Carcinoma of the gallbladder or extrahepatic bile ducts: the role of radiotherapy SHERIF S. HANNA,* MB, B CH, FRCS[C]; WALTER D. RIDER,t MB, FRCP[C], FRCR

Carcinoma of the gallbladder or extrahepatic bile ducts is a lethal disease. Few patients live for 5 years, even when the tumour is technically resectable or discovered accidentally during cholecystectomy.1'2 It appears that operation alone, even in early cases, produces unsatisfactory results. It is possible that with a combination of surgery and radiotherapy or chemotherapy, or both. survival in these cases might be improved.1 Radiation therapy has not been used extensively in the past primarily because of the concept that adenocarcinomas are inherently radioresistant. However, for a variety of reasons, radiotherapy has been used with some success in a number of cases. This has cast some doubt on the validity of this concept. For these reasons it was decided to analyse the experience of the Princess Margaret Hospital to determine if, indeed, there is a place for radiotherapy in carcinoma of the gallbladder or extrahepatic bile ducts. Methods The records of all patients registered at the Princess Margaret Hospital with the diagnosis of carcinoma of the gallbladder or extrahepatic bile ducts, exclusive of the periampullary region, from Jan. 1, 1958 to Dec. 31, 1975 inclusive were examined. During this 18-year period 68 such patients were From Princess Margaret Hospital, Toronto *Fo.erly fellow in surgical oncology, Princess Margaret Hospital; now fellow in division of general surgery, department of surgery, and in regional trauma unit, Sunnybrook Medical Centre, University of Toronto tDirector, radiation oncology, Princess Margaret Hospital, and professor of radiology, University of Toronto Reprint requests to: Dr. Sherif S. Hanna, Rm. 5430 C-5, Sunnybrook Medical Centre, 2075 Bayview Ave., Toronto, Ont. M4N 3M5

registered - 51 with carcinoma of the gallbladder and 17 with carcinoma of the extrahepatic bile ducts. Follow-up data were obtained for all 68.

The average dose in adults was 4000 rads (range, 3488 to 6000 rads) given in 20 fractions over 4 weeks. Palliative radiotherapy was defined as radiotherapy without curative intent or for alleviation of pain at a primary or secondary tumour site. The average dose in adults was 2600 rads. None of the 68 patients survived for 5 years. There was a significant difference in median survival between patients treated by curative versus palliative surgery when the data for all patients were analysed together (P < 0.006) and also when the data for the patients with carcinoma of the gallbladder were analysed separately (P < 0.002) (Figs. 1 and 2). Patients who had either curative or palliative surgery were unevenly distributed among the radiotherapy

Results

Histologic confirmation was obtained in 63 cases. The other five cases were included in the study because of characteristic findings at operation; the circumstantial evidence and the clinical course confirmed the diagnosis in all five cases. Treatment modalities and length of survival were determined in each case (Table I). Radical radiotherapy in this disease was defined as radiotherapy with curative intent to the right upper quadrant of the abdomen; seven patients also received total abdominal irradiation. I

I

Actuarial survival curves - Overall (68) - - -- curative surgery(18) -- - Palliative surgery(50)

100 fr. 801-

1b.

S

N

I

Gallbladder - Actuarial survival curves - Overall (51) - - - curative surgery(17) - Palliative surgery(34)

100

'4.

40120 I-

0

2

4

6 8 10 12 Survival from surgery (months)

14

16

]

IE

FIG. 2-Median survival of 51 patients with carcinoma of the gallbladder. Curati. te surgery resulted in significantly better (P K 0.002) survival than palliative surgei. Y. I

I

Radiation -Actuarial survival curves 100 N 801-

Radical radiation (18) Palliative radiation (31) No radiation given (19)

601 (I)

4%

40 F 20

.r

J

groups - radical, palliative and none. Most patients, however, had palliative radiotherapy since in the earlier years of this study these tumours were considered to be radioresistant and were not treated by radical radiotherapy. Although there was no difference in median survival between patients given radical versus palliative radiotherapy there was a significant difference (P = 0.018) in median survival between those given curative radiotherapy and those not given radiotherapy (Fig. 3 and Table I). In the 17 patients with carcinoma of the extrahepatic bile ducts the overall median survival was 12.1 months. One patient had curative surgery and survived 7 months, 15 patients had palliative surgery and a median survival of 12.5 months, and 1 patient had no surgery and died 12 days after presentation (at autopsy he had a tumour of the common bile duct metastasizing to the lungs). The 14 patients given radiotherapy had a median survival of 12.3 months, whereas the 3 patients who were not given radiotherapy had a median survival of 1.1 months. All these figures were too small for statistical analysis but they suggested benefit from radiotherapy. In approximately two thirds of the patients with carcinoma of the gallbladder the disease was confined to the right upper quadrant of the abdomen, whereas in about one quarter the cancer had spread elsewhere in the abdomen, and in 10% there was extraabdominal spread at the time of presentation (Table II). "Pathologist's cancer" is a term used to describe an occult cancer missed by the surgeon but discovered by the pathologist. Nine such tumours were encountered in this series; the median survival of the patients was 13.1 months as compared with 6.6 months for the rest of the patients with carcinoma of the gallbladder - a significant difference (P K 0.044) (Fig. 4). Despite their longer survival all nine patients died of their disease in less than 5 years. The only important complication of radiotherapy was radiation hepatitis, encountered in 3 out of 49 patients (6%). Two patients received no specific treatment; the other was given prednisone. All three recovered uneventfully. Chemotherapy or immunotherapy, or both, was given to 17 of the 68 patients but had no influence on survival. Discussion

Carcinomas of the gallbladder and extrahepatic bile ducts are deadly diseases with poor survival. Surgery alone has resulted in poor survival rates,

Tibt

wfU. .fr*..ia otttwwkh.

