- Email: [email protected]
Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma
-
Neoadjuvant
Chemoradiation Cholangiocarcinoma
for Extrahepatic
Kelly M. McMasters, MD, PhD, Louisville, Kentucky, Todd M. Tuttle, MD, Minneapolis, Minnesota, Steven D. Leach, MD, Nashville, Tennessee, Tyvin Rich, MD, Charlottesville, Virginia, Karen R. Cleat-y, Douglas B. Evans, MD, Steven A. Curley, MD, Houston, Texas
BACKGROUND: The prognosis for patients with extrahepatic bile duct cancer remains poor. The purpose of this study was to evaluate our initial results with preoperative chemoradiation for extrahepatic cholangiocarcinoma, in the context of our experience with conventional treatment of this disease over the past 13 years. METHODS: From 1963 through 1996, analysis of all patients treated for extrahepatic cholangiocarcinoma was performed. RESULTS: Of 91 total patients, 51 had unresectable disease and 40 underwent resection. Median survival was significantly different for patients who underwent resection (22.2 months) versus those treated palliatively (10.7 months; P
From the Division of Surgical Oncology (KMM), University of Louisville-James Graham Brown Cancer Center, Louisville, Kentucky, the Department of Surgery (TMT), Park Nicollet Clinic, Minneapolis, Minnesota, the Department of Surgery (SDL), Vanderbilt University, Nashville, Tennessee, the Department of Radiation Oncology (TR), University of Virginia, Charlottesville, Virginia, and the Departments of Pathology (KRC) and Surgical Oncology (DBE, SAC), University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Requests for reprints should be addressed to Kelly M. McMasters, MD, PhD, University of Louisville-James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, Kentucky40202. Presented at the 49th Annual Meeting of the Southwestern Surgical Congress, Ranch0 Mirage, California, April 13-16, 1997.
0 1997 by Excerpta All rights reserved.
Medica,
Inc.
L
ittle progress has been made in the treatment of cholangiocarcinoma. This disease can occur at any site in the biliary tree, and prognosis varies depending on location of the tumor. As a result, many different classification schemes have been proposed over the years. The simplest and most clinically relevant system has been suggested recently by the group at the Johns Hopkins University.’ Using these guidelines, cholangiocarcinoma was classified into three categories: intrahepatic (6% of cases), perihilar (67% of cases), and distal (27% of cases). Intrahepatic tumors are defined as those confined to the liver that do not involve the extrahepatic biliary tree, do not present with obstructive jaundice, and have no evidence of a primary tumor elsewhere. When possible, these tumors are treated by liver resection. Perihilar tumors are the most common and involve or require resection of the hepatic duct bifurcation, often with concomitant liver resection. Distal cholangiocarcinomas originate in the distal extrahepatic or intrapancreatic portion of the bile duct and are potentially amenable to pancreaticoduodenectomy.’ Cholangiocarcinoma has a propensity to spread proximally and distally within the bile duct system.2 The presence of microscopically positive resection margins clearly is associated with decreased survival. However, it is often difficult to achieve microscopically tumor free resection margins, especially for perihilar tumors. Positive bile duct margins following resection of perihilar tumors have been reported in 28% to 89% of cases.1’3-8 About 10% of patients with distal tumors have positive resection margins.’ Because surgery alone cures few patients with cholangiocarcinoma, effective multimodality treatment is needed. The best available evidence suggests that adjuvant radiotherapy does not improve survival after resection of perihilar cholangiocarcinoma. In the only reported prospective analysis, postoperative radiation therapy did not improve the length or quality of survival of patients with resected perihilar cholangiocarcinoma.’ No effective adjuvant chemotherapy regimens have been established.‘Ot’l To our knowledge, there have been no reports of preoperative (neoadjuvant) chemoradiation for extrahepatic bile duct cancer. Herein we report our initial experience with preoperative chemoradiation for the treatment of extrahepatic bile duct (perihilar and distal) cholangiocarcinoma, in the context of our results with conventional treatment for this disease over the past 13 years.
