Abstract
Background:
Gallbladder cancer (GBC) is the most common biliary malignancy frequently metastatic at diagnosis with poor prognosis. While surgery remains the standard for early-stage GBC, the role of surgery in patients with metastatic gastrointestinal cancers is expanding due to improvements in systemic therapies. We sought to evaluate the survival of patients with stage IV GBC undergoing surgery in an era of improved multi-agent systemic therapy.
Methods:
A retrospective review of the National Cancer Database was performed. Patients with stage IV GBC who underwent systemic therapy were included. Patients who received radiation therapy, palliative therapy or had missing survival data were excluded. Univariable and multivariable analysis was performed.
Results:
4,145 patients were identified between 2004–2016. Mean age was 69. Surgery combined with systemic therapy predicted improved median survival compared with chemotherapy alone (11.1mo versus 6.8mo, HR 0.65, p<0.001). Additionally, receipt of treatment after 2011 predicted improved survival (HR 0.86, p<0.001). Patients treated with multi-agent chemotherapy in combination with surgery were associated with the greatest hazard ratio benefit (0.40, p<0.001) versus single agent therapy alone.
Conclusion:
Patients with stage IV gallbladder cancer treated with a combination of surgery and chemotherapy are associated with an improved overall survival compared to chemotherapy alone. Patients receiving care during the more recent era demonstrated improved survival. These results support a role for surgery in selected patients with stage IV gallbladder cancer receiving chemotherapy.
Introduction
Gallbladder cancer (GBC) is an uncommon malignancy with a reported incidence of 1.6–2.0/100,000 in western European populations, 1.2/100,000 in the US[1–3]. Higher rates are observed in central Europe, Chile, India, Korea, and Japan[1]. There is a female predominance for the disease which peaks in the 7th decade of life[1, 4]. While rare, it is the most common biliary tract cancer representing nearly two-thirds of new diagnoses[5]. Though the underlying biology remains poorly understood, many conditions that promote an inflammatory state (cholelithiasis, chronic infection, congenital malformations of the biliary tree) are considered risk factors for cancer formation[2].
Perhaps due to a lack of early symptoms and paucity of effective screening diagnostic tools, GBC is often diagnosed at an advanced stage. According to Surveillance, Epidemiology, and End Results (SEER) statistics, 44.3% of new GBC cases have distant disease at the time of diagnoses and 39.2% are regionally advanced[3]. Additionally, it is not uncommon for GBC to be upstaged following diagnostic laparoscopy where occult nodal, liver, and peritoneal metastases may be identified in as many as 38–62% of patients [4, 6]. For these reasons, the survival of GBC patients is poor across all stages and particularly for stage IV with a median survival of less than 1 year[5, 7].
Advancements in systemic therapy regimens have led to improved outcomes for patients with advanced biliary tract cancers. The ABC-02 trial was a randomized phase III trial conducted by 37 centers in the United Kingdom in which overall survival (OS) was improved with combination of cisplatin and gemcitabine compared with gemcitabine alone for patients with locally advanced or metastatic biliary cancers including GBC (11.7 months versus 8.1, p<0.001)[8]. As a result, this regimen has become the standard of care for patients with an adequate performance status. Since that time new interest has been placed on curative intent surgery in select stage IV GBC patients initially treated with systemic therapy. Several studies have described the feasibility of this approach with noted survival benefits; however, these were limited to case series and small single institution studies[1, 5, 9, 10].
Here, we examine the oncologic outcomes of a large cohort of patients undergoing surgery for stage IV gallbladder cancer. We hypothesized that in the wake of the ABC-02 trial, multi-modality therapy including both surgery and chemotherapy would be associated with improved survival.
