Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 May 28;27(20):2434-2457.
doi: 10.3748/wjg.v27.i20.2434.

Role of modern radiotherapy in managing patients with hepatocellular carcinoma

Liang-Cheng Chen  1 , Hon-Yi Lin  1 , Shih-Kai Hung  1 , Wen-Yen Chiou  1 , Moon-Sing Lee  1
Affiliations
Review

Role of modern radiotherapy in managing patients with hepatocellular carcinoma

Liang-Cheng Chen et al. World J Gastroenterol. .

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Several treatment options are available for managing HCC patients, classified roughly as local, local-regional, and systemic therapies. The high post-monotherapy recurrence rate of HCC urges the need for the use of combined modalities to increase tumor control and patient survival. Different international guidelines offer treatment recommendations based on different points of view and classification systems. Radiotherapy (RT) is a well-known local-regional treatment modality for managing many types of cancers, including HCC. However, only some of these treatment guidelines include RT, and the role of combined modalities is rarely mentioned. Hence, the present study reviewed clinical evidence for the use of different combined modalities in managing HCC, focusing on modern RT's role. Modern RT has an increased utility in managing HCC patients, mainly due to two driving forces. First, technological advancement (e.g., stereotactic body radiotherapy and advanced proton-beam therapy) enables precise delivery of radiation to increase tumor control and reduce side effects in the surrounding normal tissue. Second, the boom in developing target therapies and checkpoint-blockade immunotherapy prolongs overall survival in HCC patients, re-emphasizing the importance of local tumor control. Remarkably, RT combines with systemic therapies to generate the systemic therapy augmented by radiotherapy effect, a benefit now being actively investigated.

Keywords: Combined treatment; Guideline; Hepatocellular carcinoma; Immunotherapy; Radiotherapy; Stereotactic body radiotherapies.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest statement: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Treatment recommendations modified in different guidelines according to the Barcelona clinic liver cancer stage. HCC: Hepatocellular carcinoma; BCLC: Barcelona clinic liver cancer; PS: Performance status; TA(C)E: Trans-arterial (chemo)embolization; TARE: Trans-arterial radioembolization; DEB-TACE: Trans-arterial chemoembolisation with drug-eluting beads; RT: Radiotherapy; SBRT: Stereotactic body radiation therapy; HAIC: Hepatic arterial infusion chemotherapy; NCCN: National Comprehensive Cancer Network; AASLD: American Association for the Study of Liver Diseases; EASL: European Association for the Study of the Liver; JSH: Japan Society of Hepatology; KLCA: Korean Liver Cancer Association; TLCA: Taiwan Liver Cancer Association; Tx: Treatments; VI+: Positive vascular or bile duct invasion.
Figure 2
Figure 2
Overview of therapeutic options and the consideration behind the combination of different combined modalities for liver cancer. RT: Radiotherapy; TA(C)E: Trans-arterial (chemo)embolization; TARE: Trans-arterial radioembolization; DEB-TACE: Trans-arterial chemoembolisation with drug-eluting beads; HAIC: Hepatic arterial infusion chemotherapy.
Figure 3
Figure 3
Current treatment recommendations based on the Barcelona clinic liver cancer stage and the potential roles of radiotherapy. HCC: Hepatocellular carcinoma; BCLC: Barcelona clinic liver cancer; PS: Performance status; TACE: trans-arterial chemoembolization; TARE: Trans-arterial radioembolization; HAIC: Hepatic arterial infusion chemotherapy; RT: Radiotherapy; CFRT: Conventionally fractionated radiotherapy; HFRT: Hypo-fractionated radiotherapy; SBRT: Stereotactic body radiation therapy; PVT: Portal vein thrombosis; STAR effect: Systemic therapy augmented by radiotherapy effect.
Figure 4
Figure 4
Proton therapy vs stereotactic body radiation therapy vs conventional radiotherapy for liver tumors. Dose distributions for a proton (left), stereotactic body radiation therapy (middle) and conventional radiotherapy (right) hepatocellular carcinoma radiotherapy plan are illustrated for comparison. RT: Radiotherapy; SBRT: Stereotactic body radiation therapy.
