Abstract
Purpose: To evaluate the outcome of patients affected by unresectable extrahepatic cholangiocarcinoma treated with radiotherapy (ERT) and concurrent gemcitabine-based chemotherapy with or without intraluminal brachytherapy (BT). Patients and Methods: Twenty-seven patients underwent weekly gemcitabine (100 mg/m2) as a 24-h infusion during the course of three-dimensional radiotherapy (50.4 Gy to the tumor and 39.6 Gy to the nodes). Among them, certain patients received a boost of intraluminal high-dose rate (HDR) brachytherapy with 192 Ir. The outcome of patients was evaluated in terms of response to therapy, local control (LC), overall survival (OS) and toxicity. Results: We analyzed a total of 27 patients with the diagnosis of unresectable, non-metastatic adenocarcinoma of the extrahepatic biliary ducts, treated with radiochemotherapy with gemcitabine. After a dose of 50 Gy, a boost of HDR intraluminal brachytherapy was administered in 6 patients (22%): 4 patients received 15 Gy and 2 patients 20 Gy. With a median follow-up of 16 months (range=3-52 months), for the entire group, 2-year LC was 29% (median=12 months), 2-year MFS was 36% (median 16 months). Two-year and three-year OS were 27% and 7% respectively, with a median of 14 months. Toxicities were acceptable. Median OS in patients treated with brachytherapy boost was 21 months versus 14 months for the group treated with gemcitabine-based radiochemotherapy only; 2-year LC was 53% versus 25%, respectively. Conclusion: Gemcitabine appears to be a potent radiation sensitizer, and when combined with radiation therapy, it shows encouraging tumor response. Moreover, patients treated with a boost of brachytherapy after radiochemotherapy seem to have a better local control with an acceptable toxicity. Further investigation is warranted to confirm these data and define the optimal combined treatments.
Extrahepatic cholangiocarcinoma is a rare neoplasm with an unfavorable prognosis (1), especially in patients with unresectable disease. Overall survival in this group of patients is 2-4 months. In order to improve treatment outcome, external-beam radiotherapy with or without intraluminal brachytherapy have been used either alone or in association with concomitant chemotherapy (2-4). But the precise role of radiation therapy (external radiotherapy with or without intraluminal brachytherapy) and chemotherapy for unresectable, non-metastatic bile duct cancer is not yet well-defined (2-5, 6-9). We analyzed the results of a phase II perspective study on patients affected by unresectable extrahepatic cholangiocarcinoma treated with external-beam radiotherapy and gemcitabine-based chemotherapy with or without a boost of intraluminal brachytherapy.
Patients and Methods
We analyzed patients with unresectable non metastatic extrahepatic bile tumors treated in our Institution between 2002 and 2009, with external-beam radiotherapy and concomitantly gemcitabine (1,000 mg/m2/weekly) in 24-h continuous infusion with or without a boost of brachytherapy. Radiotherapy was delivered with a high-energy photon (10 MV) linear accelerator. Conformal three-dimensional radiotherapy was planned: fields were arranged taking into account doses delivered to normal tissues during radiotherapy for primary tumor, according to “box-technique”. A total dose of 40 Gy was delivered to the primary tumor and regional lymph-nodes, followed by an additional 10 Gy to the primary mass and enlarged lymph-nodes.
HDR-Ir192 intraluminal brachytherapy (ILBT) was administered following completion of chemoradiation. HDR-Ir192 intraluminal brachytherapy (ILBT) was performed by transhepatic route or by endoscopic retrograde. ILBT was delivered every day using a high-intensity 192-Ir source (microSelectron remote afterloading system Nucletron) and the dose was prescribed at 10 mm from the centre of the source for a total dose of 15 Gy in 3 fractions.
Eligibility criteria. After obtaining approval from the Institutional Ethics Committee patients with histologically-proven locally advanced unresectable extrahepatic cholangiocarcinoma were enrolled in this trial.
Patients aged <75 years, Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, granulocyte count >3,000/ml, platelet count >100,000/ml and hemoglobin concentration >10 g/ml, adequate renal function (creatinine level 2-times the upper limit of normal serum value; urea nitrogen 2-times the upper limit of normal serum value) and an adequate hepatic function (total bilirubin 2-times the upper limit of normal serum value; transaminase level 2-times the upper limit of normal serum value), were eligible for study inclusion. Patients with prior chemotherapy or radiotherapy, distant metastases, secondary malignancies, uncontrolled epilepsy, or cardiopulmonary comorbidities (chronic obstructive pulmonary disease, instable angina, myocardial infarction in the previous 6 months, uncontrolled arhythmias, heart failure) were excluded from this protocol.
Patients with lesions that cannot be reached from the catheter brachytherapy for their localization or patients with eccentric lesions or of dimensions >4 cm that cause an underdosing of the target, were excluded for brachytherapy.
All patients underwent radiological and endoscopic examinations to identify the tumor origin, and histological confirmation of malignancy was obtained prior to initiation of therapy. After treatment, patients were usually evaluated by physical examination, complete blood count, blood chemistry, and abdominal US every 3 months and chest and abdominal CT every 6 months. Acute and long-term toxicities were assessed using the Common Toxicity Criteria Adverse event (CTCAE) Version 3.0.
