A Novel Clinically Based Staging System for Gallbladder Cancer

Background: Current staging systems for gallbladder cancer (GBC) are primarily based on surgical pathology and therefore are not relevant for unresectable patients and those undergoing neoadjuvant chemotherapy. Methods: Patients with a confirmed diagnosis of GBC managed at a tertiary referral center (2000–2016) were included. Independent predictors of overall survival (OS) were identified using multivariable analysis (MVA). A combination of these variables was then assessed to identify a set of factors that provided maximal accuracy in predicting OS, and a nomogram and a new staging system were created based on these factors. Harrell’s C-statistic was calculated to evaluate the predictive accuracy of the nomogram and staging system. Results: A total of 528 patients were included in the final analysis. On MVA, factors predictive of poor OS were older age, ECOG performance status, hemoglobin level <9 g/dL, presence of metastases, and alkaline phosphatase (ALP) level >200 U/L. A nomogram and a 4-tier staging system predictive of OS were created using age at diagnosis, ECOG status, tumor size, presence or absence of metastasis, and ALP level. The C-statistic for this novel staging system was 0.71 compared with 0.69 for the TNM staging system (P=.08). In patients who did not undergo surgery, the C-statistics of the novel and TNM staging systems were 0.60 and 0.51, respectively (P<.001). Conclusions: We created a novel, clinically based staging system for GBC based on nonoperative information at the time of diagnosis that was superior to the TNM staging system in predicting OS in patients who did not undergo surgery, and that performed on par with TNM staging in surgical patients.

Abstract

Background: Current staging systems for gallbladder cancer (GBC) are primarily based on surgical pathology and therefore are not relevant for unresectable patients and those undergoing neoadjuvant chemotherapy. Methods: Patients with a confirmed diagnosis of GBC managed at a tertiary referral center (2000–2016) were included. Independent predictors of overall survival (OS) were identified using multivariable analysis (MVA). A combination of these variables was then assessed to identify a set of factors that provided maximal accuracy in predicting OS, and a nomogram and a new staging system were created based on these factors. Harrell’s C-statistic was calculated to evaluate the predictive accuracy of the nomogram and staging system. Results: A total of 528 patients were included in the final analysis. On MVA, factors predictive of poor OS were older age, ECOG performance status, hemoglobin level <9 g/dL, presence of metastases, and alkaline phosphatase (ALP) level >200 U/L. A nomogram and a 4-tier staging system predictive of OS were created using age at diagnosis, ECOG status, tumor size, presence or absence of metastasis, and ALP level. The C-statistic for this novel staging system was 0.71 compared with 0.69 for the TNM staging system (P=.08). In patients who did not undergo surgery, the C-statistics of the novel and TNM staging systems were 0.60 and 0.51, respectively (P<.001). Conclusions: We created a novel, clinically based staging system for GBC based on nonoperative information at the time of diagnosis that was superior to the TNM staging system in predicting OS in patients who did not undergo surgery, and that performed on par with TNM staging in surgical patients.

Background

Gallbladder cancer (GBC), although an uncommon cancer of the gastrointestinal tract, constitutes approximately two-thirds of malignancies (80%–85%) arising from the extrahepatic biliary tract in the United States.1 The prognosis of this lethal cancer is highly dependent on tumor stage at diagnosis.2 For instance, the 5-year overall survival (OS) for patients with stage I GBC is >50%1,3 compared with <5% among those with metastatic disease.1,4 Unfortunately, most cases are diagnosed at late stages due to vague symptoms at presentation, a propensity to direct invasion to the liver, and early hematogenous and lymphatic spread. Consequently, only 10% to 30% of patients are eligible for curative-intent surgical resection at diagnosis.5

The current AJCC TNM staging system for GBC is primarily based on surgical pathology.6 It relies on accurate evaluation of tumor infiltration into the layers of gallbladder, which can only be achieved through complete surgical excision of the gallbladder. Patient-related factors, such as age and functional status, are not included in the staging system. These factors and other laboratory parameters may be helpful in the prognostication of patients with GBC who are not candidates for surgery.7,8 In addition, the current AJCC TNM staging system may not be optimal for patients undergoing neoadjuvant chemotherapy. Therefore, the current staging system is only applicable to a subset of patients with GBC who undergo upfront surgical resection. A widely applicable staging system that is based on clinical and laboratory parameters is much needed to appropriately investigate prognosis in patients who undergo neoadjuvant chemotherapy or cannot undergo surgery. To address this issue, we integrated patient- and tumor-related factors to create a novel clinical staging system. In addition, we assessed the ability of the new staging system to predict OS in a large cohort of patients with GBC managed at a tertiary referral center.

