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Radiation-Associated Liver Injury

      The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver.

      1. Clinical Significance

      The liver is an important organ with numerous functions including the production of bile, metabolism of ingested nutrients, elimination of waste products, glycogen storage, and protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper abdomen, right lower lung, distal esophagus, or whole abdomen or whole-body RT.

      2. Endpoints

      The Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, defines Grades 2, 3, 4, and 5 liver dysfunction as jaundice, asterixis, encephalopathy or coma, and death, respectively. These serious adverse events are rare after radiation therapy (RT). Acute post-RT changes in liver function tests are far more common and occur during and after RT, presumably related to self-limited liver inflammation. Such liver enzyme abnormalities are classified under the CTCAE metabolic/laboratory category. Grades 2, 3, and 4 elevations of alanine aminotransferase and aspartate aminotransferase include levels that are >2.5–5.0, >5.0–20, and >20 times the upper limit of normal, respectively. Radiographically, clinically insignificant transient declines in computed tomography (CT)-defined tissue density can be seen 2–3 months after fractionated RT. This observation by itself should not be confused with tumor progression or irreversible liver injury (
      • Yamasaki S.A.
      • Marn C.S.
      • Francis I.R.
      • et al.
      High-dose localized radiation therapy for treatment of hepatic malignant tumors: CT findings and their relation to radiation hepatitis.
      ).
      The Child-Pugh scoring system assesses liver dysfunction based on clinical and laboratory parameters (Table 1). It can be used to characterize baseline liver function and posttreatment changes in liver function.
      Table 1Child-Pugh scoring system to assess severity of liver disease
      Criterion1 point2 points3 points
      Bilirubin (total)<2 mg/dL2–3 mg/dL>3 mg/dL
      Serum albumin>3.5 g/dL2.8–3.5 g/dL<2.8 g/dL
      INR<1.71.71–2.20>2.20
      AscitesNoneControlled with medicationRefractory
      Hepatic encephalopathyNoneCTCAE Grade I-II (or controlled with medication)CTCAE Grade III-IV (or refractory)
      Abbreviations: INR = international normalized ratio; CTCAE = Common Terminology Criteria for Adverse Events.
      Patients are grouped into Child-Pugh Class A if the total score is 5–6, Class B if the score is 7–9, and Class C if the score is 10 or higher.
      RT-induced liver disease (RILD) is separated into “classic” and “nonclassic” RILD. Classic RILD involves anicteric hepatomegaly and ascites, typically occurring between 2 weeks to 3 months after therapy (
      • Lawrence T.S.
      • Robertson J.M.
      • Anscher M.S.
      • et al.
      Hepatic toxicity resulting from cancer treatment.
      ). Classic RILD also involves elevated alkaline phosphatase (more than twice the upper limit of normal or baseline value). This endpoint can occur in patients who have otherwise fairly well-functioning pretreatment livers. Pathologically, there is occlusion and obliteration of the central veins of the hepatic lobules, retrograde congestion, and secondary hepatocyte necrosis. Treatment options for RILD are limited, and liver failure and death can result.
      Nonclassic RILD, typically occurring between 1 week and 3 months after therapy, involves elevated liver transaminases more than five times the upper limit of normal or CTCAE Grade 4 levels in patients with baseline values more than five times the upper limit of normal within 3 months after completion of RT, or a decline in liver function (measured by a worsening of Child-Pugh score by 2 or more), in the absence of classic RILD. This endpoint has been described in hepatocellular carcinoma (HCC) patients who have poor liver function (hepatitis B infection, Child-Pugh Classes B and C) (
      • Xu Z.-Y.
      • Liang S.-X.
      • Zhu J.
      • et al.
      Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma.
      ,
      • Kim T.H.
      • Kim D.Y.
      • Park J.-W.
      • et al.
      Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy.
      ,
      • Cheng J.C.-H.
      • Wu J.-K.
      • Huang C.-M.
      • et al.
      Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: Dosimetric analysis and implication.
      ). CTCAE, although not as useful for classic RILD, is most useful for scoring nonclassic RILD. The underlying pathology of nonclassic RILD is unclear.
      A confounder of RILD, especially in populations with preexisting liver dysfunction, is the baseline rate of morbidity within this population due to their preexisting liver disease. In a recent randomized trial in unresectable HCC, there was a 52% rate of serious adverse events among the placebo group because of progression of cirrhosis or HCC (
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ). Another described endpoint is hepatitis B reactivation (
      • Kim J.H.
      • Park J.W.
      • Kim T.H.
      • et al.
      Hepatitis B virus reactivation after three-dimensional conformal radiotherapy in patients with hepatitis B virus-related hepatocellular carcinoma.
      ), which can contribute to liver function abnormalities. Patients at risk for hepatitis B virus (HBV) should have appropriate serum testing, and prophylactic antiretroviral therapy has been associated with a lower rate of post-RT reactivation of HBV or exacerbation.
      No established therapies for classic RILD exist, though the use of anticoagulants and steroids have been suggested. Treatment of RILD is primarily supportive, and diuretics are often used for the ascites. Although a few patients may recover, a substantial fraction will die of liver failure.

