Photodiagnosis and Photodynamic Therapy (2004) 1, 195—201
Photodynamic therapy for dysplastic Barrett’s oesophagus and early cancer Hugh Barr, M.D., Ch.M.∗ Department of Surgery, Cranfield Postgraduate Medical School in Gloucestershire, Gloucestershire Royal Hospital, Great Western Road, Gloucester GL13NN, UK Available online 8 December 2004 KEYWORDS Barrett’s oesophagus; Photodynamic therapy; Oesophageal dysplsaia
Summary Background: Cancer in the columnar-lined oesophagus develops through a multi-step process initiated by chronic gastro-oesophageal reflux progressing through metaplasia, low-grade dysplasia to high-grade dysplasia, which currently remains the best marker of cancer risk. Destruction of dysplasia using photodynamic therapy and other endoscopic methods may prevent cancer development. Methods and results: The potential problem in the columnar-lined oesophagus is surface limited to a depth of 0.6 mm. Re-surfacing the oesophagus eradicates the disease and offers the possible prevention of progression. Mucosal ablation with lasers, electro- and argon plasma coagulators, photodynamic therapy and endoscopic mucosal resection can remove dysplasia and allow regeneration of neo-squamous mucosa following acid reflux control usually with high-dose proton pump inhibitor therapy. Endoscopic mucosal resection is very effective when there is a localised visible mucosal abnormality. Multifocal dysplasia carries a greater chance of malignant degeneration, and photodynamic therapy is more useful for widespread and potentially extensive disease. The only randomised partially blinded trial for prevention of cancer in Barrett’s oesophagus has demonstrated a significant reduction in cancer progression following endoscopic photodynamic therapy. Conclusions: A multimodal approach to the management of dysplasia in Barrett’s oesophagus is necessary combining endoscopic mucosal resection, photodynamic therapy and thermal ablation. Currently dysplastic Barrett’s is the major target of therapy, the treatment of metaplasia should currently be part of an investigative study. © 2004 Elsevier B.V. All rights reserved.
Introduction Barrett’s oesophagus is a fascinating and very distinctive endoscopic and pathological condition. * Tel.: +44 8454 226679; fax: +44 8454 226679.
E-mail address: [email protected].
It would be only of minor interest were not for its potential to degenerate to cancer, and is therefore, subject to intense research and novel intervention. The normal oesophagus is lined by squamous epithelium. Following injury by chronic duodenogastro-oesophageal reflux, its repair is effected in this abnormal environment by columnar intestinal
1572-1000/$ — see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00061-4
196 and gastric cells. It is an example of phenotypic plasticity, since mucosa has adapted to hostile environmental conditions by a metaplastic response. Three distinct types of columnar metaplasia are recognised. The commonest and clinically most important is the intestinal, and this is the most likely to undergo malignant transformation to adenocarcinoma. It is uncertain as to the malignant potential of cardiac and fundic metaplasia [1,2]. Currently, adenocarcinoma of the gastrooesophageal junction is reaching epidemic proportions, and is strongly associated with Barrett’s oesophagus [3]. Over 25 years there has been a dramatic increase in oesophageal adenocarcinoma, the rate of increase exceeds that of any other cancer [4,5]. The survival trends have also shown only trivial improvement [6]. Clearly symptomatic adenocarcinoma is a lethal disease, 50% have extensive loco-regional or metastatic disease. It has been found that of those selected and considered fit for resection 73% have invasive tumours (>pT2), 60% have lymph node metastases, and 18% other metastases [7,8]. Invasive cancer (>pT1) has a devastating biological pre-determinism, approximately 90% of patients have bone marrow micrometastatic disease with viable malignant cells [9]. A median 5 year survival rate of 21% and a peri-operative mortality of 7% demonstrate the impotence of current approaches with radical surgery and multi-modal therapy [10,11]. There is a clear rationale for novel approaches and there is an intense debate [12]. Worryingly only 3.9% of patients who develop cancer have Barrett’s oesophagus diagnosed prior to this diagnosis [13]. It is clear that these patients may not seek medical advice for a symptomatic problem. Although the symptoms of chronic reflux usually precede the development of Barrett’s columnar-lined mucosa, it is in itself a resistant epithelium. This metaplasia, as an adaptive response to injury, is resistant to further injury and is less sensitive. Patients may find their symptoms improving as the condition develops. They are less aware of acid reflux than those patients with uncomplicated reflux and symptom relief is an unreliable measure of control of acid reflux [14]. An important study of individuals attending for screening sigmoidoscopy for colorectal neoplasia (patients with symptomatic reflux disease were excluded) has demonstrated that Barrett’s oesophagus can be found in 25% of male patients over the age of 50. Of these 7% had long segment disease and a further 17% short segment Barrett’s oesophagus [15]. Strategies have to be developed to detect the disease and coupled with minimally invasive methods of destruction.
