Ann Surg Oncol (2015) 22:1308–1314 DOI 10.1245/s10434-014-4146-z
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Salvage Radiation Therapy for Isolated Local Recurrence of Extrahepatic Cholangiocarcinoma After Radical Surgery: A Retrospective Study Sang-Won Kim, MD1, Do Hoon Lim, MD, PhD2, Hee Chul Park, MD, PhD2, Won Park, MD, PhD2, Joon Oh Park, MD, PhD3, and Young Suk Park, MD, PhD3 Department of Radiation Oncology, Yeungnam University Medical Center, Daegu, Republic of Korea; 2Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3 Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 1
ABSTRACT Background. This study investigated the outcomes of salvage radiation therapy (RT) for isolated local recurrence of extrahepatic cholangiocarcinoma (EHCC) after radical surgery. Methods. Between May 2003 and July 2011, 25 patients with isolated recurrence of EHCC received RT with the aim of salvage. The most common primary cancer was common bile duct cancer (n = 15) followed by hilar cholangiocarcinoma (n = 7) and pancreaticobiliary type of ampulla of Vater cancer (n = 3). The median disease-free interval from initial operation to recurrence was 12 months. The criteria for diagnosis of recurrence were based on radiographic findings with either computed tomography or positron emission tomography. The radiation dose ranged from 40 to 54 Gy (median 54 Gy), and concurrent chemotherapy was administered to 19 patients. Results. The median follow-up period was 16 months. Local progression occurred in nine patients (36 %). The 2year local failure-free survival rate was 44 % during a median follow-up period of 14 months. The 2-year overall survival rate was 55 % during a median follow-up period of 24 months. A normal level of CA 19-9 at recurrence and concurrent chemotherapy were favorable prognostic factors for both local control and overall survival. Distant metastasis developed in 11 patients, and the liver was the most
Ó Society of Surgical Oncology 2014 First Received: 24 March 2014; Published Online: 16 October 2014 D. H. Lim, MD, PhD e-mail: [email protected]
common site (n = 7) of distant metastasis. No severe radiation-induced gastrointestinal toxicities developed. Conclusion. Salvage RT with or without concurrent chemotherapy resulted in a median survival of 24 months for patients with isolated local recurrence of EHCC. The treatment was feasible and safe with minimal toxicities.
Cholangiocarcinoma is a relatively uncommon neoplasm that arises from the ductal epithelial cells of the biliary tract and tends to spread along the bile duct wall longitudinally.1 Cholangiocarcinoma is classified according to the location of origin as intrahepatic, perihilar, or distal tumor,2 and extrahepatic cholangiocarcinoma (EHCC) includes both perihilar and distal tumors. Complete surgical resection is the only potentially curative treatment3,4 for patients with EHCC, and a recent report showed that more extensive surgery resulted in improvement of overall survival.5 However, complete resection often is limited due to the lack of early screening tools and the infiltrative spreading nature of EHCC. Even if complete resection is performed, local recurrence still remains the most common pattern of failure.6,7 Positive resection margin and regional lymph node involvement (pN1) are the main causes of local recurrence after surgery. In addition, even after radical surgery with a negative resection margin (R0) or node-negative disease (pN0), local recurrence develops in up to 40 % of patients.8 When the recurrence develops in only local or regional areas, it is potentially curable, and the patients with isolated local recurrence have a chance of long-term survival with aggressive treatment. However, it is unusual to meet this clinical situation, especially in patients with EHCC,
Salvage RT for Locally Recurrent EHCC
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METHODS
TABLE 1 Patient characteristics Patients (n = 25) n (%)
Patients
Sex Male Female Median age: years (range)
18 (72) 7 (28) 62 (45–75)
ECOG performance 0
2 (8)
1
19 (76)
2
4 (16)
Primary site Hilar cholangiocarcinoma
7 (28)
Common bile duct cancer Ampulla of Vater cancer
15 (60) 3 (12)
Initial T stage T1–2
13 (52)
T3–4
12 (48)
Initial nodal involvement Negative
22 (88)
Positive
3 (12)
Histology Ductal adenocarcinoma Intraductal papillary carcinoma
24 (96) 1 (4)
Preoperative CA 19-9 level Normal (B37 U/ml)
10 (40)
Elevated ([37 U/ml)
14 (56)
Unknown
1 (4)
Disease-free interval [12 months B12 months
12 (48) 13 (52)
CA 19-9 level at recurrence Normal (B37 U/ml)
7 (28)
Elevated ([37 U/ml)
18 (72)
Radiation dose (Gy) \50
9 (36)
C50
16 (64)
Treatment method RT alone CCRT
6 (24) 19 (76)
Adjuvant chemotherapy Yes
3 (12)
No
22 (88)
ECOG Eastern Cooperative Oncology Group, CA 19-9 carbohydrate antigen 19-9, RT radiation therapy, CCRT concurrent chemoradiation therapy
and the outcome of salvage therapy for isolated local recurrence has not been reported. The current study evaluated the effect of salvage radiation therapy (RT) for patients with isolated local recurrence of EHCC after curative resection.
