Top

14-02-2017 | Hepatocellular carcinoma | Article

10. Primary Liver Cancer: Radiation Therapy Planning

Authors: Florence K. Keane, MD, Theodore Hong, MD

Publisher: Springer International Publishing

Abstract

The development of modern radiotherapy planning and delivery techniques has enabled safe and effective delivery of tumoricidal doses of liver-directed radiotherapy. With more refined assessments of hepatotoxicity risk, an increasing number of patients with primary liver cancer have received liver-directed radiotherapy, including patients who were not candidates for curative treatments such as surgical resection or orthotopic liver transplantation. In this chapter, we discuss radiotherapy planning and delivery techniques for primary liver cancers. We also discuss supporting evidence for the use of liver-directed radiotherapy in both hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

10.1 Radiation Treatment for HCC and ICC

Advances in radiotherapy treatment planning and delivery allow the safe delivery of tumoricidal doses of radiotherapy with minimal associated toxicity.
We recommend liver-directed RT in patients who are not candidates for orthotopic liver transplantation, surgical resection, or radiofrequency ablation, including patients with one or multiple lesions measuring 3–6 cm or patients with larger tumors (6–10 cm) with a sufficient volume of normal hepatic parenchyma.
- Select patients with tumor vein thrombosis with adequate hepatic function can be safely treated with liver-directed RT.
- Patients with Child-Pugh Class C cirrhosis should not be treated off-protocol.

10.2 Treatment Planning

10.2.1 Simulation

Computed tomography (CT) or magnetic resonance (MR)-based simulation.
- Four-dimensional CT (4D-CT) is needed to assess motion.
Patients are simulated supine with arms up.
Immobilization devices are used and may include thermoplastic devices or vacuum bags, with or without a body frame [1].
Patients receive both oral and multiphasic intravenous (IV) contrast at the time of simulation.

10.3 Target Identification

Both HCC and ICC have variable enhancement patterns on CT and MRI. Multiphasic intravenous (IV) contrast with arterial, portal venous, and delayed phase is needed for accurate tumor identification, as use of only one phase of contrast for target identification increases the risk of undercontouring of the target or inclusion of normal hepatic parenchyma or vasculature in the target volume. Tumor vascular invasion further complicates target identification [2].
- HCC classically exhibits rapid arterial enhancement with washout on delayed phases [3, 4], but enhancement varies based on tumor size and perfusion [4‐7]. Fig. 10.1 and Fig. 10.2
  
  Larger nodules may have a fibrous capsule which results in delayed enhancement and washout of contrast [4], while diffuse-type HCC often has minimal arterial enhancement [5]. Tumor venous thrombosis and vascular involvement may further alter enhancement patterns.
  
  On MRI, larger HCC nodules may be hyperintense on T2 series and hypointense on T1 series, while smaller nodules may be T1 isointense before rapid but transient contrast enhancement [8, 9].
  
  RTOG consensus guidelines recommend contouring the gross tumor volume (GTV) as the union of GTVs across all phases of imaging [2]. This ensures accurate identification of the target while minimizing coverage of normal hepatic parenchyma.
  
  This recommendation was supported by a series on IV contrast enhancement and target definition in HCC which demonstrated that there was no one phase which provided optimal tumor identification across tumors. Figs. 10.3 and 10.4 Moreover, a uniform expansion around the GTV from the best visualized phase was inferior when compared with a GTV comprised of the union of GTVs across all available imaging phases [7].
  
