Role of Radiotherapy in HCC

Radiotherapy (external) in
Hepatocellular Carcinoma
what do the guidelines say ?
Pratap Sagar Tiwari, MD (Internal medicine)
DM (Hepatology)
NAMS, BIR HOSPITL,
KATHMANDU, NEPAL

External beam Radiation therapy
• The external beam radiation therapy is a RX method for delivering a beam
or several beams of high-energy photons, electrons or protons through the
skin to the cancer in order to destroy the main tumor.
• The radiation tolerance of the whole liver is in the order of approx
30 Gy, which is inadequate to control gross disease of solid tumors
and therefore limits the role of radiation as a curative modality when
administered to the whole liver.
• The conventional radiation technique may damage the neighbouring
healthy liver tissue and so lies the risk of radiation-induced liver
disease (RILD).

Radiation induced Liver disease (RILD)
• Originally described by Ingold et al.,(1) is the most significant complication of RT.
• Although RILD typically occurs 4–8 weeks after termination of RT, it has been
reported to appear as early as 2 weeks or as late as 7 months after RT.(2-4)
• Among the pts receiving hepatic radiation of 30–35 Gy, ~6–66% of pts present
significant RILD.(3-5)
• There are two types of RILD: classic RILD and non-classic RILD. Pts with classic
RILD usually have symptoms of fatigue, abdominal pain, increased abdominal girth,
hepatomegaly and anicteric ascites 1–3 months after liver RT.(6) In addition, the
level of ALP ↑ by more than 2X, whereas levels of AT and bilirubin remain N.(7)
1. Ingold JA, Reed GB, Kaplan HS, Bagshaw MA. Radiation hepatitis. Am J Roentgenol Radium Ther Nucl Med 1965; 93: 200–208.
2. Benson R, Madan R, Kilambi R, Chander S. Radiation induced liver disease: a clinical update. J Egypt Natl Canc Inst 2016; 28: 7–11.
3. Khozouz RF, Huq SZ, Perry MC. Radiation-induced liver disease. J Clin Oncol 2008; 26: 4844–4845.
4. Guha C, Kavanagh BD. Hepatic radiation toxicity: avoidance and amelioration. Semin Radiat Oncol 2011; 21: 256–263.
5. Pan CC, Kavanagh BD, Dawson LA, Li XA, Das SK, Miften M et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 2010; 76: S94–100.
6. Lawrence TS, Robertson JM, Anscher MS, Jirtle RL, Ensminger WD, Fajardo LF. Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 1995; 31: 1237–1248.
7. Liang SX, Huang XB, Zhu XD, Zhang WD, Cai L, Huang HZ et al. Dosimetric predictor identification for radiation-induced liver disease after hypofractionated conformal radiotherapy for primary liver carcinoma patients with Child-Pugh Grade A cirrhosis. Radiother Oncol
2011; 98: 265–269.

Radiation induced Liver disease
• Patients who develop non-classic RILD have underlying CLD, such as LC and
viral hepatitis, and show more dysregulated hepatic functions with jaundice
and/or ↑ AT (>5x) rather than ALP. (1,2)
• The created hypoxic environment results in both the death of centrilobular
hepatocytes (HCs) and atrophy of the inner hepatic plate, hepatocellular
loss, hepatic dysfunction, hepatic sinusoidal endothelial death and HSC
activation leading to hepatic fibrosis_(3) have been detected.
• Hepatic irradiation can impairs the hepatocellular regeneration capacity
and can induce irreversible hepatic failure.(4)
1. Pan CC, Kavanagh BD, Dawson LA, Li XA, Das SK, Miften M et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 2010; 76: S94–100.
2. Cheng JC, Wu JK, Lee PC, Liu HS, Jian JJ, Lin YM et al. Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease. Int J Radiat Oncol Biol Phys 2004; 60:
1502–1509.
3. Sempoux C, Horsmans Y, Geubel A, Fraikin J, Van Beers BE, Gigot JF et al. Severe radiation-induced liver disease following localized radiation therapy for biliopancreatic carcinoma: activation of hepatic stellate cells
as an early event. Hepatology 1997; 26: 128–134.
4. Guha C, Sharma A, Gupta S, Alfieri A, Gorla GR, Gagandeep S et al. Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation. Cancer Res 1999; 59: 5871–5874.

