The treatment of patients with advanced hepatic hilar duct carcinoma is a challenging problem. The current study was performed to evaluate the outcome of patients with advanced hepatic hilar duct carcinoma who received external beam radiotherapy (EBRT) combined with transarterial chemotherapy and infusion of a vasoconstrictor.
Between April 1993 and December 2002, 23 patients with histopathologically confirmed hilar duct carcinoma entered the study. The median total dose of EBRT was 41.4 grays (Gy). Transarterial chemotherapy was performed twice during EBRT. It was comprised of an infusion of a cocktail of 20 mg of epirubicin, 10 mg of mitomycin C, and 500 mg of 5-fluorouracil and was administered 1 minute after injection of epinephrine via a catheter introduced in the hepatic arteries. After the combined treatment, the patients underwent biliary endoprosthesis after evaluation of the initial response to treatment by percutaneous transhepatic cholangiography (PTC). The initial responses based on PTC were classified into four categories: CR, no stenosis; PR, relief of stenosis/obstruction; NC, no change; and PD, progressive stenosis/obstruction. The outcome parameters were survival rates and time, as well as frequency and type of complications.
Excluding 1 patient who discontinued the treatment, the initial responses of 22 patients were 1 CR (5%), 8 PR (36%), 11 NC (50%), and 2 PD (9%). The response rate was 41%. The overall survival rates at 1 year, 2 years, and 3 years after treatment were 59%, 36%, and 18%, respectively.
Carcinoma of the hepatic hilar duct is a rare malignant neoplasm associated with poor prognosis.1–7 Despite recent advances in diagnostic and therapeutic technologies, patients with carcinoma of the hepatic hilar duct are often diagnosed in the advanced stage and the majority (approximately 58–83%) of patients can only be treated palliatively.1–7 The reported median survival time for patients with unresectable hilar duct carcinoma ranges from 3 to 11 months.4–9
To our knowlege, there currently is no standard therapy to treat patients with advanced hilar duct carcinoma. A few investigators have reported a good initial response of hilar duct carcinoma using external beam radiotherapy (EBRT) alone or in combination with brachytherapy,10–12 but others reported that EBRT had no apparent effect on either survival or late toxicity.6, 7
Bile duct carcinoma is basically less chemosensitive compared with other tumors in the gastrointestinal tract. This is believed to be due to inherent cellular resistance or poor drug delivery.13 5-fluorouracil (5-FU) is most commonly used as a single agent to treat patients with bile duct carcinoma and was reported to have response rates ranging from 10% to 20%.14 Harvey et al.15 reported that a combination of 5-FU, mitomycin C, and doxorubicin administered to 17 patients with advanced or recurrent bile duct carcinoma was an effective (a 31% response rate) and safe treatment. Several types of malignant neoplasms, such as metastatic liver tumors and head and neck carcinoma, are treated with transarterial infusion chemotherapy.16, 17 5-FU injected via the hepatic artery and conformal radiotherapy reportedly produced long-term freedom from hepatic carcinoma progression and survival for patients with bile duct carcinoma in whom intraarterial hepatic 5-FU was used as a radiosensitization.13 However, to our knowledge, no studies of independent transarterial chemotherapy for hilar duct carcinoma have been reported.
It is well known that vasoconstriction of tumor blood vessels, which are immature, is defective due to the lack of both an adrenergic nerve supply and smooth muscles in the vessel wall.18 Several studies have demonstrated that infusion of vasoconstrictors (including epinephrine, angiotensin II, vasopressin, and endothelin I) increases the tumor-to-liver blood flow ratio in liver metastasis and potentially enhances the tumor response rates to chemotherapy.19–23 However, to our knowledge there are no previous reports describing the effects of vasoconstrictors on extrahepatic bile duct tumors.
Based on the poor prognosis of patients with nonresectable hilar duct carcinoma, a prospective treatment approach was developed at Oita Medical University (Oita, Japan) in an attempt to improve the clinical outcome of these patients. Our approach combined radiotherapy and transarterial chemotherapy. In this treatment design, a vasoconstrictor was administered to enhance the effect of the transarterial chemotherapy. The current study analyzes the effects of this combination treatment in patients with nonresectable hilar duct carcinoma.
