Prognostic factors and patterns of loco-regional failure in patients with R0 resected gallbladder cancer

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https://doi.org/10.1016/j.hpb.2019.10.2447

ORIGINAL ARTICLE

Prognostic factors and patterns of loco-regional failure in patients with R0 resected gallbladder cancer Jung Ho Im1, Woo Jung Lee2, Chang Moo Kang2, Ho Kyoung Hwang2 & Jinsil Seong1 1

Departments of Radiation Oncology, and 2Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Abstract Background: In this study, risk factors for loco-regional recurrence in curative R0 resected gallbladder adenocarcinoma were investigated. Methods: Patients with gallbladder adenocarcinoma with curative R0 resections between 2000 and 2016 were retrospectively reviewed. Loco-regional failure-free survival (LRFFS) and overall survival (OS) were analyzed using the Kaplan–Meier method; prognostic factors were analyzed using the Cox proportional hazards model. Based on the identified risk factors, patients were grouped for further analysis. Results: A total of 272 patients were included for analysis; overall, 5-year LRFFS and OS were 83% and 81%, respectively. On multivariate analysis, 3 risk factors for LRFFS were identified; lymphovascular invasion, T3, and N1, by which patients were grouped; group 1 for 0 factor, group 2 for 1 factor and group 3 for 2 to 3 factors. The 5-year LRFFS in groups 1, 2, and 3 were 94%, 73%, and 40%, and the 5year OS in groups 1, 2, and 3 were 90%, 75%, and 47%, respectively. LRFFS and OS differed significantly among groups (p < 0.05). Conclusion: In patients with R0 resected gallbladder cancer, the presence of >1 risk factor increased the risk of loco-regional recurrence. Additional therapeutic strategy for these patients needs further consideration. Received 27 August 2019; accepted 30 October 2019

Correspondence Jinsil Seong, Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University Health System, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. E-mail: [email protected]

Introduction Although complete surgical resection provides a chance for cure in patients with gall bladder cancer (GBC), tumor recurrence leads to poor long term outcomes. Advanced stage and positive resection margins are associated with a high risk of recurrence.1–3 The prognosis after recurrence is extremely poor, with a 5-year overall survival (OS) rate of only 16%.4 A study reported that in patients with loco-regional recurrence, the 5-year OS was less than 10%.5 Effective adjuvant treatment is therefore necessary for extending survival in patients with GBC. However, prospective randomized controlled studies studying the effect of adjuvant treatment for GBC are scarce, and standard adjuvant treatment strategies have not been established. Recent randomized controlled studies have provided conflicting results on the benefits of adjuvant chemotherapy in biliary tract cancer.6,7

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Heterogeneous patient populations in these studies failed to demonstrate the benefit of adjuvant treatment in biliary tract cancer, and controversies persist on the role of adjuvant treatment for patients with resected GBC. Several studies have suggested that adjuvant chemoradiotherapy may improve survival in selected patients with GBC.1–3,8–12 This implies that certain subsets of high-risk patients may benefit from adjuvant chemoradiotherapy; however, the indications have not been determined. The implementation of adjuvant chemoradiotherapy requires a better understanding of loco-regional recurrence after resection for GBC. The aim of this study was to determine the risk factors for loco-regional recurrence in patients who underwent curative R0 resection for GBC, and identify the subgroup of patients who would be most likely to benefit from an adjuvant chemoradiotherapy.

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Please cite this article as: Im JH et al., Prognostic factors and patterns of loco-regional failure in patients with R0 resected gallbladder cancer, HPB, https:// doi.org/10.1016/j.hpb.2019.10.2447