Methods

Study Population

All patients diagnosed with GBC (adenocarcinoma) at Mayo Clinic Cancer Center between January 1, 2000, and December 31, 2016, were identified using the institute’s Advanced Cohort Explorer search engine. The search terms used were ICD-9-CM code 156.0, ICD-10 code C23, and/or the keywords “gallbladder cancer” or “malignant neoplasm of gallbladder.” The accuracy of GBC diagnoses obtained through the search engine was confirmed by review of patient pathology reports. Only histologically confirmed GBC-adenocarcinoma cases were included in the final analysis. Baseline characteristics, including patient demographics, ECOG performance status, CA 19-9 level, hematologic parameters (hemoglobin [HgB], platelet count, and WBC count), hepatic parameters, and radiographic findings at diagnosis before any surgical intervention, were retrospectively collected through review of electronic medical records. Extent of disease and tumor size were based on imaging study at the time of diagnosis.

Statistical Analysis

Baseline characteristics were summarized as percentages, median, and range, as appropriate. Cut points were determined for all continuous variables (ALP level, tumor size, albumin level, and WBC count) and spline curves were used to identify threshold effect.9 We used chi-square and Mann-Whitney U tests to compare categorical and continuous variables, respectively. We included all patients who met inclusion criteria in the final statistical analysis irrespective of the therapies received, because the primary goal was to assess the predictors of OS and to design a novel GBC staging system.

Factors included in the univariable analysis were determined a priori, and covariates with a significance level <.05 were included in the multivariable analysis (MVA). A model predictive of OS was developed using Cox proportional hazard regression analysis. Variables that were noted to be significant predictors of OS in MVA were then analyzed in various combinations to identify a set of variables associated with the highest C-statistics for OS; this set of variables was then used to create a nomogram predictive of OS. Each patient was then assigned a score based on the nomogram, and a staging system was created based on the scores derived from the nomogram. To compare OS between the AJCC TNM and our novel staging systems, Kaplan-Meier estimates were used to determine median OS, defined as the time period between the date of pathologic diagnosis and last follow-up or death. Median follow-up was 12 months, and follow-up was censored on June 30, 2018. Log-rank testing was used to compare OS among cancer stages.

We used the survival package in R version 3.1.2 (R Foundation for Statistical Computing) to construct the nomogram based on the prognostic factors determined by the Cox MVA. In addition, Harrel’s C-statistic was calculated to evaluate the predictive accuracy of the model and to compare with the AJCC TNM staging system. All statistical tests were 2-sided, and P<.05 was considered statistically significant.

Results

Baseline Characteristics

A total of 528 patients with GBC managed at Mayo Clinic between 2000 and 2016 met the inclusion criteria and were included in the final analysis. Median age at diagnosis was 68 years (range, 27–97 years), and 65% of the study population was female. Table 1 summarizes the demographic, clinical, and tumor characteristics at the time of GBC diagnosis. Among the 528 patients, 211 underwent definitive surgical resection of the primary tumor, 281 received chemotherapy, and 65 received radiation. The most common reason for not undergoing surgery was presence of metastatic disease at diagnosis.

Table 1.

Baseline Characteristics

Table 1.

Survival Predictors of Patients With GBC

Median follow-up of the entire cohort was 12 months. On univariable analysis, factors associated with poor OS included elderly age, higher ECOG status, albumin level <3.5 g/dL, ALP level ≥200 U/L, WBC count ≥12 × 103/mcL, HgB level ≤9 g/dL, tumor size ≥5 cm, and presence of metastatic disease at the time of diagnosis (Table 2). On MVA, age, ECOG performance status, presence of distant metastases, ALP level >200 U/L, and HgB level <9 g/dL were shown to determine median OS (Table 3). Tumor size ≥5 cm was associated with an elevated hazard ratio (HR) of 1.24 compared with tumor size <5 cm, but it did not reach statistical significance (P=.06).

