Photodynamic therapy for esophageal cancer

In photo<lynamic therapy, a photosensitizingdrug is injected and then activated by light in the red spectral region to produce reactive, highly toxic singlet oxygen, which causes cell tissue and damage. When the distinction between tumoral and normal tissue is difficult at endoscopy, photodynamic therapy,., preferable to any other conservative method of destruction. The main indications comprise genital, head and neck, bronchial, bladder and gastrointestinal tumours, particularly esophageal cancer (including squamous cell cancer and glandula r neoplasia). Esophageal tumours should be class Tl or T2, at most, and detected at endoscopy. Dysplasia which is flat, sessile and multiccntric may also be an indication for photodynamic therapy. Advanced esophageal cancers are contraindicated for photo<lynamic therapy. Can J Gastroenterol 1990;4( 9): 612-615


P l IOTODYNAMIC 11-IERAPY IS A RlRM
of photochemotherapy in which a photosensitizmg drug is inJecteJ anJ then activated by a n appropriate light wavelength, usually in the red spectral region. The activated photoscns1t1:er converts oxygen molecules in its sur· rounding into reactive, highly tOXIC singlet oxygen, which causes cell and tissue damage. The photosensittzerused in clinical app lications of photo, dynamic therapy is an hemato, porphyrin derivative; the light source~ a laser. The prolonged tumour reten, tion o( the hematoporphyrin denvattve compared to normal tissues has led to applications for tumours ( 1,2).
Photo<lynamic therapy has a sol~ experimental basis and excellent un, derlying principles, but adequate chm, cal trials to assess its practical valuc have been slow to develop. Many fac, tors account for this discrepancy. Unnl recently, it was difficult to get a regular supply of hemacoporphyrin dcrivattve. Medical laser sou rces arc sophisttcated costly, and require close technical \\11· veillance. More importantly, the inmal uses -palliation o( nonsuperficial cancer -were not shown to be favorable compared with curative anemptsonsuperficial lesions. Finally, photodynam1c therapy as a potential alternative therapy to surgery for poor surgical nsk patients has heen roorly communicateJ to clinicians so that recruitment for trials has been Jifficult.
In clinical oncology, the inJication forphotodynamic therapy is baseJ upon principles typical many type of tumour therapy.
The tumour cells should have good susceptibility to this procedure of desm1ction. This depends upon the histology and location of the tumour (geometry of irradiation).
The tumour should be superficial (classification T J ). Such lesions arc usually asymptomatic, anJ careful endoscopic screening of high risk patients is necessary to promote indications.
There should be no alternative or easy procedure of destruction (such as a local tumorectomy). When the Jistinction between tu moral and normal tissue is difficult at endoscopy, phocodynamic therapy is preferable to any other conservative metho<l of destruction.
The main indications comprise genital, head and neck, bronchial and blad..icr tumours, as well as tumours ot the digestive tract. Esophageal cancer is the most appropriate inJicarion among digestive tract tumours.