Materials & Methods
Data source:
The National Cancer Database (NCDB) is a nationwide oncology outcomes database that is used to define trends in cancer care, create regional and state benchmarks for participating hospitals, and to serve as a basis for quality improvement. A joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, the NCDB is a hospital based registry what captures 70% of newly diagnosed cancers from more than 1,500 participating facilities across the United States. The NCDB has not verified and is not responsible for the statistical analysis or interpretations provided by the investigators. After receiving appropriate IRB exemption, we queried the NCDB to conduct a retrospective review of patients with stage IV GBC treated between 2004 and 2016.
Study Patients:
We identified patients aged 18 years and older who underwent definitive surgery for GBC between 2004 and 2016 from the NCDB. Definitive surgery is defined as the most definitive procedure of the primary tumor site, in this case the gallbladder, as determined by site specific surgery code c23.9. Patients without stage IV disease, those who received palliative therapy, and those with missing surgical and treatment outcomes data were excluded. We also excluded patients who received radiation as part of their treatment as this represented a small percentage of patients, and we aimed for a clean focus on the role of both surgery and chemotherapy. Cancer sites were determined as per the SEER cancer statistics review using International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) site and histology codes: 8140, 8560, 8480, 8260, 8070, 8255, 8020, 8071, 8050[11]. Cancer stages were summarized based on the American Joint Committee on Cancer (AJCC) staging 7th edition[12]. Patient characteristics included in the analysis were age, sex, race/ethnicity, Charlson-Deyo score, location (regional), insurance status, primary site of the cancer, tumor size, positive pathological lymph nodes, days elapsed between date of definitive diagnosis and the date of starting definitive treatment among other characteristics.
Statistical Analysis:
All the statistical analysis was carried out by the Department of Biostatistics and Informatics at Emory University, using SAS 9.3. We utilized Cox proportional hazard model for our multivariable analysis after step-wise selection. Pearson Chi-square tests were used to compare clinical and pathological characteristics associated with OS outcomes.
We analysed and examined associations between OS and clinicopathological characteristics to identify predictors for improved survival outcomes, adjusted for age, sex, race/ethnicity, Charlson-Deyo score, lymph node positivity, and tumor size. Furthermore, we utilized Kaplan-Meier and log-rank tests for OS comparisons. Multivariable Cox proportional hazard regression was utilized to associate OS with pre-treatment parameters.
Results
We identified 35,797 patients diagnosed with GBC between 2004–2016. After applying our inclusion and exclusion criteria, 4,145 patients were part of our analysis [Figure 1]. These patients were further sub grouped into: no treatment (NT)(N=722), surgery without systemic therapy (SA)(N=1,319), surgery with systemic therapy (SS)(N=1,356), and systemic therapy alone (ST)(N=748). Of the 4,145 patients included in our study, the median age was 69, with majority of patients being female (70.7%), white (79.3%), and with histology consistent with adenocarcinoma (89.1%). [Table 1].
Figure 1:
Schematic depicting inclusion/exclusion criteria for patient selection and treatment group
Table 1:
Descriptive statistics of 4145 included patients with stage IV GBC from the NCDB.
