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Combined external beam radiotherapy and intraluminal high dose rate brachytherapy on bile duct carcinomas
Int. J. Radiation
Oncology
Pergamon
Biol. Phys., Vol. 29, No. 4, pp. 855-861, 1994 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360-3016/94 56.00 + .OO
0360-3016(94)E0054-N
??Brachytherapy Contribution
COMBINED EXTERNAL BEAM RADIOTHERAPY AND INTRALUMINAL DOSE RATE BRACHYTHERAPY ON BILE DUCT CARCINOMAS
HIGH
PETER FRITZ, M.D.,* HANS-JURGEN BRAMBS, M.D.,+ PETER SCHRAUBE, M.D.,* ULRICH FREUND, M.D.,+ CHRISTIANE BERNS, PHYS.* AND MICHAEL WANNENMACHER, M.D., D.D.S.* *Department of Clinical Radiology, University of Heidelberg, Im Neuenheimer Feld 400, 69 120 Heidelberg, Germany +Department of Radiology, University of Tiibingen, Hoppe-Seyler-Str. 3, 72076 Tubingen, Germany ‘Department of Clinical Radiology, Kreiskrankenhaus, Ebertplatz 12, 77654 Offenburg, Germany Purpose: The aim of this study was to investigate the effectiveness and complications of combined external beam andaluminal high dose rate irradiation and various adjuvant biliary drainage techniques on patients with bile duct carcinomas. Methods and Materials: Eighteen patients with carcinomas of the hepatic duct bifurcation and 12 patients with carcinomas of the choledochus duct or the common hepatic duct were treated with combined external beam radiotherapy and intraluminal high-dose rate brachytherapy. Nine patients received radiotherapy after palliative tumor resection and 21 patients were primarily irradiated. Twenty-five patients completed the full course of radiotherapy. On these patients, the reference doses for the external beam varied from 30 to 45 Gy and for brachytherapy from 20 to 45 Gy. Biliary drainage after radiotherapy was achieved either with percutaneous catheters, endoprosthesis, or stents. Results: The median survival for the entire group was IO months. The actuarial survival was 34% after 1 year, 18% after 2 and 3 years, and 8% after 5 years. The subgroup with palliative tumor resection exhibit a significantly better survival (median: 12.1 months vs. 7.9 months). Three patients are still living without evidence of disease since 35 to 69 months. Major complications like bacteria1 cholangitis could be lowered from 37% to 28% through exchange of percutaneous transhepatic catheters to endoprosthesis or stents. The longest lasting drainages were achieved through stents. The frequency of radiogenic ulcera were lowered from 23% to presently 7.6% after the total dose of the high dose rate afterloading boost was reduced to 20 Gy. Conclusions: The present standard treatment schedule 40 Gy for the external beam and 20 Gy (fourfold 5 Gy) for the afterloading boost seems to be appropriate and well tolerated. After radiotherapy, a permanent supply of drainage should be made with a stent. Bile ducts, Neoplasms,
Radiotherapy,
Brachytherapy.
INTRODUCTION
biliary intestinal anastomosis (4) or through interventional radiological procedures (2 1). Adenocarcinomas of the bile duct can be influenced favorably by radiotherapy. The palliative or potentially curative effect of radiotherapy should, on the other hand, not be neutralized through morbidity due to the low radiation tolerance of liver and duodenum. Presently, a promising concept consists of a combination of an external beam radiotherapy in a larger volume up to the TD 5/5 combined with an intraluminal afterloading boost in a small volume.
Carcinomas of the extrahepatic bile ducts account for 2 to 6% of the oncological patient collective. A total resection at the time of diagnosis is possible only in 5 to 30% of the cases (2, 7, 15, 20). Especially with tumors of the proximal bile duct (Klatskin tumor), a curative resection can hardly be achieved (2). Even in the rare cases that are scaled to be resectable positive margins of the specimen are very common. In the surgically treated patient collective the rate of locoregional recurrences is between 25 and 64% (7, 12, 14, 15, 23). The 5-year survival rate is below lo%, and the median survival is 7 to 20 months ( 14,24). The treatment of bile duct carcinomas is palliative in the majority of cases and its main objective is the removal of an obstructive jaundice either through surgical
Reprint
requests
METHODS
AND MATERIALS
Between 1987 and 1992, 18 patients with adenocarcinomas of the hepatic duct bifurcation and 12 patients with adenocarcinomas of the choledochus duct and/or
to: Dr. Peter Fritz.
Accepted 855
for publication
22 December
1993.
I. J. Radiation Oncology 0 Biology 0 Physics
856
Table 1. TNM-staging TX
Tl
T2
T3
NO, MO NS, MO NS, Ml
8 1 0
2 0 0
2 0 0
6 7 4
9
2
2
17
therapy:
(13%) already had distant metastases at the time of radiotherapy. On nine patients, a T-classification was not possible. Six of them had not received a laparotomy, and for three patients, the surgery report did not have sufficient data for classification. In general, an external beam irradiation in combination with a HDR afterloading boost was prescribed. One patient (No. 3 in Fig. 1) received an intraluminal irradiation only with single doses of 15 Gy in weekly intervals. The planned concomitant external beam therapy was cancelled because of rapid deterioration of the patient’s medical condition. On the same reason, four other patients did not complete the full course of radiation therapy (No. 1, 2,4, and 5 in Fig. 1). The intraluminal boost was carried out with a remote controlled afterloader’ containing a nominal 370 GBq 192 Ir stepping source. In weekly intervals, single doses of 5, 7.5, 10, or 15 Gy were applied. The most frequent used single doses were 5 Gy and 7.5 Gy. Single doses of 15 Gy were used only in the abovementioned patient. The dose specification refers to the isodose contour that runs in a 10 mm distance to the source (Fig. 2). Sixteen patients with highly stenosed tumors were irradiated once a week from the beginning and concurrently with external beam therapy, whereby, on the day of afterloading irradiation, the external beam therapy was cancelled. On 14 patients brachytherapy was given once a week after the completion of external beam
of the entire group
n = 30
Primary radiation therapy: n = 9.