METHODS From September 1, 1983 to September 1, 1996, 91 patients with the diagnosis of extrahepatic bile duct adenocarcinoma (cholangiocarcinoma) were treated at the 0002-961 o/97/$1 PII SOOO2-9610(97)00203-l
7.00
J 605
University of Texas, M.D. Anderson Cancer Center. Extrahepatic cholangiocarcinoma was classified as perihilar or distal, based upon anatomic location.’ Data were accumulated by reviewing hospital and office records, correspondence with referring physicians, and direct telephone contact with the patients or their families. Patients were evaluated with abdominal ultrasound and computed tomography (CT) scan, as well as percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiopancreatography (ERCP). Patients who were medically fit to tolerate resection and had no evidence of metastasis underwent resection with curative intent. Resection was considered to be potentially curative if all gross disease was resected. Patients with clearly unresectable disease on radiographic studies were treated with palliative biliary decompression performed surgically or with percutaneous transhepatic or ERCP-guided placement of biliary stents. Patients with unresectable disease were often treated with palliative chemoradiation. Nine patients received preoperative (neoadjuvant) chemoradiation. Chemoradiation was delivered by concomitant administration of continuous infusion 5-fluorouracil (5-FU; 300 mg/m’ per day, Monday through Friday) and external beam radiotherapy. External beam radiation therapy was delivered Monday through Friday at a dose of 1.8 Gy per day to a total dose of 50.4 Gy (n = 5) or 45 Gy (n = 2). Two patients with tumors of the intrapancreatic portion of the common bile duct received a rapid fractionation regimen of 3.0 Gy per day to a total dose of 30 Gy, the biological equivalent of the 50.4 Gy dose.” Confirmation of the histologic and cytologic diagnoses was confirmed by a single pathologist (KRC). Histologic grading of response was performed using a 0 to IV scale: 0 = no response; I = minimal response, little (< 10%) or no tumor cell destruction evident; II = moderate response, 10% to 90% of tumor cells destroyed; III = marked response, few (< 10%) viable tumor cells seen; IV = complete response, no viable tumor cells seen. This grading system has been described previously.‘2”3 Statistical analysis was performed using commercially available software (Statistica). Survival was calculated by the Kaplan-Meier method with comparison of groups using the log rank test.
RESULTS Of the total 91 patients, 48 (53%) were men, and 43 (47%) were women, with a mean age of 60 years (range 29 to 79). Overall median follow-up was 12 months. Fifty-one patients (56%) were declared unresectable on the basis of imaging studies or abdominal exploration. The majority (80%) of the unresectable patients had perihilar tumors. Forty of 91 patients (44%) underwent resection with curative intent. Among resected patients, 22 (55%) had perihilar tumors and 18 (44%) had distal tumors. Patients with perihilar tumors underwent resection of the ex, trahepatic bile duct with portal lymphadenectomy and hepaticojejunostomy. Eight patients with perihilar tumors underwent formal hepatic lobectomy, and 1 underwent segmental hepatic resection in addition to resection of the extrahepatic bile duct. Patients with distal tumors underwent pancreaticoduodenectomy. There were no perioperative 606
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AMERICAN
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1
Figure 1. Actuarial cholangiocarcinoma
survival of patients with resected versus those not resected.
Figure 2. Actuarial survival of patients who resection by location (perihilar versus distal).
underwent
extrahepatic
curative
deaths in the group who underwent potentially curative resection. Median survival rates were 10.7 months and 22.2 months for unresected and resected cholangiocarcinomas, respectively (P
1997
1 NEOADJUVANT
CHEMORADIATION
FOR
Figure 3. Actuarial survival of patients with resected tumors who underwent no radiation therapy, preoperative chemoradiation, or postoperative radiation therapy. Of the 20 patients in the postoperative radiation therapy group, 18 received concomitant 5fluorouracil infusion.