RA TIO NALE IN ESOPHAGEAL CANCER
Tumour type: Squamous cell cancer 1s the usual indication. Potential extension to severe squamous cell dysplasia is possible when the lesions are not accessible to snare resection ( ie, if lesions arc nat and multicentric).
Glandular neoplasia in the esophagus is less frequent. It develops 111 columnar mucosa, usually in relation to reflux. Neoplasia in Barrett's epithelium may be located either in the mid (circumferential columnar lining) or lower esophagus (noncircumferential lining). In the latter condition any distinction between neoplasia at the cardia and neoplasia in the esophagus is artificial. Esophageal glandular neoplasia may be classified as adenomatous dysplasia or adenocnrcinoma. Endoscopic morphology of the tumour: At the superficial stage, esophageal neoplasia does not interfere with peristabis and is not obstructive. Slight alterations in mucosa! architecture results in depression, elevation or a mixeJ pattern. In squamous neoplasia the mucosa! pattern may appear normal without coloration. After spraying with Lugol's iodine solution, the neoplastic area remains unstained in contrast to the dark hrown of the normal mucosa. In glandular neoplasia the endoscopic pattern of superficial cancer or dysplasia is characterized by longitudinal nonulcerated sessile elevations (ndenomatous type) of the mucosa which are often circumferential.
As for the geometry of irradiation, the tubular shape of the esophagus allows easy and effective irradiation without any blind areas. Evaluation of the surface of the lesion is required for dn~imetry (duration of irradiation); for this purpose the height of the lesion b the mam parameter. The circumferential light repartitor b prefcrreJ !or irrad tat ion in circumferential and noncircumferential lesions. In the latter condition, 1rrad1ation is therefore distributed in part co the normal mucosa; dosimetry should take this into account. Staging of the tumour: Following surgical treatment the tumour 1s stageJ as superficial (limited to mucosa anJ submucosa, Tl) or nonsuperficial ( muscular or periesophageal extension, T2-T 4) in the operative specimen, accmdmg to the 1987 TNM classification. Superficial cancer of the squamous muco~a may be further classified as intraepithelial (muscularis mucosae not invaded), intramucosal and submucosal. In situ malignancy (no lymphatic invasion) characterizes intraepithelial cancer; this is the only type without potential for lymphatic extension. In glandular neoplasia of the columnar-I ined epithelium, the lesion 1s classified into two groups only: intramucosal or submucosal. The potential for lymphatic extension is less in the intramucosal type versus submucosal, hut not nil.
In the absence of surgery, stagmg is Jone via endl)SCopy, computeJ tomography or echoendoscopy. The latter prnceJure characterizes the tumour CAN J GASTROENTEROL VOL 4 No 9 DECEMBER 1990 superficially, with an over 90% efficacy when rhe second hyperechoic layer is not interrupted. The superficial pattern of a tumour at endoscopy 1s confirmed at echoendoscopy in no more than 60% of cases. Furthermore, echoendoscnpy doc~ not contri hute to a distinction hetween intraepithelial and other types of superficial squamous neoplasias. Therefore, a local tumorecwmy proceJure such as phorodynamic therapy should be used in coniuncnon with systemic (chemotherapy) or regwnal (rad iotherapy) agents in a curative protocol.
The diagnosis of squamous or glandula.r dysplasia in the esophagus is hased on h1opsy at enJoscopy. Difficulties in confirming this diagnosis 111 the squamous epithelium should he kept 111 mind. Cellular alterations in reflux esophagitis shoulJ not be mistaken for premalignant change. The superficial cellular alterations connecteJ with viral infection in condyloma of the esophagus arc not linked to neoplasia, while Jysplas1a originating from the deep epithelial layer is a premalignant lesion. Dysplasia is of course always staged as superficial at echoendnscopy. Therefore, exploration 1s recommended as a further contn ii of the biopsies. Decision analysis: In esophageal squamous cell cancer the overall prognosis is very poor and treatment usually docs not achieve a cure. The selection of a nonsurgical procedure versus esophagectrnny depend~ upon patient age, tumour morphology and ass(,ciated cancerous or noncancerous diseases. When a nonsurgical protocol is adopteJ, its objective is either partial destruction of the tumour ( palliation of symptoms), extensive destruction (pal-I iat ion and prolonged evolution through a radical rmrocol), or total destruction (curative treatment).
Palliative prmocols are baseJ on widening of the esophageal lumen using a thermal neodymium Y AG (Nd:YAG) laser in monorherapy. Radical protocols in superficial and mmsuperficial cancer combine Nd:YAG laser, chemotherapy (cisplacinum rind 5-fluorouracil), and raJiotherapy. Photodynamic therapy will be useJ instead of Nd:Y AG in a limited group of patients. lt should be used when a cancer detected at endoscopy has a superficial pattern and is confirmed as superficial at echoendoscopy (Tl group). If the patient is in poor health, old or has associated disease, irradiation can be performed as monotherapy. This concerns a lso patients previously treated by radiotherapy for esophageal cancer, with recurrence of the superficial type.
lf the patient is young or in good health, the protocol is proposed as a curati ve alternative to surgery. Therefore, photodynamic therapy should always be completed by radiotherapy (60 Gy equivalent) two months later.
When the superficial pattern of the tumour at endoscopy is not confirmed at echoendoscopy (T2 classificatio n ), photodynamic therapy may still be used if there is limited invasion of the muscular layer. However, irradiat ion is performed after a chemotherapy sess ion. The multimodal protocol combines chemotherapy, photodynamic therapy and radiotherapy.
When muscular in vasion is classified as extensive at echoendoscopy, the Nd:YAG laser multimodal protocol is preferred.
In esophageal adenocarcinoma that has developed in columnar epithelium, surgical treatment ( esophagectomy) is a lways preferred in superficial and nonsuperficial cancer, as it is potentially curative. A nonsurgical protocol is adopted only if there exist contraindications to surgery (poor health status or o ld age). Then NJ:YAG laser and/or scenting arc adapted to the treatment of advanced cancer. Photodynarnic therapy should be proposed if a superficial pattern at endoscopy is confirmed at ec hoendoscopy; this concerns very few patients.
In dysplasia, indications fo r photodynamic therapy should be developed for the treatment of flat, sessile and multicencric lesions. Treatment of these depends on the promotion of carefu l endoscopic screening of the esophageal mucosa. In severe dysplasia the choice is hetween radical surgery for a premalignant lesion and local destruct ion hy photodynamic t h erapy. Dysplasia of t he squamous epith elium in association with cancer should be 614 treated simultaneously with the main tumour. Severe dysplasia occurring in a flat condyloma will he treated by this procedure. Dysplasia of columnar-lined epith elium is more common and may be detected during s ur vei ll ance of a Barrett's esophagus. The response of columnar dysplastic mucosa to photodynamic therapy is quite specific. After destruction, healing should be p laced under the control of an antisecretory agenr (a proton pump inhibitor) and/or surgical correction of t he reflux. The regenerated mucosa may revert to squamous in the treated area.