This study was approved by the institutional review board at Samsung Medical Center. Between May 2003 and July 2011, 33 patients with isolated local recurrence of EHCC and ampulla of Vater cancer received salvage RT at Samsung Medical Center. All the patients were considered to have either unresectable disease that encased a major vessel or a high probability of risk for morbidity after reoperation, as determined by the surgeon. With curative intent, we performed salvage RT with or without concurrent chemotherapy. To make the patient cohort homogeneous, we excluded six patients with intestinal type ampulla of Vater cancer. Two patients who did not complete RT due to an increased bilirubin level and development of liver metastasis during RT also were excluded from this study cohort. The patient characteristics are summarized in Table 1. The median age of the patients was 62 years (range 45– 75 years). Common bile duct (CBD) tumor was the most common cancer (n = 15) followed by hilar cholangiocarcinoma (n = 7) and pancreaticobiliary type ampulla of Vater cancer (n = 3). The median disease-free interval from initial diagnosis of cancer to recurrence was 12 months. Three patients showed regional lymph node involvement at initial surgery but refused adjuvant treatment after surgery. Diagnosis for Recurrence The local recurrence was diagnosed mainly from clinical studies such as computed tomography (CT), positron-emission tomography (PET), and tumor marker such as carbohydrate antigen 19-9 (CA 19-9). Either development of a new mass or gradually increased lesion size around the prior tumor bed shown on follow-up CT images was considered to be a typical feature of recurrent disease. To confirm the recurrence from CT findings, PET was recommended, and 16 patients underwent PET-CT. The increased fluodeoxyglucose uptake shown on PET correlated with the lesion shown on CT was considered to be additional evidence for recurrence. The tumor marker CA 19-9 was measured in all patients. An elevated level of CA 19-9 was helpful for the diagnosis of recurrence, and the CA 19-9 level was normal in seven patients, only one of whom was not examined with PET. Figure 1 shows an example of diagnosis for isolated local recurrence with CT and PET. The histologic confirmation was performed for one patient via biopsy with laparotomy.
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FIG. 1 Diagnosis of isolated local recurrence of extrahepatic bile duct cancer. a Immediate postoperative image. The patient underwent segmental bile duct resection and hepatojejunostomy. b Computed tomography (CT) image 1 year after surgery. The soft tissue-like
lesion (black arrow) developed at the anastomosis site. c Positron emission tomography (PET)-CT image confirmed recurrent disease. The level of CA 19-9 was 1146.0 U/ml
Treatment
patients. After completion of concurrent chemoradiotherapy (CCRT), three patients received adjuvant chemotherapy. Two patients received a combination of cisplatin and capecitabine, and one patient received gemcitabine alone.
All the patients underwent CT simulation. The gross total volume (GTV) was the recurrent mass seen on CT. The clinical target volume (CTV) was the GTV plus a 0.5to 1.0-cm margin, and the regional lymph nodes were included in the CTV. The planning target volume (PTV) was individualized according to setup uncertainty and respiratory movement of CTV. Three-dimensional conformal RT was planned using multiple fields, and the CTV was irradiated with 44 to 45 Gy at a daily dose of 1.8 or 2.0 Gy. The secondary CT simulation then was performed to shrink the field, and an additional 9 to 10 Gy in five fractions was boosted to the GTV. Concurrent chemotherapy was administered to 19 patients. Intravenous 5-fluorouracil (5-FU) (500 mg/m2/ day) was administered on days 1 to 3 and days 20 to 22 of RT for 10 patients, and capecitabine (850 mg/m2/day) was administered orally during the entire course of RT for 9
Statistical Analysis The end points of this study were local failure-free survival (LFFS), progression-free survival (PFS), and overall survival (OS). Survival was calculated from initiation of RT to the event of interest or death. In this study, LFFS was defined as increased size of recurrent mass or appearance of a new lesion within the RT field, PFS was defined as the first failure of either local progression or distant metastasis, and OS was defined as the time to the death by any cause. All survival rates were estimated using the Kaplan–Meier method. Statistical significance was evaluated by the log-rank test. All analyses were performed with SPSS version 20.0.1 (SPSS Inc., Chicago, IL, USA).
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100 90 80 70 60 50 40 30 20
(a)
10 0 0
12
24
36
48
Local failure-free survival rate (%)
Local failure-free survival rate (%)
Salvage RT for Locally Recurrent EHCC
100 90 80 70
Normal
60 50 40
Elevated
30 20
(b)
10 0 0
60
12
Local failure-free survival rate (%)
24
36
48
60
Months
Months 100 90 80 70 60
CCRT
50 40 30 20
RT alone
10
(c)
0 0
12
24
36
48
60
Months
FIG. 2 Local failure-free survival. a Local failure-free survival rate of all patients. b Local failure-free survival rate according to CA 19-9 level at the time of recurrence. c Local failure-free survival rate according to treatment method
RESULTS
TABLE 2 Pattern of failure Patients (n = 25)
Survival and Prognostic Factors The 2-year LFFS rate was 44 % (median 14 months; range 2–54 months). The CCRT group had a better 2-year LFFS than the RT alone group (53 vs 0 %; p = 0.009). Elevated CA 19-9 level at the time of recurrence had a negative influence on LFFS (67 vs 29 %; p = 0.037) (Fig. 2). The median PFS was 9 months, with a 1-year rate of 34 % and a 2-year rate of 15 %. The CCRT group had significantly longer median PFS than the RT alone group (10 vs 4 months; p = 0.003). The patients with normal CA 19-9 levels at the time of recurrence had significant improvement in their median PFS compared with those who had an elevated CA 19-9 level (20 vs 6 months; p = 0.010). At the time of study, 12 patients were alive. The 2-year OS rate was 55 % during a median follow-up period of 24.1 months (range 3–54 months). The median OS time was significantly longer in the CCRT group than in the RT alone group (27 vs 8 months; p = 0.043). Likewise, the patients with an elevated CA 19-9 level at the time of recurrence had a worse OS survival than those with a normal CA 19-9 level (p = 0.003).
