Aust. N.Z. J . Surg. (1996) 66, 14-11

ORIGINAL ARTICLE

INTRALUMINAL BRACHYTHERAPY IN BILE DUCT CARCINOMAS

JOHN LEUNG,* MICHAEL GUINEY~ AND RAM D A S ~ *Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales and 'Peter MacCallum

Institute, Melbourne, Victoria, Australia

Background: Cholangiocarcinoma of the biliary tract is a rare tumour which has been treated with surgery, radiotherapy, chemotherapy, bypass procedures and stenting. Surgery remains the only curative treatment for these tumours, but a large proportion are unresectable. Intraluminal brachytherapy has been reported as an effective treatment for localized cholangio- carcinoma of the biliary tract. The purpose of our study was to analyse the survival of patients with biliary tract carcinoma treated with iridium- 192 brachytherapy. Methods: A retrospective review of patients treated at Peter MacCallum was undertaken. From 1989 to 1994, 16 patients underwent brachytherapy via a transhepatic approach for cholangiocarcinoma. There were 12 male and four female patients. The median age was 65 (range 40-83). All patients had cholangiocarcinoma. Prior treatment included complete resection in three, partial resection in one, bypass procedures in eight, endoscopic stents in five and external biliary drainage in 15 of the 16 patients. One patient had received external beam irradiation. Results: The median survival was 23 months and 61% survived 1 year. The most common acute complication was cholangitis seen in four patients and the most common late complications were duodenal ulcer seen in two patients and cholangitis seen in two patients. Conclusions: We conclude that iridium-192 brachytherapy is a safe effective treatment for biliary tract carcinoma but a com- parison between surgery and stenting would be of value. However, the cost of brachytherapy is not cheap and its value in this regard should be carefully analysed.

Key words: biliary tract, brachytherapy, iridium, irradiation, survival.

INTRODUCTION Cholangiocarcinoma of the biliary tract is a rare tumour which has been treated with various combinations of surgery, external beam irradiation, stenting, chemotherapy and more recently intraluminal brachytherapy.

Surgery remains the only curative treatment for these tumours. However, 70-80% are unresectable due to invasion of adjacent blood vessels, extensive intraductal involvement, lymph node involvement, peritoneal seeding or poor patient condition.' There is also a high morbidity and mortality asso- ciated with surgery.*

Many patients have received palliation consisting of external irradiation and chemotherapy, with varying su~cess.3.~ External beam irradiation has the disadvantage of including radio- sensitive normal tissue in the treatment field. Damage to the liver or intestine can occur and this may result in significant morbidity and m~r ta l i ty .~

Biliary obstruction has been managed by palliative decom- pression techniques, usually by surgical bypass or more recently by the insertion of endoscopic and percutaneous stenk5a6 This approach does have limitations. There is a high morbidity from early cholangitis (lo%), inadequate drainage (10-30%) and stent obstruction (20-30%).' Survival is poor with an average of 6 months duration and pain is a frequent problem.'

The luminal access afforded by percutaneously placed drains has stimulated interest in the application of iridium- I92 radia- tion sources to treat these tumours.

Correspondence: John Leung. 3 Sutherland Road, Armadale, Vic.

Accepted for publication 5 July 1995.

3143, Australia.

METHODS This report is a retrospective review of 16 cases with cholan- giocarcinoma of the biliary tract. These patients were referred to the Peter MacCallum Institute for intraluminal brachytherapy between 1989 and 1994. Information was obtained from hos- pital records, referring physicians and family members.

Patients The 16 patients ranged in age from 40 to 83 years with a median of 64.5 years. There were 12 males and four females. All patients had tumour diagnosed by endoscopic or laparotomy procedure. Histological verification of cholangiocarcinoma was obtained in all the patients. Three of the 16 had tumours confined to the common bile duct. The others had tumour at multiple sites. All the patients had treatment before intraluminal brachytherapy. Three of the 16 were assumed to have had complete resection, one a partial resection, eight had bypass procedures, five had endoscopic stents and 15 had external biliary drains. One patient had received prior external beam irradiation of 40 Gy in 20 frac- tions. No patients had received prior chemotherapy.

Techniques Biliary intubation Percutaneous transhepatic intubation of the bile ducts was performed according to standard techniques. Drainage was established in all cases.

lntraluminal radiation therapy All 16 cases were treated with intraluminal radiation. Iridium- 192 was employed as the radi- ation source. In the diagnostic radiology suite, under sterile conditions and fluoroscopic control, a flexible guide wire was passed through the biliary stent to a point past the stenosis. This

INTRALUMINAL BRACHYTHERAPY IN BILE DUCT CARCINOMAS 75

position was marked and the wire removed leaving the draining tube in position. Subsequently, dummy sources were inserted and orthogonal films were used to confirm the correct position.