METHOD OF PHOTODYNAMIC THERAPY
The photosensitizing agent hematoporphyrin denvative, or its dimeric ether, DHE, is injected inrrnvenously in the course of a DW 5% perfusion. The dosage most often used is 2.0 to 2. 5 mg/kg body weight. Endoscopic irradiation is performed using a monochromatic (630 nm) laser beam of red light transmitted through a flexible quartz fibre. The argon pumped-dye laser is still the standard equipment. The delivered light dose should he in the range of lOO to 200 J/cm 2 , with a power density in the range of 100 to 500 mW/cm 2 . Tumour necrosis beg in s within 24 h; its duration varies according to tumour depth ( one week to one month). Stricture may resu lt from the treatment of circumferential lesions at the healing stage. The major toxicity of photodynamic therapy is skin photosensitivity, which can be prevented by protection of the patient from direct sunlight during t he first month. Other side effects reported inc lude nausea, vomiting and liver tox icity. Usually these are very mild.
During For one full month after treatment, the patients avoided direct exposure to sunlight. Photo<lynam1c therapy was proposed as monothcraP'f in half of the patients. The other ha~ was included in a mu lt1modal protocol receiving chemotherapy (cisplatinum 5-fluorouracil and/or radiotherapy) (31. Radiation began after an interval of two months following photodynam1c therapy, to prevent cutaneous com, plications of phntosensitization.

RESULTS OF PHOTODYNAMIC
THERAPY It is not c lear whether photo, dynamic therapy in nonsupcrfic1al esophageal cancer offers any advantage over Nd:Y AG laser therapy. Indee~ photodynarnic therapy in such cases ij often associated with prolonged tumour necrosis re~ult ing in impaired relief ci dysphagta; there is a risk of complications such as perforation, hemorrhage o r inflammatory stricture. Furthermore, prompt regrowth of the tumour is tht r ule. McCaughan (4) treated 40 patients (adenocarcinoma and squamous cell cancer). Jm (5) treated 20 patients with squamous cell cancer and 71 with adva nced cancer of the cardia. Thomas (6) treated 15 patients with squamous cell cancer. Due to poor results observed in the fir~t cases, advanced squamous cell cancer and C AN J GAsrnOENT l:.ROL V OL 4 No 9 DECEMBER 1990 adenocarcinoma were consiJereJ n~ contrninJicarions to rhotndynamic therapy.
Results obtained in superficial squamous cell cancer are much hetter. Tian (7) treated 13 raciencs with good results in 12. Four complete renuss1uns in six treated patients were reported hy Hayarn (8); five of six were reported by Tajiri (8) and six of eight hy Monnier (10).
In the author's senes ( l 00 pat1ems treated) good results were ohrnincd only in superficial neoplasia determined by endoscopy. Prompt recurrence occurred in all other cases. The rate of complete tumo ur destruction assessed by a negative biopsy at endoscopy three months after trearmem reached 75% in superficial cancers confirmed at echocndoscopy (Tl) and only 50% in false superficial ca ncers (T2 protocol. The superficial lesion cla,. sificd :;is severe dysplasia "ia hiorsy is an elective in<l1cat1on for photnJynamic therapy. Cases with mo<lerate dysplasia shou ld be included in a survei llance program and nm treated at this stage. Indications in squamous ncoplas1a suggc~t that photodynamic therapy is an alrcmauvc to surgery (es<>phagcctomy) m patients with superficial cancer such a~ those detected at endoscopy. The altcrnanve is accepted m 'low nsk' and young patients when the tumour is staged Tl ar echoenJoscopy. Phmodynamic rherapy is then included in a multimndal protocol and the patients receive a course of radiauon ( without chemotherapy) two months after the laser treatment. When the tumour is srnged T2 at ec hoc ndoscopy, photodynamic therapy is preferred to surgery only in poor risk pntienb. Chemotherapy is included from the beginning of the protocol and radiotherapy performed 21 month:. later. In severe squamous cell dysplasia associatc<l with retlux csophagim or papilloma virus mfccrion (cnn<lylnm,1), photodynamic therapy is an elective indication with lesions which arc flat and multicentric. Paticn1s with moderate dysplasia should not he treated and should he included in a surv (•illancc program. R10l 1985;19UI 5. 8