  Fig. 10.3
  Lack of overlap between gross tumor volume (GTV) as contoured on the arterial phase (red), portal venous phase (blue), and delayed phase (yellow) for a patient with hepatocellular carcinoma. Images are shown on the portal venous phase (left panel) and arterial phase (right panel)
  
  Fig. 10.4
  Lack of overlap between gross tumor volume (GTV) as contoured on the arterial phase (red), portal venous phase (green), and delayed phase (yellow) for a patient with hepatocellular carcinoma. Images are shown on the arterial phase
  
  ×
  
  ×
  
  Fig. 10.1
  Hepatocellular carcinoma with best visualization in the arterial phase. Lesion one shows arterial enhancement (a) and venous washout (b). Lesion two also shows arterial enhancement (c) and venous washout (d)
  
  Fig. 10.2
  Hepatocellular carcinoma with best visualization in the portal venous phase. Lesion one shows worst visualization in the arterial phase (a) and best visualization in the portal venous phase (b). Lesion two also shows worst visualization in the arterial phase (c) and best visualization in the portal venous phase (d)
  
  ×
  
  ×
- ICC typically shows delayed enhancement [7, 10‐13], but some lesions may appear more similar to HCC, with arterial enhancement and rapid venous washout [14].
  
  Consensus guidelines are not yet available for ICC, but due to the variable enhancement patterns seen in ICC [7], all available phases of multiphasic imaging should be evaluated to identify the GTV.
MRI and MR-based simulation
- Some lesions may be more visible on MRI than on CT Fig. 10.5.
  
  Fig. 10.5
  Intrahepatic cholangiocarcinoma as seen on the arterial phase of a contrast-enhanced CT (left panel) and on a contrast-enhanced T1 sequence of an MRI (right panel)
  
  ×
- Hepatic MRI with contrast may also help distinguish tumor from perfusion abnormalities in patients with severe cirrhosis [15].
- MRIs should be carefully reviewed during treatment planning to ensure accurate target identification and coverage.
  
  CT-MRI fusions are challenging due to potential organ deformation between series. Suboptimal fusion may lead to target overcontouring [2]. Placement of MR-compatible fiducial markers and obtaining an MRI in the RT treatment may assist with registration.
  
  MR-based simulation removes the need for fusion with the planning CT, but is not yet widely available.

10.4 Target Motion Assessment and Management

Patients should have a four-dimensional (4D) CT [16] for treatment planning, as a free-breathing CT may not provide adequate assessment of organ motion.
- An internal target volume (ITV) may be constructed to account for target motion.
Placement of fiducial markers in the normal hepatic parenchyma prior to simulation facilitates measurement of the liver and target motion. Motion of the target can be compared to the movement of the fiducial markers [16‐18]. Fiducial markers are also essential for patient setup and treatment delivery.
Patients with significant target or organ motion require further intervention to monitor and/or decrease motion.
- In active breathing control [19‐21] or respiratory gating, the patient’s respiratory cycle is tracked throughout treatment, with delivery of radiotherapy limited to select phases of the respiratory cycle.
  
  Active breathing control reduces intra-fraction variability, but there may be persistent variability between fractions [22].
  
  Active breathing control has been employed with both photon [23, 24] and proton [25] RT.
- Abdominal compression [21, 26‐28] causes a small degree of organ deformation [29] and does not reduce organ motion in all patients [27], but in some patients, it significantly reduces organ motion [16, 26, 29].

10.5 Treatment Delivery Technique

Assessment of patient setup and target position will depend on the type of radiotherapy used as well as the delivery system.
- On-board cone-beam CTs such as on the Elekta Synergy® and on the Varian Trilogy® can be used to assess fiducial and soft tissue position before treatment, in between treatment fields, and after treatment.
- CyberKnife® tracks the position of implanted fiducial markers using real-time orthogonal X-rays and adjusts treatment delivery accordingly.

10.6 Development of Modern Liver: Directed RT

In the era of two-dimensional (2D) RT, treatment often required radiation of the entire liver, which carried risk of hepatotoxicity and resulting risk of radiation-induced liver disease (RILD). Liver-directed RT was largely relegated to the palliative setting.
- RILD can develop as early as 2 weeks and as late as 4 months after the completion of RT and is characterized by the triad of hepatomegaly, ascites, and an increase in alkaline phosphatase with minimal increase in bilirubin.
- The risk of developing RILD varies based on the RT dose, volume of the liver irradiated, and underlying hepatobiliary function [30].
  