      3. Challenges Defining Volumes

      The liver is relatively easy to identify on CT images. If intravenous and oral contrast are not used, the left border can be indistinct against the heart or stomach. Ideally, the liver parenchyma (minus the biliary duct system and vasculature) should be distinguished as the “functional” component. Literature concerned with modeling liver tolerance to RT typically defines normal liver volume as the total liver minus gross tumor volume (
      • Cheng J.C.-H.
      • Wu J.-K.
      • Huang C.-M.
      • et al.
      Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: Dosimetric analysis and implication.
      ,
      • Dawson L.A.
      • Normolle D.
      • Balter J.M.
      • et al.
      Analysis of radiation-induced liver disease using the Lyman NTCP model.
      ), presuming that minimal function remains in liver tumors themselves.
      Extensive work involving fluoroscopy, four-dimensional CT, and cine-magnetic resonance imaging has described liver motion due to breathing and the effect of this motion on delivered RT dose. Regular breathing can result in liver tumor displacement ≥2 cm. Strategies to manage this motion include abdominal compression, shallow breathing, breath holding, deformation modeling, gated treatments, and real-time tumor tracking (
      • Shirato H.
      • Seppenwoolde Y.
      • Kitamura K.
      • et al.
      Intrafractional tumor motion: Lung and liver.
      ,
      • Brock K.K.
      • McShan D.L.
      • Ten Haken R.K.
      • et al.
      Inclusion of organ deformation in dose calculations.
      ,
      • Rosu M.
      • Dawson L.A.
      • Balter J.M.
      • et al.
      Alterations in normal liver doses due to organ motion.
      ,
      • Dawson L.A.
      • Brock K.K.
      • Kazanjian S.
      • et al.
      The reproducibility of organ position using active breathing control (ABC) during liver radiotherapy.
      ,
      • Guckenberger M.
      • Sweeney R.A.
      • Wilbert J.
      • et al.
      Image-guided radiotherapy for liver cancer using respiratory-correlated computed tomography and cone-beam computed tomography.
      ). Attempts to assess/compensate for liver motion are essential for stereotactic RT and are advisable in other circumstances, especially when the normal liver volume irradiated poses a substantial risk of RILD.

      4. Review of Dose–Volume Data

      The liver parenchyma is composed of numerous functional subunits. This parallel architecture allows the liver to tolerate substantial focal injury prior to any clinical sequelae. In noncirrhotic patients, surgical resection that leaves only a 20–25% liver remnant has been shown to be well tolerated (
      • Penna C.
      • Nordlinger B.
      Colorectal metastasis (liver and lung).
      ). Because of this redundant capacity, partial liver irradiation to high doses is possible if adequate normal liver parenchyma can be spared. Preexisting liver dysfunction secondary to comorbid conditions such as hepatitis B/C infection and cirrhosis may render patients more susceptible to RT-induced liver injury.

       Whole liver RT

      The classic paper by Ingold (1965) is the first report of a dose–complication relationship for whole-liver RT (
      • Ingold J.A.
      • Reed G.B.
      • Kaplan H.S.
      • et al.
      Radiation hepatitis.
      ). RILD occurred in 1/8 patients who received 30–35 Gy over 3–4 weeks and 12/27 (44%) patients who received >35 Gy. In the 1991 report by Emami, the total dose 5/5 for whole-liver radiation was estimated to be 30 Gy in 2-Gy fractions (
      • Emami B.
      • Lyman J.
      • Brown A.
      • et al.
      Tolerance of normal tissue to therapeutic irradiation.
      ). More recent experiences include the Radiation Therapy Oncology Group 84-05 dose escalation study of accelerated hyperfractionation in which it was observed that 0/122 patients who received 27–30 Gy in twice daily 1.5 Gy fractions of whole-liver radiation therapy experienced RILD, whereas 5/51 (9.8%) who received 33 Gy in 1.5-Gy fractions developed RILD (
      • Russell A.H.
      • Clyde C.
      • Wasserman T.H.
      • et al.
      Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: Results of the RTOG dose escalating protocol.
      ).

