Major hepatectomy for perihilar cholangiocarcinoma

J Hepatobiliary Pancreat Sci (2010) 17:463–469 DOI 10.1007/s00534-009-0206-3

TOPICS

A new era of surgical treatment of hilar cholangiocarcinoma: comparison of leading Eastern and Western centers

Major hepatectomy for perihilar cholangiocarcinoma Michiaki Unno • Yu Katayose • Toshiki Rikiyama • Hiroshi Yoshida Kuniharu Yamamoto • Takanori Morikawa • Hiroki Hayashi • Fuyuhiko Motoi • Shinichi Egawa

•

Received: 1 August 2009 / Accepted: 1 September 2009 / Published online: 26 November 2009 Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2009

Abstract Background/purpose Hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma involving the hepatic hilus are defined as ‘‘perihilar cholangiocarcinoma’’. The principle of surgical treatment is hemi-hepatectomy or trisectionectomy of the liver, caudate lobectomy, and resection of the extrahepatic bile duct for complete resection of the tumor. The aim of this study was to review the outcomes of major hepatectomy for perihilar cholangiocarcinoma. Methods Using the Kaplan–Meier method and the Cox proportional hazards model, we analyzed the results in 125 patients with perihilar cholangiocarcinoma who had undergone major hepatectomy. Results Right hepatectomy, right trisectionectomy, left hepatectomy, and left trisectionectomy were performed in 66, 8, 49, and 2 patients, respectively. Curative resection was achieved in 79 patients (63.2%). Mortality and morbidity rates were 8.0 and 48.7%, respectively. The overall 1-, 3-, and 5-year survival rates of all patients were 73.2, 36.7, and 34.7%, respectively. The median survival was 26.8 months. Multivariate analysis showed that the independent prognostic factors for overall survival were gender, histopathological grading, curative resection, and American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) pT. Conclusions Major hepatectomy for perihilar cholangiocarcinoma was acceptable and showed satisfactory outcomes. For long-term survival in these patients, the surgeon should aim for complete resection of the tumor with negative margins.

Keywords Perihilar cholangiocarcinoma Intrahepatic cholangiocarcinoma Surgical resection Major hepatectomy

Introduction Perihilar cholangiocarcinoma is one of the most difficult carcinomas to treat because of its anatomical location and vascular proximity. Perihilar cholangiocarcinoma is divided into two categories, hilar cholangiocarcinoma that originates from the extrahepatic bile duct, and intrahepatic cholangiocarcinoma involving the hepatic hilus. These categories appear to have different prognoses, but the surgical treatment of intrahepatic cholangiocarcinoma is identical or very similar to that of hilar cholangiocarcinoma. Many articles and reviews have reported that aggressive surgical approaches such as hemihepatectomy or trisectionectomy, caudate lobectomy, bile duct resection, and lymphadenectomy might bring about a better prognosis [1–3]. The aim of the present study was to review the longterm outcomes of major hepatectomy for perihilar cholangiocarcinoma, including hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma involving the hepatic hilus, at a single center and to characterize the prognostic factors affecting the long-term outcome.

Patients and methods M. Unno (&) Y. Katayose T. Rikiyama H. Yoshida K. Yamamoto T. Morikawa H. Hayashi F. Motoi S. Egawa Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan e-mail: [email protected]

Patients In this retrospective study, medical records were identified for all cases of perihilar cholangiocarcinoma. From January 2001 through December 2008, 104 consecutive patients

123

464

with hilar cholangiocarcinoma and 21 consecutive patients with intrahepatic cholangiocarcinoma involving the hepatic hilus received hemihepatectomy/trisectionectomy with caudate lobectomy, bile duct resection, and lymphadenectomy at our department at Tohoku University Hospital. Patients with perihilar cholangiocarcinoma and other advanced cancers at different sites (e.g., gastric cancer or colon cancer) were excluded from this study. The mean age was 65.7 years (range 41–82 years). Ninety-three patients were males and 32 were females. Six patients who underwent resection of the bile duct without major hepatectomy and two patients with other cancers were excluded from this study. Consequently, the total number of patients who underwent resection in this period was 133. The anatomical extent of the bile duct involvement was typed by the classification of Bismuth and Corlette [4]: type I, n = 2 (1.6%); type II, n = 23 (18.4%); type IIIa, n = 33 (26.4%); type IIIb, n = 24 (19.2%); type IV, n = 43 (34.4%).

