Adjuvant chemoradiotherapy vs chemotherapy for resectable biliary tract cancer: a propensity score matching analysis based on the SEER database

The increasing prevalence of tumors in the biliary tract (intrahepatic bile ducts, extrahepatic bile ducts, and gallbladder) is well-recognized, especially in developing countries [1]. However, its prognosis is still poor, of which the 5-year survival rates are less than 20% [2]. Biliary tract cancer (BTC) is a heterogeneous tumor with obvious differences in etiology, molecular features, treatment options, prognosis, and natural history for each subgroup [3]. Radical resection is the most effective method to cure BTC patients. Nevertheless, even with complete resection, previous studies found that about two-thirds of patients might have disease recurrence, of which 15 to 59% might have local regional recurrence [4, 5]. Therefore, in recent years, numerous efforts have been made in exploring the optimal strategy of postoperative adjuvant therapies [including radiotherapy (RT), chemotherapy (CT), and chemoradiotherapy (CRT)] for resected BTC to reduce the probability of recurrence and metastasis, so as to improve the survival. But the clinical benefit of adjuvant therapy is controversial. Until 2019, the randomized phase III BILCAP trial indicated that capecitabine adjuvant CT for 6 months following radical resection of BTC could significantly improve the relapse-free survival (RFS) and median overall survival (OS) [6], which is recommended as the new standard of adjuvant treatment in the American Society of Clinical Oncology (ASCO) guidelines [7]. Nevertheless, the lack of randomized trials and available data from small, single-institution studies led to no consensus on adjuvant CRT. Although ASCO treatment recommendations for patients with resected BTC include CT alone or in combination with RT [7], the most effective adjuvant strategy still needs to be further explored.

The specific aim of this study was to compare the impact of adjuvant CRT and CT on radically resected patients with BTC based on the Surveillance, Epidemiology and End Results (SEER) database. We evaluated the impact of CRT and CT on OS in the primary cohort. We also conducted univariate and multivariate Cox model to analyzed variables in correlation with OS. Propensity-score matching (PSM) was used to minimize the co-funding effects by nonrandom selection bias. In addition, we explored the subgroup of patients that can potentially gain benefits from adjuvant CRT. To our knowledge, it is the largest sample size analysis comparing the impact of adjuvant CRT with CT on the survival of patients with BTC based on SEER database in recent 10 years.

In past years, gemcitabine based postoperative adjuvant CT regimen did not obtain positive results in two phase 3 studies of PRODIGE-12/ACCORD-18 [8] and BCAT [9]. Until recently, in the phase III BILCAP trial, prespecified per-protocol analysis showed patients received capecitabine as adjuvant therapy had better OS and RFS compared with those with observation (53 months vs. 36 months, p = 0.028; 24.4 months vs. 17.5 months, p = 0.033) [6]. According to the results of BILCAP trial, adjuvant CT with capecitabine has become the standard of care for patients with BTC after radical surgical resection [6]. However, based on the adjuvant CT, controversy continues over the role of additional RT in BTC due to lacking large, prospective clinical trials. In our retrospective analysis, compared to adjuvant CT, CRT was expected to improve survival significantly for BTC, particularly GBCA, whereas no significant benefit in patients with IHBDC or EHBDC has been observed. Moreover, specific sub-cohorts of patients, age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph nodes disease could benefit from adjuvant CRT after PSM.