MATERIALS AND METHODS
Patient Selection Criteria
The patients included in the study satisfied the following criteria: histopathologically or cytologically confirmed cholangiocarcinoma; a performance status of 0–2 as determined by the World Health Organization (WHO) criteria; and no active synchronous carcinoma. In addition, patients were required to have adequate bone marrow function (leukocyte count ≥ 4000/μL), a platelet count ≥ 50,000/μL, and adequate renal (serum creatinine concentration < 1.5 mg/dL) and liver function after biliary drainage (total bilirubin [T-Bil] level ≤ 4.0 mg/dL, serum transaminase level ≤ 80 IU/L). Patients with distant metastases, active synchronous malignancy, or uncontrolled concurrent medical illness were excluded. The patients fully understood the risks and benefits of the combination treatment and signed an informed consent form according to institutional regulations.
Sixty-four patients with suspected hilar duct carcinoma underwent diagnostic percutaneous transhepatic cholangiography (PTC) between April 1993 and December 2002 (Table 1). Forty-one of these patients were excluded from the current study because 25 patients were surgical candidates and 16 had unresectable lesions but did not satisfy the above criteria. Therefore, 23 patients with unresectable hilar duct carcinoma entered the study. The study sample included 15 men and 8 women with a median age of 67 years (range, 48–83 years).
Table 1. Patient Characteristics
No. of patients
WHO: World Health Organization. LN: lymph nodes; LN0: no enlargement of lymph nodes; LN1: enlargement of regional lymph nodes; LN2: enlargement of paraaortic lymph nodes.
Modification of the original Bismuth–Corlette classification.
Extent of ductal involvement and portal/hepatic arterial involvement
These findings were assessed by PTC, computed tomography (CT) scans, and angiography performed by three radiologists (S.M., H.K., and E.K.) and the final diagnosis was reached by consensus. Tumors were classified into one of four anatomic types using a modification of the original Bismuth–Corlette classification.3 None of the lesions were classified as type I or type II because these types represent resectable lesions. Four lesions were classified as type III (lesions involving the biliary confluence and extending into one of the main hepatic ducts) and 19 lesions were classified as type IV (extension of the lesion to involve the secondary bile duct or the main trunk of the hepatic artery or portal vein).
The hilar duct carcinomas were classified into two types after CT scans: infiltrative type and mass-forming type. The infiltrative type (n = 13 carcinomas) was defined as a lesion with ductal wall thickness < 5 mm without mass formation as observed on after contrast-enhanced CT scan. All other lesions were classified as the mass-forming type (n = 10 carcinomas).
Lymph node enlargement
A positive finding of lymph node enlargement was determined as a maximum dimension of > 10 mm as observed on a CT scan. Regional lymph nodes were classified as LN1 and paraaortic lymph nodes were classified as LN2. Twelve lesions (9 LN1 lesions and 3 LN2 lesions) were classified as a CT scan-positive lymph node enlargement.
Biliary drainage and endoprosthesis
All patients underwent percutaneous-transhepatic biliary drainage (PTBD) with two or three 7-French or 10-French drainage tubes. After the combined treatment, all patients underwent biliary endoprosthesis with self-expandable metallic stents after the evaluation of the initial response to treatment by PTC.
The two opposing fields technique using 10-megavolt X-rays was employed. The clinical target volume was designed to adequately cover the tumor volume, with a margin of ≥ 2 cm, as well as the primary lymphatic drainage. The radiation fields were shaped on the basis of the findings of CT scan and PTC (Fig. 1). The prescribed beam dose was 1.8 or 2.0 Gy per fraction, 5 times a week, for a total dose of 41.4 Gy.
