Neoadjuvant Chemotherapy for Intrahepatic, Perihilar, and Distal Cholangiocarcinoma: a National Population-Based Comparative Cohort Study

Cholangiocarcinoma (CCA) is a rare, primary malignancy of the biliary system that arises from intra- and extrahepatic biliary tract epithelium. Anatomically, CCA are divided into intrahepatic CCA (iCCA), perihilar CCA (hCCA), and distal CCA (dCCA). Surgical resection remains the only potential for cure in localized disease; however, both local and distant relapses are common, even after complete resection.^1,2 This has provided rationale to explore the role of adjuvant therapy, including radiation, chemoradiotherapy, and adjuvant chemotherapy (AC). The oncological benefits of AC have been corroborated in a number of studies and clinical trials^3‐7 and, today, AC is recommended in a majority of clinical guidelines.⁸

While neoadjuvant chemotherapy (NAC) has been linked to improved oncological outcomes in the setting of several gastrointestinal malignancies such as esophageal, gastric, and pancreatic cancer,^9‐11 the role of NAC in the management of localized CCA remains unclear.¹² Existing evidence has largely been limited to retrospective studies and often examines NAC’s role prior to orthotopic liver transplantation.¹³ To date, comparable short- and long-term outcomes have been observed among resectable tumors that undergo upfront resection and advanced CCA treated with NAC, followed by surgery.^14‐16 Indeed, NAC may provide an advantage in the setting of large, locally advanced tumors with the goal of ultimate conversion to resectable disease.¹⁴ For example, in one study, NAC was associated with improved survival, compared to AC in CCA; however, stratification relative to CCA subtypes was not addressed separately.¹⁷

As such, the aim of this study was to investigate the role of NAC in iCCA, hCCA, and dCCA by performing a large, nationwide, high-quality, retrospective analysis study. Using contemporary data from the National Cancer Data Base (NCDB), the present sought to examine the association of NAC with survival among anatomical CCA subtypes, separately.

The role of neoadjuvant chemotherapy in patients with cholangiocarcinoma (CCA) remains unclear owing to a lack of prospective or large studies to date. The present study, which examined 9411 patients, found that neoadjuvant chemotherapy (NAC) versus surgery alone was associated with improved OS for CCA when stratified by anatomical location. Moreover, while NAC compared to AC was similarly associated with increased OS, this effect did not persist after performing sensitivity analyses among patients treated with NAC and AC among all three subtypes of CCA. Findings from this study suggest that overall compliance, rather than sequence, of multimodality therapy may impact OS for CCA anatomical subgroups and support the potential role for NAC in the management of this disease.

NAC represents an appealing approach in oncology, as it can potentially control disease progression, reduce tumor volume, increase R0 resection rates, and possibly avoid non-curative resections among patients who progress on systemic therapy. Although randomized trials are ongoing, to date there is a lack of robust data evaluating NAC’s role in the management of CCA, as the majority of the literature is derived from small retrospective studies.^11,12,16 For example, a single-center study of 74 patients with locally advanced iCCA has demonstrated that treatment with NAC, followed by surgery, provided similar short- and long-term results, compared to patients with initially resectable ICC who had upfront surgery.¹⁶ This suggests that NAC may be utilized as a first-line treatment for locally advanced iCCA in an effort to downstage locally advanced disease and increased likelihood of resectability. Results from this report are consistent with these findings, as iCCA patients treated with NAC, followed by surgery achieved improved OS, compared to upfront resection or resection followed by AC (p = 0.0029; Fig. 1). In this regard, it is important to underline that the decision for different treatments is tailored for each patient based both on the clinical stage and clinical conditions, rather than the pathological state alone. Recently, a report from NCBD similarly linked NAC with longer OS in a select group of patients with CCA when compared to upfront resection, followed by AC.¹⁷ The present study is different, as it uses a more contemporary edition of NCDB and further stratifies CCA anatomically into iCCA, hCCA, and dCCA, and we have analyzed all the subtypes separately.

Interestingly, after sensitivity analyses, OS was comparable among patients receiving NAC or AC in this study. These findings signal that compliance with multimodal therapy, which includes surgery and systemic therapy, rather than sequencing may affect the oncologic outcomes we observed in this retrospective study. Importantly, AC and NAC patients are likely heterogeneous. First, patients selected for upfront surgery likely had anatomically resectable cancers at diagnosis, whereas NAC patients were more likely to include locally advanced or borderline resectable tumors. As guidelines do not uniformly recommend NAC for CCA, NAC may represent a viable approach in the management of locally advanced CCAs, irrespective of anatomical subtype. Second, it is possible that NAC patients were perceived to have poor performance status precluding upfront surgery. Similarly, given comparable OS for AC and NAC, NAC may be considered in circumstances where rehabilitation prior to surgery is possible. In addition, patients who underwent NAC and had subsequent disease progression will not be included inherently in the NCDB and hence excluded from this analysis. Last, as patients who underwent NAC and had subsequent disease progression were not included in this analysis, it is likely that NAC is a useful tool to select for more favorable biology and ultimately avoid non-curative resections. While the lack of important granular data on disease progression and treatment selection rationale may have led to selection bias, it is not possible to determine to what degree competing biases affected outcomes in this report.

The retrospective nature of this study and inherent limitations with the NCDB database limits the conclusions that we can draw from these results. First, despite attempting to statically correct for confounders through multivariable and sensitivity analyses, treatment selection bias may not have been entirely accounted for. Specifically, patients selected for surgery first and those who remained eligible to receive AC were likely better overall performers and therefore had improved OS. As NAC arguably also selected for better tumor biology, it remains unclear how sequence impacts survival in this setting. Second, important granular details including type of chemotherapy treatment regimen, duration, dosage, and response are missing in NCDB. In this regard, differences in chemotherapeutic regimens could have played a considerable role when interpreting outcomes. Also, it was not possible to compare the regimen of perioperative chemotherapy (NAC plus AC) in the three CCA subgroups, given the small number of patients who received such treatment. This would have provided a better understanding of the role of perioperative chemotherapy in CCA. Third, data on mode of recurrences and disease-free survival are missing from this dataset which further limits interpretation. Fourth, the exact causes of death are not reported on NCBD, and this could potentially lead to bias when calculating OS, as death may be related to side effects of chemotherapy, surgical complications, or other factors without being directly related only to the disease itself. Fifth, included in the multivariable regression model were factors which may have been affected by NAC such as margin status and tumor grade. As NCDB does not include details on pathological response to NAC, it is possible those factors were artificially improved for patients receiving upfront therapy thereby diminishing their true effect on OS. Moreover, age was treated as a categorical variable, and it is possible that selected cutoffs did not coincide with measurable effects. Finally, as NCBD includes only Commission on Cancer Hospitals, our findings might not be generalizable to broader population or other community hospitals.

In summary, notwithstanding several limitations, in this retrospective study which used a contemporary national dataset, we found that NAC, followed by surgery for iCCA, hCCA, and dCCA, was associated with increased survival, compared with SA, regardless of nodal or margin status. While an incremental advantage of NAC, compared to AC was not observed on sensitivity analysis, those results highlight that careful and interdisciplinary evaluation should incorporate NAC in the management of CCA and warrant the need of large multicenter studies or randomized trials to refine its role.