Patient characteristics and demographics

The analytic cohort included seventy-eight patients (Table 1). Most were white males with good performance status (91.8% ECOG 0–1), without known risk factors for BTC. The majority of patients did not have cirrhosis, ascites, or encephalopathy at presentation; most had an ALBI grade of 2. The median CA19-9 blood level at diagnosis (before initiating any oncologic treatment and after biliary decompression in cases of biliary obstruction) was 63 U/ml. The most common type of BTC was intrahepatic, followed by hilar and extrahepatic. Four patients were diagnosed with gallbladder cancer, and a similar number with intrahepatic and hepatocellular carcinoma (HCC). Over a third of the tumors presented with regional nodal disease, most commonly portocaval. Nearly half presented with a locally advanced stage, and a quarter of the patients had vascular involvement when they were diagnosed.

Table 1 Patient characteristics of the entire cohortTreatment details for the entire cohort

Table 2 details the oncologic treatment of the entire cohort. Most patients received a hypofractionated RT regimen (2.01–5 Gy per fraction) and concurrent 5FU-based chemotherapy (either 5FU or capecitabine). The median BED10 was 73.1 Gy. A similar number of patients received proton therapy compared to photon-based RT. Approximately half of the patients received chemotherapy either before or after RT. Among the 37 patients who did not receive systemic therapy, over half were unable to do so due to poor performance status and comorbidities (Supplementary Table 1). In 18.9% of these cases, the medical oncologist recommended systemic chemotherapy, but the patients declined. Of the 41 patients who did receive systemic treatment, most underwent chemotherapy prior to starting RT (Supplementary Table 2). The most common regimen was a combination of GemCis (Supplementary Table 3). Only a small minority of patients received second and third-line systemic therapies.

Table 2 Radiation treatment details of the entire cohortClinical outcomes and patterns of failure

Of the 78 patients in the study, five patients (6.4%) had documented grade (G)3 and above gastrointestinal toxicity (three patients with G3, one G4, and one died from RT-induced enteritis), four patients (5.1%) experienced G3 fatigue, two patients (2.6%) had G3 abdominal pain and non-had G3 and above skin toxicity.

Fifty-nine (77.6%) died during the follow-up period, with a median OS of 12.3 months after RT (Supplementary Fig. 1); twenty (27.0%) had a local recurrence in the irradiated field as the first site of failure, and thirty-seven (47.4%) developed distant metastasis (Table 3). The most common sites of metastatic spread following RT were the peritoneum and liver, while the most common cause of death was liver failure followed by biliary sepsis. In patients with a local recurrence, the median time to recurrence was 30.1 months (Supplementary Fig. 2), while the median metastasis-free survival was 11.0 months (Supplementary Fig. 3). In patients who developed distant metastasis, the median time to death after metastatic disease was 4.9 months, while in patients with a local recurrence, the median time to death after diagnosis of progression at the RT site was 5.1 months.

Table 3 Clinical outcomes and patterns of failureUnivariate and multivariate Cox regression analysis for predictors of OS after RT

Table 4 shows the results of a univariate Cox proportional hazard analysis for OS after RT using the patient’s age (above vs. under 70 years), gender, ECOG performance status, ALBI grade, type of biliary cancer (intrahepatic vs. hilar vs. extrahepatic vs. gallbladder) vascular involvement, clinical stage, GTV volume (above vs. under median value of 64.3 cm³), CEA blood levels at diagnosis (above vs. under median value of 2.4 ng/ml), CA19-9 blood levels at diagnosis (above vs. under median value of 63 U/ml), RT modality (protons vs. photons vs. mixed), BED10 (above vs. under median 73.1 Gy), concurrent chemotherapy during RT and systemic chemotherapy other than concurrent (before or after RT). Parameters that reached a P < 0.1 level of statistical significance in the univariate analysis were selected for inclusion in a multivariate Cox proportional hazard analysis. In addition, given previous studies demonstrating an association between clinical stage and treatment outcomes in BTC patients, we included clinical stage in the multivariate analysis [17, 19]. In the multivariate Cox regression, CA19-9 above the median value was a significant predictor of OS with a hazard ratio (HR) of 2.621 (P = 0.003). In addition, a higher ALBI grade was also associated with a statistically significant decreased OS after RT (HR = 1.952, P = 0.021).

Table 4 Univariate and multivariate Cox regression analysis for OS after RTImpact of CA19-9 blood levels at the presentation on clinical outcomes after RT

Supplementary Table 4 compares the characteristics of patients with CA19-9 blood levels at presentation over and under the median value of ≤ 63 U/ml. Patients with high CA19-9 blood levels had comparable mean age, ethnicity, ECOG performance status, and prevalence of encephalopathy, ascites, and cirrhosis at diagnosis. In addition, there was no difference in the prevalence of vascular involvement as assessed by imaging scans or tumor diameter. However, compared to patients with low CA19-9 blood levels, patients with a high biomarker level had a higher clinical stage, with 60.0% diagnosed with a stage III disease compared to 28.6%, and had significantly worse ALBI grade. There was no clinically significant difference in the RT regimens, i.e., BED10, number of fractions or dose per fraction, concurrent chemotherapy, and systemic therapy (Supplementary Table 5). However, the outcome of patients with high CA19-9 at presentation treated with RT was dismal, with a median survival of 7.6 months after RT compared with 19.7 months in patients with low CA19-9 levels (P < 0.001, Fig. 1). There was no difference in local recurrence-free survival between patients with high and low CA19-9 blood levels at presentation (P = 0.833, Fig. 2); however, patients with high CA19-9 had shorter metastasis-free survival (P = 0.009, Fig. 3).

Fig. 1

Overall survival of unresectable BTC patients who received RT were stratified based on their plasma CA19-9 levels at presentation, above and below the median of 63 U/ml

Fig. 2

Local recurrence-free survival of unresectable BTC patients who received RT were stratified based on their plasma CA19-9 levels at presentation, above and below the median of 63 U/ml

Fig. 3

Metastasis-free survival of unresectable BTC patients who received RT were stratified based on their plasma CA19-9 levels at presentation, above and below the median of 63 U/ml

Combining CA19-9 blood levels at presentation and ALBI grade to predict survival after RT in unresectable BTC patients

CA19-9 blood levels at presentation and ALBI grade at baseline were significant predictors of poor survival after RT in our multivariate Cox proportional hazard model in patients with unresectable BTC. To further identify a subgroup of patients who may benefit from RT as opposed to patients where RT should be avoided, we created a new variable combining CA19-9 and ALBI grade (Fig. 4). Patients with CA19-9 blood levels at presentation under (or equal) the median value of 63 U/ml and ALBI grade 1 at baseline had a median survival of 24.0 months after RT. Patients with CA19-9 blood levels at presentation over the median value of 63 U/ml and ALBI grade 2 or 3 at baseline had a median survival of 6.3 months after RT. All other patients (i.e., patients with CA19-9 blood levels at presentation under (or equal) the median value of 63 U/ml or ALBI grade 1 at baseline) had a median survival of 14.4 months after RT.

Fig. 4

A model combining CA19-9 blood levels at presentation and ALBI grade to predict overall survival after RT in unresectable BTC patients