Therapeutic window of Liver RT: how can it be improved ?
• Though with palliative intent, whole liver RT can be utilized, eg for pain control in
primary or mostly metastatic liver disease, but when being used for potentially
curative intent, the “therapeutic window” whole liver RT is essentially
nonexistent .
1. Factors to consider: Individualizing dosage for each pt based on tumor size,
and/or liver function, minimizing the Out-of-field disease progression, proper
Response assessment with the use of Functional imaging such as FDG-PET and
others.
2. Either there should be effective strategies to protect against or reverse RILD or
there should be modalities where high dose RT is delivered precisely in the
tumor bed only sparing the functional liver tissue.
Now with the advent of three-dimensional treatment, planning with dose-volume histogram analysis (DVH) and
stereotactically guided radiotherapy can now be employed to obtain the precise delivery of radiation.

Radiotherapy Modalities
1. Two-Dimensional Photon Therapy ("Conventional" Radiation Therapy)
2. 3D Conformal Radiation Therapy (3D-CRT): using CT imaging to plan RX . Allows
the tumor and normal organs to be defined in three dimensions, as opposed to
using the "flat" image of an x-ray. Beams are then arranged to best avoid normal
organs, while delivering an optimal dose of radiation to the tumor.
3. Intensity Modulated Radiation Therapy (IMRT): with the potential to lower the
high doses of radiation to the healthy structures. Similar to 3D CRT, the tumor
and normal organs are outlined on the CT with 3-dimensional information.
Multiple beams are positioned at various points to optimally deliver the
radiation. However, in IMRT, these beams are divided into a grid-like pattern,
separating the one big beam into numerous smaller "beamlets." Special software
is used to determine the best pattern of beamlets, in order to deliver the optimal
amount of radiation to the tumor while sparing normal organs as much as
possible.

Radiotherapy Modalities
4. Stereotactic Hypofractionated Body Radiation Therapy (SBRT/SHORT):
involves delivering a high dose of radiation very precisely to a tumor. SRT
delivers radiation from numerous different angles to focus the radiation at one
small point, like a magnifying glass. This is similar to IMRT but it involves fewer
treatments (called "fractions"). “Less (< 5) fractionations and a higher
fractional dose”
5. Proton Therapy: It is a type of radiation that utilizes a particle, the proton.
The advantage of protons is that the depth at which they release their energy
can be precisely controlled. Using computer software, the protons can be
directed to release their energy precisely within the tumor, without any of the
energy exiting out of the back of the tumor. For eg, if the back edge of the
tumor is located against the spinal cord, it may be possible to spare any
radiation dose to the spinal cord using protons.

European Association for the Study of the Liver and
European Organization for Research and Treatment
of Cancer (EASL-EORTC) 2018 Guideline
• External beam radiotherapy is under investigation. So far there is no robust
evidence to support this therapeutic approach in the management of HCC
(evidence low; recommendation weak).
EASL GUIDELINE 2018;Journal of Hepatology 2018 vol. 69 j 182–236)

Level of Evidence and Grade of Recommendations (adapted from
GRADE system)

American Association for the Study of Liver Diseases
(AASLD) 2018
• SHOULD ADULTS WITH CIRRHOSIS AND HCC (T2 OR T3, NO VASCULAR
INVOLVEMENT) WHO ARE NOT CANDIDATES FOR RESECTION OR
TRANSPLANTATION BE TREATED WITH TACE, TARE, OR EXTERNAL
RADIATION?