  Retrospective series of whole liver RT reported rates of RILD of 44 % in patients receiving ≥ 35 Gy [31] and 10 % in patients receiving 33 Gy in 1.5 Gy twice-daily fractions [32].
  
  In patients with cirrhosis, the risk of RILD or other treatment-related toxicities increases.
  
  Dose-escalation protocols conducted at the University of Michigan of liver-directed RT for patients with hepatocellular carcinoma, cholangiocarcinoma, and liver metastases reported an increased risk of RILD in patients with HCC with underlying cirrhosis as compared to patients with liver metastases [33].
  
  A retrospective study of 92 patients with HCC treated with SBRT between 2007 and 2009 included 68 patients with CP A cirrhosis (73.9 %) and 24 patients (26.1 %) with CP B cirrhosis.
  
  CP B cirrhosis was associated with a significantly increased risk of grade ≥2 RILD [34].

Conformal radiotherapy
- The development of modern RT planning and delivery techniques enabled safe delivery of tumoricidal doses of RT and more refined assessments of hepatotoxicity risk based on the interaction between radiotherapy dose, tumor volume, and the volume of irradiated and unirradiated hepatic parenchyma [35, 36].
- A series of dose-escalation protocols conducted at the University of Michigan on hyperfractionated conformal RT with concurrent arterial chemotherapy based RT dose on a maximum 10–15 % risk of RILD as calculated by a normal tissue complication probability (NTCP) model [33].
  
  The effective liver volume (Veff) parameter was used in the NTCP model to calculate dose and enabled comparison of different RT plans.
  
  A total of 128 patients (46 patients with liver metastases, 35 patients with HCC, and 46 patients with cholangiocarcinoma) were treated to a median dose of 60.75 Gy in twice-daily 1.5 Gy fractions.
  
  Median overall survival was 15.8 months.

Stereotactic body radiotherapy (SBRT)
- SBRT uses multiple conformal beams to deliver high doses of RT with rapid dose falloff. With the development of SBRT and associated stereotactic techniques, the use of liver-directed RT has continued to increase.
- Prospective Phase I and II trials of liver SBRT conducted at Princess Margaret Hospital treated 102 patients with HCC to a median dose of 36 Gy in six fractions (range 24–54 Gy) [37].
  
  The majority of patients had underlying cirrhosis: 38 % had hepatitis C-related cirrhosis, 38 % had hepatitis B-related cirrhosis, and 25 % had alcohol-related cirrhosis. Fifty-five percent of patients had tumor venous thrombosis.
  
  CT simulation
  
  Patients had a multiphasic CT with or without MRI for treatment planning.
  
  Custom immobilization was used, with 51 % requiring abdominal compression and 49 % receiving active breathing control.
  
  Targets
  
  Gross tumor volume (GTV): the area of arterial enhancement and venous washout as seen on CT and/ or MRI
  
  Clinical target volume (CTV) 1, CTV1: GTV and contrast-enhancing tumor thrombus
  
  CTV2: optional volume, consisted of a 5-mm expansion around the GTV, as well as any areas of nonenhancing venous thrombosis
  
  Planning target volumes (PTV): up to 5-mm expansion on CTV1 and CTV2, adjusted based on target motion and patient immobilization
  
  RT dose to PTV1 was determined based on the maximum allowed Veff (limited to 60 % in Trial 2) and ranged from 30 to 54 Gy in six fractions.
  
  Fractions were delivered every other day over 2 weeks.
  
  The dose to tumor venous thrombosis plus the PTV margin could be limited to 30 Gy if needed for normal tissue toxicity.
  
  The dose to PTV2 (which included nonenhancing tumor thrombus) was recommended to be 27 Gy but was not mandated.
  
  Results
  
  Median OS was 17 months. Local control at 1 year was 87 %.
  
  Grade ≥ 3 toxicity was seen in 30 % of patients.
  
  There was no classic RILD.
  
