Primary Liver Cancer: Radiation Therapy Planning



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)



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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





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    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)


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    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.

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          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

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          Oct 18, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Primary Liver Cancer: Radiation Therapy Planning

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