidence. This confirmed thatthe incidence of post-procedure stricture formation wasrelated to the light dose delivered. At 115 J/cm 15.3% ofpatients developed severe strictures (where more than 6dilatations were required) and 17% of patients had resid-ual HGD/T1 disease. At 85 J/cm 5.6% patients had severestrictures but 31.6% patients had residual HGD/T1 disease.This showed that decreasing light dose reduces strictureformation but it also increases the risk of residual dis-ease. The UK clinical PDT study group recommend a totallight dose of 200 J/cm [19]. Clearly further studies arerequired to define the optimum laser light dosimetry fortreatment of both pre-malignant and malignant lesions. Ourunit policy for the treatment of HGD or treatment of earlyT1 tumours with Photofrin involves a light dosimetry of100 J/cm with 300 J/cm for the palliation of oesophagealcarcinoma.

Although photosensitizers are currently activated bylasers it may be possible to achieve this simply by whitelight illumination from the endoscope alone. This would sig-nificantly increase the applicability and cost effectivenessof the treatment and studies are currently assessing thisfurther [20].

Safety

Although PDT is a safe procedure, both early and late compli-cations may be encountered. The early complications afterPDT relate to local effects of tumour necrosis and effecton surrounding non-diseased tissues. Common complicationsimmediately post-procedure can be substernal chest painand odynophagia (in approx. 10% due to oesophagitis [21]),dysphagia due to oedema, fever, leukocytosis, pleural effu-sions (3% [22]) and sometimes pneumonia (1% [23]). Patientsmay also develop cardiovascular complications such as atrialfibrillation and congestive cardiac failure. Late complica-tions relate mainly to photocutaneous reactions, strictureformation and late severe complications such as fistula orperforation. The incidence of this is summarised in Table 2.

Oesophageal cancer—–incidence and

epidemiology

The incidence of oesophageal cancer, particularly adenocar-cinoma, has been on the increase in the last 30 years in the

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Table 2 Safety of PDT

Photosensitization reactions Stricture/sten

Porfirmer sodium 6—19% [22,25] 2—50% [17,22,mTHPC 8—10% [26] 5—8% [12,26]5ALA 0 [26,27] 0 [26,27]

153

K. Scotland has the highest incidence of adenocarcinoman men in the world [28]. During the period 1971—1998 thege-standardised incidence rates for oesophageal cancer inhe UK rose by 70% for males and 35% for females [29].here are approximately 7500 new cases of oesophagealancer diagnosed each year in the UK, with a M:F ratiof 5:3 [30]. Worldwide it is the eighth commonest form ofalignancy [31] although this increases to being the fourth

ommonest in developing countries [32]. Generally patientsn the UK (and Northern Europe) are elderly [33] with aoor prognosis with average 5-year survival of less than 10%33]. Only one in three patients progress to surgery [34],ith a 5-year survival in operated patients of 10—25% [30]eaning palliation is frequently the only form of treatment

n offer.

arrett’s epithelium

arrett’s epithelium of the oesophagus is a pre-malignantondition in which the stratified squamous epithelium ofhe lower oesophagus is replaced with intestinal-like colum-ar epithelium. Barrett’s is accepted to be primarily relatedo chronic gastroesophageal reflux disease although theetiology is multifactorial. In certain cases for unknown rea-ons Barrett’s epithelium may progress sequentially throughetaplasia, low and high grade dysplasia to adenocarci-

oma. The risk of progression to cancer is similar for short<3 cm) and long (>3 cm) segments [35].

Approximately 1 in 150 of patient’s with Barrett’s meta-lasia will develop a cancer [36] (although conversion ratesre likely to be higher in areas with the highest incidencef adenocarcinoma). The rate of progression from low gradeysplasia to neoplasia is between 10% and 28% [37] wheres the rate of progression from high grade dysplasia toeoplasia has been quoted between 14% and 80% [37]. Fur-hermore when surgical resections for HGD are examined byhe pathologist invasive carcinoma is actually found in 30%f the specimens [38]. This data would therefore suggesthat the target group should be those with HGD to preventrogression to carcinoma.