AASLD 2018: Recommendations
9A. The AASLD recommends LRT over no treatment .
Quality/Certainty of Evidence:
• TACE: Moderate
• Transarterial Bland Embolization: Very Low
• TARE: Very Low
• External Radiation: Very Low
Strength of Recommendation: Strong
9B. The AASLD does not recommend one form of LRT over another.
Quality/Certainty of Evidence: Very low
Strength of Recommendation: Conditional

Note: Implication of the strength of a recommendation
Strong
• Population: Most people in this situation would want the recommended course of
action and only a small proportion would not.
• Health care workers: Most people should receive the recommended course of action.
• Policy makers: The recommendation can be adapted as policy in most situations.
Conditional
• Population: The majority of people in this situation would want the recommended
course of action, but many would not.
• Health care workers: Be prepared to help patients make a decision that is consistent
with their values using decision aids and shared decision making.
• Policy makers: There is a need for substantial debate and involvement of
stakeholders

Practice Guidance by the AASLD :
Treatment recommendations according to BCLC Stage.
Marrero et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology, VOL.
68, NO. 2, 2018

National Comprehensive Cancer Network (NCCN)
Guidelines version 1.2018; HCC
bb:case series and single arm studies demonstrate safety and efficacy of radiation therapy in selected cases.
Note: this is a screenshot taken from the guideline.

Radiation Therapy
• EBRT is a Rx option for pts with unresectable disease, or for those who are medically
inoperable due to comorbidity.
• All tumors irrespective of the location may be amenable to radiation therapy (3D-CRT,
IMRT, or SBRT). IGRT is strongly recommended when using EBRT,IMRT and SBRT to
improve treatment accuracy and reduce treatment related toxicity.
• Hypofractionation with photons (SBRT) is an acceptable option though treatment at
centers with experience is recommended.
• Dosing for SBRT is generally in 30-50 Gy in 3-5 fractions, depending on underlying liver
function. >5 fractions may be used if clinically indicated.
• SBRT can be considered as an alternative to the
ablation/embolization techniques or when these therapies have
failed or are contraindicated.
Modified from NCCN clinical Practice guidelines in oncology. Hepatobiliary cancers. Version 1.2018

• SBRT (1-5 fractions) is often used for pts with 1 to 3 tumors.
• SBRT could be considered for larger lesions or more extensive disease, if there is
sufficient uninvolved liver and liver radiation tolerance can be respected.
• There should be no extrahepatic disease or it should be minimal .
• The majority of data on radiation for HCC tumors arises from pts with CP A, safety
data are limited for pts with CP B or poorer liver function.
• Those with CP B can be safely treated, but may require dose modifications.
• The safety of liver radiation for HCC in pts with CP C has not been established.
• Palliative EBRT is appropriate for symptom control and/or prevention of
complications from metastatic HCC lesions.
Modified from NCCN clinical Practice guidelines in oncology. Hepatobiliary cancers. Version 1.2018

The Asia-Pacific Primary Liver Cancer Expert
(APPLE) 5th Consensus Guidelines 2014
• In early and intermediate stage HCC: if standard treatment is not
compatible, RT, including EBRT and SIRT can be considered.
• In locally advanced stage HCC: combined EBRT with TACE or
hepatic arterial infusion chemotherapy, and SIRT can be
considered.
• In terminal stage HCC: EBRT can be considered for palliation of
symptoms and reduction of morbidity caused by the primary
tumor or its metastases.