H. Barr
Rationale for endoscopic therapy It is a true to say that a patient will not develop oesophageal cancer if the oesophagus is removed. Surgery can be performed with increasing safety and completely prevents progression of dysplasia to cancer. The mortality of oesophagectomy is variable but remains at 11% [16]. Pre-operative risk analyses of patients with adenocarcinoma have shown that they have very extensive co-morbidity accompanying this disease. Patients are usually overweight with significant cardiac and respiratory problems. Careful patient selection can reduce operative mortality from 9.4 to 1.6% [17]. The consequence is that many patients are considered unsuitable, or the patients expresses a preference not to undergo the risk. Surgical resection for high-grade dysplasia and occult cancer still has an early mordibity of over 50% and late morbidity of 26% and the actuarial survival of patients was only 79% at 5 years [18]. Therefore, surgery remains radical prophylaxis only available to some patients, and offering massive macroscopic morbid solution for a microscopic mucosal problem. A major predictor of 5-year survival following surgery is the stage at which disease is detected (70%, mucosal cancer, 20%, invasive) [19]. Surveillance of patients at increased risk of cancer may detect earlier stage disease at a potentially curative stage [20,21]. The major problem with surveillance is the reliability of detection for the individual patient. It is protocol driven depending on a pre-determined biopsy regimen, at pre-determined intervals in asymptomatic patients with endoscopically invisible disease, and absence of objective pathology [22]. The biomarker that triggers a response is high-grade dysplasia. However, is this a reliable biomarker for future or already present cancer [23,24].
Rationale, methods, and results of endoscopic mucosal resection (Figs. 1—3) Oesophageal endoscopic mucosal can be performed using a variety of techniques, some of which are still evolving. At present they usually involve the creation of a pseudopolyp by submucosal injection or suction. The polyp is then snared and removed (Figs. 1—3). Alternatively a variceal band is placed round the base with subsequent snare/diathermy removal above or below the band The risk of perforation is an ever present concern, and made be a particular problem of multiple resections are performed.
Photodynamic therapy for dysplastic Barrett’s oesophagus and early cancer
Figure 1. A nodular area of adenocarcinoma in Barrett’s oesophagus, prior to endoscopic mucosal resection.
Figure 2. An area of macroscopic abnormality containing high-grade dysplasia prior to endoscopic mucosal resection.
Endoscopic mucosal resection avoids one of the major concerns associated with mucosal ablative techniques. That is that both thermal destruction and PDT, do not allow histological analysis. Barrett’s oesophagus is plagued with diagnostic inconsistencies, associated with sampling error and pathological interpretation [22] Unfortunately current staging techniques with magnification and chromoendoscopy and endoscopic ultrasound have proved not reliable enough. Chromoendoscopy is associated with several problems. Staining takes several steps and is often patchy and uneven in areas of
Figure 3. Part of the area in Fig. 1 immediately after removal with endoscopic mucosal resection.
197
dysplasia and cancer [25]. Although endoscopic ultrasound is used in the selection of patients for ablative therapies it is also unreliable. It can confirm the integrity of the hyperechoic submucosal layer. It is not very useful for subtle mucosal changes, and the diagnosis of dysplasia [26]. Thus, there is a clear rationale for endoscopioc mucosal resection, which will allow accurate staging and important prognostic information. Patients with small lesions (mean 9 mm) were well treated by endoscopic mucosal resection. The success rate was lower in the larger oesophageal lesions. The major problem was the development of metachronous lesions in 30% of the patients. The authors concluded that endoscopic mucosal resection was appropriate for discrete lesions but recommended photo dynamic therapy for highgradedysplasia without a visible lesion [27,28]. Subsequently, attempts have been made to remove the whole Barrett’s mucosa (12 patients), at 9 months follow-up period, no metachronous lesions were found, but strictures had developed in two patients [29]. The major concern regarding EMR is of incomplete excision. The lateral margins were found to be positive in up to 40% of patients and further EMS was necessary. The need for continued surveillance may be regarded as a drawback for endoscopic therapy in upper gastrointestinal neoplasia, but is essential no matter which method is used. My practice is to use endoscopic mucosal resection for visible macroscopic abnormalities either as definitive treatment or prior to using photodynamic therapy to ablate the entire metaplastic segment.
Rationale, methods and results of photodynamic therapy (Figs. 4—6) It is important to match the depth of ablation to the depth of the diseased Barrett’s mucosa. Initial investigation indicates that the potential problem of high-gradedysplasia in the oesophagus and in Barrett’s mucosa may be limited to a depth of 0.6 mm from the lumen [30]. Despite these data it does not necessarily imply that this should be the depth of ablation and photodynamic therapy. An equally important question remains as to what structures must be preserved to allow squamous reepithelisation, and, what is the mechanism of this re-epithelialisation. Detailed histological findings suggest three possible mechanisms for neosquamous regeneration: encroachment from adjacent squamous epithelium, extension from oesophageal gland duct epithelium to form squamous islands,
198
Figure 4. An area of Barrett’s oesophagus prior to treatment with Photofrin photodynamic therapy. There was biopsy proven high-grade dysplasia.
Figure 5. Endoscopic appearance of oesophagus, 6 weeks after photodynamic therapy with Photofrin.
and squamous metaplasia within Barrett’s epithelium itself. The latter suggests the existence of pluripotential stem cells in Barrett’s mucosa [31] (Figs. 4—6). The major advantage for photodynamic therapy is that the whole segment can be treated, eradicating all potentially diseased areas. There is clear evidence that dysplasia in Barrett’s oesophagus is often multi-focal [32]. All the abnormal and Barrett’s epithelium should be destroyed. Areas of dysplasia are very heterogeneous and are often completely invisible to standard white light endoscopy. Following photodynamic therapy com-
Figure 6. Area of treated dysplastic Barrett’s oesophagus, 4 months after photodynamic therapy. There is a stricture present.