Transarterial chemotherapy with concurrent infusion of a vasoconstrictor
Transarterial chemotherapy with concurrent infusion of a vasoconstrictor (TACCIV) was performed twice in the patients, at the beginning and during exposure to 24–30 Gy of EBRT. There was a mean interval of 26 days (range, 20–34 days) between the first and second TACCIV. The first TACCIV was performed 2–9 days before the initiation of ERBT. TACCIV was performed with a 4-French catheter introduced through the right femoral artery into the proper hepatic artery, common hepatic artery, or the origin of the right and left hepatic arteries.
To determine the interval between infusions of epinephrine and anticancer drugs, as well as the duration of the infusion of anticancer drugs, the first 4 patients underwent serial hepatic angiography and CT scans during hepatic angiography before and at 0 seconds, 30 seconds, 60–90 seconds, 180–240 seconds, and 300–420 seconds after the infusion of epinephrine. The concentration of contrast materials in the tumor was observed mainly from 1 minute to 3–5 minutes after the infusion of epinephrine (Fig. 2), infused at a dosage of 2–4 μg per injection via the catheter over a period of 1 minute. Based on the data described earlier, 1 minute after the infusion of epinephrine, administration of epirubicin (3–10 mg per injection), mitomycin C (1–5 mg per injection), and 5-FU (70–250 mg per injection) commenced via the same catheter and continued for 3–10 minutes with confirmation of vasoconstriction status using periodic test injections of small volumes of contrast medium. This infusion was repeated two to five times, depending on the length of time for vasoconstriction. The total dosages of drugs used in the procedures for each treatment were 8–10 μg of epinephrine, 20 mg of epirubicin, 10 mg of mitomycin C, and 500 mg of 5-FU. The interval between the first infusion and the next infusion was approximately 3 minutes.
For the last 7 patients recruited to the study, further maintenance treatment with TACCIV was performed 2 or 3 times with an interval of 4 months, limited to within 1 year after the initial treatment. This was simply a protocol change adopted from June 2000 and was applied to the patients regardless of the initial treatment results provided informed consent was obtained from them.
Adverse side effects
Adverse side effects were evaluated using WHO standard criteria.24 Hematologic parameters were assessed weekly and all other adverse reactions were evaluated during and after treatment.
Two radiologists (S.M. and H.K.) independently assessed the initial treatment effects by PTC obtained within 1 week after treatment completion. Differences between the assessments of the two observers were resolved by consensus. The objective response based on PTC was classified into four categories as follows: complete response (CR), no stenosis; partial response (PR), relief of stenosis/obstruction; no change (NC), no significant change of stenosis/obstruction; progressive deterioration (PD), progressive stenosis/obstruction. For patients who survived > 6 months after treatment, the duration of the jaundice-free period was also assessed.
The tumor responses for the various groups of patients were evaluated by the chi-square test. If individual groups of patients comprised fewer than five patients in a 2 × 2 comparison, the Fisher exact test was utilized. The overall survival was measured from the time of study entry until death according to the Kaplan–Meier method. Univariate analysis of the prognostic factors was performed with log-rank tests. P < 0.05 denoted the presence of a statistically significant difference.
Treatment Completion Rate
One patient (type IV; mass-forming type; LN2) discontinued the combined treatment at a dosage of 26 Gy of EBRT and 1 cycle of TACCIV because of hematologic toxicity (Grade 4 leukocytopenia and Grade 4 thrombocytopenia) and severe nausea/emesis. She improved approximately 1 month later, after medical treatment. Therefore, this combined therapy was completed according to schedule in 22 patients, a treatment completion rate of 96% (22 of 23 patients). The side effects and treatment effects mentioned are based on the 22 patients who completed the treatment.
Adverse Side Effects
Hematologic toxicity was assessed based on the WHO classification. Acute and subacute adverse side effects less than Grade 3 were observed in 4 of 22 patients (18%). All improved within 2 weeks without any treatment. Grade 3 leukocytopenia and Grade 4 thrombocytopenia were observed in one patient each just before the completion of the combination treatment. The patient with Grade 4 thrombocytopenia was treated with a blood platelet transfusion. With regard to other forms of Grade 3 toxicity, one patient developed acute cholangitis after completion of the combination treatment. This was believed to be due to an infection in the PTBD tube and the patient recovered after tube replacement. Grade 1/2 complications were observed in six patients. Of these, gastric ulceration and gastritis were observed in two patients each after the second session of TACCIV and improved with medical treatment such as H2-blockers. In addition, acute cholecystitis and cholangitis were observed in one patient each after the completion of the treatment. The acute cholecystitis was considered to be the result of a transient occlusion of the cholecystic duct because it developed just after the biliary endoprosthesis. These complications improved after intravenous administration of antibiotics.