| Age at Diagnosis | Mean | 68.06 |
| Median | 69 | |
| Minimum | 24 | |
| Lower Quartile | 60 | |
| Upper Quartile | 77 | |
| Interquartile Range | 17 | |
| Maximum | 90 | |
| Standard Deviation | 11.96 | |
| Missing | 0 | |
| Category | Value | N (%) |
| Sex | Male | 1213 (29.3) |
| Female | 2932 (70.7) | |
| Race category, 3-levels | White | 3289 (79.3) |
| Black | 575 (13.9) | |
| Asian/Other | 281 (6.8) | |
| Charlson-Deyo Score | 0 | 2905 (70.1) |
| 1 | 918 (22.1) | |
| 2+ | 322 (7.8) | |
| Year of Diagnosis | 2004–2010 | 2104 (50.8) |
| 2011–2015 | 2041 (49.2) | |
| Insurance Status (3-level category) | Not insured | 179 (4.4) |
| Private Insurance | 1282 (31.6) | |
| Public Insurance: Medicaid, Medicare, Other Government | 2602 (64.0) | |
| Missing | 82 | |
| Facility Type | Community Cancer Program | 387 (9.5) |
| Comprehensive Community Cancer Program | 1628 (39.9) | |
| Academic/Research Program | 1525 (37.3) | |
| Integrated Network Cancer Program | 545 (13.3) | |
| Missing | 60 | |
| Histology | 8020: Undifferentiated, NOS | 14 (0.3) |
| 8050: Papillary Type Carcinoma | 4 (0.1) | |
| 8070: Epidermoid Type Carcinoma | 54 (1.3) | |
| 8071: Squamous Cell Carcinoma | 8 (0.2) | |
| 8140: Adenocarcinoma | 3693 (89.1) | |
| 8255: Adenocarcinoma, mixed sub-type | 38 (0.9) | |
| 8260: Papillary Adenoma | 55 (1.3) | |
| 8480: Adenocarcinoma, Mucinous sub-type | 138 (3.3) | |
| 8560: Adenocarcinoma, mixed subtype (Adeno-squamous) | 141 (3.4) | |
| AJCC Pathologic T | p0/p1/p1A/p1B | 92 (2.4) |
| p2 | 755 (19.3) | |
| p3 | 1461 (37.4) | |
| p4 | 397 (10.2) | |
| pIS/pX | 1206 (30.8) | |
| Missing | 234 | |
| AJCC Pathologic N | p0 | 702 (18.2) |
| p1 | 876 (22.7) | |
| p2 | 218 (5.7) | |
| pX | 2057 (53.4) | |
| Missing | 292 | |
| AJCC Pathologic M | p1 | 3389 (96.1) |
| pX | 136 (3.9) | |
| Missing | 620 | |
| Treatment Started, Days from Diagnosis | Mean | 10.42 |
| Standard Deviation | 21.03 | |
| Definitive Surgical Procedure, Days from Diagnosis | Mean | 9.85 |
| Standard Deviation | 35.89 | |
| Surgical Margins Status at any CoC Facility | No residual tumor All margins are grossly and microscopically negative | 1010 (25.9) |
| Residual tumor, NOS Involvement is indicated, but not otherwise specified | 582 (14.9) | |
| Microscopic residual tumor Cannot be seen by the naked eye | 529 (13.6) | |
| Macroscopic residual tumor, Gross tumor of the primary site which is visible to the naked eye | 180 (4.6) | |
| Margins not evaluable, Cannot be assessed (indeterminate) | 145 (3.7) | |
| No primary site surgery | 1456 (37.3) |
We compared 1-, 3-, and 5- year survival between the four groups and found that all three therapeutic groups (SA, SS, ST) demonstrated an association with improved survival compared with patients undergoing no treatment (NT)(p<0.001) [Figure 2]. Patients who underwent SS were associated with the greatest improvement in 1-, 3-, and 5-year survival (46.9%, 11.9%, 7.0%, respectively), as compared with NT (8.2%, 2.2%, 1.7%, p<0.001). Significant improvements in 1-, 3-, and 5-year survival as compared to NT was also predicted in SA, and ST treatment groups (18.0%, 5.2%, 3.6%; and 27.6%, 3.1%, 3.1%, p<0.001). Interestingly, when we compared the survival curve of the patients treated with SA versus ST there was a trend towards a predicted increase in survival in the ST group during the initial 20 months; however, after this time point SA was associated with improved survival.
Figure 2:
Survival by treatment group. Patients in the SS treatment group were associated with significantly improved survival compared to ST (MS 10.8mo versus 6.8mo, MVA HR 0.65, p<0.001). Median survival for NT and S were poor (1.6mo and 3.3mo respectively). MVA comparisons versus systemic therapy alone. 95% CI shown. Abbreviations: NT: no treatment, SA: surgery alone, SS: Surgery and systemic therapy, ST: Systemic therapy alone, CI: confidence interval, MVA: multi-variable analysis.