Volume 29, Number 4, 1994
n = 21, postoperative
18 8 4
radiation
common hepatic duct were referred to our Department of Radiotherapy. Nine patients received radiotherapy after palliative tumor resection (5 X R2-resection, 3 X Rlresection, 1 X RO-resection). Twenty-one patients were irradiated primarily after inoperability was established either through a diagnostic laparotomy (15 patients) or through radiological imaging (six patients). All bile duct carcinomas were histologically proven. In 24 patients the specimen were obtained along with a diagnostic laparotomy or a limited resection of the tumor. Six patients underwent biopsy only during a transhepatic cholangioscopy, a laparoscopy or a CT guided percutaneous biopsy. According to the TNM classification from 1987, 17 patients (57%) had liver infiltration (Table 1). Twelve patients (40%) had surgically evaluated or computertomographitally imaged locoregional lymphomas. Four patients 100
GY 80
D
40
0 S
2
4
6
8
10
12
14
16
18
U
U
20
22
u
24
uu
26
28
30
uu
Fig. 1. Individual reference doses for the entire group (n = 30). Each column represents one patient. The lower parts of the columns exhibit the total doses for the external beam. The upper parts of the columns show the total afterloading doses above the crosslines and the dose per fraction below. The columns marked with an “U” represent the patients on which a duodenal ulcer occurred. The columns marked with a “c” identify the patients on which the afterloading boost was given concurrently with external beam therapy.
’Gamma Med III, Isotopentechnik, Haan, Germany.
Dr. Sauerwein,
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I. J. Radiation Oncology 0 Biology 0 Physics
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0
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Fig. 4. Actuarial survival of patients undergoing resection with postoperative radiation therapy (OP: n = 9) compared with patients receiving primary irradiation (0 OP: n = 2 1).
tients with tumor resections, which were mainly palliative, exhibit an improved median survival for 4.2 months (7.9 vs. 12.1 months). Tumors of the common bile duct showed a slightly better median survival than Klatskin tumors or tumors of the common hepatic duct (10.9 vs. 7.9 months), though the difference was statistically not significant. At target day 3 patients were still alive (No. 6, 2 1, and 29 in Fig. 1). These patients (2 X choledochus duct-tumors, 1 X Klatskin tumor), who were recurrencefree for 35, 60, and 69 months, showed the following characteristics: Tl-2, NO, MO stage, and condition after palliative tumor resection (2 X Rl-resection, 1 X R2-resection). The majority of the patients died of local persistence or recurrence of tumor or local nodes (14/27 = 52%). Obstructive jaundice or bowel obstruction was in these patients the most common final cause of death. Five patients (5/27 = 18%) died of liver metastases (3/5) or disseminated intraperitoneal metastases (2/5). Four patients (4/27 = 15%) died of gastrointestinal bleeding, caused by progression of tumor in three cases and a radiogenic ulcer in one case. Two patients died from intercurrent disease and in two, the cause of death was unclear. Referring to the cause of complications it is necessary to distinguish between drainage-caused and radiogenic complications (Table 2). The most frequent complications
Volume 29, Number 4, 1994
were caused by long-term percutaneous biliary drainages that led to attacks of fever and icterus as sign of bacteriocholangitis (37%) and as a consequence, to abscesses of the liver in two patients. One ulcer in the antrum of the stomach and six ulcera in the duodenal bulb have to be interpreted as radiogenic complications. All duodenal ulcera were located at the posterior wall of the duodenal bulb. This can be explained through the small distance of the duodenal wall to the choledochus duct. The duodenal bulb represents the dose-limiting organ of risk for afterloading therapy in this location. Figure 1 shows that ulcera occurred-with one exception-in patients that received high total afterloading doses (37.5-45 Gy). Three duodenal stenoses originated from ulcera. Two duodenal stenoses originated from duodenal oedema. One stenosis had to be treated surgically. All radiogenic ulcera were treated conservatively. However, one patient died of acute ulcera bleeding in another hospital. After radiotherapy, 12 patients received definite percutaneous transhepatic biliary drainage (PTD). These PTD-patients needed 38 catheters until their death, that means an average change twice. The PTD-catheters were exchanged for endoprosthesis or stent in 16 patients. The removal or exchange of PTD led to a lower rate of cholangitis. Percutaneous biliary drainages were used on average for 3.5 months. All had to be exchanged because of occlusion or infection. Compared to PTD, plastic endoprostheses used in seven cases showed no advantage in functional ability and occluded after an average 3.6 months, mainly because of incrustation. The longest lasting drainages were achieved through stent implantation in 10 patients (average 7.5 months). One stent occluded after 1.5 months due to detritus. Two stents occluded after 3 and 10 months because of progressing tumor growth. Seven stent implants remained in full function for over a period of 3 to 20 months until the day of evaluation or death. In connection with a removal of an obstructed or infected PTD or endoprosthesis, nine patients tried to stay without any drainage. Five patients died after 3 to 14 months free of jaundice without drainage. On three patients, a reinsertion was necessary due to a malign reocclusion. One patient is still living free of recurrence without drainage for 60 months.
DISCUSSION Table 2. Complications due to drainage or radiotherapy (XRT)
Recurrent cholangitis (D) Choledochoduodenal fistula (D) Duodenal ulcer (XRT) Duodenal stenosis (XRT)
(D)
Entire collective (n = 30)
Subgroup with standard treatment (n = 13)
1 l/30 (37%)
3/13 (23%)
l/30 (3.5%) 7/30 (23%) 5/30 (17%)
l/13 (7.6%) -
Radiotherapy for bile duct carcinomas is presently on the level of a Phase II study. Up to now there are no results of a randomized study. The optimal radiotherapy for bile duct carcinomas is not known. The published follow-up studies are difficult to interpret because of low patient number, missing, or inaccurate staging, as a staging classification exists only since 1987 as well as the high heterogeneity of surgical pretreatment and the radiotherapeutical methods themselves. Often gallbladder carcinomas and bile duct carcinomas were summarized (19).