No failure
4
Locoregional (within RT field)
10
Distant (outside RT field)
11
Liver
7
Lymph nodes
4
Peritoneal seeding
2
Lung
1
Chest wall
1
Unknown
1
RT radiation therapy
Other factors such as sex, age, performance status, location of primary cancer, disease-free interval between initial surgery and recurrence, initial CA 19-9 level, and radiation dose were not statistically significant. Pattern of Failure Four patients did not experience any progression of disease during the study. Table 2 shows the patterns of failure during the follow-up period. Local failure (i.e.,
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TABLE 3 Treatment-related toxicities (CTCAE version 4.0) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Hematologic Anemia
11
11
2
1
0
Leukocytopenia
14
3
5
3
0
9
13
2
1
0
Anorexia
10
9
6
0
0
Nausea/vomiting
13
7
5
0
0
Diarrhea
18
3
4
0
0
Abdominal soreness
20
2
3
0
0
Thrombocytopenia Gastrointestinal
CTCAE Common Terminology Criteria for Adverse Events
increased size of recurrent mass after RT or appearance of a new lesion within the RT field) occurred for 10 patients (40 %). Distant metastasis outside the RT field developed in 15 cases involving 11 patients (44 %). The liver was the most common involvement site (n = 7) followed by lymph nodes (2 paraaortic, 1 mesenteric, 1 supraclavicular, 2 peritoneal seeding, 1 chest wall, 1 lung). One patient experienced concomitant development of local failure and distant metastasis. Treatment-Related Toxicities Treatment-related toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Acute toxicities during or immediately after RT are summarized in Table 3. Hematologic toxicities exceeding grade 3 developed in three patients, and all the patients received granulocyte-colony-stimulating factor or transfusion during hospitalization. Severe gastrointestinal toxicities of grade 3 or greater did not develop. DISCUSSION Complete resection is the mainstay of treatment for patients with EHCC.3,4 However, many patients present with locally advanced disease due to difficulty in early detection of disease and longitudinal spread of tumor along the biliary tract. Although complete resection is achieved, the most common pattern of failure for EHCC is locoregional recurrence.6,7 This implies that postoperative RT can decrease locoregional recurrence and eventually increase OS. However, no prospective randomized trials have studied adjuvant RT due to the rarity of the disease. Although the conclusion from many retrospective studies at a single institution about the role of adjuvant RT remains controversial8–10 two recently published meta-analyses showed that EHCC patients treated with adjuvant therapy
including RT had a lower risk of dying than patients treated with surgery alone, especially patients with lymph nodepositive or R1 disease.11,12 In contrast, whether patients with R0 or pN0 disease are candidates for postoperative RT still is uncertain. Borghero et al.8 reported that patients at high risk for local recurrence (R1pN1) treated with surgery followed by adjuvant chemoradiation experience survival equivalent to that of patients at standard risk (R0pN0) treated with surgery alone. In this study, both groups had similar 5-year locoregional recurrence rates (38 vs 37 %), but the 37 % rate in the standard-risk group leaves room for further improvement using adjuvant local therapy. No studies have been performed to prove the effect of adjuvant RT for patients with R0pN0, and National Comprehensive Cancer Network (NCCN) guidelines recommend not only observation but also fluoropyrimidine-based adjuvant treatment. However, considering the high rates of locoregional recurrence, adjuvant RT can be an option to decrease locoregional recurrence, and a prospective randomized trial should be conducted. Isolated local recurrence after definitive treatment is potentially curable with aggressive local treatment methods. Despite high rates of locoregional recurrence of EHCC, the clinical outcome of salvage treatment has not been investigated, and there is no generally accepted standard treatment. The current study is the only study to assess the role of salvage RT for isolated local recurrence in patients with EHCC. Recently, Roeder et al.13 reported the outcome of local treatment including explolaparotomy, intraoperative RT, and external beam RT for patients with isolated local recurrences of pancreatic cancer. Of 36 patients, 6 (17 %) lived longer than 3 years. Similarly, 4 (16 %) of 25 patients survived longer than 3 years in this study. Three ampulla of Vater cancer cases were included in the current study. Ampulla of Vater cancer is classified into pancreaticobiliary type and intestinal types based on the epithelium of origin. Anatomically, ampulla of Vater includes the papilla, a common channel, the distal common bile duct, and the distal main pancreatic duct. The ampullary papilla is covered by intestinal mucosa, whereas other regions are lined with simple mucinous epithelium resembling that of the pancreaticobiliary tree. Intestinal ampullary carcinoma originates from the intestinal epithelium overlying the ampulla, and pancreaticobiliary ampullary carcinoma originates from the mucosa of the distal common bile duct, the distal pancreatic duct, or the common ampullary channel. Generally, the pancreaticobiliary type has a worse prognosis associated with adverse pathologic features such as advanced T stage, high rate of lymph node metastasis, and perineural invasion, similar to the prognosis of distal common bile duct cancer.14
Salvage RT for Locally Recurrent EHCC