       Partial liver RT

      Table 2 summarizes the toxicity reported after partial liver RT for primary liver cancer and small volume metastatic disease. In most, the key factor predicting RILD was baseline liver condition. Two studies noted a dosimetric parameter associated with increased toxicity risk: mean dose and V30 (volume receiving ≥30 Gy). In each series where mean normal liver dose was reported, patients with RILD had a higher mean dose than those without RILD.
      Table 2Series of fractionated partial liver irradiation and rates of RILD
      Study groupnDiagnosisBaseline Child-Pugh scorePrescription dose fractionationCrude percent RILDMean normal liver dose in patients with vs. without RILDFactors associated with RILD
      Michigan
      • Dawson L.A.
      • Normolle D.
      • Balter J.M.
      • et al.
      Analysis of radiation-induced liver disease using the Lyman NTCP model.
      ,
      • Jackson A.
      • Ten Haken R.K.
      • Robertson J.M.
      • et al.
      Analysis of clinical complication data for radiation hepatitis using a parallel architecture model.
      203
      Patients also received FUdR or BUdR; in this series the mean normal liver dose was calculated as corrected for 1.5 Gy twice-daily equivalent dose, and the comparison of patients with vs. without RILD refers to the median value of mean normal liver dose, whereas for other series the comparison is between the average (mean) of mean normal liver dose in each group.
      PLC + LMC203 A1.5 Gy twice daily9.4% (19/203)37 Gy vs. 31.3 GyPLC vs. LMC mean liver dose
      Taipei
      • Wu D.H.
      • Liu L.
      • Chen L.H.
      Therapeutic effects and prognostic factors in three-dimensional conformal radiotherapy combined with transcatheter arterial chemoembolization for hepatocellular carcinoma.
      89
      At least 77% of patients in these series also received transarterial chemoembolization (TACE).
      HCC68 A

      21 B
      1.8–3.0 Gy19% (17/89)23 Gy vs. 19 GyHBV, liver cirrhosis
      Shanghai
      • Xu Z.-Y.
      • Liang S.-X.
      • Zhu J.
      • et al.
      Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma.
      ,
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      109
      At least 77% of patients in these series also received transarterial chemoembolization (TACE).
      PLC93 A

      16 B
      4–6 Gy15.6% (17/109)24.9 Gy vs. 19.9 GyLiver cirrhosis
      Guangdong
      • Wu D.H.
      • Liu L.
      • Chen L.H.
      Therapeutic effects and prognostic factors in three-dimensional conformal radiotherapy combined with transcatheter arterial chemoembolization for hepatocellular carcinoma.
      94∗∗HCC43 A

      51 B
      4–8 Gy17% (16/94)

      Note: 4 fatal
      Not statedLiver cirrhosis
      S. Korea (Seong, Park)
      • Cheng J.C.-H.
      • Wu J.-K.
      • Lee P.C.-T.
      • et al.
      Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.
      158
      At least 77% of patients in these series also received transarterial chemoembolization (TACE).
      HCC117 A

      41 B
      1.8 Gy7% (11/158)Not statedDose
      S. Korea (Kim)
      • Kim T.H.
      • Kim D.Y.
      • Park J.-W.
      • et al.
      Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy.
      105
      At least 77% of patients in these series also received transarterial chemoembolization (TACE).
      HCC85 A