  Seven patients died within a year after RT. Five patients experienced liver failure, two of whom had massive TVT progression. In one patient, HCC invading the common bile duct likely led to cholangitis. One patient experienced a fatal duodenal bleed after re-irradiation for retroperitoneal nodal disease.
- RTOG 1112 [38]: currently accruing randomized Phase III trial of sorafenib with or without SBRT in patients with unresectable BCLC stage B (intermediate) or C (advanced) HCC who were refractory to TACE or are not candidates for RFA or TACE.
  
  Patients may be treated with protons or photons.
  
  Randomization
  
  Randomized to daily sorafenib vs. SBRT followed by daily sorafenib.
  
  Patients are stratified prior to randomization by presence/ absence of vascular invasion, cirrhosis etiology (hepatitis B, hepatitis C, or others), region of treatment site, and extent of HCC volume relative to liver volume.
  
  Simulation: Patients must be immobilized with custom immobilization.
  
  Liver-protocol CT with multiphasic IV contrast
  
  4D-CT to assess motion, with exhale breath-hold or average-phase CT used as baseline CT for planning.
  
  Targets
  
  GTV includes parenchymal and vascular disease as seen on arterial, portal venous, and/or delayed phases of CT and/or MR imaging.
  
  Note that tumor venous thrombus may be best seen on venous phase imaging.
  
  Non-tumor thrombus should not be included in the GTV.
  
  CTV: No standard expansion on the GTV.
  
  A CTV margin to include areas at high risk for microscopic disease is optional. These include areas of non-tumor thrombus and sites of prior arterially directed or ablative therapies.
  
  PTV: The minimum PTV margin is a 4-mm expansion in all directions around the CTV. The maximum PTV margin should ideally be ≤ 10 mm.
  
  PTV margin also based on whether the patient is treated with protons or photons.
  
  Dose
  
  The maximum possible dose based on normal tissue tolerances and the mean liver dose should be delivered.
  
  Assessment of the effective liver volume (Veff) is optional.
  
  There are six possible dose levels based on the mean liver dose (MLD). These doses correspond to the photon doses and the RBE-weighted dose for protons.
  
  MLD ≤ 13 Gy (Veff<25 %) corresponds to PTV dose of 50 Gy.
  
  MLD ≤ 15 Gy (Veff 25–29 %) corresponds to PTV dose of 45 Gy.
  
  MLD ≤ 15 Gy (Veff 30–34 %) corresponds to PTV dose of 40 Gy.
  
  MLD ≤ 15.5 Gy (Veff 35–44 %) corresponds to PTV dose of 35 Gy.
  
  MLD ≤ 16 Gy (Veff 45–54 %) corresponds to PTV dose of 30 Gy.
  
  MLD ≤ 17 Gy (Veff 55–64 %) corresponds to PTV dose of 27.5 Gy.
  
  Treatment is delivered in five fractions, with a time interval of 24 to 72 h between fractions.
  
  Prescription isodose must cover ≥95 % of the PTV.
  
  Organs at risk: Constraints include the following items:
  
  Liver: As noted above, the PTV prescription dose is determined based on the mean liver dose.
  
  As a guideline, the liver volume (liver – GTVs) should consist of a volume > 700 cc, with V10Gy < 70 %.
  
  Spinal cord + 5-mm expansion: D_{0.5 cc} ≤ 25 Gy
  
  Esophagus: D_{0.5 cc} ≤ 32 Gy
  
  Stomach, duodenum, small bowel: D_{0.5 cc} ≤ 30 Gy
  
  Large bowel: D_{0.5 cc} ≤ 32 Gy
  
  Kidney (bilateral mean dose) < 10 Gy
  
  It is recommended to avoid hot spots in the common bile duct, keeping D_{0.5 cc} ≤ 50 Gy.
  
  Adjacent bowel may limit or prevent safe RT delivery, particularly SBRT which relies on delivery of a high dose per fraction. For lesions which are close to bowel, placement of a biologic mesh spacer may sufficiently displace bowel to allow safe administration of RT [39].
  
  Treatment delivery requires IGRT with either cone-beam CT or orthogonal kV images with fiducial markers.
Charged particle therapy
- Charged particle therapy, including proton therapy and carbon ion therapy, is characterized by sharp dose falloff which in turn minimizes exit dose (Fig. 10.6).
  
