Adjuvant Chemoradiotherapy is Associated with

Adjuvant Chemoradiotherapy is Associated with Improved Survival for Patients with Resected Gallbladder Carcinoma: A Systematic Review and Meta-analysis Byoung Hyuck Kim, Jeanny Kwon, Eui Kyu Chie, Kyubo Kim, Young Hoon Kim, Dong Wan Seo, Amol K. Narang & Joseph M. Herman Annals of Surgical Oncology ISSN 1068-9265 Ann Surg Oncol DOI 10.1245/s10434-017-6139-1

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Author's personal copy Ann Surg Oncol DOI 10.1245/s10434-017-6139-1

ORIGINAL ARTICLE – HEPATOBILIARY TUMORS

Adjuvant Chemoradiotherapy is Associated with Improved Survival for Patients with Resected Gallbladder Carcinoma: A Systematic Review and Meta-analysis Byoung Hyuck Kim, MD1, Jeanny Kwon, MD, PhD2, Eui Kyu Chie, MD, PhD1,3, Kyubo Kim, MD, PhD4, Young Hoon Kim, MD, PhD5, Dong Wan Seo, MD, PhD6, Amol K. Narang, MD, PhD7, and Joseph M. Herman, MD, PhD7 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea; 2Department of Radiation Oncology, Chungnam National University College of Medicine, Daejeon, Korea; 3Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea; 4Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Korea; 5Department of General Surgery, Dong-A University College of Medicine, Busan, Korea; 6Department of Gastroenterology, Asan Medical Center, University of Ulsan Medical College, Seoul, Korea; 7Department of Radiation Oncology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD

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ABSTRACT Background. The impact of adjuvant radiotherapy (ART) on survival from gallbladder carcinoma (GBC) remains underexplored, with conflicting results reported. A systematic review and meta-analysis was performed to clarify the impact of ART in GBC. Methods. A systematic literature search of several databases was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, from inception to August 2016. Studies that reported survival outcomes for patients with or without ART after curative surgery were included.

Byoung Hyuck Kim and Jeanny Kwon have contributed equally to this work.

Electronic supplementary material The online version of this article (doi:10.1245/s10434-017-6139-1) contains supplementary material, which is available to authorized users.

Results. All the inclusion criteria was met by 14 retrospective studies including 9364 analyzable patients, but most of the studies had a moderate risk of bias. Generally, the ART group had more patients with unfavorable characteristics than the group that had surgery alone. Nevertheless, the pooled results showed that ART significantly reduced the risk of death (hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.44–0.67; p \ 0.001) and recurrence (HR 0.61; 95% CI 0.38–0.98; p = 0.04) of GBC compared with surgery alone. Exploratory analyses demonstrated a survival benefit from ART for a subgroup of patients with lymph node-positive diseases (HR 0.61; p \ 0.001) and R1 resections (HR 0.55; p \ 0.001), but not for patients with lymph node-negative disease (HR 1.06; p = 0.78). No evidence of publication bias was found (p = 0.663). Conclusions. This study is the first meta-analysis to evaluate the role of ART and to provide supporting evidence that ART may offer survival benefits, especially for high-risk patients. However, further confirmation with a randomized prospective study is needed to clarify the subgroup of GBC patients who would benefit most from ART.

Ó Society of Surgical Oncology 2017 First Received: 20 June 2017 E. K. Chie, MD, PhD e-mail: [email protected] K. Kim, MD, PhD e-mail: [email protected]

Gallbladder cancer (GBC) is one of the most aggressive tumors of the biliary tract, and complete surgical resection is the only potentially curative strategy.1,2 However, even after oncologic resection, including partial hepatectomy and regional lymph node (LN) dissection, many patients

Author's personal copy B. H. Kim et al.