      20 B
      2.0 Gy12.3% (13/105)25.4 Gy vs. 19.1 GyTotal liver volume receiving 30 Gy or more above 60%
      Abbreviations: HBV = hepatitis B viral infection; HCC = hepatocellular carcinoma; PLC = primary liver cancer; LMC = liver metastatic disease; RILD = radiation-induced liver damage.
      Patients also received FUdR or BUdR; in this series the mean normal liver dose was calculated as corrected for 1.5 Gy twice-daily equivalent dose, and the comparison of patients with vs. without RILD refers to the median value of mean normal liver dose, whereas for other series the comparison is between the average (mean) of mean normal liver dose in each group.
      At least 77% of patients in these series also received transarterial chemoembolization (TACE).
      The University of Michigan (UM) has extensively investigated RT dose escalation of primary and metastatic liver cancers since 1987. Using CT-based RT planning, the parameter effective volume (Veff) of normal liver irradiated was defined as the normal liver volume, which, if irradiated to the prescribed dose, would be associated with the same normal tissue complication probability (NTCP) as the non-uniform dose delivered. An analysis of 203 patients treated with three-dimensional conformal RT, and concurrent hepatic arterial chemotherapy, demonstrated that small portions of the liver can be irradiated to a very high dose (up to 90 Gy) if the Veff was low (
      • Dawson L.A.
      • Normolle D.
      • Balter J.M.
      • et al.
      Analysis of radiation-induced liver disease using the Lyman NTCP model.
      ). Mean liver dose was also a strong predictor of RILD in the UM series (see “Mathematical/Biological Models”).
      Dose–volume limit recommendations are discussed in the Recommended Dose–volume Limits section. Regarding risk, in general, the risks reported in the studies cited within this review are realistic estimates, as the follow-up durations in the studies are greater than the 3–4 months within which RILD typically occurs.

      5. Factors Affecting Risk

      Preexisting liver dysfunction may render patients more susceptible to RT-induced liver injury (Table 2). Patients with Child-Pugh B or C scores have a higher risk of RT-related problems than those with Child-Pugh A scores (
      • Xu Z.-Y.
      • Liang S.-X.
      • Zhu J.
      • et al.
      Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma.
      ,
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ,
      • Hata M.
      • Tokuuye K.
      • Sugahara S.
      • et al.
      Proton beam therapy for hepatocellular carcinoma patients with severe cirrhosis.
      ,
      • Wu D.H.
      • Liu L.
      • Chen L.H.
      Therapeutic effects and prognostic factors in three-dimensional conformal radiotherapy combined with transcatheter arterial chemoembolization for hepatocellular carcinoma.
      ). Additional factors reportedly associated with a higher risk of RILD include hepatitis B carrier status (
      • Cheng J.C.-H.
      • Wu J.-K.
      • Lee P.C.-T.
      • et al.
      Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.
      ), prior transcatheter arterial chemoembolization (
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ), concurrent chemotherapy (
      • Dawson L.A.
      • Normolle D.
      • Balter J.M.
      • et al.
      Analysis of radiation-induced liver disease using the Lyman NTCP model.
      ), portal vein tumor thrombosis (
      • Kim T.H.
      • Kim D.Y.
      • Park J.-W.
      • et al.
      Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy.
      ,
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ,
      • Seong J.
      • Park H.C.
      • Han K.H.
      • et al.
      Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: A retrospective study of 158 patients.
      ), tumor stage (
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ), male sex (
      • Dawson L.A.
      • Normolle D.
      • Balter J.M.
      • et al.
      Analysis of radiation-induced liver disease using the Lyman NTCP model.
      ), and Cancer of the Liver Italian Program staging system (
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ,
      • Seong J.
      • Park H.C.
      • Han K.H.
      • et al.
      Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: A retrospective study of 158 patients.
      ).
      Although it is likely that the risk of liver injury relates to the dose per fraction received by portions of the liver, it is difficult to characterize the magnitude of any effect because most series include patients treated within a narrow range of dose per fraction. Furthermore, with any size fraction given to the tumor, the adjacent normal liver receives a broad range of doses because of beam entrance/exit zones and penumbra, further complicating the analysis. The topic of dose modeling is discussed further in Mathematical/Biological Models, and the topic of hypofractionation is discussed further in the Special Situations section.

