Prediction of survival with second-line therapy in biliary tract cancer: Actualisation of the AGEO CT2BIL cohort and European multicentre validations

Abstract

Background: The benefit of second-line chemotherapy (L2) over standard first-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) chemotherapy in advanced biliary tract cancer (aBTC) is unclear. Our aim was to identify and validate prognostic factors for overall survival (OS) with L2 in aBTC to guide clinical decisions in this setting. Methods: We performed a retrospective analysis of four prospective patient cohorts: a development cohort (28 French centres) and three validation cohorts from Italy, UK and France. All consecutive patients with aBTC receiving L2 after GEMCIS/GEMOX L1 between 2003 and 2016 were included. The association of clinicobiological data with OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. Results: The development cohort included 405 patients treated with L1 GEMOX (91%) or GEMCIS. Of them, 55.3% were men, and median age was 64.8 years. Prior surgical resection was observed in 26.7%, and 94.8% had metastatic disease. Performance status (PS) was 0, 1 and 2 in 17.8%, 52.4% and 29.7%, respectively. Among 22 clinical parameters, eight were associated with OS in univariate analysis. In multivariate analysis, four were independent prognostic factors (p < 0.05): PS, reason for L1 discontinuation, prior resection of primary tumour and peritoneal carcinomatosis. The model had the Harrell's concordance index of 0.655, a good calibration and was validated in the three external cohorts (N Z 392). Conclusion: We validated previously reported predictive factors of OS with L2 and identified peritoneal carcinomatosis as a new pejorative factor in nearly 800 patients. Our model and score may be useful in daily practice and for future clinical trial design. ª

Prognostic Factors for Overall Survival in Advanced Intrahepatic Cholangiocarcinoma Treated with Yttrium-90 Radioembolization

“…Additionally, previous surgical therapy can rather be seen as a surrogate marker for relapse or progressive disease, rather than a real prognostic factor for survival. Interestingly, a predictive model based on 405 patients with biliary tract cancer revealed improved survival of patients who had undergone surgical resection of the primary tumor [24]. However, it has to be noted that this cohort included patients with various biliary tract cancers, including extrahepatic manifestation, in whom an R0 resection can be achieved much more frequently.…”

Fluropyrimidine single agent or doublet chemotherapy as second line treatment in advanced biliary tract cancer

“…In summary, we previously showed that all patients with aBTC do not benefit from L2 administration and that the CT2BIL score (mainly driven by ECOG PS) may be useful in this setting. 7 In this article, our results suggest that FP monotherapy is as active as FP doublets in aBTC in L2, regardless of the patient PS and platinum sensitivity status, and could be a therapeutic option in this setting. This would warrant further prospective evaluation in randomized controlled trials.…”

“…7 We also identified absence of primary tumor resection, L1 discontinuation for progression, presence of peritoneal carcinomatosis, and high carbohydrate antigen 19-9 (CA19-9) serum level as other independent prognostic biomarkers for OS in this setting. 7 Second-line therapies for aBTC are as well heterogeneous, with no high-level prospective evidence available until recently. 8,9 In routine clinical practice, most patients receive fluoropyrimidine (FP, ie, intravenous 5-fluorouracil [5FU] or oral capecitabine) in monotherapy or combined with platinum or irinotecan, based on retrospective cohorts or small single-arm phase II studies.…”

“…Due to the high prognostic weight of ECOG PS, we preplanned to perform subgroup analyses according to ECOG PS (0-1 vs 2). 7 Following the results of the ABC-06 trial, we also considered an exploratory analysis according to platinum sensitivity. 11…”

“…8,9 In routine clinical practice, most patients receive fluoropyrimidine (FP, ie, intravenous 5-fluorouracil [5FU] or oral capecitabine) in monotherapy or combined with platinum or irinotecan, based on retrospective cohorts or small single-arm phase II studies. 3,[5][6][7][8][9] Recently, a randomized phase II study reported improved progression-free survival (PFS) using capecitabine plus irinotecan (XELIRI regimen) L2 over single agent irinotecan (median PFS: 3.7 vs 2.4 months, P = .036), with an acceptable safety profile. 10 Moreover, the ABC-06 phase III study, presented at ASCO 2019, showed the superiority of 5FU, folinic acid and oxaliplatin (FOLFOX regimen) over best supportive care in patients with aBTC previously treated with GEMCIS and ECOG PS 0-1 (median OS: 6.2 vs 5.3 months, hazard ratio [HR]: 0.69, P = .031), with preliminary results suggesting a more pronounced benefit in platinum-resistant (defined by progression within the first 3 months after the last cycle of GEMCIS L1) or refractory (progression during GEMCIS L1) patients.…”