Role of chemoradiation in gallbladder cancer—a single institution retrospective analysis

Introduction

Gallbladder cancer and cancers of the extrahepatic ducts account for approximately 12,200 cases annually in the United States, resulting in 3,700 deaths (1). The incidence rate is 1–2 cases per 100,000, signifying a gradual decline over the past 30 years (2). The disease is more prevalent in women, with shorter median survival, relapse time, and shorter recurrence after recurrence compared to hilar cholangiocarcinoma (3). Risk factors include cholelithiasis, porcelain gallbladder (7–15%), anomalous pancreaticobiliary duct junction, and primary sclerosing cholangitis.

Most patients remain asymptomatic, but symptoms such as pain, anorexia, nausea/vomiting, and obstructive jaundice may develop. In some cases, a palpable gallbladder in a jaundiced patient, known as the Courvoisier sign, can be identified (4). Adenocarcinoma is the most common histological feature, followed by squamous cell or adenosquamous carcinoma, similar to other gastrointestinal malignancies (5). The 5-year survival rate is about 10% (6), with the prognosis significantly influenced by the stage of the disease. Node-positive disease often results in dismal outcomes. Thus, most patients with muscle-invasive (T2) disease require interval portal lymphadenectomy for accurate staging (7).

Surgery remains the only curative treatment option for incidental gallbladder cancer with Tis or T1a staging (6). However, given the poor prognosis for patients with T stages equal to or greater than two and nodal disease, consideration of adjuvant therapy is crucial (3). According to the National Comprehensive Cancer Network (NCCN), standard options typically include adjuvant fluoropyrimidine chemoradiation (CRT), fluoropyrimidine, or gemcitabine chemotherapy (CT). A Surveillance, Epidemiology, and End Results (SEER) database revealed a nonsignificant improvement in survival when comparing adjuvant therapy with surgery, the most considerable survival benefit being in cases of nodal involvement (8). While adjuvant therapy in gallbladder cancer has shown improved outcomes, underpowered trials, and data dilution from including other biliary tract cancers make informed decision-making challenging.

The lack of high-quality, data-driven evidence often results in treatment regimens shaped by institutional protocols and personal preferences. This led to significant underutilization of adjuvant therapy approaches (9). To better comprehend the role of adjuvant CRT therapy in localized gallbladder cancer and patients with unresectable disease, we conducted a retrospective analysis to study the outcomes of gallbladder malignancy in patients at our institution. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-186/rc).

Methods

We retrospectively collected data on patients with gall bladder cancer treated at tertiary-level cancer center, University of Alabama at Birmingham between January 2005 and June 2015 using a standardized data collection tool (Redcap). We obtained Institutional Review Board approval before conducting the study. To be included in the study, participants had to meet the following requirements: age >18 years, and their tumor had to be located in the gallbladder and undergo definitive surgery. There were also exclusion criteria: patients with multiple primary tumors, those diagnosed with carcinoma in situ, those with incomplete information regarding their cancer type, unknown surgical method, and those with incomplete follow-up information, and those who passed away within 30 days of diagnosis. Stage 4b patients were not included as they were deemed unresectable. The variables assessed included: basic demographics (age, race, insurance status, residence), symptoms at presentation, including imaging/laboratory data, functional status, stage at presentation, presence of biliary stents, histology of pathology, and CT used. The American Joint Committee on Cancer (AJCC), 2017, eighth edition, tumor-node-metastasis (TNM) staging for gallbladder cancer system was used.

Statistical analysis

Survival outcomes were compared between patients who received different treatments. We conducted all statistical analyses using SAS software version 8.2 (SAS Institute Inc., Cary, NC, USA) and generated survival curves with Prism 8 (GraphPad Software Inc., San Diego, CA, USA). Patient survival rates were evaluated using the Kaplan-Meier method, and survival rate comparisons across two or more groups were analyzed using the log-rank test. During the development of the Cox regression model, we first performed univariate analysis to identify statistically significant variables suggesting predictors of overall survival (OS). Taking into account data integrity, we included some variables as continuous variables in the regression model. Variables that were significant in univariate analysis were then incorporated into the Cox regression model (using a backward method) for multivariate analysis, helping us to evaluate for any independent factors that influenced patient prognosis. OS was defined as the time between surgery and death or censored at the last follow-up date. Progression-free survival (PFS) was defined as the time to recurrence or death. All tests were two-sided, and we deemed a P value of less than 0.05 as statistically significant.