859
Combined treatment on bile duct carcinomas 0 P. FRITZ et al. Table 3. Results of external
beam radiotherapy
of bile duct carcinomas Survival (absolute)
Author
n
Abe (1981) Hishikawa (1983) Fogel ( 1984) Flickinger ( 199 1)
59 25 32 55
Dose (GY)
1 year
2 year
3 year
4 year
25-40 40-60 50 45
44% 32%
18% 12%
6% 7%
-
XRT IORT External-beam External-beam External-beam
The following discussion is based on collectives with more than 10 patients. Mean, respective median survivals of about 10 months can be achieved with both, either an intraoperative or an external beam irradiation (1, 5, 6, 12) (Table 3). The treatment with brachytherapy only seems to be slightly less successful (11, 22, 25) (Table 4). The low survival rates reported by Ries ef al. (25) were the result of mainly high tumor stages. Referring to the better results of Nunnerly et al. (22), not all tumor diagnoses were histologically confirmed (only 23/30 patients). In series treated with external beam and afterloading boost, the mean survival was stable with or slightly above 10 months (3, 13, 18, 26) (Table 5). This is an indication for the advantage of a combined treatment, which still has to be confirmed through controlled clinical studies. Although, the question for the optimal radiotherapy can presently not be answered, we favor the combination of external beam and intraductal boost in the ratio of reference doses of 2/3 to l/3. In most cases, the limitation to only brachytherapy does not meet the mainly extensive tumor growth. Apart from radiobiologic considerations, the clinical data allows no clear decision to the dose rate alternatives of the afterloading boost “continuous LDR- vs. fractionated HDR-
Table 4. Results of intracavitary Intracavitary
10.2 3/9.2* 11 9
1 4%
irradiation.” In general, the median survival for the nonstratified irradiated patient collective is 10 months and the 5-year survival rate below 10%. Concerning indications for radiotherapy, the following can be said: The most common situation is the palliative radiotherapy of an inoperable tumor. Because of improvements of interventional radiological procedures for biliary decompression, the primary objective for radiotherapy is no longer the reduction of tumor stenoses but in retarding or avoiding a renewed obstruction. Up to now it is unknown, whether adjuvant radiotherapy has advantages towards an alone palliative drainage. According to Gonzales et al. (8), adjuvant radiotherapy after palliative drainage could only lead to a marginal improvement for average survival (Table 6). On the other hand, the possibility of a local control of inoperable bile duct tumors were reported from autopsies. In this clinical situation, prospective studies are warranted to establish the possible value of irradiation combined with a palliative drainage. We see a clear indication for radiotherapy in postoperative situations. Gonzales et al. (8) found a statistically significant advantage in survival after palliative resection and postoperative irradiation toward a patient collective
irradiation
of bile duct carcinomas
irradiation
Survival (absolute)
Author
II
Dose rate
GY
Ref. point
1 year
2 year
5 year
Ries (1988) Hendrickx (1990) Nunnerly ( 1990)
23 22 30
HDR LDR LDR
1O-40 60-80 40-50
10 mm 6mm 5mm
3% 70%
0% 16%
0% 3%
Table 5. Results of combined
external
beam and intracavitary
Intracavitary
Author
n
External beam GY)
Cameron (1982) Johnson (1985) Meyers (1988) Veeze-Kuijpers ( 1990) Present series ( 1994)
26 11 27 42 30
30-50 40-55 30-45 30-40 40-45
Dose rate LDR LDR LDR LDR HDR
GY 25 31-106 30-50 15-25 20-45
Median/mean* (months)
irradiation
irradiation
Median /mean* (months) 4 8 16.8*
of bile duct carcinomas
Survival (live table)
1
Ref. point
year
2 year
3 year
5 year
5mm 10 mm 10 mm
57% 46% 34%
45% 18% 18%
30% 13% 18%
8%
Median/mean* (months) 18.8 8.3* 11.5 10 10
860
I. J. Radiation Oncology 0 Biology 0 Physics Table 6. Results of different treatment modalities in carcinomas of the proximal bile duct [modified according to a survey by Gonzales et al. (8)]
Number of series
Number of patients
17 23
480 341
12 5
179 79
Treatment Biliary drainage Biliary drainage + XRT Palliative resection Palliative resection + XRT
* In only few papers surveyed vival rates were reported.
3-Year survival*
Mean survival (months)
12-30%
10.0 + 7.8 12.5 f 4.8
lo-18% 25-3 1%
13.9 + 5.3 2 1.5 f 5
by Gonzales et
al. annual
sur-
only treated with surgery in a EORTC trial analyzing the retrospective data of seven centers on 112 patients with Klatskin tumors (mean survival 19 vs. 8,25 months, p = 0.0001). This trend is supported by other series, too (9, 17, 26) (Table 6). In our patient collective, the actuarial survival after postoperative irradiation was superior to primary irradiation. Based on our patient collective, we cannot answer the question whether radiotherapy was beneficial in postoperative setting. There is no doubt that tumors with advanced liver infiltration or gross lymph node involvement were excluded from the attempt of curative or limited surgery. On the surgically treated patients, the reported tumor diameters ranged from 3 to 4.5 cm. Four of the nine surgically treated patients had tumors of the common hepatic duct or the choledochus duct. Five of the operated patients had regional lymph nodes that could be removed along with the resection of the primary. On this background the better survival of “surgery and postoperative irradiation” is more likely the result of the earlier disease of these patients and the part of distal bile duct carcinomas than of the multimodality treatment itself. Concerning the adequate reference dose, Gonzalez et al. found a significant improvement of results in the range of 40 to 50 Gy, in comparison to doses < 40 Gy. On the other hand, survival could not be improved with doses > 50 Gy. The reason for ineffectivity of higher doses was
Volume 29, Number 4, 1994
not discussed. The afterloading boost had no significant influence on survival. The frequency of drainage-associated bacterio-cholangitis with its complications (abscess of the liver and sepsis) is stated with 12 to 100% in the radiotherapeutically treated patient collectives (10, 11, 17, 22). Lokich et al. (16) found an incidence for cholangitis between 26 and 47% for 464 patients who were not irradiated but supplied with PTD. Repeated bacteria-cholangitis occurred in our patient collective, especially with long-term percutaneous transhepatic drainages, and could be lowered from 37% to presently 28% due to rapidly exchange to endoprosthesis or stents after the brachytherapy was finished. Therefore, possibilities for improvements regarding the frequency of cholangitic complications are likely in the reduction of time for which the PTD is used. We think that a permanent supply of drainage is necessary, as a radiofibrosis of the bile duct or hepatoduodenal ligament is possible, which may lead to a benign reocclusion. On the other hand, a repeated obstructive jaundice through a recurrence can be postponed. The frequency of gastrointestinal ulcera after combined radiotherapy of bile ducts ranges from 11 to 38% in literature (5, 10, 13). There is a lack of data in the literature about the impact of the sequence of brachytherapy application on the frequency of ulcer formation. In our collective, three out of seven ulcers occurred with concurrent afterloading and external beam therapy. But this patient numbers are too small to draw definite conclusions. Because the afterloading boost has been reduced to 20 Gy (4 X 5 Gy), the present incidence of ulcera is 7.6% in our collective. According to our present state of knowledge, the following recommendations can be made: (a) External beam irradiation should be the main component of the radiotherapeutical method. The role of brachytherapy needs further investigations. (b) Cooperative clinical trials are mandatory to establish the value of primar radiotherapy. (c) According to the data of Gonzales et al. (S), postoperative radiotherapy after tumor reduction leads to an improvement of survival and might give the chance of curation. (d) After radiotherapy, a permanent supply of drainage should be made with a stent.