When combined with systemic therapy, patients treated with surgery (SS) demonstrated an association with significant improvement in median OS as compared with ST (11.1 months versus 6.8 months, p<0.001)[Figure 2]. When compared with NT, all other categories (SS, ST, SA) were associated with significant improvements in OS with the greatest survival benefit observed in the SS group (MVA HR 0.29 SS, 0.45 ST, 0.57 S, p<0.001) [Figure 2]. Upon reanalysis with ST as a baseline for comparison, SS continued to demonstrate a significant association with improved survival (HR 0.65. p<0.001) [Figure 2]. As would be expected, patients who received surgery alone were associated with worse 30-day and 90-day mortality (20.4%, 49.03%, respectively) as compared with NT ( 0.0%, 33.3%), SS (1.8%, 11.7%), and ST (0.0%, 0.0%), treatment groups (p<0.001)[Figure 2].
Other factors which were independently associated with improved survival included female sex (HR 0.92, p<0.001), receiving multi-agent or single-agent chemotherapy (HR 0.46, 0.54, versus NT, respectively), and receiving treatment after 2011 (HR 0.86, p<0.001) [Table 2]. Worse survival outcomes were seen with older age (greater than median 69) (HR 1.19, p<0.001), and a Charlson-Deyo score of ≥1 (HR 1.15, p<0.001). Patients treated at community cancer programs, comprehensive community cancer programs, and integrated network cancer programs, were associated with worse survival compared to treatment at academic/research programs (HR 1.39, 1.34, 1.30 respectively, p<0.001).
Table 2:
Top: Univariate analysis of overall survival. Bottom: Combined Univariate and Multivariate analysis of overall survival. 95% confidence intervals and hazard ratios shown. Significance calculated as p<0.005, highlighted in bold. Comparison groups in bold. Abbreviations: HR: hazard ratio.
| Univariate analysis | N | HR (95% CI) | P Value | ||||
|---|---|---|---|---|---|---|---|
| Grade category | Moderately differentiated | 1163 | 1.14 (0.97–1.33) | 0.11 | |||
| Poorly/Undiffer entiated | 1543 | 1.56 (1.33–1.81) | <.001 | ||||
| Well differentiated | 209 | - | - | ||||
| Chemotherap y at any CoC Facility | Single-agent chemotherapy | 587 | 0.54 (0.49–0.60) | <.001 | |||
| Multiagent chemotherapy | 1335 | 0.46 (0.42–0.50) | <.001 | ||||
| None | 1278 | - | - | ||||
| Univariate analysis | Category | Univar iate N | Univariate HR (95% CI) | Univariate P value | Multivariate N | Multivariate HR (95% CI) | Multivariate P value |
| Facility Type | Community Cancer Program | 387 | 1.57 (1.39–1.76) | <.001 | 382 | 1.39 (1.23–1.56) | <.001 |
| Comprehensive Community Cancer Program | 1628 | 1.41 (1.31–1.52) | <.001 | 1614 | 1.34 (1.24–1.44) | <.001 | |
| Integrated Network Cancer Program | 545 | 1.32 (1.19–1.46) | <.001 | 540 | 1.30 (1.17–1.45) | <.001 | |
| Academic/Rese arch Program | 1525 | - | - | 1469 | - | - | |
| Facility region | South | 1408 | 1.16 (1.06–1.27) | <.001 | 1376 | 1.11 (1.01–1.21) | 0.029 |
| Midwest | 1120 | 1.21 (1.10–1.32) | <.001 | 1087 | 1.16 (1.05–1.27) | 0.003 | |
| West | 701 | 1.08 (0.97–1.20) | 0.14 | 637 | 1.11 (1.00–1.24) | 0.059 | |
| Northeast | 916 | - | - | 905 | - | - | |
| Sex | Female | 2932 | 0.93 (0.87–1.00) | 0.046 | 2834 | 0.92 (0.85–0.98) | 0.016 |