Figure 5
Figure 5
Potential mechanism of stereotactic body radiation therapy combined with systemic therapy to induce the systemic therapy augmented by radiotherapy effect (also known as immunotherapy and stereotactic ablative radiotherapy) for liver tumors. Stereotactic body radiation therapy (SBRT) induces antigen release and immunogenic cell death, activation of several transcription factors and signal pathways, as well as dendritic cell antigen presentation and maturation, resulting in proliferation of tumor-specific T cells and immune-mediated cytotoxicity. SBRT combined with Immune-checkpoint inhibitors augmented the tumoricidal effect by upregulates major histocompatibility complex and FAS on tumor cells, increasing susceptibility to T-cell-mediated cell death. MHC: Major histocompatibility complex; TCR: T cell receptor; FAS-L: FAS ligand.
Figure 6
Figure 6
Cartoon and case illustrations of simultaneously integrated boost, modified simultaneously integrated boost, combined simultaneously integrated boost and simultaneously integrated protection, and simultaneously integrated inner-escalated boost dose-prescription techniques. A: A simple cartoon figure representing original simultaneously integrated boost (SIB) dose prescription. Original SIB is prescribed in different doses per fraction to different target regions according to the risk levels of recurrence. For example, uniform doses per fraction may be given at planning target volume (PTV) high, intermediate, and low with 240 centigray (cGy) (simultaneously integrated boost), 180-200 cGy (traditional dose per fraction), and 160 cGy (inferior to the traditional dose) in the same fractions, respectively; B: A simple cartoon figure representing a modified SIB dose prescription. Traditionally, radiotherapy is prescribed as a uniform dose per fraction (e.g., 200 cGy) on PTV, which provides a homogeneous dose to cover clinical target volume (CTV) and gross target volume (GTV). Recently, to maximally enhance the possibility of tumor control, a modified SIB technique is applied using a planned non-homologous dose distribution, i.e., escalating a simultaneous intra-tumor boost (e.g., 220-240 cGy per fraction) in addition to a traditional covering dose to the PTV (e.g., 200 cGy per fraction) in the same treatment fractions; C: A simple cartoon figure representing combined modified SIB and simultaneously integrated protection (SIP) dose prescription. To reduce treatment toxicities to adjacent critical organs/tissue, SIP was developed in conjunction with modified SIB. SIP prescribes an inferior-to-traditional dose per fraction, e.g., 150 cGy, to the overlapping region between the PTV and the extended critical organ volume (as shown by the long arrow); D: A simple cartoon figure representing simultaneously integrated inner-escalated boost (SIEB) dose prescription. For further enhanced therapeutic gain (i.e., increased tumor control and decreased treatment toxicity) in managing patients with unresectable liver tumors, we applied a secondary modified SIB (also termed SIEB). SIEB further escalates the intra-tumor boost (e.g., 240-260 cGy per fraction) based on a planned generally attenuated peri-tumor dose (e.g., 120-150 cGy per fraction delivered to the PTV), administered simultaneously. The intra-tumor SIEB boost volume is delineated as a uniform-inner-shrinkage area from the GTV with a margin of 1-10 mm (i.e., a geometrically central zone), depending on the tumor size, the intensity of the dose escalation, the level of liver preservation, the closeness of the gastrointestinal organs to the irradiation targets, and the patient's condition. Note that an additional most-inner SIEB boost volume with the highest dose per fraction (e.g., 260-300 cGy or higher) might be considered for highly selected patients with very bulky tumors. E: A clinical case with SIEB dose prescription. The blue, purple, and red lines show the PTV, CTV, and GTV of the irradiating target, respectively. In this case, based on the physician’s choice and the patient’s condition, a dose per fraction of 120 cGy was prescribed to the PTV, 150 cGy to the CTV, and 200 cGy to the GTV. Finally, in the yellow-outlined region, 280 cGy per fraction was simultaneously delivered to the SIEB boost volume. A total of 30 fractions were given, generating total doses levels of 3600 cGy, 4500 cGy, 6000 cGy, and 7400 cGy to the PTC, CTV, GTV, and SIEB boost volume, respectively. Note that the most peripheral dose per fraction of 120 cGy was chosen mainly due to a very close distance between the PTV and an adjacent critical organ, i.e., the duodenum. This short-distance closeness could easily lead irradiation to harm the duodenum under the context of daily organ motion. SIB: Simultaneously integrated boost; SIP: Simultaneously integrated protection; SIEB: Simultaneously integrated inner-escalated boost; PTV: Planning target volume; CTV: Clinical target volume; GTV: Gross target volume.