REFERENCES 1. Abe, M.; Takahashi, M. Intraoperative radiotheray: The Japanese experience. Int. J. Radiat. Oncol. Biol. Phys. 7: 863-868; 1981. 2. Adson, M. A.; Fomell, M. D. Hepato biliary cancer: Surgery consideration. Mayo Clin. Proc. 56:686; 198 1. 3. Cameron, J. L.; Broe, P.; Zuidema, G. Proximal bile duct tumors: Surgical management with silastic transhepatic biliary stents. Ann. Surg. 196:412-4 19; 1982. 4. Deveraux, D. F.; Greco, R. S. Biliary enteric bypass for malignant obstruction. Cancer 58:981-986; 1986. 5. Flickinger, J. C.; Epstein, A. H.; Iwatsuki, S.; Carr, B. I.; Starzl, T. E. Radiation therapy for primary carcinoma of the exrahepatic biliary system. Cancer 68:289-294; 199 1.
6. Fogel, T. D.; Weissberg, J. B. The role of radiation therapy in carcinoma of the extra hepatic bile ducts. Int. J. Radiat. Oncol. Biol. Phys. 10:2251-2258; 1984. Gibby, D. G.; Hanks, J. B.; Wanebo, H. J.; Kaiser, D. L.; Tegtmeyer, C. J.; Chandler, J. G.; Jones, R. S. Bile duct carcinoma: Diagnosis and treatment. Ann. Surg. 202: 1391441; 1985. Gonzalez, D.; Gerard, J. P.; Maners, A. W.; De la LandeGuyaux, B.; Van Dijk-Milatz, A.; Meerwaldt, J. H.; Bossel, J. F.; Van Dijk, J. D. P. Results of radiation therapy in carcinoma of the proximal bile duct (Klatskin tumor). Semin. Liver Disease 10:131-141; 1990. Grove, M. K.; Hermann, R. E.; Vogt, D. P.; Broughan,
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T. A. Role of radiation after operative palliation in cancer of the proximal bile ducts. Am. J. Surg. 16 1:454-458; 199 1. Hayes, J. K.; Sapozink, M. D.; Miller, F. J. Definitive radiation therapy in bile duct carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 15:735-744; 1988. Hendrickx, Ph.; Luska, Cl.; Junker, D.; Grate, R. Ergebnisse der perkutan transluminalen Bestrahlung von Gallenwegskarzinomen mit 192~Iridium. Strahlenther. Onkol. 166: 392-396; 1990. Hishikawa, Y.; Shimada, J.; Miura, T.; Imajyo, Y. Radiation therapy of carcinoma of the extrahepatic bile ducts. Radiology 146:787-789; 1983. Johnson, D. W.; Safai, C.; Goffinet, D. R. Malignant obstructive jaundice: Treatment with external beam and intracavitary radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 1 I:41 1-416: 1985.
14. Kinamy, Y.; Miyazak, 1. Operative results of extrahepatic bile duct carcinoma. Chir. Gastroenterol. 13: 187- 195; 1979. 15. Kopelson, G.; Galbadini, J.; Warshaw, A. L.; Gunderson, L. L. Patterns of failure after curative surgery for extrahepatic tract carcinoma: Implications for adjuvant therapy. Int. J. Radiat. Oncol. Biol. Phys. 7:4 13-4 17; 198 1. 16. Lokich, J. J.; Kane W. F. Biliary tract agement guidelines Oncol. 5:969-975;
R. A.; Harrison, D. A.; MC Dermott, obstruction secondary to cancer: Manand selected literature review. J. Clin. 1987.
17. Mahe, M.; Romestaing, P.; Talon, B.; Ardiet, J.-M.; Salerno, N.; Sentenac 1.; Gerard, J.-P. Radiation therapy in extrahepatic bile duct carcinoma. Radiother. Oncol. 2 1: 12 l- 127; 1991.