J Hepatobiliary Pancreat Sci (2010) 17:463–469

Results Surgical procedure As shown in Table 1, 66 of the 125 patients (52.8%) underwent right hepatectomy, caudate lobectomy, and resection of the extrahepatic duct. Four of these 66 patients underwent pancreatoduodenectomy simultaneously. Eight patients (6.4%) underwent right trisectionectomy. Fortynine patients (39.2%) received left hepatectomy, caudate lobectomy, and resection of the extrahepatic bile duct, and one patient received pancreatoduodenectomy simultaneously. Two patients (1.6%) underwent left trisectionectomy. Portal embolization (PE) was performed in 46 of the 125 patients (36.8%). PE was performed only in patients with right-sided hepatectomy (62.2% of those with rightsided hepatectomy). The number of patients with combined portal vein resection and reconstruction increased year by Table 1 Patient demographics

Surgical procedures

Age (years)

The surgical procedures were as follows: (1) preoperative biliary drainage to reduce the serum bilirubin concentration below 2 mg/dl; (2) endoscopic biliary drainage was preferable to biliary drainage; (3) preoperative percutaneous transhepatic portal embolization was performed when the volume of the liver remnant was estimated to be less than 40%; (4) determining and planning the operative procedures for hilar resection with hemihepatectomy plus caudate lobectomy was done by simulation with multidetector row computed tomography (CT); (5) skeletonization of the portal vein and hepatic artery with nodal clearance around the head of the pancreas; (6) portal vein resection and reconstruction before hepatic dissection if necessary; (7) the resection margins of the bile duct were investigated by frozen section; (8) lymph nodes in the hepatoduodenal ligament, around the head of pancreas, and around the common hepatic artery were completely removed; (9) lymph nodes in the paraaortic region were removed if possible with a curative resection.

Gender

Statistical analysis

123

Mean 65.7 (%)

Male

93

74.4

Female

32

25.6

Right hepatectomy

66

52.8

(?PD)

(4)

Operation

Right trisectionectomy

8

6.4

Left hepatectomy

49

39.2

(?PD)

(1)

Left trisectionectomy Combined vascular resection Portal vein resection Hepatic artery resection None

2

1.6

42

33.6

4

3.2

79

63.2

Bismuth–Corlette classification I

2

1.6

II

23

18.4

IIIa

33

26.4

IIIb

24

19.2

IV

43

34.4

104

83.2

21

16.8

I

30

24.0

II

69

55.2

III IV

8 18

6.4 14.4

Hilar/intrahepatic Hilar

Patient survival was calculated using the Kaplan–Meier method, including deaths from all causes. Univariate comparisons of survival and multivariate analysis were performed using the Cox proportional hazards model. Results were considered significant when the P values were less than 0.05. The statistical analyses were performed using statistical analysis software (JMP7.0 for Mac, SAS Institute Inc. Cary, NC).

Range 41–82

Intrahepatic AJCC/UICC staging

PD pancreaticoduodenectomy, AJCC/UICC American Joint Committee on Cancer/International Union Against Cancer


465

year, resulting in 33.6% of all patients having these procedures. On the other hand, there were only 4 patients with hepatic artery resection (3.2%). Curative resection with negative histological margins (R0) was achieved in 79 patients (63.2%) and microscopic margin involvement (R1) was seen in 28 patients (22.4%). In 18 patients (14.4%), distant metastases were found; in peritoneal dissemination (n = 2), liver metastasis (n = 8), and paraaortic lymph node metastasis (n = 8); this was considered as R2 resection. Postoperative morbidity and mortality Since 2003, we have classified the perioperative complications using the classification of Clavien [5]. When the postoperative complication was defined as grade III or more, the morbidity rate was 48.7% (54/111). Liver insufficiency defined as hyperbilirubinemia ([10 mg/dl) occurred in 15 patients. Other complications were renal failure in 5 patients, bleeding in 4 patients, and methicillinresistant Staphylococcus aureus (MRSA) sepsis in 3 patients. Ten of the 125 patients (8.0%) died from operative complications, including liver failure (n = 3), rupture of a pseudoaneurysm of the hepatic artery (n = 3), disseminated intravascular coagulation (DIC; n = 2), adult respiratory distress syndrome (ARDS; n = 1), and MRSA sepsis (n = 1). Histopathology

