Radiotherapy of Liver Cancer Jinsil Seong Editor 123 Radiotherapy of Liver Cancer Jinsil Seong Editor Radiotherapy of Liver Cancer Editor Jinsil Seong Department of Radiation Oncology Yonsei Cancer Center Yonsei University College of Medicine Seoul Korea ISBN 978-981-16-1814-7 ISBN 978-981-16-1815-4 (eBook) https://doi.org/10.1007/978-981-16-1815-4 © Springer Nature Singapore Pte Ltd. 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Preface Liver cancer is the world’s leading cancer not only in incidence but also in lethality. Considering its age prevalence in 4th to 6th decades, which are the main axis of socioeconomic activity, liver cancer needs special attention to overcome. During the past decades, efforts have been focused on how to improve therapeutic outcome in parallel with how to detect early cancer. Actually there has been remarkable development particularly in the therapeu- tic aspect. Radiotherapy is one of the major cancer therapy modalities. However, it has long been underestimated in the management of liver cancer. It could be attributable to the old concept that required the whole liver as a volume to be irradiated while radiation dose tolerance of the whole liver is far less than that for tumor control. Now, we have gone through two big changes: first, a con- ceptual change of a focal but not whole liver as a radiation volume and, sec- ond, more importantly, emergence of modern radiotherapy technology to deliver therapeutic dose precisely to the tumor while avoiding radiosensitive adjacent organ. Consequently, we have witnessed a rapid increase in clinical application of radiotherapy for liver cancer, followed by numerous reports of excellent outcomes. Despite clinical demand, the guidance available to clinicians has remained limited on radiotherapy of liver cancer. This book was intended to address this deficit on the basis of the best available evidence by providing up-to-date information on all aspects of radiotherapy for liver cancer, from the basic sci- ence to clinical practice. The first two sections explain the relevant basic sci- ence and present detailed information on the available technologies and techniques, including the most recent advances. The radiotherapy strategies appropriate in different patient groups are then fully described, covering the use of ablative, adjuvant, neoadjuvant, definitive radiotherapy, radiotherapy as a bridge to liver transplantation, and palliative radiotherapy. The final sec- tion addresses a range of specific issues of concern to the clinician. As an editor, I am very honored to invite world-class experts in liver can- cer as contributors to this book. Thank you so much for your time and dedica- tion! I am quite sure that Radiotherapy of Liver Cancer will be an ideal reference for clinical radiation oncologists, radiation oncology residents, oncologists, and hepatologists. Seoul, Korea Jinsil Seong v Contents Part I Basic Science in Radiotherapy of Liver Cancer 1 Principle of Cancer Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . 3 Victor Ho-Fun Lee and Anne Wing-Mui Lee 2 Radiobiology of the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Rafi Kabarriti and Chandan Guha 3 Imaging Anatomy for the Radiation Oncologist . . . . . . . . . . . . . 31 Yeun-Yoon Kim and Jin-Young Choi 4 Functional Assessment of Liver for Radiation Oncologist . . . . . 51 Jun Yong Park 5 Antiviral Therapy in Liver Cancer . . . . . . . . . . . . . . . . . . . . . . . . 59 Bo Hyun Kim and Joong-Won Park Part II Technologies and Techniques in Radiotherapy of Liver Cancer 6 Technological Advances in Radiotherapy . . . . . . . . . . . . . . . . . . . 73 Belal Abousaida, Cheng-en Hsieh, Bhanu P. Venkatesulu, and Sunil Krishnan 7 Basics of Ablative Radiotherapy: The Background Knowledge Necessary to Practicing Stereotactic Body Radiotherapy for Hepatocellular Carcinoma . . . . . . . . . . . . . . . . 93 Alejandra Méndez Romero, Steven Habraken, and Dave Sprengers 8 Image-Guided Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Pablo Munoz-Schuffenegger, Teo Stanescu, and Laura A. Dawson 9 Particle Beam Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Masashi Mizumoto, Yoshito Oshiro, and Hideyuki Sakurai 10 Internal Radiotherapy Using Radionuclides . . . . . . . . . . . . . . . . 139 Aaron Kian-Ti Tong, David Chee-Eng Ng, and Pierce Kah-Hoe Chow vii viii Contents Part III R adiotherapeutic Strategies in Liver Cancer 11 Therapeutic Guidelines for Patients with Liver Cancer from the Perspective of Radiation Oncologists . . . . . . . . . . . . . . . . . . . 155 Chai Hong Rim and Jinsil Seong 12 Ablative Radiation Therapy for Early Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Naoko Sanuki, Atsuya Takeda, and Yuichiro Tsurugai 13 Transarterial Chemoembolization Plus External Beam Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Woong Sub Koom and Hwa Kyung Byun 14 Definitive Radiotherapy for Locally Advanced Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Sang Min Yoon 15 Neoadjuvant Radiotherapy Converting to Curative Resection . 209 Gi Hong Choi 16 Bridging Therapy for Liver Transplantation . . . . . . . . . . . . . . . . 215 Pablo Munoz-Schuffenegger, Tommy Ivanics, Marco P. A. W. Claasen, Laura A. Dawson, and Gonzalo Sapisochin 17 Palliative Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Zhao-Chong Zeng and Qian-Qian Zhao Part IV S pecific Issues 18 Multidisciplinary Team Approaches for the Management of Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 Kwang-Hyub Han 19 Response Evaluation After Radiotherapy . . . . . . . . . . . . . . . . . . 285 Cheng-Hsiang Lo, Jen-Fu Yang, Po-Chien Shen, and Wen-Yen Huang 20 Liver Hypertrophy Following Radiotherapy . . . . . . . . . . . . . . . . 295 Chai Hong Rim and Jinsil Seong 21 Hepatic Dysfunction Following Radiotherapy and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Do Young Kim 22 Lymphopenia Following Radiotherapy for Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 Hwa Kyung Byun and Jinsil Seong 23 Perspectives of Radiotherapy in Immuno- oncology Era . . . . . . . 325 Yvonne Chiung-Fang Hsu and Jason Chia-Hsien Cheng Part I Basic Science in Radiotherapy of Liver Cancer 1 Principle of Cancer Radiotherapy Victor Ho-Fun Lee and Anne Wing-Mui Lee Abstract tumors. Further radiation dose escalation in the form of hypofractionated stereotactic body Radiotherapy is one of the most common radiation therapy (SBRT) is also now feasible, types of nonsurgical anticancer treatment which delivers a high dose of radiation to the modality, employed in more than 50% of tumors while sparing the adjacent normal cases. Almost half of cancer patients are cured organs from unnecessary irradiation, leading of their cancer by radiotherapy as part of their to a much better tumor response and favorable anticancer treatment. Radiotherapy kills can- safety profile. Furthermore, endovascular cer by the use of ionizing radiation which radioembolization with radioisotope also pro- causes permanent and irreversible double- duced encouraging results in the treatment of strand DNA breaks in cancer cells leading to unresectable HCC. In this chapter, we will cell death. Unfortunately, it can also kill nor- describe how radiotherapy works in cancer mal cells leading to acute and chronic cells and elucidate different types of radiation treatment- related complications. Traditionally, therapy for HCC. radiotherapy was seldom employed in the treatment of hepatocellular carcinoma (HCC) Keywords because of the risk of severe and sometimes irreversible radiation-induced liver injury Radiotherapy · External beam radiotherapy · (RILD), since a large volume of normal liver Charged particle therapy · Radioembolization · which took into account the physiological Radiation-induced liver injury movement of the liver and the tumors inside during breathing might be irradiated. However, with the advent of new radiation technologies 1.1 Introduction and motion management devices, radiation therapy can now be safely delivered to liver Radiotherapy is an effective and commonly used treatment modality in the treatment of many can- cer types. The treatment objective can be either V. H.-F. Lee · A. W.-M. Lee (*) radical (aiming at cure) or palliative (aiming at Department of Clinical Oncology, LKS Faculty of symptom relief). Forty percent of patients cured Medicine, The University of Hong Kong, of their cancer have received radiotherapy as a Hong Kong, Hong Kong part of their therapy, either on its own or in com- Clinical Oncology Center, The University of Hong bination with surgery or chemotherapy or more Kong-Shenzhen Hospital, Shenzhen, China recently targeted therapy and immunotherapy e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2021 3 J. Seong (ed.), Radiotherapy of Liver Cancer, https://doi.org/10.1007/978-981-16-1815-4_1 4 V. H.