H. Barr plete control of the underlying gastro-oesophageal reflux disease, usually with proton pump inhibitors, or less often by surgical fundoplication, is essential. The end point of treatment is re-epithelization of the Barrett’s segment with neo-squamous epithelium. Continued surveillance is still necessary since the phenotype expressed may still have malignant potential and cancer has occurred some tome after apparently successful ablation [33]. Treatment must be constrained because patients are often completely asymptomatic, only a small proportion of patients with metaplastic or low-grade dysplastic epithelium are at risk of neoplastic progression, and any method must have minimal complications. There have been three major photosensitiser used for photodynamic therapy in treatment of oesophageal dysplsaia and early cancer. Exogenous photosensitisation with haematoporphyrin based agents such as Photofrin, and meso-tetra(mhydroxyphenyl) chlorin (mTHPC). The other photosensitiser is 5-aminolaevulinic acid (5-ALA), which is used to generate protoporphyrin IX (PPIX), an endogeneous photosensitiser. There is now consistent data demonstrating the effectiveness of the Photofrin for the eradication of early adenocarcinoma and dysplasia arising from Barrett’s oesophagus. The method of treatment involves the administration of 2 mg/kg of Photofrin (now PhotBarr, Axcan Pharma, Montreal) 48 h prior to irradiation with light (630 nm). A diffuser or a windowed centring balloon allows more accurate and even light dosimetry. The length of the light-delivering device can be 3, 5 and 7 cm. It is recommended that no more than 7 cms of Barrett’s oesophagus treated at one session. The power density used is 400 mW/cm2 to provide an energy density of 130 J/cm2 from the diffuser to the mucosa. Treatment can be performed on an outpatient basis and patients must all received profound acid suppression with proton pump inhibitor therapy. Direct sunlight must be avoided for a period of 4—6 weeks. Some patients may develop small unilateral or even bilateral pleural effusions. Cutaneous photosensitivity can be a significant problem for up to 2 months. Approximately 30% developed significant strictures. These usually respond to endoscopic oesophageal dilatation. Overall the results of photodynamic therapy are very encouraging, with 75—80% of the Barrett’s mucosa being converted to neo-squamous mucosa. Complete eradication of all metaplastic epithelium occurred in 43 of 100 patients. Dysplasia disappeared in 78 of 100 patients, although 11 developed dysplasia during follow-up and required repeat treatment. Thirteen patients were treated for early cancer (T1—12 patients; T2—1 patient), and in ten the tumour was
Photodynamic therapy for dysplastic Barrett’s oesophagus and early cancer
Table 1
199
Photodynamic therapy for the eradication of early cancer and dysplasia in Barrett’s oesophagus.
Number of patients
Photosensitiser
Months of follow-up
Cancer/HGD eradicated (%)
No metaplasia (%)
References
15 82 58
ALA Photofrin MTHPC
1—11 4—84 2—48
86—100 93—100 74
0—205 24
[37,38] [34,35,45,46] [42—44]
eradicated [34,35]. The endoscopic appearances may well be dramatic with considerable inflammation and necrosis 9 (Fig. 5). The results of the large randomised trial indicate that Photofrin PDT for high-grade dysplasia will reduce progression to cancer at the 2 year follow-up, 13% of patients treated with PDT developed cancer compared with 28% treated with omeprazole only [36]. Photodynamic therapy, using endogeneous photosensitisation with 5-ALA, has been reported as very effective for the eradication of high-grade dysplasia and early cancer arising in Barrett’s oesophagus [37,38]. There is extensive data on the uptake and distribution of the generated photosensitisers in gastrointestinal mucosa. In experimental Barrett’s like oesophagus protoporphyrin IX (PpIX) was generated in the epithelial cells whether squamous or columnar, with maximum levels occurring 3 h after oral administration or intravenous injection. The uptake in the mucosa was 3.5 times greater than in the muscularis propria. There was little difference between oral or parenteral administration of the 5-ALA [39]. These studies have supplied important reasons for the mucosal localisation of PpIX. The muscularis contains more iron and has a reduced activity of one of the rate controlling enzymes. porphobilinogen deaminase. Clinical studies of the PpIX distribution following oral 5-ALA have confirmed the mucosal accumulation relative to surrounding tissues. There was little difference in accumulation when the oral dose was increased from 60 to 75 mg/kg, and carcinomatous tissue produced PpIX in similar quantities to dysplastic and metaplastic epithelium. Following the accumulation of PpIX, a photodynamic action will only occur following light irradiation. Initially all treatment parameters were empirically selected. An elegant study in an experimental model of Barrett’s-like oesophagus has confirmed that the most appropriate time for light irradiation is 2—3 h after 5-ALA administration [39]. This time interval appears critical to achieve mucosal destruction while sparing oesophageal function. The clinical studies of 5-ALA photodynamic therapy have demonstrated eradication of dysplasia and T1 tumours. A prospective randomised trial of the treatment of low-grade dysplasia using 5-ALA and
irradiation with green light rather than the usual 630 nm red light has again confirmed how effective this treatment is in reversing dysplasia and also metaplasia. Healing proceeded with the regeneration of neo-squamous epithelium [40]. A variation of 5-ALA photodynamic therapy involves the direct endoscopic spraying of the agent combined with sodium bicarbonate as a mucolytic onto dysplastic Barrett’s oesophagus. A period of time is allowed for local absorption and then the area is irradiated with light. The response following this technique was variable with 2 of 9 patients failing to show any response [41]. The use of mTHPC as a photosensitiser has been report in the oesophagus for the treatment of early cancers [42]. It is a very potent agent and produces very effective ablation of both early cancer and dysplasia. The most recent reported series demonstrated that after a median follow-up of 17 months, 8 of 11 patients were clear of cancer and all four patients treated for high-grade dysplasia in Barrett’s oesophagus were clear. There were two very serious complications, with one patient dying of an aorto-oesophageal fistulae and one patient developing a tracheo-oesophageal fistula [43]. An important observation was that the aorto-oesophageal fistula may have been due to excessive light dose. The results of photodynamic therapy using the three photosensitisers for the endoscopic treatment of dysplasia and early cancer in the oesophagus are summarized in Table 1. All those patients treated endoscopically for dysplasia or early cancer should receive life long biopsy surveillance. In addition some of these patients may develop invasive cancer under the neo-squamous epithelium.