As a serum tumor marker, CA 19-9 is widely used for colorectal cancer and pancreatic cancer. Its value for diagnosis is relatively low. However, it is an important prognostic factor for pancreatic cancer. A recent prospective study showed that postsecretion CA 19-9 predicted OS for pancreatic cancer patients treated with adjuvant CCRT.15 Little is known about the effectiveness of CA 199 as a prognostic factor for EHCC. In the current study, the CA 19-9 level at recurrence was a strong prognostic factor for both LFFS and OS. Park et al.10 also demonstrated that postoperative CA 19-9 level was an independent predictor of OS and PFS for patients with resected EHCC. This implies that elevation in the level of CA 19-9 might indicate vigorous activity of the residual tumor burden. In the current study, histologic confirmation for a diagnosis of recurrence was performed for only one patient because relaparotomy for recurrent pancreaticobiliary tract cancer involves considerable morbidity and mortality.16 It is debatable whether diagnosis of recurrence with radiologic findings and tumor marker is acceptable. Clinicians commonly use PET as the clinical tool for diagnosis, staging, and treatment response. Yet the role of PET scans in detecting recurrence of EHCC still is equivocal because reported studies are limited. According to Corvera et al.,17 PET had a sensitivity of 89 % and a specificity of 100 %. Considering this result, with help of conventional imaging such as CT and magnetic resonance imaging/magnetic resonance cholangiopancreatography plus tumor marker, it seems reasonable to diagnose recurrence with noninvasive methods. With salvage RT, the 2-year LFFS rate of 44 % is a somewhat disappointing result. A total of 10 patients (40 %) showed disease progression within the irradiated field, and almost all of these events (9 of the 10) occurred within 1 year after completion of RT. The suboptimal radiation dose and the lack of concurrent chemotherapy for six of the patients may be one explanation. Radiobiologically, a radiation dose of 45 to 54 Gy is not a sufficient tumoricidal dose for gross tumor. Considering the promising results with the radiation dose–response relationship for EHCC in some studies, a dose escalation of more than 54 Gy should be achieved.18,19 However, a conventional RT technique has the limitation of delivering a high dose due to the proximity of radiation-sensitive organs such as the duodenum or small intestine. Interstitial brachytherapy or IORT can be an alternative for delivering a high dose with less toxicity. However, these techniques are difficult to apply in a clinical situation due to their invasiveness. High-precision RT using intensity-modulated and imageguided RT can deliver a high dose with minimal toxicities. Distant metastasis in 15 cases involving 11 patients (44 %) highlights another problem even with initially isolated local recurrence. Therefore, we need further investigation
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of effective systemic therapies as well as a local method for local tumor control. To our knowledge, this is the first report regarding salvage treatment for isolated local recurrence of EHCC. Salvage RT with concurrent chemotherapy is feasible for isolated local recurrence of EHCC. Selected patients managed with aggressive local treatment methods can be expected to be long-term survivors. To overcome the low LFFS rate, radiation dose escalation using a precise RT technique with concurrent use of a novel radiosensitizer is warranted. There should also be similar improvement in systemic adjuvant chemotherapy to decrease distant metastasis and prolong OS. ACKNOWLEDGMENT This study was supported by Samsung Medical Center Grant GFO1130081. CONFLICT OF INTEREST no competing interests.
The authors declare that they have
REFERENCES 1. Longmire WP, McArthur MS, Bastounis EA, Hiatt J. Carcinoma of the extrahepatic biliary tract. Ann Surg. 1973;178:333–45. 2. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–73; discussion 473–65. 3. Reding R, Buard JL, Lebeau G, Launois B. Surgical management of 552 carcinomas of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded): results of the French Surgical Association Survey. Ann Surg. 1991;213:236–41. 4. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(Suppl 6):VI1–9. 5. Kondo S, Takada T, Miyazaki M, et al. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. J Hepatobiliary Pancreat Surg. 2008;15:41–54. 6. Kopelson G, Galdabini J, Warshaw AL, Gunderson LL. Patterns of failure after curative surgery for extrahepatic biliary tract carcinoma: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys. 1981;7:413–7. 7. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689–700. 8. Borghero Y, Crane CH, Szklaruk J, et al. Extrahepatic bile duct adenocarcinoma: patients at high risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard risk treated with surgery alone. Ann Surg Oncol. 2008;15:3147–56. 9. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinoma: postoperative radiotherapy does not improve survival. Ann Surg. 1995;221:788–97; discussion 797–88. 10. Park JH, Choi EK, Ahn SD, et al. Postoperative chemoradiotherapy for extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys. 2011;79:696–704. 11. Bonet Beltran M, Allal AS, Gich I, Sole JM, Carrio I. Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies. Cancer Treat Rev. 2012;38:111–19.
1314 12. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and metaanalysis. J Clin Oncol. 2012;30:1934–40. 13. Roeder F, Timke C, Uhl M, et al. Aggressive local treatment containing intraoperative radiation therapy (IORT) for patients with isolated local recurrences of pancreatic cancer: a retrospective analysis. BMC Cancer. 2012;12:295. 14. Kim WS, Choi DW, Choi SH, Heo JS, You DD, Lee HG. Clinical significance of pathologic subtype in curatively resected ampulla of Vater cancer. J Surg Oncol. 2012;105:266–72. 15. Berger AC, Garcia M, Jr., Hoffman JP, et al. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol. 2008;26:5918–22.
S.-W. Kim et al. 16. Zacharias T, Oussoultzoglou E, Jaeck D, Pessaux P, Bachellier P. Surgery for recurrence of periampullary malignancies. J Gastrointest Surg. 2009;13:760–7. 17. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg. 2008;206:57–65. 18. Alden ME, Mohiuddin M. The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys. 1994;28:945– 51. 19. Crane CH, Macdonald KO, Vauthey JN, et al. Limitations of conventional doses of chemoradiation for unresectable biliary cancer. Int J Radiat Oncol Biol Phys. 2002;53:969–74.