861
18. Meyers, W. C.; Scott, J. R. Internal irradiation for bile duct cancer. World J. Surg. 12:99-104; 1988. 19. Mittal, B.; Deutsch, M.; Iwatsuki, S. Primary cancers of extrahepatic biliary passages. Int. J. Radiat. Oncol. Biol. Phys. 11:849-854; 1985. 20. Mizumoto, R.; Kawarada, Y.; Suzuki, H. Surgical treatment of hilar carcinoma of the bile duct. Surg. Gynecol. Obstet. 162:153-158; 1986. 21. Mueller, P. R.; Ferrucci, J. T. Percutaneous biliary drainage: Current techniques. Appl. Radiol. May/June:53-57; 1983. H. B.; Obst, D.; Karani, J. B. Interventional 22. Nunnerley, radiology of the biliary tract. Intraductal radiation. Radiol. Clin. North Am. 28:1237-1240; 1990. 23. Ottow, R. J.; August, D. A.; Sugarbaker, P. H. Treatment of proximal biliary tract carcinoma: An overview of techniques and results. Surgery 97:251-262; 1985. 24. Pichlmayer, R.; Ringe, B.; Lauchart, W.; Bechstein, W. 0.; Gubernatis, G.; Wagner, E. Radical resection and liver grafting as the two main components of surgical strategy in the treatment of proximal bile duct cancer. World J. Surg. 12:68-77; 1988. 25. Ries, G. Palliative endoluminal HDR-Iridium-192 afterloading irradiation of biliary malignancies. Proceedings third international HDR remote afterloading symposium, San Diego, 28-30 April, 1989. Published by: Health Service Consultans, Robert F. O’Connor, 829 Lakeview Drive, South China, ME 04358. 26. Veeze Kuijpers, B.; Meerwaldt, J. H.; Lameris, J. S.; Van Blankenstein, M.; Van Putten, W. L. J.; Terpstra, 0. T. The role of radiotherapy in the treatment of bile duct carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 18:63-57; 1990.
Oncology
Pergamon
Biol. Phys., Vol. 29, No. 4, pp. 855-861, 1994 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360-3016/94 56.00 + .OO
0360-3016(94)E0054-N
??Brachytherapy Contribution
COMBINED EXTERNAL BEAM RADIOTHERAPY AND INTRALUMINAL DOSE RATE BRACHYTHERAPY ON BILE DUCT CARCINOMAS
HIGH
PETER FRITZ, M.D.,* HANS-JURGEN BRAMBS, M.D.,+ PETER SCHRAUBE, M.D.,* ULRICH FREUND, M.D.,+ CHRISTIANE BERNS, PHYS.* AND MICHAEL WANNENMACHER, M.D., D.D.S.* *Department of Clinical Radiology, University of Heidelberg, Im Neuenheimer Feld 400, 69 120 Heidelberg, Germany +Department of Radiology, University of Tiibingen, Hoppe-Seyler-Str. 3, 72076 Tubingen, Germany ‘Department of Clinical Radiology, Kreiskrankenhaus, Ebertplatz 12, 77654 Offenburg, Germany Purpose: The aim of this study was to investigate the effectiveness and complications of combined external beam andaluminal high dose rate irradiation and various adjuvant biliary drainage techniques on patients with bile duct carcinomas. Methods and Materials: Eighteen patients with carcinomas of the hepatic duct bifurcation and 12 patients with carcinomas of the choledochus duct or the common hepatic duct were treated with combined external beam radiotherapy and intraluminal high-dose rate brachytherapy. Nine patients received radiotherapy after palliative tumor resection and 21 patients were primarily irradiated. Twenty-five patients completed the full course of radiotherapy. On these patients, the reference doses for the external beam varied from 30 to 45 Gy and for brachytherapy from 20 to 45 Gy. Biliary drainage after radiotherapy was achieved either with percutaneous catheters, endoprosthesis, or stents. Results: The median survival for the entire group was IO months. The actuarial survival was 34% after 1 year, 18% after 2 and 3 years, and 8% after 5 years. The subgroup with palliative tumor resection exhibit a significantly better survival (median: 12.1 months vs. 7.9 months). Three patients are still living without evidence of disease since 35 to 69 months. Major complications like bacteria1 cholangitis could be lowered from 37% to 28% through exchange of percutaneous transhepatic catheters to endoprosthesis or stents. The longest lasting drainages were achieved through stents. The frequency of radiogenic ulcera were lowered from 23% to presently 7.6% after the total dose of the high dose rate afterloading boost was reduced to 20 Gy. Conclusions: The present standard treatment schedule 40 Gy for the external beam and 20 Gy (fourfold 5 Gy) for the afterloading boost seems to be appropriate and well tolerated. After radiotherapy, a permanent supply of drainage should be made with a stent. Bile ducts, Neoplasms,
Radiotherapy,
Brachytherapy.
INTRODUCTION
biliary intestinal anastomosis (4) or through interventional radiological procedures (2 1). Adenocarcinomas of the bile duct can be influenced favorably by radiotherapy. The palliative or potentially curative effect of radiotherapy should, on the other hand, not be neutralized through morbidity due to the low radiation tolerance of liver and duodenum. Presently, a promising concept consists of a combination of an external beam radiotherapy in a larger volume up to the TD 5/5 combined with an intraluminal afterloading boost in a small volume.
Carcinomas of the extrahepatic bile ducts account for 2 to 6% of the oncological patient collective. A total resection at the time of diagnosis is possible only in 5 to 30% of the cases (2, 7, 15, 20). Especially with tumors of the proximal bile duct (Klatskin tumor), a curative resection can hardly be achieved (2). Even in the rare cases that are scaled to be resectable positive margins of the specimen are very common. In the surgically treated patient collective the rate of locoregional recurrences is between 25 and 64% (7, 12, 14, 15, 23). The 5-year survival rate is below lo%, and the median survival is 7 to 20 months ( 14,24). The treatment of bile duct carcinomas is palliative in the majority of cases and its main objective is the removal of an obstructive jaundice either through surgical
Reprint
requests
METHODS
AND MATERIALS
Between 1987 and 1992, 18 patients with adenocarcinomas of the hepatic duct bifurcation and 12 patients with adenocarcinomas of the choledochus duct and/or
to: Dr. Peter Fritz.
Accepted 855
for publication
22 December
1993.