  There are multiple techniques for the delivery of proton therapy, including passive scattering and pencil beam scanning.
  
  Fig. 10.6
  Proton therapy plan for a patient with intrahepatic cholangiocarcinoma. The CTV is the solid red line
  
  ×
- There is growing interest in the use of charged particle therapy in the treatment of both ICC and HCC as the properties of charged particle therapy can be exploited to maximize the dose to the tumor while minimizing dose to normal hepatic parenchyma.
  
  A retrospective series of 318 patients with HCC treated with proton therapy at the University of Tsukuba reported 5-year OS of 44.6 % with only five cases of grade ≥ 3 toxicity [40].
  
  A Phase II multi-institutional trial of hypofractionated proton radiotherapy for 92 patients with HCC or ICC demonstrated impressive overall survival and local control rates at 2 years [41]. Two-year overall survival rates were 63.2 % for HCC and 45.8 % for ICC, while 2-year local control rates were 94.8 % for HCC and 94.1 % for ICC.
  
  Dose was adjusted based on mean liver dose as well as proximity to the porta hepatis.
  
  Peripheral tumors (located > 2 cm from the porta hepatis) received a planned dose of 67.5 GyE in 15 fractions.
  
  Central tumors (located within 2 cm of the porta hepatis) received a planned dose of 58.05 GyE in 15 fractions.
  
  RT dose was also adjusted to maintain a mean liver dose ≤ 24 GyE.
  
  There were low rates of toxicity, with four patients (4.8 %) experiencing grade ≥ 3 toxicity and only three patients (3.6 %) experiencing a decline in Child-Pugh score from CP A to CP B.

Intensity-modulated rad iotherapy (IMRT)
- Similarly to SBRT, IMRT allows for increased conformality of dose around target volumes while sparing uninvolved tissues.
- NRG GI001 [42]: currently accruing randomized Phase III trial of gemcitabine and cisplatin with or without focal hypofractionated radiation therapy for unresectable intrahepatic cholangiocarcinoma.
  
  Patients may be treated with either protons or photons.
  
  Randomization
  
  Randomized to chemotherapy alone (gemcitabine/cisplatin x 5 cycles) versus sequential chemoradiotherapy (gemcitabine/cisplatin x 1 cycle followed by radiotherapy followed by gemcitabine/cisplatin x 4 cycles). Patients in either arm may receive maintenance gemcitabine.
  
  Patients are stratified prior to randomization by tumor size and the presence of satellite lesions.
  
  Simulation: Patients must be immobilized with custom immobilization.
  
  Liver-protocol CT with multiphasic IV contrast
  
  4D-CT to assess motion, with exhale breath-hold or average-phase CT used as baseline CT for planning
  
  Targets
  
  GTV includes parenchymal and nodal disease as seen on arterial, portal venous, and/or delayed phases of CT and/ or MR imaging.
  
  CTV: CTV expansion on the GTV is optional.
  
  PTV: The minimum PTV margin is a 4-mm expansion in all directions around the CTV. The maximum PTV margin is 20 mm.
  
  PTV margin also based on whether the patient is treated with protons or photons.
  
  Dose
  
  Prescription dose is based on the proximity of the PTV to the porta hepatis and the mean liver dose.
  
  Tumors located within 2 cm of the porta hepatis are restricted to a maximum dose of 58.05 Gy (or 58.05 Gy(E)).
  
  The maximum dose for peripheral tumors (located > 2 cm beyond the porta hepatis) is 67.5 Gy (or 67.5 Gy(E)).
  
  Dose is then determined based on the mean liver dose, defined as the liver minus GTV. These are four possible dose levels, all of which correspond to the photon dose or the RBE-weighted dose for protons and are delivered in 15 daily fractions.
  
  MLD ≤ 22 Gy corresponds to PTV dose of 67.5 Gy.
  
  MLD ≤ 24 Gy corresponds to PTV dose of 58.05 Gy.
  