negative margins (I’
COMMENTS Surgical resection of extrahepatic cholangiocarcinoma is rarely curative. Postoperative chemotherapy and radiation therapy, alone or in combination, appear to have little impact on the natural history of this disease. New approaches are clearly warranted. We evaluated our initial experience with preoperative chemoradiation using continuous infusion 5-FU as a radiation sensitizer. Importantly, this approach appears safe. The treatment was generally well tolerated and was not associated with an increased rate of anastomotic leak or other major intra-abdominal complications. Efficacy remains to be established. Three of 9 patients (33%) who received preoperative chemoradiation experienced a pathologic complete response to induction chemoradiation. Two of these patients had perihilar tumors, one of whom is alive and well 6 months postoperatively. The other patient died of a massive myocardial infarction 11 months postoperatively and had no evidence of recurrence at autopsy (the same patient whose postoperative course was complicated by supraventricular tachycardia and pulmonary edema). The remaining complete responder had a distal lesion and died with extensive liver metastasis 12 months following resection. Another patient with a perihilar tumor had a complete pathologic response of the primary tumor, but had microscopic disease in two lymph nodes; this patient is alive and free of disease at 32 months. Others THE AMERICAN
EXTRAHEPATIC
CHOLANGIOCARCINOMA/MCMASTERS
ET AL 1
have demonstrated some antitumor activity of S-FUbased chemoradiation against biliary tract cancers when used as the primary treatment modality.‘4 Patients with distal common bile duct cancers are generally considered to have a better prognosis than patients with perihilar tumors. 1~10,15-17In this series, the survival of patients with distal tumors was significantly shorter than those with perihilar tumors. Furthermore, 4 patients with distal cholangiocarcinomas treated with preoperative chemoradiation died of their disease within a relatively short time. These patients presented with a large mass in the area of the pancreatic head and were initially thought to have pancreatic adenocarcinoma. The poor survival of these patients may be due to the locally advanced nature of their cholangiocarcinoma at presentation, putting them at very high risk for the development of metastatic disease. None of the 5 patients with perihilar cholangiocarcinoma treated with preoperative chemoradiation have recurred, although 1 has died of comorbid disease. All had negative resection margins. While the number of patients is small, these data suggest that preoperative chemoradiation may increase the likelihood of obtaining tumor-free resection margins in patients with perihilar cholangiocarcinoma. Whether or not this leads to improved survival remains to be determined. In conclusion, these preliminary data suggest that preoperative chemoradiation for extrahepatic cholangiocarcinoma can be performed safely and is associated with a high rate of pathologic complete response. Importantly, preoperative chemoradiation may improve the ability to achieve tumor-free resection margins, especially for perihilar tumors. Additional multicenter trials of preoperative chemoradiation are warranted.
REFERENCES 1. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463-475. 2. Weinbren K, Mutum SS. Pathological aspects of cholangiocarcinema. Pathology. 1983;139:217-238. 3. Pichlmayr R, Weimann A, Klempnauer J, et al. Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg. 1996;224:628-638. 4. Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for cholangiocarcinoma. Arch Surg. 1995;130:270-276. 5. Nagorney DM, Donohue JH, Farrell MB, et al. Outcomes after curative resections of cholangiocarcinoma. Arch Surg. 1993;128:871-877. 6. Ogura Y, Mizumoto R, Tabata M, et al. Surgical treatment of carcinoma of the hepatic duct confluence: analysis of 55 resected carcinomas. World ] Surg. 1993;17:85-93. 7. Bengmark S, Ekberg H, Evander A, et al. Major liver resection for hilar cholangiocarcinoma. Ann Surg. 1988;207:120-125. 8. Iida S, Tsuzuki T, Ogata Y, et al. The long term survival of patients with carcinoma of the main hepatic duct junction. Cancer. 1987;60:1612-1619. 9. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinema. Postoperative radiotherapy does not improve survival. Ann Surg. 1995;221:788-798. 10. Vauthey J-N, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Sem Liver Dis. 1994;14: 109-114. JOURNAL
OF
SURGERY@
VOLUME
174
DECEMBER
1997
607
NEOADJUVANT
CHEMORADIATION
FOR
EXTRAHEPATIC
CHO
11. Curley SA, Levin B, Rich TA. Liver and bile ducts. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE, eds. Clinical Oncology. New York: Churchill Livingstone; 1995:1305-1372. 12. Evans DB, Abbruzzese JL, Sleary KR, et al. Rapid-fractionation pre-operative chemoradiation for malignant periampullary neoplasms. .I R Coil Surg Ebb. 1995;40:319-323. 13. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127:1335-1339. 14. Whittington R, Neuberg D, Tester WJ, et al. Protracted intravenous fluorouracil infusion with radiation therapy in the
-
management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial. J Clin Oncol. 1995;13:227-232. 15. Pitt HA, Dooley WC, Yeo CJ, Cameron JL. Malignancies the biliary tract. Gun Probl Surg. 1995;32:3-90.
of
16. Tompkins RK, Saunders K, Roslyn JJ, Longmire WP Jr. Changing patterns in diagnosis and management of bile duct cancer. Ann Surg. 1990;211:614-621. 17. Alden ME, Waterman
FM, Topham AK, et al. Cholangiocarcinema: clinical significance of tumor location along the extrahepatic bile duct. Radioloo. 1995;197:511-516.