Consensus on Stereotactic Body Radiation Therapy
for Small-Sized HCC at the 7th Asia-Pacific Primary
Liver Cancer Expert Meeting
• SBRT may be an effective therapeutic option for early-stage or small-sized
HCC, especially if surgical resection or percutaneous ablative therapies are
difficult, unfeasible, or rejected.
• SBRT can also be used as a salvage treatment for tumor recurrence after
local radical therapies or for residual cancer after surgical resection or
percutaneous ablative attempts.
• In addition, SBRT may act as a bridge to LT or serve as an adjuvant
treatment for intrahepatic tumors with incomplete iodized oil retention.
Zeng et al. Consensus on Stereotactic Body Radiation Therapy for Small-Sized Hepatocellular Carcinoma at the 7th Asia-Pacific Primary Liver Cancer Expert Meeting. Liver Cancer. 2017
Nov; 6(4): 264–274.
Note: Early-stage HCC is defined as a solitary tumor ≤5 cm in MD or as multiple nodules (≤3 total) ≤3 cm in MD, without
vascular invasion/extrahepatic metastasis and with CP A or B . Not all tumors of small size are qualified as early stage
because intrahepatic recurrences of HCC or CP C score may apply .

Tumor with vascular invasion.
The tumor invading the vena cava is enhanced in arterial phase and shows a defect in portal phase on dynamic computed
tomography (A and B). An axial view of radiation dose distribution. The isodose lines (white lines) from inner to outer
represent 40, 30, 20, and 10 Gy, respectively (C).
Sanuki N, et al. Role of stereotactic body radiation therapy for hepatocellular carcinoma. World J Gastroenterol. 2014 Mar 28; 20(12): 3100–3111.

Korean Liver Cancer Study Group (KLCSG) and
National Cancer Center, Korea (NCC)
• According to the guidelines, RT is an alternative option for mUICC stage I
patients who are not candidates for resection or RFA.
• For a stage II single tumor >2 cm without vascular invasion, RT is also an
alternative option.
• RT is recommended as one of the best options for a stage II single tumor ≤2
cm with vascular invasion, and a stage III single tumor >2 cm with vascular
invasion.
• For stage IV patients with lymph node or extrahepatic metastases, RT is
suggested as an alternative, while sorafenib is recommended as the best
option.

Modified Union for International Cancer Control Staging System

Case of HCC located in the hepatic hilum
Surgical resection would have required a right lobectomy. Percutaneous ablative therapy was impossible due to
involvement of the biliary system and large vessels near the tumor.
Axial and coronal views of a tumor with partial lipiodol deposit (A arrows).
Axial and coronal views of radiation dose distribution (C and D). The isodose lines (white lines) from inner to outer
represent 40, 30, 20, and 10 Gy, respectively.

• SBRT is feasible for lesions that are not eligible for surgery or percutaneous
ablation. For example, patients whose lesions are located in a central portal
area or regions adjacent to great vessels or the biliary system are good
candidate for SBRT.
• In addition, lesions located just below the diaphragm or at the surface of
the liver are also excellent targets for SBRT.

Future Directions for RT in HCC
• RT for Downstaging Prior to Liver Transplantation
• Combining RT With Immunotherapy for HCC
• Use of Radiosensitizers
• Biomarkers
• Expanding therapeutic window for RT
• Managing RILD

RT for Downstaging Prior to LT
• LT is an established RX for early-stage HCC that eliminates the liver tumor(s),
removes the major organ at risk for disease progression, and allows recovery
of liver function.
• The Milan criteria were established to select pts with limited disease burden
who are likely to have favorable oncologic outcomes following LT (1).
• For pts who are initially outside of transplant criteria, liver-directed
treatments such as TACE, RFA, and/or radioembolization have
“downstaged” pts to be within criteria in 24% to 69% of cases (2).
1. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–699.
2. Gordon-Weeks AN, Snaith A, Petrinic T, et al. Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria.
Br J Surg. 2011;98(9):1201–1208.

• Reports on the use of RT as a means to downstage HCC pts prior to LT are
limited.
• In One case report, conventionally fractionated RT (54 Gy in 27 fractions) was
used to treat a 7.6cm lesion that had progressed after TACE (1). The pt had a
complete radiographic response and underwent LT, and explant pathology
revealed a complete pathologic response.
• Given that excellent local control rates that have been observed when SBRT
has been used for inoperable HCC pts, it can be believed that SBRT should be
compared with other liver-directed treatments as a means for downstaging
pts who are outside of transplant criteria.
1. Wigg A, Hon K, Mosel L, et al. Down-staging of hepatocellular carcinoma via external-beam radiotherapy with subsequent liver transplantation: a case report. Liver Transpl.
2013;19(10):1119–1124.