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Salvage Radiation Therapy for Isolated Local Recurrence of Extrahepatic Cholangiocarcinoma After Radical Surgery: A Retrospective Study Sang-Won Kim, MD1, Do Hoon Lim, MD, PhD2, Hee Chul Park, MD, PhD2, Won Park, MD, PhD2, Joon Oh Park, MD, PhD3, and Young Suk Park, MD, PhD3 Department of Radiation Oncology, Yeungnam University Medical Center, Daegu, Republic of Korea; 2Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3 Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 1
ABSTRACT Background. This study investigated the outcomes of salvage radiation therapy (RT) for isolated local recurrence of extrahepatic cholangiocarcinoma (EHCC) after radical surgery. Methods. Between May 2003 and July 2011, 25 patients with isolated recurrence of EHCC received RT with the aim of salvage. The most common primary cancer was common bile duct cancer (n = 15) followed by hilar cholangiocarcinoma (n = 7) and pancreaticobiliary type of ampulla of Vater cancer (n = 3). The median disease-free interval from initial operation to recurrence was 12 months. The criteria for diagnosis of recurrence were based on radiographic findings with either computed tomography or positron emission tomography. The radiation dose ranged from 40 to 54 Gy (median 54 Gy), and concurrent chemotherapy was administered to 19 patients. Results. The median follow-up period was 16 months. Local progression occurred in nine patients (36 %). The 2year local failure-free survival rate was 44 % during a median follow-up period of 14 months. The 2-year overall survival rate was 55 % during a median follow-up period of 24 months. A normal level of CA 19-9 at recurrence and concurrent chemotherapy were favorable prognostic factors for both local control and overall survival. Distant metastasis developed in 11 patients, and the liver was the most
Ó Society of Surgical Oncology 2014 First Received: 24 March 2014; Published Online: 16 October 2014 D. H. Lim, MD, PhD e-mail: [email protected]
common site (n = 7) of distant metastasis. No severe radiation-induced gastrointestinal toxicities developed. Conclusion. Salvage RT with or without concurrent chemotherapy resulted in a median survival of 24 months for patients with isolated local recurrence of EHCC. The treatment was feasible and safe with minimal toxicities.
Cholangiocarcinoma is a relatively uncommon neoplasm that arises from the ductal epithelial cells of the biliary tract and tends to spread along the bile duct wall longitudinally.1 Cholangiocarcinoma is classified according to the location of origin as intrahepatic, perihilar, or distal tumor,2 and extrahepatic cholangiocarcinoma (EHCC) includes both perihilar and distal tumors. Complete surgical resection is the only potentially curative treatment3,4 for patients with EHCC, and a recent report showed that more extensive surgery resulted in improvement of overall survival.5 However, complete resection often is limited due to the lack of early screening tools and the infiltrative spreading nature of EHCC. Even if complete resection is performed, local recurrence still remains the most common pattern of failure.6,7 Positive resection margin and regional lymph node involvement (pN1) are the main causes of local recurrence after surgery. In addition, even after radical surgery with a negative resection margin (R0) or node-negative disease (pN0), local recurrence develops in up to 40 % of patients.8 When the recurrence develops in only local or regional areas, it is potentially curable, and the patients with isolated local recurrence have a chance of long-term survival with aggressive treatment. However, it is unusual to meet this clinical situation, especially in patients with EHCC,
Salvage RT for Locally Recurrent EHCC
1309
METHODS
TABLE 1 Patient characteristics Patients (n = 25) n (%)
Patients
Sex Male Female Median age: years (range)
18 (72) 7 (28) 62 (45–75)
ECOG performance 0
2 (8)
1
19 (76)
2
4 (16)
Primary site Hilar cholangiocarcinoma
7 (28)
Common bile duct cancer Ampulla of Vater cancer
15 (60) 3 (12)
Initial T stage T1–2
13 (52)
T3–4
12 (48)
Initial nodal involvement Negative
22 (88)
Positive
3 (12)
Histology Ductal adenocarcinoma Intraductal papillary carcinoma
24 (96) 1 (4)
Preoperative CA 19-9 level Normal (B37 U/ml)
10 (40)
Elevated ([37 U/ml)
14 (56)
Unknown
1 (4)
Disease-free interval [12 months B12 months
12 (48) 13 (52)
CA 19-9 level at recurrence Normal (B37 U/ml)
7 (28)
Elevated ([37 U/ml)
18 (72)
Radiation dose (Gy) \50
9 (36)
C50
16 (64)
Treatment method RT alone CCRT
6 (24) 19 (76)
Adjuvant chemotherapy Yes
3 (12)
No
22 (88)
ECOG Eastern Cooperative Oncology Group, CA 19-9 carbohydrate antigen 19-9, RT radiation therapy, CCRT concurrent chemoradiation therapy
and the outcome of salvage therapy for isolated local recurrence has not been reported. The current study evaluated the effect of salvage radiation therapy (RT) for patients with isolated local recurrence of EHCC after curative resection.