See this image and copyright information in PMC

References

    1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, Abdel-Rahman O, Abdelalim A, Abdoli A, Abdollahpour I, Abdulle ASM, Abebe ND, Abraha HN, Abu-Raddad LJ, Abualhasan A, Adedeji IA, Advani SM, Afarideh M, Afshari M, Aghaali M, Agius D, Agrawal S, Ahmadi A, Ahmadian E, Ahmadpour E, Ahmed MB, Akbari ME, Akinyemiju T, Al-Aly Z, AlAbdulKader AM, Alahdab F, Alam T, Alamene GM, Alemnew BTT, Alene KA, Alinia C, Alipour V, Aljunid SM, Bakeshei FA, Almadi MAH, Almasi-Hashiani A, Alsharif U, Alsowaidi S, Alvis-Guzman N, Amini E, Amini S, Amoako YA, Anbari Z, Anber NH, Andrei CL, Anjomshoa M, Ansari F, Ansariadi A, Appiah SCY, Arab-Zozani M, Arabloo J, Arefi Z, Aremu O, Areri HA, Artaman A, Asayesh H, Asfaw ET, Ashagre AF, Assadi R, Ataeinia B, Atalay HT, Ataro Z, Atique S, Ausloos M, Avila-Burgos L, Avokpaho EFGA, Awasthi A, Awoke N, Ayala Quintanilla BP, Ayanore MA, Ayele HT, Babaee E, Bacha U, Badawi A, Bagherzadeh M, Bagli E, Balakrishnan S, Balouchi A, Bärnighausen TW, Battista RJ, Behzadifar M, Bekele BB, Belay YB, Belayneh YM, Berfield KKS, Berhane A, Bernabe E, Beuran M, Bhakta N, Bhattacharyya K, Biadgo B, Bijani A, Bin Sayeed MS, Birungi C, Bisignano C, Bitew H, Bjørge T, Bleyer A, Bogale KA, Bojia HA, Borzì AM, Bosetti C, Bou-Orm IR, Brenner H, Brewer JD, Briko AN, Briko NI, Bustamante-Teixeira MT, Butt ZA, Carreras G, Carrero JJ, Carvalho F, Castro C, Castro F, Catalá-López F, Cerin E, Chaiah Y, Chanie WF, Chattu VK, Chaturvedi P, Chauhan NS, Chehrazi M, Chiang PP, Chichiabellu TY, Chido-Amajuoyi OG, Chimed-Ochir O, Choi JJ, Christopher DJ, Chu DT, Constantin MM, Costa VM, Crocetti E, Crowe CS, Curado MP, Dahlawi SMA, Damiani G, Darwish AH, Daryani A, das Neves J, Demeke FM, Demis AB, Demissie BW, Demoz GT, Denova-Gutiérrez E, Derakhshani A, Deribe KS, Desai R, Desalegn BB, Desta M, Dey S, Dharmaratne SD, Dhimal M, Diaz D, Dinberu MTT, Djalalinia S, Doku DT, Drake TM, Dubey M, Dubljanin E, Duken EE, Ebrahimi H, Effiong A, Eftekhari A, El Sayed I, Zaki MES, El-Jaafary SI, El-Khatib Z, Elemineh DA, Elkout H, Ellenbogen RG, Elsharkawy A, Emamian MH, Endalew DA, Endries AY, Eshrati B, Fadhil I, Fallah Omrani V, Faramarzi M, Farhangi MA, Farioli A, Farzadfar F, Fentahun N, Fernandes E, Feyissa GT, Filip I, Fischer F, Fisher JL, Force LM, Foroutan M, Freitas M, Fukumoto T, Futran ND, Gallus S, Gankpe FG, Gayesa RT, Gebrehiwot TT, Gebremeskel GG, Gedefaw GA, Gelaw BK, Geta B, Getachew S, Gezae KE, Ghafourifard M, Ghajar A, Ghashghaee A, Gholamian A, Gill PS, Ginindza TTG, Girmay A, Gizaw M, Gomez RS, Gopalani SV, Gorini G, Goulart BNG, Grada A, Ribeiro Guerra M, Guimaraes ALS, Gupta PC, Gupta R, Hadkhale K, Haj-Mirzaian A, Hamadeh RR, Hamidi S, Hanfore LK, Haro