Conclusions Photodynamic therapy is an essential method for the treatment of dysplasia in Barrett’s oesophagus. However, it should be used in combination with other methods. If a patient has a macroscopic abnormality, then my initial strategy is to perform endoscopic mucosal resection. This will allow full histological assessment and provided evidence of
200 deeper invasion. I would then proceed to treat the whole Barrett’s area with Photofrin photodynamic therapy. If there were residual areasof metaplasia then these would be treated with thermal laser therapy or Argon Plasma Coagulation. I prefer to use Photoifrin PDT if there is any hint of macroscopic abnormality and ALA/PDT for patients with an entirely innocent looking oesophagus with only biopsy evidence of dysplasia. The complication rate of photosensitivity and stricture is much higher using Photofrin and this must be explained fully to the patient.
References [1] Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett’s esophagus: the AGA Chicago Workshop. Gastroenterology 2004;127:310—30. [2] Falk GW. Barrett’s esophagus. Gastroenterology 2002;122:1569—91. [3] Solaymani-Dodaran M, Logan RFA, West J, Card T, Coupland C. Risk of oesophageal cancer in Barrett’s oesophagus and gastro-oesophageal reflux. Gut 2004;53:1070—4. [4] Wei JT, Shaheen NJ. The changing epidemiology of esophageal adenocarcinoma. Semin Gastrointest Dis 2003;14:112—27. [5] Serag EL. The epidemic of esophageal adenocarcinoma. Gastroenterol Endosc Clin N Am 2002;31:421—40. [6] Mason AC, Eloubeidi MA, Serag EL. Temporal trends in survival of patients with esophageal adenocarcinoma. 1973—1997. Gastroenterology 2001;122:A30. [7] Reynolds JC, Waronker M, Pacquing MS, Yassin RR. Barrett’s esophagus: reducing the risk of progression to adenocarcinoma. Gastroenterol Clin N Am 2000;28:917—45. [8] Bollschweiler E, Schroder W, Holscher AH, Siewert JR. Preoperative risk analysis in patients with adenocarcinoma or squamous cell carcinoma of the oesophagus. Br J Surg 2000;87:1106—10. [9] O’Sullivan GC, Sheehan D, Clarke Q, et al. Micrometastases in esophagogastric cancer: high detection rate in resected rib segments. Gastroenterology 1999;116:543—8. [10] Kelsen D. Multimodality therapy for adenocarcinoma of the esophagus. Gastroenterol Clin N Am 1997;26:635—45. [11] Ellis FH. Standard resection for cancer of the esophagus and cardia. Surg Oncol Clin N Am 1999;8:279—94. [12] Barr H, Fitzgerald RC. Ablative mucosectomy is the procedure of choice to prevent Barrett’s cancer. Gut 2003;52:14—7. [13] Corley DA, Levin TR, Habel LA, Weiss NS, Buffler PA. Surveillance and survival in Barrett’s adenocarcinomas: a population-based study. Gastroenterology 2002;122:633—40. [14] Tremble KC, Pryde A, Heading RC. Lowered oesophageal sensory thresholds in patients with symptomatic but not excessive gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GERD. Gut 1995;37:7—12. [15] Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett’s esophagus in assymptomatic individuals. Gastroenterology 2002;123:461—7. [16] Bachmann MO, Alderson D, Edwards D, et al. Cohort study in South and West England of the influence of specialization on the management and outcome of patients with oesophageal and gastric cancers. Br J Surg 2002;89:914—22.
H. Barr [17] Bollschweiler E, Schroder W, Holscher AH, Siewert JR. Preoperative risk analysis in patients with adenocarcinoma or squamous cell carcinoma of the oesophagus. Br J Surg 2000;87:1106—10. [18] Zaninotto G, Parenti AR, Ruol A, Costantini M, Merigliano S, Ancona E. Oesophageal resection for high-grade dysplasia in Barrett’s oesophagus. Br J Surg 2000;97:1102—5. [19] Farrow DC, Vaughan TL. Determinants of survival following the diagnosis of esophageal adenocarcinoma (United States). Cancer Causes Control 1996;7:322—7. [20] Peters JH, Clark GWB, Ireland AP, Chandrasoma P, Smyrk TC, DeMeester TR. Outcome of adenocarcinoma arising in Barrett’s esophagus in endoscopically surveyed and nonsurveyed patients. Thorac Cardiovasc Surg 1994;108:813—22. [21] Fountoulakis A, Zafirellis KD, Dolan K, Dexter SPL, Martin IG, Sue-Ling HM. Effect of surveillance of Barrett’s oesophagus on the clinical outcome of oesophageal cancer. Br J Surg 2004;91:997—1003. [22] Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett’s esophagus: a reaffirmation. Hum Pathol 2001;32:368—78. [23] Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett’s esophagus: baseline histology and flow cytometry identify low- highrisk patient subsets. Am J Gastroenterol 2000;95:1669— 76. [24] Schnell TG, Sontag SJ, Chejfec G, et al. Long-term nonsurgical management of Barrett’s esophagus with high-grade dysplasia. Gastroenterology 2001;120:1607—19. [25] Connor MJ, Sharma P. Chromoendoscopy and magnification endoscopy in Barrett’s esophagus. Gastrointest Endosc Clin N Am 2003;13:269—77. [26] Owens MM, Kimmey MB. The role of endoscopic ultrasound in the diagnosis and management of Barrett’s esophagus. Gastrointest Endosc Clin N Am 2003;13:325—34. [27] Ell C, May A, Gossner L, Pech O, et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s esophagus. Gastroenterology 2000;118:670—7. [28] May A, Gossner L, Pech P, et al. Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s oesophagus: acute-phase and intermediate results of a new treatment approach. Eur J Gastro Hep 2002;14:1085—91. [29] Seewald S, Akaraviputh T, Seitz U, et al. Circumferential endoscopic mucosal resection and complete removal of Barrett’s epithelium: a new approach to management of Barrett’s esophagus containing high-grade intraepithelial neoplasia and intramucosal carcinoma. Gastrointest Endosc 2003;57:854—9. [30] Ackroyd R, Brown NJ, Stephenson TJ, Stoddard CJ, Reed MW. Ablation treatment for Barrett oesophagus: what depth of tissue destruction is needed. J Clin Pathol 1999;52:509—12. [31] Biddlestone LR, Barham CP, Wilkinson SP, Barr H, Shepherd NA. The histopathology of treated Barrett’s Oesophagus: squamous re-epithelialisation following acid suppression, laser and photodynamic therapy. Am J Surg Pathol 1998;22:239—45. [32] Buttar NS, Wang KK, Sebo TJ, et al. Extent of high-grade dysplasia in Barrett’s esophagus correlates with risk of adenocarcinoma. Gastroenterology 2001;120:1630—9. [33] Barr H. Barrett’s esophagus: treatment with 5aminolevulinic acid photodynamic therapy. Gastrointest Endosc Clin N Am 2000;10:421—38. [34] Overholt BF, Panjepour M, Haydek JM. Photodynamic therapy for Barrett’s esophagus: follow-up in 100 patients. Gastrointest Endosc 1999;49:1—7.
Photodynamic therapy for dysplastic Barrett’s oesophagus and early cancer [35] Overholt BF, Panjehpour M, Halberg DL. Photodynamic therapy of Barrett’s oesophagus with dysplasia and/or early stage carcinoma: long-term results. Gastrointest Endosc 2003;58:193—8. [36] Overholt BF, Lightdale CJ, Wang K, et al. 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):A20—151. [37] 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;114:447—55. [38] Barr H, Shepherd NA, Dix A, Roberts DJH, Tan WC, Krasner N. Eradication of high-gradedysplasia in columnarlined (Barrett’s) oesophagus using photodynamic therapy with endogenously generated protoporphyrin IX. Lancet 1996;348:584—5. [39] Van Den Boogert J, Van Hillesberger R, De Rooij FWM, et al. 5-Aminolaevulinic acid-induced protoporphyrin accumulation in tissues: pharmacokinetics after oral or intravenous administration. J Photochem Photobiol B: Biol 1998;44:29—38. [40] Ackroyd R, Brown NJ, Davis MF, et al. Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospective,
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double blind, randomised, placebo-controlled trial. Gut 2000;47:613—7. Ortner M, Zumbusch K, Liebtruth J, et al. Photodynamic therapy in Barrett’s esophagus after local administration of 5-aminolaevulinic acid. Gastroenterology 1997;112: A633. Grosjean P, Savary JF, Wagniers G, et al. Tetra(mhydroxyphenyl) chlorin clinical photodynamic therapy of early bronchial and oesophageal cancers. Las Med Sci 1996;11:227—35. Jamieson NF, Thorpe S, Mosse A, Bown SG, Lovat LG. Photodynamic therapy using MTHPC for early Barrett’s-associated cancer. Gut 2003;52(Suppl 1):170. Gossner L, May A, Pech O, et al. Photodynamic therapy of Barrett’s esophagus with dysplasia or early cancer. Gastroenterology 1999;116:G1811. Wang KK, WongKeeSong LM, Nourbakhsh L, et al. Can consistent tissue necrosis be achieved during photodynamic therapy for high-grade dysplasia or cancer within Barrett’s esophagus? Gastroenterology 1997;112: 676. Spinelli P, Dal Fante M, Mancici A, et al. Endoscopic photodynamic therapy of early cancer and severe dysplasia of the esophagus. In: Spinelli P, Dal Fante M, Marchesini R, editors. Photodynamic therapy and biomedical lasers. Amsterdam: Elsevier Science Inc; 1992. p. 262—5.
Photodynamic therapy for dysplastic Barrett’s oesophagus and early cancer Hugh Barr, M.D., Ch.M.∗ Department of Surgery, Cranfield Postgraduate Medical School in Gloucestershire, Gloucestershire Royal Hospital, Great Western Road, Gloucester GL13NN, UK Available online 8 December 2004 KEYWORDS Barrett’s oesophagus; Photodynamic therapy; Oesophageal dysplsaia
Summary Background: Cancer in the columnar-lined oesophagus develops through a multi-step process initiated by chronic gastro-oesophageal reflux progressing through metaplasia, low-grade dysplasia to high-grade dysplasia, which currently remains the best marker of cancer risk. Destruction of dysplasia using photodynamic therapy and other endoscopic methods may prevent cancer development. Methods and results: The potential problem in the columnar-lined oesophagus is surface limited to a depth of 0.6 mm. Re-surfacing the oesophagus eradicates the disease and offers the possible prevention of progression. Mucosal ablation with lasers, electro- and argon plasma coagulators, photodynamic therapy and endoscopic mucosal resection can remove dysplasia and allow regeneration of neo-squamous mucosa following acid reflux control usually with high-dose proton pump inhibitor therapy. Endoscopic mucosal resection is very effective when there is a localised visible mucosal abnormality. Multifocal dysplasia carries a greater chance of malignant degeneration, and photodynamic therapy is more useful for widespread and potentially extensive disease. The only randomised partially blinded trial for prevention of cancer in Barrett’s oesophagus has demonstrated a significant reduction in cancer progression following endoscopic photodynamic therapy. Conclusions: A multimodal approach to the management of dysplasia in Barrett’s oesophagus is necessary combining endoscopic mucosal resection, photodynamic therapy and thermal ablation. Currently dysplastic Barrett’s is the major target of therapy, the treatment of metaplasia should currently be part of an investigative study. © 2004 Elsevier B.V. All rights reserved.
