Arterial Perfusion Imaging–Defined Subvolume of Intrahepatic Cancer

Purpose

To assess whether an increase in a subvolume of intrahepatic tumor with elevated arterial perfusion during radiation therapy (RT) predicts tumor progression after RT.

Methods and Materials

Twenty patients with unresectable intrahepatic cancers undergoing RT were enrolled in a prospective, institutional review board–approved study. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed before RT (pre-RT), after delivering ∼60% of the planned dose (mid-RT) and 1 month after completion of RT to quantify hepatic arterial perfusion. The arterial perfusions of the tumors at pre-RT were clustered into low-normal and elevated perfusion by a fuzzy clustering-based method, and the tumor subvolumes with elevated arterial perfusion were extracted from the hepatic arterial perfusion images. The percentage changes in the tumor subvolumes and means of arterial perfusion over the tumors from pre-RT to mid-RT were evaluated for predicting tumor progression post-RT.

Results

Of the 24 tumors, 6 tumors in 5 patients progressed 5 to 21 months after RT completion. Neither tumor volumes nor means of tumor arterial perfusion at pre-RT were predictive of treatment outcome. The mean arterial perfusion over the tumors increased significantly at mid-RT in progressive tumors compared with the responsive tumors (P=.006). From pre-RT to mid-RT, the responsive tumors had a decrease in the tumor subvolumes with elevated arterial perfusion (median, −14%; range, −75% to 65%), whereas the progressive tumors had an increase of the subvolumes (median, 57%; range, −7% to 165%) (P=.003). Receiver operating characteristic analysis of the percentage change in the subvolume for predicting tumor progression post-RT had an area under the curve of 0.90.

Conclusion

The increase in the subvolume of the intrahepatic tumor with elevated arterial perfusion during RT has the potential to be a predictor for tumor progression post-RT. The tumor subvolume could be a radiation boost candidate for response-driven adaptive RT.

Introduction

High-dose, conformal radiation therapy (RT) can control intrahepatic cancers (1). Conventional RT delivers uniformly distributed dose to a target volume. Considering the heterogeneity of tumors, specific subvolumes in the tumors may be more active or aggressive; thus, targeting these subvolumes with higher dose of RT could improve the rates of local tumor control (2). Technological advancements in RT allow delivery of a high-precision, nonuniform dose painting in the target volume. To take advantage of this, one would need to detect and visualize the active or aggressive target for dose intensification.

The concept of biological target volumes determined by physiological, metabolic, and molecular imaging has been proposed by Ling et al (2). In the last several years, physiological and metabolic imaging have shown the potential for assessment and prediction of tumor response and/or outcome to RT in the tumors of various types 3, 4. However, the heterogeneous distributions of physiological and biological parameters within the tumors were largely ignored in most of these studies. Recently, a globally initiated fuzzy clustering technique has been proposed to extract tumor subvolumes from perfusion images in head and neck cancers (HNC) and brain metastases 5, 6. Both studies found that the early change in the subvolumes extracted from blood-volume images by the techniques and assessed during RT predicted post-RT response better than using the change in the mean blood volume over the whole tumor 5, 6. Tumor subvolumes that correlated with local failure could represent the active or aggressive subvolume of the tumor, and could potentially be targeted by high-precision and high-dose RT to improve treatment outcomes.

Arterial vascularization is a common characteristic of the intrahepatic cancers, which presents as an abnormal increase in arterial perfusion and a decrease in portal venous perfusion 7, 8, 9. An effective therapy would lead to disruption of tumor vasculature, resulting in early reduction of blood perfusion 10, 11. Quantitative hepatic perfusion derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been evaluated for assessment of tumor response to anti-angiogenic therapy and other treatment regimens for intrahepative cancers 12, 13, 14. However, these studies assessed changes only in the means of arterial perfusion over the tumors, and neglected regional tumor perfusion heterogeneity. Given the heterogeneous tumor biology, response of the aggressive tumor component to therapy could be a better indicator of the whole tumor response to treatment. Thus, an intensified treatment of the subvolume of the heterogeneous intrahepatic cancer, which is at high risk for progression, could yield better tumor control.

In this study of RT, we hypothesized that an early increase in the subvolume of the intrahepatic cancer with elevated arterial perfusion during RT could predict tumor progression post-RT. We extracted tumor subvolumes with elevated arterial perfusion from quantitative hepatic arterial perfusion images in the patients who had unresectable intrahepatic cancers and were treated with RT, and then evaluated a change in the tumor subvolume from pre-RT to mid-RT for predicting post-RT tumor progression.