JM, Hasankhani M, Hasanzadeh A, Hassen HY, Hay RJ, Hay SI, Henok A, Henry NJ, Herteliu C, Hidru HD, Hoang CL, Hole MK, Hoogar P, Horita N, Hosgood HD, Hosseini M, Hosseinzadeh M, Hostiuc M, Hostiuc S, Househ M, Hussen MM, Ileanu B, Ilic MD, Innos K, Irvani SSN, Iseh KR, Islam SMS, Islami F, Jafari Balalami N, Jafarinia M, Jahangiry L, Jahani MA, Jahanmehr N, Jakovljevic M, James SL, Javanbakht M, Jayaraman S, Jee SH, Jenabi E, Jha RP, Jonas JB, Jonnagaddala J, Joo T, Jungari SB, Jürisson M, Kabir A, Kamangar F, Karch A, Karimi N, Karimian A, Kasaeian A, Kasahun GG, Kassa B, Kassa TD, Kassaw MW, Kaul A, Keiyoro PN, Kelbore AG, Kerbo AA, Khader YS, Khalilarjmandi M, Khan EA, Khan G, Khang YH, Khatab K, Khater A, Khayamzadeh M, Khazaee-Pool M, Khazaei S, Khoja AT, Khosravi MH, Khubchandani J, Kianipour N, Kim D, Kim YJ, Kisa A, Kisa S, Kissimova-Skarbek K, Komaki H, Koyanagi A, Krohn KJ, Bicer BK, Kugbey N, Kumar V, Kuupiel D, La Vecchia C, Lad DP, Lake EA, Lakew AM, Lal DK, Lami FH, Lan Q, Lasrado S, Lauriola P, Lazarus JV, Leigh J, Leshargie CT, Liao Y, Limenih MA, Listl S, Lopez AD, Lopukhov PD, Lunevicius R, Madadin M, Magdeldin S, El Razek HMA, Majeed A, Maleki A, Malekzadeh R, Manafi A, Manafi N, Manamo WA, Mansourian M, Mansournia MA, Mantovani LG, Maroufizadeh S, Martini SMS, Mashamba-Thompson TP, Massenburg BB, Maswabi MT, Mathur MR, McAlinden C, McKee M, Meheretu HAA, Mehrotra R, Mehta V, Meier T, Melaku YA, Meles GG, Meles HG, Melese A, Melku M, Memiah PTN, Mendoza W, Menezes RG, Merat S, Meretoja TJ, Mestrovic T, Miazgowski B, Miazgowski T, Mihretie KMM, Miller TR, Mills EJ, Mir SM, Mirzaei H, Mirzaei HR, Mishra R, Moazen B, Mohammad DK, Mohammad KA, Mohammad Y, Darwesh AM, Mohammadbeigi A, Mohammadi H, Mohammadi M, Mohammadian M, Mohammadian-Hafshejani A, Mohammadoo-Khorasani M, Mohammadpourhodki R, Mohammed AS, Mohammed JA, Mohammed S, Mohebi F, Mokdad AH, Monasta L, Moodley Y, Moosazadeh M, Moossavi M, Moradi G, Moradi-Joo M, Moradi-Lakeh M, Moradpour F, Morawska L, Morgado-da-Costa J, Morisaki N, Morrison SD, Mosapour A, Mousavi SM, Muche AA, Muhammed OSS, Musa J, Nabhan AF, Naderi M, Nagarajan AJ, Nagel G, Nahvijou A, Naik G, Najafi F, Naldi L, Nam HS, Nasiri N, Nazari J, Negoi I, Neupane S, Newcomb PA, Nggada HA, Ngunjiri JW, Nguyen CT, Nikniaz L, Ningrum DNA, Nirayo YL, Nixon MR, Nnaji CA, Nojomi M, Nosratnejad S, Shiadeh MN, Obsa MS, Ofori-Asenso R, Ogbo FA, Oh IH, Olagunju AT, Olagunju TO, Oluwasanu MM, Omonisi AE, Onwujekwe OE, Oommen AM, Oren E, Ortega-Altamirano DDV, Ota E, Otstavnov SS, Owolabi MO, P A M, Padubidri JR, Pakhale S, Pakpour AH, Pana A, Park EK, Parsian H, Pashaei T, Patel S, Patil ST, Pennini A, Pereira DM, Piccinelli C, Pillay JD, Pirestani M, Pishgar F, Postma MJ, Pourjafar H, Pourmalek F, Pourshams