DISCUSSION Jameson Forster, MD (Kansas City, Kansas): I congratulate Dr. McMasters and his coauthors on an important contribution to the treatment of a difficult problem, the patient with cholangiocarcinoma who may or may not be resectable. His retrospective review focused on 9 patients out of 91 who were treated with preoperative chemotherapy in the form of continuous infusion of 5FU and radiation therapy with an external beam using three different regimens. Five patients received additional radiation therapy, 3 intraoperatively and 2 in the postoperative period. This study can be considered a phase I type of investigation, which demonstrated the feasibility of the preoperative technique in that the surgical procedure went without a hitch. There was a profound response with one third of the patients having no evidence of tumor in the resected specimen and all treated patients having negative margins. Unfortunately, there was no purported survival advantage in this group of patients other than the clear advantage of being resectable. I am particularly interested in finding enabling methods for resection in patients with this disease. My first question involves selection criteria; of the 9 patients, 6 were felt to be unresectable at the time that they were evaluated. By what criteria did your group decide to treat just the 6 patients with unresectable disease? By what criteria were they different from the other 51 who were not resected, or not exposed to this treatment? For what type of patient is this therapy truly useful? In Table I, all of the patients with perihilar disease are doing well following this therapy. All of the 5 patients with perihilar disease have no evidence of recurrence. One died of an MI and did not have disease. No patient did well who had distal disease. Don’t you feel that we should concentrate on perihilar processes alone with this modality? The final questions are: Did you follow blood levels of CA-19-9 with this population? Particularly, does normalization of the level indicate a response to therapy? Could you use that as a way of deciding on whom you should operate? I certainly agree with you that this is an exciting therapy and that a multicenter trial would be appropriate. Roman0 Delcore, MD (Kansas City, Missouri): Dr. McMasters has certainly demonstrated that neoadjuvant chemoradiation therapy is helpful and can be carried out with almost no morbidity in your group of unresectable patients. In view of these results, have you considered the 606
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potential use of a similar regimen, preoperatively, for all patients with this disease? Clayton Shatney, MD (San Jose, California): I did not catch how you established the diagnosis preoperatively that you had a cancer so you could apply the treatment. Secondly, I did not appreciate how far down from bifurcation you would begin counting a distal lesion. The reason I ask is that I have a patient right now with a stricture that looks like it is prob a bl y malignant that is between the cystic duct entrance and the hilum. Would this be considered a perihilar lesion since it is above the cystic duct entrance into the CBD, or is this a distal lesion? Terence Wade, MD (St. Louis, Missouri): I rise, as usual, to bring a little skepticism. You followed the first rule of publishing. That is, when you have only one positive answer put it in the title, which you did. Second, you called for a multi-institutional trial. If you do that, I would suggest that you should include a nonoperative nonresected group since you had a large number of complete pathologic responses. It may be that surgery offers very little in this disease, which is one thing that needs to be determined, as well as whether chemotherapy and radiation therapy add anything.
CLOSING Kelly M. McMasters, MD, PhD: Dr. Forster asked how we selected patients for this protocol. In fact, 4 of the patients who had distal tumors had masses on CT scan when they presented. They were thought to have pancreatic tumors and had diagnosis of adenocarcinoma on fine needle aspiration. They were found later to have cholangiocarcinoma after being treated on a protocol that was similar to that which we use for pancreatic cancer. The patients with perihilar tumors were those thought to be unresectable at previous operation or on preoperative imaging studies. We are now starting to include patients who do not necessarily have unresectable disease as we feel more comfortable with this. Dr. Forster noted that this was like a phase I study and, in fact, that is how we feel about this. We certainly cannot make any firm conclusions about the efficacy of this treatment at this time. It seems promising that we were able to operate on these people and not have major complications, and we had some pathologic responses that seemed promising. CA-19-9 was not evaluated in this series. That may be something that will be promising to look at in the future. I do agree that we should probably focus our attention only on patients with perihilar tumors with this disease. DECEMBER
1997
[ NEOADJUVANT
CHEMORADIATION
FOR
It was also asked how the diagnosis was established. On most of the patients, the diagnosis was established by fine needle aspiration biopsy, either on CT-guided biopsy or by brushings and washings at ERCP or percutaneous transhepatic methods. Some had intraoperative biopsies. Dr. Shatney asked about the classification of perihilar versus distal tumors. The patient you described has a perihilar tumor, because he or she would require resection of the bifurcation, but probably not a pancreaticoduodenectomy.
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ET Al L
i It may well be that we should include a nonoperative arm in future studies of this modality. It is clear that the prognosis of patients who do not undergo resection is dismal, however, and that if operation is possible with negative margins, this is the only thing that offers a chance at long-term survival. If, in fact, this modality can improve the rate with which we achieve a negative margin resection, we may be able to improve the results of resection for this tumor.
