Impact of Variability in Portal Venous Phase Acquisition Timing in Tumor Density Measurement and Treatment Response Assessment: Metastatic Colorectal Cancer as a Paradigm

Abstract

Purpose: New response patterns to anticancer drugs have led tumor size-based response criteria to shift to also include density measurements. Choi criteria, for instance, categorize antiangiogenic therapy response as a decrease in tumor density > 15% at the portal venous phase (PVP). We studied the effect that PVP timing has on measurement of the density of liver metastases (LM) from colorectal cancer (CRC).

Methods: Pretreatment PVP computed tomography images from 291 patients with LM-CRC from the CRYSTAL trial (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer; ClinicalTrials.gov identifier: NCT00154102) were included. Four radiologists independently scored the scans' timing according to a three-point scoring system: early, optimal, late PVP. Using this, we developed, by machine learning, a proprietary computer-aided quality-control algorithm to grade PVP timing. The reference standard was a computer-refined consensus. For each patient, we contoured target liver lesions and calculated their mean density.

Results: Contrast-product administration data were not recorded in the digital imaging and communications in medicine headers for injection volume (94%), type (93%), and route (76%). The PVP timing was early, optimal, and late in 52, 194, and 45 patients, respectively. The mean (95% CI) accuracy of the radiologists for detection of optimal PVP timing was 81.7% (78.3 to 85.2) and was outperformed by the 88.6% (84.8 to 92.4) computer accuracy. The mean ± standard deviation of LM-CRC density was 68 ± 15 Hounsfield units (HU) overall and 59.5 ± 14.9 HU, 71.4 ± 14.1 HU, 62.4 ± 12.5 HU at early, optimal, and late PVP timing, respectively. LM-CRC density was thus decreased at nonoptimal PVP timing by 14.8%: 16.7% at early PVP ( P < .001) and 12.6% at late PVP ( P < .001).

Conclusion: Nonoptimal PVP timing should be identified because it significantly decreased tumor density by 14.8%. Our computer-aided quality-control system outperformed the accuracy, reproducibility, and speed of radiologists' visual scoring. PVP-timing scoring could improve the extraction of tumor quantitative imaging biomarkers and the monitoring of anticancer therapy efficacy at the patient and clinical trial levels.

Fig 1.

Study overview. First, two pairs of experienced radiologists individually performed a visual scoring of each scan’s PVP (portal venous phase) timing based on a three-point scoring system. Any scan with differing scores was reevaluated by both radiologists and a consensus score was reached. Using these values, a computer-aided scoring algorithm of the PVP timing (CASA_PVP) was developed. Potentially misclassified PVP timings were detected by the CASA_PVP and referred to the radiologists for a new consensus reading. The results of this new consensus reading then served as the reference standard for grading the accuracy of visual and computer scoring methods, as well as for studying the density variation of colorectal cancer with liver metastases due to PVP timing.

Fig 2.

PVP (portal venous phase) timing and region of interest (ROI) selection. Relative contrast enhancement of soft tissues at (A) early, (B) optimal, and (C) late PVP timing. (A–C) ROIs were delineated in normal tissues (ie, aorta, portal vein, inferior vena cava, liver, spleen, and kidney), as illustrated in the circles (excluding psoas). (D, E) All patients had computed tomography acquisition intended at PVP, although we sometimes observed significant differences in the acquisition timing between (D) baseline (early) and (E) follow-up (optimal), even within the same patient, as demonstrated by the computed tomography scans in this figure.

Fig 3.

Computer-aided scoring output. Output in the form of isoprobability curves indicating the probability that PVP timing is optimal (eg, 0.5 = 50%). This study used a cutoff of 0.5 to determine optimal PVP. For comparison, cases are also color coded by their visual consensus scores (blue: early, 1; gold: optimal, 2; red: late, 3). Most of the discrepancies in both human and computer scoring were between scores 2 and 3. HU, Hounsfield unit; PVP, portal venous phase.

Fig 4.

LM-CRC density variability. (A) There was a significant decrease (P < .001) in the density of LM-CRCs at nonoptimal PVP timing (early, 1; or late, 3). (B) The density of the LM-CRC is a function of the density in the portal vein (R² = 0.23; P < .001): A decrease of 50 HU in portal vein density triggers a 15% (10 HU) decrease in LM-CRC density. HU, Hounsfield unit; LM-CRC, colorectal cancer with liver metastases; PVP, portal venous phase.

Fig 5.

Validation of our observations by the comparison of baseline (BL) and follow-up (FU) computed tomography scans. (A) The mean treatment-induced change in tumor density at 8 weeks was −0.9 HU. (B) The mean change in tumor density when the PVP timing was worsened, the same, or better than baseline is shown from the left to the right. The mean density change was, respectively, −8.4 HU, −2.1 HU, and +3.3 HU. These data confirm our conclusion that change in PVP timing will lead to a mimicking or masking of treatment-induced change in tumor vascularity. HU, Hounsfield unit; LM-CRC, colorectal cancer with liver metastases; PVP, portal venous phase.

Fig A1.

Density variability of colorectal cancer tumors with liver metastases by computed tomography scanner manufacturer. HU, Hounsfield unit; PVP, portal venous phase.

Fig A2.

Peak contrast enhancement of soft tissues and LM-CRC is observed at optimal PVP timing. HU, Hounsfield unit; IVC, inferior vena cava; LM-CRC, colorectal cancer with liver metastases; PVP, portal venous phase.