Radiobiology of the Liver

Advancements in imaging and radiation treatment planning have resulted in the increasing use of radiation therapy (RT) for liver cancer. However, Radiation-induced liver disease (RILD) remains a major limitation of RT. The pathophysiology, diagnosis, and treatment of RILD are discussed in this chapter. Classic RILD manifests with hepatomegaly, anicteric ascites, and thrombocytopenia, and alkaline phosphatase elevated out of proportion to other liver enzymes, 1–3 months after liver RT. The pathological hallmark is that of veno-occlusive disease (VOD) and sinusoidal obstructive syndrome (SOS). In addition to endothelial cell damage, hepatic stellate cell activation is noted in patients with severe congestive changes of classic RILD. There are multiple clinically useful tools, such as Model for End-Stage Liver Disease (MELD), Child–Turcotte–Pugh (CTP) classification, ALBI and PALBI grades to quantify liver function changes following RT. Other more interventional laboratory measures that have been investigated to measure liver function include Indocyanine green (ICG) and HepQuant SHUNT test that require administration of ICG or cholate and measuring their clearance rates. Potential biomarkers of liver toxicity include those related to endothelial injury and increased expression of adhesion molecules, pro-inflammatory and procoagulant cytokines. In patients suspected of developing classic RILD, early diagnosis and intervention can potentially improve outcomes. Baseline and serial imaging using ultrasound, portal venous perfusion imaging by dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) may help detect early signs suggestive of VOD/SOS and more importantly to exclude diagnoses other than VOD/SOS. The current management of RILD is mostly supportive with no approved pharmacologic therapy to date. Strategies to potentially treat RILD including TGFβ inhibition, Hedgehog inhibition, CXCR4 inhibition, hepatocyte transplantation, and bone marrow-derived stromal cell therapy are currently under investigation. Taking advantage of radiation as an immunomodulatory drug for in situ tumor vaccination provides the rationale for combining SBRT with immunotherapy for the treatment of liver cancer.