JOURNAL
OF SURGERY@
VOLUME
174
DECEMBER
1997
609
Neoadjuvant
Chemoradiation Cholangiocarcinoma
for Extrahepatic
Kelly M. McMasters, MD, PhD, Louisville, Kentucky, Todd M. Tuttle, MD, Minneapolis, Minnesota, Steven D. Leach, MD, Nashville, Tennessee, Tyvin Rich, MD, Charlottesville, Virginia, Karen R. Cleat-y, Douglas B. Evans, MD, Steven A. Curley, MD, Houston, Texas
BACKGROUND: The prognosis for patients with extrahepatic bile duct cancer remains poor. The purpose of this study was to evaluate our initial results with preoperative chemoradiation for extrahepatic cholangiocarcinoma, in the context of our experience with conventional treatment of this disease over the past 13 years. METHODS: From 1963 through 1996, analysis of all patients treated for extrahepatic cholangiocarcinoma was performed. RESULTS: Of 91 total patients, 51 had unresectable disease and 40 underwent resection. Median survival was significantly different for patients who underwent resection (22.2 months) versus those treated palliatively (10.7 months; P
From the Division of Surgical Oncology (KMM), University of Louisville-James Graham Brown Cancer Center, Louisville, Kentucky, the Department of Surgery (TMT), Park Nicollet Clinic, Minneapolis, Minnesota, the Department of Surgery (SDL), Vanderbilt University, Nashville, Tennessee, the Department of Radiation Oncology (TR), University of Virginia, Charlottesville, Virginia, and the Departments of Pathology (KRC) and Surgical Oncology (DBE, SAC), University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Requests for reprints should be addressed to Kelly M. McMasters, MD, PhD, University of Louisville-James Graham Brown Cancer Center, 529 S. Jackson Street, Louisville, Kentucky40202. Presented at the 49th Annual Meeting of the Southwestern Surgical Congress, Ranch0 Mirage, California, April 13-16, 1997.
0 1997 by Excerpta All rights reserved.
Medica,
Inc.
L
ittle progress has been made in the treatment of cholangiocarcinoma. This disease can occur at any site in the biliary tree, and prognosis varies depending on location of the tumor. As a result, many different classification schemes have been proposed over the years. The simplest and most clinically relevant system has been suggested recently by the group at the Johns Hopkins University.’ Using these guidelines, cholangiocarcinoma was classified into three categories: intrahepatic (6% of cases), perihilar (67% of cases), and distal (27% of cases). Intrahepatic tumors are defined as those confined to the liver that do not involve the extrahepatic biliary tree, do not present with obstructive jaundice, and have no evidence of a primary tumor elsewhere. When possible, these tumors are treated by liver resection. Perihilar tumors are the most common and involve or require resection of the hepatic duct bifurcation, often with concomitant liver resection. Distal cholangiocarcinomas originate in the distal extrahepatic or intrapancreatic portion of the bile duct and are potentially amenable to pancreaticoduodenectomy.’ Cholangiocarcinoma has a propensity to spread proximally and distally within the bile duct system.2 The presence of microscopically positive resection margins clearly is associated with decreased survival. However, it is often difficult to achieve microscopically tumor free resection margins, especially for perihilar tumors. Positive bile duct margins following resection of perihilar tumors have been reported in 28% to 89% of cases.1’3-8 About 10% of patients with distal tumors have positive resection margins.’ Because surgery alone cures few patients with cholangiocarcinoma, effective multimodality treatment is needed. The best available evidence suggests that adjuvant radiotherapy does not improve survival after resection of perihilar cholangiocarcinoma. In the only reported prospective analysis, postoperative radiation therapy did not improve the length or quality of survival of patients with resected perihilar cholangiocarcinoma.’ No effective adjuvant chemotherapy regimens have been established.‘Ot’l To our knowledge, there have been no reports of preoperative (neoadjuvant) chemoradiation for extrahepatic bile duct cancer. Herein we report our initial experience with preoperative chemoradiation for the treatment of extrahepatic bile duct (perihilar and distal) cholangiocarcinoma, in the context of our results with conventional treatment for this disease over the past 13 years.