PDT has been used to treat high grade dysplasia in Bar-ett’s epithelium, and both early and advanced oesophagealarcinomas. With an increase in Barrett’s epithelium andubsequent oesophageal adenocarcinoma then there is alson increase in the target population suitable for PDT.

DT in high grade dysplasia (HGD) in Barrett’s

nd early oesophageal carcinoma

urrently oesophagogastrectomy is the gold standardreatment for HGD and early oesophageal malignancy—carcinoma in situ or T1/T2 invasive carcinoma of the

osis requiring dilatation Perforation Fistula formation

24] 1—2% [22,25] 2% [23]5% 10.5% [12]0 [14,26,27] 0%

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esophagus. Survival rates with surgery have improved withecent studies quoting >50% 5-year survival rate [39]. Thiss for a number of reasons: the type of tumour is changingadenocarcinoma more than squamous, in distal oesopha-us which is more likely to be completely resected) ands often picked up earlier on Barrett’s surveillance; bet-er patient selection with improved imaging techniques andhe use of neoadjuvent therapies [39]. Surgery, however,an be associated with substantial morbidity (pulmonaryomplications 25%, anastomotic leaks 10—15% [34], cardio-ascular complications 11% [40,41]) and mortality 5—8.8%n large centres in the UK, below the national averagef 10% [40]. Some long-term outcomes of patients havingesophagectomy for HGD shows that although no mortal-ty 29% did have complications [42]. Quality of life scoresn this study were also equal to those of healthy individu-ls however post-operative morbidity included reflux 59%,ysphagia 28% and diarrhoea 55% [42]. It may thereforee suggested that oesophagectomy is not suitable in theore elderly, frail patient or those with significant mul-

iple medical co-morbidity. Oesophagectomy for HGD orarly cancer may also be considered by some, to be anxtremely invasive treatment for what is mucosal diseasethe author does however; recognise that approximately 40%f oesophagectomy specimens removed for HGD do con-ain occult adenocarcinoma [43]). This means a minimallynvasive treatment alternative for HGD and early cancer isherefore clearly needed. PDT is a mucosal ablative treat-ent for such patients which can be used as a sole treatment

r in combination with endoscopic mucosal resection (EMR).ther mucosal ablative treatments include thermal photo-oagulation with standard laser or argon plasma coagulation44].

PDT has several advantages over surgery [45] in thatt is comparatively simple, non invasive, can be targetedccurately, can be used multiple times without the doseimitations of treatments such as radiotherapy and has rel-tively few side effects. Although PDT can occur on anutpatient basis we admit our patients for the admin-stration of the photosensitizer and for up to 2—3 dayshereafter. This in our experience often however relates tohe patient’s age and social circumstances with patients asertiary referrals often travelling long distances from home.DT is less technically challenging than EMR although no ran-omised trial exists comparing the two minimally invasiveechniques. Clinical experience with thermal techniques isimited. A randomised controlled trial in Sheffield [46] ofALA PDT versus argon plasma coagulation in 68 patientshowed them both to be effective for ablating non-dysplasticarrett’s oesophagus. Argon plasma coagulation appearingore effective with 33/34 (97%) patients having complete

blation of Barrett’s mucosa compared to 17/34 (50%) inhe PDT group. A further randomised trial [47] in Liver-ool compared endoscopic ablation of dysplastic Barrett’sucosa using photofrin PDT and argon plasma coagulation

APC). This showed them to be equally effective with allatients having a reduction in the length of Barrett’s epithe-

ium. There were 13 patients in each group and at 4 monthsysplasia eradication was 56% in the APC and 77% in the PDTroups, with follow up at 12 months showing APC 67% andDT 77%. Dysplasia eradication therefore appeared bettern the PDT group.