In the afterloading suite, the iridium strand was advanced through the stent to the predetermined distance. A microselec- tron remote afterloading machine was used. After a predeter- mined time, the microselectron automatically retrieved the radioactive sources. All patients were treated as inpatients. They were treated in a room isolated from the rest of the ward.

Dosimetry was calculated by the physicist according to a standard formula for a linear array of sources and expressed at a point I cm from the array (Figs 1, 2).

measured from the date of presentation at Peter MacCallum Cancer Institute. The estimated median survival was 23 months (95% confidence interval: 8-27 months, Brookmeyer-Crowley method). The estimated percentage surviving at 1 year was 61% and at 2 years was 42%. Of the seven patients who were alive at last contact, four had no evidence of disease, two were alive

Treatment Eight patients had one intraluminal treatment, seven patients had two treatments and one had three treatments. The median dose was 60 Gy (range 10.4-60) for the first treatment, 38 Gy (range 30-60) for the second, and 60 Gy for the third treatment. The median dose rate was 1.72 G y h (range 0.92-4.73) for the first treatment, 1.60 (1.04-3.01) for the second and 3.67 for the third. The duration of treatment was 24.45 h (range 4.5- 39.9) for the first treatment, 24.75 (15.6-34.8) for the second and 16.35 for the third.

The source length was usually6 cm. The median source activity was 495.15 MBq/cm and ranged from 124.2 to 73 1.7 for the first treatment, 4 12.5 for the second and 503.1 for the third.

RESULTS Survival

The survival curve was estimated using the Kaplan-Meier product-limit method and is depicted in Fig. 3. Survival was

Fig. 2. The isodose distribution plotted on radiographic film. The dose falls rapidly away the further the distance from the sources.

0 1 2 3 4 5

Years following presentation

Fig. 3. Overall survival for all patients. The numbers in brackets refer to the number of patients at risk at the beginning of each Fig. 1. Radiograph of the biliary tree with the radioactive sources

in position. year.

LEUNG ET AL. 76

with disease, and one patient went interstate and was lost to follow up with the status of the disease unknown. Of the nine patients who died, five died of disease, one died from bladder carcinoma, one died from septicaemia, one from duodenal ulcer and one patient died with the cause of death unknown.

Patterns of failure Local failure was defined as progression within the tumour bed. This occurred in five patients and was assessed by endoscopic or radiological means. Failure outside the tumour bed occurred in four patients. Two patients had disease in the liver only, one in the hilar lymph nodes and liver, and one in the chest wall and ribs. Both local failure and distant metastases occurred in two of these patients. It was unknown whether treatment failure occurred in three patients. One of these patients died of unknown causes, one was alive with disease status unknown and one was alive with disease. Two patients died of other causes and four patients remain alive with no evidence of disease.

An assessment of time to failure would have been desirable as this would indicate the length of benefit the patients received. This was difficult to assess due to the retrospective nature of the review. However, on reviewing the case histories, the disease was controlled in most patients until near time of death. The only exceptions were the two patients who died of septi- caemia and from an unknown cause.

Morbidity of treatment A number of patients experienced cholangitis. Four patients experienced it as an acute complication of the procedure. The cholangitis was easily controlled with antibiotics. One patient had a gastrointestinal haemorrhage which was minor and resolved; another had mild nausea and another mild abdominal pain.

Late complications were defined as occurring 1 month or more after the intraluminal brachytherapy. One patient had a duodenal ulcer which caused mild abdominal pain for 2 months requiring no therapy. Two had several episodes of cholangitis requiring antibiotics. Two had mild intermittent abdominal pain of unknown aetiology lasting for several months, but not requir- ing medication.

DISCUSSION The management of cholangiocarcinomas remains a problem for all oncologic disciplines. Failure to control the disease is the norm with biliary obstruction, hepatic failure and sepsis occurring.8 Long-term survivors are rare and most patients suc- cumbed within 6 months?-8 Surgery remains the only curative treatment, but cure is achieved in a minority of cases and mor- bidity is considerable.ls2 Many lesions (7040%) are considered unresectable at diagnosis.'.2 Percutaneous and endoscopically placed stents have been effective in relieving jaundice and pru- ritus. However, cholangitis is common and survival remains short from 2 to 6 month^.^-^ External beam irradiation with or without chemotherapy has been ~ s e d ' , ~ . ~ . ' ~ for unresectable tumours. However, external beam irradiation is limited by the tolerance of surrounding normal tissue structures such as liver, small bowel and kidneys. It is generally contended that 60 Gy is required to sterilize macroscopic disease.' This dose is not

possible if a large part of surrounding normal tissue is included.'