Table 2.

Univariable Cox Proportional Hazard Regression for Predictors of Survival

Table 2.
Table 3.

Multivariable Cox Proportional Hazard Regression for Predictors of Survival

Table 3.

Development of Nomogram and Novel Staging System

Based on the multivariable Cox proportional hazard regression model for OS, age at diagnosis, ECOG performance status, distant metastases, ALP level, HgB level, and tumor size were assessed in various combinations to identify which set of variables was associated with the highest C-statistics. Although tumor size did not reach statistical significance in the MVA, it was included in this assessment because of the trend toward statistical significance. Among these variables, a combination of age at diagnosis, ECOG performance status, ALP level, presence of metastasis, and tumor size was found to be associated with the highest C-statistics and was then included to create a nomogram predictive of OS (Figure 1). Age >50 years carried the most weight in this nomogram, followed by an ECOG status of 3–4 and the presence of metastasis. Based on the nomogram, OS in a patient with GBC could be predicted using the 5 variables in combination or in isolation. Using the sum of all points, the estimated probabilities of median OS could be obtained on the horizontal axes below the individual variable scoring card. The total points for the scores ranged from 0 to 30, and the Harrell’s C-statistic for OS prediction was 0.71. Given the poor outcomes of patients with ECOG performance status of 3–4, MVA was performed including only patients with an ECOG performance status of 0 to 2. Interestingly, similar results were obtained in the MVA when the analysis was restricted to an ECOG performance status of 0 to 2 (supplemental eTable 1, available with this article at JNCCN.org).

Figure 1.
Figure 1.

Overall survival prediction nomogram for patients with gallbladder cancer.

Abbreviations: ALP, alkaline phosphatase; PS, performance status.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 2; 10.6004/jnccn.2019.7357

Based on the nomogram, an individual total score predictive of OS for each patient was estimated. Subsequently, patients with scores of 0 to 21.9, 22 to 25.9, 26 to 29.9, and ≥30 were classified into stages I (n=168), II (n=79), III (n=64), and IV (n=217), respectively.

Survival Based on Proposed Staging System

On individual stage-wise (AJCC TNM staging) analysis, median OS of patients with stage I, II, III, and IV GBC was 89.2, 38.1, 19.0, and 6.8 months, respectively (Figure 2A), compared with 35.1, 20.5, 14.8, and 6.2 months, with corresponding HRs of 1.0 (referent), 1.5 (95% CI, 1.08–2.05), 2.4 (95% CI, 1.75–3.41), and 6.39 (95% CI, 4.91–8.31), respectively (P<.02), based on the novel system (Figure 2B). This difference in HRs among the stages remained significant after adjusting for therapies received (P<.001). The C-statistic for the novel staging system was 0.71 compared with 0.69 for the AJCC TNM staging system, indicating a similar performance in predicting survival (P=.086).

Figure 2.
Figure 2.

Overall survival of patients with gallbladder cancer (entire cohort) classified by (A) the AJCC TNM staging system and (B) the novel clinical staging system.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 2; 10.6004/jnccn.2019.7357

Comparison of Staging Systems Based on Receipt of Surgical Therapy

A total of 211 patients underwent surgical resection of the primary tumor, among whom 127, 52, 23, and 9 were classified as having stage I, II, III, and IV GBC, respectively, using AJCC TNM staging. Median OS for AJCC TNM stage I, II, III, and IV disease was 89.2, 38.1, 22.1, and 9.4 months, respectively (P<.001; Figure 3A), compared with 37.2, 30.4, 15.5, and 7.8 months, respectively, using the novel system (P<.001; Figure 3B). Figure 3C shows the median OS of nonsurgical patients with GBC classified by AJCC TNM staging. Median OS for stage I was not reached, but was 8.0, 5.7, and 7.1 months for stage II, III, and IV, respectively. However, using the novel system in nonsurgical patients, median OS for stage I, II, III, and IV was 15.6, 11.4, 10.7, and 5.0 months, with HRs of 1.0 (referent), 1.92 (95% CI, 0.83–4.43), 1.35 (95% CI, 0.58–3.14), and 3.37 (95% CI, 1.74–6.51), respectively (overall P<.001) (Figure 3D). The C-statistics of nonsurgical patients using AJCC TNM staging and the new staging system were 0.51 and 0.60, respectively (P<.001), suggesting that the discriminating power of this novel system is superior to the AJCC TNM staging system in nonsurgical patients.