Combining RT With Immunotherapy for HCC
• There is a growing body of evidence indicating that RT may enhance the
antitumor effects of immunotherapeutic agents.
• A number of preclinical studies have demonstrated synergy between RT and
agents targeting immune checkpoint proteins, such as CTLA-4 (1,2) and PD-1
(3,4). Clinical trials are now testing combinations of RT and various forms of
immunotherapy (5,6).
• This strategy is particularly appealing, as conforming RT to a small target
volume may enhance the efficacy of immunotherapy, leading to eradication
of untreated macroscopic lesions and/or occult microscopic disease.
pd1 inhibitors: Nivolumab, Pembrolizumab, Durvalumab
ctla4 inhibitors: Ipilimumab, Tremelimumab
James Allison & Tasuku Honjo
Note: References are at the end of slides. Pic taken from wikipedia
PD-1: programmed cell death-1
CTLA-4: cytotoxic T lymphocyte-associated protein 4

Use of Radiosensitizers
• While classical radiosensitizers have been studied in HCC as well, clinical
results thus far have been less encouraging.
• In a prospective trial performed by the RTOG in the 1980s, nearly 200 HCC
pts were treated with whole liver RT using either conventional fractionation
(21.0 Gy in 3.0 Gy daily fractions) or a hyperfractionated schedule (24.0 Gy in
1.2 Gy fractions given twice daily) with concurrent doxorubicin and 5-FU (1).
• Increased toxicity rates were seen in pts treated with hyperfractionated RT,
yet response rates were only approximately 20% in both groups. Median
survival was approximately five months in each arm.
1. Stillwagon GB, Order SE, Guse C, et al. 194 hepatocellular cancers treated by radiation and chemotherapy combinations: toxicity and response: a Radiation Therapy Oncology
Group Study. Int J Radiat Oncol Biol Phys. 1989; 17(6):1223–1229.

Expanding therapeutic window for RT
• Another concept is that the role of RT in HCC may expand if effective treatments
for liver disease become available.
• Hepatocyte transplantation (HT) has already been proposed as an alternative to LT
for the RX of metabolic and end-stage liver diseases (1).
• Mouse models have demonstrated the potential of using HT to ameliorate RILD (2).
• Preclinical studies have also shown that multipotent bone marrow–derived cells
have therapeutic potential in LC (3).
• Further development of strategies to improve the hepatic function of HCC pts prior
to therapy would minimize the risk of treatment-related toxicity, and/or reverse
treatment sequelae would expand the therapeutic window for RT in HCC.
1. Strom SC, Chowdhury JR, Fox IJ. Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis. 1999;19(1):39–48.
2. Guha C, Sharma A, Gupta S, et al. Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation. Cancer Res. 1999;59(23):5871–5874.
3. Kallis YN, Alison MR, Forbes SJ. Bone marrow stem cells and liver disease. Gut. 2007;56(5):716–724.