      6. Mathematical/Biological Models

      The Lyman NTCP model has been applied by numerous groups. From the series referenced in Table 2, the range of estimates of the parameters generated among patients with Child-Pugh A or better liver function and no HBV infection are as follows: n, 0.86–1.1; m, 0.12–0.31; and TD50, 39.8–46.1 Gy (
      • Dawson L.A.
      • Normolle D.
      • Balter J.M.
      • et al.
      Analysis of radiation-induced liver disease using the Lyman NTCP model.
      ,
      • Cheng J.C.-H.
      • Wu J.-K.
      • Lee P.C.-T.
      • et al.
      Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.
      ). For patients with HBV or Child-Pugh B dysfunction, the ranges are: n = 0.26–0.7, m = 0.4–0.43, TD50 = 23–50 Gy (
      • Xu Z.-Y.
      • Liang S.-X.
      • Zhu J.
      • et al.
      Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma.
      ,
      • Cheng J.C.-H.
      • Wu J.-K.
      • Lee P.C.-T.
      • et al.
      Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.
      ). These patients with worse liver dysfunction likely have lower TD50 values within the previous range, though this needs to be clarified in future studies.
      Analysis of UM patients treated for primary hepatobiliary cancer or 98 metastases with concurrent continuous hepatic arterial floxuridine (FUdR) or bromodeoxyuridine (BUdR) and RT in twice daily 1.5 Gy fractions revealed a strong correlation of RILD with the mean liver dose. No classic RILD was observed when the mean liver dose was <31 Gy, with or without chemotherapy. For patients treated with FUdR, the mean liver doses associated with 5% risk of classic RILD was 28 Gy for primary and 32 Gy for metastatic liver cancer (corrected to 2 Gy fraction equivalent doses using the linear-quadratic [LQ] model, assuming an α/β = 2 Gy). Based on these observations and derived Lyman model parameter estimates, the partial volume tolerance of the liver for a defined allowable risk of RILD can be graphed (Figure 1) for a 5% risk of RILD. With “n” of approximately 1 in the Lyman NTCP model, a large volume effect is seen and a strong correlation of NTCP with mean liver dose is revealed. Again based on the UM data, Figure 2 demonstrates the relationship between mean liver dose and NTCP for RILD for patients with primary or metastatic liver tumors.
      Figure thumbnail gr1
      Fig. 1Reference dose vs effective volume for 5% isotoxicity curve for classic radiation-induced liver disease after conformal radiation therapy, delivered in 1.5 Gy twice-daily fractionation, for primary or metastatic tumors. Redrawn from
      (
      • Dawson L.A.
      • Normolle D.
      • Balter J.M.
      • et al.
      Analysis of radiation-induced liver disease using the Lyman NTCP model.
      )
      . The shaded areas around each curve represent the 80% confidence limits, which overlap above a reference dose of approximately 45 Gy.
      Figure thumbnail gr2
      Fig. 2Mean liver dose, corrected with LQ modeling for 2.0 Gy fractions vs. Lyman normal tissue complication probability (NTCP) of classic radiation-induced liver disease (RILD) for primary and metastatic liver cancer, redrawn from
      (
      • Dawson L.A.
      • Ten Haken R.K.
      Partial volume tolerance of the liver to radiation.
      )
      .
      When a similar analysis was conducted on different populations from Taiwan (
      • Cheng J.C.-H.
      • Wu J.-K.
      • Lee P.C.-T.
      • et al.
      Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.
      ) and China (
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ), with a majority of patients having HBV infections, the tolerance of the liver to radiation was less predictable, and the most common effect consisted of elevation of transaminases rather than RILD. HCC patients who were HBV carriers or had Child-Pugh B cirrhosis had a greater susceptibility to RILD and had a smaller volume effect on normal liver response according to Lyman modeling. For patients with HBV treated in Taiwan, Lyman NTCP parameters for classic and nonclassic RILD are: n 0.26, m 0.4, and TD50 50 Gy (
