Technical advances in liver cancer imaging, radiation planning, methods to account for breathing motion during radiation delivery and image guidance at the time of radiation delivery have made it possible to deliver high-dose radiation safely to focal liver metastases, while sparing irradiation of the uninvolved liver, using a variety of radiation fractionation schedules.In most studies, higher doses of radiation have been associated with more durable local control rates than lower doses, regardless of the fractionation schedule.  Since the late 1980s at the University of Michigan, a series of phase I/II trials for patients with unresectable intrahepatic cancer have investigated dose-escalated conformal radiation therapy delivered concurrently with hepatic arterial chemotherapy (predominantly floxuridine [0.2 mg/kg/day]). In one of the first studies, the objective response rate of 22 patients with unresectable CRC liver metastases, treated with as much as 72.6 Gy at 1.5 Gy twice daily, was 50% (2 complete remission, 9 partial response, 11 stable disease),with a median survival of 20 months. Similar results were obtained in subsequent studies, including the most recent study in which the prescription dose was individualized based on the volume of liver irradiated and risk of toxicity, allowing higher doses (as much as 90 Gy at 1.5 Gy twice daily) to be delivered safely to more patients. The median survival of 47 patients with liver metastases (median diameter ∼10 cm) treated on this study was 17.2 months.

Stereotactic body radiation therapy (SBRT), referring to a limited number of high-dose fractions delivered very conformally to targets, using biologic doses of radiation higher than those used in standard fractionation, has also been used to treat liver metastases. Safety of 1- to 10-fraction SBRT has been described in several retrospective series and more recently confirmed in prospective dose escalation studies. Blomgren and colleagues from Sweden first reported a response rate of 43% for 14 liver metastases treated with 20 to 45 Gy in one to four fractions, with a prolonged time to maximal response (e.g., maximal response at 16 months for a 13-cm liver metastases). No liver toxicity was seen in patients with metastases, but hemorrhagic gastritis was seen in one patient. In an update in 1998, the local control rate was 95% with a mean survival of 17.8 months for 21 liver metastases.SBRT (20 Gy × 2 or 15 Gy × 3) has also been used safely in patients with recurrent liver metastases following hepatic resection for CRC metastases, with no serious toxicity and local control 13 to 101 months following surgery. A prospective study of escalated single-fraction SBRT (14 Gy to 26 Gy) did not find a maximal tolerated dose in 60 liver tumors (56 metastases) with a median tumor size of 10 mL (1–132 mL) and found an actuarial local control rate of 81% at 18 months following SBRT. SBRT delivered in three fractions (37.5 Gy total) has also been reported to be safe in small liver metastases, with 2-year local control and survival rates of 61% and 41%, respectively.  A North American prospective study confirmed the safety of three-fraction SBRT in 18 patients with 25 tumors of maximal diameter 6 cm. A Canadian prospective study has shown the feasibility of delivering six-fraction SBRT using an individualized dose allocation approach as first described by the Michigan group, for liver cancers ranging from 3 to 3,000 mL.

More recently, outcomes following SBRT for 174 liver metastases from colorectal, pancreatic, breast, and lung cancer in 69 patients were reported. The median dose delivered was 48 Gy (range 30–55 Gy) at 2 to 6 Gy per fraction. The local control was 76% and 57% at 10 and 20 months, respectively, with an overall medial survival of 14.5 months. No grade 3 toxicity was reported. Based on this experience, 10-fraction SBRT is being studied in a Radiation Therapy Oncology Group study that is now open.
 