Introduction Barrett’s oesophagus is a fascinating and very distinctive endoscopic and pathological condition. * Tel.: +44 8454 226679; fax: +44 8454 226679.
E-mail address: [email protected].
It would be only of minor interest were not for its potential to degenerate to cancer, and is therefore, subject to intense research and novel intervention. The normal oesophagus is lined by squamous epithelium. Following injury by chronic duodenogastro-oesophageal reflux, its repair is effected in this abnormal environment by columnar intestinal
1572-1000/$ — see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00061-4
196 and gastric cells. It is an example of phenotypic plasticity, since mucosa has adapted to hostile environmental conditions by a metaplastic response. Three distinct types of columnar metaplasia are recognised. The commonest and clinically most important is the intestinal, and this is the most likely to undergo malignant transformation to adenocarcinoma. It is uncertain as to the malignant potential of cardiac and fundic metaplasia [1,2]. Currently, adenocarcinoma of the gastrooesophageal junction is reaching epidemic proportions, and is strongly associated with Barrett’s oesophagus [3]. Over 25 years there has been a dramatic increase in oesophageal adenocarcinoma, the rate of increase exceeds that of any other cancer [4,5]. The survival trends have also shown only trivial improvement [6]. Clearly symptomatic adenocarcinoma is a lethal disease, 50% have extensive loco-regional or metastatic disease. It has been found that of those selected and considered fit for resection 73% have invasive tumours (>pT2), 60% have lymph node metastases, and 18% other metastases [7,8]. Invasive cancer (>pT1) has a devastating biological pre-determinism, approximately 90% of patients have bone marrow micrometastatic disease with viable malignant cells [9]. A median 5 year survival rate of 21% and a peri-operative mortality of 7% demonstrate the impotence of current approaches with radical surgery and multi-modal therapy [10,11]. There is a clear rationale for novel approaches and there is an intense debate [12]. Worryingly only 3.9% of patients who develop cancer have Barrett’s oesophagus diagnosed prior to this diagnosis [13]. It is clear that these patients may not seek medical advice for a symptomatic problem. Although the symptoms of chronic reflux usually precede the development of Barrett’s columnar-lined mucosa, it is in itself a resistant epithelium. This metaplasia, as an adaptive response to injury, is resistant to further injury and is less sensitive. Patients may find their symptoms improving as the condition develops. They are less aware of acid reflux than those patients with uncomplicated reflux and symptom relief is an unreliable measure of control of acid reflux [14]. An important study of individuals attending for screening sigmoidoscopy for colorectal neoplasia (patients with symptomatic reflux disease were excluded) has demonstrated that Barrett’s oesophagus can be found in 25% of male patients over the age of 50. Of these 7% had long segment disease and a further 17% short segment Barrett’s oesophagus [15]. Strategies have to be developed to detect the disease and coupled with minimally invasive methods of destruction.
H. Barr
Rationale for endoscopic therapy It is a true to say that a patient will not develop oesophageal cancer if the oesophagus is removed. Surgery can be performed with increasing safety and completely prevents progression of dysplasia to cancer. The mortality of oesophagectomy is variable but remains at 11% [16]. Pre-operative risk analyses of patients with adenocarcinoma have shown that they have very extensive co-morbidity accompanying this disease. Patients are usually overweight with significant cardiac and respiratory problems. Careful patient selection can reduce operative mortality from 9.4 to 1.6% [17]. The consequence is that many patients are considered unsuitable, or the patients expresses a preference not to undergo the risk. Surgical resection for high-grade dysplasia and occult cancer still has an early mordibity of over 50% and late morbidity of 26% and the actuarial survival of patients was only 79% at 5 years [18]. Therefore, surgery remains radical prophylaxis only available to some patients, and offering massive macroscopic morbid solution for a microscopic mucosal problem. A major predictor of 5-year survival following surgery is the stage at which disease is detected (70%, mucosal cancer, 20%, invasive) [19]. Surveillance of patients at increased risk of cancer may detect earlier stage disease at a potentially curative stage [20,21]. The major problem with surveillance is the reliability of detection for the individual patient. It is protocol driven depending on a pre-determined biopsy regimen, at pre-determined intervals in asymptomatic patients with endoscopically invisible disease, and absence of objective pathology [22]. The biomarker that triggers a response is high-grade dysplasia. However, is this a reliable biomarker for future or already present cancer [23,24].
Rationale, methods, and results of endoscopic mucosal resection (Figs. 1—3) Oesophageal endoscopic mucosal can be performed using a variety of techniques, some of which are still evolving. At present they usually involve the creation of a pseudopolyp by submucosal injection or suction. The polyp is then snared and removed (Figs. 1—3). Alternatively a variceal band is placed round the base with subsequent snare/diathermy removal above or below the band The risk of perforation is an ever present concern, and made be a particular problem of multiple resections are performed.