Ethical statement

The retrospective study conformed to the provisions of the Declaration of Helsinki (as revised in 2013) and was conducted in accordance with the standard research regulations. The study was approved by the Institutional Review Board of the University of Alabama at Birmingham (No. 151217003), and in alignment with institutional policies. The need for informed consent was waived due to the retrospective nature of this study. Patient data were de-identified and handled with confidentiality to ensure patient privacy and protection.

Results

Patient characteristics

In the evaluation of 93 patients diagnosed with gallbladder cancer: the median age was 65.6 years, with a majority of the patients (66.7%) being females. Most patients were Caucasians (67.7%), followed by African Americans (30.1%).

The most common type of tumor was adenocarcinoma. According to the AJCC 2017 staging, 30% of the patients were diagnosed at an early stage (stage I & II). The median time to start CT after surgery was 1.5 months. The treatment details were as follows: 10.8% of the patients received adjuvant CT with gemcitabine; 14.0% received both adjuvant CT and radiation; fluoropyrimidine was used as a radiation sensitizer; 2.2% received neoadjuvant CT (CT given before surgery to shrink the tumor); 1.1% received neoadjuvant CT and radiation; 5.4% received palliative CT. In 48.0% of the patients, no postoperative CT was administered. The treatment modality was unknown in 17.2% of the patients. These findings gave insights into the demographics of gallbladder cancer patients, the nature of the tumors, the stage at diagnosis, and the treatment approaches used at the tertiary-level cancer center (Table 1).

Survival analysis

On univariate analysis, albumin >3.5 g/dL, uninvolved margins, absence of lymphovascular invasion, and peri-neural invasion were favorable predictors of OS and PFS (Table 2). However, there was no statistical significance in multivariate analysis owing to the small sample size. The median follow-up was 20.2 months. The median survival for the study cohort of 93 patients was 19.1 months, with a 5-year survival rate of 20% (Figure 1). Stage-specific OS rates for early stages (1 & 2) at 5 years was 53.1% vs. 10.8% for late stages (3 & 4) (Figure 2). For the cohort assessment who underwent any form of adjuvant therapy (CT or CRT), the median survival with surgery alone was 27.4 vs. 24.3 months with no statistical significance (P=0.6429, Figure 3). Among the patients who received any adjuvant CT or CRT (n=31), the median survival was higher for the patients who received CRT compared to CT (54.4 vs. 15.6 months, P=0.0048; Figure 4). The median OS in stage 3–4 patients with surgery alone vs. adjuvant CT/CRT was 5.5 vs. 28.7 months, respectively (P=0.0061; Figure 5). The PFS for the same group was 4.6 vs. 17.5 months (P=0.0052; Figure 6).

Figure 1 Median 5-year OS of study cohort. OS, overall survival.

Figure 2 OS stage 1 & 2 vs. 3 & 4. NA, not available; OS, overall survival.

Figure 3 OS surgery alone vs. surgery plus adjuvant treatment (all stages). OS, overall survival.

Figure 4 OS of patients: surgery plus chemotherapy vs. surgery plus chemotherapy plus radiation. Chemo, chemotherapy; rad, radiation; OS, overall survival.

Figure 5 OS of stage 3 & 4 patients: surgery alone vs. surgery plus adjuvant treatment. OS, overall survival.

Figure 6 PFS of stage 3 & 4 patients: surgery alone vs. surgery plus adjuvant treatment. PFS, progression-free survival.

Discussion

Patients diagnosed with gall bladder cancers frequently face a generally unfavorable prognosis. Treatment-wise survival analysis revealed that most patients underwent surgical procedures, as surgery is the definitive treatment for gallbladder cancers. Patients diagnosed at stage I are prime candidates for extensive surgery. Even though surgical resection is a commonly employed treatment approach for patients at higher stages, there is a significant risk of distant metastasis and a consequent decrease in the 5-year survival rate. As a result, additional or adjuvant therapy is strongly recommended for these patients (10,11). A comprehensive treatment plan that combines surgery and adjuvant therapy is adopted for those with stages III and IV. Even though the usage of adjuvant therapy in these patients remained low, there is a paradigm shift in incorporating adjuvant therapy routinely with recent data based on the BILCAP study. However, the role of chemoradiotherapy remains undefined, though some studies suggest that postoperative adjuvant radiotherapy could benefit selected patients.

