This is a retrospective analysis of the adjuvant treatment of individuals with CCA using a large population database (NCDB). Although CCA is the most common biliary malignancy, it remains rare overall and the data on adjuvant therapy is evolving. Our analysis of a nationwide longitudinal dataset allows for description of care patterns across the US and its territories. This allows for a patterns of care analysis that would not be feasible using single institution or prospective data. We found that a large number of patients did not receive any adjuvant therapy after surgery. Among patients who did receive adjuvant therapy, CRT was the most commonly utilized modality followed by CT alone and RT alone.
The median time to initiation of adjuvant therapy was 59 days, which is largely consistent with the timing requirements on the SWOG and BILCAP studies.12, 13 We identified a number of patient characteristics that were associated with timing of initiation of adjuvant therapy. Many of these characteristics are consistent with expectation. Age over 65, for example, was associated with delay in initiation of adjuvant therapy, and increased comorbidity score was associated with initiating treatment among the final quartile of patients. Surgical approaches for cholangiocarcinoma vary with location and tumor size, however for most patients it often requires hemi-hepatectomy and bile duct resection.19 This is a major surgery with risks of both peri-operative morbidity and mortality.20, 21 Outcomes have been previously shown to be worse in elderly patients with increased comorbidity, therefore it is unsurprising these patients would be afforded a longer post-operative recovery period.22 Larger tumors and higher grade disease were associated with less likelihood of treatment delay; both of these factors have previously been shown to have negative impact on outcomes, which may influence providers to be more aggressive initiating adjuvant therapy in these patients.23, 24 Extrahepatic tumors were more likely to be treated among the first quartile of patients, which may be a result of differences in surgical techniques and associated recovery times between tumor locations.25–27
We also identified some predictors of delay that were less expected, including treatment with RT alone as well as black and Hispanic race. As RT alone is not a guideline-supported option for adjuvant therapy, patients treated with RT alone may represent a cohort that is unable to recover adequately from surgery to be treated with CT or CRT.11 The finding of black and Hispanic patients having an increased likelihood of treatment delay is a concerning one. While this has not been previously documented in patients with CCA, numerous studies in other malignancies have shown an increased likelihood in therapy delay for minority patients.28, 29 The explanation for this is complex and multifactorial, with previously explored contributors including decreased access to healthcare resources, distrust in the medical system, language barriers, health literacy, and biases from the medical system.30–32 Our findings underscore the continued need for improvements in the equitability of access to timely care for black and Hispanic patients in our medical system.
We identified a number of factors that were associated with decreased OS after propensity score weighting and doubly robust estimation. The majority of these, such as Charlson scores of 1 or higher, positive LVSI, positive margins, lymph node positivity, tumors larger than 2 cm, age > 65, high grade disease, and node positivity are consistent with previously known prognostic factors in CCA.2, 33, 34
An important novel finding of our study is the finding that delays in initiation beyond the median time point of 59 days were associated with decrements in OS. While this has not been previously described in CCA, there are a number of malignancies in which delay to adjuvant therapy has been shown to be associated with worse outcomes.28, 35, 36 However, in pancreatic ductal adenocarcinoma, the EPSAC-3 showed that completion of chemotherapy rather than early initiation was prognostic, and there was no survival decrement with delay of inititiation up to 12 weeks.37 While there are likely a number of patients in whom early initiation of adjuvant therapy is not feasible due to the significant potential morbidity associated with surgery for this disease, these results suggest that timely initiation of adjuvant therapy should be the goal when possible. These findings are especially pertinent in the era of COVID-19 as many cancer therapy patients experience treatment delays. While there may be some patients in whom treatment delay is a reasonable approach for decreasing exposure risk, CCA patients may not be an appropriate group for this mitigation strategy.
This study has several limitations, including those inherent in large database analyses. Confounding bias may have been introduced into this data set because the NCDB does not include information on patient symptoms, specific comorbid conditions or palliative interventions. To address the possibility of known confounders, we performed propensity score-matching by IPTW and doubly-robust estimation, which can significantly reduce selection bias.38, 39 However, it is difficult to control for all unknown confounders outside of a setting of a randomized clinical trial. It is possible, therefore, that factors such as disease biology, which we are unable to control for, may be associated with delays in therapy and influence our results. Additionally, we are unable to evaluate local recurrence or disease specific survival as these outcomes are not recorded in the NCDB. Thus, this data set could not be analyzed for these outcomes, nor determine whether disease control was associated with overall survival in our patient cohort. Finally, we did not have any information regarding the morbidity associated with surgery which may contribute to both timing of adjuvant therapy survival outcomes. Due to these limitations, these findings are hypothesis generating and require further study to confirm the findings.