I. J. Radiation Oncology 0 Biology 0 Physics
856
Table 1. TNM-staging TX
Tl
T2
T3
NO, MO NS, MO NS, Ml
8 1 0
2 0 0
2 0 0
6 7 4
9
2
2
17
therapy:
(13%) already had distant metastases at the time of radiotherapy. On nine patients, a T-classification was not possible. Six of them had not received a laparotomy, and for three patients, the surgery report did not have sufficient data for classification. In general, an external beam irradiation in combination with a HDR afterloading boost was prescribed. One patient (No. 3 in Fig. 1) received an intraluminal irradiation only with single doses of 15 Gy in weekly intervals. The planned concomitant external beam therapy was cancelled because of rapid deterioration of the patient’s medical condition. On the same reason, four other patients did not complete the full course of radiation therapy (No. 1, 2,4, and 5 in Fig. 1). The intraluminal boost was carried out with a remote controlled afterloader’ containing a nominal 370 GBq 192 Ir stepping source. In weekly intervals, single doses of 5, 7.5, 10, or 15 Gy were applied. The most frequent used single doses were 5 Gy and 7.5 Gy. Single doses of 15 Gy were used only in the abovementioned patient. The dose specification refers to the isodose contour that runs in a 10 mm distance to the source (Fig. 2). Sixteen patients with highly stenosed tumors were irradiated once a week from the beginning and concurrently with external beam therapy, whereby, on the day of afterloading irradiation, the external beam therapy was cancelled. On 14 patients brachytherapy was given once a week after the completion of external beam
of the entire group
n = 30
Primary radiation therapy: n = 9.
Volume 29, Number 4, 1994
n = 21, postoperative
18 8 4
radiation
common hepatic duct were referred to our Department of Radiotherapy. Nine patients received radiotherapy after palliative tumor resection (5 X R2-resection, 3 X Rlresection, 1 X RO-resection). Twenty-one patients were irradiated primarily after inoperability was established either through a diagnostic laparotomy (15 patients) or through radiological imaging (six patients). All bile duct carcinomas were histologically proven. In 24 patients the specimen were obtained along with a diagnostic laparotomy or a limited resection of the tumor. Six patients underwent biopsy only during a transhepatic cholangioscopy, a laparoscopy or a CT guided percutaneous biopsy. According to the TNM classification from 1987, 17 patients (57%) had liver infiltration (Table 1). Twelve patients (40%) had surgically evaluated or computertomographitally imaged locoregional lymphomas. Four patients 100
GY 80
D
40
0 S
2
4
6
8
10
12
14
16
18
U
U
20
22
u
24
uu
26
28
30
uu
Fig. 1. Individual reference doses for the entire group (n = 30). Each column represents one patient. The lower parts of the columns exhibit the total doses for the external beam. The upper parts of the columns show the total afterloading doses above the crosslines and the dose per fraction below. The columns marked with an “U” represent the patients on which a duodenal ulcer occurred. The columns marked with a “c” identify the patients on which the afterloading boost was given concurrently with external beam therapy.
’Gamma Med III, Isotopentechnik, Haan, Germany.
Dr. Sauerwein,
42781
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858
I. J. Radiation Oncology 0 Biology 0 Physics
0.6
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II=21
I.
0
0
10
20
30
40
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60 month8
Fig. 4. Actuarial survival of patients undergoing resection with postoperative radiation therapy (OP: n = 9) compared with patients receiving primary irradiation (0 OP: n = 2 1).
tients with tumor resections, which were mainly palliative, exhibit an improved median survival for 4.2 months (7.9 vs. 12.1 months). Tumors of the common bile duct showed a slightly better median survival than Klatskin tumors or tumors of the common hepatic duct (10.9 vs. 7.9 months), though the difference was statistically not significant. At target day 3 patients were still alive (No. 6, 2 1, and 29 in Fig. 1). These patients (2 X choledochus duct-tumors, 1 X Klatskin tumor), who were recurrencefree for 35, 60, and 69 months, showed the following characteristics: Tl-2, NO, MO stage, and condition after palliative tumor resection (2 X Rl-resection, 1 X R2-resection). The majority of the patients died of local persistence or recurrence of tumor or local nodes (14/27 = 52%). Obstructive jaundice or bowel obstruction was in these patients the most common final cause of death. Five patients (5/27 = 18%) died of liver metastases (3/5) or disseminated intraperitoneal metastases (2/5). Four patients (4/27 = 15%) died of gastrointestinal bleeding, caused by progression of tumor in three cases and a radiogenic ulcer in one case. Two patients died from intercurrent disease and in two, the cause of death was unclear. Referring to the cause of complications it is necessary to distinguish between drainage-caused and radiogenic complications (Table 2). The most frequent complications
Volume 29, Number 4, 1994
were caused by long-term percutaneous biliary drainages that led to attacks of fever and icterus as sign of bacteriocholangitis (37%) and as a consequence, to abscesses of the liver in two patients. One ulcer in the antrum of the stomach and six ulcera in the duodenal bulb have to be interpreted as radiogenic complications. All duodenal ulcera were located at the posterior wall of the duodenal bulb. This can be explained through the small distance of the duodenal wall to the choledochus duct. The duodenal bulb represents the dose-limiting organ of risk for afterloading therapy in this location. Figure 1 shows that ulcera occurred-with one exception-in patients that received high total afterloading doses (37.5-45 Gy). Three duodenal stenoses originated from ulcera. Two duodenal stenoses originated from duodenal oedema. One stenosis had to be treated surgically. All radiogenic ulcera were treated conservatively. However, one patient died of acute ulcera bleeding in another hospital. After radiotherapy, 12 patients received definite percutaneous transhepatic biliary drainage (PTD). These PTD-patients needed 38 catheters until their death, that means an average change twice. The PTD-catheters were exchanged for endoprosthesis or stent in 16 patients. The removal or exchange of PTD led to a lower rate of cholangitis. Percutaneous biliary drainages were used on average for 3.5 months. All had to be exchanged because of occlusion or infection. Compared to PTD, plastic endoprostheses used in seven cases showed no advantage in functional ability and occluded after an average 3.6 months, mainly because of incrustation. The longest lasting drainages were achieved through stent implantation in 10 patients (average 7.5 months). One stent occluded after 1.5 months due to detritus. Two stents occluded after 3 and 10 months because of progressing tumor growth. Seven stent implants remained in full function for over a period of 3 to 20 months until the day of evaluation or death. In connection with a removal of an obstructed or infected PTD or endoprosthesis, nine patients tried to stay without any drainage. Five patients died after 3 to 14 months free of jaundice without drainage. On three patients, a reinsertion was necessary due to a malign reocclusion. One patient is still living free of recurrence without drainage for 60 months.