After our retrospective analysis of patients with gallbladder malignancy, it was apparent how dismal the survival rates were in this group, while at the same time, it drove the impetus to explore potential treatment modalities to improve outcomes. Most patients presented with a clinical stage ≥3 which profoundly impacts the OS. The association of tobacco and alcohol on gallbladder cancer in our study showed no strong link, but this is certainly not the case for other biliary tract malignancies (12). The role of albumin as an independent risk factor of the OS in gallbladder patients stems from it being a barometer of inflammation and malnutrition (13). With increased lymphovascular/peri-neural invasion and surgical margins involved, there is an impact on PFS & OS and the treatment modalities that need to be utilized.

For the whole cohort assessment (n=93) who underwent any form of adjuvant therapy (CT or CRT), there was no significant difference between surgery alone vs. adjuvant therapy (P=0.6429). Among the patients with all stages who received any adjuvant CT or CRT (n=31), the median survival was higher for those who received CRT compared to CT (54.4 vs. 15.6 months, P=0.0048). This group included high-risk stage 4a patients who had portal vein, hepatic vein, or local organ involvement. For stages 1–3, surgery (n=16) with CRT had a median OS of 58.1 vs. 20.5 months (P=0.004) compared to surgery followed by CT. The median OS in stage 3–4 patients with surgery alone vs. adjuvant CT/CRT was 5.5 vs. 28.7 months, respectively (P=0.0061). This suggests the benefit of radiation in the adjuvant setting in selected high-risk patients.

The most critical factor predicting local recurrence and survival is the presence of residual cancer after surgical resection (14). Thus, the current standard of care is to undergo a secondary hepatic resection in patients diagnosed with incidental gallbladder cancer after cholecystectomy. This often leads to upstaging of disease by identification of liver invasion in a significant proportion of patients (15). In addition, the presence of lymph node metastasis also affects survival, as demonstrated by the inferior survival in our stage 3 and 4 patients. Extended cholecystectomy thus translates to a survival benefit by improving the accuracy of staging and also by resection of residual disease even in patients treated with CRT (16,17).

Adjuvant treatment with radiation has shown improvements in survival outcomes across multiple studies (18), likely due to improvement in local control, and the benefit appears limited to patients with regional lymph node, vascular or liver involvement. Adjuvant CRT with a 5-fluorouracil (5-FU)-based regimen has improved local control and survival (17,19). The meta-analysis by Wang et al. showed improvements mainly in patients with T2–4 or node-positive disease (20). An analysis of 5,029 patients with T1–3N0–1 gall bladder cancer from the National Cancer Data Base (NCDB) demonstrated improved 3-year OS with CRT with no benefit in node-negative patients (9). However, another analysis of the NCDB shows that the survival benefit with adjuvant therapy in T2–3 node-positive disease is not sustained at 5 years follow-up (21).

The benefit of adjuvant therapy, as evident in our analysis, appears most established in patients with locally advanced disease who receive adjuvant CRT with a 5-FU-based regimen (10). Interestingly, node positivity seems to predict a better response to CRT compared to CT (22), suggesting that radiation continues to play a role in node-positive disease. This study also demonstrated that patients with T2 or T3 disease with unknown lymph node status had improved survival with CRT, highlighting the need to adopt intensification strategies, especially if lymph node status is unknown.

While adjuvant radiation-based approaches have demonstrable local control and a survival benefit, there continues to be a high distant failure rate, highlighting the need for a practical systemic treatment approach (23,24). The traditional gemcitabine and platinum-based regimen has improved OS and PFS across multiple randomized studies (25,26) in advanced gallbladder cancer. The study by Takada et al. (27) was one of the early studies to show the benefit of a maintenance CT regimen after surgical resection. Recently, adjuvant capecitabine for eight cycles in patients with completely resected gall bladder cancer demonstrated a significant improvement in OS (53 for capecitabine vs. 36 months for observation, P=0.028) (28). However, the dosing used in the study (1,250 mg/m² twice daily 14/21 days) may be intolerable for many patients and will likely require dose reductions.