Figure 3.
Figure 3.

Overall survival of patients with gallbladder cancer classified by the (A) AJCC TNM staging system in those who underwent surgical resection of primary tumor, (B) newly proposed clinical staging system in the resection cohort, (C) AJCC TNM staging system in nonsurgical cohort, and (D) novel clinical staging system in nonsurgical cohort.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 2; 10.6004/jnccn.2019.7357

Discussion

A broader, effective staging system based on nonoperative information is required for accurate prognostication of patients with GBC who do not undergo surgical resection. In addition, this system would help adequately stratify patients with GBC in clinical trials evaluating neoadjuvant therapies. Using data from 528 patients with GBC treated at Mayo Clinic Cancer Centers, we developed a novel staging system that provides stage-wise information on OS irrespective of surgery. All variables used in the new staging system were obtained at initial presentation and therefore applicable to all patients with GBC irrespective of therapies received. Our novel staging system had excellent discriminatory capabilities in predicting the OS of patients with GBC at each stage. In addition, our scoring system had a higher concordance score in nonsurgical patients with GBC, indicating better prognostic performance compared with the AJCC TNM staging system. Within the nonsurgical group, most patients were not candidates for aggressive surgery due to presence of metastatic disease at diagnosis. Our novel staging system can help further identify patients who have a better prognosis within this subset, in whom aggressive therapeutic interventions may be reasonable. Conversely, our staging system can also help identify those with a very poor prognosis within the subset of patients with metastatic disease in whom aggressive interventions may be futile. The ability to provide additional prognostication of nonsurgical patients is one of the major advantages of this novel staging system over AJCC TNM staging. In addition, the novel staging system performed on par with the AJCC TNM staging system in patients who underwent surgery, making it more widely applicable across all patients with GBC. Furthermore, the novel staging system includes clinical and laboratory information that is relatively inexpensive and typically obtained as part of standard practice in patients with GBC.

In a recent analysis of 278 patients with cholangiocarcinoma from both community and academic centers identified in the National Cancer Database, Yadav et al10 reported superior OS among patients who received neoadjuvant chemotherapy compared with those who underwent surgery and adjuvant chemotherapy. Patients who received neoadjuvant chemotherapy also showed a superior R0 resection rate. Because the current AJCC TNM staging system for GBC is primarily based on surgical pathology, our novel staging system may be useful for patients with GBC who are not candidates for resection and for designing clinical trials in the setting of neoadjuvant chemotherapy.

Several OS-predicting nomograms have been developed using single-center GBC cohorts and the SEER database.1114 The focus of some of these nomograms was to determine OS in patients with GBC who received radical surgery.5,13 A single-center study from China that included 142 patients with GBC showed that disease stage at diagnosis, resection status, presence of jaundice, and elevated CA 19-9 levels predicted OS.14 Using the SEER database, Zhang et al13 demonstrated that tumor size, tumor grade at diagnosis, nodal positivity, and receipt of chemotherapy predicted OS. Two other SEER database studies proposed nomograms to determine the role of adjuvant therapy (radiation or chemoradiation) in node-positive GBC.11,12 Although all of these nomograms were shown to be superior compared with the AJCC TNM staging system, they all used data from the pathologic and histologic analysis of the tumor. In contrast, the staging system we developed was primarily based on patient demographics, imaging, and laboratory data and can be effectively used in nonsurgical patients as well. Moreover, our novel staging system is relatively easy to apply using baseline laboratory and imaging studies commonly conducted at the community and tertiary care centers. Table 4 summarizes the major studies that developed predictive scoring systems/nomograms in GBC management.

Table 4.

Comparison of Major Studies That Developed Predictive Nomograms in GBC

Table 4.