The basic theory of intraluminal radiation therapy is an attractive one. Iridium-192 is a gamma emitter and there is a rapid decline in radiation intensity in tissue away from the radi- ation source. This allows the delivery of high doses of radiation to a well-defined and limited volume while minimizing expo- sure to adjacent tissues. The idea of intraluminal implantation with a radiation source is not a recent one. In 1935 Walters and Olson" used intraluminal radiation in a patient with unresect- able carcinoma of the bile duct at the Mayo Clinic. Intraluminal brachytherapy is particularly suitable for cholangiocarcinomas of the bile duct which although unresectable due to local exten- sion are frequently localized.I2

The benefit of brachytherapy may be its ability to maintain ductal patency. This would delay biliary obstruction and its attendant fatal complications. Hence, survival may be increased despite lack of regional control. Shapiro et aLI3 reported a mean patency rate of 18 months and a mean sur- vival of 19 months. There are several reports on the use of brachytherapy alone. Fletcher et al.I4 reported on a series of 19 patients with a median survival of 11 months and nearly 50% surviving more than 1 year. Karani et al.15 reported on a median survival of 16.8 months in their series of 30 patients. Veeze-Kuijpers et al. from Rotterdam reported on a median survival of 10 months and 14% 2 year survival in 42 patients who had 25-30 Gy of intraluminal brachytherapy andor 30-40 Gy of external beam treatment.16 Hiritsuka et al. used intracatheter gold grains instead of iridium- 1 92.17 They thought gold had the following advantages: (i) its length could quite easily be changed in accordance with the length of the stenosis; (ii) it has a shorter half life compared to iridium; and (iii) in Japan, gold grains can be purchased on a weekly basis, so treatment plans can be made easily." The median survival of their study was 7-9 months.I7

There are numerous studies using external beam irradiation combined with intraluminal bra~hytherapy.~.'~*'~-*~ The median survival has all been in the order of 12-15 months. Alden et ~ 1 . ~ ~ found those receiving greater than 55 Gy had a median survival of 24 months compared to 6 months for those receiving less than 55 Gy. Veeze-Kuijpers and associatesI6 found a 10 month median survival for his group as a whole.

In our study, which used intraluminal radiation alone, there was a high median dose and eight patients received more than one intraluminal treatment. The doses chosen compare to other series.I4-l6 However, in the first few patients, we used a smaller dose until we were satisfied that patients could tolerate the higher dose. The median survival was 23 months which com- pares favourably with the literature.l"I6. A large proportion of our patients were deemed to have unresectable tumours. However, some surgeons attempted complete resections. We acknowledge that patients with this turnour. have a poor prog- nosis, but the aim of brachytherapy was not just simple palli- ation. The doses chosen were in the order of 60Gy, which is a well established dose reserved for radical treatment.' Despite attempts at complete resection in three patients, the referring clinicians believed that locoregional failure was still a high pos- sibility. We approached these patients with radical intent.

Since these patients have a poor prognosis, a consideration of how many obtained symptomatic relief and the duration of relief may be relevant. Unfortunately, this was difficult to deter- mine due to the retrospective nature of the study. However, on

INTRALUMINAL BRACHYTHERAPY IN BILE DUCT CARCINOMAS 77

reviewing the case histories, nearly all patients were controlled until the time of death. The exceptions were the two patients who died of septicaemia and from an unknown cause.

We generally did not give our patients external beam radio- therapy as our feeling was that the combination of the two was not necessarily superior to intraluminal radiation alone.

Brachytherapy is expensive. Patients must be admitted as inpatients for several days, have expensive radioactive sources inserted and be connected to machines which store the radio- active sources. The staff required include radiation oncologists, radiologists, physicists, radiographers and nursing staff. In our study, cholangitis occurred in several patients. This necessitated further admissions with appropriate treatment. The cost per patient was estimated to be thousands of dollars. It is difficult to do a cost-benefit analysis, but a comparison with other modalities is interesting. Surgical treatment would require several days of hospital admission with support staff. Patients with stents may be treated quickly, but in our series several had stents and were referred because of blockage. External beam irradiation may be administered on an outpatient basis, but to give the same dose as brachytherapy would also require a high cost.*'

We conclude that intraluminal brachytherapy is a useful alternative in the treatment of unresectable biliary tract carci- noma, allowing a high localized tumour dose to be given, while sparing adjacent normal tissue with minimal complications. This technique at present should be employed in specialty centres.

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