Endoscopy: Biliary Tract. Photodynamic therapy for cholangiocarcinoma. Part 1

Part 1

By Norman E. Mar con

Division of Gastroenterology The Wellesley Hospital Site, University of Toronto

160 Wellesley Street East Toronto, Ontario M4Y 1J3, Canada

Tel.: +1-4.16-926-7763, fax: +1-416-926-4951

Bile duct carcinoma is an uncom­mon malignant tumor, which occurs more frequently in the elderly. Several predisposing factors include ulcerative colitis, sclerosing cholangitis, an anoma­lous long pancreatic biliary channel, Clonorchis sinensis infestation, and possibly trans­duodenal sphincterotomy for benign disease.

Biliary carcinoma is tradition­ally classified as occurring in the lower third (intrapancreatic portion), middle third (from the cystic duct to the superior border of the pancreas) or upper third (the common hepatic duct and confluence of the right and left hepatic ducts). About 35% of the lesions arise in the middle or lower third, and diffuse types account for 10%, whereas 55% occur in the upper third. Bismuth and Corlette (Surg Gynecol Obstet 1975; 140:170) described patterns of tumor involvement of the proximal biliary system. In type I, the cancer extends to, but does not involve, the bifurcation; in type II, the cancer involves the bifur­cation but does not extend into either hepatic duct; type III (a and b) involves the bifurcation and unilateral hepatic duct, without extension into secondary radicles on either the right or left side; and type IV extends up into the secondary radicals bilaterally.

Tumors of the middle and distal third of the bile duct often cause biliary obstruction when they are quite small, and if oper­able are usually well served by resection. In contrast, cancers of the proximal third may involve predominantly the right or left hepatic duct, allowing drainage through the uninvolved duct, thereby preventing clinical jaundice until the tumors either become locally advanced or metastatic. Surgery with excision of the tumor and intra­hepatic bile ducts often requires hepatic and vascular resection. In one series, a survival after resection aiming at "cure" was 66% at one year and 26% at five years (Klempnauer et al. J Clin Oncol 1997; 15:947). In those who underwent palliative surgi­cal bypass, the one-year and five-year survival rates were 21% and 2%, respectively Since the procedure-related morbidity and mortality is significantly lower using endoscopic meth­ods, insertion of either a plastic or metal stent is the method of choice for palliation. Although metal stent placement results in higher patency, the survival time is not increased compared to that with plastic endoprostheses.

Technical success, with effective drainage, is achieved in 91 %, with a median survival time of 149 days in Bismuth type I and 84 days for type II (Polydo-rou etal. Grot 1991; 32:685, Ducreux et al. Dig Dis Sci 1992; 37:778). In type III, the drainage results are tragically poor, with a 30-day mortality of 32% and a median survival of only 70 days (Bismuth et al. Ann Surg 1992; 215:31). These studies demon­strate that stenting fails to prolong the relief of jaundice and the symptoms of pruritus, anorexia, diarrhea, and altered sleep pattern. These failures are reflected by a poor performance status on the Karnofsky index or QLQ-C 30 (quality-of-life questionnaire).

There is therefore a great deal of scope for improvement. Ortner et al. (1998) bring a fresh outlook, with the application of photodynamic therapy (PDT) using the photosensitizer Photo-frin. In summary, she and her colleagues treated nine patients with Bismuth III and IV cholan­giocarcinoma in whom plastic stent insertion failed to produce an adequate improvement in drainage. After intraluminal PDT, the bilirubin level fell significantly in all patients. This was associated with a significant improvement in the Karnofsky score and no mortalities within 30 days, with a median survival time of 439 days. In two patients, no further stent place­ment was required after PDT ablation.

What is PDT? It is a unique treatment modality involving the use of an instrument (a laser) and a photosensitive drug. Although PDT has been clinically used in the gastrointestinal tract since the early 1980s, it did not achieve wide acceptance in the gastroenterology community until the last five years, and then it was mainly for the treatment of various stages of cancer in the esophagus (Lightdale et al. Gast-rointest Endose 1995; 42:307,

Sibille et al. Gastroenterology 1995; 108:537). The sensitizer is activated by applying laser light in the red spectrum (630 nm). The only photosensitizer com­mercially available, and with widespread regulatory approval, is Photofrin (porfimer, dihemato-porphyrin ether) (QLT, Vancou­ver, Canada). With this drug and laser wavelength, destruction into the tumor is 3-5 mm. Laser light is delivered directly to the tumor via a diffusing fiber passed through a trans-sphincteric or percutaneous miniscope. A photochemical reaction (light plus drug) results in the release of locally toxic singlet oxygen, which destroys the microvascu-lature of the tumor, resulting in necrosis, sloughing, and hope­fully improved lumen patency. If the tumor is superficial, PDT may be curative, as in the esophagus (Gossner et al. Gast-

roenterology 1998; 114:448).

In the study by Ortner et al., nine patients had not responded with a decrease in jaundice, despite presumably adequately placed stents through and above the stenosis. They received Photofrin (2 mg/kg i.v.), and 48 hours later the stent was removed and intraluminal photoactivation using an argon dye laser (wavelength 630 nm, 310mW/cm², 180j/cm²) treatment was carried out using diffusing tips of 2-5 cm or 4 cm. The laser light was delivered via a mother/daughter system through the baby scope channel. These fibers have a metallic tip to facilitate placement under fluoroscopic control. The light exposure time for treatment was only between 10 and 16 minutes. Immediately after the light treatment, the plastic stents were replaced.