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J. Gray, G. Fullarton

igh grade dysplasia

ndoscopic treatment of HGD with PDT has been shown toe both safe and effective [48]. The main adverse events arehotosensitivity reactions and stricture formation. Overholtt al. [49] reported long-term follow up of 65 patients withGD treated with Porfimer PDT. The mean follow up was0.65 months. 60/65 (94%) patients had elimination of HGD./65 (4.6%) developed subsquamous adenocarcinoma andfurther 4 (4.9%) developed subsquamous non-dysplasticetaplastic epithelium. The intention to treat success rateas 77.5% for those with HGD although the stricture rate was0%. Wolfsen et al. [50] looked retrospectively at patientsho had had porfimer PDT for HGD and early cancer. 34/48atients had HGD. Of these 19/34 (56%) had complete abla-ion after one treatment and those with residual diseasehen had argon plasma coagulation leading to 34/34 (100%)blation of Barrett’s in the HGD group. A retrospective study51] showed PDT to be effective in ablating HGD in theajority of cases with 80.9% patients having a complete

esponse while 9.5% had a partial response. There has onlyeen one randomised controlled trial [52,53] looking at PDTith porfimer sodium ablation of high-grade dysplasia inarrett’s epithelium in conjunction with acid suppressionompared to acid suppression alone. In this initial 2 year trialblation of HGD was achieved in 77% of patients receivingDT with porfimer sodium and omeprazole 20 mg twice dailyompared to 39% in the group receiving omeprazole 20 mgwice daily alone (p < 0.0001). The trial follow up was con-inued over 5 years to assess the long-term effect on cancerevelopment in HGD. Patients underwent surveillance endo-copies with 2 cm, four quadrant biopsies every 3 months. Atyears PDT was significantly more effective than omepra-

ole alone in preventing progression to cancer (p = 0.027)ith about twice the likelihood of cancer occurring withmeprazole alone (29%) compared to PDT and omeprazole15%). The excellent initial results of this trial maintainedt 2 years led to the regulatory approval of porfimer sodiumDT in Barrett’s HGD in Canada, USA, Japan and Europe. Thiss the first trial to demonstrate a decrease in oesophagealancer development with any therapeutic regime andffers great encouragement for the future. Photofrin hasow also been granted approval in the UK by NICENational Institute of Clinical Excellence) for use in Barrett’spithelium [48].

ALA has also been assessed in dysplastic Barrett’s epithe-ium. Several studies have shown ALA induced PDT to beafe and effective in the ablation of Barrett’s metaplasia.maller studies have assessed ALA treatment in HGD. Goss-er et al. [54] treated nine patients with HGD in Barrett’spithelium with 5ALA PDT. All nine patients had eradicationf the HGD with a mean follow up of 16.9 months. Pecht al. [55] reported their experience with ALA PDT in 35atients with Barrett’s HGD. Thiry-four out of 35 patientsad a complete response during a median follow up of 37onths. Barr et al. [56] used 5ALA along with omeprazole

0 mg daily in five patients with HGD in Barrett’s epithelium

nd achieved complete ablation and no recurrence by 26—44onths.mTHPC with green light activation at 514 nm has been

sed in the ablation of HGD in 12 patients with completelearance of dysplastic tissue [13]. M THPC has also been

Photodynamic therapy in oesophageal dysplasia and cancer

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Figure 1 Neosquamous oesophageal epithelium.

used with red light activation to clear three of four patientswith HGD although two serious complications occurred dur-ing this study [12].

Whatever mucosal ablative technique is used in HGD it isimportant to remember that surveillance must continue asthe oesophagus re-epithelialises, however, as the destruc-tion may be incomplete [57] and remaining metaplasticareas may still have oncological potential. The major con-cern with PDT is it involves the potential for cancer cellsto develop beneath the neo-squamous epithelium (Fig. 1).There have been several reports of columnar epithelialremnants persisting beneath the new squamous epitheliumwhichever method of mucosal ablation of Barrett’s epithe-lium is used [58,59]. Van Laethem et al. [60] described acase report where intramucosal adenocarcinoma was foundin squamous re-epithelialisation of Barrett’s oesophagus thathad been ablated with argon plasma coagulation. The ade-nocarcinoma was found 18 months after complete squamousre-epithelialisation and presented as a bulging area cov-ered with squamous epithelium. Such an adenocarcinomamay have originated from residual metaplastic glands buriedunder the neo-squamous epithelium, although it is difficultto exclude a pre-existing tumour. The significance of such‘‘buried columnar glands’’ is yet to be determined there-fore continued surveillance of neo-squamous epithelium isadvised.