  If MLD > 24 Gy, PTV dose decreases to 45 Gy.
  
  MLD of 27 Gy corresponds to PTV dose of 37.5 Gy.
  
  Prescription isodose must cover ≥95 % of the PTV.
  
  Organs at risk: Constraints include the following items:
  
  Liver: As noted above, the PTV prescription dose is determined based on the mean liver dose.
  
  The volume of uninvolved liver (liver – GTVs) should be > 700 cc, with V10 Gy < 80 %.
  
  Spinal cord + 5-mm expansion: D_{0.5 cc} ≤ 37.5 Gy
  
  Duodenum, small bowel, esophagus: D_{0.5 cc} ≤ 45 Gy
  
  Stomach: D_{0.5 cc} ≤ 40 Gy
  
  Large bowel: D_{0.5 cc} ≤ 48 Gy
  
  Kidney (bilateral mean dose): ≤ 12 Gy
  
  It is recommended to avoid hot spots in the common bile duct, keeping D_{0.5 cc} ≤ 70 Gy.
  
  Treatment delivery requires IGRT with either cone-beam CT or orthogonal kV images with fiducial markers.

10.7 Dose and Fractionation

The optimal dose and fractionation pattern for HCC and ICC are not yet known. Responses have been seen with lower doses of radiotherapy, particularly in series of patients with early-stage disease or compromised hepatobiliary function, but there is a suggestion that higher doses of radiotherapy may be associated with improved local control and survival.

In a series of 82 patients with HCC treated with three-fraction SBRT (median dose 51 Gy, range 33–60 Gy), 2-year local control was 87 %, and 2-year overall survival was 63 %. For patients who were treated with median doses ≥ 54 Gy, local control and overall survival rates were 100 % and 68 % after 4.5 years of follow-up [43].
In ICC, a retrospective analysis of 79 patients with unresectable disease (median tumor size 7.9 cm) treated with chemotherapy followed by radiotherapy reported a median 3-year OS of 44 %, with a significant improvement in both overall survival and local control in patients who received BED > 80.5 Gy [44].
- Median RT dose and fractionation were 58.05 Gy in 15 fractions (BED 80.5 Gy).
- 3-year OS was 73 % with BED > 80.5Gy vs. 38 % with BED < 80.5 Gy (P=0.017), while 3-year local control was 78 % with BED > 80.5Gy vs. 48 % with BED < 80.5 Gy (P=0.04).

Conclusions

Liver-directed radiation therapy is a safe and effective treatment modality for patients with both hepatocellular carcinoma and intrahepatic cholangiocarcinoma.
Treatment options for hepatic malignancies include conformal radiotherapy, SBRT, IMRT, and charged particle therapy. These treatment modalities enable delivery of tumoricidal doses of radiotherapy while sparing maximal volumes of normal hepatic parenchyma.
Further study is needed to determine the optimal dose and fractionation pattern for both HCC and ICC.
Ongoing trials will provide valuable prospective data on the optimal role of RT in the treatment of advanced unresectable HCC and ICC.

Lo SS, Fakiris AJ, Chang EL, et al. Stereotactic body radiation therapy: a novel treatment modality. Nat Rev Clin Oncol. Jan 2010;7(1):44–54.CrossRefPubMed

Hong TS, Bosch WR, Krishnan S, et al. Interobserver variability in target definition for hepatocellular carcinoma with and without portal vein thrombus: radiation therapy oncology group consensus guidelines. Int J Radiat Oncol Biol Phys. 2014;89(4):804–13.CrossRefPubMedPubMedCentral

Araki T, Itai Y, Furui S, Tasaka A. Dynamic CT densitometry of hepatic tumors. AJR Am J Roentgenol. 1980;135(5):1037–43.CrossRefPubMed

Baron RL, Oliver 3rd JH, Dodd 3rd GD, Nalesnik M, Holbert BL, Carr B. Hepatocellular carcinoma: evaluation with biphasic, contrast-enhanced, helical CT. Radiology. 1996;199(2):505–11.CrossRefPubMed

