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Keywords:

  • hilar cholangiocarcinoma;
  • photodynamic therapy;
  • neoadjuvant therapy;
  • liver resection;
  • liver transplantation

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Only 20–30% of patients with hilar cholangiocarcinomas (CC) are candidates for potentially curative resection. However, even after curative (R0) resection, these patients have a disease recurrence rate of up to 76%. The current prospective Phase II study investigated photodynamic therapy (PDT) as a neoadjuvant treatment for CC.

METHODS

Seven patients with advanced proximal bile duct carcinoma were evaluated. Patients were treated with PDT at the area of tumor infiltration and 2 cm beyond and underwent surgery after a median period of 6 weeks (range, 3–44 weeks).

RESULTS

One patient had a Bismuth–Corlette Type II tumor, two patients had Type IIIa, one patient had Type IIIb, and three patients had Type IV. Cholestasis parameters after PDT decreased significantly. No relevant adverse events from PDT occurred except for minor intraoperative phototoxicity in one patient. Three patients underwent right-sided liver resections, two patients underwent left-sided liver resections, and one patient received a combined hilar resection with partial pancreatoduodenectomy (PD) due to tumor extension into the distal bile duct. Liver transplantation and PD were performed in another patient. In all patients, R0 resection was achieved. Four patients developed minor surgical complications, even though the bilioenteric anastomoses were sewn to PDT-pretreated bile ducts. No viable tumor cells were found in the inner 4 mm layer of the surgical specimens. The PDT-pretreated epithelium of the tumor-free proximal resection margins exhibited only minimal inflammatory infiltration. Tumors recurred in 2 patients 6 and 19 months after surgery. The 1-year recurrence free survival rate was 83%.

CONCLUSIONS

Neoadjuvant PDT for hilar CC is a low-risk procedure with efficient selective destruction of the superficial 4 mm layer of bile duct tumor without complications exceeding series without neoadjuvant PDT. Neoadjuvant PDT should be evaluated prospectively to determine whether it reduces the rate of local disease recurrence after potentially curative resection. Cancer 2003;97:2783–90. © 2003 American Cancer Society.

DOI 10.1002/cncr.11401

Cholangiocarcinoma (CC) has an incidence of about 2000–3000 new cases in the United States and about 600–900 new cases in Germany.1 Tumors occur most commonly at the biliary confluence at the hilum of the liver (so-called Klatskin tumors) and comprise 40–60% of all CC tumors. The prognosis for patients is very poor because most of them become symptomatic at an advanced stage of disease. Only 20–30% of patients with hilar CCs are candidates for potentially curative resection.2, 3 Except for a pilot study of patients with extensive preoperative chemoradiation,4 liver transplantation for hilar CC had been abandoned because of the poor long-term survival of patients.1 Extensive surgical strategies afford the best chance of long-term survival. In 2 studies,2, 3 5-year survival rates of 37–56% were achieved after resection with histologically negative margins (R0 resection). However, even after radical surgical approaches and R0 resection, disease recurrence rates of up to 76% occurred at the area of anastomosis or intrahepatically.5 The spread of tumor along or within the intrahepatic bile ducts is the principal factor for disease recurrence. Due to anatomic restrictions, resection is feasible only in patients with short tumor-free margins. Resection of the right hepatic duct is limited by the region of the first segmental ramification, which regularly occurs within 1 cm from the hepatic hilum. Even during surgery, tumor extension is often difficult to define. Local ablation of spreading tumor and dysplastic epithelium near or within the region of the first segmental ramification of the left and right hepatic duct before surgery may decrease the rate of tumor recurrence.