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Methods The records of all patients with GBC adenocarcinoma who underwent curative R0 resection between 2000 and 2016 were retrospectively analyzed. The exclusion criteria were as follows: (1) double primary cancers, (ii) administration of neoadjuvant treatment or adjuvant radiotherapy. In all patients, the disease stage was classified based on the American Joint Committee on Cancer staging system, 8th Edition. R0 resection was defined as achieving negative margin at cystic duct and circumferential margin and absence of cancer cells within 1 cm at the hepatic margin on pathologic examination based on the primary or if performed, secondary operation. The Severance Hospital Institutional Review Board approved this retrospective study. Surgical standardization in GB cancer is a difficult issue, which has led to establish several consensuses guidelines.13–15 Based on these guidelines, a surgical principle has been shared and kept in our institute involving no gallbladder perforation, R0 resection (including bile duct resection, liver resection if necessary), and adequate regional lymph node dissection. Simple cholecystectomy was defined as cholecystectomy without hepatic resection or lymph node dissection. Surgeons decided on the extent of resection considering the intraoperative findings or patient’s age and comorbidity. The standard surgical procedure was radical cholecystectomy (cholecystectomy and segment 4b/5 liver resection around the GB bed), with a margin of approximately 2 cm. The scope for additional or combined resection (major hepatectomy, extrahepatic bile duct resection, pylorus preserving pancreatoduodectomy) was determined by tumor extent. Radical second surgery was usually performed in patients with at least T2 tumors, who had previously undergone simple cholecystectomy. Adjuvant chemotherapy was determined according to the physician’s discretion. Individual gastroenterologists or medical oncologists selected various treatment approaches according to their personal experience and preferences. A median of six cycles of adjuvant chemotherapy were administered. All patients were followed-up 1 month after surgery and at every 3 months for the first 12 months, and every 6–12 months beyond the first year. Initial disease recurrence was determined from imaging studies (computed tomography, magnetic resonance imaging, and positron emission tomography) and pathological studies of histological specimens, with the majority being made by radiological evaluation. Loco-regional recurrence was defined as any recurrence in the surgical bed, porta hepatis, and regional or retroperitoneal lymph nodes.4,5,16–18 Distant recurrence was defined as the appearance of disease in the discontiguous liver, peritoneum, or other organs. The last followup date was March 14, 2019. Survival was calculated from the date of surgical resection. All events were measured from the date of surgery to the date of recurrence. Survival rates were calculated using Kaplan–Meier methods, and were compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards

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model and the hazard ratio with a 95% confidence interval was used for determining the prognostic factors. Variables were included during multivariate analysis based on statistical significance on univariate analysis and clinical relevance. A p-value of <0.05 indicated statistical significance.

Results Patient characteristics The patients who had double primary cancers (N = 6, 2%) and who received neoadjuvant treatment (N = 27, 8%) or adjuvant radiotherapy (N = 27, 8%) were excluded. The remaining 272 (82%) patients were included for analysis. The patient and tumour characteristics are shown in Table 1. The median number of dissected lymph nodes was 14 (range: 1–48). Survival outcomes and patterns of failure At the end of the follow-up period, 50 (18%) patients had died, and 37 (14%) patients were lost to follow up. During follow-up, 63 (23%) patients developed recurrence. Of the survivors, the median follow-up was 60 (range: 3–210) months. The 5-year OS and loco-regional failure-free survival (LRFFS) rates were 81% and 83%, respectively. The median interval between surgical resection and diagnosis of recurrence was 12 (range: 2 to 74) months. Loco-regional recurrences were the first event in 39 (14%) patients, and distant relapse occurred in 42 (15%); 18 (7%) had both, loco-regional relapse and distant recurrence. The liver was the most common site for distant recurrence (22 patients, 8%). Risk factors related to loco-regional failure-free and overall survival The results of uni and multi-variate analysis for LRFFS and OS have been summarized in Tables 1, 2, respectively. Patients were categorized into 3 loco-regional recurrence risk groups according to the number of risk factors they possessed among the following 3 factors: lymphovascular invasion, T3, and N1. Patients in group 1 did not demonstrate any risk factors (N = 178, 65%). Group 2 was defined as those who had 1 risk factor (N = 63, 23%), and group 3 was defined as those who possessed 2 or 3 risk factors (N = 31, 11%). Patterns of first failures were analyzed by number of risk and factors and treatment combinations (Table 3). The 5-year LRFFS in groups 1, 2, and 3 were 94%, 73%, and 40%, respectively (Fig. 1a), and the 5year OS in groups 1, 2, and 3 were 90%, 75%, and 47%, respectively (Fig. 1b). LRFFS and OS were significantly different among the 3 groups (p < 0.05).

Discussion This study intended to analyze the patterns of initial failure in patients with GBC and identify a subgroup of patients that may obtain benefit from adjuvant chemoradiotherapy. This

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Please cite this article as: Im JH et al., Prognostic factors and patterns of loco-regional failure in patients with R0 resected gallbladder cancer, HPB, https:// doi.org/10.1016/j.hpb.2019.10.2447

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Table 1 Patient and tumour characteristics and univariate analysis

of prognostic factors for loco-regional failure-free and overall survival Prognostic factor

5-year survival rate (%) LRFFS

Age (years)

p-value

OS

0.328

 65 (N = 148)

81

> 65 (N = 124)

87

Sex

0.646 83 79

0.749

Male (N = 111)

85

Female (N = 161)

83

Operative procedures

0.898 82 81

0.092

0.266

Cholecystectomy (N = 22)

86

80

Cholecystectomy + LN (N = 55)

93

91

Others (N = 195)