Fig. 1 Overall Kaplan–Meier survival curves for all patients undergoing major hepatectomy, caudate lobectomy, resection of the bile duct, and regional lymphadenectomy for perihilar cholangiocarcinoma. The overall 1-, 3-, and 5-year survival rates were 73.2, 36.7, and 34.7%, respectively, and the median survival time was 26.8 months

Overall survival The overall survival rate was calculated by the Kaplan– Meier method, including deaths from all causes. The median follow-up period was 18.5 months (range 0.2– 99 months). The overall 1-, 3-, and 5-year survival rates for all the patients in this study were 73.2, 36.7, and 34.7%, respectively (Fig. 1). The median survival time was 26.8 months. The results of univariate analyses by Cox regression are shown in Table 2 and the results of multivariate analyses are summarized in Table 3. Statistically significant variables in the univariate analyses were as follows: gender (male vs. female), procedures (right-sided vs. left-sided), AJCC/UICC pT (pT1/2 vs. pT3/4), AJCC/UICC pN (pN0 vs. pN1), AJCC/UICC pM (pM0 vs. pM1), histopathological grading (G1 vs. G2 vs. G3), and curative resection (R0 vs. R1/2), whereas there were no significant differences in age, vascular resection (none vs. portal vein vs. hepatic artery), Bismuth–Corlette classification (I vs. II vs. IIIa vs. IIIb vs. IV), or tumor type (hilar vs. intrahepatic). The positive variables were then considered for multivariate analyses. As shown in Table 3, multivariate analysis indicated that the variables gender (P = 0.0003), histopathological grading (P = 0.0127), curative resection (P = 0.0174), and AJCC/UICC pT (P = 0.0453)

Cumulative Survival Rate

Twenty-seven tumors (21.6%) were papillary or well-differentiated adenocarcinoma (G1), 83 (66.4%) were moderately differentiated (G2), and 15 (12.0%) were poorly differentiated. Pathologically positive lymph nodes were found in 59 patients (47.2%). The remaining 66 patients

(52.8%) were node-negative. The primary tumors were classified as follows, according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) 6th edition as: pT1, n = 6 (4.8%); pT2, n = 34 (27.2%); pT3, n = 76 (60.8%); and pT4, n = 9 (7.2%). Taken together, the final staging obtained was as follows: stage 1, n = 30 (24.0%); stage II, n = 69 (55.2%); stage III, n = 8 (6.4%); and stage IV, n = 18 (14.4%).

73.2%

36.7%

34.7%

Survival time in months No. at risk

125

79

45

20

11

10

123

466


Table 2 Univariate analyses of survival after resection Variable

n

Median survival (95% CI)

Age

125

Table 3 Multivariate analysis of survival after resection P value

Variable

Hazard ratio

Gender 0.0989

Gender

0.0002

Male

93

21.8 (18.1–26.8)

Female

32

NA

Procedure Right-sided Left-sided Vascular resection Portal vein Hepatic artery None

21.4 (16.0–27.0)

42

33.2 (25.3–NA)

41

24.2 (11.2–37.7)

80

II

23

24.3 (18.5–NA)

IIIa

33

22.9 (12.2–37.7)

IIIb

24

NA (21.4–NA)

IV

43

21.4 (11.1–32.7)

pT1/pT2

40

NA (24.3–NA)

pT3/pT4

85

22.9 (21.4–35.9)

66 59

33.2 (24.3–NA) 18.7 (11.2–27.0)

pM0

107

31.7 (24.2–62.0)

pM1

18

0.0813 0.50 0.0127* 2.74 5.04 0.0174* 0.48

Discussion

8.3 (6.0–12.7) 0.0004

G1

27

NA (35.9–NA)