experience a relapse, and the reported 5-year survival rate for advanced cases is 40% at best.2–4 Because of the high distant metastasis rate, much effort has focused on the application of various types of adjuvant chemotherapy, although the role of adjuvant radiotherapy (ART) remains, at best, controversial. Still, many patients treated with surgery alone succumb to uncontrolled locoregional diseases.2,4–7 Literature on the patterns of GBC failure remains inconclusive. However, considerable locoregional recurrences have been reported and may support the need for incorporating ART into the treatment plan.3,8,9 Unfortunately, high-quality clinical evidence is difficult to obtain due to the relative rarity of GBC and the scarcity of ongoing trials for ART. With regard to the level of evidence, several recent studies have suggested that the average results from observational studies generally produce estimates similar to those of randomized controlled trials.10,11 Based on these findings, a meta-analysis may be an alternative approach to estimation of comparative results. However, no meta-analysis to date has evaluated the impact of ART in GBC. Several retrospective studies assessing the role of ART with larger cohorts have been published recently but were not been included in the previous meta-analysis for biliary tract cancers.12–17 Thus, a more comprehensive and credible analysis focusing on ART was deemed possible by inclusion of recently published articles. Therefore, a systematic review and meta-analysis focusing on the impact of ART in GBC was performed to clarify its role, and to identify patients who would most likely benefit from ART. METHODS Literature Search Strategy The methods applied for the current meta-analysis were similar to those reported in previous publications.18,19 Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic search was performed to screen studies that analyzed overall survival (OS) or disease-free survival (DFS) for patients who underwent resection followed by ART for GBC.20 Using a predefined strategy, a comprehensive review was performed from inception to August 2016 in the following databases: MEDLINE via PubMed, EMBASE, and the Cochrane Library (see Supplementary Methods). Study Selection Criteria Studies eligible for the meta-analysis included those with patients who underwent any type of cholecystectomy followed by ART as an experimental group (irrespective of concurrent chemotherapy) and studies with patients who

underwent resection alone without adjuvant treatment as a comparator group. Studies with unclear comparator groups were excluded. To reduce heterogeneity across the studies, several exclusion criteria were used (see Supplementary Methods). Data Extraction Data extraction was performed independently by two authors (B.H.K. and J.K.) to rule out the subjective effect (see Supplementary Methods). For situations in which the description was insufficient in the original report or existed as unpublished data (abstract only), additional information was obtained through personal communication with the corresponding author of the study. Risk of Bias Assessment The Risk-of-Bias-Assessment Tool for Observational Studies (RoBANS) was initially considered because there were no randomized trials21 (see Supplementary Methods). Statistical Analysis The hazard ratio (HR) for ART on OS or DFS was used as an effect size.22,23 The pooled HR was calculated using the random-effects model. The level of heterogeneity between studies was evaluated with the Cochrane Q test and the I2 statistic.24 Planned subgroup analyses were performed to investigate the sources of heterogeneity across the studies. The contour-enhanced funnel plot method together with Egger’s regression test also was used to assess publication bias and a potential small study effect (see Supplementary Methods). RESULTS Study Selection and Characteristics After screening for the inclusion criteria and review of the full texts of potentially eligible studies, 14 nonrandomized observational studies were identified.9,12–17,25–31 (Fig. 1). The selected set of studies included a total of 9364 analyzable patients, of whom 2405 received ART and 6959 received surgery alone. The detailed characteristics of the included studies are summarized in Table 1. All the studies except one reported OS as a survival outcome (Kim et al.9 reported DFS and not OS). Neither LRC nor DFS was not reported well in the majority of the publications. In terms of patient characteristics, the median age ranged from 53 to 73 years, and a considerable proportion of patients (range 32–100%) underwent radical surgeries

Author's personal copy Adjuvant Radiotherapy in Gallbladder Cancer FIG. 1 Study selection process

504 Papers potentially relevant 298 From EMBASE 203 From PubMed 3 From Cochrane 0 From manual search 138 Excluded (duplicated)

366 Screened for eligibility using titles and abstracts

319 Excluded 185 Irrelevant topic 69 Review or case report 12 Combined palliative cases 18 No comparators 8 No adjuvant treatment 17 Insufficient data 5 Overlapping 5 Duplicate 47 Assessed for eligibility 33 Excluded 1 Review or case report 1 Combined palliative cases 8 No comparators 2 No adjuvant treatment 15 Insufficient data 6 Overlapping 14 Studies included in meta-analysis

