Within the past two decades, major progress has been made in biliary endoscopy both with stenting and with ablative therapy. A primary goal in patients with malignant biliary lesions who are not candidates for surgery is to provide localized and efficient necrosis of the lesions. This article summarizes the current literature on biliary tumor ablation with photodynamic therapy and radiofrequency ablation. Prognosis, treatment technique, potential complications, treatment efficacy, and controversies are discussed.
Key points
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Most patients with hilar cholangiocarcinoma have unresectable disease and require palliation with biliary stenting.
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Photodynamic therapy (PDT) is a local ablative method that uses a systemic photosensitizing agent that preferentially accumulates in malignant cells and is activated by a nonthermal light causing destruction of the malignant cells through a process mediated by oxygen-free radicals.
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Potential treatment options for PDT include palliation in combination with chemotherapy, palliation in combination with stenting, postoperatively for recurrent tumor, or downstaging a patient for curative surgery.
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Radiofrequency ablation (RFA) using thermal energy is emerging as a potentially effective treatment of malignant biliary occlusion and has been used before insertion of biliary stents and as a treatment of metal stent occlusion.
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In the limited existing studies, RFA was effective in achieving local tumor control and may offer a therapeutic option for patients with recurrent or primary cholangiocarcinoma.
Introduction
The incidence of cholangiocarcinoma accounts for 2% of all gastrointestinal malignancies, and fewer than 20% of patients are considered to have resectable tumors at the time of diagnosis. Given that most cholangiocarcinomas are unresectable, the goal of intervention is biliary decompression. Jaundice, pruritis, secondary biliary cirrhosis, cholangitis, coagulopathy, and weight loss are consequences of obstruction. Recent data have suggested that it is useful to drain more than 50% of the liver volume for favorable long-term results. Metal stents (bare metal mesh) are usually preferred and carry the advantage of longer duration of patency compared with plastic stents. There is controversy over unilateral versus bilateral stents in unresectable hilar biliary obstruction, as only a portion of the liver will be drained with a single stent. Tumor ablation combined with stenting can reduce cholestasis and improve median survival time in patients with cholangiocarcinoma. Photodynamic therapy (PDT) and, more recently, radiofrequency ablation (RFA), have been used as adjuvant therapies to improve results of biliary stenting. Ultimately, endoscopic biliary drainage may enable patients to receive additional chemotherapy.
Introduction
The incidence of cholangiocarcinoma accounts for 2% of all gastrointestinal malignancies, and fewer than 20% of patients are considered to have resectable tumors at the time of diagnosis. Given that most cholangiocarcinomas are unresectable, the goal of intervention is biliary decompression. Jaundice, pruritis, secondary biliary cirrhosis, cholangitis, coagulopathy, and weight loss are consequences of obstruction. Recent data have suggested that it is useful to drain more than 50% of the liver volume for favorable long-term results. Metal stents (bare metal mesh) are usually preferred and carry the advantage of longer duration of patency compared with plastic stents. There is controversy over unilateral versus bilateral stents in unresectable hilar biliary obstruction, as only a portion of the liver will be drained with a single stent. Tumor ablation combined with stenting can reduce cholestasis and improve median survival time in patients with cholangiocarcinoma. Photodynamic therapy (PDT) and, more recently, radiofrequency ablation (RFA), have been used as adjuvant therapies to improve results of biliary stenting. Ultimately, endoscopic biliary drainage may enable patients to receive additional chemotherapy.
Photodynamic therapy
Photodynamic Therapy Technique
Preparation
Antibiotic prophylaxis should be given to patients with anticipated incomplete biliary drainage. There are multiple photosensitizing agents available for cholangiocarcinoma, with hematoporphyrin derivatives (eg, Photofrin II, Photosan-3) being the most commonly used. This intravenous agent preferentially accumulates in cancer cells. For instance, Porfimer sodium (Photofrin; Axcan Pharma Inc, Birmingham, AL), which is the only photosensitizer approved by the Food and Drug Administration (FDA), is injected intravenously at a dosage of 2 mg/kg body weight 48 hours before laser activation. All the procedures are done under general anesthesia. Considerations before ablation therapy include assessing resectability or not, determination of atrophic segments, antibiotic prophylaxis, and patient education ( Box 1 ).
