Despite advances in first-line chemoimmunotherapy and molecularly targeted treatments, therapeutic options remain limited for patients with advanced biliary tract cancer (BTC) following disease progression. For patients without actionable molecular alterations, cytotoxic chemotherapy continues to play an important role in second-line treatment. However, identifying prognostic factors and understanding the impact of chemotherapy on quality of life (QoL) are essential for individualising treatment decisions.
The phase III ABC-06 trial established modified FOLFOX as a reference second-line treatment following progression on cisplatin–gemcitabine. A further analysis of the trial has now examined the prognostic significance of routinely measured serum tumour markers and the impact of FOLFOX on patient-reported QoL.
Published online on June 25, 2026, in ESMO Open, the study was titled “Prognostic markers, quality of life (QoL) and value of health (V-He) in advanced biliary cancers (ABC) treated with second-line active symptom control (ASC) alone or ASC with oxaliplatin–5-FU chemotherapy (ASC + FOLFOX) in the randomised phase III, multicentre, open-label ABC-06 clinical trial.”
The study was authored by A. Lamarca, D.H. Palmer, H.S. Wasan, P.J. Ross, Y.T. Ma, A. Arora, S. Falk, R. Gillmore, J. Wadsley, K. Patel, A. Anthoney, A. Maraveyas, T. Iveson, J.S. Waters, C. Hobbs, T. Macdonald, D. Ryder, J. Ramage, L.M. Davies, J.A. Bridgewater, and J.W. Valle, on behalf of the Advanced Biliary Cancer (ABC) Working Group.
Study Design and Objectives
ABC-06 was a multicentre, open-label, randomised phase III trial conducted across 20 centres in the United Kingdom. The trial enrolled 162 patients with advanced BTC, including cholangiocarcinoma, gallbladder cancer, and ampullary cancer, who had experienced disease progression following first-line cisplatin–gemcitabine and had an ECOG performance status of 0–1.
Patients were randomly assigned 1:1 to receive active symptom control (ASC) alone (n = 81) or ASC combined with modified FOLFOX (n = 81). FOLFOX was administered every two weeks for up to 12 cycles. The original trial demonstrated a statistically significant overall survival (OS) benefit with FOLFOX, with median OS of 6.2 versus 5.3 months (adjusted hazard ratio [HR] 0.69; 95% CI 0.50–0.97; P = 0.031).
The current analysis focused on two aspects of second-line treatment: the prognostic value of baseline carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and cancer antigen 125 (CA125), and the impact of FOLFOX on patient-reported QoL.
Tumour marker analyses were exploratory and post hoc, while QoL assessment was a prespecified secondary endpoint of the original trial. Elevated baseline tumour markers were defined as values greater than 1.5 times the upper limit of normal. QoL and health status were assessed using validated instruments, including EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D questionnaires.
Baseline Tumour Markers and Survival Outcomes
Baseline CA19-9 measurements were available for 135 of the 162 patients, of whom 92 (68.1%) had elevated levels and 43 (31.9%) had lower levels. In the pooled analysis of both treatment arms, elevated baseline CA19-9 was associated with significantly shorter survival outcomes. Median overall survival (OS) was 4.4 months in patients with elevated CA19-9 compared with 6.4 months in those with lower levels (HR 1.97; 95% CI 1.33–2.93; P < 0.001). Similarly, median progression-free survival (PFS) was 3.2 versus 5.0 months, respectively (HR 1.53; 95% CI 1.05–2.23; P = 0.027).
When the analysis was restricted to patients receiving FOLFOX, elevated baseline CA19-9 remained significantly associated with shorter OS (P = 0.004), although the association with PFS did not reach statistical significance (P = 0.072).
A further analysis included 120 patients with baseline measurements available for all three tumour markers: CA19-9, CEA, and CA125. After adjustment for treatment allocation and predefined stratification factors, including platinum sensitivity, albumin level, and disease stage, all three markers were independently associated with OS. Elevated CA19-9 was associated with an adjusted HR of 1.56 (95% CI 1.03–2.35), elevated CEA with an adjusted HR of 1.60 (95% CI 1.06–2.43; P = 0.026), and elevated CA125 with an adjusted HR of 1.70 (95% CI 1.13–2.56; P = 0.011).
The analysis also assessed overall survival according to the number of elevated baseline tumour markers. Median OS progressively decreased from 8.9 months in patients with no elevated markers to 7.0 months with one elevated marker, 4.0 months with two, and 3.2 months when all three markers were elevated. These exploratory findings suggest that the combined assessment of CA19-9, CEA, and CA125 may help characterise prognosis and could be evaluated as a stratification approach in future clinical trials, pending external validation.
