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Medical Radiology · Radiation Oncology
Series Editors: Nancy Y. Lee · Jiade J. Lu

Branislav Jeremić
Editor

Advances in
Radiation Oncology
in Lung Cancer
Third Edition
Medical Radiology

Radiation Oncology

Series Editors
Nancy Y. Lee
Jiade J. Lu
Medical Radiology - Radiation Oncology is a unique series that aims to
document the most innovative technologies in all fields within radiology,
thereby informing the physician in practice of the latest advances in diagnostic
and treatment techniques.
The contents range from contemporary statements relating to management
for various disease sites to explanations of the newest techniques for tumor
identification and of mechanisms for the enhancement of radiation effects,
with the emphasis on maximizing cure and minimizing complications.
Each volume is a comprehensive reference book on a topical theme, and
the editors are always experts of high international standing. Contributions
are included from both clinicians and researchers, ensuring wide appeal.
Branislav Jeremić
Editor

Advances in Radiation
Oncology in Lung
Cancer
Third Edition
Editor
Branislav Jeremić
School of Medicine
University of Kragujevac
Kragujevac, Serbia

ISSN 0942-5373     ISSN 2197-4187 (electronic)

Medical Radiology
ISSN 2731-4715        ISSN 2731-4723 (electronic)
Radiation Oncology

ISBN 978-3-031-34846-4    ISBN 978-3-031-34847-1 (eBook)

https://doi.org/10.1007/978-3-031-34847-1

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2005, 2011, 2023
This work is subject to copyright. All rights are solely and exclusively licensed 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.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are
exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in
this book are believed to be true and accurate at the date of publication. Neither the publisher nor
the authors or the editors give a warranty, expressed or implied, with respect to the material
contained herein or for any errors or omissions that may have been made. The publisher remains
neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
For
Aleksandra and Marta.
Preface

Worldwide, there is an estimated 19.3 million new cancer cases with almost
10.0 million cancer deaths occurred in 2020. Lung cancer is now the second
most commonly diagnosed cancer, with an estimated 2,206,771 new cases
annually occurring. It, however, remains the leading cause of cancer death,
with an estimated 1.8 million deaths (18%). Due to continuing efforts of the
tobacco industry shifting its focus from developed to a developing world,
more than 50% of new cases continue to occur in the latter one in the past
decade. It is, therefore, not unexpectedly a big burden to national health care
systems worldwide with hundreds of thousands of patients succumbing to it
every year.
Radiation therapy remains the cornerstone of modern treatment
approaches, regardless of histology and stage of the disease. It is used in both
curative and palliative setting, being the most cost-effective treatment option
in lung cancer. Recent decades witnessed important technological and bio-
logical developments which enabled continuous and efficient adaptation to
the growing demands to offer precision medicine in the twenty-first century.
Together with other two treatment modalities, surgery and systemic therapy,
it successfully evolves focusing on both patient and society needs. Indeed,
there seems to be very few competitors among medical disciplines that have
so broadly embraced scientific novelties such as computer-driven technologi-
cal aspects as is the case with radiation therapy.
This, updated and third edition of the book initially published in 2004 and
2011, respectively, remains focused upon constant research and development
in the field of radiation oncology as the indispensable part of our comprehen-
sive and hopefully orchestrated approach in the diagnosis and treatment of
lung cancer. While the intervening 10 years may deem too short for any major
leaps in this field, I am sure this third edition will stand the test of time as the
necessary checkpoint in the global development in this field.
To demonstrate this premise, while many chapters of the first and the sec-
ond edition respectively remained, many are updated and, furthermore, many
are completely new additions, bringing more substance to keep the pace with
the most recent scientific achievements in the field, becoming new standards
of care almost daily. Various, non-radiation oncology aspects are again
included in the book with the same goal. Ultimately, the book is composed in
such a way to enable both radiation oncologists and other lung cancer special-
ists benefit from reading it.

vii
viii Preface

As with the previous two efforts, I have had great pleasure and very much
privilege of having a distinguished faculty joining me. They dedicated their
professional lives to the fight against lung cancer, having continuously pro-
vided substantial contribution in this field. They painstakingly focused on
more comprehensive understanding of basic premises of biology and technol-
ogy, its successful incorporation in the diagnosis and treatment of the disease
and finally ending up in state-of-the-art approaches in the third decade of the
new millennium.
I would also like to thank my former and current staff colleagues with
whom I have collaborated around the world, especially those still living and
working in developing countries. From such collaboration, I grew up not only
as a better and more mature medical professional but also a better human
being. I would also like to express my gratitude to Alexander von Humboldt
Foundation, Bonn, Germany, for their continuous support since 1998. Without
them all it would simply be impossible to imagine both the final shape of the
book and its timely delivery.