There is very little information in the literature lookingat the cost of PDT as a treatment of high grade dysplasiain Barrett’s epithelium. The only study assessing cost of PDTfor use in high grade dysplasia is by Hur et al. [61] comparingPDT, oesophagectomy and intensive endoscopic surveillancefor Barrett’s. This paper shows that there is increased lifeexpectancy and so PDT was cost effective when comparedto endoscopic surveillance and surgical oesophagectomy.

Early oesophageal cancer

Patients require appropriate staging to confirm the diag-nosis of intramucosal carcinoma (CIS or T1) with both alocal assessment by endoscopic ultrasound (EUS) and aCT chest/abdomen. EUS is more accurate in assessing theoesophageal wall in terms of depth and can give evidence of

any regional lymph node involvement giving a more accurateT and N stage [62].

We have recently demonstrated the importance ofEUS in the selection of patients who will benefit from

wowd

155

DT for early cancer [17]. This study demonstrated thatDT with sodium porfimer could produce complete endo-copic and histological response in 9/9 patients withp to two treatment sessions at a median follow upf 30 months (range 2—56 months) in patients whoad EUS confirmed early oesophageal cancer (CIS or T1)17].

Sibille et al. [63] retrospectively studied 123 patientso assess the feasibility of PDT as curative treatment inarly oesophageal cancer. Eighty out of 88 patients hadre-operative EUS staging. They were staged as T1 or T2.DT was part of a multimodal therapeutic approach in 67atients, with radiotherapy applied in 58 cases 2 monthsfter PDT and combined chemotherapy and radiotherapyn 18 patients. Nine patients had chemotherapy alone withDT. At 6 months complete response was shown in 91% of the1 group and 78% of the T2 group although this was not sig-ificantly different. Recurrence was not described for thetaged sub groups such as T1, T2, PDT alone or PDT mul-imodal therapy groups but recurrence was more commonn adenocarcinoma (75%) compared to squamous cell carci-oma (28.5%). However overall local tumour recurrence was6% of all patients and patients with local recurrence didespond to repeat PDT. Sixteen were repeated due to initialncomplete response and 28 because of tumour recurrencefter initial complete response. Five-year survival was simi-ar in T1 and T2 groups being 33% and 36%, respectively. Thiss comparable to the overall survival rate in all 123 patientsf 25%. The disease specific survival rate was 74 ± 5%. Theelatively low survival rate reflected the poor clinical sta-us of the patients being treated, with most of them havingevere medical co-morbidities.

Overall current evidence suggests that PDT with sodiumorfimer can be a curative option in patients witharly oesophageal cancer being particularly useful inatients with significant co-morbidities which precludesurgery.

There have been a two small studies looking at the com-ination of EMR and PDT. In one study [64] 17 patientsith early adenocarcinoma in Barrett’s epithelium were

reated with EMR and PDT. Seven patients had T0 and0 had T1 disease. Four weeks after EMR, PDT was giveno all patients to remove any occult lesions. The mar-ins had involvement of cancer in three cases and EMRmproved staging in eight patients (47%). Sixteen patientsad no recurrence at a median follow up of 13 months.ne patient developed invasive carcinoma and had anesophagectomy but histology actually revealed no resid-al cancer. Complications included minor bleeding after EMRn one patient (6%), stricture formation in five patients30%), cutaneous phototoxicity in two patients (12%) andupraventricular tachycardia in one patient (6%). Othernteresting findings were eradication of Barrett’s in nineatients and in those with remaining Barrett’s no dyspla-ia was identified. A further retrospective study looked athree patients that had had EMR and PDT 6 weeks lateror early adenocarcinoma (T1N0M0) [65]. At a median fol-

ell, with no evidence of Barrett’s metaplasia, or dysplasian surveillance endoscopies. Post-procedure complicationsere limited to self limiting dysphagia and some chestiscomfort.

