Barr by pengxiuhui


									                                                                            Gastrointestinal Cancers

                      Photodynamic Therapy for Oesophageal Cancer and Dysplasia

        a report by
        Hugh Barr

        Foundation Dean, Faculty of Medicine and Bioscience, Cranfield Postgraduate Medical School,
        Gloucestershire Royal Hospital

Although considered a novel form of therapy,                  All photosensitisers have a specific action spectrum (the
photodynamic therapy (PDT) is based on natural and            wavelengths of light that are absorbed to produce an
universal     photobiological      reactions.    Basic        effect). On the delivery of light, the photosensitiser is
photodestructive and photosynthetic reactions started         excited to a higher state. It then transfers this light
to evolve over 2,700 million years ago within                 energy to another molecule, usually oxygen, to
bacteria. The exploitation of the fundamental process         produce toxic, highly reactive species that destroy
of photodestruction can eradicate diseased tissue with        tissue. A critical threshold level of toxic photoproduct
great precision.                                              is required because the cells have developed
                                                              mechanisms to withstand this oxidative damage. Once            Hugh Barr is the Foundation Dean
The aim of PDT in the oesophagus is the targeted              these defences are overwhelmed, the cell is fatally            of the Faculty of Medicine and
                                                                                                                             Bioscience at Cranfield Postgraduate
local destruction of abnormal cancerous or pre-               wounded and necrosis or apoptosis is inevitable.               Medical School, Gloucestershire Royal
cancerous tissue. It is a minimally invasive therapy,                                                                        Hospital. He previously served as
                                                                                                                             Director of the Postgraduate Medical
with the advantage that the normal architecture and           It is possible to generate a photosensitiser within the        School. In 1994, Dr Barr took up an
some normal tissue can be preserved. The technique            cells by exploiting the natural porphyrin bio-                 academic appointment as Clinical
relies on the generation or the administration of a           synthesis pathway. If 5-aminolaevulinic acid (5-ALA,           Professor of Medicine at Cranfield
                                                                                                                             University, having worked as a
photosensitiser, which localises within the dysplastic        a precursor of haemoglobin) is administered in                 Consultant General and
or cancerous tissue. At certain times after                   excess, the result is an intracellular accumulation of         Gastrointestinal Surgeon at
                                                                                                                             Gloucestershire Royal Hospital since
administration, there exists a concentration                  the endogenous photosensitiser protoporphyrin IX
                                                                                                                             1992. He also held two named
differential of 2:1 to 3:1 between the cancer and             (PpIX). The level of systemic photosensitisation is            Professorships of the Royal College of
normal structures. Selective tumour destruction can           minimised to a few hours and the 5-ALA can be                  Surgeons of Edinburgh: the Hunertian
                                                                                                                             Professor 1990–1991 and the Lister
be achieved if the photosensitiser is administered            administered orally, dissolved in fruit juice.                 Professor 1987–1988. A fellow of
under certain dosage conditions. This is at present                                                                          the Royal Colleges of Surgeons of
not fully exploited in clinical situations.1 In addition,     A major disadvantage appears to be that the depth of           London and Edinburgh, Dr Barr
                                                                                                                             serves as councillor and secretary of
very precise targeting of the light delivery at               necrosis is very limited and eradication of tumours            the British Medical Laser Association
endoscopy to the area of disease produces a highly            deeper than 2mm may be difficult. Early studies in             and has been elected to the Council
                                                                                                                             of the British Society of
localised effect. There is clear attraction of this dual      the oesophagus indicated that necrosis does occur,             Gastroenterology (2005) and the
selectivity to minimise non-essential damage. PDT             but eradication of macroscopic tumours was                     Oesophageal Section (2005). He is
requires a photosensitiser, light, oxygen and a substrate     difficult.2–4 This critical limitation may be usefully         the Clinical Lead for Research at the
                                                                                                                             Three Counties Cancer Centre in the
to interact with and destroy. Generally, a synthetic          exploited if therapy is designed to eradicate high-            National Cancer research Network.
photosensitiser is administered intravenously, with a         grade dysplasia in Barrett’s oesophagus. The depth of          Moreover, Dr Barr is a member of
                                                                                                                             the South West National Health
period of time (48 to 72 hours) allowed for its               damage is much greater for the systemically                    Service (NHS) Research and Education
preferential retention or accumulation in the tissue          administered photosensitisers.                                 Committee, the Development
prior to activation with appropriate wavelength light,                                                                       Committee and the Gloucestershire
                                                                                                                             Research Consortium, and Honorary
usually from a laser. Photosensitisers accumulate in          Methodology of PDT                                             Senior Research Fellow in the
rapidly growing tissue, blood vessels and the supporting                                                                     Department of Clinical Pharmacology
                                                                                                                             to the University of Oxford. He is
tissue that grows with malignant tumours. A period of         The methodology of PDT depends on the nature of
                                                                                                                             also the author or co-author of over
general photosensitivity will occur with most agents.         the photosensitiser. To generate protoporphyrin IX             100 papers in peer-reviewed journals
                                                                                                                             and 25 book chapters. While
                                                                                                                             completing his post-graduate surgical
1. Barr H, Tralau C J, Boulos P B, Krasner N, Clark C G, Bown S G, “Selective destruction of dimethyl-hydrazine rat          training, Dr Barr received several
   colon cancer using phthalocyanine photodynamic therapy”, Gastroenterology (1990);98: pp. 1,532–1,537.                     medals and prizes, including the
2. Barr H, Dix A J, Kendall C, Stone N, “The potential for photodynamic therapy in the management of Upper                   Medical Institution Research Medal
                                                                                                                             and the Hopkins Endoscopy
   Gastrointestinal Disease”, Aliment. Pharmacol. Ther. (2001):15(3): pp. 311–321.                                           Prize of the British Society of
3. Barr H, Shepherd N A, Dix A, Roberts D J H, Tan W C, Krasner N, “Eradication of high grade dysplasia in columnar-         Gastroenterology, among others. Dr
                                                                                                                             Barr earned his medical degree at
   lined (Barrett’s) oesophagus using photodynamic therapy with endogenously generated protoporphyrin IX”, Lancet            the University of Liverpool.
   (1996);348: pp. 584–585.
4. Gossner L, Stolte M, Stroke R et al., “Photodynamic therapy of high-grade dysplasia and early stage carcinomas by means
   of 5-aminolaevulinic acid”, Gastroenterology (1998);114: pp. 447–455.
EUROPEAN GASTROENTEROLOGY REVIEW 2006                                                                                                                          17
             Gastrointestinal Cancers