Photodynamic therapy for dysplastic Barrett’s oesophagus and early cancer
Figure 1. A nodular area of adenocarcinoma in Barrett’s oesophagus, prior to endoscopic mucosal resection.
Figure 2. An area of macroscopic abnormality containing high-grade dysplasia prior to endoscopic mucosal resection.
Endoscopic mucosal resection avoids one of the major concerns associated with mucosal ablative techniques. That is that both thermal destruction and PDT, do not allow histological analysis. Barrett’s oesophagus is plagued with diagnostic inconsistencies, associated with sampling error and pathological interpretation [22] Unfortunately current staging techniques with magnification and chromoendoscopy and endoscopic ultrasound have proved not reliable enough. Chromoendoscopy is associated with several problems. Staining takes several steps and is often patchy and uneven in areas of
Figure 3. Part of the area in Fig. 1 immediately after removal with endoscopic mucosal resection.
197
dysplasia and cancer [25]. Although endoscopic ultrasound is used in the selection of patients for ablative therapies it is also unreliable. It can confirm the integrity of the hyperechoic submucosal layer. It is not very useful for subtle mucosal changes, and the diagnosis of dysplasia [26]. Thus, there is a clear rationale for endoscopioc mucosal resection, which will allow accurate staging and important prognostic information. Patients with small lesions (mean 9 mm) were well treated by endoscopic mucosal resection. The success rate was lower in the larger oesophageal lesions. The major problem was the development of metachronous lesions in 30% of the patients. The authors concluded that endoscopic mucosal resection was appropriate for discrete lesions but recommended photo dynamic therapy for highgradedysplasia without a visible lesion [27,28]. Subsequently, attempts have been made to remove the whole Barrett’s mucosa (12 patients), at 9 months follow-up period, no metachronous lesions were found, but strictures had developed in two patients [29]. The major concern regarding EMR is of incomplete excision. The lateral margins were found to be positive in up to 40% of patients and further EMS was necessary. The need for continued surveillance may be regarded as a drawback for endoscopic therapy in upper gastrointestinal neoplasia, but is essential no matter which method is used. My practice is to use endoscopic mucosal resection for visible macroscopic abnormalities either as definitive treatment or prior to using photodynamic therapy to ablate the entire metaplastic segment.
Rationale, methods and results of photodynamic therapy (Figs. 4—6) It is important to match the depth of ablation to the depth of the diseased Barrett’s mucosa. Initial investigation indicates that the potential problem of high-gradedysplasia in the oesophagus and in Barrett’s mucosa may be limited to a depth of 0.6 mm from the lumen [30]. Despite these data it does not necessarily imply that this should be the depth of ablation and photodynamic therapy. An equally important question remains as to what structures must be preserved to allow squamous reepithelisation, and, what is the mechanism of this re-epithelialisation. Detailed histological findings suggest three possible mechanisms for neosquamous regeneration: encroachment from adjacent squamous epithelium, extension from oesophageal gland duct epithelium to form squamous islands,
198
Figure 4. An area of Barrett’s oesophagus prior to treatment with Photofrin photodynamic therapy. There was biopsy proven high-grade dysplasia.
Figure 5. Endoscopic appearance of oesophagus, 6 weeks after photodynamic therapy with Photofrin.
and squamous metaplasia within Barrett’s epithelium itself. The latter suggests the existence of pluripotential stem cells in Barrett’s mucosa [31] (Figs. 4—6). The major advantage for photodynamic therapy is that the whole segment can be treated, eradicating all potentially diseased areas. There is clear evidence that dysplasia in Barrett’s oesophagus is often multi-focal [32]. All the abnormal and Barrett’s epithelium should be destroyed. Areas of dysplasia are very heterogeneous and are often completely invisible to standard white light endoscopy. Following photodynamic therapy com-
Figure 6. Area of treated dysplastic Barrett’s oesophagus, 4 months after photodynamic therapy. There is a stricture present.
H. Barr plete control of the underlying gastro-oesophageal reflux disease, usually with proton pump inhibitors, or less often by surgical fundoplication, is essential. The end point of treatment is re-epithelization of the Barrett’s segment with neo-squamous epithelium. Continued surveillance is still necessary since the phenotype expressed may still have malignant potential and cancer has occurred some tome after apparently successful ablation [33]. Treatment must be constrained because patients are often completely asymptomatic, only a small proportion of patients with metaplastic or low-grade dysplastic epithelium are at risk of neoplastic progression, and any method must have minimal complications. There have been three major photosensitiser used for photodynamic therapy in treatment of oesophageal dysplsaia and early cancer. Exogenous photosensitisation with haematoporphyrin based agents such as Photofrin, and meso-tetra(mhydroxyphenyl) chlorin (mTHPC). The other photosensitiser is 5-aminolaevulinic acid (5-ALA), which is used to generate protoporphyrin IX (PPIX), an endogeneous photosensitiser. There is now consistent data demonstrating the effectiveness of the Photofrin for the eradication of early adenocarcinoma and dysplasia arising from Barrett’s oesophagus. The method of treatment involves the administration of 2 mg/kg of Photofrin (now PhotBarr, Axcan Pharma, Montreal) 48 h prior to irradiation with light (630 nm). A diffuser or a windowed centring balloon allows more accurate and even light dosimetry. The length of the light-delivering device can be 3, 5 and 7 cm. It is recommended that no more than 7 cms of Barrett’s oesophagus treated at one session. The power density used is 400 mW/cm2 to provide an energy density of 130 J/cm2 from the diffuser to the mucosa. Treatment can be performed on an outpatient basis and patients must all received profound acid suppression with proton pump inhibitor therapy. Direct sunlight must be avoided for a period of 4—6 weeks. Some patients may develop small unilateral or even bilateral pleural effusions. Cutaneous photosensitivity can be a significant problem for up to 2 months. Approximately 30% developed significant strictures. These usually respond to endoscopic oesophageal dilatation. Overall the results of photodynamic therapy are very encouraging, with 75—80% of the Barrett’s mucosa being converted to neo-squamous mucosa. Complete eradication of all metaplastic epithelium occurred in 43 of 100 patients. Dysplasia disappeared in 78 of 100 patients, although 11 developed dysplasia during follow-up and required repeat treatment. Thirteen patients were treated for early cancer (T1—12 patients; T2—1 patient), and in ten the tumour was
Photodynamic therapy for dysplastic Barrett’s oesophagus and early cancer
Table 1
199
Photodynamic therapy for the eradication of early cancer and dysplasia in Barrett’s oesophagus.
