PDT involves the use of a nontoxic photosensitizer, which selectively accumulates in malignant tissue, and laser photoactivation to destroy malignant cells. Ortner et al. reported on the first randomized, controlled trial of biliary double stenting with and without Photofrin PDT in 39 patients with nonresectable, large (>3 cm diameter, ~80% tumor node metastases stage IV, bismuth type IV), proximal cholangiocarcinoma (47). Criteria of successful stenting had to be fulfilled before randomization, but successful biliary drainage (decrease in bilirubin levels >50% within one week) (Fig. 4) before randomization was obtained in only 21% of patients in both groups, as shown in earlier studies (48). Stent exchanges were performed every three months in both groups. PDT procedures necessitated initial stent removal, final insertion of a new set of endoprostheses, and confinement of patients in a darkened room for three to four days after injection. PDT was repeated if any follow-up examination showed evidence of residual tumor in the bile duct (70% of patients; mean number of PDT sessions, 2.4; range, 1-5). PDT resulted in improved biliary drainage (successful drainage, 72%), Karnofsky index (P < 0.01), and quality-of-life (P < 0.001), and prolongation of median survival (493 days vs. 98 days; relative hazard, 0.21 [confidence interval (CI), 0.12-0.35]; P < 0.0001, evidence level 1b). PDT was generally well tolerated (including mild, transient photosensitivity, 10% of patients), and burden of treatment was lower than with stenting alone (P < 0.001). Stenoses were seen in only two patients and were easily managed by further stenting. This trial was terminated prematurely because further randomization was deemed unethical. However, as patients successfully stented a month before screening were excluded, these results may be applicable only to those patients not helped by conventional biliary stenting, and the observed survival benefit may have been caused by relief of cholestasis rather than by tumor reduction. Indeed, patients in the PDT study arm did develop progressive disease and metastases, as previously reported (47). A recent phase II study in 24 patients with Bismuth type III/IV cholangiocarcinoma showed that the median survival after PDT was not statistically different significantly from a retrospectively analyzed historical control group of 20 patients treated
only with biliary drainage (9.9 months vs. 5.6 months; level 4 evidence) (49). Another phase II study investigated PDT as a neoadjuvant treatment in seven patients with advanced proximal bile duct carcinoma. In all patients, R0 resection was achieved. No viable tumor cells were found in the inner 4-mm layer of the surgical specimens. Biliary leakage did not occur, even though the bilio-enteric anastomoses were sewn to PDT-pretreated bile ducts. The one-year recurrence-free survival rate was 83% (19). A longer-term follow-up of an enlarged cohort of 23 patients showed less good results: median survival after treatment was 11.2 months for patients without distant metastases and 9.3 months for all patients. Four-year survival was less than 5% showing that although PDT appears effective for nonresectable hilar cholangiocarcinoma it does not prevent progression of the disease (50). In a recent randomized trial, 32 patients with nonresectable biliary duct carcinoma were treated with pros-theses + PDT or with prostheses alone. The median survival after randomization was seven months for the control group and 21 months for the PDT group (P = 0.0109; evidence level 1b). However, four patients showed infectious complications after PDT versus one patient in the control group (51).
The assessment of the direct antitumor efficacy of PDT remains difficult due to the type of the tumor, which is essentially infiltrative. However, percutaneous transhepatic PDT was evaluated with monthly intraductal ultrasonography. At three months after PDT, the mean thickness of tumor mass had decreased from 8.7 ± 3.7 mm to 5.8 ± 2.0 mm (P < 0.01). At four months, the thickness of the mass had increased to 7.0 ± 3.7 mm. The median survival of the 24 patients was long: 19 ± 5.9 months (52).
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