This study was approved by the institutional review board at Samsung Medical Center. Between May 2003 and July 2011, 33 patients with isolated local recurrence of EHCC and ampulla of Vater cancer received salvage RT at Samsung Medical Center. All the patients were considered to have either unresectable disease that encased a major vessel or a high probability of risk for morbidity after reoperation, as determined by the surgeon. With curative intent, we performed salvage RT with or without concurrent chemotherapy. To make the patient cohort homogeneous, we excluded six patients with intestinal type ampulla of Vater cancer. Two patients who did not complete RT due to an increased bilirubin level and development of liver metastasis during RT also were excluded from this study cohort. The patient characteristics are summarized in Table 1. The median age of the patients was 62 years (range 45– 75 years). Common bile duct (CBD) tumor was the most common cancer (n = 15) followed by hilar cholangiocarcinoma (n = 7) and pancreaticobiliary type ampulla of Vater cancer (n = 3). The median disease-free interval from initial diagnosis of cancer to recurrence was 12 months. Three patients showed regional lymph node involvement at initial surgery but refused adjuvant treatment after surgery. Diagnosis for Recurrence The local recurrence was diagnosed mainly from clinical studies such as computed tomography (CT), positron-emission tomography (PET), and tumor marker such as carbohydrate antigen 19-9 (CA 19-9). Either development of a new mass or gradually increased lesion size around the prior tumor bed shown on follow-up CT images was considered to be a typical feature of recurrent disease. To confirm the recurrence from CT findings, PET was recommended, and 16 patients underwent PET-CT. The increased fluodeoxyglucose uptake shown on PET correlated with the lesion shown on CT was considered to be additional evidence for recurrence. The tumor marker CA 19-9 was measured in all patients. An elevated level of CA 19-9 was helpful for the diagnosis of recurrence, and the CA 19-9 level was normal in seven patients, only one of whom was not examined with PET. Figure 1 shows an example of diagnosis for isolated local recurrence with CT and PET. The histologic confirmation was performed for one patient via biopsy with laparotomy.
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FIG. 1 Diagnosis of isolated local recurrence of extrahepatic bile duct cancer. a Immediate postoperative image. The patient underwent segmental bile duct resection and hepatojejunostomy. b Computed tomography (CT) image 1 year after surgery. The soft tissue-like
lesion (black arrow) developed at the anastomosis site. c Positron emission tomography (PET)-CT image confirmed recurrent disease. The level of CA 19-9 was 1146.0 U/ml
Treatment
patients. After completion of concurrent chemoradiotherapy (CCRT), three patients received adjuvant chemotherapy. Two patients received a combination of cisplatin and capecitabine, and one patient received gemcitabine alone.
All the patients underwent CT simulation. The gross total volume (GTV) was the recurrent mass seen on CT. The clinical target volume (CTV) was the GTV plus a 0.5to 1.0-cm margin, and the regional lymph nodes were included in the CTV. The planning target volume (PTV) was individualized according to setup uncertainty and respiratory movement of CTV. Three-dimensional conformal RT was planned using multiple fields, and the CTV was irradiated with 44 to 45 Gy at a daily dose of 1.8 or 2.0 Gy. The secondary CT simulation then was performed to shrink the field, and an additional 9 to 10 Gy in five fractions was boosted to the GTV. Concurrent chemotherapy was administered to 19 patients. Intravenous 5-fluorouracil (5-FU) (500 mg/m2/ day) was administered on days 1 to 3 and days 20 to 22 of RT for 10 patients, and capecitabine (850 mg/m2/day) was administered orally during the entire course of RT for 9
Statistical Analysis The end points of this study were local failure-free survival (LFFS), progression-free survival (PFS), and overall survival (OS). Survival was calculated from initiation of RT to the event of interest or death. In this study, LFFS was defined as increased size of recurrent mass or appearance of a new lesion within the RT field, PFS was defined as the first failure of either local progression or distant metastasis, and OS was defined as the time to the death by any cause. All survival rates were estimated using the Kaplan–Meier method. Statistical significance was evaluated by the log-rank test. All analyses were performed with SPSS version 20.0.1 (SPSS Inc., Chicago, IL, USA).
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100 90 80 70 60 50 40 30 20
(a)
10 0 0
12
24
36
48
Local failure-free survival rate (%)
Local failure-free survival rate (%)
Salvage RT for Locally Recurrent EHCC
100 90 80 70
Normal
60 50 40
Elevated
30 20
(b)
10 0 0
60
12
Local failure-free survival rate (%)
24
36
48
60
Months
Months 100 90 80 70 60
CCRT
50 40 30 20
RT alone
10
(c)
0 0
12
24
36
48
60
Months
FIG. 2 Local failure-free survival. a Local failure-free survival rate of all patients. b Local failure-free survival rate according to CA 19-9 level at the time of recurrence. c Local failure-free survival rate according to treatment method
RESULTS
TABLE 2 Pattern of failure Patients (n = 25)
Survival and Prognostic Factors The 2-year LFFS rate was 44 % (median 14 months; range 2–54 months). The CCRT group had a better 2-year LFFS than the RT alone group (53 vs 0 %; p = 0.009). Elevated CA 19-9 level at the time of recurrence had a negative influence on LFFS (67 vs 29 %; p = 0.037) (Fig. 2). The median PFS was 9 months, with a 1-year rate of 34 % and a 2-year rate of 15 %. The CCRT group had significantly longer median PFS than the RT alone group (10 vs 4 months; p = 0.003). The patients with normal CA 19-9 levels at the time of recurrence had significant improvement in their median PFS compared with those who had an elevated CA 19-9 level (20 vs 6 months; p = 0.010). At the time of study, 12 patients were alive. The 2-year OS rate was 55 % during a median follow-up period of 24.1 months (range 3–54 months). The median OS time was significantly longer in the CCRT group than in the RT alone group (27 vs 8 months; p = 0.043). Likewise, the patients with an elevated CA 19-9 level at the time of recurrence had a worse OS survival than those with a normal CA 19-9 level (p = 0.003).