     PDT, 30–75mg/kg of 5-ALA dissolved in orange                 methods when compared with the insertion of an
     juice is given orally to the patients. Endoscopic light      oesophageal prosthesis. A large randomised
     irradiation occurs some three to six hours later.            multicentre trial of 236 patients compared PDT with
     Other photosensitisers are administered through              thermal laser therapy. Both were as effective for the
     slow intravenous injection. If Photofrin is used, a          initial palliation of malignant dysphagia, but the
     dose of 2mg/kg is injected 48 hours prior to                 effect was maintained for longer in the patients
     endoscopic light delivery. Tetra (m-hydroxyphenyl)           treated with PDT. Objective tumour response was
     chlorin (mTHPC) is injected at a dose of                     32% after PDT and 20% after laser therapy. In
     0.15mg/kg, four days prior to treatment.                     addition, nine patients had a complete tumour
                                                                  response following PDT compared with only two in
     Endoscopy is usually performed with topical                  the other group. PDT was associated with temporary
     anaesthesia and intravenous sedation on an out-              photosensitivity (19%) but was easier to perform and
     patient basis. Patients photosensitised using 5-ALA          associated with fewer perforations (PDT: 1%;
     often require a prolonged endoscopy (30 to 40                thermal laser:7%).8 The most noticeable finding is
     minutes) and may notice local discomfort and                 that patients treated with PDT have a period of
     irritation during light irradiation. The treatment           prolonged palliation similar to that in patients treated
     times are considerably shorter for Photofrin (eight to       with combined techniques of laser therapy and
     10 minutes) and mTHPC (two minutes). The aim is              intraluminal radiotherapy. This prolonged response is
     to deliver an even, light dose to a defined                  often associated with greater improvement in quality
     circumferential area of the oesophagus; windowed             of life. PDT alone provides a prolonged response and
     balloons are usually the easiest to use.5 When the           appears highly effective for palliation. The greatest
     laser fibre has been inserted, the correct wavelength        improvement in oesophageal luminal size is achieved
     of light is chosen: PpIX: 630nm; Photofrin: 630nm;           using Photofrin PDT. Also, one month after therapy,
     or mTHPC: 652nm. Non-laser light devices are also            there is still a significant maintenance of luminal
     highly effective.                                            diameter and the dysphagia-free interval is much
                                                                  longer – on average more than 80 days.9
     Advanced Oesophageal Cancer
                                                                  Curative Therapy for
     Endoscopic therapy has been a mainstay for the               Oesophageal Cancer
     palliation of dysphagia caused by advanced
     oesophageal cancer. At the time of diagnosis, the            Radical therapy – particularly surgical excision of
     tumour is often not curable and aggressive therapy is        upper gastrointestinal cancers – is a highly morbid
     inappropriate. PDT may be particularly useful for            and complex procedure for patients, who are often
     patients with very long, tortuous tumours,                   elderly and frail. If the disease is limited, the
     oesophageal prostheses overgrown or blocked by               possibility of local targeted therapy is very attractive.
     tumour and high cervical oesophageal tumours. This           Surveillance of patients with columnar-lined
     therapy is much easier to administer than                    (Barrett’s) oesophagus and previous squamous cell
     photothermal laser therapy and other thermal                 carcinomas of the upper aero-digestive tract can
     therapies. In view of the fact that direct visualisation     detect very early asymptomatic cancers. Today, there
     is not necessary, the problems that limit thermal            are several methods for destruction of localised
     therapy – including smoke and debris – are not               mucosal disease at endoscopy. Endoscopic PDT for
     encountered, the overall effect is not so operator-          both early squamous cell carcinoma and
     dependent and it is more predictable.6 There may be          adenocarcinoma has been followed by prolonged
     an increased danger of fistulation, haemorrhage and          survival. Patients with T1 cancers (smaller than 2cm)
     perforation if the tumour is invading the tracheo-           and T2 cancers (2–4cm) (staged using endoscopic
     bronchial tree or is a deeply locally invasive T4            ultrasound) have been treated using endoscopic
     lesion.7 This is a problem with all destructive              PDT. The disease-specific five-year survival was