Photodynamic therapy (PDT) has led to remarkable regression of malignant tumors.6–9 PDT is a two-step procedure; a photosensitizing drug known to accumulate in tumor cells is administered, after which the tumor is exposed to laser light of appropriate wavelength. The activated photosensitizer forms cytotoxic reaction products, including singlet oxygen radicals, that destroy cancer and neovascular cells and induce tumor thrombosis.10–13 In some studies, PDT has been used in the palliative management of hilar CCs.14, 15 These authors reported that the median survival time of patients was prolonged compared with other published reports and that patients' perception of their quality of life increased dramatically. In a single case, neoadjuvant PDT for hilar CC showed efficacious tumor destruction confined to the superficial 4 mm depth of the bile duct tumor and high tumor selectivity in the resected bile duct specimen.16 The current Phase II study investigated the feasibility of neoadjuvant PDT for selective tumor destruction and whether it has adverse effects on the following surgical procedure. The secondary goal of the study was to evaluate the short-term tumor recurrence rate.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Protocol and Patients

A single-arm study design was chosen for this new therapeutic approach to this rare tumor. The study protocol was conducted in accordance with the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the University of Leipzig. All patients gave written, informed consent for PDT before surgery. Criteria for inclusion were advanced proximal bile duct carcinoma (Bismuth–Corlette Types III and IV or Type II with wide extension to the distal bile duct). Criteria for exclusion were poor surgical risk (Class IV of Dripps-American Surgical Association Classification17), limiting the patient's ability to undergo major surgery, tumor metastases, age older than 75 years, encasement or thrombosis of the main portal vein, poor kidney or liver function (creatinine level > 3 mg/dL, international normalized ratio of prothrombin time > 2.2), severe empyematous cholangitis, acute porphyria, leukopenia (leukocyte count < 2000/cmm), thrombocytopenia (< 50,000/cmm), other malignancies, and previous therapeutic procedures for hilar CC. Between January 1997 and October 2001, 10 patients with hilar CC (3 women and 7 men) with a median age of 58 years (range, 43–72 years) were enrolled in the study. Seven patients remained for further analysis after 1 patient declined to undergo surgery after PDT, another was excluded for poor liver function (this patient had empyematous cholangitis, which was revealed at PDT), and the third patient had a poor surgical risk due to a cardiac infarction 2 weeks before surgery.

Clinical Staging

The clinical tumor stage was assessed by transabdominal duplex ultrasound (US), endoscopic retrograde cholangiography (ERC) including multiple biopsies from the bile duct stenosis, intraductal ultrasonography (IDUS) using a 15 MHz/6 F transducer (SSD-550; ALOKA, Tokyo, Japan), computed tomography scan (CT) with contrast media, and magnetic resonance cholangiography (MRC) / magnetic resonance imaging (MRI) with a Magnetom Vision (1.5 Tesla; Siemens, Erlangen, Germany) in turbo spin technique enhanced with paramagnetic ferrous oxides (Endorem; Guerbet GmbH, Sulzbach, Germany). Digital subtraction angiography (DSA) was used in selected patients to rule out vascular involvement. Longitudinal extension of the tumor was categorized according to the modified Bismuth–Corlette classification.18 The Bismuth–Corlette categories were assessed before PDT by MRC, as well as by ERC with IDUS to take radiographs of the precise location of the margins of mucosal infiltration by the tumor. This yielded a precise preoperative “mapping” of longitudinal extension of the tumor in the biliary tree. The depth of tumor infiltration was measured by MRI scan and IDUS. Regional lymph nodes and liver metastases were evaluated by CT and MRI scans and by US. Within 5 days before surgery, all patients were reevaluated by MRI scan and ERC with IDUS and exchange of endoprostheses to check for cholangitis and gross tumor necroses. Tumor extension, pathologic staging, and grading were definitively classified in the en bloc resected specimen according to the International Union Against Cancer classification of 1997.19