No failure
4
Locoregional (within RT field)
10
Distant (outside RT field)
11
Liver
7
Lymph nodes
4
Peritoneal seeding
2
Lung
1
Chest wall
1
Unknown
1
RT radiation therapy
Other factors such as sex, age, performance status, location of primary cancer, disease-free interval between initial surgery and recurrence, initial CA 19-9 level, and radiation dose were not statistically significant. Pattern of Failure Four patients did not experience any progression of disease during the study. Table 2 shows the patterns of failure during the follow-up period. Local failure (i.e.,
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S.-W. Kim et al.
TABLE 3 Treatment-related toxicities (CTCAE version 4.0) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Hematologic Anemia
11
11
2
1
0
Leukocytopenia
14
3
5
3
0
9
13
2
1
0
Anorexia
10
9
6
0
0
Nausea/vomiting
13
7
5
0
0
Diarrhea
18
3
4
0
0
Abdominal soreness
20
2
3
0
0
Thrombocytopenia Gastrointestinal
CTCAE Common Terminology Criteria for Adverse Events
increased size of recurrent mass after RT or appearance of a new lesion within the RT field) occurred for 10 patients (40 %). Distant metastasis outside the RT field developed in 15 cases involving 11 patients (44 %). The liver was the most common involvement site (n = 7) followed by lymph nodes (2 paraaortic, 1 mesenteric, 1 supraclavicular, 2 peritoneal seeding, 1 chest wall, 1 lung). One patient experienced concomitant development of local failure and distant metastasis. Treatment-Related Toxicities Treatment-related toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Acute toxicities during or immediately after RT are summarized in Table 3. Hematologic toxicities exceeding grade 3 developed in three patients, and all the patients received granulocyte-colony-stimulating factor or transfusion during hospitalization. Severe gastrointestinal toxicities of grade 3 or greater did not develop. DISCUSSION Complete resection is the mainstay of treatment for patients with EHCC.3,4 However, many patients present with locally advanced disease due to difficulty in early detection of disease and longitudinal spread of tumor along the biliary tract. Although complete resection is achieved, the most common pattern of failure for EHCC is locoregional recurrence.6,7 This implies that postoperative RT can decrease locoregional recurrence and eventually increase OS. However, no prospective randomized trials have studied adjuvant RT due to the rarity of the disease. Although the conclusion from many retrospective studies at a single institution about the role of adjuvant RT remains controversial8–10 two recently published meta-analyses showed that EHCC patients treated with adjuvant therapy
including RT had a lower risk of dying than patients treated with surgery alone, especially patients with lymph nodepositive or R1 disease.11,12 In contrast, whether patients with R0 or pN0 disease are candidates for postoperative RT still is uncertain. Borghero et al.8 reported that patients at high risk for local recurrence (R1pN1) treated with surgery followed by adjuvant chemoradiation experience survival equivalent to that of patients at standard risk (R0pN0) treated with surgery alone. In this study, both groups had similar 5-year locoregional recurrence rates (38 vs 37 %), but the 37 % rate in the standard-risk group leaves room for further improvement using adjuvant local therapy. No studies have been performed to prove the effect of adjuvant RT for patients with R0pN0, and National Comprehensive Cancer Network (NCCN) guidelines recommend not only observation but also fluoropyrimidine-based adjuvant treatment. However, considering the high rates of locoregional recurrence, adjuvant RT can be an option to decrease locoregional recurrence, and a prospective randomized trial should be conducted. Isolated local recurrence after definitive treatment is potentially curable with aggressive local treatment methods. Despite high rates of locoregional recurrence of EHCC, the clinical outcome of salvage treatment has not been investigated, and there is no generally accepted standard treatment. The current study is the only study to assess the role of salvage RT for isolated local recurrence in patients with EHCC. Recently, Roeder et al.13 reported the outcome of local treatment including explolaparotomy, intraoperative RT, and external beam RT for patients with isolated local recurrences of pancreatic cancer. Of 36 patients, 6 (17 %) lived longer than 3 years. Similarly, 4 (16 %) of 25 patients survived longer than 3 years in this study. Three ampulla of Vater cancer cases were included in the current study. Ampulla of Vater cancer is classified into pancreaticobiliary type and intestinal types based on the epithelium of origin. Anatomically, ampulla of Vater includes the papilla, a common channel, the distal common bile duct, and the distal main pancreatic duct. The ampullary papilla is covered by intestinal mucosa, whereas other regions are lined with simple mucinous epithelium resembling that of the pancreaticobiliary tree. Intestinal ampullary carcinoma originates from the intestinal epithelium overlying the ampulla, and pancreaticobiliary ampullary carcinoma originates from the mucosa of the distal common bile duct, the distal pancreatic duct, or the common ampullary channel. Generally, the pancreaticobiliary type has a worse prognosis associated with adverse pathologic features such as advanced T stage, high rate of lymph node metastasis, and perineural invasion, similar to the prognosis of distal common bile duct cancer.14
Salvage RT for Locally Recurrent EHCC