(equal to or more than those who undergo the typical extended cholecystectomy [EC]). With regard to the proportion of patients with microscopic residuum (R1), advanced T stage, as well as nodal involvement, the ART group had more patients with unfavorable characteristics than the surgery-alone group, although an exact comparison was difficult to make due to missing data. Concurrent chemotherapy regimens also were variable among the studies, with 5-fluorouracil (5-FU) or gemcitabine more commonly administered when reported. The ART dose consistently ranged from 40 to 50 Gy. Risk-of-Bias Assessment A summary of the risk-of-bias assessment is provided in Table S1. All 14 studies were retrospective analyses, and most had a moderate risk of bias. Commonly identified concerns included participant selection and confounding variables. As previously mentioned, the distribution of risk

factors was skewed against the ART group, and survival analyses were performed without adjustment for confounding variables, more often in older studies. Impact of ART on OS The main results of 13 individual studies that reported on OS are summarized in Fig. 2a. The pooled results demonstrated that ART significantly reduced the risk of death compared with surgery alone (HR 0.54; 95% confidence interval [CI] 0.44–0.67; p \ 0.001). Significant heterogeneity existed between the included studies (I2 index, 61%; p = 0.002), mainly due to two studies, by Gold et al.29 and Kim et al.,9 which reported the largest favorable effects of ART. After exclusion of these two studies, the heterogeneity was deemed insignificant (I2 index, 32%; p = 0.14), whereas the effects of ART still remained significant despite the slightly reduced effect size (HR 0.63; 95% CI 0.54–0.74; p \ 0.001; Fig. S1).

Author's personal copy B. H. Kim et al. TABLE 1 Characteristics of included studies Author

Institution (country) Study period

Todoroki et al.25

Median Extent of age (years) surgery (%)

No. of patients Adjuvant treatment S

S ? RT RT dose Median (range)

Concurrent CTx

University of Tsukuba (Japan)

1976–1996 64

C EC (86)

38

47

IORT 21 Gy (15–30) or EBRT 40 Gy (24.8–54.0)

Lindell et al.26 University hospital (Sweden)

1991–1999 62

C EC (100)

10

10

IORT 20 Gy ? EBRT 40 Gy Yes, 5-FU

Kanazawa Medical Center (Japan)

1994–2004 73

C ? LND (100)

13

5

Balachandran et al.28

SGPGIMS (India)

1989–2000 53

EC (32)

44

73

Gold et al.29

Mayo clinic (USA)

1985–2004 63

EC (75)

48

25

EBRT 50.4 Gy (19.75–54.0)

Yes, 5-FU

Kim et al9

Samsung Medical Center (Korea)

1994–2007 61

C EC (60)

47

36

EBRT 44–45 Gy

Partly yes, 5-FU/ Cis/Cap

Cho et al.30

National Cancer Center (Korea)

2001–2009 NR

EC (100)

28

40

EBRT 45 Gy

Yes, 5-FU/ Cis ? Cap/ Gem

Lee et al.13

Dong-A University (Korea)

1994–2011 63

EC (71)

83

62

NR

Yes, 5-FU/Gem

Lim et al.12

Asan Medical Center (Korea)

1999–2009 63

EC (61)

224

55

NR

Partly yes, NR

Ito et al.

27

Hyder et al.14 SEER (USA)

1988–2009 72

C EC (61)

894

894

Wang et al.15

1985–2008 61

C EC (100)

44

68

Hoehn et al.16 NCDB (USA)

1998–2006 NR

NR

Kothari et al.31

Moffitt Cancer Center (USA)

2000–2010 NR

C EC (64)

39

Kim et al.17

10 Multicenter (USA)

2000–2015 67

C EC (77)

186

6 Multicenter (USA)

Author

EBRT 45.2 Gy (45.0–56.7)

No

NR

Yes, NR

NR

Partly yes, NR

EBRT 50.4 Gy (37.8–68.0)

Partly yes,

NR

5-FU/Cap/Gem Yes, NR

34

NR

No

44

NR

Yes, Gem/ Gem ? Cis/ others

5261 1012

Margin involvement

T stage distribution

LN-positive

S (%)

S ? RT (%)

S (%)

S ? RT (%)

S (%)

S ? RT (%)

50

59

C T2 (100)

C T2 (100)

NR

NR

Lindell et al.

