Improving Treatment Response Prediction for Chemoradiation Therapy of Pancreatic Cancer Using a Combination of Delta-Radiomics and the Clinical Biomarker CA19-9

Abstract

Recently we showed that delta radiomics features (DRF) from daily CT-guided chemoradiation therapy (CRT) is associated with early prediction of treatment response for pancreatic cancer. CA19-9 is a widely used clinical biomarker for pancreatic cancer. The purpose of this work is to investigate if the predictive power of such biomarkers (DRF or CA19-9) can improve by combining both biomarkers. Daily non-contrast CTs acquired during routine CT-guided neoadjuvant CRT for 24 patients (672 datasets, in 28 daily fractions), along with their CA19-9, pathology reports and follow-up data were analyzed. The pancreatic head was segmented on each daily CT and radiomic features were extracted from the segmented regions. The time between the end of treatment and last follow-up was used to build a survival model. Patients were divided into two groups based on their pathological response. Spearman correlations were used to find the DRFs correlated to CA19-9. A regression model was built to examine the effect of combining CA19-9 and DRFs on response prediction. C-index was used to measure model effectiveness. The effect of a decrease in CA19-9 levels during treatment vs. failure of CA19-9 levels to normalize on survival was examined. Univariate- and multivariate Cox-regression analysis were performed to determine the effect of combining CA19-9 and DRFs on survival correlations. Spearman correlation showed that CA19-9 is correlated to DRFs (Entropy, cluster tendency and coarseness). An Increase in CA19-9 levels during treatment were correlated to a bad response, while a decline was correlated to a good response. Incorporating CA19-9 with DRFs increased the c-index from 0.57 to 0.87 indicating a stronger model. The univariate analysis showed that patients with decreasing CA19-9 had an improved median survival (68 months) compared to those with increasing levels (33 months). The 5-years survival was improved for the decreasing CA19-9 group (55%) compared to the increasing group (30%). The Cox-multivariate analysis showed that treatment related decrease in CA19-9 levels (p = 0.031) and DRFs (p = 0.001) were predictors of survival. The hazard-ratio was reduced from 0.73, p = 0.032 using CA19-9 only to 0.58, p = 0.028 combining DRFs with CA19-9. DRFs-CA19-9 combination has the potential to increasing the possibility for response-based treatment adaptation.

Keywords: CA19-9; biomarkers; chemo-radiation therapy; pancreatic cancer; response assessment; survival.

Figure 1

Work flow of combining the delta-radiomic and CA19-9.

Figure 2

Changes of selected delta radiomic features [(A) Entropy and (B) cluster tendency] as a function of increasing treatment fraction. Each dot represents the average value of all good responders for a treatment time point.

Figure 3

(A) Comparison of the DRF (cluster tendency) values between the two response groups and the t-test p-value, and (B) a t-test comparison of weekly DRFs between the good and bad response groups for the DRF (cluster tendency). The boxplots show the median and interquartile range for each response group and the diamond data point in the middle represents the mean of the group.

Figure 4

(A) Comparison of the changes in the normalized CA19-9 levels between the two response groups and the t-test p-value, and (B) a t-test comparison of weekly changes of CA19-9 between the good and bad response groups, indicating that their significant changes began at the fourth week of the treatment.

Figure 5

Weekly change of the CA19-9 as function of treatment response. For instance, 1. Bad represent all available fractions within the first week acquired from all patients in the bad response group.

Figure 6

The c-index of the prediction model based on DRFs or CA19-9 alone and their combination.

Figure 7

Average weekly changes of the combined biomarker (CA19-9 and DRFs) showing that the detection of good and bad responders begins at the third week during the treatment.

Figure 8

Survival curve as a function of the normalized CA19-9 changes between the increasing and decreasing CA19-9 groups without (left) and with (right) adding DRFs.