Neoadjuvant PDT and Biliary Drainage

Sodium porfimer (Photofrin; QLT Pharmaceuticals, Vancouver, Canada), a partially purified hematoporphyrin derivative, was injected intravenously at a dose of 2 mg/kg body weight 24–48 hours before PDT. Photoactivation was performed in one or two sessions in the tumor stenosis and in the bile duct adjacent to the stenosis. The tumor stenosis and the bile duct branches proximal to the tumor margins were intubated with a translucent ERC cannula (outer diameter 1.7 mm; Microvasive No. 4341; Boston Scientific, Watertown, MA) into which a 400 μm thin quartz fiber with a cylindrical light diffuser of appropriate length and radiopaque markers at the tip (Lightstic; Rare Earth Medical, West Yarmouth, MA) was inserted under fluoroscopic control. The entire tumor stenoses and the adjacent segments of the bile ducts proximal and distal to the tumor margins were exposed to laser light over a distance of 2.0–2.5 cm as follows. The quartz fiber was coupled to an argon-dye laser system (Lambda Plus PDL-2; Coherent, Dieburg, Germany) tuned to the 630 nm wavelength. The power emitted by the diffuser tip through the ERC cannula had been calibrated to 0.4 W/cm before PDT and checked thereafter using an integrating sphere power meter (PDM-10; IMM-Messtechnologie GmbH, Unterschleissheim, Germany). The average of both measurements was used to calculate the light dose. The tumor stenoses, 2–4 mm wide, were exposed to laser light for 10 minutes. The surface area was calculated as 0.94 cm2 per cm length for 3 mm wide stenoses, the light dose (= power [watts] × time [seconds]/tumor surface [cm2]) as 242 ± 20 joules per cm2 of tumor surface (mean ± standard deviation [SD]; 9 PDTs). Following PDT, 1 or 2 endoprostheses (9 or 11.5 F; Cotton-Leung; Cook Deutschland GmbH, Mönchengladbach, Germany) were inserted to drain both liver lobes. Antibiotic prophylaxis (ceftriaxone or ciprofloxacin) was administered during the hospital stay for PDT and in patients with a history of empyematous cholangitis during the interval before surgery. The interval was within 21–70 days after the last PDT session, except for 1 patient who had been referred on Day 308 for a combined liver transplantation (LTX) and Kausch–Whipple partial pancreatoduodenectomy (PD).

Surgery

The surgical procedures comprised hilar resection, left hemihepatectomy (Segments 1–4), right-sided hemihepatectomy (Segments 5–8), right trisegmentectomy (Segments 1 and 4–8), LTX, or PD. Resections were performed en bloc based on the tumor margins derived from the detailed preoperative imaging studies. Resections were considered curative (R0 resection) when there was no evidence of gross residual disease (R2 resection) or microscopic infiltration of the resection and dissection margins (R1 resection). This classification was used despite the reservation that doubts exist as to whether lymph node–positive tumors are surgically curable. Hilar resection included resection of the extrahepatic suprapancreatic bile duct and lymph node dissection of the hepatoduodenal ligament to the level of the common hepatic artery. It was performed routinely in addition to the liver resection and in one patient with Bismuth–Corlette Type II carcinoma without liver resection, but including PD. The caudate lobe was resected for all tumors involving the left hepatic duct and in any case when considered necessary to obtain complete tumor clearance. In the case of left-sided hemihepatectomy, the resection of the right hepatic duct was limited by its first segmental ramification, which regularly occurs within 1 cm from the hepatic hilum. Right-sided hepatic resections are differentiated as anatomic hemihepatectomy and trisegmentectomy. Because of the more distant ramification of the left hepatic duct into segmental ducts 2 and 3, which may extend 5 cm from the hepatic hilum, more radical longitudinal and lateral resections by right trisegmentectomy are possible on the left side than by left-sided hemihepatectomy on the right side. Additional segmental resection of the portal vein or hepatic artery was performed in the case of tight adherence to the resected specimens, which at surgery could not be judged with respect to its pathologic quality. Biliary-enteric reconstruction was done with a Roux-en-Y jejunum segment. In one patient with an advanced Bismuth–Corlette Type IV tumor, LTX and PD were performed as has been described by Neuhaus et al.3 The histopathologic resection and dissection margins were assessed for the microscopic presence or absence of tumor. The median follow-up time after surgery was 16 months (range, 9–40 months).