DISCUSSION Table 2. Complications due to drainage or radiotherapy (XRT)
Recurrent cholangitis (D) Choledochoduodenal fistula (D) Duodenal ulcer (XRT) Duodenal stenosis (XRT)
(D)
Entire collective (n = 30)
Subgroup with standard treatment (n = 13)
1 l/30 (37%)
3/13 (23%)
l/30 (3.5%) 7/30 (23%) 5/30 (17%)
l/13 (7.6%) -
Radiotherapy for bile duct carcinomas is presently on the level of a Phase II study. Up to now there are no results of a randomized study. The optimal radiotherapy for bile duct carcinomas is not known. The published follow-up studies are difficult to interpret because of low patient number, missing, or inaccurate staging, as a staging classification exists only since 1987 as well as the high heterogeneity of surgical pretreatment and the radiotherapeutical methods themselves. Often gallbladder carcinomas and bile duct carcinomas were summarized (19).
859
Combined treatment on bile duct carcinomas 0 P. FRITZ et al. Table 3. Results of external
beam radiotherapy
of bile duct carcinomas Survival (absolute)
Author
n
Abe (1981) Hishikawa (1983) Fogel ( 1984) Flickinger ( 199 1)
59 25 32 55
Dose (GY)
1 year
2 year
3 year
4 year
25-40 40-60 50 45
44% 32%
18% 12%
6% 7%
-
XRT IORT External-beam External-beam External-beam
The following discussion is based on collectives with more than 10 patients. Mean, respective median survivals of about 10 months can be achieved with both, either an intraoperative or an external beam irradiation (1, 5, 6, 12) (Table 3). The treatment with brachytherapy only seems to be slightly less successful (11, 22, 25) (Table 4). The low survival rates reported by Ries ef al. (25) were the result of mainly high tumor stages. Referring to the better results of Nunnerly et al. (22), not all tumor diagnoses were histologically confirmed (only 23/30 patients). In series treated with external beam and afterloading boost, the mean survival was stable with or slightly above 10 months (3, 13, 18, 26) (Table 5). This is an indication for the advantage of a combined treatment, which still has to be confirmed through controlled clinical studies. Although, the question for the optimal radiotherapy can presently not be answered, we favor the combination of external beam and intraductal boost in the ratio of reference doses of 2/3 to l/3. In most cases, the limitation to only brachytherapy does not meet the mainly extensive tumor growth. Apart from radiobiologic considerations, the clinical data allows no clear decision to the dose rate alternatives of the afterloading boost “continuous LDR- vs. fractionated HDR-
Table 4. Results of intracavitary Intracavitary
10.2 3/9.2* 11 9
1 4%
irradiation.” In general, the median survival for the nonstratified irradiated patient collective is 10 months and the 5-year survival rate below 10%. Concerning indications for radiotherapy, the following can be said: The most common situation is the palliative radiotherapy of an inoperable tumor. Because of improvements of interventional radiological procedures for biliary decompression, the primary objective for radiotherapy is no longer the reduction of tumor stenoses but in retarding or avoiding a renewed obstruction. Up to now it is unknown, whether adjuvant radiotherapy has advantages towards an alone palliative drainage. According to Gonzales et al. (8), adjuvant radiotherapy after palliative drainage could only lead to a marginal improvement for average survival (Table 6). On the other hand, the possibility of a local control of inoperable bile duct tumors were reported from autopsies. In this clinical situation, prospective studies are warranted to establish the possible value of irradiation combined with a palliative drainage. We see a clear indication for radiotherapy in postoperative situations. Gonzales et al. (8) found a statistically significant advantage in survival after palliative resection and postoperative irradiation toward a patient collective
irradiation
of bile duct carcinomas
irradiation
Survival (absolute)
Author
II
Dose rate
GY
Ref. point
1 year
2 year
5 year
Ries (1988) Hendrickx (1990) Nunnerly ( 1990)
23 22 30
HDR LDR LDR
1O-40 60-80 40-50
10 mm 6mm 5mm
3% 70%
0% 16%
0% 3%
Table 5. Results of combined
external
beam and intracavitary
Intracavitary
Author
n
External beam GY)
Cameron (1982) Johnson (1985) Meyers (1988) Veeze-Kuijpers ( 1990) Present series ( 1994)
26 11 27 42 30
30-50 40-55 30-45 30-40 40-45
Dose rate LDR LDR LDR LDR HDR
GY 25 31-106 30-50 15-25 20-45
Median/mean* (months)
irradiation
irradiation
Median /mean* (months) 4 8 16.8*
of bile duct carcinomas
Survival (live table)
1
Ref. point
year
2 year
3 year
5 year
5mm 10 mm 10 mm
57% 46% 34%
45% 18% 18%
30% 13% 18%
8%
Median/mean* (months) 18.8 8.3* 11.5 10 10
860
I. J. Radiation Oncology 0 Biology 0 Physics Table 6. Results of different treatment modalities in carcinomas of the proximal bile duct [modified according to a survey by Gonzales et al. (8)]
Number of series
Number of patients
17 23
480 341
12 5
179 79
Treatment Biliary drainage Biliary drainage + XRT Palliative resection Palliative resection + XRT
* In only few papers surveyed vival rates were reported.