METHODS From September 1, 1983 to September 1, 1996, 91 patients with the diagnosis of extrahepatic bile duct adenocarcinoma (cholangiocarcinoma) were treated at the 0002-961 o/97/$1 PII SOOO2-9610(97)00203-l
7.00
J 605
University of Texas, M.D. Anderson Cancer Center. Extrahepatic cholangiocarcinoma was classified as perihilar or distal, based upon anatomic location.’ Data were accumulated by reviewing hospital and office records, correspondence with referring physicians, and direct telephone contact with the patients or their families. Patients were evaluated with abdominal ultrasound and computed tomography (CT) scan, as well as percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiopancreatography (ERCP). Patients who were medically fit to tolerate resection and had no evidence of metastasis underwent resection with curative intent. Resection was considered to be potentially curative if all gross disease was resected. Patients with clearly unresectable disease on radiographic studies were treated with palliative biliary decompression performed surgically or with percutaneous transhepatic or ERCP-guided placement of biliary stents. Patients with unresectable disease were often treated with palliative chemoradiation. Nine patients received preoperative (neoadjuvant) chemoradiation. Chemoradiation was delivered by concomitant administration of continuous infusion 5-fluorouracil (5-FU; 300 mg/m’ per day, Monday through Friday) and external beam radiotherapy. External beam radiation therapy was delivered Monday through Friday at a dose of 1.8 Gy per day to a total dose of 50.4 Gy (n = 5) or 45 Gy (n = 2). Two patients with tumors of the intrapancreatic portion of the common bile duct received a rapid fractionation regimen of 3.0 Gy per day to a total dose of 30 Gy, the biological equivalent of the 50.4 Gy dose.” Confirmation of the histologic and cytologic diagnoses was confirmed by a single pathologist (KRC). Histologic grading of response was performed using a 0 to IV scale: 0 = no response; I = minimal response, little (< 10%) or no tumor cell destruction evident; II = moderate response, 10% to 90% of tumor cells destroyed; III = marked response, few (< 10%) viable tumor cells seen; IV = complete response, no viable tumor cells seen. This grading system has been described previously.‘2”3 Statistical analysis was performed using commercially available software (Statistica). Survival was calculated by the Kaplan-Meier method with comparison of groups using the log rank test.
RESULTS Of the total 91 patients, 48 (53%) were men, and 43 (47%) were women, with a mean age of 60 years (range 29 to 79). Overall median follow-up was 12 months. Fifty-one patients (56%) were declared unresectable on the basis of imaging studies or abdominal exploration. The majority (80%) of the unresectable patients had perihilar tumors. Forty of 91 patients (44%) underwent resection with curative intent. Among resected patients, 22 (55%) had perihilar tumors and 18 (44%) had distal tumors. Patients with perihilar tumors underwent resection of the ex, trahepatic bile duct with portal lymphadenectomy and hepaticojejunostomy. Eight patients with perihilar tumors underwent formal hepatic lobectomy, and 1 underwent segmental hepatic resection in addition to resection of the extrahepatic bile duct. Patients with distal tumors underwent pancreaticoduodenectomy. There were no perioperative 606
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AMERICAN
JOURNAL
OF SURGERY@
VOLUME
174
1
Figure 1. Actuarial cholangiocarcinoma
survival of patients with resected versus those not resected.
Figure 2. Actuarial survival of patients who resection by location (perihilar versus distal).
underwent
extrahepatic
curative
deaths in the group who underwent potentially curative resection. Median survival rates were 10.7 months and 22.2 months for unresected and resected cholangiocarcinomas, respectively (P
1997
1 NEOADJUVANT
CHEMORADIATION
FOR
Figure 3. Actuarial survival of patients with resected tumors who underwent no radiation therapy, preoperative chemoradiation, or postoperative radiation therapy. Of the 20 patients in the postoperative radiation therapy group, 18 received concomitant 5fluorouracil infusion.