| Male | 1213 | - | - | 1171 | - | - | |
| Race category | Black | 575 | 0.94 (0.86–1.03) | 0.205 | 554 | 1.02 (0.93–1.13) | 0.638 |
| Asian/Other | 281 | 0.82 (0.72–0.93) | 0.002 | 262 | 0.91 (0.80–1.05) | 0.193 | |
| White | 3289 | - | - | 3189 | - | - | |
| Age category (median) | Greater than 69 y.o. | 1984 | 1.51 (1.42–1.61) | <.001 | 1952 | 1.19 (1.10–1.28) | <.001 |
| Less than or equal to 69 y.o. | 2161 | - | - | 2053 | - | - | |
| Charlson-Deyo Score | 1 | 918 | 1.20 (1.11–1.30) | <.001 | 910 | 1.15 (1.07–1.25) | <.001 |
| 2+ | 322 | 1.67 (1.48–1.88) | <.001 | 318 | 1.44 (1.27–1.62) | <.001 | |
| 0 | 2905 | - | - | 2777 | - | - |
Further subgroup analysis of patients who underwent surgery combined with multi-agent chemotherapy predicted the greatest improvement in survival as compared with those receiving single agent chemotherapy alone (HR 0.40, p<0.001) [Table 3]. Surgery in combination with single-agent chemotherapy, as well multi-agent chemotherapy alone, were also predictive of improved survival when compared with single agent chemotherapy alone (HR 0.47, 0.71, respectively p<0.001).
Table 3:
Subgroup univariate analysis of overall survival in patients selected by type of chemotherapy received. Abbreviations: HR: hazard ratio.
| Treatment group | N | Hazard Ratio (95% CI) | HR P-Value |
|---|---|---|---|
| Surgery + Multi-Agent Chemotherapy | 795 | 0.40 (0.34–0.47) | <0.001 |
| Surgery + Single-Agent Chemotherapy | 377 | 0.47 (0.39–0.57) | <0.001 |
| Multi-Agent Chemotherapy Alone | 511 | 0.71 (0.60–0.85) | <0.001 |
| Single Agent Chemotherapy Alone | 177 | - | - |
Discussion
The results of the present work suggests that in select patients with stage IV GBC, surgery when combined with chemotherapy may result in improved survival as compared with surgery or chemotherapy alone. This effect of surgery combined with chemotherapy appeared robust with associated improvements in survival over chemotherapy alone regardless of whether patients received single- or multi-agent regimens on sub-group analysis. The observation that patients treated after 2011 were associated with improved OS on multivariable analysis highlights a potential effect of modern chemotherapy protocols instituted after the results of the ABC and ABC-02 trials. Consistent with this idea is the observation in our study that patients who received surgery combined with multiagent chemotherapy were associated with the greatest improvement in OS compared with those receiving single agent therapy alone.
Our results are consistent with a recent review of the SEER database which identified 4527 patients with advanced gallbladder cancer (combining stages III and IV)[5]. In this retrospective review, surgery combined with chemotherapy was also associated with improvements in OS when compared to no treatment[5]. However, they reported no comparisons in OS between treatment groups. Given that the standard of care is systemic therapy alone, we feel the most valuable comparison in our study is that of the ST vs. SA groups, as well how the NT group compares to the other three treatment groups. Our study is further distinguished by focussing on patients with only stage IV disease and examining outcomes based on single vs. multi-agent chemotherapy.