The objective responses based on PTC consisted of CR in 1 patient (5%), PR in 8 patients (36%), NC in 11 patients (50%), and PD in 2 patients (9%). There was a 41% initial response rate. With regard to the anatomic types, the objective response was better in patients with Bismuth type III (100%; 4 PR) than in patients with Bismuth type IV (28%; 1 CR, 4 PR, 11 NC, and 2 PD) (P = 0.01). With regard to the morphologic type, the objective response was better in 12 patients classified as having infiltrative-type tumors (58%; 1 CR, 6 PR, and 5 NC) than in the 10 patients classified as having mass-forming type tumors (20%; 2 PR, 6 NC, and 2 PD; P = 0.09).
The overall survival rates (Kaplan–Meier) for all 22 patients are shown in Figure 3. The median follow-up was 17 months (range, 5–43 months) and the 1-year, 2-year, and 3-year survival rates for the entire cohort were 59%, 36%, and 18%, respectively. The median survival time was 19.5 months. In patients with the infiltrative-type tumor, the survival rates were 75% at 1 year, 50% at 2 years, and 32% at 3 years, which were significantly better than the survival rates for patients with the mass-forming type tumor (40% at 1 year, 20% at 2 years, and 0% at 3 years; P = 0.01). The median survival time also was found to be better in patients with the infiltrative-type tumor (25.7 months vs. 12.9 months; Fig. 4). For patients with Bismuth type III versus Bismuth type IV tumors, the 1-year survival rates were 75% versus 56% (Fig. 5). There were no significant differences with regard to the survival rates based on the Bismuth type (P = 0.15). The 1-year survival rates for patients with LN0, LN1, and LN2 disease were 64%, 67%, and 0%, respectively. The median survival time was worse for patients with LN2 (7.1 months) compared with patients with LN0 (22.7 months) or LN1 (18.3 months; Fig. 6). The survival time was > 3 years in 3 patients (38.6 months, 41.4 months, and 42.5 months, respectively). Log-rank analysis did not identify a significant independent prognostic factor.
We also evaluated the duration of jaundice during the period from biliary endoprosthesis to recurrent jaundice among patients who survived > 6 months after treatment. At the time of last follow-up, 18 patients were still alive at or 6 months after the completion of the combination treatment. Four of these 18 patients (22%) required re-PTBD because of recurrent obstructive jaundice. The median jaundice-free duration was 14 months (range, 4–41 months).
Despite recent developments in diagnostic and therapeutic technology, carcinoma of the hepatic hilar duct remains among the most difficult malignancies to treat. The survival rates after surgical resection are better than those after palliative treatment and were reported to be 45–87% at 1 year, 21–30% at 3 years, and 11–21% at 5 years.2–5 However, curative surgical resection can be performed in only 30–40% of patients with hilar duct carcinoma, even in recent reports.2, 5 Patients with unresectable hilar duct carcinomas often are treated by biliary drainage with or without radiotherapy.8–11 The reported median survival for patients who received palliative biliary drainage alone ranged from 3–8 months.8, 9
Several retrospective studies demonstrated that radiotherapy prolonged survival in these patients.10, 11 However, to our knowledge, most of these studies included patients with common or distal bile duct carcinoma, who have a better prognosis than patients with hilar duct carcinoma. In 1985, Karani et al.12 reported excellent results after brachytherapy alone for hilar duct carcinoma. In their study, the median survival was 16.8 months. However, the clinical characteristics of their patients might be different from those enrolled in the current study because the resectability of hilar duct carcinoma has improved based on advances in surgical techniques in recent years.