Statistical Analysis

The results are expressed as means ± SD. The differences between variables were analyzed with the Student t test using SPSS 8.0 software (SPSS, Chicago, IL). A P value of less than 0.05 (two-tailed) was significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Results of the Initial Evaluation

All patients suffered from jaundice. Before therapy, the mean values of serum total bilirubin, alkaline phosphatase, and gamma glutamyl transferase (γGT) were 279.4 ± 85.8 μmol/L (normal value, < 27), 13.2 ± 2.1 μkat/L (normal value, < 4.4), and 15.9 ± 5.2 μkat/L (normal value, < 0.5), respectively. Assessment of the C-reactive protein (CRP) value displayed a mean value of 53.7 ± 16.7 mg/dL (normal value, < 5). Table 1 shows tumor staging before treatment. According to the Bismuth–Corlette classification, one patient had Type II, two patients had Type IIIa, one patient had Type IIIb, and three patients had Type IV tumors. Compared with the definitive classification by the surgeon, Patient 5 was overstaged initially by ERC/MRC (Type IV by ERC/MRC vs. Type IIIa during surgery). The combination of MRI/IDUS showed a median tumor depth of 5 mm (range, 2–6 mm). In Patient 6, MRI, CT, and transabdominal US revealed suspicious lymph nodes. Biopsies from the bile duct stenosis revealed dysplasia without proven malignancy in Patients 1, 2, and 3 but no malignancy in the other 4 patients in the presence of a mass lesion on IUDS and MRI. An earlier laparotomy of one patient in another hospital before referral to our center had detected malignancy in a resected lymph node. The DSA performed in Patients 4 and was negative for tumor infiltration of the portal vein, but showed compression of the right hepatic artery in Patient 6.

Table 1. Tumor Staging before Treatment
Patient no.Bismuth–Corlette stageaTumor depth (mm)bLymph node involvementcBiopsy
  • L: left hepatic duct; C: common hepatic duct; R: right hepatic duct.

  • a

    Diagnosed by endoscopic retrograde cholangiography, magnetic resonance cholangiography, and intraoperative finding.

  • b

    Measured by magnetic resonance imaging (MRI) and intraductal ultrasonography.

  • c

    Evaluated by computed tomography scan in combination with MRI and ultrasonography.

  • d

    Preoperative Stage IV.

1II (L 0.5 cm, C 3 cm)5NoneDysplasia
2IV (L 3 cm, R 1.5 cm, C 3 cm)6NoneDysplasia
3IV (L 4.5 cm, R 1.5 cm, C 2 cm)2NoneDysplasia
4IIIa (L 0.5 cm, R 1.5 cm, C 2 cm)5NoneNegative
5IIIa (L 2 cm, R 4 cm, C 1 cm)d2NoneNegative
6IIIb (L 3.8 cm, R 0.5 cm, C 2.2 cm)41.5 cmNegative
7IV (L 1.5 cm, R 3.5 cm, C 2 cm)5NoneNegative

Neoadjuvant PDT

Patients were treated with PDT at the area of tumor infiltration and 2 cm beyond the tumor margins in 1 or 2 sessions followed by the insertion of endoprostheses. Patient 3 had recurrent cholangitis, which was treated successfully with antibiotics. A temporary slight elevation of transaminases, CRP, and leukocytes was seen in all patients 3–7 days after PDT (data not shown). The mean value of cholestasis parameters measured 1 week after PDT revealed a relevant decrease (bilirubin: 29.4 ± 8.5 vs. 279.4 ± 85.8 μmol/L; P < 0.05, alkaline phosphatase: 10.4 ± 2.7 vs.13.2 ± 2.1 μkat/L; ns, and γGT: 4.9 ± 1.1 vs. 15.9 ± 5.2 μkat/L; P = 0.06). This was correlated well with the reopening of previously occluded bile ducts assessed by control ERC and MRI after PDT. The median hospital stay for the PDT procedure was 10 days (range, 7–30 days). The hospital duration included a 24–48-hour interval between the administration of sodium porfimer and the first laser light treatment, a second ERC (with/without laser light exposure) for flushing the biliary tree free from sludge and debris, insertion of the endoprostheses, and a follow-up of 5–7 days with daily monitoring of inflammation, cholestasis, and liver function markers. Patient 3 remained in the hospital for 30 days for the treatment of cholangitis. All patients were readmitted 5 days before surgery for control ERC with IDUS and MRI. No relevant adverse events were caused by PDT except moderate epigastric distress for 1–3 days, an increase of less than 4 times in aminotransferase levels, a systemic inflammatory reaction lasting 5–8 days (maximum CRP, 65 ± 40 mg/dL; leukocyte count, 10,900 ± 5500 per mm3), and intraoperative phototoxicity (n = 1) that was confined to the subcapsular layer of the photosensitized liver and did not lead to liver dysfunction.