      • Cheng J.C.-H.
      • Wu J.-K.
      • Lee P.C.-T.
      • et al.
      Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease.
      ).
      The Shanghai group likewise noted differences in Lyman model parameter estimates based on baseline liver dysfunction, with less volume effect for Child-Pugh B relative to Child-Pugh A (
      • Xu Z.-Y.
      • Liang S.-X.
      • Zhu J.
      • et al.
      Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma.
      ,
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ); in this series, fraction sizes were 4–6 Gy (see Table 2). For the patients with Child Pugh B liver dysfunction treated with 4–6 Gy per fraction, Lyman parameters for classic or nonclassic RILD are n 0.7, m 0.43, and TD50 23 Gy (
      • Xu Z.-Y.
      • Liang S.-X.
      • Zhu J.
      • et al.
      Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma.
      ). From these patients treated with 4–6 Gy per fraction, the mean liver doses associated with a 5% risk of liver toxicity were estimated to be 23 Gy and 6 Gy for Child-Pugh A and B patients, respectively.
      One report of damage injury model parameterization of the early UM data led to local damage parameters of D50 = 42 Gy, k = 2; and fraction of liver injury required for RILD parameters of F50 = 0.5, σ = 0.05 (
      • Jackson A.
      • Ten Haken R.K.
      • Robertson J.M.
      • et al.
      Analysis of clinical complication data for radiation hepatitis using a parallel architecture model.
      ). A subsequent analysis of 203 UM patients led to a lower threshold and a shallower slope for the population cumulative functional reserve: F50 = 0.4, σ = 0.08; however, the confidence limits on these parameters were very large (
      • Dawson L.A.
      • Ten Haken R.K.
      Partial volume tolerance of the liver to radiation.
      ). In another analysis from the National Taiwan University group, including patients with HCC and gastric cancer patients, valid fits were only obtained for the non-HBV carriers with local damage parameters of D50 = 25 Gy, k = 60; and fraction of liver injury required for RILD parameters of F50 = 0.59, σ = 0.12 (
      • Cheng J.C.-H.
      • Liu H.-S.
      • Wu J.-K.
      • et al.
      Inclusion of biological factors in parallel-architecture normal-tissue complication probability model for radiation-induced liver disease.
      ), but these parameters have high uncertainty.
      Limited data about the utility of V30 exist from studies of mostly HCC patients, with both classic and nonclassic RILD combined together. V30 was found to be useful in segregating higher risk patients from lower risk patients in some studies at cutoff levels of 28–60% (
      • Kim T.H.
      • Kim D.Y.
      • Park J.-W.
      • et al.
      Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy.
      ,
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ,
      • Yamada K.
      • Izaki K.
      • Sugimoto K.
      • et al.
      Prospective trial of combined transcatheter arterial chemoembolization and three-dimensional conformal radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma.
      ); however, the effect of V30 is not uniformly observed (
      • Cheng J.C.-H.
      • Wu J.-K.
      • Huang C.-M.
      • et al.
      Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: Dosimetric analysis and implication.
      ). Other studies suggest the importance of V20-V40 (
      • Kim T.H.
      • Kim D.Y.
      • Park J.-W.
      • et al.
      Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy.
      ) and V5-V40 (
      • Liang S.-X.
      • Zhu X.-D.
      • Xu Z.-Y.
      • et al.
      Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: The risk factors and hepatic radiation tolerance.
      ), but only for Child-Pugh Grade A patients in the latter study. The critical volume model is discussed in the Special Situations section.