     5. Panjehpour M, Overholt B F, Haydek J M, “Light sources and delivery devices for photodynamic therapy in the
        gastrointestinal tract”, Gastrointest. Endosc. Clin. N. Am. (2000);10: pp. 513–532.
     6. Heier S K, Rothman K A, Heier L M, Rosenthal W S, “Photodynamic therapy for obstructing esophageal cancer: light
        dosimetry and a randomized comparison with Nd:YAG laser therapy”, Gastroenterology (1995);109: pp. 63–72.
     7. Moghissi K, Dixon K, Thorpe J A C, Stringer M, Moore P J, “The role of photodynamic therapy in inoperable oesophageal
        cancer”, Eur. J. Cardiothorac. Surg. (2000);17: pp. 95–100.
     8. Lightdale C J, Heier S K, Marcon N E, McCaughan J S, Gerdes H, Overholt B F, Sivak M V, Steigmann G V, Nava
        H R, “Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of
        esophageal cancer: a multicentre randomized trial”, Gastrointest. Endosc. (1995);42: pp. 507–512.
     9. Barr H, Kendall C, Stone N, “Photodynamic therapy for oesophageal cancer. A realistic and useful option”, Technology
        in Cancer Research and Treatment (2003);2: pp. 65–75.
18                                                                      EUROPEAN GASTROENTEROLOGY REVIEW 2006
                                           Photodynamic Therapy for Oesophageal Cancer and Dysplasia