50

50

C T2 (100)

C T2 (80)

20

30

NR

Ito et al.27 Balachandran et al.28

31 NR

60 NR

NR C T2 (86)

NR C T2 (89)

NR 57

NR 42

NR NR

Gold et al.29

Todoroki et al.25 26

Median follow-up (months)

12

0

0

C T2 (21)

C T2 (80)

13

56

45a

9

0

0

C T2 (100)

C T2 (100)

NR

NR

NR

30

11

8

T2/3 (100)

T2/3 (100)

43

70

NR

Lee et al.13

11

12

C T2 (63)

C T2 (89)

11

19

NR

Lim et al.12

36

64

NR

NR

43

67

17

Hyder et al.14

NR

NR

C T3 (35)

C T3 (37)

37

36

NR

Wang et al.15

9

37

C T3 (16)

C T3 (57)

18

63

47a

Hoehn et al.16

13

20

C T2 (58)

C T2 (81)

40

63

NR

Kothari et al.31

NR

NR

NR

NR

NR

NR

28

Kim et al

Cho et al.

No

Author's personal copy Adjuvant Radiotherapy in Gallbladder Cancer TABLE 1 continued Author

Kim et al.17

Margin involvement

T stage distribution

LN-positive

Median follow-up (months)

S (%)

S ? RT (%)

S (%)

S ? RT (%)

S (%)

S ? RT (%)

14

18

C T2 (87)

C T2 (97)

27

55

26

Some information was filled in and corrected by contacting authors of each study via email LN lymph node, S surgery, RT radiotherapy, CTx chemotherapy, EC extended cholecystectomy, IORT intraoperative radiotherapy, EBRT external beam radiotherapy, NR not reported, 5-FU 5-fluorouracil, C cholecystectomy, LND lymph node dissection, Cis cisplatin, Cap capecitabine, Gem gemcitabine, SEER Surveillance, Epidemiology, and End Results database, NCDB National Cancer Data Base a

Follow-up period for surviving patients

A

Forest plot of hazard ratios for overall survival

Study

Weight

Hazard Ratio IV, Random, 95% Cl

Todoraki 1999 Lindell 2003 Itoh 2005 Balalchandran 2006 Gold 2009 Cho 2010 Lee 2012 Lim 2013 Hyder 2014 Wang 2015 Kithari 2015 Hoehn 2015 Kim Y 2016

9.8% 1.5% 0.7% 9.6% 4.9% 0.9% 9.2% 10.2% 16.6% 5.9% 5.2% 16.8% 8.7%

0.48 [0.30, 0.77] 0.59 [0.14, 3.18] 2.87 [0.23, 35.05] 0.39 [0.24, 0.63] 0.30 [0.18, 0.69] 0.70 [0.08, 6.30] 0.54 [0.32, 0.89] 0.73 [0.47, 1.15] 0.66 [0.56, 0.78] 0.78 [0.38, 1.62] 0.36 [0.16, 0.79] 0.77 [0.66, 0.90] 0.25 [0.15, 0.43]

Total (95% Cl)

100.0%

0.54 [0.44, 0.67]

Heterogenity: Chi = 30.80, df = 12 (P = 0.002); I2 = 61% Test for overall effect: Z = 5.60 (P < 0.00001)


2

B

0.1 0.2 0.5 1 2 5 10 Favor adjuvant RT Favor surgery alone

Forest plot of hazard ratios for disease-free survival

Study

Weight

Gold 2009 Kim WS 2010 Cho 2010 Wang 2015 Kim Y 2016

19.4% 23.7% 11.8% 19.3% 25.7%


1.36 [0.67, 0.81 [0.48, 0.28 [0.09, 0.48 [0.24, 0.48 [0.27,

100.0%

Total (95% Cl) 2


2.75] 1.38] 0.86] 0.98] 0.68]

0.61 [0.38, 0.98] 2

Heterogenity: Chi = 10.57, df = 4 (P = 0.03); I = 62% Test for overall effect: Z = 2.05 (P = 0.04)

1 2 5 10 0.1 0.2 0.5 Favor adjuvant RT Favor surgery alone

FIG. 2 Forest plot for hazard ratios of a overall survival and b disease-free survival

To investigate other potential sources of heterogeneity, planned subgroup analyses were performed (Fig. 3). However, no significant differences in the effect of ART between the subgroups were detected using the mixed-effects analysis. All the subgroups, categorized by study

level, showed beneficial effects from ART irrespective of publication year (p = 0.12), HR calculation method (p = 0.33), scale of study (p = 0.38), or type of adjuvant treatment (p = 0.17).

Author's personal copy B. H. Kim et al.

Subgroup

No. of studies

Test for overall effect Z P

Favor Adjuvant RT

Favor Surgery alone

Ovreall survival HR (95% CI)

Publication year 1999-2010

6

5.45