156 J. Gray, G. Fullarton

Palliation of advanced oesophageal carcinoma

PDT has become an accepted method of palliation in thepatients with advanced inoperable oesophageal cancer [66]along with other options including laser, argon-plasma coag-ulation, chemically induced tumour necrosis, self expandingstents, radiotherapy and chemotherapy. In addition PDT canbe used alone or in combination with any of the abovetechniques although combination treatment has not beensubject to careful clinical trials.

PDT is appropriate for patients with obstructive endo-luminal lesions (Fig. 2) particularly those in the upper(post-cricoid and cervical) oesophagus or in the lowerthird of the oesophagus crossing the gastro-oesophagealjunction, recurrence of tumour after surgical resection orchemoradiotherapy and for tumour overgrowth in stents.Tight fibrotic carcinomas and post-radiotherapy stricturingtumours are not suitable for PDT. Other contraindicationswould be patients with portal hypertension, porphyria orhypersensitivity to porphyrins, hepatic impairment, and theexistence of a tracheo-oesophageal fistula or bleeding fromthe oesophageal tumour [19].

Several uncontrolled trials have documented objec-tive and patient reported response rates of 60% or more[21,22,67]. Other trials comparing Nd:YAG laser to sodiumporfimer PDT have suggested that both methods requireapproximately two treatments to achieve adequate clini-cal response [25,68]. Lightdale [25] compared laser ablationwith sodium porfimer PDT in a multicentred randomisedstudy treating 218 patients. There was no significant dif-ference between the two in terms of dysphagia scores at1 month but PDT was the safer method resulting in fewerperforations and had the better objective tumour response.Hier et al. also published results of a phase 3 trial of sodiumporfimer PDT versus Nd:YAG laser [68] where 22 patientswere randomised to PDT and 20 to Nd:YAG. At 4 weeksPDT treated patients had significant improvement in theirdysphagia grade and performance status (p < 0.006). Theduration of response was also better in the PDT group butsurvival was similar at 145 days for PDT and 128 days forNd:YAG.

In our own unit we have also demonstrated sodiumporfimer PDT’s efficacy in the palliation of advancedoesophageal cancer [69]. In 30 of our patients treatedwith palliative intent for advanced oesophageal cancer withmetastatic disease and previously failed therapies dysphagiascores were measured before and after PDT. The dysphagiascore ranged from 4 to 1 with 4 being inability to swallow.

Figure 2 Endoscopic view of obstructing tumour pre- andpost-PDT.

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igure 3 Effect of photofrin PDT on dysphagia score.

he median dysphagia score one month after treatment fellignificantly (p < 0.001) (Fig. 3) and the median survival wasmonths (range 1—34 months).It is interesting to compare these results with other pal-

iative methods. We previously assessed in a randomisedtudy of 50 patients the performance of plastic and metallictents in the palliation of oesophageal cancer [70]. Metallictent patients had a median survival of 107 days comparedith 62 days in the plastic stent group. Therefore in a sim-

lar cohort of patients, survival post-PDT appeared somehat improved. In our own last 25 patients treated with

odium porfimer PDT for palliation of oesophageal cancerur median survival is further improved at 197 days. This sur-ival benefit has also been noted after PDT at other tumourites such as cholangiocarcinoma [71]. This improved sur-ival rate may be due to better tumour ablation howeverDT may also induce a systemic effect with an improvedmmune response in these patients.

Another area of combination therapy which requirestudy is PDT and radiotherapy. PDT destroys local diseasend radiotherapy treats loco-regional disease. Sanfillippo etl. [72] retrospectively looked at the cases of three patients,wo oesophageal cancer patients were treated with com-ined chemotherapy and external beam radiation (55.8 and0.4 Gy) followed by intraluminal brachytherapy (12 and5 Gy at 1 cm). These patients then received sodium por-mer PDT for recurrence. A third patient with non-smallell cancer was treated with external beam radiation (60 Gy)ollowed by intraluminal brachytherapy (36.1 Gy at 1 cm)nd then received PDT for recurrence. One oesophagealatient developed a tracheoesophageal fistula requiringstent and the other developed quadriplegia due to an