There is now a well-established relationship in the management of a number of solid organ cancers between advancements in systemic therapies applied to patients with stage IV disease and the use of definitive surgery. Surgery is now the standard of care for patients with hepatic metastatic colorectal cancer, appendiceal, renal and ovarian cancer[13–16]. Generally, patients with stage IV GBC are not considered for resection due to overall poor outcomes, and concern for significant complication risk. However, heterogeneity in the behaviour of these rare cancers necessitates further study. One recent case controlled investigation revealed TNM stage was predictive of survival outcomes, identifying that while patients with stage IIIa/b disease benefitted from adjuvant therapy following surgical resection, patients with stage IVa/b did not see similar effects[17]. This study did observe differences in survival based on nodal status and the presence of metastases suggesting differential benefits may be obtained with a neoadjuvant treatment protocol[17]. A separate meta-analysis encompassing 8 studies and 474 patients undergoing definitive resection attempts to clarify a role for neoadjuvant therapy in advanced (Stage III/IV) gallbladder cancer patients[7]. This analysis revealed improvements in OS when neoadjuvant therapy was combined with R0 resection, without comparing patients with stage III versus stage IV disease[7]. This study was also limited in that 20% of neoadjuvant responsive patients did not undergo surgery suggesting selection bias may also have influenced study results[7].
Our study has limitations in addition to the standard limitations of a retrospective study. We are unable to distinguish patient outcomes based on the specific type of chemotherapy protocol they received though multi-agent chemotherapy was associated with a lower hazard ratio for death than single-agent chemotherapy. The NCDB only specifies if the chemotherapy regimen was single- or multi- agent and does not provide information about the dose, duration, or the response to therapy. Our analysis does not distinguish between patients who received chemotherapy before surgery, and those who received post-operative treatment; thus we are unable to determine if there is a difference in outcomes between those two groups. We were also not able to determine if the volume and location of metastatic disease correlated with outcome.
Another limitation of this study is an understanding of the specific factors that went into patient selection for surgery. We found that age and performance status (Charlson-Deyo score) were predictive of outcome and thus we feel that these are factors that certainly should be considered. However, more importantly we think that response and duration of that response to chemotherapy is the most important tool to discriminate patients with a less aggressive disease biology. At our center we typically will not consider a patient for resection who does not demonstrate a response to chemotherapy that lasts at least 6–12 months. With respect to the volume and site of metastatic disease we feel that patients with liver oligo metastatic disease are the best candidates while patients with liver and peritoneal or portal lymph node metastases are poor candidates. We typically use FDG-PET scans in our evaluation to rule out patients with extrahepatic disease and perform a diagnostic laparoscopy at the time of surgery to rule out peritoneal disease. NCDB does not provide data on recurrence or data on additional treatments the patient may have received later in their course of the disease. Despite these limitations, our study’s strength is that it is one of the largest comparisons of survival outcomes in resected stage IV gallbladder cancer patients, and it is unique in that it able to distinguish outcomes based on receipt of single-, versus multi-agent chemotherapy regimens.
Conclusion
We have demonstrated using a large national database that surgery, when combined with chemotherapy, is associated with a significant improvement in survival in highly selected stage IV gallbladder cancer patients as compared to patients treated with either surgery or chemotherapy alone. These effects are enhanced with the use of multi-agent chemotherapy. Further studies should focus on defining selection criteria for surgery as well as identifying biomarkers that may predict this population of patients at diagnosis to assist in patient selection. For now, response to systemic therapy with disease control for 6–12 months is a reasonable tool to assist with this.
Synopsis:
The role of surgery for stage IV gallbladder cancer is undefined. Review of the National Cancer Database predicts survival improvement for surgery combined with chemotherapy, favoring multi-agent regimens. In select patients with stage IV gallbladder cancer, surgery may be beneficial.
