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. 2022 Feb;42(2):458-467.
doi: 10.1111/liv.15117. Epub 2021 Dec 10.

Pattern of progression of intrahepatic cholangiocarcinoma: Implications for second-line clinical trials

Francesco Tovoli  1 , Ingrid Garajová  2 , Fabio Gelsomino  3 , Massimo Iavarone  4 , Piera Federico  5 , Massimiliano Salati  3 , Matilde Corianò  2 , Francesco Caputo  3 , Stefania De Lorenzo  6 , Alessandro Granito  1   7 , Matteo Renzulli  8 , Bruno Daniele  5 , Fabio Piscaglia  1   7
Affiliations

Pattern of progression of intrahepatic cholangiocarcinoma: Implications for second-line clinical trials

Francesco Tovoli et al. Liver Int. 2022 Feb.

Abstract

Background: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remains poor. Recently, the ABC-06 trial reported the superiority of FOLFOX vs clinical observation as a second-line treatment. Still, the survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post-progression survival (PPS), similar to hepatocellular carcinoma.

Methods: Multicentre retrospective evaluation of consecutive iCCA patients who progressed after frontline systemic treatment with gemcitabine as monotherapy or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH).

Results: We included 206 patients from 5 centres. The median OS was 14.1 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were previous surgery 0.699 [0.509-0.961], performance status >2.445 [1.788-3.344], permanent first-line discontinuation 16.072 [5.102-50.633], registration of ascites 2.226 [1.448-3.420] or bilirubin >3 mg/dl 3.004 [1.935-4.664] during the follow-up, and disease progression 2.523 [1.261-5.050]. The appearance of NEH independently predicted OS 2.18 [1.55-3.06] in patients with radiological progression. Amongst 138 patients eligible for second-line treatment, PPS was 16.8 and 5.9 months in cases without and with NEH, respectively (P = .001). Progression owing to NEH lesions was an independent predictor of PPS 1.873 [1.333-2.662], together with performance status, time to progression to the frontline treatment, bilirubin >3 mg/dl and ascites.

Conclusions: PPS of iCCA is influenced by progression pattern, with important implications for second-line trial design and analysis.

Keywords: biliary tract cancer; cholangiocarcinoma; liver cancer; outcome; prognosis.

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Conflict of interest statement

The authors declare that the following financial interests/personal relationships may be considered as potential competing interests: FT: consultant for Bayer and Eisai, the advisory board for Guerbet, lecture fees from Ipsen; MI: speaking and teaching for Bayer, Gilead Science, Janssen, BTG, AbbVie and consultant for BCG; AG: consultant for Bayer; BD: honoraria from Ipsen, AstraZeneca, Incyte, Lilly, Eisai, Bayer, Roche and MSD; FP: consultant for AstraZeneca, Bayer AG, EISAI, GE and Tiziana life sciences; speaker's bureau honoraria from Bayer AG, Bracco, EISAI and Laforce and research contract with Esaote; IG, FG, PF, MS, MC, FC, SD, MR: no conflicts to declare.

Figures

FIGURE 1
FIGURE 1
Post‐progression survival stratified according to the pattern of progression in patients with radiological tumour progression (A) and eligible for second‐line trials under 3 different scenarios: (B) performance status 0–1, total bilirubin <3 mg/dl, no clinically relevant ascites, any gemcitabine‐containing first‐line treatment; (C) same as previous but allowing only patients who received gemcitabine‐platinum first‐line treatment; (D) same as previous but limited to patients who received gemcitabine‐cisplatin as a first‐line treatment
FIGURE 2
FIGURE 2
Post‐progression survival curves estimated from the Cox model in TNM Stage 4 patient candidates to second‐line trial divided according to the absence or presence of new extrahepatic lesions (n = 86). TNMp‐4A: Patients TNM Stage 4 under first‐line treatment with progression owing to the growth of existing nodules or new intrahepatic sites. TNMp‐4B: Patients TNM Stage 4 under first‐line treatment with progression owing to new extrahepatic lesions
FIGURE 3
FIGURE 3
Survival curves of the Association des Gastro‐Entérologues Oncologues (AGEO) CT2BIL score amongst the 119 patients who received second‐line treatment, stratified according to the pattern of radiological progression under first‐line treatment
See this image and copyright information in PMC

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