Kanematsu M, Semelka RC, Leonardou P, Mastropasqua M, Lee JK. Hepatocellular carcinoma of diffuse type: MR imaging findings and clinical manifestations. J Magn Reson Imaging (JMRI). 2003;18(2):189–95.CrossRef

Honda H, Tajima T, Kajiyama K, et al. Vascular changes in hepatocellular carcinoma: correlation of radiologic and pathologic findings. AJR Am J Roentgenol. 1999;173(5):1213–7.CrossRefPubMed

Niska J, Keane FK, Wolfgang J, et al. Impact of IV contrast enhancement phase on target definition for Hepatocellular Carcinoma(HCC) and Intrahepatic Cholangiocarcinoma(IHC): observations from patients enrolled on a prospective phase II trial. Pract Radiat Oncol. 2015; (In press).

Rummeny E, Weissleder R, Stark DD, et al. Primary liver tumors: diagnosis by MR imaging. AJR Am J Roentgenol. Jan 1989;152(1):63–72.CrossRefPubMed

Yamashita Y, Hatanaka Y, Yamamoto H, et al. Differential diagnosis of focal liver lesions: role of spin-echo and contrast-enhanced dynamic MR imaging. Radiology. 1994;193(1):59–65.CrossRefPubMed

10.

Kim TK, Choi BI, Han JK, Jang HJ, Cho SG, Han MC. Peripheral cholangiocarcinoma of the liver: two-phase spiral CT findings. Radiology. 1997;204(2):539–43.CrossRefPubMed

11.

Iavarone M, Piscaglia F, Vavassori S, et al. Contrast enhanced CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis. J Hepatol. 2013;58(6):1188–93.CrossRefPubMed

12.

Valls C, Guma A, Puig I, et al. Intrahepatic peripheral cholangiocarcinoma: CT evaluation. Abdom Imaging. 2000;25(5):490–6.CrossRefPubMed

13.

Miura F, Okazumi S, Takayama W, et al. Hemodynamics of intrahepatic cholangiocarcinoma: evaluation with single-level dynamic CT during hepatic arteriography. Abdom Imaging. 2004;29(4):467–71.CrossRefPubMed

14.

Kim SA, Lee JM, Lee KB, et al. Intrahepatic mass-forming cholangiocarcinomas: enhancement patterns at multiphasic CT, with special emphasis on arterial enhancement pattern--correlation with clinicopathologic findings. Radiology. 2011;260(1):148–57.CrossRefPubMed

15.

Lee JM, Zech CJ, Bolondi L, et al. Consensus report of the 4th International Forum for Gadolinium-Ethoxybenzyl-Diethylenetriamine Pentaacetic Acid Magnetic Resonance Imaging. Korean J Radiol. 2011;12(4):403–15.CrossRefPubMedPubMedCentral

16.

Heinzerling JH, Anderson JF, Papiez L, et al. Four-dimensional computed tomography scan analysis of tumor and organ motion at varying levels of abdominal compression during stereotactic treatment of lung and liver. Int J Radiat Oncol Biol Phys. 2008;70(5):1571–8.CrossRefPubMed

17.

Lax I, Blomgren H, Naslund I, Svanstrom R. Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects. Acta Oncol. 1994;33(6):677–83.CrossRefPubMed

18.

Langen KM, Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys. 2001;50(1):265–78.CrossRefPubMed

19.

Blomgren H, Lax I, Naslund I, Svanstrom R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol. 1995;34(6):861–70.CrossRefPubMed

20.

Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2008;26(4):657–64.CrossRefPubMed

21.

Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing control (ABC) to reduce margin for breathing motion. Int J Radiat Oncol Biol Phys. 1999;44(4):911–9.CrossRefPubMed

22.

Eccles C, Brock KK, Bissonnette JP, Hawkins M, Dawson LA. Reproducibility of liver position using active breathing coordinator for liver cancer radiotherapy. Int J Radiat Oncol Biol Phys. 2006;64(3):751–9.CrossRefPubMed

23.