Biomarkers
• The presence of HCC and therapeutic interventions can lead to critical
modifications in the tumor microenvironment and the surrounding normal tissue
compartment. Measuring these changes could provide valuable predictive
information regarding treatment efficacy and toxicity.
• Alpha-fetoprotein is well-established as a blood-based tumor marker in HCC (1).
AFP-L3 (2), Des-gamma-carboxyprotrombin (DCP), Hepatocyte growth factor
(HGF) (3), Alpha-L-fucosidase (AFU) (4) and so on.
• Biomarkers of liver injury might aid with therapeutic decisions and/or prompt
initiation of measures to mitigate treatment-related toxicities (5).
• While several biomarkers for liver injury have been studied (6), radiation-specific
toxicity biomarkers in HCC have not been identified. This area warrants additional
attention.
1. Marrero JA. Screening tests for hepatocellular carcinoma. Clin Liver Dis. 2005; 9(2):235–251, vi.
2. Yamagata Y, Shimizu K, Nakamura K, et al. Simultaneous determination of percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein and alpha-fetoprotein concentration using the LiBASys clinical auto-analyzer. Clin Chim Acta. 2003;327(1-2):59–67.
3. Yamazaki H, Oi H, Matsumoto K, et al. Biphasic changes in serum hepatocyte growth factor after transarterial chemoembolization therapy for hepato-cellular carcinoma. Cytokine. 1996;8(2):178–182.
4. Ishizuka H, Nakayama T, Matsuoka S, et al. Prediction of the development of hepato-cellular-carcinoma in patients with liver cirrhosis by the serial determinations of serum alpha-L-fucosidase activity. Intern Med. 1999;38(12):927–931.
5. Seidensticker M, Seidensticker R, Damm R, et al. Prospective randomized trial of enoxaparin, pentoxifylline and ursodeoxycholic acid for prevention of radiation-induced liver toxicity. PLoS One. 2014;9(11):e112731.
6. Flores A, Marrero JA. Emerging trends in hepatocellular carcinoma: focus on diagnosis and therapeutics. Clin Med Insights Oncol. 2014;8:71–76.

Managing RILD
• Radioprotectors, which are used in combination therapy with RT, have been
recently reported to protect nontumorous liver tissue from RID.
• Amifostine, a radioprotective drug, is clinically used to treat H&N cancer in
combination therapy with RT.(1) Amifostine has also been shown to protect
HCs from radiation-induced damage without compromising the killing effect
of RT in tumor cells in the livers of rats.(2)
• In a phase I clinical study, amifostine demonstrated radioprotective effects
in the nontumorous liver tissues of RT pts with primary or metastatic
intrahepatic cancer.(3)
• In addition, melatonin, has been shown to exert a radioprotective effect in
the radiation-treated liver by decreasing oxidative stress in rats.(4)
1. Brizel DM, Wasserman TH, Henke M, Strnad V, Rudat V, Monnier A et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000; 18: 3339–3345.
2. Symon Z, Levi M, Ensminger WD, Smith DE, Lawrence TS. Selective radioprotection of hepatocytes by systemic and portal vein infusions of amifostine in a rat liver tumor model. Int J Radiat Oncol Biol Phys 2001; 50:
473–478.
3. Feng M, Smith DE, Normolle DP, Knol JA, Pan CC, Ben-Josef E et al. A phase I clinical and pharmacology study using amifostine as a radioprotector in dose-escalated whole liver radiation therapy. Int J Radiat Oncol Biol
Phys 2012; 83: 1441–1447.
4. Taysi S, Koc M, Buyukokuroglu ME, Altinkaynak K, Sahin YN. Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced oxidative injury in the rat liver. J Pineal Res 2003; 34: 173–177.

References: Combining RT With Immunotherapy for HCC
1. Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after
treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin
Cancer Res. 2005;11(2 Pt 1):728–734.
2. Yoshimoto Y, Suzuki Y, Mimura K, et al. Radiotherapy-induced anti-tumor immunity contributes to
the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse
model. PLoS ONE. 2014;9(3):e92572.
3. Verbrugge I, Hagekyriakou J, Sharp LL, et al. Radiotherapy increases the permissiveness of
established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res.
2012;72(13):3163–3174.
4. Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term
survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343–349.
5. Seung SK, Curti BD, Crittenden M, et al. Phase 1 study of stereotactic body radiotherapy and
interleukin-2–tumor and immunological responses. Sci Transl Med. 2012;4(137):137ra74.
6. Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces systemic
lymphoma regression: a phase I/II study. J Clin Oncol. 2010;28(28):4324–4332.

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