As a serum tumor marker, CA 19-9 is widely used for colorectal cancer and pancreatic cancer. Its value for diagnosis is relatively low. However, it is an important prognostic factor for pancreatic cancer. A recent prospective study showed that postsecretion CA 19-9 predicted OS for pancreatic cancer patients treated with adjuvant CCRT.15 Little is known about the effectiveness of CA 199 as a prognostic factor for EHCC. In the current study, the CA 19-9 level at recurrence was a strong prognostic factor for both LFFS and OS. Park et al.10 also demonstrated that postoperative CA 19-9 level was an independent predictor of OS and PFS for patients with resected EHCC. This implies that elevation in the level of CA 19-9 might indicate vigorous activity of the residual tumor burden. In the current study, histologic confirmation for a diagnosis of recurrence was performed for only one patient because relaparotomy for recurrent pancreaticobiliary tract cancer involves considerable morbidity and mortality.16 It is debatable whether diagnosis of recurrence with radiologic findings and tumor marker is acceptable. Clinicians commonly use PET as the clinical tool for diagnosis, staging, and treatment response. Yet the role of PET scans in detecting recurrence of EHCC still is equivocal because reported studies are limited. According to Corvera et al.,17 PET had a sensitivity of 89 % and a specificity of 100 %. Considering this result, with help of conventional imaging such as CT and magnetic resonance imaging/magnetic resonance cholangiopancreatography plus tumor marker, it seems reasonable to diagnose recurrence with noninvasive methods. With salvage RT, the 2-year LFFS rate of 44 % is a somewhat disappointing result. A total of 10 patients (40 %) showed disease progression within the irradiated field, and almost all of these events (9 of the 10) occurred within 1 year after completion of RT. The suboptimal radiation dose and the lack of concurrent chemotherapy for six of the patients may be one explanation. Radiobiologically, a radiation dose of 45 to 54 Gy is not a sufficient tumoricidal dose for gross tumor. Considering the promising results with the radiation dose–response relationship for EHCC in some studies, a dose escalation of more than 54 Gy should be achieved.18,19 However, a conventional RT technique has the limitation of delivering a high dose due to the proximity of radiation-sensitive organs such as the duodenum or small intestine. Interstitial brachytherapy or IORT can be an alternative for delivering a high dose with less toxicity. However, these techniques are difficult to apply in a clinical situation due to their invasiveness. High-precision RT using intensity-modulated and imageguided RT can deliver a high dose with minimal toxicities. Distant metastasis in 15 cases involving 11 patients (44 %) highlights another problem even with initially isolated local recurrence. Therefore, we need further investigation
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of effective systemic therapies as well as a local method for local tumor control. To our knowledge, this is the first report regarding salvage treatment for isolated local recurrence of EHCC. Salvage RT with concurrent chemotherapy is feasible for isolated local recurrence of EHCC. Selected patients managed with aggressive local treatment methods can be expected to be long-term survivors. To overcome the low LFFS rate, radiation dose escalation using a precise RT technique with concurrent use of a novel radiosensitizer is warranted. There should also be similar improvement in systemic adjuvant chemotherapy to decrease distant metastasis and prolong OS. ACKNOWLEDGMENT This study was supported by Samsung Medical Center Grant GFO1130081. CONFLICT OF INTEREST no competing interests.
The authors declare that they have
REFERENCES 1. Longmire WP, McArthur MS, Bastounis EA, Hiatt J. Carcinoma of the extrahepatic biliary tract. Ann Surg. 1973;178:333–45. 2. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463–73; discussion 473–65. 3. Reding R, Buard JL, Lebeau G, Launois B. Surgical management of 552 carcinomas of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded): results of the French Surgical Association Survey. Ann Surg. 1991;213:236–41. 4. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(Suppl 6):VI1–9. 5. Kondo S, Takada T, Miyazaki M, et al. Guidelines for the management of biliary tract and ampullary carcinomas: surgical treatment. J Hepatobiliary Pancreat Surg. 2008;15:41–54. 6. Kopelson G, Galdabini J, Warshaw AL, Gunderson LL. Patterns of failure after curative surgery for extrahepatic biliary tract carcinoma: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys. 1981;7:413–7. 7. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689–700. 8. Borghero Y, Crane CH, Szklaruk J, et al. Extrahepatic bile duct adenocarcinoma: patients at high risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard risk treated with surgery alone. Ann Surg Oncol. 2008;15:3147–56. 9. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinoma: postoperative radiotherapy does not improve survival. Ann Surg. 1995;221:788–97; discussion 797–88. 10. Park JH, Choi EK, Ahn SD, et al. Postoperative chemoradiotherapy for extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys. 2011;79:696–704. 11. Bonet Beltran M, Allal AS, Gich I, Sole JM, Carrio I. Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies. Cancer Treat Rev. 2012;38:111–19.
1314 12. Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and metaanalysis. J Clin Oncol. 2012;30:1934–40. 13. Roeder F, Timke C, Uhl M, et al. Aggressive local treatment containing intraoperative radiation therapy (IORT) for patients with isolated local recurrences of pancreatic cancer: a retrospective analysis. BMC Cancer. 2012;12:295. 14. Kim WS, Choi DW, Choi SH, Heo JS, You DD, Lee HG. Clinical significance of pathologic subtype in curatively resected ampulla of Vater cancer. J Surg Oncol. 2012;105:266–72. 15. Berger AC, Garcia M, Jr., Hoffman JP, et al. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol. 2008;26:5918–22.
S.-W. Kim et al. 16. Zacharias T, Oussoultzoglou E, Jaeck D, Pessaux P, Bachellier P. Surgery for recurrence of periampullary malignancies. J Gastrointest Surg. 2009;13:760–7. 17. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg. 2008;206:57–65. 18. Alden ME, Mohiuddin M. The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys. 1994;28:945– 51. 19. Crane CH, Macdonald KO, Vauthey JN, et al. Limitations of conventional doses of chemoradiation for unresectable biliary cancer. Int J Radiat Oncol Biol Phys. 2002;53:969–74.