Dawson LA, Eccles C, Craig T. Individualized image guided iso-NTCP based liver cancer SBRT. Acta Oncol. 2006;45(7):856–64.CrossRefPubMed

24.

Dawson LA, Brock KK, Kazanjian S, et al. The reproducibility of organ position using active breathing control (ABC) during liver radiotherapy. Int J Radiat Oncol Biol Phys. 2001;51(5):1410–21.CrossRefPubMed

25.

Hong TS, DeLaney TF, Mamon HJ, et al. A prospective feasibility study of respiratory-gated proton beam therapy for liver tumors. Pract Radiat Oncol. 2014;4(5):316–22.CrossRefPubMed

26.

Case RB, Sonke JJ, Moseley DJ, Kim J, Brock KK, Dawson LA. Inter- and intrafraction variability in liver position in non-breath-hold stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2009;75(1):302–8.CrossRefPubMed

27.

Eccles CL, Patel R, Simeonov AK, Lockwood G, Haider M, Dawson LA. Comparison of liver tumor motion with and without abdominal compression using cine-magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 2011;79(2):602–8.CrossRefPubMed

28.

Dawson LA, Ten Haken RK, Lawrence TS. Partial irradiation of the liver. Semin Radiat Oncol. Jul 2001;11(3):240–6.CrossRefPubMed

29.

Eccles CL, Dawson LA, Moseley JL, Brock KK. Interfraction liver shape variability and impact on GTV position during liver stereotactic radiotherapy using abdominal compression. Int J Radiat Oncol Biol Phys. 2011;80(3):938–46.CrossRefPubMed

30.

Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat Oncol. 2005;15(4):279–83.CrossRefPubMed

31.

Ingold JA, Reed GB, Kaplan HS, Bagshaw MA. Radiation hepatitis. Am J Roentgenol Radium Ther Nucl Med. 1965;93:200–8.PubMed

32.

Russell AH, Clyde C, Wasserman TH, Turner SS, Rotman M. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: results of the RTOG dose escalating protocol. Int J Radiat Oncol Biol Phys. 1993;27(1):117–23.CrossRefPubMed

33.

Ben-Josef E, Normolle D, Ensminger WD, et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol. 2005;23(34):8739–47.CrossRefPubMed

34.

Jung J, Yoon SM, Kim SY, et al. Radiation-induced liver disease after stereotactic body radiotherapy for small hepatocellular carcinoma: clinical and dose-volumetric parameters. Radiat Oncol. 2013;8:249.CrossRefPubMedPubMedCentral

35.

McGinn CJ, Ten Haken RK, Ensminger WD, Walker S, Wang S, Lawrence TS. Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model. J Clin Oncol. Jun 1998;16(6):2246–52.PubMed

36.

Dawson LA, McGinn CJ, Normolle D, et al. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol. 2000;18(11):2210–8.PubMed

37.

Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol. 2013;31(13):1631–9.CrossRefPubMed

38.

Clinicaltrials.gov identifier NCT01730937. Accessed 30 Sept 2015.

39.

Yoon SS, Aloia TA, Haynes AB, et al. Surgical placement of biologic mesh spacers to displace bowel away from unresectable liver tumors followed by delivery of dose-intense radiation therapy. Pract Radiat Oncol. 2014;4(3):167–73.CrossRefPubMed

40.

Nakayama H, Sugahara S, Tokita M, et al. Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience. Cancer. 2009;115(23):5499–506.CrossRefPubMed

41.

Hong TS, Wo JY, Beow YY, et al. A multi-institutional phase II study of high dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2015; (In press)

42.

Clinicaltrials.gov identifier NCT02200042. Accessed 31 Mar 2016.

43.

Jang WI, Kim MS, Bae SH, et al. High-dose stereotactic body radiotherapy correlates increased local control and overall survival in patients with inoperable hepatocellular carcinoma. Radiat Oncol. 2013;8:250.CrossRefPubMedPubMedCentral

44.

Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol. 2016;34(3):219–26.CrossRefPubMed