Footnotes
Disclosures:
Research reported in this publication was supported in part by the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Anthony Casabianca: Study Concepts, Study Design, data analysis and interpretation, manuscript preparation, manuscript editing, manuscript review. Vasileios Tsagkalidis: Study Concepts, manuscript editing. Paul Burchard: Study Concepts, manuscript editing. Alexander Chacon: Study Concepts, manuscript editing. Alexa Melluci: Study Concepts, manuscript editing. Alexandra Reitz: Study Concepts, manuscript editing. David Swift: Study Concepts, manuscript editing. Ashely McCook: Data Acquisition, Control of Data and Algorithms, statistical analysis. Jeffrey Switchenko: Data Acquisition, Control of Data and Algorithms, statistical analysis. Mihir Shah: Study Concepts, Study Design, data analysis and interpretation, manuscript preparation, manuscript editing, manuscript review. Darren Carpizo: Study Concepts, Study Design, data analysis and interpretation, manuscript editing, manuscript review
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References:
- 1.Castelo Branco M, et al. , Gallbladder Cancer: Complete Resection after Second Line Treatment in Stage IV Disease. Journal of Gastrointestinal Cancer, 2019. 50(3): p. 564–567. [DOI] [PubMed] [Google Scholar]
- 2.Valle JW, et al. , Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 2016. 27: p. v28–v37. [DOI] [PubMed] [Google Scholar]
- 3.Institute NC, SEER Explorer: An interactive website for SEER cancer statistics. 2021. [Google Scholar]
- 4.Gamboa AC and Maithel SK, The Landmark Series: Gallbladder Cancer. Ann Surg Oncol, 2020. 27(8): p. 2846–2858. [DOI] [PubMed] [Google Scholar]
- 5.Mao W, et al. , Treatment of advanced gallbladder cancer: A SEER-based study. Cancer Medicine, 2020. 9(1): p. 141–150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Aloia TA, et al. , Gallbladder cancer: expert consensus statement. HPB (Oxford), 2015. 17(8): p. 681–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hakeem AR., Papoulas M, and Menon KV, The role of neoadjuvant chemotherapy or chemoradiotherapy for advanced gallbladder cancer – A systematic review. European Journal of Surgical Oncology, 2019. 45(2): p. 83–91. [DOI] [PubMed] [Google Scholar]
- 8.Valle J, et al. , Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med, 2010. 362(14): p. 1273–81. [DOI] [PubMed] [Google Scholar]
- 9.Kang MJ, et al. , Role of radical surgery in patients with stage IV gallbladder cancer. HPB : the official journal of the International Hepato Pancreato Biliary Association, 2012. 14(12): p. 805–811. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Kondo S, et al. , Five-year survivors after aggressive surgery for stage IV gallbladder cancer. J Hepatobiliary Pancreat Surg, 2001. 8(6): p. 511–7. [DOI] [PubMed] [Google Scholar]
- 11.World Health O, International classification of diseases for oncology (ICD-O) – 3rd edition, 1st revision. 3rd ed. ed. 2013, Geneva. [Google Scholar]
- 12.Edge SB, et al. , AJCC cancer staging manual. Vol. 649. 2010: Springer; New York. [Google Scholar]
- 13.Adam R. and Vinet E, Regional treatment of metastasis: surgery of colorectal liver metastases. Ann Oncol, 2004. 15 Suppl 4: p. iv103–6. [DOI] [PubMed] [Google Scholar]
- 14.Ito K, et al. , Surgical treatment of hepatic colorectal metastasis: evolving role in the setting of improving systemic therapies and ablative treatments in the 21st century. Cancer J, 2010. 16(2): p. 103–10. [DOI] [PubMed] [Google Scholar]
- 15.Aletti GD, et al. , Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol, 2006. 107(1): p. 77–85. [DOI] [PubMed] [Google Scholar]
- 16.Flanigan RC, et al. , Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med, 2001. 345(23): p. 1655–9. [DOI] [PubMed] [Google Scholar]
- 17.Yuza K, et al. , Outcome of radical surgery for gallbladder carcinoma according to TNM stage: implications for adjuvant therapeutic strategies. Langenbecks Arch Surg, 2021. 406(3): p. 801–811. [DOI] [PubMed] [Google Scholar]