Are Early CA19-9 Changes Associated With Survival?
Investigators also explored whether changes in CA19-9 during the first four weeks of FOLFOX treatment were associated with clinical outcomes. Paired baseline and week 4 CA19-9 measurements were available for 37 patients receiving FOLFOX. Of these, 17 (45.9%) had stable or decreasing CA19-9 levels, while 20 (54.1%) demonstrated an increase.
Patients with stable or decreasing CA19-9 had numerically longer median radiological PFS than those with increasing levels (4.3 versus 3.3 months), although the difference was not statistically significant (P = 0.81). Among 23 patients with elevated CA19-9 at baseline, median PFS was 5.7 versus 3.2 months, respectively, but this difference also remained nonsignificant (P = 0.23). Week 4 CA19-9 changes were not significantly associated with OS.
Therefore, although baseline CA19-9 demonstrated prognostic value, this exploratory analysis did not establish the clinical utility of early CA19-9 changes during second-line FOLFOX treatment.
Quality of Life With Second-Line FOLFOX
Beyond survival outcomes, the investigators evaluated whether the addition of chemotherapy affected patients’ quality of life. Of the 162 randomised patients, 138 had completed at least one eligible QoL questionnaire at baseline. The analysis of time to deterioration in global health status included 76 patients: 36 receiving ASC alone and 40 receiving ASC plus FOLFOX.
QoL deterioration was defined as a reduction of at least 10 points in the EORTC QLQ-C30 global health status score. No statistically significant difference in time to QoL deterioration was observed between treatment arms (adjusted HR 0.97; 95% CI 0.48–1.97; P = 0.937). Descriptive analyses comparing baseline and month 4 assessments provided further insights.
Within the ASC-alone arm, comparisons between baseline and month 4 showed statistically significant declines in several QoL domains, including global health status, physical functioning, social functioning, and role functioning. EQ-5D utility scores also declined, while nausea and pain scores increased.
In contrast, patients receiving FOLFOX did not demonstrate statistically significant within-arm deterioration across these assessed domains. For example, mean global health status scores decreased from 67 to 53 in the ASC-alone arm, compared with 66 to 58 in the FOLFOX arm.
Similarly, mean physical functioning scores declined from 74 to 59 with ASC alone and from 78 to 66 with FOLFOX. Although these descriptive findings suggest that FOLFOX may help maintain aspects of patient-reported QoL, the analysis did not demonstrate a statistically significant between-arm difference in time to deterioration.
Clinical Implications
The findings provide additional information about prognosis and patient-reported outcomes in advanced BTC. First, baseline CA19-9, CEA, and CA125 were independently associated with OS, with numerically shorter median OS observed as the number of elevated markers increased. Their combined assessment could potentially support risk stratification in future clinical trials, although external validation is needed.
Importantly, these markers were evaluated for their prognostic significance, rather than their ability to predict the relative benefit of FOLFOX compared with ASC alone. Consequently, the findings do not establish a biomarker-based strategy for selecting patients for second-line chemotherapy. Second, the absence of a significant difference in time to QoL deterioration provides additional context for the previously demonstrated survival benefit of FOLFOX. Among patients receiving FOLFOX with evaluable questionnaires, no statistically significant within-arm deterioration was observed in several assessed QoL domains between baseline and month 4.
However, several limitations should be considered. The tumour marker analyses were post hoc, with incomplete data and relatively small subgroups. Serum marker concentrations may also be influenced by nonmalignant conditions, including biliary obstruction and infection. The QoL analyses were limited by modest sample sizes, missing follow-up data, and assessments conducted at relatively widely spaced intervals. Additionally, routine radiological follow-up differed between the treatment groups, complicating some PFS comparisons.
Conclusion
This further analysis of the phase III ABC-06 trial highlights the prognostic relevance of baseline CA19-9, CEA, and CA125 in patients with advanced biliary tract cancer receiving second-line management. Median overall survival was numerically shorter in patients with a greater number of elevated baseline tumour markers, supporting further investigation of their combined use in prognostic stratification.
At the same time, adding FOLFOX to active symptom control was not associated with a statistically significant difference in time to QoL deterioration, and descriptive patient-reported outcomes suggested relative stability across several QoL domains during chemotherapy. Together, these findings add to the evidence supporting FOLFOX as a second-line treatment option for appropriate patients with advanced BTC while highlighting the importance of integrating prognostic assessment and quality-of-life considerations into clinical care.
The full article is available in ESMO Open.
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