unaffected by the addition of chemotherapy or                     of 18.6 months (p=0.006).12 The major problem in
radiotherapy and was comparable with survivals                    the PDT group was stricture formation in 36%,
following surgery or chemo-radiotherapy at 74%.10                 with photosensitivity (usually mild) in 68%.
The highly influential paper by Sibille et al.                    Although the data is only preliminary, it clearly
demonstrated that if the disease was entirely local,              establishes that PDT is now a highly effective
PDT with Photofrin allowed a realistic chance of                  treatment for the eradication of high-grade
disease eradication. Further studies have indicated               dysplasia in Barrett’s oesophagus.13 This trial has
that PDT and endoscopic mucosal resection are                     now been subjected to a cost analysis, which has
effective in maintaining local cancer control.11 A very           shown that photodynamic ablation of high-grade
important comparison of patients with early cancer –              dysplasia is the most cost-effective.14
some treated through surgical resection and some by
PDT in the same unit by one surgeon – has shown                   PDT following photosensitisation with 5-ALA has
no difference in survival.12                                      also been very effective for the treatment of high-
                                                                  grade dysplasia in Barrett’s oesophagus.3,4 These
PDT for Pre-cancer and Dysplasia                                  important clinical studies have demonstrated
                                                                  eradication of the dysplasia and tumours less than
Recently, a very important study addressing the                   2mm deep. An excellent prospective randomised trial
fundamental problem of cancer prevention in                       of the treatment of low-grade dysplasia using ALA
patients with high-grade dysplasia in Barrett’s                   and irradiation with green light – rather than the
oesophagus      has    been     completed.      The               usual 630nm red light – has, again, confirmed
photosensitiser used was Photofrin (now                           how effective this treatment is in reversing
PhotoBarr). The patients, all of whom were                        dysplasia/metaplasia.14 Large series of Photofrin PDT
confirmed to have high-grade dysplasia in Barrett’s               are very encouraging, with 75% to 80% of the
oesophagus, were randomised (2:1) such that 138                   Barrett’s mucosa being converted to neo-squamous
had PDT and omeprazole and 70 received                            mucosa. Complete eradication of all metaplastic
omeprazole only. Patients could receive up to three               epithelium occurred in 43 of 100 patients. Dysplasia
photodynamic treatments of the area of dysplasia in               disappeared in 78 of 100 patients, although 11
the Barrett’s oesophagus on separate occasions. It is             developed dysplasia during follow-up and required
important to note that more than 485 patients                     repeat treatment. Residual areas of abnormal mucosa
(with a diagnosis of high-grade dysplasia) had to be              are best treated with thermal ablation using a laser or
screened to enter 208 patients with confirmed                     the argon plasma coagulator.16
high-grade dysplasia. After a 24-month follow-up,
ablation of all areas of high-grade dysplasia was                 Summary
noted in 76.8% of patients after PDT versus 38.6%
in the omeprazole group (p≤0.0001). After two                     PDT today has an established role for the treatment
years, 53% of PDT-treated patients remained                       of oesophageal neoplasia. This therapy is highly
without evidence of high-grade dysplasia and all of               effective for eradication of disease and patients have
the patients treated with omeprazole had relapsed.                prolonged survival if the disease is localised. Next,
After a mean follow-up of 24.2 months, 13% of                     the treatment of dysplasia and pre-cancerous change
PDT-treated patients had disease progression to                   has to be proven to be both effective and cost-
cancer compared with 28% after a mean follow-up                   effective as a solution. ■

10. Sibille A, Lambert R, Souquet J-C, Sabben G, Descos F, “Long-term survival after photodynamic therapy for esophageal
    cancer”, Gastroenterology (1995);108: pp. 3,378–3,344.
11. Grosjean P, Monnier P, “Photodynamic therapy and mucosectomy for early squamous cell carcinomas in the oesophagus and
    tracheobronchial tree”, Eur. J. Surg. Oncol. (1998);24: p. 234.
12. Moghissi K, Dixon K, “Photodynamic therapy (PDT) in esophageal cancer: A surgical view opf its indications based on
    14 years experience”, Technology in Cancer Research and Treatment (2003);2: pp. 319–326.
13. Overholt B F, Lightdale C J, Wang K, Canto M, Burdick S, Barr H, Macron N, Haggitt R C, Bonner M,
    Taylor S L, Depot M, “International Multicenter Partially Blinded Randomised Study of the Efficacy of Photodynamic
    Therapy (PDT) using Porfimer Sodium (POR) for the ablation of High-Grade Dysplasia (HGD) in Barrett’s Esophagus
    (BE): Results of 24 Month Follow-up”, Gastroenterology (2003);124(Suppl 1): pp. A20–151.
14. Shaheen N J, Inadomi J M, Overholt B F, Sharma P, “What is the best management strategy for high grade dysplasia in
    Barrett’s oesophagus? A cost effectiveness analysis”, Gut (2004);53: pp. 1,736–1,744.
15. Ackroyd R, Brown N J, Davis M F, Stephenson T J, Marcus S L, Stoddard C J, Johnson A G, Reed M W R,
    “Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospective, double blind, randomized, placebo controlled trial”,
    Gut (2000);47: pp. 613–617.
16. Overholt B F, Panjepour M, Haydek J M, “Photodynamic therapy for Barrett’s esophagus:follow-up in 100 patients”,
    Gastrointest. Endosc. (1999);49: pp. 1–7.
EUROPEAN GASTROENTEROLOGY REVIEW 2006                                                                                                19

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