Radiation Induced Liver Toxicity
Authors: Dutta Debnarayan , Sreenija Yarlagadda 
Published: July 2022

Liver was always considered to be ‘highly sensitive’ to radiation therapy (RT) and was not considered ‘safe’ for radiation therapy treatment. The most significant radiation induced liver toxicity was described by Ingold et al. as “Radiation hepatitis.” Historically, radiation to liver lesions with curative intent or incidental exposure during adjacent organ treatment or total body irradiation implied whole organ irradiation due to lack of high precision technology. Whole organ irradiation led to classic clinical picture termed as “Radiation Induced Liver Disease (RILD).” In conventional fractionation, the whole liver could be treated only to the doses of 30–35Gy safely, which mostly serves as palliation rather than cure. With the advent of technological advancements like IMRT, especially stereotactic radiation therapy (SBRT), the notion of highly precise and accurate treatment has been made practically possible. The toxicity profile for this kind of focused radiation was certainly different from that of whole organ irradiation. There have been attempts made to characterize the effects caused by the high precision radiation. Thus, the QUANTEC liver paper distinguished RILD to ‘classic’ and ‘non-classic’ types. Classic RILD is defined as ‘anicteric hepatomegaly and ascites’, and also can also have elevated alkaline phosphatase (more than twice the upper limit of normal or baseline value). This is the type of clinical picture encountered following irradiation of whole or greater part of the organ. Non-classic RILD is defined by elevated liver transaminases more than five times the upper limit of normal or a decline in liver function (measured by a worsening of Child-Pugh score by 2 or more), in the absence of classic RILD. In patients with baseline values more than five times the upper limit of normal, CTCAE Grade 4 levels are within 3 months after completion of RT. This is the type of RILD that is encountered typically after high-dose radiation to a smaller part of liver. It is commonly associated with infective etiology. Emami et al. reported the liver tolerance doses or TD 5/5 (5% complication rate in 5 years) as 50 Gy for one-third (33%) of the liver, 35 Gy for two-thirds (67%) of the liver, and 30 Gy for the whole liver (100%). Liver function (Child Pugh Score), infective etiology, performance status and co-morbidities influence the radiation induced toxicity. Lyman–Kutcher–Burman (LKB)-NTCP model was used to assess dose-volume risk of RILD. Lausch et al. at London Regional Cancer Program (LRCP), developed a logistic TCP model. Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reported recommendations that mean normal liver dose should be <18 Gy for baseline CP-A patients and < 6 Gy for those with CP-B, for a 6-fraction SBRT regimen. The University of Colorado phase 1 clinical trial of SBRT for liver metastases described the importance of the liver volume spared, that is, ‘critical volume model.’ It is estimated that a typical normal liver volume is approximately 2000 mL and specified that a minimum volume of 700 mL or 35% of normal liver should remain uninjured by SBRT i.e. at least 700 mL of normal liver (entire liver minus cumulative GTV) had to receive at total dose less than 15 Gy. In treatment regimen of 48 Gy in 3 fractions, CP-A patients were required to either limit the dose to 33% of the uninvolved liver (D33%) < 10 Gy and maintain the liver volume receiving <7 Gy to <500 cc. In more conservative treatment regimen, such as in 40 Gy in 5 fractions schedule, CP-B7 patients had to meet constraints of D33% < 18 Gy and/or > 500 cc receiving <12 Gy. The concept of body surface area (BSA) and Basal Metabolic Index (BMI) guided estimation of optimal liver volume is required to estimate the liver volume need to be spared during SBRT treatment. Radiation induced liver injury is potentially hazardous complication. There is no definitive treatment and a proportion of patient may land up in gross decompensation. Usually supportive care, diuretics, albumin supplement, and vitamin K replacement may be useful. Better case selection will avert incidence of RILD. Precise imaging, contouring, planning and respecting normal tissue constraints are critical. Radiation delivery with motion management and image guidance will allow delivery of higher dose and spare normal liver and hence will improve response to treatment and reduce RILD.