      7. Special Situations

      Most clinical data published involves analyses of conventionally fractionated or hyperfractionated treatment involving daily prescription doses to the tumor in the range of 2 Gy or less. Consequently, the daily doses received by surrounding normal liver parenchyma are even lower. Current interest in the use of stereotactic body radiation therapy (SBRT) raises questions about the extent to which observations made using low dose per fraction are applicable to the setting of SBRT, where the daily prescription dose to the tumor is on the order of 10 Gy or higher, and portions of the normal liver will receive doses in that range. Use of the models discussed in Mathematical/Biological Models should be done with caution, as the LQ conversion for larger fraction sizes will likely be inadequate.
      SBRT produces transient hypodensity on CT scan that appears within months after treatment and then resolves (
      • Herfarth K.K.
      • Hof H.
      • Bahner M.L.
      • et al.
      Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors.
      ). RILD after SBRT occurs in fewer than 5% of cases with careful patient selection and technique. Mendez-Romero (median follow-up, 12.9 months) observed 1 classic and 1 nonclassic case of RILD among 8 patients with HCC treated with SBRT for liver tumors; another patient with baseline Child-Pugh B liver dysfunction and HCC experienced portal hypertension and concomitant nonhepatic infection and died 2 weeks after treatment. No Grade 4 or 5 toxicity occurred among the 17 patients with liver metastases, suggesting that patients with HCC are more susceptible to SBRT-related toxicity, especially if there is underlying liver dysfunction (
      • Mendez Romero A.
      • Wunderink W.
      • Hussain S.M.
      • et al.
      Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study.
      ). In a Phase II study of 61 patients treated with SBRT for colorectal metastases treated with 15 Gy × 3 within 5–8 days, Hoyer (median follow-up 4.3 years) observed severe toxicity in 1 patient that was possibly related to SBRT (60% of liver received ≥10 Gy, median dose 14.4 Gy in three fractions). This patient died of hepatic failure 7 weeks post-RT, but the exact cause was unclear (
      • Hoyer M.
      • Roed H.
      • Traberg Hansen A.
      • et al.
      Phase II study on stereotactic body radiotherapy of colorectal metastases.
      ). In a Princess Margaret Hospital study of 41 patients treated with SBRT, using an NTCP estimate for dose in six fractions (median, 36.0 Gy; range, 24.0–54.0 Gy) and with a median follow-up 17.6 months, for HCC or intrahepatic cholangiocarcinoma, 17% experienced progression from Child-Pugh A to B within 3 months after RT (median mean liver dose, 17.5 Gy; range, 5.2–25.2 Gy, in six fractions) (
      • Tse R.V.
      • Hawkins M.
      • Lockwood G.
      • et al.
      Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma.
      ). In contrast, in 68 patients with liver metastases treated with SBRT (28–60 Gy, in six fractions), the risk of any serious liver toxicity within 3 months was very low (95% confidence interval 0–5.3%), despite similar doses delivered to the liver (median mean liver dose, 16.9 Gy; range, 3–22 Gy, in six fractions) (
      • Lee M.T.
      • Kim J.J.
      • Dinniwell R.
      • et al.
      Phase I study of individualized stereotactic body radiotherapy of liver metastases.
      ).
      In the University of Colorado (UC) trial of SBRT for liver metastases (median follow-up, 12.9 months), a modification of the critical volume model (
      • Yaes R.J.
      • Kalend A.
      Local stem cell depletion model for radiation myelitis.
      ) was applied. For liver SBRT, the fundamental premise is that to preserve adequate liver function, a minimum volume of normal liver must be spared from receiving a dose that might render it nonfunctional. This minimum “critical volume” was estimated from partial hepatectomy series to be 700 mL; the maximum dose allowed to this critical volume was estimated to be 15 Gy in three fractions (based on LQ conversion, α/β = 3 Gy) (
      • Schefter T.E.
      • Kavanagh B.D.
      • Timmerman R.D.
      • et al.
      A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases.
      ). No RILD or other severe toxicity has been observed to date after SBRT given according to these constraints (
      • Kavanagh B.D.
      • Schefter T.E.
      • Cardenes H.R.
      • et al.
      Interim analysis of a prospective phase I/II trial of SBRT for liver metastases.
      ).
      Comparisons between SBRT and conventional fractionation or hyperfractionation must be approached cautiously, given uncertainties in the models used to calculate biological equivalence. Recently, Tai combined LQ and Lyman modeling to generate parameters based on clinical data that may be used to estimate equivalent doses based on differing fraction size (
      • Tai A.
      • Erickson B.
      • Khater K.A.
      • et al.
      Estimate of radiobiologic parameters from clinical data for biologically based treatment planning for liver irradiation.
      ), but Park has noted problems in the application of LQ modeling for SBRT and offered an alternative survival curve formulation (
      • Park C.
      • Papiez L.
      • Zhang S.
      • et al.
      Universal survival curve and single fraction equivalent dose: Useful tools in understanding potency of ablative radiotherapy.
      ). For the purpose of offering a visual example of the typical dose–volume histograms (DVHs) used in those settings, Figure 3 includes mean DVHs from the UM hyperfractionated experience and the UC SBRT experience, but these should not be interpreted as an ideal DVH for these situations. Regarding the UM data, the doses shown in Figure 3A have been corrected to 1.5 Gy per fraction (using LQ model, α/β = 2.5 Gy) and radiation was given with hepatic arterial FUdR (
      • Dawson L.A.
      • Biersack M.
      • Lockwood G.
      • et al.
      Use of principal component analysis to evaluate the partial organ tolerance of normal tissues to radiation.
      ). The UC data represent DVHs from the first 18 patients treated (
      • Schefter T.E.
      • Kavanagh B.D.
      • Timmerman R.D.
      • et al.
      A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases.
      ).
      Figure thumbnail gr3
      Fig. 3Characteristic normal liver (minus gross tumor volume) DVHs for low (a) or high (b) dose per fraction. (a) Mean normal liver DVHs from the University of Michigan for 204 patients who did or did not experience radiation-induced liver disease (RILD). (b) Mean normal liver dose–volume histogram from the University of Colorado SBRT Phase I trial with no RILD observed. See text for additional details.
      One additional potential concern related to the use of high dose per fraction treatment is the observation of extrahepatic portal vein occlusion after high-dose intraoperative radiation therapy. Mitsunaga et al. observed 12 cases of extrahepatic portal vein occlusion among 53 patients who underwent pancreaticoduodenectomy for periampullary disease followed by 20 Gy intraoperative radiation therapy to the resection bed (
      • Mitsunaga S.
      • Kinoshita T.
      • Kawashima M.
      • et al.
      Extrahepatic portal vein occlusion without recurrence after pancreaticoduodenectomy and intraoperative radiation therapy.
      ).

