Clinical role of tumour markers in advanced biliary cancers (ABC) treated with second-line active-symptom-control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC plus mFOLFOX) in the randomised phase III, multi-centre, open-label ABC-06 trial

Abstract

Background: The ABC-06 clinical trial stablished ASC+mFOLFOX as the standard of care treatment after Cisplatin and Gemcitabine (CisGem) for ABC. Methods: Within the ABC-06 study, patients (pts) diagnosed with ABC (chol- angiocarcinoma, gallbladder or ampullary cancer) with progression after CisGem were randomised (1:1) to ASC+mFOLFOX or ASC. Tumour markers (CA19.9, CEA and CA125), were scheduled at baseline (BSL) and at every follow-up visit. This post-hoc analysis explored if changes (stable/reducing vs increasing) of Ca19.9 at week 4 from initiation of ASC+mFOLFOX was associated with radiological progression-free survival (PFS). Secondary end-points included impact of raised BSL Ca19.9 (defined as x1.5 ULN) and chemotherapy-induced changes on overall survival (OS). CEA and CA125 were also analysed. Results: Out 162 pts randomised, BSL Ca19.9 data was available for 135 pts. Paired BSL and week-4 Ca19.9 data was available for 37 pts in the ASC+mFOLFOX arm: Ca19.9 was stable/reducing in 17 (45.9%) and increasing in 20 pts (54.1%). Stable/ reducing Ca19.9 showed a numerically longer median radiological PFS (4.3 months (m) vs 3.3m) but differences did not reach statistical significance (HR 1.08 (95% CI 0.55-2.14); p¼0.81). When restricted to patients with raised BSL Ca19.9 (23 pts), impact on PFS was more marked (5.7m vs 3.2m), but remained non-significant (HR 1.68 (95% CI 0.70-4.01); p¼0.23). Stable/reducing Ca19.9 at week 4 did not impact significantly on OS (p¼0.56 (regardless of BSL Ca19.9 level; 37 pts); p¼0.84 (if raised BSL Ca19.9; 23 pts)). Raised BSL Ca19.9 was associated both with shorter unadjusted clinical median PFS (3.2m vs 5.0m; HR 1.53 (95% CI 1.05-2.23); p¼0.027) and un- adjusted OS (4.4m vs 6.4m; HR 1.97 (95% CI 1.33-2.93); p When Cox Regression model (120 pts) for OS exploring the prognostic roles of raised BSL Ca19.9, CEA and CA125 was adjusted for pre-defined stratification factors (platinum sensitivity, albumin, and stage) and randomised trial arm, each raised tumour marker had an independent impact (HR 1.56 (95% CI 1.03 to 2.35); p¼0.03 / HR 1.60 (95% CI 1,06 to 2.43) p¼0.026 / HR 1.70 (95% CI 1.13 to 2.56); p¼0.011 for Ca19.9, CEA and CA125, respectively). Unadjusted median OS was 8.9m if all tumour markers at BSL were non- raised, and 7.0m, 4.0m, 3.2m in the event of having 1, 2 or 3 raised BSL tumour markers. Conclusions: For ABC patients treated with second-line ASC+mFOLFOX, utility of Ca19.9 measured at week-4 after chemotherapy initiation is limited; raised BSL Ca19.9, CEA and CA125 have independent prognostic roles and future studies may need to consider these (individually or pooled) as stratification factors.