Surgical Procedures and Complications

The results of the surgical procedures are summarized in Table 2. Three patients underwent right-sided and two patients left-sided liver resections. In Patients 3 and 7 with Type IV tumors, curative R0 resection was achieved by left hemihepatectomy (Segments 1–4) and right trisegmentectomy (Segments 1, 4–8), respectively. Additional resection of the right hepatic artery and portal vein was performed in Patient 6 due to intraoperative suspicion of tumor infiltration, which was confirmed by histology. Patient 1 underwent hilar resection, including 10 mm long and 15 mm long portions of the right and left hepatic ducts, respectively, and concomitant partial pancreatoduodenectomy due to tumor extension into the distal bile duct. In Patient 2, who had a good general condition, we found an advanced Bismuth–Corlette Type IV tumor, liver fibrosis, and lymph node metastases in the hepatoduodenal ligament based on cryostatic section histology during the first laparotomy. This patient underwent a combined LTX and PD procedure after a waiting time of 11 months following neoadjuvant PDT. Immunosuppression consisted of tacrolimus and prednisolone, which were followed by sirolimus monotherapy because of its potential antitumoral activity.20 Two patients developed bile leakages from the hepatic resection line that requiredpercutaneous (Patient 7) and surgical drainage (Patient 6). In addition, reoperation was necessary for Patient 2 due to insufficiency of the pancreatic anastomosis and for Patient 4 because of an infected subdiaphragmatic hematoma. In all patients with curative resection, the bilioenteric anastomoses were sewn to PDT-pretreated bile duct branches (pretreated segments in the biliary tree orifices that measured 0.5–1.0 cm). No functionally relevant stricture formation was observed at the bilioenteric anastomoses sewn to pretreated bile duct branches during the follow-up period (absent cholestatic parameters, absence of intrahepatic cholestasis due to normal CT scans), although minor, functionally irrelevant stenoses could not be excluded. The median hospital stay after surgery was 16 days (range, 12–35 days).

Table 2. Surgical Procedures and Follow-Up
Patient no.Surgical proceduresComplicationsFollow-up (mos)Status
  1. LTX: liver transplantation; PD: partial pancreatoduodenectomy; S: segments.

1Hilar resection, PD 36Dead (tumor)
2LTX, PDInsufficiency of the pancreatic anastomosis40Alive
3Left hemihepatectomy (S1–4) 9Dead (tumor)
4Right hemihepatectomy (S5–8)Subdiaphragmatic hematoma29Alive
5Right hemihepatectomy (S5–8) 16Alive
6Left hemihepatectomy (S1–4), resection of right hepatic artery and portal veinBile leakage15Alive
7Right trisegmentectomy (S1, 4–8)Bile leakage12Alive

Histopathology

The histopathologic results are shown in Table 3. In all patients, curative (R0) resection was achieved. Lymph node metastases occurred in Patients 2–4. Patients 3 and 6 had microscopically venous infiltration and Patients 1–3 and 7 had lymph vessel infiltration. The grading category was moderately differentiated (Grade 2) in 6 patients and well differentiated (Grade 1) in 1 patient. Histopathologic analysis of the surgical specimens revealed that the wall of the tumor stenosis contained necroses with brown pigment of degraded photosensitizer and a dense inflammatory infiltrate in the inner layer within 4 mm from the lumen. No viable tumor cells were found in this inner layer (Fig. 1A). In the deeper layers (i.e., 5–8 mm from the luminal surface), some viable tumor nests without brown pigment deposits were present in lymphatic spaces and around nerve sheets in the periductal connective tissue in most of the cases. Therefore, the tumoricidal depth of the applied PDT procedure using sodium porfimer extended to 4 mm. The tumoricidal effect was selective and complete. The PDT-pretreated epithelium of the tumor-free proximal resection margins exhibited only minimal inflammatory infiltration (Fig. 1B). In contrast with our findings in tumor areas, we failed to detect necrosis or ulcerations. The muscular and connective tissue within the tumor region and the PDT-pretreated sections of the tumor-free bile duct was preserved.