      8. Recommended Dose–Volume Limits

      All dose–volume recommendations are associated with some uncertainty. Nevertheless, the data for RILD estimates have been reasonably well studied and analyzed. Long-term liver injury or biliary duct system damage is less well understood, because few patients have been followed for 5 or more years. Broad guidelines for normal liver dose constraints, for 5% or less risk of RILD, are offered as follows.

       Palliative whole-liver doses

      • Liver metastases
        • ≤ 30 Gy, in 2 Gy per fraction
        • 21
          Gy in seven fractions (
          • Leibel S.A.
          • Guse C.
          • Order S.E.
          • et al.
          Accelerated fractionation radiation therapy for liver metastases: Selection of an optimal patient population for the evaluation of late hepatic injury in RTOG studies.
          )
      • Primary liver cancers
        • ≤ 28 Gy, in 2 Gy per fraction
        • 21
          Gy in seven fractions (
          • Abrams R.A.
          • Cardinale R.M.
          • Enger C.
          • et al.
          Influence of prognostic groupings and treatment results in the management of unresectable hepatoma: Experience with Cisplatinum-based chemoradiotherapy in 76 patients.
          )

       Therapeutic partial liver RT (standard fractionation)

      Mean normal liver dose (liver minus gross tumor volume)
      • < 28 Gy in 2-Gy fractions for primary liver cancer
      • < 32 Gy in 2-Gy fractions for liver metastases

       Nonuniform liver recommendations (SBRT, three to six fractions)

      Mean normal liver dose (liver minus gross tumor volume)
      • < 13 Gy for primary liver cancer, in three fractions
      • < 18 Gy for primary liver cancer, in six fractions
      • < 15 Gy for liver metastases, in three fractions
      • < 20 Gy for liver metastases, in six fractions
      • < 6 Gy for primary liver cancer, Child-Pugh B, in 4–6 Gy per fraction (for classic or nonclassic RILD)
      • Critical volume model-based
      • ≥ 700 mL of normal liver receives ≤ 15 Gy in three to five fractions

      9. Future Toxicity Studies

      • A.
        Prospective studies with dose-volume data and serial long-term clinical/objective outcomes are needed. Differences in dose per fraction should also be considered.
      • B.
        The impact of clinical variables (e.g., pre-RT liver function) and other therapies (e.g., chemotherapy) that may impact the liver's functional reserve need to be assessed.
      • C.
        The timeframe for post-RT liver regeneration has not been well characterized.
      • D.
        An improved understanding of the biological pathophysiology of RT-induced liver injury, especially for nonclassic RILD, is needed, with an emphasis on identifying opportunities for injury mitigation by modulation of key signaling pathways (e.g., transforming growth factor-β) (
        • Anscher M.S.
        • Crocker I.R.
        • Jirtle R.L.
        Transforming growth factor-beta 1 expression in irradiated liver.
        ). In this setting, pretreatment pathologic evaluation of the nonmalignant liver could potentially be useful for predicting the NTCP and may be a subject for future research.
      • E.
        RT effects on nonparenchymal structures within the liver (e.g., biliary duct tolerance).
      • F.
        Spatial variation in radiation sensitivity.

      10. Toxicity Scoring

      Studies of RT-induced liver injury should separately record the incidence of classic and non-classic RILD. Preexisting liver dysfunction, as measured by the Child-Pugh score, should be recorded, as well as any change in status of Child-Pugh score after treatment. The use of CTCAE criteria for elevations of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, platelet count, bilirubin, albumin, and prothrombin time is advisable to promote consistency of reporting. Screening for and treatment of hepatitis B and/or C before RT is recommended.

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