pidural abscess arising from a fistula within the diseasedortion of the oesophagus. The lung cancer patient had aassive haemoptysis after the procedure and died 2 days

ater—–post-mortem showed necrotising arteritis of the rightulmonary artery. This suggests that patients with PDT andxternal beam radiation are more at risk of complicationslthough this may be related to the radiotherapy dose deliv-red. However a further study by Maier et al. [73] reviewing3 patients after endoluminal palliation, found 15 to havead PDT, brachyradiotherapy and external beam irradiation.he combined multimodal approach showed a median sur-ival of 16.8 months. The severe complication rate was 5.7%

nd mortality was1.9%. This study concluded that the use ofDT combined with irradiation was associated with accept-ble survival rate, low rates of complications and reasonableuality of life. The benefit of combination PDT and radio-herapy may relate to the ability of Photofrin to act as a

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radiosensitizing agent [73—75]. This is an exciting area andfurther studies are required to define the true efficacy andsafety of combined PDT and radiotherapy.

The cost of PDT has always been raised as a concern par-ticularly as the photosensitizer is expensive and specialisedlaser equipment is required. We have recently looked at thecost effectiveness of PDT compared with metallic stents ina retrospective study. This demonstrated that although theoverall cost of palliation of oesophageal cancer was moreexpensive with PDT compared to metallic stents, a pro-longed survival in the PDT group led to a slight cost benefitin terms of cost per day survival in the PDT group [76].

It is important to assess the effect of palliative thera-pies on the quality of life of patients. Prospective studiescomparing PDT with other palliative techniques shouldassess their impact on patient’s quality of life to deter-mine the optimal oesophageal cancer palliation. Currentevidence however suggests that PDT offers good palliationof oesophageal cancer compared to other techniques.

Future directions for PDT

PDT has become an established palliative treatment foradvanced oesophageal cancer and is safe, simple and effec-tive. It leads to an improvement in dysphagia scores, hasbeen shown to increase length of survival and has accept-able side effects for this group of patients with advanceddisease. Photofrin is the only photosensitizer which hasa licence for use in oesophageal disease both for thepalliation of oesophageal cancer and now for the treat-ment of high grade dysplasia in Barrett’s epithelium andearly oesophageal cancer. Safety and efficacy has beenshown for this using porfimer sodium (Photofrin) PDT [25]though continued surveillance is required and more thanone PDT course may need to be applied. Future randomisedstudies comparing PDT with other palliative techniqueswill establish its true place in oesophageal cancerpalliation.

There are several areas of PDT where developments couldlend to future benefit. Photosensitizers which could be takenorally with improved tumour localisation and increasedtumouricidal effects with minimal collateral tissue damagewould be desirable. Photosensitizers with an improved phar-macokinetic profile which would allow it to reach its peakconcentration in several hours but be excreted promptlywould also be an advantage. This in turn would meandecreased side effects such as photosensitivity and stric-ture occurrence. The use of combination photosensitizerswhich target tumour stroma and vascular elements as wellas cellular components may prove beneficial [77].

An improved laser delivery with better assessed lightdosimetry which would provide adequate depth of penetra-tion and tumour destruction in large tumours but superficialmucosal ablation without stricturing in HGD and early cancerwould be helpful. It may be that lasers will not be requiredat all and endoscopic white light activation may be ade-

quate. This would decrease the cost of PDT, improve itssafety profile and greatly increase the applicability of thistreatment.

Better light delivery systems with improved laser fibreswith more targeted diffusers such as better balloons would

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ocalise treatment and decrease damage to normal sur-ounding tissue.

The combination of PDT with other modalities suchs EMR (endomucosal resection), local chemotherapy andadiotherapy which may have an additive effect needs fur-her study.

onclusion

n the future PDT will become a more refined treat-ent modality as photosensitizers, light dosimetry and

ight delivery systems are modified. PDT will continue toave a definite clinical role in the palliation of advancedesophageal cancer and will establish its role further in thereatment of pre-malignant disease of the oesophagus andn early oesophageal carcinoma.

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