Number of patients
Photosensitiser
Months of follow-up
Cancer/HGD eradicated (%)
No metaplasia (%)
References
15 82 58
ALA Photofrin MTHPC
1—11 4—84 2—48
86—100 93—100 74
0—205 24
[37,38] [34,35,45,46] [42—44]
eradicated [34,35]. The endoscopic appearances may well be dramatic with considerable inflammation and necrosis 9 (Fig. 5). The results of the large randomised trial indicate that Photofrin PDT for high-grade dysplasia will reduce progression to cancer at the 2 year follow-up, 13% of patients treated with PDT developed cancer compared with 28% treated with omeprazole only [36]. Photodynamic therapy, using endogeneous photosensitisation with 5-ALA, has been reported as very effective for the eradication of high-grade dysplasia and early cancer arising in Barrett’s oesophagus [37,38]. There is extensive data on the uptake and distribution of the generated photosensitisers in gastrointestinal mucosa. In experimental Barrett’s like oesophagus protoporphyrin IX (PpIX) was generated in the epithelial cells whether squamous or columnar, with maximum levels occurring 3 h after oral administration or intravenous injection. The uptake in the mucosa was 3.5 times greater than in the muscularis propria. There was little difference between oral or parenteral administration of the 5-ALA [39]. These studies have supplied important reasons for the mucosal localisation of PpIX. The muscularis contains more iron and has a reduced activity of one of the rate controlling enzymes. porphobilinogen deaminase. Clinical studies of the PpIX distribution following oral 5-ALA have confirmed the mucosal accumulation relative to surrounding tissues. There was little difference in accumulation when the oral dose was increased from 60 to 75 mg/kg, and carcinomatous tissue produced PpIX in similar quantities to dysplastic and metaplastic epithelium. Following the accumulation of PpIX, a photodynamic action will only occur following light irradiation. Initially all treatment parameters were empirically selected. An elegant study in an experimental model of Barrett’s-like oesophagus has confirmed that the most appropriate time for light irradiation is 2—3 h after 5-ALA administration [39]. This time interval appears critical to achieve mucosal destruction while sparing oesophageal function. The clinical studies of 5-ALA photodynamic therapy have demonstrated eradication of dysplasia and T1 tumours. A prospective randomised trial of the treatment of low-grade dysplasia using 5-ALA and
irradiation with green light rather than the usual 630 nm red light has again confirmed how effective this treatment is in reversing dysplasia and also metaplasia. Healing proceeded with the regeneration of neo-squamous epithelium [40]. A variation of 5-ALA photodynamic therapy involves the direct endoscopic spraying of the agent combined with sodium bicarbonate as a mucolytic onto dysplastic Barrett’s oesophagus. A period of time is allowed for local absorption and then the area is irradiated with light. The response following this technique was variable with 2 of 9 patients failing to show any response [41]. The use of mTHPC as a photosensitiser has been report in the oesophagus for the treatment of early cancers [42]. It is a very potent agent and produces very effective ablation of both early cancer and dysplasia. The most recent reported series demonstrated that after a median follow-up of 17 months, 8 of 11 patients were clear of cancer and all four patients treated for high-grade dysplasia in Barrett’s oesophagus were clear. There were two very serious complications, with one patient dying of an aorto-oesophageal fistulae and one patient developing a tracheo-oesophageal fistula [43]. An important observation was that the aorto-oesophageal fistula may have been due to excessive light dose. The results of photodynamic therapy using the three photosensitisers for the endoscopic treatment of dysplasia and early cancer in the oesophagus are summarized in Table 1. All those patients treated endoscopically for dysplasia or early cancer should receive life long biopsy surveillance. In addition some of these patients may develop invasive cancer under the neo-squamous epithelium.
Conclusions Photodynamic therapy is an essential method for the treatment of dysplasia in Barrett’s oesophagus. However, it should be used in combination with other methods. If a patient has a macroscopic abnormality, then my initial strategy is to perform endoscopic mucosal resection. This will allow full histological assessment and provided evidence of
200 deeper invasion. I would then proceed to treat the whole Barrett’s area with Photofrin photodynamic therapy. If there were residual areasof metaplasia then these would be treated with thermal laser therapy or Argon Plasma Coagulation. I prefer to use Photoifrin PDT if there is any hint of macroscopic abnormality and ALA/PDT for patients with an entirely innocent looking oesophagus with only biopsy evidence of dysplasia. The complication rate of photosensitivity and stricture is much higher using Photofrin and this must be explained fully to the patient.
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