In the early 1960s it was found that doses greater than 30 Gy at 2 Gy per fraction to the whole liver led to an unacceptable risk of liver toxicity. Eight fractions of 2.25 Gy to the whole liver was found to be safe, but a small increase in fraction size to 3.5 Gy was reported in 1973 to be associated with an unacceptable rate of liver toxicity (8 of 25 patients). The tolerance of the liver to whole-organ irradiation does not seem to be substantially altered by the concomitant use of fluoropyrimidines. In contrast, whole-liver irradiation in combination with alkylating agents or mitomycin C is associated with an increased risk of liver toxicity. Liver toxicity following irradiation has historically been referred to as “radiation hepatitis” and more recently termed “radiation-induced liver disease" (RILD), because there is no evidence of hepatitis on pathologic examination. This complication is a clinical syndrome consisting of anicteric ascites and painful hepatomegaly, occurring in the absence of disease progression, usually within 3 months following a course of radiation therapy. Laboratory evaluation demonstrates a marked elevation of alkaline phosphatase out of proportion to the modest increases in the transaminases. Although the majority of patients recover from RILD, it may progress to liver failure and death. The pathophysiology of RILD is not well understood. Pathologically, venoocclusive disease, similar to that seen following bone marrow translation, is seen.

Partial liver radiation therapy was first reported in 1965 by Ingold and associates, who safely delivered as much as 55 Gy to parts of the liver. Others confirmed that high-dose radiation therapy could be delivered safely, as long as a substantial portion of the normal liver was spared. Conformal radiation planning permits portions of the liver to be treated with doses of radiation far higher than what the entire liver can tolerate so long as a sufficient volume of uninvolved liver can be spared from irradiation, similar to how a surgeon can resect a substantial fraction of the liver if the remaining liver is functional. Conformal radiation treatment planning allows the fraction of uninvolved liver irradiated to be quantified. Theoretical models have been proposed to estimate the volume dependence of normal tissue tolerance—referred to as normal tissue complication probability (NTCP) models.  Such an NTCP model has been used to describe the partial liver tolerance of 203 patients treated with conformal hyperfractionated radiation therapy and hepatic arterial floxuridine (17 of whom developed RILD). This analysis found that that mean liver dose can provide an estimate of the risk of RILD occurring, with a 5% risk of toxicity following 32 Gy and 37 Gy in 1.5 Gy twice daily for patients with primary liver cancer and metastases, respectively.

The partial volume tolerance of the liver to hypofractionation or SBRT has not been well established, partially in that the majority of clinical SBRT experience has not required large liver volumes to be irradiated. Guidelines used in SBRT planning include sparing of 30% and 50% of the liver from 12 Gy and 7 Gy, respectively, for three- and one-fraction SBRT), and ensuring that at least 700 mL of uninvolved liver receives less than 15 Gy in three fractions. Dawson and coworkers have shown the feasibility of using an NTCP model for allocation of six-fraction SBRT in over 80 patients, with a wide range of liver volumes irradiated.

The safe delivery of high-dose ⁹⁰Y to small volumes seems consistent with the partial volume estimates from conformal radiation and SBRT series, where the upper limit on the dose of radiation that can be delivered to an effective liver volume irradiated of 20% or less has not been established. The lack of a validated dose distribution in ⁹⁰Y treatment makes partial liver tolerance analysis challenging for ⁹⁰Y therapy.

Extrapolation of NTCP models and partial liver tolerances to different centers must be done with caution, because the results may not be valid for different patient populations treated with different treatments. The partial liver tolerance to irradiation, especially in diseased livers and following SBRT and ⁹⁰Y, should be measured and validated in prospective studies.

Although it is becoming established that radiation therapy, delivered using conformal radiotherapy, SBRT, brachytherapy, or ⁹⁰Y microspheres, can be used safely to treat liver metastases with the potential for sustained local control, recurrences outside the irradiated volume are not infrequent, providing a rationale for combining radiation therapy with other therapies. One possibility would be to combine radiation therapy with repeated cycles of modern hepatic arterial and systemic chemotherapy. More potent radiation tumor sensitizers could also be explored. Studies of targeted therapies combined with radiotherapy should be considered, given the radiation sensitization properties of many targeted agents and survival gains observed following the combination of radiation and targeted agents in other clinical sites.Conversely, normal-tissue radiation protectors, as well as more technologic advances, may allow higher doses to be delivered to more tumors safely. For instance, the free-radical scavenger amifostine protects the normal liver (but not tumor) from radiation in preclinical studies. It is hoped that these approaches will permit a greater fraction of patients to benefit from high-dose therapy and will increase local control in patients with localized unresectable intrahepatic cancers.