. ranging from 0 to 10% at 5 years for carcinoma of the gallbladder"3-7 and 0 to 4.8% at 5 years for carcinoma of the extrahepatic bile ducts.5'8'9 If survival rates are to improve, new methods of management have to be used. There has been very little in the literature about the use of radiotherapy in the treatment of these neoplasms,'0 for it is generally thought that adenocarcinomas are inherently radioresisttant." We have shown that this concept is fallacious. Cellular radioresistance can be considered only after rigorous exclusion of all extrinsic factors such as misguided radiation beams, disappearance rate, tumour sterilization and tumour behaviour.'2 It is true, however, that adenocarcinomas are slower to respond to radiotherapy than squamous cell carcinomas. This, among other factors, led in the past to the erroneous concept that adenocarcinomas do not respond to radiotherapy. Diagnosis is usually made at the time of laparotomy and should be followed by resection or biliary decompression to allow improvement in the

patient's hepatic function and prevent early death due to hepatic failure. We suggest that adjuvant radical radiotherapy be given postoperatively, as radiation has shown a glimmer of hope in an otherwise desolate field. Radiotherapy should be explored further in the treatment of these neoplasms. There is some evidence from this report and others"13 that postoperative radiotherapy prolongs survival. The quality of survival was generally good. Although biliary decompression should always be attempted, some patients in our series were referred for radiotherapy after laparotomy without biliary decompression. Palliation with radiotherapy only was good in these patients. Green, Mikkelson and Kernen'4 have reported similar experience with two cases. Radiotherapy is acceptable as adjuvant treatment because it is safe: morbidity is minimal and it never results in death. Kim and associates'5 reported 2 cases of radiation hepatitis out of 117 consecutive cases of lymphoma (frequency, 1.7%) in which total abdominal irradiation was given;

the two patients recovered spontaneously. Our three patients with radiation hepatitis also recovered spontaneously. The technique of radiotherapy is still evolving. All the patients in our series who were treated with curative intent received radical local radiotherapy to the right upper quadrant of the abdomen. In 22% of patients who were treated radically, total abdominal irradiation (2000 rads) was given first, then the primary site in the right upper quadrant was irradiated (2000 rads). The reason for total abdominal irradiation is transcoelomic spread; this occurred in 23.5% of our cases and in an even higher percentage of autopsy cases in another study.16 We acknowledge the help of Mrs. Joan Reid and Miss Theresa Chua from the department of biostatistics of the Princess Margaret Hospital in preparing the statistical data in this paper. This work was funded by the Gordon Richards Fellowship of the Ontario division of the Canadian Cancer Society. References 1. Moosst AR, ANAGNOST M, HALL AW, et al: The continuing challenge of gallbladder cancer. Am I Surg 130: 57, 1975 2. APPLEMAN RM, MORLOCK CG, DAHLIN DC,

et al: Long term survival in carcinoma of the gallbladder. Surg Gynecol Obstet 117: 459, 1963 3. STRAUGH GO: Primary carcinoma of the gallbladder: presentation of seventy cases from the Rhode Island Hospital and a cumulative review of the last ten years of the American literature. Surgery 47: 368, 1960 4. SOLAN MJ, JACKSON BT: Carcinoma of the gallbladder. A clinical appraisal and review of 57 cases. Br I Surg 58: 593, 1971 5. SHANI M, HART 3, MODAN B, et al: Cancer of the biliary system: a study of 445 cases. Br I Surg 61: 98, 1974 6. KEILL RH, DEwEESE M5: Primary carcinoma of the gallbladder. Am J Surg 125: 729, 1973 7. VADHEIM JL, GRAY HK, DOCKERTY MB: Car-

cinoma of the gallbladder; a clinical and pathologic study. Am I Surg 63: 173, 1944

I

5

100

I

8. JOHNSON FW, GsLsoosu' RB: Carcinoma of the gallbladder and extrahepatic biliary tree. Am Surg 40: 456, 1974

I

Gallbladder-Actuarial survival curves - - - Pathologist's cA (9) -

-'

9. wARREN

Not pathologist's cA(42)

80

KW,

MOUNTAIN JC,

LLOYD-JONES

w: Malignant tumours of the bile-ducts. Dr I Surg 59: 501, 1972 10. ORLOFF MJ, CHARTERS AC: Tumours of the gallbladder and bile ducts, in Gastroenterology, BOCKUS HL (ed), vol 3, chap 127, sect 8, Philadelphia, Saunders, 1976, p 836 11. MOERTEL GC: Extrahepatic bile ducts, in Cancer Medicine, sect 24, chap 5, HOLLAND JF, FREI E (eds), Philadelphia, Lea & Febiger, 1973. p 1555 12. RIDER WD: Radiosensitivity - what is it? Laryngoscope 81: 1045, 1971

. 60 .3

13. ACKERMAN LV, DEL REGATO JA: Cancer of

. 40

the digestive tract - gallbladder,in Cancer Diagnosis, Treatment and Prognosis, Alimentary Tract Cancer, 4th ed, St Louis, Mosby, 1970, p 591

/

14. GREEN

20

N,

MIEKELSON

WP,

KERNEN

JA:

Cancer of the common hepatic bile ducts palliative radiotherapy. Radiology 109: 687, 1973 15. KIM TH, PANAHON AM, FRIEDMAN M, et al:

0

2

4

12 10 8 6 Survival from surgery(months)

14

16

18

FIG. 4-Median survival of 9 patients with "pathologistts cancer" was sigaificantly better (P