negative margins (I’
COMMENTS Surgical resection of extrahepatic cholangiocarcinoma is rarely curative. Postoperative chemotherapy and radiation therapy, alone or in combination, appear to have little impact on the natural history of this disease. New approaches are clearly warranted. We evaluated our initial experience with preoperative chemoradiation using continuous infusion 5-FU as a radiation sensitizer. Importantly, this approach appears safe. The treatment was generally well tolerated and was not associated with an increased rate of anastomotic leak or other major intra-abdominal complications. Efficacy remains to be established. Three of 9 patients (33%) who received preoperative chemoradiation experienced a pathologic complete response to induction chemoradiation. Two of these patients had perihilar tumors, one of whom is alive and well 6 months postoperatively. The other patient died of a massive myocardial infarction 11 months postoperatively and had no evidence of recurrence at autopsy (the same patient whose postoperative course was complicated by supraventricular tachycardia and pulmonary edema). The remaining complete responder had a distal lesion and died with extensive liver metastasis 12 months following resection. Another patient with a perihilar tumor had a complete pathologic response of the primary tumor, but had microscopic disease in two lymph nodes; this patient is alive and free of disease at 32 months. Others THE AMERICAN
EXTRAHEPATIC
CHOLANGIOCARCINOMA/MCMASTERS
ET AL 1
have demonstrated some antitumor activity of S-FUbased chemoradiation against biliary tract cancers when used as the primary treatment modality.‘4 Patients with distal common bile duct cancers are generally considered to have a better prognosis than patients with perihilar tumors. 1~10,15-17In this series, the survival of patients with distal tumors was significantly shorter than those with perihilar tumors. Furthermore, 4 patients with distal cholangiocarcinomas treated with preoperative chemoradiation died of their disease within a relatively short time. These patients presented with a large mass in the area of the pancreatic head and were initially thought to have pancreatic adenocarcinoma. The poor survival of these patients may be due to the locally advanced nature of their cholangiocarcinoma at presentation, putting them at very high risk for the development of metastatic disease. None of the 5 patients with perihilar cholangiocarcinoma treated with preoperative chemoradiation have recurred, although 1 has died of comorbid disease. All had negative resection margins. While the number of patients is small, these data suggest that preoperative chemoradiation may increase the likelihood of obtaining tumor-free resection margins in patients with perihilar cholangiocarcinoma. Whether or not this leads to improved survival remains to be determined. In conclusion, these preliminary data suggest that preoperative chemoradiation for extrahepatic cholangiocarcinoma can be performed safely and is associated with a high rate of pathologic complete response. Importantly, preoperative chemoradiation may improve the ability to achieve tumor-free resection margins, especially for perihilar tumors. Additional multicenter trials of preoperative chemoradiation are warranted.
REFERENCES 1. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463-475. 2. Weinbren K, Mutum SS. Pathological aspects of cholangiocarcinema. Pathology. 1983;139:217-238. 3. Pichlmayr R, Weimann A, Klempnauer J, et al. Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg. 1996;224:628-638. 4. Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for cholangiocarcinoma. Arch Surg. 1995;130:270-276. 5. Nagorney DM, Donohue JH, Farrell MB, et al. Outcomes after curative resections of cholangiocarcinoma. Arch Surg. 1993;128:871-877. 6. Ogura Y, Mizumoto R, Tabata M, et al. Surgical treatment of carcinoma of the hepatic duct confluence: analysis of 55 resected carcinomas. World ] Surg. 1993;17:85-93. 7. Bengmark S, Ekberg H, Evander A, et al. Major liver resection for hilar cholangiocarcinoma. Ann Surg. 1988;207:120-125. 8. Iida S, Tsuzuki T, Ogata Y, et al. The long term survival of patients with carcinoma of the main hepatic duct junction. Cancer. 1987;60:1612-1619. 9. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinema. Postoperative radiotherapy does not improve survival. Ann Surg. 1995;221:788-798. 10. Vauthey J-N, Blumgart LH. Recent advances in the management of cholangiocarcinomas. Sem Liver Dis. 1994;14: 109-114. JOURNAL
OF
SURGERY@
VOLUME
174
DECEMBER
1997
607
NEOADJUVANT
CHEMORADIATION
FOR
EXTRAHEPATIC
CHO
11. Curley SA, Levin B, Rich TA. Liver and bile ducts. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE, eds. Clinical Oncology. New York: Churchill Livingstone; 1995:1305-1372. 12. Evans DB, Abbruzzese JL, Sleary KR, et al. Rapid-fractionation pre-operative chemoradiation for malignant periampullary neoplasms. .I R Coil Surg Ebb. 1995;40:319-323. 13. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127:1335-1339. 14. Whittington R, Neuberg D, Tester WJ, et al. Protracted intravenous fluorouracil infusion with radiation therapy in the
-
management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial. J Clin Oncol. 1995;13:227-232. 15. Pitt HA, Dooley WC, Yeo CJ, Cameron JL. Malignancies the biliary tract. Gun Probl Surg. 1995;32:3-90.
of
16. Tompkins RK, Saunders K, Roslyn JJ, Longmire WP Jr. Changing patterns in diagnosis and management of bile duct cancer. Ann Surg. 1990;211:614-621. 17. Alden ME, Waterman
FM, Topham AK, et al. Cholangiocarcinema: clinical significance of tumor location along the extrahepatic bile duct. Radioloo. 1995;197:511-516.