The results of the current study showed favorable treatment results (median survival, 19.5 months; survival rate at 1 year, 59%). Although there was no evidence of the major factor that affected the treatment results, the possibility exists that the concurrent infusion of a vasoconstrictor with the anticancer agents led to these good treatment effects.19–23 Several vasoconstrictors (including epinephrine, angiotensin II, vasopressin, and endothelin I) have been used for this purpose in experimental studies.19, 20 In the current study, we used epinephrine as the vasoconstrictor agent because it is easily available and often used in angiography. The main disadvantage of this agent for use with chemotherapy is its short duration (1–3 minutes) of effective vasoconstriction in the normal hepatic parenchyma. To our knowledge, the effects and toxicity of continuous injection of epinephrine currently are unknown. In the current study, serial injections of small amounts of the vasoconstrictor agent were applied with anticancer agents. Recent experimental studies of continuous injection of various vasoconstrictor agents such as angiotensin II, vasopressin, and endothelin I showed that the tumor-to-normal liver ratio was increased transiently during the infusion of each agent, except for endothelin I, which increased the ratio throughout the infusion.19 Prolonged infusion is favorable for influencing certain anticancer agents such as 5-FU. Therefore, prolonged infusion chemotherapy with concurrent infusion of long-acting vasoconstrictors such as endothelin I may enhance the effects of anticancer agents.
Several factors, such as radiation dose, local tumor extension, tumor volume, and lymph node metastasis, influence the prognosis of patients with hilar duct carcinoma. Several groups demonstrated that the radiation dose was well correlated with the survival of patients with bile duct carcinoma.25, 26 Therefore, most patients with bile duct carcinoma in recent studies were treated using combined EBRT and intraluminal brachytherapy. Some of these studies demonstrated the utility of a boost brachytherapy for prolongation of survival.26 The radiation dose escalation protocol might increase the risk of treatment-related complications such as the development of gastroduodenal ulcers, bowel stricture, biliary-enteric fistulas, and cholangitis. Gonzalez et al.27 warned against radiation dose escalation. They investigated the effects and complications associated with brachytherapy combined with EBRT with a total dose of 50–68 Gy in 109 patients with proximal bile duct carcinoma (including 71 patients who received tumor resection). In their study, brachytherapy was not superior to EBRT alone and, therefore, they concluded that high radiation doses could be dangerous and have a detrimental effect on the prognosis.
In the current study, we identified some factors that significantly influenced the prognosis of patients. The prognosis of patients with a mass-forming type tumor was poorer compared with patients with an infiltrative-type tumor (median survival: 25.7 vs. 12.9 months). Because the tumor volume in the mass-forming type most likely is larger than that in the infiltrative type, EBRT with a mean dose of 40 Gy in the current series might be less effective in patients with a mass-forming type tumor than in those with an infiltrative type tumor. In the mass-forming type, an escalation radiation dose with brachytherapy might be useful. However, the effective target dosage with brachytherapy cannot cover the entire tumor. Recently, the application of stereotactic radiotherapy to hepatic tumors has been reported.28, 29 These studies described good local control of tumors and suggested that the method might become a feasible treatment for hepatic tumors in the future. The addition of stereotactic radiotherapy to the adequate radiation dose in our protocol should enhance the local control of hilar duct carcinoma, especially of the mass-forming type.
The current study has some limitations. First, there were not enough patients to clarify the usefulness of this treatment protocol. Second, this was not a prospective comparative study setting with a control group. Therefore, the major factor causing the favorable treatment results was unclear. A prospective comparative trial is required to evaluate the relative efficacy of this treatment protocol. For example, a group of patients treated with radiation alone and a group treated with combination therapy of radiation and transarterial chemotherapy without the infusion of a vasoconstrictor should be prepared as controls.
Although further studies with larger population samples and a prospective comparative study are required, the combination of radiotherapy and TACCIV is believed to be an effective and safe treatment for patients with advanced hepatic hilar duct carcinoma and appears to improve the clinical outcome of these patients.