In our analysis, we found that age at diagnosis, ECOG performance status, anemia (HgB level <9 g/dL), presence of metastases, and higher ALP levels (>200 U/L) were independent predictors of OS. Several prior studies have evaluated prognostic factors in GBC,1519 and a wide range of variables predictive of OS in GBC has been identified. However, most of these studies identified surgically obtained pathologic information in addition to clinical variables. Furthermore, most large studies on prognostic factors in GBC are from Asia, but whether those findings would be applicable to patients in the United States is unclear, because the underlying tumor biology may vary by geographic region.2023 To the best of our knowledge, this is the largest study from a single institution in the United States to evaluate prognostic factors in patients with GBC. Among the prognostic factors identified in this study, presence of distant metastases and ECOG performance status 3–4 were the strongest predictors of OS. Interestingly, we found that CA 19-9 level did not influence OS in the patient cohort. Although elevated levels of CA 19-9 have been reported in patients with advanced GBC, only a few studies have shown an association with OS.14,2426 In addition, the studies that demonstrated a potential association of CA 19-9 level with median OS predominantly included patients who underwent surgical resection of the primary tumor, and involved only a small cohort of patients.14,26

Our study has limitations inherent to its retrospective nature. First, the novel staging system was primarily based on data from patients with GBC managed at a tertiary care institution. However, this study includes the largest cohort of patients with GBC at all stages of disease, and therefore the distribution of stages in this cohort reflects the proportions of patients with GBC typically seen in regular practice. Furthermore, patients were selected from 3 major sites at Mayo Clinic Cancer Centers spread across the nation, allowing for generalization to the broader population. Moreover, the follow-up duration was long enough to have an adequate number of patients with the outcome of interest, so that statistically robust models predicting mortality could be generated. Second, we did not collect data on the sites and numbers of metastases due to the difficulty of quantifying them based on the available imaging studies. However, because no prior data are available to suggest that the number and sites of metastasis may influence outcomes, and because patients with stage IV disease have poor OS, this lack of data collection is unlikely to influence the present study. Third, there was a lack of internal and external validation of our proposed scoring system. Although we were able to compare concordance scores with the AJCC TNM staging system in the same cohort, because of the relatively small number of patients with GBC, we were unable to internally validate the new staging system. External validation of the proposed staging system in an independent cohort is required to determine whether it can be generalized to other institutions. Nonetheless, we obtained a C-statistic for the new staging system comparable to that of the AJCC TNM staging system, which also supports the utility of the novel staging system in nonsurgical patients with GBC. Finally, it is possible that missing data may have influenced the results.

Conclusions

We created a novel, clinically based staging system for patients with GBC based on nonoperative information at the time of diagnosis. We found this system to be superior to the AJCC TNM staging system in predicting OS in patients who do not undergo surgery, and to perform on par with the AJCC TNM staging in predicting OS among surgical patients. This novel staging system may be useful for patients with GBC who are not candidates for resection, and for designing clinical trials in the setting of neoadjuvant chemotherapy.

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Submitted May 8, 2019; accepted for publication September 4, 2019.Previous presentation: This work was presented as a poster at the ASCO 2019 Gastrointestinal Cancers Symposium; January 17–19, 2019; San Francisco, California.Author contributions: Concept and design: Yadav, Tella, Mahipal. Acquisition, analysis, or interpretation of data: Yadav, Tella, Prasai, Mara, Mahipal. Drafting of manuscript: Yadav, Tella, Kommalapati. Critical revision of manuscript for important intellectual content: All authors. Approval of final manuscript: All authors. Yadav, Tella, and Mahipal had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.Disclaimer: The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study protocol was approved by the Mayo Clinic Committee on Human Research.Correspondence: Amit Mahipal, MD, MPH, Department of Oncology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55906. Email: mahipal.amit@mayo.edu

Supplementary Materials

  • View in gallery

    Overall survival prediction nomogram for patients with gallbladder cancer.

    Abbreviations: ALP, alkaline phosphatase; PS, performance status.

  • View in gallery

    Overall survival of patients with gallbladder cancer (entire cohort) classified by (A) the AJCC TNM staging system and (B) the novel clinical staging system.

  • View in gallery

    Overall survival of patients with gallbladder cancer classified by the (A) AJCC TNM staging system in those who underwent surgical resection of primary tumor, (B) newly proposed clinical staging system in the resection cohort, (C) AJCC TNM staging system in nonsurgical cohort, and (D) novel clinical staging system in nonsurgical cohort.

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