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Resectable versus unresectable disease
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Surgery is indicated for resectable disease
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Determine what area of the liver is atrophic and not draining
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Liver metastasis versus cholangiocarcinoma
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Patients with liver metastasis are not candidates for photodynamic therapy (PDT)
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Antibiotic therapy is required for prevention of cholangitis
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Patients need to be educated about PDT side effects: photosensitivity
Patient position/approach
Patients are placed in the prone or supine position. Endoscopic retrograde cholangiopancreatography (ERCP) is performed as a standard of care at the time of PDT.
Technique/procedure
Forty-eight hours after systemic administration of the photosensitizing agent, light activation is performed using a quartz fiber mounted with a cylindrical diffuser tip coupled to a diode laser emitting a particular wavelength.
Endoscopic retrograde cholangiography is performed using a large-channel duodenoscope. After cannulation into the biliary tract, a cholangiogram is performed to help define the anatomic distribution of malignant tissue. Then, selective bougie and balloon dilation of the stricture(s) to be treated is performed.
PDT is delivered through a 3.0-m-length fiber with a 2.5-cm-long cylindrical diffuser at its distal end (Pioneer Optics, Windsor Locks, CT). The diffuser can be inserted into a 10-F sheath of a plastic stent delivery system and placed at the level of the stricture being treated ( Figs. 1–3 ). Alternatively, cholangioscopy can be used as a platform to administer PDT.
A diode laser system (InGaAIP Laser Diode; Diomed Inc, Andover, MA) with a maximum power output of 2000 mW and a wavelength of 633 ± 3 nm is used as a light source. Photoactivation is performed at 630 nm with a light dose of 180 J/cm 2 , fluence of 0.250 W/cm 2 , and irradiation time of 750 seconds (3).
At the completion of the laser application, plastic endoprostheses or external drainage tubes are inserted given that the PDT site induces swelling and coagulation necrotic changes for up to a 1 week after PDT (4). The depth of tumor necrosis with hematoporphyrin derivates is 4 to 6 mm ( Fig. 4 ), thus primary tumors with deeper invasion cannot be eradicated with this method alone.
Photodynamic Therapy Complications/Management
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Most of the complications with PDT are from the ERCP and the biliary stenting themselves
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A relevant side effect of PDT includes phototoxicity, which can last 4 to 6 weeks after drug administration
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Cutaneous complications include the following:
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Serious phototoxicity requiring oral corticosteroid treatment
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Herpes zoster requiring hospitalization and intravenous antiviral treatment
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Erythema multiforme drug reaction requiring symptomatic treatment with antihistamines, analgesics, and local skin care
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Postoperative Care
Antibiotics should be continued in cases of incomplete biliary drainage. Postoperatively, patients treated with PDT are advised to remain out of direct sunlight because porfimer sodium may cause prolonged photosensitivity lasting 30 to 90 days. The photosensitivity effects of the drug last 4 to 6 weeks in decreasing intensity ; therefore, repeated PDT sessions are often necessary. PDT is typically repeated at 3-month intervals, at which time all stents should be replaced.
Outcomes
Potential treatment options for PDT include palliation in combination with chemotherapy, palliation in combination with stenting, postoperatively for recurrent tumor, or downstaging option for a patient before curative surgery ( Table 1 ). PDT with chemotherapy and more than 2 sessions of PDT were significant independent predictors of longer survival in advanced cholangiocarcinoma in the study by Hong and colleagues ( P = .013). In a prospective randomized trial, patients receiving PDT with chemotherapy showed higher 1-year survival rate compared with those with PDT alone (76.2% vs 32%, P = .003) and prolonged overall survival (median 17 vs 8 months, P = .005). Combination of stenting and subsequent PDT prolonged survival over stenting alone (493 vs 98 days, P <.0001). In Lee and colleagues’ review article, it was concluded that PDT improves survival and quality of life, and reduces tumor growth while treating cholestasis. In Leggett and colleagues’ review article, compared with biliary stenting, PDT was associated with a statistically significant increase in the length of survival (weighted mean difference [WMD] 265 days), improvement in Karnofsky scores (WMD 7.74), and a trend for decline in serum bilirubin (WMD −2.92 mg/dL).
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