Table 3. Histopathology
Patient no.pTNMUICC stageGradeR classification
  1. UICC: International Union Against Cancer; G2: moderately differentiated; RO: no macroscopic or microscopic residual tumor; G1: well-differentiated.

1ypT2N0M0V0L1IIG2R0
2ypT2N1M0V0L1IIIG2R0
3ypT3N2M0V1L1IVaG2R0
4ypT3N1M0V0L0IVaG2R0
5ypT1bN0M0V0L0IG1R0
6ypT3N0M0V1L0IVaG2R0
7ypT3N0M0V0L1IVaG2R0
thumbnail image

Figure 1. Histologic findings in the resected bile duct specimen. (A) Representative view of the inner 4 mm thick layer of the common duct stenosis. Note the lack of vital tumor cells and the inflammatory cell infiltrate present in the layer. In addition, the upper layer is detached by the effect of photdynamic treatment. (B) Proximal resection margin of the hepatic duct. This segment had been exposed to a laser light dose of 240 joules per cm2. There is moderate mucosal inflammatory infiltrate and an intact biliary epithelium and muscular layer. Hematoxylin and eosin stain, original magnification × 40.

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Follow-Up

Five of the patients are alive without recurrence of hilar CC. Two patients developed clinically proven tumor recurrence. In Patient 1, jaundice and an elevated level of CA 19-9 (169.8 U/mL) was observed 19 months after surgery. A CT scan and an MRI scan showed a tumor mass of 8 × 5 × 4 cm. The patient was treated initially with 4 cycles of cisplatin (50 mg/m2) and doxorubicin (50 mg/m2). Because of poor response, this patient also received a combination of 5-fluorouracil (5-FU; 2 × 500 mg/m2) and radiotherapy (45 Gy of photon–standing field radiation). Patient 3 developed tumor recurrence 6 months after surgery. He received a sequential chemotherapy regimen of 5-FU, doxorubicin, and mitomycin C21, 22 and a protocol of 5-FU and leucovorin.23 At 36 months and 9 months after surgery, respectively, both patients died of tumor progression.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Most malignant tumors of the proximal common bile duct and its bifurcation are differentiated adenocarcinomas with small tumor mass at diagnosis.24, 25 The tumor location in the hepatic hilum and the type of growth strongly reduce the chances of cure. Patients who achieved 5-year survival almost exclusively received a a curative resection (R0). However, in the majority of patients (up to 76%), hilar CC recurs because of lymphatic extension, multifocal extension in the bile ducts, and microscopic tumor extension through perineural spaces, predominantly as longitudinal spread along the biliary tree rather than lateral spread into adjacent organs.18, 26–32

Tumors at the hepatic confluence are difficult to stage and differentiate from benign fibrosing disease because some diagnostic imaging techniques do not discriminate reliably between these lesions.33, 34 A careful evaluation of a patient's medical history combined with the use of several diagnostic imaging devices allows a secure diagnosis of the disease, even without a positve biopsy result. It is often very difficult to obtain a histologically confirmed diagnosis in patients with hilar CC due to the desmoplastic nature of the lesion, which drastically reduces the yield of biopsies.1 Tumor extension according to the Bismuth–Corlette classification, based on preoperative ERC and MRI, must be revised occasionally after surgery. For example, Patient 5 was restaged because sludge or debris (e.g., after PDT) in the bile duct branches was not differentiated accurately from tumor extension by imaging techniques.35 In addition, the diagnosis of hilar CC is complicated by the infiltrative extension of the tumor that even during surgery can hardly be defined and often exceeds its palpable confines.