-F. Lee and A. W.-M. Lee [1]. Radical treatment can be as the definitive more recently selective internal radiation ther- therapy (e.g., for head and neck, skin or prostate apy, also known as radioembolization, are the cancers), neoadjuvant prior to surgery (e.g., most commonly used radiation modalities for chemoradiotherapy for esophageal or rectal HCC. cancer), or adjuvant following definitive treat- ment (e.g., for head and neck and breast cancers). 1.2 External Beam Radiotherapy Different histological cancer types possess dif- ferent inherent radiation sensitivities, which deter- This is the most common type of radiotherapy mine whether radiotherapy should be considered employed to treat HCC. The high-energy (6–20 as part of anticancer treatment and also the dose megavoltage) photons generated are able to pen- essential to achieve the treatment objective as etrate deep enough to reach and kill the tumor mentioned above. HCC is considered moderately cells. In general, high-energy fast moving elec- sensitive to radiation, when compared to the more trons are first produced by the powerful electron sensitive types including small-c ell carcinoma, gun which accelerate through the electromagnet seminoma, and lymphoma, and the less sensitive in the linear accelerator and ultimately collide types like sarcoma and melanoma. with the target to generate X-rays. The linear Radiation therapy can be broadly classified accelerator is housed in a specially-made bunker and delivered in four main ways: (1) external surrounded by thick concrete and lead walls beam radiotherapy in which the radiation (pho- which offer radiation protection and safety tons, electrons, and charged particle) is emitted (Fig. 1.1). The international unit to describe radi- by an external machine passing through the skin ation prescription and absorption is Gray (Gy), before reaching the tumors, (2) implanted radio- which is defined as 1 Gy = 1 J/Kg. Conventional isotopes in the form of brachytherapy, (3) inter- radical radiotherapy is usually given in multiple nal radiation therapy in which the radioisotopes sessions (fractions) every day, 5 days per week, through injection or ingestion are preferentially lasting for 5–7 weeks, depending on the dose to taken up by specific body tissues, and (4) selec- be prescribed. The concept of fractionation is to tive internal radiation therapy or endovascular enhance the therapeutic ratio or therapeutic win- radiation therapy in which radioisotopes are dow so that a high radiation dose can be delivered injected into the tributaries of the feeding ves- to the tumor cells while adequate time is allowed sels which offer blood supply to the tumors for repair and repopulation of the adjacent nor- (Table 1.1). External beam radiotherapy and mal cells (Fig. 1.2). Table 1.1 Types and clinical indications of radiotherapy used Types Clinical indications Photons Capable of penetrating into the deeper structures of the body while relatively sparing the skin. Suitable for deep-seated tumors, for example, bladder and rectal cancers. Electrons Capable of delivering high radiation dose up to a few centimeters depth from the skin surface with little dose beyond. Most suitable as superficial treatment for skin cancers. Charged particle Capable of depositing most of its energy at a specific and characteristic depth after tissue therapy penetration with high precision. Most suitable for pediatric tumors, brain tumors, and spinal tumors. Radioisotopes Interstitial, Radioisotopes placed inside the tumors, or the lumens or cavities of the patient’s body. implanted, or Examples include iodine-125 interstitial brachytherapy for prostate cancer and iridium-192 intracavitary intracavitary brachytherapy for cervical cancer. Ingested or Radioisotopes ingested or injected which are preferentially taken up by specific body tissues/ injected cells with preferential avidity with these radioisotopes. Examples include iodine-131 for thyroid cancer and Radium-223 for bone metastasis of prostate cancer. Endovascular Radioisotopes injected intravascularly into the feeding vessels supplying the tumors. An example is transarterial radioembolization with yttrium-90 microspheres for liver cancer.