Combining CT with CRT could improve distant and local recurrence rates. There appears to be a benefit of CT in addition to the CRT backbone in the retrospective study by Lim et al., demonstrating improved disease-free survival and OS rates (29). The single-arm SWOG S0809 study, which treated patients with four cycles of gemcitabine plus Xeloda followed by concurrent capecitabine-based CRT, demonstrated promising efficacy and feasibility of sequential therapy, but 2-year recurrence rates remained close to 50% (30). Our study signaled a significant difference between CRT and CT alone that needs further validation in a larger cohort.

The retrospective nature of this study lends itself to several limitations—most significantly being the small sample size. This study relied on records, so they’re dependent on the accuracy of those records while transitioning to an electronic medical record system (31). This study only shows associations, not cause-and-effect relationships. The treatment modality was unknown in 17.2% of the patients. The mean number of nodes included in lymphadenectomy needed to be improved, and there was the possibility of missing data with pathology reports. This variability is likely attributable to the lack of standardized guidelines concerning the number of lymph nodes to be removed during surgery.

Additionally, discrepancies in staging could stem from changes in staging criteria between 2010 and 2017. Moreover, the single-center studies may not represent the wider population, as they reflect the specific patient population and treatment practices at the tertiary-level cancer center. In addition, patients selected for intensive adjuvant strategies using CT with or without radiation are often in better overall health, which could have affected the survival benefit in our study due to selection bias.

Nevertheless, the strength of our study is that it provides important insights into the best treatment modality for an aggressive form of malignancy. This is valuable for generating hypotheses that can be tested in future prospective studies. The lack of high-quality randomized data on this rare malignancy remains a challenge. Still, our retrospective study with a larger population of 93 patients provides insight into CT or CRT’s role. Also, examining our study cohort shows that the makeup is diverse. Further research on multidisciplinary approaches for gall bladder cancer management is needed, particularly at advanced stages.

Conclusions

The dismal relapse and survival rates of gallbladder cancer make adjuvant therapy critical in improving outcomes.

Adjuvant radiation or CRT can offer potential benefits in treating gallbladder cancer. However, its use is generally individualized based on factors such as the stage of the disease, the patient’s overall health status, the risk of recurrence, and the potential benefits and risks of intensive CT. Patients should have a detailed discussion with their oncologist to make an informed decision about their treatment plan. We have examined different treatment modalities related to CT and CRT combined with surgery, demonstrating significant disease control. These results will require further validation in prospective cohort studies.