As early as in 2012, a pivotal meta-analysis evaluated CT, RT, or CRT compared with surgery alone for 6712 BTC patients from twenty studies, indicating that receiving adjuvant CT or CRT in resected BTC showed a greater survival benefit than RT alone (OR, 0.39, 0.61, and 0.98, respectively; p < 0.02), especially in those with LN-positive and R1 disease [10]. In 2015, SWOG S0809, a prospective single-arm phase II study, tested the adjuvant CT and CRT in patients with resected EHBDC or GBCA and demonstrated promising therapeutic efficacy [11]. In this analysis, the median OS was 35 months, with 2-year survival of 65%. For patients with R0, the median survival time was 34 months (2-year survival rate, 67%), whereas the median OS was 35 months for R1 patients with 2-year survival rate of 60% [11]. However, the relative value of postoperative adjuvant CRT versus CT is not clear. Several small retrospective studies have illustrated that CRT could enhance outcomes in patients with BTC compared with CT. Patients with EHBDC, hilar cholangiocarcinoma or nonhilar extrahepatic bile duct cancer (NH-EHBDC) also experienced survival benefits from CRT, particularly those with a high risk of tumor relapse [12, 13]. Moreover, Kim et al. [14] analyzed 92 patients who had undergone curative resection for BTC and received adjuvant CRT or CT. In this series, adjuvant CRT had numerically higher OS (30.1 months vs. 26.0 months, p = 0.222) and significantly better RFS (13.8 and 11.2 months, p = 0.014) than CT. Baeza et al. [15] analyzed 49 macroscopically complete resected GBCA patients treated with adjuvant CRT, and reported a favorable 5-year OS of 52%. These findings highlight the critical role of adjuvant CRT in patients who performed surgical resection for BTC. However, several studies have indicated that there were no significant differences in OS between adjuvant CT and CRT treatment [16, 17]. One study reported that the CRT group had comparable DFS (p = 0.089) and OS (p = 0.299) compared to the CT group in perihilar cholangiocarcinoma (PHC) patients with R1 resection [16]. Wan et al. [17] suggested adjuvant CT and CRT have similar effects on stage II GCB patients, and neither improves survival. Given the inconsistent results and small sample size of these data, we conducted this present study to compare adjuvant CT and CRT in patients with resected BTC based on SEER database.

Liver was the most common relapse site for BTC, followed by a local site, peritoneum and abdominal lymph nodes [9]. Both GCBA and EHBDC show high incidences of local invasion, lymph node metastasis, and distant metastasis [18, 19], while IHBDC tends to be predominantly intrahepatic recurrence, which possibly result in limited benefit from the additional adjuvant RT. Those may explain why CRT obviously improved outcomes of GCBA patients but had no significant benefit in patients with IHBDC or EHBDC in our report. In keeping with our findings, a recent nomogram model built from SEER GBCA database indicated that CRT outperformed CT for all patient subsets, those patients with T2 or node-positive disease were predicted to have survival advantage from CRT [20]. Retrospective studies also showed that resected GBCA patients with lymph nodes positive or R1 resections might derive the greatest benefit from adjuvant CRT [13, 21]. Chang, W.I. et al. [13] demonstrated that in patients with NH-EHBDC, those who had high-risk features such as nodal involvement, pT3 stage, poorly differentiated tumor, tumor size ≥ 5 cm, or R1 resection experienced a survival benefit from adjuvant CRT. Therefore, adjuvant CRT should be recommended for specific subsets of patients following surgical resection.

Nonetheless, our study still has a few limitations. Firstly, as a retrospective study of the database, treatment and selection bias cannot be avoided. Therefore, PSM analysis was used to reduce the bias. Secondly, SEER lacks information on disease recurrence; thus, we chose OS as our primary endpoint. Furthermore, the SEER database cannot provide detailed information about CT, including specific CT regimens and cycles and RT, including the RT dose, target area of RT and RT technique. In addition, SEER does not have information regarding performance status, therapeutic toxicity, and complications. We believe this diversity may represent more realistic survival situation in real world. Despite those limitations, SEER provides us with an extensive series of BTC patients, making it possible to make clinical decisions for rare tumors based on available large cohorts.

In conclusion, our analysis demonstrates that patients with BTC, particularly those with GBCA, age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, none removed lymph nodes disease may derive the most significant benefit from adjuvant CRT. There were no survival differences between CRT and CT group in patients with IHBDC and EHBDC. More large-scale prospective randomized clinical trials are warranted to investigate the effect of adjuvant CRT on BTC.