80

Second operation

79 0.738

Yes (N = 75)

81

No (N = 197)

84

Histologic grade

0.120 89 79

<0.001

WD (N = 116)

94

MD/PD/Unknown (N = 156)

75

Lymphovascular invasion

<0.001 91 75

<0.001

<0.001

Yes (N = 40)

42

53

No (N = 232)

90

86

Perineural invasion

<0.001

<0.001

Yes (N = 28)

52

41

No (N = 244)

87

86

T stage

<0.001

<0.001

T1 (N = 61)

97

94

T2 (N = 171)

85

85

T3 (N = 40)

54

N stage

51 <0.001

<0.001

N0 (N = 216)

88

84

N1 (N = 50)

64

73

N2 (N = 6)

83

Adjuvant chemotherapy

p-value

44 0.002

<0.001

Yes (N = 59)

70

66

No (N = 213)

87

86

LRFFS, loco-regional failure-free survival; OS, overall survival; LN, lymph node dissection; WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated.

retrospective study investigated patients with GBC who underwent curative R0 resection without adjuvant radiotherapy; the initial loco-regional recurrence rate was 14%. On multivariate analysis, the risk factors of LRFFS were lymphovascular invasion, T3, and N1. The loco-regional recurrence rates, 5-year LRFFS, and 5-year OS in patients with >1 risk factors were found to be 52%, 40%, and 47%, respectively. These finding suggests that HPB xxxx, xxx, xxx

adjuvant chemoradiotherapy may need to be considered in these patients. Complete surgical resection remains the only potentially curative treatment; however, many patients develop recurrence. The prognosis of GBC remains poor, with the 5-year OS rate at only 15–30%.19,20 Therefore, effective adjuvant treatment strategies are necessary for extending survival in patients with GBC undergoing curative resection. Adjuvant radiotherapy and chemotherapy has been employed to reduce loco-regional recurrence or distant metastases. However, owing to the heterogeneity of treatment strategies in studies and the availability of conflicting evidence from literature, controversies persist on the optimal adjuvant treatment for GBC. Prospective randomized controlled and retrospective studies have failed to demonstrate clear benefits of adjuvant chemotherapy. In the Phase III PRODIGE 12-ACCORD 18 trial, adjuvant GEMOX failed to show improvement in OS in patients with resected biliary tract cancer.6 On per-protocol analysis, the BILCAP trial reported that adjuvant capecitabine possibly improved survival in patients with resected biliary tract cancer.7 On subgroup analysis in the intention-to-treat population, adjuvant capecitabine did not demonstrate any improvement of OS in patients with muscle-invasive GBC (hazard ratio: 0.84; 95% confidence interval: 0.43–1.63). These two prospective studies, which comprised heterogeneous populations with respect to tumor site, TNM stage, and resection margin, were relatively underpowered to demonstrate the survival benefits of adjuvant chemotherapy. A retrospective study reported that patients with lymph node-positive or T3-4 disease obtained survival benefit from adjuvant chemotherapy.21 Other studies have reported that adjuvant chemotherapy alone does not improve OS.2,10,22 These studies demonstrate the conflicting evidence on adjuvant chemotherapy for GBC; therefore, further studies investigating the benefits of adjuvant chemotherapy are of utmost necessity. The current available literature does not provide any consensus regarding adjuvant chemoradiotherapy. To the best of the author’s knowledge, there are no prospective randomized controlled studies of adjuvant chemoradiotherapy in GBC. Although one study has reported no benefit with adjuvant chemoradiotherapy,22 many retrospective studies have reported improvements in survival with chemoradiotherapy in GBC.1– 3,8–12 However, the indications for adjuvant chemoradiotherapy have not been established. Several studies have demonstrated that adjuvant chemoradiotherapy significantly improves survival in patients with GBC who have positive lymph nodes2,3,8 or higher T stage.2,3 Other studies have reported that adjuvant chemoradiotherapy may offer some benefit in patients with positive surgical margins.1,11 Therefore, it is essential to identify those who may obtain survival benefits from adjuvant chemoradiotherapy. The loco-regional recurrence rates for GBC following curative resection alone has been reported to be 17%–67%.5,9,12,23

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Please cite this article as: Im JH et al., Prognostic factors and patterns of loco-regional failure in patients with R0 resected gallbladder cancer, HPB, https:// doi.org/10.1016/j.hpb.2019.10.2447

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Table 2 Multivariate analyses of prognostic factors for loco-regional failure-free and overall survival

Variable

LRFFS

OS

HR (95% CI)

p-value

HR (95% CI)

p-value

Histologic grade WD

Reference

MD/PD/Unknown

1.590 (0.638–3.962)