Acknowledgments

The de-identified data used in the study is derived from the electronic medical record using a standardized data collection tool (Redcap). The abstract of this study was presented in the 2022 ASCO and permission has been obtained from the Journal of Clinical Oncology for the reuse of the abstract.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-186/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-186/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-186/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-186/coif). RKP serves as a consultant for Ipsen, Seagen, and Exelixis. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The retrospective study conformed to the provisions of the Declaration of Helsinki (as revised in 2013) and was conducted in accordance with the standard research regulations. The study was approved by the Institutional Review Board of the University of Alabama at Birmingham (No. 151217003), and in alignment with institutional policies. The need for informed consent was waived due to the retrospective nature of this study. Patient data were de-identified and handled with confidentiality to ensure patient privacy and protection.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
2. Carriaga MT, Henson DE. The histologic grading of cancer. Cancer 1995;75:406-21. [Crossref] [PubMed]
3. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-13. [Crossref] [PubMed]
4. Blackstock AW, Benson AB, Kudo M, et al. Safety and Efficacy of amplitude-modulated radiofrequency electromagnetic fields in advanced hepatocellular carcinoma. 4Open 2021;4:3.
5. Roa I, de Aretxabala X, Araya JC, et al. Preneoplastic lesions in gallbladder cancer. J Surg Oncol 2006;93:615-23. [Crossref] [PubMed]
6. Shindoh J, de Aretxabala X, Aloia TA, et al. Tumor location is a strong predictor of tumor progression and survival in T2 gallbladder cancer: an international multicenter study. Ann Surg 2015;261:733-9. [Crossref] [PubMed]
7. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 2000;232:557-69. [Crossref] [PubMed]
8. Horgan AM, Amir E, Walter T, et al. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 2012;30:1934-40. [Crossref] [PubMed]
9. Mitin T, Enestvedt CK, Jemal A, et al. Limited Use of Adjuvant Therapy in Patients With Resected Gallbladder Cancer Despite a Strong Association With Survival. J Natl Cancer Inst 2017; [Crossref] [PubMed]
10. Khosla D, Agrawal S. Adjuvant Therapy in Gallbladder Cancers. In: Kumar Shukla V, Pandey M, Dixit R, editors. Gallbladder Cancer: Current Treatment Options. Singapore: Springer Nature Singapore; 2023:145-57.
11. Park Y, Kim K, Park HJ, et al. Role of Adjuvant Treatment in High-risk Patients Following Resection for Gallbladder Cancer. In Vivo 2022;36:961-8. [Crossref] [PubMed]
12. McGee EE, Jackson SS, Petrick JL, et al. Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies. J Natl Cancer Inst 2019;111:1263-78. [Crossref] [PubMed]
13. Xu WY, Zhang HH, Yang XB, et al. Prognostic significance of combined preoperative fibrinogen and CA199 in gallbladder cancer patients. World J Gastroenterol 2018;24:1451-63. [Crossref] [PubMed]
14. Kresl JJ, Schild SE, Henning GT, et al. Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys 2002;52:167-75. [Crossref] [PubMed]
15. Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC). J Surg Oncol 2008;98:485-9. [Crossref] [PubMed]
16. González ME, Giannini OH, González P, et al. Adjuvant radio-chemotherapy after extended or simple cholecystectomy in gallbladder cancer. Clin Transl Oncol 2011;13:480-4. [Crossref] [PubMed]
17. Balachandran P, Agarwal S, Krishnani N, et al. Predictors of long-term survival in patients with gallbladder cancer. J Gastrointest Surg 2006;10:848-54. [Crossref] [PubMed]
18. Mojica P, Smith D, Ellenhorn J. Adjuvant radiation therapy is associated with improved survival for gallbladder carcinoma with regional metastatic disease. J Surg Oncol 2007;96:8-13. [Crossref] [PubMed]
19. Cho SY, Kim SH, Park SJ, et al. Adjuvant chemoradiation therapy in gallbladder cancer. J Surg Oncol 2010;102:87-93. [Crossref] [PubMed]
20. Wang SJ, Lemieux A, Kalpathy-Cramer J, et al. Nomogram for predicting the benefit of adjuvant chemoradiotherapy for resected gallbladder cancer. J Clin Oncol 2011;29:4627-32. [Crossref] [PubMed]
21. Mantripragada KC, Hamid F, Shafqat H, et al. Adjuvant Therapy for Resected Gallbladder Cancer: Analysis of the National Cancer Data Base. J Natl Cancer Inst 2016;109:djw202. [Crossref] [PubMed]
22. Hoehn RS, Wima K, Ertel AE, et al. Adjuvant Therapy for Gallbladder Cancer: an Analysis of the National Cancer Data Base. J Gastrointest Surg 2015;19:1794-801. [Crossref] [PubMed]
23. Alam MN, Agrawal S, Rastogi N, et al. Consolidation chemoradiation (cCTRT) improves survival in responders to first-line chemotherapy (CT) in locally advanced gallbladder cancer (LA-GBC): A new standard of care? Indian J Cancer 2022;59:577-83. [PubMed]
24. Wang J, Narang AK, Sugar EA, et al. Evaluation of Adjuvant Radiation Therapy for Resected Gallbladder Carcinoma: A Multi-institutional Experience. Ann Surg Oncol 2015;22:S1100-6. [Crossref] [PubMed]
25. Sharma A, Dwary AD, Mohanti BK, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol 2010;28:4581-6. [Crossref] [PubMed]
26. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81. [Crossref] [PubMed]
27. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002;95:1685-95. [Crossref] [PubMed]
28. Primrose JN, Fox R, Palmer DH, et al. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. J Clin Oncol 2017;35:abstr 4006.
29. Lim KH, Oh DY, Chie EK, et al. Adjuvant concurrent chemoradiation therapy (CCRT) alone versus CCRT followed by adjuvant chemotherapy: which is better in patients with radically resected extrahepatic biliary tract cancer?: a non-randomized, single center study. BMC Cancer 2009;9:345. [Crossref] [PubMed]
30. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma. J Clin Oncol 2015;33:2617-22. [Crossref] [PubMed]
31. Fietkau R, Ghadimi M, Grützmann R, et al. Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: First results of the CONKO-007 trial. J Clin Oncol 2022;40:4008. [Crossref]