The current prospective study shows the effectiveness and limitations of neoadjuvant PDT with sodium porfimer among patients with hilar CC. As a neoadjuvant treatment, PDT can be used when it achieves complete phototoxic destruction of all tumor cells and penetration of the entire tumor by photoactivating laser light, when it spares the tumor-free epithelium and connective and muscular tissue of the bile duct wall, and when the side effects are tolerable and resective surgery within a short period of time is feasible. Photodynamic treatment with sodium porfimer has been used successfully as a neoadjuvant treatment for centrally located lung carcinoma36, 37 and for hilar CC.16 In a previous study, hilar CC showed a 2-fold enrichment of porfimer-specific fluorescence of the surrounding tissue 18–36 hours after administration of sodium porfimer.38 In the current study, the phototoxic effect on tumor cell nests was complete but limited to a tumoricidal depth of 4 mm tissue penetration, presumably because of light absorption by hemoglobin at 630 nm wavelength. In most bile duct carcinomas (i.e., pT1 and pT2 tumors), the lateral tumor extension within reactive desmoplastic tissue is about twice as large.24, 39, 40 Therefore, PDT of localized hilar CC will not be potentially curative until the procedure can be improved to exert selective tumor destruction for a wall thickness of 8–10 mm. However, the 4 mm deep tumoricidal tissue penetration of the red laser light irradiation should reach the entire bile duct wall at the tumor margins, where neoadjuvant PDT could purge the subepithelial tissue and fibromuscular layer from malignant cells. This is especially important in the context that extensive resection of the left or right hepatic duct (opposite to the liver resection side) beyond the proximal tumor margin is limited due to anatomic restrictions. The viability of the PDT-pretreated right and left hepatic ducts at the resection line was demonstrated by the uncomplicated healing of the bilioenteric anastomoses and the lack of anastomotic strictures after a median follow-up of 16 months. No relevant adverse events from PDT occurred except for intraoperative phototoxicity, which was confined to the subcapsular layer of the photosensitized liver and did not lead to liver dysfunction. To prevent cholangitis, the time from PDT to surgery had been bridged by insertion of biliary endoprostheses to drain both liver lobes.

In a study by Neuhaus et al.,3 surgical radicality was the most relevant determinant of patient survival. Hilar resection as the only procedure is not potentially curative. More extensive resections, especially right trisegmentectomies and LTX in combination with PD, not only resulted in an increased rate of R0 resections but also allowed the inclusion of patients with tumors once deemed to be unresectable. The combined LTX and PD procedure as proposed by Neuhaus at al.3 offers the advantages of a no-touch technique that eliminates the need for dissection of the hepatoduodenal ligament and yields wide tumor-free margins. However, LTX is not superior to liver resection in terms of the overall actuarial survival and should be reserved for exceptional cases.41 In these patients, PDT may be studied further as a bridging therapy, possibly combined with radiochemotherapy, during the waiting time before LTX. Another study, involving 95 patients with hilar CC, showed a difference of 28% in 1-year survival rates for patients who underwent R0 (1-year survival rate of 86%) and R1 resections (1-year survival rate of 58%). This finding demonstrates the importance of curative (R0) resection.3 Following PDT, curative resection was achieved in all our patients, including three patients with Bismuth–Corlette Type IV extension. Four patients (57%) had surgical complications, a finding supported by other studies.42 Therefore, neoadjuvant PDT did not increase the rate of surgical complications. No perioperative mortality was observed, compared with 6% and 7.4% in 2 larger studies.2, 3 The 1-year survival rate of 83% in the current study, which involved a relatively small number of patients, is similar to the results of several reported series after R0 resection.43 In a study of 71 patients with hilar CC, tumor resection was combined with postperative irradiation (52 patients) or preoperative plus postoperative irradiation (19 patients).44 Although the 1-year survival rate was similar to that in our study, Gonzalez-Gonzalez et al. warned that high radiation doses could be dangerous and could worsen the prognosis. In this series, late complications consisted of duodenal stenosis, upper digestive tract bleeding, and cholangitis, adverse effects that are not seen with neoadjuvant PDT treatment.

In conclusion, neoadjuvant PDT for hilar CC is a low-risk procedure with efficient selective tumor destruction of CC within a superficial 4 mm layer. Postoperative complications are similar to series without neoadjuvant PDT. In the future, neoadjuvant PDT might achieve curative resection of hilar CC in a higher percentage of patients and might reduce the rate of local disease recurrence after curative resection. In addition, new photosensitizers should be developed for PDT that provide tumoricidal tissue penetration to at least a depth of 8 mm.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES