The role of radiation therapy in cancer of the extra-hepatic biliary system: An analysis of thirteen patients and a review of the literature of the effectiveness of surgery, chemotherapy

hf. 1. Radiation Oncology Biol. Phyx, 1977, Vol. 2. pp. 88S894. Pergamon Press. Printed in the U S.A.

??Original Contribution

THE ROLE OF RADIATION THERAPY IN CANCER OF THE EXTRA-HEPATIC BILIARY SYSTEM:

AN ANALYSIS OF THIRTEEN PATIENTS AND A REVIEW OF THE LITERATURE OF THE EFFECTIVENESS OF SURGERY,

CHEMOTHERAPY AND RADIOTHERAPY?

GENE KOPE:LSON, A.B.,S LEON HARISIADIS, M.D.,§ PATRICIA TRETTER, M.D.7 and CHU H. CHANG, M.D.11

Division of Raldiotherapy, Department of Radiology, College of Physicians and Surgeons, Columbia- Presbyterian Medical Center, New York, 10032, U.S.A.

An analysis of the role of radiotherapy in the management of gallbladder (GB) and extra-hepatic bile duct (EHBD) cancer iis based upon thirteen patients irradiated in our hospital and a review of the literature. These patients were treated as part of curative or palliative management in conjunction with surgery, after surgical failure or recurrence, and as the only palliative modality. Doses ranged from 3800 to 7225 rad.

Signillcant palliation was obtained in 92% of the patients; average total billrubin value decreased from 9.1 mg.% before to 1.7 mg.% after radiotherapy. The mean survival of all patients was 12.7 months after surgery (7.1 in (GB, 16.1 in EHBD), and was 7.3 months after initiation of radiotherapy (6.3 in GB, 8.0 in EHBD). Two patients were alive and well with no evidence of disease 12 and 16 months after radiotherapy, and local tumor control was achieved in two. Complications included possible biliary fibrosis.

Based upon a critical review of the surgical, chemotherapeutic, and radiotherapeutic literature, it is concluded that present surgical therapy fails because of extensive regional disease in which local recurrences follow various simple and radical surgical maneuvers; palliative surgery often fails. Survival rates have been poor following any therapy at present, although encouraging results are seen with carefully planned megavoltage radiotherapy.

A proposal iis made to evaluate the role of radiotherapy systematically: as part of curative therapy post-operatively to decrease local recurrences and to increase the length and quality of survival; to treat incfsional recurrences; as part of advanced disease management to increase the effectiveness and length of palliation; and i!n conjunction with chemotherapy to further consolidate therapeutic gains made with radiotherapy alone.

Radiotherapy, Gallbladder neoplasms -radiotherapy, Bile duct neoplasms-radiotherapy, Bile duct-radiation effects, Gallbladder-radiation effects, Radiation injuries.

INTRODUCTION

Survival figures are distressingly poor for gallbladder (GB) and extrahepati.c bile duct (EHBD) cancer. Recent studies give an overall 5-year survival rate of 6-7% in GB cancer4(‘,55,61,65,6 and less than 5% in EHBD cancer,22*72,99.109 although the prognosis is not so dismal in periampullary tumors.6*7~‘2~51~‘02*‘@j

We have studied our hospital records of 13 patients who received radiotherapy for GB and EHBD cancer, and have reviewed the literature with special re- ference to the cause of surgical failure and the role of radiotherapy and chemotherapy in the treatment of these tumors.

Although several textbooks”252.73 state that radiation METHODS AND MATERIALS therapy has no role in the management of these A review of the case registry at the Division of tumors, to our knowledge this has never been sub- Radiotherapy of the Columbia-Presbyterian Medical stantiated. Center revealed 15 patients with a diagnosis of GB or

tThis investigation was supported in part by United States Public Health Service Training Grant No. 5 TOl-CA 05181 from the National Cancer Institute.

*Senior Medical Student, College of Physicians and Sur- geons, Columbia University. After 20 June 1977: Associate Resident, Department of Radiation Medicine, Mas- sachusetts General Hospital, Boston, MA 02114, U.S.A.

OAssistant Professor of Clinical Radiology. TAssociate Professor of Clinical Radiology.

883

[/Professor of Radiology and Director, Division of Radiotherapy.

Reprint requests to: Leon Harisiadis, M.D., Division of Radiotherapy, Columbia-Presbyterian Medical Center, 622 West 168th Street, New York, NY 10032, U.S.A. Acknowledgements-The authors would like to thank Miss Susanne Thomasian and Mrs. Mindy Printz-Kopelson for their help in the preparation of this manuscript.

884 Radiation Oncology 0 Biology 0 Physics September-October 1977, Volume 2, No. 9 and No. 10

EHBD carcinoma who were treated with radiotherapy between January 1958 (the beginning of the installation of the Betatron) and December 1976, inclusive. Two patients were excluded from further analysis since they did not complete their planned courses of radiotherapy: one refused further therapy after receiving only 600 rad of a planned 4000 rad; in the other patient, therapy was terminated halfway through the course because the patient developed progressive respiratory failure because of pulmonary metastases, of which she died. The remaining 13 patients constitute this series.

The clinical status of these patients prior to radiotherapy is summarized in Table 1. The mean age of the group was 60 years. Local tumor extension to the porta hepatis (vessels, nodes, and/or adjacent bile ducts) occurred in 11 of the 13 patients. Additional sites of regional extension included the gastro-hepatic

ligament and adjacent peritoneum. Liver involvement was by local extension (single tumor mass in the liver adjacent to primary tumor) in 4 patients and via presumed hematogenous dissemination (multiple nodules in various lobes) in 2 patients. Distant peri- aortic lymph nodal metastases occurred in 2 patients. No other distant metastases were evident prior to initiation of radiotherapy.

Surgery consisted of attempted curative procedures in 2 patients (patients 1 and lo), palliative procedures in 5 (patients 2, 3, 7, 9 and 13), and biopsy only in 6 (patients 4, 5, 6, 8, 11 and 12).

In two patients (patients 9 and lo), local tumor recurrence developed after the first surgical procedure; this was confirmed in each patient by biopsy only at a second surgical procedure prior to radiotherapy.

The time between initial surgery and radiotherapy

Table 1. Status of patients prior to radiotherapy

Patient Age, Primary No. Sex site

Tumor extension prior to radiotherapy

Distant Regional metastases Surgery

Time between first surgery and

initiation of radiotherapy (weeks)

1 62, F GB CBD, CD, PN No

2 53, F

3 70, F

4 70, F

GB CBD, PH, L L

GB PH No

GB L

5 42, F GB

L, peri- aortic nodes No

6 70, F CBD 7 42, F CBD 8 44,M CBD

No Bx. No T-tube drainage No Bx.

9

10

11

12

13

68, M

69, M

CBDt

CHD, PH, L, adjacent peritoneum RHD, LHD, PN CD, PH PHL, L, gastro- hepatic ligament HDB No

CBDt CD, PH No

72, M

57, M

CBD, CD CBD, CD, CHD CHD

PH No

PH, L

62, M No

Peri- aortic nodes No

Cholecystectomy; Cholecystojejunostomy; Partial CBD excision Hepaticocholangio jejunostomy Cholecysto- jejunostomy Bx.

12t

2.5

1.0

2.0

Bx. 1.5

1.5 2.0 2.0

T-tube drainage; Bx. of recurrence-? Modified Whipple procedure; Bx. of recurrencet Bx.

401

(4 years, 4 months, 2 weeks)t

2.0

1.5 Bx.

Cholecystectomy; T-tube drainage

3.0

See text. SLiver involvement is considered by local extension or hematogenous dissemination as defined in the text.

GB = Gallbladder; CBD = Common Bile Duct; CD = Cystic Duct; L = Liver; CHD = Common Hepatic Duct; RHD = Right Hepatic Duct; LHD = Left Hepatic Duct; HDB = Hepatic Duct Bifurcation; PH = Porta Hepatic; PN = Microscopic Perineural Invasion; Bx. = Biopsy Only.

Biliary system radiotherapy ??G. KOPELSON et al. 885

usually was approxima.tely 2 weeks. In patient 1, a 4 month delay resulted from poor wound healing and pneumonia which was treated successfully with anti- biotics prior to radiotherapy. In patients 9 and 10, there were longer delays because radiotherapy was given only after the local recurrence had developed.

Indications for radiation therapy included: no im- provement in jaundice or worsening of jaundice after surgery (patients 2, 6 and 7), tumor was close to the surgical margin (patient l), tumor recurrence after surgery (patients 9 and lo), palliation since only a biopsy was done (patients 4, 5, 6, 8, 11 and 12), and hope to improve palliation with surgery and radiotherapy (patients 2 and 13).

Adjuvant chemotherapy was used in 6 patients, consisting of 5-fluoro-uracil (12.5-15.0 mg/kg), which

was given: prior to radiotherapy (patient 9), during the first 3 days of radiotherapy (patients 4, 5 and 8), or begun only after radiotherapy (patients 1 and 10). All patients who received the chemotherapy continued to receive it at monthly cycles after the completion of radiotherapy. Streptozotocin was used in 1 GB patient also.

The radiotherapy modalities and dosages are listed in Table 2. Because of the rarity of these tumors, no specific treatment protocol was used during the 19 years encompassed by this study; rather, each attending radiotherapist individualized treatment. Parallel opposed alternating anterior and posterior fields to the right upper quadrant were used. All fields were not treated daily, although such technique is recommended. Cholecystograms, clips placed at sur-

Table 2. Summary of radiotherapy technique and results

Dose @ad/ Patient fractions/ Total bilirubin ((mg.%) Palliation efficacy*

No. elapsed days) Modalities Before RT After RT Pain Pruritus Mass Adjuvant chemotherapy

1 5000/25/41 6-MeV, 22.5-MeV 1.0 0.5 SFU, Strep 2 4550123132 6-MeV 3.0 0 Yes Yes 3 4550/15/21 6-MeV 14.4 2.1 Yes Yes 4 3800/22/40 6-MeV, @‘Co 0.3 0.5 Yes Yes 5FU 5 4550/25/46 6-MeV 5.8 0.5 Yes Yes Yes 5FU 6 7225129139 22.5-MeV 16.8 2.0 Yes 7 5998/26/52 22.5-MeV 15.0 5.6 Yes Yes Yes 8 5000/29/46 6-MeV 15.0 1.2 Yes Yes Yes 5FU 9 6000/30/46 6-MeV 2.0 0.6 Yes 5FU

10 6000/30/40 @co 17.0 Yes Yes 11 3800/25/35 22.5-MeV 21.5 1 Yes 12 4400/25/32 6-MeV 1.3 0 No No No SFU 13 5000/25/33 22.5-MeV 12.0 2.1 Yes Yes

Survival (months)7 After:

Surgical diagnosis

Initiation of radiotherapy Comment

15.8 12.8 3.5 2.8 3.7 3.5 5.2 5.0 7.5 7..3

2.8 2.3 6.2 6.0

12.5 12.10 26.0 16.10 53.8 2.10

8.2 7.8 7.2 7.10

12.0 11 .I0

Incisional recurrencet Diversionary patency and decrease of bile duct dilatationt Cause of death unknown Died of metastatic hepatic failure Died of metastatic intestinal obstruction; local tumor control at autopsyt; adrenal cellular changes at autopsyt Lost to F/U Cause of death unknown a&w, NED a&w, Ned; fiberoptic evidence of local tumor control?-; ? bile duct fibrosist Lost to F/U: radiation hepatic scan changest Lost to F/U Died of metastatic hepatic failure Died of gastrointestinal hemorrhage and hepatic metastases

tSee text. R.T. = Radiotherapy; :)FU = 5-FluoroUracil; Strep = Streptozotocin; a&w = alive and well; NED = no evidence of disease;

F/U = follow-up. *Alleviation of pain and/or pruritus and/or mass shrinkage; responses are only tabulated in those patients with such symptoms

and signs present prior to radiotherapy. PNot recorded. ITo date or to death or to last follow-up.

886 Radiation Oncology 0 Biology 0 Physics September-October 1977, Volume 2, No. 9 and No. 10

gery, and post-operative T-tube cholangiograms were used often to determine the treatment field. Portal size was approximately 10 X 10 to 16 X 16 cm. for the initial 2000-2500 rad; then field sizes usually were reduced for the remainder. Hepatic shields usually were added after 3000rad, although the tumor bed (determined by the procedures mentioned above) received the total dose.

RESULTS [TABLE 21 During the course of radiotherapy, successful pal-

liation (alleviation of jaundice and /or pain and/or pruritus and/or mass shrinkage) was obtained in 12 of 13 patients (92%). Symptoms and signs which were abnormal prior to radiotherapy were palliated successfully in 7 of 8 patients for pain (SS%), 9 of 10 patients for pruritus (90%), and 6 of 7 patients for mass shrinkage (86%). In 9 patients in whom laboratory values were recorded both before and at the completion of radiotherapy, the average total bilirubin value decreased from 9.1 mg.% before to 1.7 mg.% after. In patient 2, although no laboratory data was obtained after radiotherapy, there was cholangiographic evidence after radiotherapy that the surgical diversion was patent and that the previous bile duct dilatation had decreased. This documented relief of obstructive jaundice occurred both in those irradiated patients who did and who did not receive adjuvant chemotherapy. It also was achieved in those irradiated patients who were biopsied only and in those whose surgical palliative biliary diversion was failing. In fact, the only patient who did not respond to radiotherapy (patient 10) had both hepatic and distant metastases prior to radiotherapy, and he died of these.

The survival after diagnosis of all patients ranged from 2.8 to 53.8 months, had a mean of 12.7 months (7.1 in GB patients and 16.1 in EHBD patients), and had a median of 7.5 months (5.2 in GB patients and 10.1 in EHBD patients).

The survival after initiation of radiotherapy in all patients ranged from 2.0 to 16.0 months, had a mean of 7.3 months (6.3 in GB patients and 8.0 in EHBD patients), and had a median of 7.0 months (5.0 in GB patients and 7.4 in EHBD patients).

Analysis of the 10 patients with complete follow-up to date or to death (excluding patients 6, 10 and 11) revealed the mean survival after diagnosis was 10.0 months (7.1 in GB patients and 12.8 in EHBD patients), and the median was 7.4 months (5.2 in GB patients and 12.0 in EHBD patients). The mean survival after initiation of radiotherapy was 8.3 months (6.3 in GB patients and 10.4 in EHBD patients), and the median was 7.2 months (5.0 in GB patients and 11.0 in EHBD patients).

In patients in whom the cause of death was known,

3 died of liver metastases (patients 4, 10 and 13); in 2 of these 3, both liver involvement and distant metastases were evident prior to radiotherapy. One patient (patient 5), died with widespread metastatic disease (ileal metastasis causing intestinal obstruction).

The two patients treated most recently (patients 8 and 9) were alive and well without evidence of disease after 12 and 16 months post-radiotherapy, respectively.

Aspects of local control and complications will be discussed later.

DISCUSSION FAILURE OF PRESENT THERAPY

Distant disease Patients do not usually present with distant disease

already evident on admission. In those series listing the general type of therapy used at presentation (i.e. curative, palliative, or inoperable), 500 of 1998 (25.0%) GB patients, 8.21,33.36,41.50.J6.61,65-67,72.76,87.94,98,l09

and 65 of 475 (13.7%) EHBD patients 2,6.27.30,38,51,54,70.72.102.104.108.109 reviewed from the literature were judged “inoperable” at presentation. In many series, however, it often was unclear if “inoperable” meant that such extensive regional disease was present as to preclude curative resection or whether distant metastases were present. In addition, many surgical series have excluded such “inoperable” patients from study, and other studies provide insuffi- cient data. However, it can be concluded that most patients do not present with widely disseminated tumor.

Failure of curative surgery GB Cancer. After routine cholecystectomy many

patients are found to have occult carcinoma present in the resected gallbladder without further therapy being done; at surgery others are found to have apparent localized cancer which then is treated with curative intent by simple cholecystectomy. Several authors believe that simple cholecystectomy is curative for localized disease because in their own series, the only “cures” (i.e. S-year survivors) were in this category.9*‘s”‘g’

However, a review of the literature of the known incidence of local recurrences in series giving specific follow-up of patients (Table 3) reveals that patients eventually failed because of such local recurrences.

In terms of early deaths, of 110 patients reviewed from seven series who died within 5 years after “curative” simple cholecystectomy, 95 (86%) died because of or with a local tumor recurrence (Table 3). This undoubtedly is why a recent review of eleven series could find only 30 reported 5-year survivors after “curative” simple cholecystectomy;’ 2 other cases have been reported recently.”

Biliary system radiotherapy 0 G. KOPELSON et al. 887

Table 3. Local recurrences after “curative” surgery for extra-hepatic biliary system cancer (in reported series with specific follow-up of patients)

Ref.

In GB tumors after simple cholecystectomy -Early recurrences (< 5 years)

No. patients not surviving 5 years: No. Dying with and/or because of

local recurrence: -L.ate recurrences (2 5 years)

No. patients alive at 5 years after surgery:

No. developing local recurrences at last follow-up:

In GB tumors after radical surgery No. patients not surviving 5 years:

No. Dying with and/or because of local recurrence:

In EHBD tumors after “curative” surgery No. patients who survived post-

operative period:

No. known to have developed local recurrence:

110 8, 24, 35, 67, 86, 94, 98

95 (86%)

23 4, 8, 9, 24, 35, 56, 59, 93

11(48%)

16 24

12 (75%)

70 2, 3, 20, 22, 27, 54, 63, 71, 102, 107

18 (26%)

Besides this early failure from local recurrence, analysis of some of those patients and others who were alive 5 years after such curative surgery (Table 3), reveals that 11 of 23 patients (48%) developed late local recurrence, and one patient had a local recurrence 30 years after surgery.59

papillary adenocarcinomas.4~8~“~28~36~65~72 However, it has been shown that this tumor type is not localized” and spreads to local lymph nodes very early.“’ Longer follow-up of these patients reveals that they also die soon of local recurrences.98

Anatomically, there is a basis for these surgical failures from simple cholecystectomy: undetected microscopic residual disease in nodes or adjacent organs left behind after surgery. The anatomic location of the GB allows direct extension to adjacent organs and lymphatic involvement. The incidence of positive local nodes ranges from 25.8% in individual series” to 51.8% in a recent cumulative review.% And indeed this may occur even though only apparent localized, occult tumor is seen in the GB itself.23 Localized hepatic involvement, mainly via direct extension, has been shown to exist in 51.5% of clinical series and 65.6% of autopsy series.% Recently, survival has been correlated with depth of invasion and graded histology via a proposed staging system.” In another small series, microinvasive carcinoma found after routine cholecystectomy had a worse prognosis than did carcinoma in *situ.’ Thus in any patient with direct gross or microscopic extension through the GB wall or with definite or clinically undetected lymph node metastases, there will be increased risk for microscopic residual disease and therefore local recurrence after surgery.

Because of this early nodal and hepatic involvement, more extensive surgical procedures have been proposed, ranging from wedge resection of the hepatic GB combined with en bloc nodal dissection** to hepatic lobectomy.@’ However, in only 28.7% of patients is such a radical procedure theoretically possible; and because of the patients’ general condition, concomitant diseases, or lack of technical skill, it can only be performed in 7.9% of patients.% In addition, such surgery has a high operative mortality, ranging from 14% with wedge liver resection to 35% with right hepatic lobectomy.98 This rises to 40-50% in patients with moderate liver invasion.33

Unfortunately, the results of radical surgery are not very encouraging. A recent review found only 10 reported S-year survivors of extensive “curative” surgery? 2 additional 5-year survivors have been reported from Boston.“*“’

And this radical procedure itself usually does not extirpate all of the tumor; of 16 patients treated for cure with cholecystectomy and wedge liver resection who did not survive for 5 years, 12 of these had local residual carcinoma in the common ducts, local nodes and liver (Table 3).

Several reports claim that the histology of the The incidence of incisional metastases after simple tumor is an extremely important factor affecting or radical surgery will be discussed later. prognosis because many of the 5-year survivors had EHBD cancer. The mode of spread of these tumors

888 Radiation Oncology 0 Biology 0 Physics September-October 1977, Volume 2, No. 9 and No. IO

is through the bile duct wall early,** even with small tumors3’ causing extensive regional disease in 75% of patients even before the jaundice begins.” They also spread along the bile duct, and this may not be appreciated on gross examination.‘7*42 A literature review of eleven surgical and autopsy series ~~**~~~~~~~~~~~~~~‘~80.~~.1~~~~~ shows that 155 patients of

376 (41%) had lymph node involvement and 133 patients of 371 (36%) had liver involvement, common in all types of tumor locations. Nodal metastases without apparent local extension also have been described.82 Perineural invasion occurs in more than 60% of patients,47,57.93 and this will be mentioned again later.

Curative procedures for EHBD tumors have varied with the tumor location. Hepatic ductal region tumors have been treated with tumor resection and hepatic- enteric anastamosis,70.92 hepatic lobectomy with intrahepatic-cholangio-jejunostomy,27.64”os and total hepatectomy with liver transplantation.27 Mid-ductal region tumors (cystic duct and proximal common bile duct) have been treated with resection and end-to-end or biliary-enteric anastamosis5’,” and distal common bile duct tumors have been treated with pancreatico- duodenectomy.6.22.79~‘~~‘W

However, although occasional long-term survivors have been described,3,‘2*38*5’,a2~102 “curative” surgery generally is not highly curative. A literature review of 16 series 2,6.20,22,27,38,45,51,54,70.93.99,104,105,108.109 reveals a cumulative average survival in 94 patients treated with “curative” surgery was 16.9 months.

One reason for failure is the high surgical mortality (death within 1 month after surgery) after “curative” procedures. Of 368 patients in 13 series reviewed from the literature 2~6~7~12~20~22~27~49~63~70~93.102

post-operative mortality rate. there was an 18%

A second reason is that local recurrences occur after this “curative” surgery. A literature review of 10 series in which follow-up of patients with reason for failure was given (Table 3) shows that 26% of patients are known to have developed a local recurrence.

This high rate of local recurrence is seen even when surgical margins are clear and nodes are nega- tive,** and has been related to the high incidence of perineural invasion,47,68 the difficulty in appreciating intraductal tumor infiltration,” the leaving behind of tumor cells at curative surgery,68V’04 and the recent finding that these tumors might be multicentric within the biliary system-thus making local curative resection inadequate.”

This local recurrence rate must in fact be even higher, since there are so few long-term survivors and the average survival time is only 16.9 months (see above). In addition, patients die not from extensive distant nor hepatic metastatic disease but from local recurrence with extensive unrelieved biliary obstruc-

tion leading to hepatocellular failure.22~43~68~Y7~‘o’~‘02 Therefore, one must infer that localized disease is still present even after “curative” surgery to cause local recurrences in much greater numbers than the above 26% incidence would indicate.

Failure of palliative surgery Most patients with GB cancer have such extensive

regional disease that curative surgery is precluded and palliative biliary diversionary procedures alone must suffice.44.62*98 However, palliative surgery in GB cancer carries a fairly high surgical mortality of 13.7%.% It is successful only in 51% of patients, with an average survival after palliation of 4.6 months.%

Most patients with EHBD cancer can only receive surgical palliation for similar reasons as GB patients, 2.6,12.20,22.27.30,38,45,51.54.57,68.73,93,99,102.104,106.109 thus, these patients have known tumor left behind after surgery. This group also has a high surgical mortality and poor prognosis. A literature review reveals that of 149 patients from 9 series, there was 31% post- operative mortality;2~6~27*43~4s~49~93~102~’~ and of 157 patients from 17 series, the average survival was only 9.3 months after surgery. 2,6,17,20,22,34,43,49,51,54,63,70,&1.106

Course of conservatively managed patients A recent review showed that patients who are only

biopsied at surgery or those untreated by surgery had a mean survival of. 1.1 months for GB tumors;98 and of 125 patients. reviewed from 11 series, the mean survival . was* 2.7 months for EHBD tumors 20,34.41.4~54,P3,76.80.93,,~~~109 This latter group also had

* an extremely .high su;gical morfality; of 64 patients reviewed from sixseries;th&post-operative mortality was 91%. 34X45V~93*‘?2;‘W Of &t&e; in this very advanced disease group’ the reason for death may very well have been the extent of tumor rather than operative factors.’ ’ ’ I ,’

Failure of chemotherapy Most authors concur that chemotherapy has had

little success in the palliative or curative management of GB or EHBD tumors,9~32~38~““‘~73~98.108~109 although some patients do show objective responses usually lasting a few months,‘9.52*53*85 but occasionally to years, 19*5499~‘02 to various agents, mainly Sfluorouracil. These variable results, from no response to apparent long-term successes, are seen because in some in- stances chemotherapy was added as part of curative treatment for local disease, and in other cases was only used after extensive regional and/or metastatic disease was present. In addition, in many patients radiotherapy was used in addition to

Biliary system radiotherapy 0 G. KOPILSON el al. 889

chemotherapy;38,56,%*99 the direct effects of the latter are thus difficult to distinguish. The possible value of such combination radiotherapy-chemotherapy will be discussed later.

RADICtTHERAPY

Radiation therapy has not been used often in the management of these tumors. Early workers suggested palliative radiothlerapy for squamous cell tumors but cited no cases;“‘*’ others achieved some palliation by infusions of “‘I-Rose Bengal.’ The reported use of radiotherapy for GB and EHBD cancer follows:

GB cancer. Lam@ treated three patients with radium implants but gave no follow-up. Ackerman and de1 Regato reported 1 patient who presented with invasion through and beyond the GB wall and vessels; the patient was griven intensive post-operative @‘Co and remained well for 5 years. Friedlands palliated 1 patient with locally recurrent leionmyosar- coma with a dose of 6000 rad (@‘Co) achieving both relief of pain and decrease in tumor mass; the patient died 5 months later. Moossa et a1.56 described 9 patients with apparently advanced disease who were treated with unspecified radiation doses: 3 with radiotherapy alone, 2 with combined surgery and radiotherapy, and 4 with combined chemotherapy and radiotherapy. The only follow-up was of the 2 treated by surgery and radiotherapy: 1 died of residual disease 2.5 years later; in the other patient (whose tumor was anaplastic and had extended to the subserosal fat with lymphatic and perineural invasion), the patient was alive and well ,without recurrence after 2 years at the time of the report. The author suggested that radiotherapy might improve the poor results of surgery. Krain& claimed that 2% of GB cancer patients in California were given radiotherapy only as the primary curative modality, and 22% were given combined surgery and radiotherapy; however, specific survival statistics based upon modality were not given. Vaittener? found that 24 patients with localized disease who were treated by “curative” surgery (most by simple cholecystectomy) had a median survival of 29 months; but those 7 patients who were given postoperative radiotherapy (unspecified dose) had a much longer me:dian survival of 63 months. However, the numbers were too few to be of statis- tical significance. Finally, Treadwell and Hardin% treated patients post-operatively by radiotherapy only (3 patients) and by radiotherapy and chemotherapy (6 patients). Doses ranged from 1000 to 4500r (dose not otherwise specified). Increased survival and better palliation was noted in patients receiving such adjunctive therapy after surgery, although there was no distinction made in evaluating results as to which adjunctive therapies were used. The authors sug-

gested the use of such additional therapy in these patients.

EHBD cancer. Walters and Olson’00 described a patient with papillary adenocarcinoma of the duct bifurcation which was incompletely excised; the patient was given interstitial radium implants for 140 mg-hr, had a decrease in jaundice, and survived 2.5 months. Ariel and Pack’ described 2 patients who received 6000r (dose not otherwi‘se specified) external radiotherapy who survived 11.5 and 32 months after diagnosis. Van Heerden et a/.% described 2 patients who were given palliative radiotherapy with biliary diversion and chemotherapy for common bile duct and common hepatic duct lesions; the survived 5 and 24 months. Whelton et a!.‘@’ mentioned 5 patients who were given 5000 rad external radiotherapy (“Co) with palliative bypass surgery; they survived an average of 27 months after surgery and 18 months after initiation of radiotherapy. Green et al.” described 4 patients who were given palliative radiotherapy (2000- 5300 rad, @‘Co) for common hepatic duct tumors; they survived an average of 11.5 months after surgery. Terblanche et a1.88-w described 5 patients who were given radiotherapy (6000R: unspecified) in conjunction with palliative surgery for hepatic duct lesions. One patient died of the disease after 5 years; 1 patient was alive with recurrence after 2.5 years; but 3 patients were alive and well without recurrence after 2.5, 3.75 and 3.75 years. The author suggested that radiotherapy in conjunction with diversion might be curative.88 KrainM claimed that 19% of patients in California were given radiotherapy as part of initial management of this disease (2% radiotherapy only, 17% radiotherapy plus surgery); but no survival statistics according to modality were given. Finally, Hudgins and Meoz37 treated 3 patients with 5000 rad and obtained relief of obstructive jaundice for 6, 6 and 1 months after radiotherapy. They suggested that radiotherapy should be used in the palliative management of these tumors.

Some indications for radiation therapy in the management of these tumors include:

To increase survival. As seen earlier, the mean and median survivals after diagnosis in the GB group were 7.1 and 5.2 months, respectively; and after initiation of radiotherapy were 6.3 and 5.0 months, respectively. These figures appear to be higher than the previously-cited figures of 1.1 months for the no-treatment group and 4.6 months for the surgical palliation group.

In the EHBD group, the mean and median survivals after diagnosis were 16.1 and 10.1 months, respectively, and after initiation of radiotherapy were 8.0 and 7.4 months, respectively. This appears to be higher than the previously-cited figures of : 2.7 months for the no-treatment group and 9.3 months for the

890 Radiation Oncology 0 Biology ??Physics September-October 1977, Volume 2. No. Y and No. IO

palliative surgery group. However these data appear not to be as good as the 16.9 months for the curative surgery group.

However, the 3 patients in our series who received radiotherapy with curative intent (patients 1, 9 and (lo), has an average survival of at least 31.9 months after diagnosis and 10.6 months after initiation of radiotherapy. Of course our series is retrospective and not randomized, and the number of patients discussed above is far too small to make a truly valid comparison; however, these data would suggest that post-operative radiotherapy can increase the length and quality of survival in both EHBD and GB cancer patients in comparison with surgery alone (curative or palliative), chemotherapy, or the conservatively managed group. Also, most patients in our series and those in the literature had fairly extensive regional disease and/or distant metastases when they were given radiotherapy; thus, increases in survival should be expected if patients with earlier disease receive radiotherapy. Finally, larger series of patients are needed in properly controlled and randomized series in order to completely evaluate the added survival provided by post-operative radiotherapy.

To achieve local tumor control. As seen from earlier discussion, most patients with these tumors who are treated with curative or palliative surgery develop and/or die because of locally recurrent tumor and not because of distant metastases. Thus control of tumor at the primary site is the major therapeutic objective in the management of this disease at present.

These tumors are not as radioresistant as was thought formerly. Green et al.” reported one patient in whom apparent local tumor control was achieved after 2000rad because at autopsy “there was no evidence of persistent cancer”, although serial sec- tions were not obtained. In our patient 9, a post- radiation (6000 rad) flexible fiberoptic-scope bile duct cannulation revealed that “no obvious tumor was seen. The bifurcation was sharp, and bile flowed from the right and left hepatic ducts”. In patient 5, the autopsy report read that after 4550 rad “the gallbladder received the highest dose of radiation, as a result of which, there are almost no malignant cells. The hepatic and common bile ducts were patent without evidence of tumor”, even though the tumor had been there at the biopsy only surgery which was performed prior to radiotherapy.

Thus there was no evidence of local tumor recurrence in the primary site after radiotherapy, and local tumor control was achieved. A few histologically- intact cells that persist after radiotherapy do not necessarily indicate later local tumor growth.83

For palliation. As seen earlier, surgical palliation fails as often as it succeeds? indeed 3 patients in our

series (patients 3, 6 and 7), 1 in the series of Green et al.,3’ and 2 in the series of Hudgins and Meoz” were specifically given radiotherapy because surgery failed; 6 of our patients had no surgical palliation done at all. Yet in our series, radiotherapy achieved a 92% success rate with palliation, and this occurred even in patients who were not given palliative surgery. Thus radiotherapy can successfully palliate patients in combination with surgery, even when surgical palliation either was not attempted or had failed. And although the number of patients discussed is small, this 92% success rate in radiotherapeutic palliation appears to be much higher than the 51% with surgery.98

For suture line recurrences. Incisional recurrences after surgery have been described previously for GB 40,60,87.98 and EH~D2.43.63.89,‘~ tumors_

Radiotherapy has been of value in these patients, although Tanga and Ewing” described a suture-line recurrence that was unresponsive to an unspecified dose of radiation. But Pack et a1.60 described a patient who was treated with local radiotherapy (unspecified dose) and who survived 5 months, only to die of liver failure. Vaittinen% described a patient who was treated successfully with radiotherapy (unspecified dose) for such a lesion and who died 10 years later of generalized carcinomatosis; presumably this local radiotherapy succeeded in sterilizing the incisional recurrence. Kaplan4 described a patient with an incisional recurrence who was treated successfully with 800r (dose not otherwise specified) external radiotherapy and 3000 mg-hr of radium implantation.

Unfortunately, our patient 1 developed such a recurrence after radiotherapy. One of us (L.H.) has computed that the skin was in fact underdosed (approximately 2000 rad) in this patient because 22 MeV X-rays were used. We suggest that a bolus on the skin be used in the incision area to prevent such incisional metastases whenever megavoltage radiotherapy is used.

In combination with chemotherapy. The combined use of radiotherapy-chemotherapy has been reported sporadically in the past.38,56*%*99 In our series, the mean and median survivals after diagnosis of the group (patients 1, 4, 5, 8, 9 and 12) receiving combined radiotherapy-chemotherapy (12.4 and 10.0 months, respectively) appears to be slightly higher than the remaining group receiving radiotherapy alone (11.5 and 6.2 months, respectively). Also, the two patients presently alive and well without evidence of disease (patients 8 and 9) did receive such combined therapy. It should be noted, however, that documented relief of obstructive jaundice in our series occurred after radiotherapy whether or not chemotherapy was used.

Larger series obviously are needed in order to


completely evaluate -the potentials of combined modality adjunctive therapy in these tumors.

COMPLICATIONS

Radiotherapy in this group of patients was tolerated quite well. In patient 1, a liver scan after 3000rad showed an area of decreased uptake about the porta hepatis that later resolved; such subclinical liver changes were expected. 39*78 Complaints which were unrelated to the primary disease but could be related to the irradiation of intestinal epithelium within the portals (proximal small bowel), such as diarrhea, often were not mentioned in the charts and thus are difficult to evaluate; most patients ex- perienced nausea and slight vomiting however. Also, patient 5 showed pyknotic adrenal cellular changes; adrenal and kidney changes can be expected if the entire kidney is included in the irradiated field. 74*7J*77

After receiving 600Orad, patient 9 was evaluated four months later via fiberoptic-scope for residual bile duct pathology. Although no tumor was found, there was “slight narrowing of the right hepatic duct for 1 cm with no proximal dilation. . . the bifurcation (of the hepatic ducts) was sharp, and bile flowed from the right and left hepatic ducts”; on cholangiogram, the “right hepatic duct seemed narrow”. Liver function tests all were normal, and the patient was asymp- tomatic.

The effects of radiotherapy on the human extra- hepatic biliary system are not well known. Case and Warthin14 found swollen bile duct walls and bile duct atrophy at autopsy of three patients who were given intensive abdominal radiotherapy. Warrenlo reviewed earlier work and found that heavy doses produced inflammation and necrosis of the GB. Ariel and Pack’ described one patient who had moderate cholangitis at autopsy 2 months after receiving 15 mCi of 13’1- Rose Bengal for GB cancer; this was thought to be the result of excretion of the radioactive dye in the bile. Recently, Green et ~1.~’ reported that 1 of 4 patients at autopsy had extensive fibrosis of the common hepatic and common bile ducts after radiotherapy; however repeated T-tube manipulation was felt to be the cause.

Patient 9 was subjected to two surgical procedures plus chemotherapy and1 radiotherapy. He was asymp- tomatic when this fibrosis was seen, and there was no evidence of hindrance of bile flow nor proximal dilation. Thus even if radiation were the cause of this fibrosis, it caused no physiological problems.

Although part of the pancreas was within the radiation fields, there was no evidence in our patients that pancreatic fibrosis’b16*69*‘03 resulted.

CONCLUSIONS After a review of our series of 13 patients and an

extensive critical literature review of surgery, chemotherapy, and radiotherapy in the management of GB and EHBD tumors, we have drawn the following conclusions:

1. Most patients neither present with nor die of distant metastatic disease; thus, local and regional tumor control is at present the primary therapeutic objective. With increasing local control resulting from adjuvant radiotherapy, distant metastases may be- come more of a problem.

2. Curative surgery has a high post-operative mortality; most of these patients die eventually because of or with local recurrent tumor. Very few long-term survivors have been reported.

3. Palliative surgery has a high post-operative mortality, a low survival rate, and it fails as often as it succeeds.

4. Data presented here suggests that radiation therapy can increase the length and quality of survival and be of definite palliative benefit in patients on whom curative surgery and palliative surgery has been performed. It also is a considerable benefit for patients in whom surgical recurrence has occurred, and for those patients in whom surgical palliation has failed or in whom biopsy only was done.

5. These tumors are not particularly radioresistant, and local tumor control can be achieved with radiotherapy.

6. Incisional recurrences can be eradicated successfully with radiotherapy.

7. Chemotherapy alone may be of some transient palliative benefit in some patients, although combination with radiotherapy may further improve results.

Post-operative radiotherapy has been shown to decrease local tumor recurrence in many types of tumors;‘* approximately 4500-5000rad in 4-5 weeks has been shown to sterilize small foci of adenocar- cinema in other sites;26 it seems reasonable that this will be true in extrahepatic biliary system tumors as well.

1. Post-operative radiotherapy be given after curative surgery especially in those patients with inadequate surgical margins and/or locally aggressive tumors to increase the length and quality of survival by decreasing the incidence of local recurrences (and by decreasing incisional metastases).

We propose that the role of radiotherapy in the management of these tumors should be evaluated systemically as follows:

2. Post-operative radiotherapy be given as primary curative modality to sterilize tumors in those patients with occult GB tumors who refuse a second, more

892 Radiation Oncology ??Biology 0 Physics

radical procedure, and in those patients with known tumor left behind at curative surgery.

3. Post-operative radiotherapy be given after palliative or exploratory surgery; or when palliative surgery has failed, to increase the effectiveness of palliation and to increase local control.

4. Radiotherapy be used in patients needing relief

September-October 1977, Volume 2. No. 9 and No. 10

of obstructive jaundice and in whom surgery is refused and/or contraindicated.

5. Radiotherapy be used to treat incisional metastases.

6. Combination radiotherapy-chemotherapy be used to possibly further augment the gains achieved above.

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Documents

The role of radiation therapy in cancer of the extra-hepatic biliary system: An analysis of thirteen patients and a review of the literature of the effectiveness of surgery, chemotherapy