DISCUSSION Jameson Forster, MD (Kansas City, Kansas): I congratulate Dr. McMasters and his coauthors on an important contribution to the treatment of a difficult problem, the patient with cholangiocarcinoma who may or may not be resectable. His retrospective review focused on 9 patients out of 91 who were treated with preoperative chemotherapy in the form of continuous infusion of 5FU and radiation therapy with an external beam using three different regimens. Five patients received additional radiation therapy, 3 intraoperatively and 2 in the postoperative period. This study can be considered a phase I type of investigation, which demonstrated the feasibility of the preoperative technique in that the surgical procedure went without a hitch. There was a profound response with one third of the patients having no evidence of tumor in the resected specimen and all treated patients having negative margins. Unfortunately, there was no purported survival advantage in this group of patients other than the clear advantage of being resectable. I am particularly interested in finding enabling methods for resection in patients with this disease. My first question involves selection criteria; of the 9 patients, 6 were felt to be unresectable at the time that they were evaluated. By what criteria did your group decide to treat just the 6 patients with unresectable disease? By what criteria were they different from the other 51 who were not resected, or not exposed to this treatment? For what type of patient is this therapy truly useful? In Table I, all of the patients with perihilar disease are doing well following this therapy. All of the 5 patients with perihilar disease have no evidence of recurrence. One died of an MI and did not have disease. No patient did well who had distal disease. Don’t you feel that we should concentrate on perihilar processes alone with this modality? The final questions are: Did you follow blood levels of CA-19-9 with this population? Particularly, does normalization of the level indicate a response to therapy? Could you use that as a way of deciding on whom you should operate? I certainly agree with you that this is an exciting therapy and that a multicenter trial would be appropriate. Roman0 Delcore, MD (Kansas City, Missouri): Dr. McMasters has certainly demonstrated that neoadjuvant chemoradiation therapy is helpful and can be carried out with almost no morbidity in your group of unresectable patients. In view of these results, have you considered the 606
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potential use of a similar regimen, preoperatively, for all patients with this disease? Clayton Shatney, MD (San Jose, California): I did not catch how you established the diagnosis preoperatively that you had a cancer so you could apply the treatment. Secondly, I did not appreciate how far down from bifurcation you would begin counting a distal lesion. The reason I ask is that I have a patient right now with a stricture that looks like it is prob a bl y malignant that is between the cystic duct entrance and the hilum. Would this be considered a perihilar lesion since it is above the cystic duct entrance into the CBD, or is this a distal lesion? Terence Wade, MD (St. Louis, Missouri): I rise, as usual, to bring a little skepticism. You followed the first rule of publishing. That is, when you have only one positive answer put it in the title, which you did. Second, you called for a multi-institutional trial. If you do that, I would suggest that you should include a nonoperative nonresected group since you had a large number of complete pathologic responses. It may be that surgery offers very little in this disease, which is one thing that needs to be determined, as well as whether chemotherapy and radiation therapy add anything.
CLOSING Kelly M. McMasters, MD, PhD: Dr. Forster asked how we selected patients for this protocol. In fact, 4 of the patients who had distal tumors had masses on CT scan when they presented. They were thought to have pancreatic tumors and had diagnosis of adenocarcinoma on fine needle aspiration. They were found later to have cholangiocarcinoma after being treated on a protocol that was similar to that which we use for pancreatic cancer. The patients with perihilar tumors were those thought to be unresectable at previous operation or on preoperative imaging studies. We are now starting to include patients who do not necessarily have unresectable disease as we feel more comfortable with this. Dr. Forster noted that this was like a phase I study and, in fact, that is how we feel about this. We certainly cannot make any firm conclusions about the efficacy of this treatment at this time. It seems promising that we were able to operate on these people and not have major complications, and we had some pathologic responses that seemed promising. CA-19-9 was not evaluated in this series. That may be something that will be promising to look at in the future. I do agree that we should probably focus our attention only on patients with perihilar tumors with this disease. DECEMBER
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It was also asked how the diagnosis was established. On most of the patients, the diagnosis was established by fine needle aspiration biopsy, either on CT-guided biopsy or by brushings and washings at ERCP or percutaneous transhepatic methods. Some had intraoperative biopsies. Dr. Shatney asked about the classification of perihilar versus distal tumors. The patient you described has a perihilar tumor, because he or she would require resection of the bifurcation, but probably not a pancreaticoduodenectomy.
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i It may well be that we should include a nonoperative arm in future studies of this modality. It is clear that the prognosis of patients who do not undergo resection is dismal, however, and that if operation is possible with negative margins, this is the only thing that offers a chance at long-term survival. If, in fact, this modality can improve the rate with which we achieve a negative margin resection, we may be able to improve the results of resection for this tumor.
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