Reference 0.319

1.949 (0.883–4.301)

0.098

Lymphovascular invasion No

Reference

Yes

4.532 (2.107–9.745)

Reference <0.001

1.817 (0.887–3.723)

0.103

Perineural invasion No

Reference

Yes

0.932 (0.369–2.356)

Reference 0.882

1.603 (0.708–3.628)

0.257

T stage T1

Reference

T2

1.930 (0.425–8.770)

0.395

Reference 2.280 (0.665–7.811)

0.190

T3

6.750 (1.323–34.456)

0.022

5.556 (1.442–21.409)

0.013

N stage N0

Reference

N1

2.277 (1.175–4.412)

0.015

Reference 1.513 (0.821–2.789)

0.184

N2

0.811 (0.103–6.389)

0.842

3.465 (1.003–11.970)

0.049

LRFFS, loco-regional failure-free survival; OS, overall survival; WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated.

Table 3 Patterns of first recurrence according to loco-regional

recurrence risk group Loco-regional recurrence risk group

Patterns of failure LRF

DF

LRF + DF

9

11

3

Group 1 Total (N = 178) Surgery alone (N = 166)

9

9

3

Surgery with adjuvant CTx (N = 12)

0

2

0

Group 2 Total (N = 63)

14

15

5

Surgery alone (N = 38)

10

9

4

Surgery with adjuvant CTx (N = 25)

4

6

1

Group 3 Total (N = 31)

16

16

10

Surgery alone (N = 9)

5

3

2

Surgery with adjuvant CTx (N = 22)

11

13

8

CTx, chemotherapy; LRF, loco-regional failure; DF, distant failure. Group 1 included patients with no risk factor (T3, N1, lymphovascular invasion). Group 2 included patients with 1 risk factor (T3, N1, lymphovascular invasion). Group 3 included patients with 2 or 3 risk factors (T3, N1, lymphovascular invasion).

However, studies on the prognostic factors that influence LRFFS are limited. In this study, lymphovascular invasion, T3, and N1 were found to confer high risk of loco-regional failure. T2 was HPB xxxx, xxx, xxx

not found to be significantly associated with loco-regional failure. In the study by Kim et al., T2 disease was significantly associated with loco-regional control.5 The discrepancy in the risk factors may partly be attributed to a smaller sample size, which was as low as 70 in that study; the median follow-up period was also short, at 23 months. From the current results patients with lymphovascular invasion, T3, and N1 would seem to be the best group of patients to enroll in a trial using adjuvant chemoradiotherapy. The current data would suggest including patients with none of the above identified risk factors would put patients at risk of harm with little likelihood of providing benefit. In this study, in patients with at least two risk factors among lymphovascular invasion, T3, and N1, the loco-regional failure rate and 5-y LRFFS were 52% was 40%, respectively. Therefore, further studies should be performed to confirm whether adjuvant chemoradiotherapy can increase clinical outcomes. The current study has several limitations. First, this is a nonrandomized retrospective study, with a probability of unrecognized bias. The small number of patients with three locoregional recurrence risk factors is another limitation of this study. Further larger studies investigating this limitation are needed in the future. In conclusion, lymphovascular invasion, T3, and N1 disease was significantly increased loco-regional recurrence in patients with GBC adenocarcinoma following curative R0 resection, and the presence of more than two risk factors conferred a higher risk of loco-regional failure and death. The results of this study may be useful in helping design future trials for adjuvant

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Figure 1 Comparison of loco-regional failure-free survival (A) and overall survival (B) curves based on loco-regional recurrence risk groups.

Group 1 included patients with no risk factor (T3, N1, lymphovascular invasion). Group 2 included patients with 1 risk factor (T3, N1, lymphovascular invasion). Group 3 included patients with 2 or 3 risk factors (T3, N1, lymphovascular invasion)

chemoradiotherapy in patients who have undergone potentially curative resection for GBC.

7. Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D et al. (2019) Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 20:663–673.

Funding source

8. Cho SY, Kim SH, Park SJ, Han SS, Kim YK, Lee KW et al. (2010) Adjuvant chemoradiation therapy in gallbladder cancer. J Surg Oncol

None.

102:87–93. 9. Gu B, Qian L, Yu H, Hu J, Wang Q, Shan J et al. (2018) Concurrent

Conflicts of interest

chemoradiotherapy in curatively resected gallbladder carcinoma: a

None declared.

propensity score-matched analysis. Int J Radiat Oncol Biol Phys 100: 138–145. 10. Tran Cao HS, Zhang Q, Sada YH, Chai C, Curley SA, Massarweh NN.

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