Statistical analysis. Statistical analysis was performed by MedCalc (www.medcalc.be). Local control rates and OS were calculated using the Kaplan-Meier method (10). Cox proportional hazards regression model was used to analyze the effect of covariates on clinical outcome.
The original sample size of 27 patients was calculated by the single proportion-powered analyses design (Systat 11, SPSS Science, Chicago, IL, USA) to detect an improvement in OS rate of 20% in regard to the 2-years OS reported in a previous study using concurrent radiochemotherapy with gemcitabine, that is reported at 25% (11).
Results
We analyzed a total of 27 patients with unresectable, non-metastatic adenocarcinoma of the extrahepatic biliary ducts, treated in our Institution between February 2002 and December 2009. Patients' characteristics are summarized in Table I.
The majority of patients had carcinomas located in proximal bile duct segment (66.6%); 9 patients had tumors in distal segments. Clinical stage according to the TNM staging system was T2 in 19.2%, T3 in 38.4%, T4 in 42.4%. Eleven patients (40.7%) were node-positive at diagnosis. Twenty-six patients received gemcitabine (100 mg/m2/weekly) in continuous infusion during ERT. One patient received only external-beam irradiation without chemotherapy for co-existent severe cardiovascular disease. After a dose of 50 Gy, a boost HDR intraluminal brachytherapy was administered in 6 patients (22%): 4 patients received 15 Gy and 2 patients 20 Gy. Planned concurrent gemcitabine dose intensity was 100 mg/m2/weekly.
Patients' characteristics.
Acute toxicities.
All enrolled patients were evaluable for therapeutic response. According to imaging assessment, 22 patients showed stable disease after treatment and 4 patients disease progression. The response of 1 patient was not available. With a median follow-up of 16 months (range=3-52 months), 2-year LC was 29% (median=12 months), 2-year MFS was 36% (median=16 months). Two-year and three-year OS were 27% and 7% respectively, with a median of 14 months.
Overall survival.
Median OS in patients treated with brachytherapy boost was 21 months vs. 14 months in the group treated with gemcitabine-based radiochemotherapy (Figure 1) only; 2-year LC was 53% versus 25%, respectively (Figure 2).
Treatment was generally well-tolerated. The incidence of acute hematological and gastrointestinal toxicity is reported in Table II. Ten patients (37%) suffered greater than grade 2 acute toxicity according to the RTOG scale. Grade 3 gastrointestinal toxicity occurred in 4 patients (no-brachytherapy group) and one patient experienced grade 4 gastrointestinal toxicity (no-brachytherapy group). Four patients had a grade 3 hematological toxicity and in 1 patient a grade 4 hematological toxicity (no-brachytherapy group) was observed. Neither patients showed late toxicities.
Discussion
Treatment of patients with locally advanced extrahepatic cholangiocarcinoma is still under debate due to the limitation of clinical experience. It has been difficult to clarify differences and impacts of different therapeutic modalities due to the small sizes of previous published studies. The efficacy of radiochemotherapy has not been established due to conflicting reports without randomized trials. There were survival improvements in 5-FU-based radiochemotherapy with a response rate of 28.6% and a median survival of 22 months with a 1-year OS rate of 68% (11). Data from the literature are heterogeneous (e.g. inclusion of different cancer types, imbalances in resection state) while reporting differing results, also with different types of chemotherapies. Gemcitabine appears to be a potent radiation sensitizer, and when combined with radiation therapy, it has shown encouraging tumor responses. However, several retrospective analyses on radiochemotherapy are available, mainly suggesting different drugs and radiation doses of 40-54 Gy (12, 13). Thus, the optimal radiation dose in the definitive treatment of biliary cancers has not yet been defined. There exist strong limitations of higher radiation doses concerning radiosensitive organs at risk such as gastrointestinal structures and the liver. One strategy to escalate RT dose to the tumor by sparing normal tissue at risk is the intraluminal brachytherapy boost. Its potential advantages include administration of high radiation doses with rapid dose fall-off over a short distance from the radioactive source, thus sparing adjacent normal tissues and localizing dose to the tumor and peritumoral tissues. Some authors have reported a correlation of improvement in survival with the use of BT, while others have shown no obvious benefit (14-18).
Local control.
In highly selected patients neoadjuvant protocols, combining neoadjuvant radiotherapy, chemosensitization, and orthotopic liver transplantation, can be reserved.
In our study, we found a better local control in patients who underwent a boost of intraluminal brachytherapy, even if there was no impact on overall survival. The treatments were safe and well-tolerated. Only a few patients were treated with brachytherapy boost because of the toxicity due to external-beam radiotherapy.
This study shows different limitations. It was conducted on a reduced number of patients with tumors at different sites of extrahepatic bile ducts, without a control group. However, all treated patients were followed by the same team of diagnosticians, endoscopists, surgeons, and radiotherapists. In particular, patients underwent radiation therapy with the same procedures of external beam, brachytherapy, concomitant chemotherapy, and target definition.
From our data it appears that patients with locally advanced biliary tract cancer treated with 5-FU-based radiochemotherapy plus a boost of brachytherapy have a better local control with an acceptable toxicity. To confirm these data and define optimal combined treatment further investigations are necessary.
- Received November 11, 2015.
- Revision received December 15, 2015.
- Accepted January 4, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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