A, Prakash S, Prasad N, Qorbani M, Rabiee M, Rabiee N, Radfar A, Rafiei A, Rahim F, Rahimi M, Rahman MA, Rajati F, Rana SM, Raoofi S, Rath GK, Rawaf DL, Rawaf S, Reiner RC, Renzaho AMN, Rezaei N, Rezapour A, Ribeiro AI, Ribeiro D, Ronfani L, Roro EM, Roshandel G, Rostami A, Saad RS, Sabbagh P, Sabour S, Saddik B, Safiri S, Sahebkar A, Salahshoor MR, Salehi F, Salem H, Salem MR, Salimzadeh H, Salomon JA, Samy AM, Sanabria J, Santric Milicevic MM, Sartorius B, Sarveazad A, Sathian B, Satpathy M, Savic M, Sawhney M, Sayyah M, Schneider IJC, Schöttker B, Sekerija M, Sepanlou SG, Sepehrimanesh M, Seyedmousavi S, Shaahmadi F, Shabaninejad H, Shahbaz M, Shaikh MA, Shamshirian A, Shamsizadeh M, Sharafi H, Sharafi Z, Sharif M, Sharifi A, Sharifi H, Sharma R, Sheikh A, Shirkoohi R, Shukla SR, Si S, Siabani S, Silva DAS, Silveira DGA, Singh A, Singh JA, Sisay S, Sitas F, Sobngwi E, Soofi M, Soriano JB, Stathopoulou V, Sufiyan MB, Tabarés-Seisdedos R, Tabuchi T, Takahashi K, Tamtaji OR, Tarawneh MR, Tassew SG, Taymoori P, Tehrani-Banihashemi A, Temsah MH, Temsah O, Tesfay BE, Tesfay FH, Teshale MY, Tessema GA, Thapa S, Tlaye KG, Topor-Madry R, Tovani-Palone MR, Traini E, Tran BX, Tran KB, Tsadik AG, Ullah I, Uthman OA, Vacante M, Vaezi M, Varona Pérez P, Veisani Y, Vidale S, Violante FS, Vlassov V, Vollset SE, Vos T, Vosoughi K, Vu GT, Vujcic IS, Wabinga H, Wachamo TM, Wagnew FS, Waheed Y, Weldegebreal F, Weldesamuel GT, Wijeratne T, Wondafrash DZ, Wonde TE, Wondmieneh AB, Workie HM, Yadav R, Yadegar A, Yadollahpour A, Yaseri M, Yazdi-Feyzabadi V, Yeshaneh A, Yimam MA, Yimer EM, Yisma E, Yonemoto N, Younis MZ, Yousefi B, Yousefifard M, Yu C, Zabeh E, Zadnik V, Moghadam TZ, Zaidi Z, Zamani M, Zandian H, Zangeneh A, Zaki L, Zendehdel K, Zenebe ZM, Zewale TA, Ziapour A, Zodpey S, Murray CJL. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol . 2019;5:1749–1768. - PMC - PubMed
    1. Chiang CJ, Yang YW, Chen JD, You SL, Yang HI, Lee MH, Lai MS, Chen CJ. Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan. Hepatology . 2015;61:1154–1162. - PubMed
    1. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, Jafri W, Payawal DA, Ohki T, Ogasawara S, Chen PJ, Lesmana CRA, Lesmana LA, Gani RA, Obi S, Dokmeci AK, Sarin SK. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int . 2017;11:317–370. - PMC - PubMed
    1. Yuen MF, Hou JL, Chutaputti A Asia Pacific Working Party on Prevention of Hepatocellular Carcinoma. Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol . 2009;24:346–353. - PubMed
    1. Yun BY, Lee HW, Min IK, Kim SU, Park JY, Kim DY, Ahn SH, Kim BK. Prognosis of Early-Stage Hepatocellular Carcinoma: Comparison between Trans-Arterial Chemoembolization and Radiofrequency Ablation. Cancers (Basel) . 2020;12 - PMC - PubMed