G2

83

24.2 (18.8–31.7)

G3

15

10.3 (2.8–NA)

R0

79

36.0 (25.3–NA)

R1 ? R2

46

16.9 (7.4–21.8)

104

25.3 (18.8–32.7)

21

35.9 (11.1–NA)

Curative resection

0.0001

Tumor type

0.4805

CI confidence interval; NA not available

contributed to prolonged survival. Figure 2 shows the Kaplan–Meier curves according to gender (Fig. 2a), histopathological grading (Fig. 2b), curative resection (Fig. 2c), and AJCC/UICC pT (Fig. 2d). As shown in Fig. 2c, the 3- and 5-year survivals in patients with R0 resection were 49.6 and 46%, respectively, and the median survival time for these patients was 36 months, which was significantly better than that in patients who had R1/R2 resection (16.9 months).

123

G3/G1 R0/R1

\0.0001

Histopathological grading

Intrahepatic

0.830 1.06

Curative resection

0.0276

AJCC/UICC pM

Hilar

0.0453* 0.529

0.0139

AJCC/UICC pN pN0 pN1

pM0/pM1

NA

AJCC/UICC pT

1.66

AJCC/UICC pM Histopathological grading G2/G1

0.0732 2

pT1 ? pT2/pT3 ? pT4 pN0/pN1

26.8 (21.3–62.0)

I

0.0759

AJCC/UICC pN

NA (18.1–NA)

Bismuth–Corlette classification

Procedures Right-sided/left-sided

0.4111 4

0.0003* 3.71

AJCC/UICC pT 0.0237

74

Male/female

P value

Both hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma originate from the epithelial cells of biliary ducts. However, whether the prognosis of both is the same or different still remains controversial. Sano et al. [6] reported that the overall survival of hilar cholangiocarcinoma was significantly better than that of intrahepatic cholangiocarcinoma involving the hepatic hilus, and they mentioned that the two entities appeared to show different biological behaviors. On the other hand, Ebata et al. [7] reported that the difference in survival was marginal and that survival rates were similar for each stage, and they emphasized that combining hilar cholangiocarcinoma and intrahepatic cholangiocarcinoma involving the hepatic hilus under the term ‘‘perihilar cholangiocarcinoma’’ was valid. We compared the treatment outcomes in major hepatectomy to exclude bias in the operative procedures. In the results of our study, there was no significant difference between the groups in the overall survival. Thus, our results support the identity of both entities. All of the surgical procedures in the present study were hemihepatectomy or trisectionectomy with caudate lobectomy and resection of the extrahepatic bile duct. The overall survival of patients with left-sided hepatectomy was significantly better than that of those with right-sided hepatectomy in the univariate analysis, but the difference was marginal in the multivariate analysis. It is possible that left-sided hepatectomy causes less operative stress. The operative mortality in the present study was 8.0%. Previous studies after 2001 have reported that the rate of


467

a

b 70.0%

P=0.0003 Female (n=32)

Male (n=93) 26.0%

P=0.0127



70.0%

22.7%

70.0%

93

16

10

7

7

53

29

10

4

3

c

27.8%

27.8%

27

17

13

7

G2 G3

83

57

30

11

5

5

15

5

2

2

2

2

4

3

d P=0.0174

Cumulative Survival Rate R0

27.0%

G1

49.6%

46.0%

R0 (n=79)

R1/R2 (n=46) 19.0%

19.0%

P=0.0453 60.3%

76

R1/R2 49

57 22

33 12

15 5

10 1

52.8%

pT1/pT2 (n=40)

27.1% pT3/pT4 (n=85)

27.1%

Survival time in months


32.7%



Male

26

G1 (n=27)

G3 (n=15)

Survival time in months No. at risk Female 32

70.0%

G2 (n=83)

