The liver is susceptible to radiation induced liver disease (RILD) which is irreversible, and must be prevented. Liver transplant is required for radiation hepatic injury. RILD is a vague to intense RUQ abdominal pain followed by hepatomegaly and ascites leading to weight gain. Ascites develops 2 to 4 months after irradiation. Chemo-radiation induced liver disease may surface sooner in 1-4 weeks. Anicteric ascities, jaundice, elevated LFTs tremor, hepatic encephalopathy or coma are manifestations of RILD. Classic RILD is due to central vein thrombosis leading to retrograde congestion and hemmorhage. This progresses to hepatic fibrosis, cirrhosis and failure. A non-classic RILD results in markedly elevated transaminases or decline in liver function.
The liver moves with the respiratory cycle. The liver structure is a parallel structure with redundant functional subunits. The overall volume irradiated is an important parameter. Michigan reported 9 of 33 who received whole liver radiation developed late radiation toxicity versus none of 46 who underwent partial liver radiation. Taipei demonstrated toxicity with a mean liver dose of 25 Gy but no toxicity with a mean liver dose of 20 Gy.
Because of the parallel architecture of the liver, partial volumes can be irradiate to fairly high doses. Michigan demonstrated no late liver toxicity with a mean liver dose < 31 Gy. The risk of complications was strongly associated with the volume of liver irradiated. Primary hepatocellular cancer increases the liver sensitivity to radiation and increases the risk of RILD at a given dose. Additional risk factors include HBV infections, and poor pre-existing liver disease. Using Michigan data the following doses for healthy liver TD5 were found to be:
SBRT/IGRT for primary and metastatic liver lesions have been shown by the University of Colorado and Indiana University to tolerate 30 Gy to the lesion with small volumes of liver. In a subsequent study no RILD was sen in patients in which liver volumes less than 700 ml received more than 15 Gy in 3 fractions. PMH treated 41 patients with primary hepatocellular cancer or intrahepatic cholangiocarcinoma treated to 24 to 60 Gy in 6 fractions. No RILD or Grade 3 liver toxicity was seen, but acute liver enzyme elevation was seen in 24%, acute grade 3 nausea was seen in 7%, and transient bilary obstruction was seen in 5%.
For patients with liver metastases undergoing partial liver toxicity risk is dependent on the volume of liver irradiated. Partial volumes can tolerate relatively high doses. Liver tolerances are lower for primary liver cancers who are more apt to have underlying liver disease.
The primary toxicity criteria for CTCAE are clinical jaundice (grade 2), asterixis (grade 3) and encephalopathy or coma (grade 4).
The stomach and small bowel are sensitive to radiation. Radiation enteritis includes dyspepsia, gastric ulcers, diarrhea, bowel obstruction, ulceration, fistula and perforation. Nausea and vomiting occur hours after radiation to the stomach or small bowel. Gastric secretions are reduced after 15-20 Gy. Suppression can continue for 6 months to years after RT. 50 Gy is a limiting dose at which recovery is is never complete. Ulcers are the most common gastric complication. Gastric ulcers present with pain, dyspepsia and occasionally hemmorhage and perforation. Hemmorrhage and perforation can be lethal. Ulcers are typically in the antral portion and develop between 2 and 12 months post radiation. Pyloric obstruction is a later complication due to fibrosis from healing.
The small bowel symptoms include an early onset of hypermobility after modest doses of radiation with malabsorption of fat. Usually recovery at doses less than 40 to 45 Gy is complete although there may be a persistence of small bowel dysfunction and cramping. Surgery will likely precipitate a more serious course of injury. If an obliterative arteritis develops, the risk of infract and perforation remains despite recovery.
Defining small bowel volumes is difficult and the bowel is mobile. There are two general schools of thought: contour the "bowel bag" or contour the bowel itself with the addition of contrast. Many oral contrast agents will create very bright bowel on CT causing treatment planning systems that take into account inhomogeneity to ascribe a higher electron density, thus altering the dose. Milk (in patients who are lactose tolerant) can highlight the bowel without excess contrast.
Accurate dose-volume relationships is difficult due to the bowel mobility. Late radiation injury to gastric components has been reported as low as 50 Gy. Walter Reed Army Medical Center reported 4% toxicity at dose < 50 Gy v. 16% at over 50 Gy. Perforation rates were the same in those dose cohorts.
There is a demonstrated volume effect on the bowel. The risk of bowel obstruction and field size was examined in rectal cancers with an increase in bowel obstruction risk to 30% when L1/L2 was set as the superior border, but only 9% (which is still high) when the field was confined to the pelvis only. University of Michigan examined bowel toxicity when treating liver and found a consistent dose threshold of 60 Gy for bleeding, without a large volume effect.
Total dose, (doses in excess of 40 to 50 Gy) increases the risk of late complications. Dose per fraction is also important, prior abdominal surgery (bowel obstruction risk), concurrent chemotherapy all increase risk of bowel complications. EORTC demonstrated a 3% risk if there was no hisotry of abdominal surgery and a 12% risk if there was prior abdominal surgery. William Beaumont data suggests that volume of bowel exposed to radiation > 5 Gy to 40 Gy correlates with risk of acute grade 3 toxicity. The small bowel V15 is considered highly significant. IMRT has been shown to reduce the anticipated rate of grade 2 or higher diarrhea rom 40% to 27% with further reductions using IGRT.
Using the entire small bowel potential space (bowel bag volume method) the recommended V45 - V50 should be < 195 ml. When using the visualized bowel loops, the V15 should be < 120 ml. These dose constraints are for acute toxicity and may help reduce late toxicity. The stomach should be kept to < 45 Gy.