Baseline splenic volume as a surrogate marker of FOLFIRINOX efficacy in advanced pancreatic carcinoma

Abstract

Background: The FOLFIRINOX regimen is the standard first-line treatment for advanced pancreatic adenocarcinoma (aPDAC). However, because of its potential toxicity, predictive biomarkers could help clinical decision-making.

Methods: A cohort of 97 aPDAC patients treated with first-line FOLFIRINOX were studied. The association between splenic volume and progression-free survival (PFS) and overall survival (OS) was evaluated using univariate and multivariable Cox analyses. The external validation cohort was composed of 117 patients treated with Gemcitabine and 52 patients treated with FOLFIRINOX.

Results: In the training cohort, the splenic volume of 97 patients was measured at baseline and at the end of therapy. The spleen size increased in 81% of patients, with at least a 50% increase in 27% of patients. Baseline splenomegaly predicted PFS (HR 1.812, 95% CI = [1.036-3.169]; p = 0.03) and OS (HR 1.983, 95% CI = [1.085-3.624]; p = 0.02) in the training cohort. These results were then validated in an external cohort of patients who were treated with FOLFIRINOX excluding those in the control cohort who were treated with gemcitabine. In a multivariate model based on the CoxBoost method, the following were selected as predictive markers of FOLFIRINOX efficacy (AUC = 0.81): performance status, liver metastasis, baseline Ca199 and CEA levels and baseline splenomegaly. The predictive ability of the model was validated in the external cohort that was also treated with FOLFIRINOX.

Conclusions: Baseline splenomegaly is a predictive marker of a poor response to FOLFIRINOX in aPDAC and remained predictive when associated with other clinical variables.

Keywords: FOLFIRINOX; advanced pancreatic carcinoma; biomarker; splenic volume.

Figure 1. Evolution of the splenic volume

Waterfall plot showing for each patient the percentage change in splenic volume between the start of treatment and the first evaluation CT-scan (between 2 and 3 months after the initiation of therapy), respectively in the training (A), validation (B) and gemcitabine (C) cohorts. Patients were sorted by increasing order of splenic volume change. The horizontal red line represents the median percentage of the splenic volume change.

Figure 2. Prognostic role of the pre-treatment splenic volume in the training cohort

Kaplan–Meier estimates for progression-free survival (A) and for overall survival (B) in the training cohort; patients were stratified according to the splenic volume (mL): abnormal splenic volume (≥340; in red) or normal splenic volume (<340; in blue). ^*P-value < 0.05; ^**P-value < 0.01; ^***P-value < 0.001; ns: not significant.

Figure 3. Prognostic role of the composite biomarker on progression-free survival

Kaplan–Meier estimates for progression-free survival in the training (A) and in the validation (B) cohorts; patients were stratified according to the level of the composite variable: low risk of progression (in blue) or high risk of progression (in red). The cut-off was chosen to obtain specificity of 100% and sensitivity of 49% in the training cohort. ^*P-value < 0.05; ^**P-value < 0.01; ^***P-value < 0.001; ns: not significant.