Patients
Between June 2016 and March 2020, 35 BTC patients were enrolled. Allpatients had histologically or cytologically proven advanced or recurrent BTC with at least one measurable lesion. Twenty-one patients (60.0%) had intrahepatic cholangiocarcinoma, 10 (28.6%) had extrahepatic cholangiocarcinoma, 2 (5.7%) had gallbladder cancer and 2 (5.7%) had ampulla of Vater cancer (Table 1). Twenty-six patients (74.3%) presented with an advanced disease including 21 (60.0%) metastatic and 5 (8.6%) locally advanced diseases, and 9 (25.7%) had a recurrent disease. The polymorphisms of UGT1A1 were wild-type (*1/*1) in 21 (60.0%) and heterozygous-type in 14 including *1/*28 in 9 (25.7%) and *1/*6 in 5 (14.3%). At the time of data cut-ff on September 2021, 9 patients were still alive but no patients were on the planned treatment of FOLFIRINOX.
Treatment exposure
The median number of treatment cycles was 11 (range, 1-63). The median relative dose intensities of oxaliplatin, irinotecan, bolus fluorouracil, infusional fluorouracil, and leucovorin were 62.8%, 60.2%, 13.1%, 76.5%, and 80.0%, respectively. Dose reduction and treatment delay occurred in 30 patients (85.7%). Neutropenia was the most frequent cause for both dose reduction and treatment delay (74.3% and 77.1%, respectively).
Efficacy
After a median follow-up of 13.9 months, the median PFS and OS were 7.4 (80% confidence interval [CI], 5.5-7.5) and 14.7 (80% CI, 11.8-15.7) months, respectively (Figure 1 and Table 2). The 12-month PFS and OS rate were 12.9 (80%CI, 14.5-32.4) % and 57.1 (80% CI, 45.7-67.0) %, respectively. Since the lower limit value of 80% CI of the median PFS did not exceed 6.0 months, this study failed to achieve the primary endpoint to verify the safety and efficacy of FOLFIRINOX in a phase III trial.
As shown in Table 3, post-hoc analysis showed that PFS was significantly associated with primary cancer and CEA level at baseline, but not with disease extension, tumor size and CA19-9 level at baseline. On the other hand, no factors were significantly associated with OS.
A complete response was achieved in 1 (2.9%), partial response in 10 (28.6%) and stable disease in 15 (42.9%), giving an ORR of 31.4% and DCR of 74.3% (Table 2). Best change in tumor volume of the target lesion is shown in Figure 2. Of note, 8 patients (22.9%) had a remarkable tumor shrinkage by more than 40% from baseline.
Among 24 patients in whom CA19-9 was elevated (> 37 IU/L) at baseline, CA19-9 was reduced by more than 50% compared to pretreatment level in 9 patients (37.5%), which was associated with tumor response (ORR of 71.4% in CA19-9 responder vs. 11.8% in non-responder, data not shown).
Adverse events
All eligible patients were evaluated for toxicities. Grade 3 or 4 adverse events occurred in 31 patients (88.6%). As shown in Table 4, the major grade 3-4 adverse events included neutropenia (54.3%), leukopenia (34.4%), galactolipid galactosyltransferase increased (20.0%), febrile neutropenia (17.1%), thrombocytopenia (8.6%), cholangitis (8.6%), anemia, nausea, diarrhea, and peripheral sensory neuropathy (2.9% each). There were no treatment-related deaths in this study.
Seven episodes of febrile neutropenia accounted in 6 patients mainly during the first two cycles, and a total of 28 sessions of G-CSF was used in 14 patients (40.0%) to control febrile neutropenia as well as severe neutropenia. The G-CSF usage decreased as the number of cycles increased (12 times during the first cycle, 5 times during the second cycle and 3 times each during the third and fourth cycles). Biliarytract-related events were reported in 8 patients, including cholangitis (n = 6), obstructive jaundice (n = 1) and biliary tract infection (n = 1), and an increased level of blood bilirubin (n = 1), all of which were unrelated to the study treatment. For patients with (n = 8) or without (n = 27) a biliary stent, febrile neutropenia was observed in 3 (37.5%) and 3 (11.1%), respectively and cholangitis was observed in 4 (50.0%) and 2 (7.4%), respectively.
Post-study treatment
At the time of final follow-up, all patients had discontinued the planned treatment of FOLFIRINOX because of disease progression in 26 (74.3%), unacceptable toxicity in 4 (11.4%; prolonged neutropenia in 2, continuous gastrointestinal bleeding in 1, severe acute respiratory syndrome coronavirus-2 infection in 1), withdrawal of consent in 2 (5.7%), or conversion surgery with curative intent after remarkable tumor shrinkage in 3 (8.6%). Twenty-five patients (71.4%) received second-line chemotherapy (GC in 18, GCS in 4, GC combined with fluorouracil in 2 and S-1 in 1), and 14 patients (40.0%) received third-line chemotherapy (S-1 in 7, GC or gemcitabine in 2 each, GS or clinical trial in 1 each). In total, four patients were converted to be surgical candidates after chemotherapy and they subsequently underwent surgery, resulting in R0 resection in 3. Notably, the surgical specimen revealed a pathologic complete response in one patient with initially metastatic intrahepatic cholangiocarcinoma.