3-Year survival*
Mean survival (months)
12-30%
10.0 + 7.8 12.5 f 4.8
lo-18% 25-3 1%
13.9 + 5.3 2 1.5 f 5
by Gonzales et
al. annual
sur-
only treated with surgery in a EORTC trial analyzing the retrospective data of seven centers on 112 patients with Klatskin tumors (mean survival 19 vs. 8,25 months, p = 0.0001). This trend is supported by other series, too (9, 17, 26) (Table 6). In our patient collective, the actuarial survival after postoperative irradiation was superior to primary irradiation. Based on our patient collective, we cannot answer the question whether radiotherapy was beneficial in postoperative setting. There is no doubt that tumors with advanced liver infiltration or gross lymph node involvement were excluded from the attempt of curative or limited surgery. On the surgically treated patients, the reported tumor diameters ranged from 3 to 4.5 cm. Four of the nine surgically treated patients had tumors of the common hepatic duct or the choledochus duct. Five of the operated patients had regional lymph nodes that could be removed along with the resection of the primary. On this background the better survival of “surgery and postoperative irradiation” is more likely the result of the earlier disease of these patients and the part of distal bile duct carcinomas than of the multimodality treatment itself. Concerning the adequate reference dose, Gonzalez et al. found a significant improvement of results in the range of 40 to 50 Gy, in comparison to doses < 40 Gy. On the other hand, survival could not be improved with doses > 50 Gy. The reason for ineffectivity of higher doses was
Volume 29, Number 4, 1994
not discussed. The afterloading boost had no significant influence on survival. The frequency of drainage-associated bacterio-cholangitis with its complications (abscess of the liver and sepsis) is stated with 12 to 100% in the radiotherapeutically treated patient collectives (10, 11, 17, 22). Lokich et al. (16) found an incidence for cholangitis between 26 and 47% for 464 patients who were not irradiated but supplied with PTD. Repeated bacteria-cholangitis occurred in our patient collective, especially with long-term percutaneous transhepatic drainages, and could be lowered from 37% to presently 28% due to rapidly exchange to endoprosthesis or stents after the brachytherapy was finished. Therefore, possibilities for improvements regarding the frequency of cholangitic complications are likely in the reduction of time for which the PTD is used. We think that a permanent supply of drainage is necessary, as a radiofibrosis of the bile duct or hepatoduodenal ligament is possible, which may lead to a benign reocclusion. On the other hand, a repeated obstructive jaundice through a recurrence can be postponed. The frequency of gastrointestinal ulcera after combined radiotherapy of bile ducts ranges from 11 to 38% in literature (5, 10, 13). There is a lack of data in the literature about the impact of the sequence of brachytherapy application on the frequency of ulcer formation. In our collective, three out of seven ulcers occurred with concurrent afterloading and external beam therapy. But this patient numbers are too small to draw definite conclusions. Because the afterloading boost has been reduced to 20 Gy (4 X 5 Gy), the present incidence of ulcera is 7.6% in our collective. According to our present state of knowledge, the following recommendations can be made: (a) External beam irradiation should be the main component of the radiotherapeutical method. The role of brachytherapy needs further investigations. (b) Cooperative clinical trials are mandatory to establish the value of primar radiotherapy. (c) According to the data of Gonzales et al. (S), postoperative radiotherapy after tumor reduction leads to an improvement of survival and might give the chance of curation. (d) After radiotherapy, a permanent supply of drainage should be made with a stent.
REFERENCES 1. Abe, M.; Takahashi, M. Intraoperative radiotheray: The Japanese experience. Int. J. Radiat. Oncol. Biol. Phys. 7: 863-868; 1981. 2. Adson, M. A.; Fomell, M. D. Hepato biliary cancer: Surgery consideration. Mayo Clin. Proc. 56:686; 198 1. 3. Cameron, J. L.; Broe, P.; Zuidema, G. Proximal bile duct tumors: Surgical management with silastic transhepatic biliary stents. Ann. Surg. 196:412-4 19; 1982. 4. Deveraux, D. F.; Greco, R. S. Biliary enteric bypass for malignant obstruction. Cancer 58:981-986; 1986. 5. Flickinger, J. C.; Epstein, A. H.; Iwatsuki, S.; Carr, B. I.; Starzl, T. E. Radiation therapy for primary carcinoma of the exrahepatic biliary system. Cancer 68:289-294; 199 1.
6. Fogel, T. D.; Weissberg, J. B. The role of radiation therapy in carcinoma of the extra hepatic bile ducts. Int. J. Radiat. Oncol. Biol. Phys. 10:2251-2258; 1984. Gibby, D. G.; Hanks, J. B.; Wanebo, H. J.; Kaiser, D. L.; Tegtmeyer, C. J.; Chandler, J. G.; Jones, R. S. Bile duct carcinoma: Diagnosis and treatment. Ann. Surg. 202: 1391441; 1985. Gonzalez, D.; Gerard, J. P.; Maners, A. W.; De la LandeGuyaux, B.; Van Dijk-Milatz, A.; Meerwaldt, J. H.; Bossel, J. F.; Van Dijk, J. D. P. Results of radiation therapy in carcinoma of the proximal bile duct (Klatskin tumor). Semin. Liver Disease 10:131-141; 1990. Grove, M. K.; Hermann, R. E.; Vogt, D. P.; Broughan,
Combined treatment on bile duct carcinomas 0 P. FRITZefa/.
10.
11.
12.
13.
T. A. Role of radiation after operative palliation in cancer of the proximal bile ducts. Am. J. Surg. 16 1:454-458; 199 1. Hayes, J. K.; Sapozink, M. D.; Miller, F. J. Definitive radiation therapy in bile duct carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 15:735-744; 1988. Hendrickx, Ph.; Luska, Cl.; Junker, D.; Grate, R. Ergebnisse der perkutan transluminalen Bestrahlung von Gallenwegskarzinomen mit 192~Iridium. Strahlenther. Onkol. 166: 392-396; 1990. Hishikawa, Y.; Shimada, J.; Miura, T.; Imajyo, Y. Radiation therapy of carcinoma of the extrahepatic bile ducts. Radiology 146:787-789; 1983. Johnson, D. W.; Safai, C.; Goffinet, D. R. Malignant obstructive jaundice: Treatment with external beam and intracavitary radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 1 I:41 1-416: 1985.
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