9

No. at risk pT1/pT2

40

26

16

10

4

3

1

pT3/pT4

85

53

29

10

7

7

Fig. 2 Postoperative survival in resected patients with perihilar cholangiocarcinoma. a Comparison of survival according to gender, male or female. b Comparison of survival according to the histopathological grading, well differentiated (G1), moderately

differentiated (G2), or poorly differentiated (G3). c Survival in patients with R0 resection compared with survival in those with R1/ R2 resection. d Survival in patients with pT1/pT2 tumor compared with survival in those with pT3/pT4 tumor

perioperative mortality ranged from 0 to 15% (Table 4) [8–33]. Recent improvements in perioperative management and precise preoperative diagnoses may have decreased the mortality rate [34, 35]. However, the risks of major hepatectomy, such as liver insufficiency, bleeding from a pseudoaneurysm, and infections with multidrug resistant bacteria, still remain. In the present study, the overall 5-year survival rate was 34.7% and the median survival time was 26.8 months. Previous studies after 2001 have reported 5-year survival rates ranging from 12 to 44% (Table 4). The prognostic factors in the present retrospective study were investigated by the Cox proportional hazards model. The results indicated that the independent prognostic factors for long-term outcome were gender, UICC pT, histological grading, and R0 resection. Many clinicopathological factors have been reported to have a positive or

negative impact on survival, including R0 resection [8, 11, 17, 22, 23, 25, 28, 36], pN0 [11, 12, 25, 28], UICC pT [37] histopathological grading [3, 8, 14, 22, 38], and gender [3, 13]. R0 resection was one of the stronger predictive factors revealed by multivariate analysis in the present study. Because gender, pN0, UICC pT, and histopathological grading were determined at the time of operation, we emphasize that the surgeon’s goal for a patient’s long-term survival is the complete resection of the tumor with negative margins. In conclusion, hemihepatectomy or trisectionectomy for patients with perihilar cholangiocarcinoma is tolerable in terms of safety and shows satisfactory outcomes. Patients who are female, and have well-differentiated adenocarcinoma, R0 resection, and pT1/pT2 show better prognoses.

123

468


Table 4 Previous reports of surgical resection for hilar or perihilar cholangiocarcinoma (since 2001) Authors

n

Mortality (%)

MST

3-year survival (%)

5-year survival (%) 27

Jarnagin et al. [8]

80

10

35

–

Kawarada et al. [9]

87

2.3

–

34.1

26.3

Capussotti et al. [10]

36

2.8

14

40.8

27.2

Kawasaki et al. [11]

79

1.3

37.4 (R0)

52 (R0)

39.9 (R0)

26.3 (R1)

24.2 (R1)

6 (R1)

Seyama et al. [12]

58

0

47

54.8

40

Rea et al. [13]

46

9

27.6

39

26

Kondo et al. [14]

40

0

27

40

–

Ijitsma et al. [15]

42

12

19

37

22

Hemming et al. [16]

80

9

40

–

35

26 301

7.6 7.6

20 24

31 –

12 22

45

8.9

26

58 (R0)

41 (R0)

24 (R1)

24 (R1) 27

Lai and Lau [17] Nishio et al. [18] Silva et al. [19] Dinant et al. [20] Sano et al. [21]

99

15

–

37

102

0

34

47.7

44

Witzigmann et al. [22]

60

8.3

22.8

30

22

Abdel Wahab et al. [23]

73

11

–

18.5

13

Cheng et al. [24]

75

13.3

35.5

44.4

12

Hasegawa et al. [25]

49

2

45.5

–

39.7

Maeno et al. [26]

21

9.5

35.7

–

33.7

Baton et al. [27]

59

5

32

45

20

161

7

–

52*

41*

Otani et al. [29]

27

0

23

44.4

26.7

Hidalgo et al. [30]

44

6.8

–

43

28

Ito et al. [31]

38

0

55

Konstadoulakis et al. [32] Murakami et al. [33]

59 42

6.8 7

– 21.5

48.9 42

34.9 30

8

26.8

36.7

34.7

Miyazaki et al. [28]

Our study

125

31

MST medial survival time, * non-vascular resection and R0 Acknowledgments We thank Brent Bell for reading the manuscript and Emiko Shibuya for technical assistance. 6.

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