Belgrade, Serbia Branislav Jeremić

Contents

Part I Basic Science of Lung Cancer


Genomic Alterations in Lung Cancer��������������������������������������������������    3
Daniel Morgensztern

Epigenetic Events in Lung Cancer ������������������������������������������������������   17
Octavio A. Romero and Montse Sanchez-Cespedes

Part II Clinical Investigations

Interventional Pulmonology������������������������������������������������������������������   35

Branislav Perin and Bojan Zarić

Pathology of Lung Cancer��������������������������������������������������������������������   45
Mari Mino-Kenudson

Role of Radiologic Imaging in Lung Cancer ��������������������������������������   67
Salome Kukava and George Tsivtsivadze

Place and Role of PET/CT in the Diagnosis and Staging
of Lung Cancer��������������������������������������������������������������������������������������   85
Salome Kukava and Michael Baramia

Surgical Staging of Lung Cancer���������������������������������������������������������� 113
Jarrod Predina, Douglas J. Mathisen, and Michael Lanuti

Part III Basic Treatment Considerations


Surgical Workup and Management of Early-Stage
Lung Cancer ������������������������������������������������������������������������������������������ 131
Stephanie H. Chang, Joshua Scheinerman, Jeffrey Jiang,
Darian Paone, and Harvey Pass

Radiation Biology of Lung Cancer������������������������������������������������������ 151
Jose G. Bazan

Radiation Time, Dose, and Fractionation in the Treatment
of Lung Cancer�������������������������������������������������������������������������������������� 171
David L. Billing and Andreas Rimner

ix
x Contents


Optimizing Lung Cancer Radiotherapy Treatments
Using Personalized Dose-Response Curves ���������������������������������������� 189
Joseph O. Deasy, Jeho Jeong, Maria Thor, Aditya Apte,
Andrew Jackson, Ishita Chen, Abraham Wu, and Andreas Rimner
Tumor Motion Control�������������������������������������������������������������������������� 213
Hiroki Shirato, Shinichi Shimizu, Hiroshi Taguchi,
Seishin Takao, Naoki Miyamoto, and Taeko Matsuura

PET and PET/CT in Treatment Planning ������������������������������������������ 237
Michael MacManus, Sarah Everitt, and Rodney J. Hicks

Target Volume Delineation in Non-­small Cell Lung Cancer�������������� 255
Jessica W. Lee, Haijun Song, Matthew J. Boyer,
and Joseph K. Salama

The Radiation Target in Small Cell Lung�������������������������������������������� 271
Gregory M. M. Videtic
Radiation Sensitizers ���������������������������������������������������������������������������� 285
Mansi K. Aparnathi, Sami Ul Haq, Zishan Allibhai,
Benjamin H. Lok, and Anthony M. Brade

Radioprotectors in the Management of Lung Cancer������������������������ 303
Zhongxing Liao, Ting Xu, and Ritsuko Komaki

Chemotherapy for Lung Cancer���������������������������������������������������������� 321
Mariam Alexander, Elaine Shum, Aditi Singh,
and Balazs Halmos

Targeted Therapies in Non-small Cell Lung Cancer�������������������������� 347
Jessica R. Bauman and Martin J. Edelman

Immunotherapy of Lung Cancer���������������������������������������������������������� 371
Igor Rybkin and Shirish M. Gadgeel

Combined Radiotherapy and Chemotherapy:
Theoretical Considerations and Biological Premises�������������������������� 385
Michael K. Farris, Cole Steber, Corbin Helis,
and William Blackstock

Mechanisms of Action of Radiotherapy and Immunotherapy
in Lung Cancer: Implications for Clinical Practice���������������������������� 399
Kewen He, Ugur Selek, Hampartsoum B. Barsoumian,
Duygu Sezen, Matthew S. Ning, Nahum Puebla-Osorio,
Jonathan E. Schoenhals, Dawei Chen, Carola Leuschner,
Maria Angelica Cortez, and James W. Welsh

Part IV Current Treatment Strategies in Early-­Stage

Non-small Cell Lung Cancer


Early Non-small Cell Lung Cancer: The Place of Radical
Non-SABR Radiation Therapy ������������������������������������������������������������ 417
Tathagata Das and Matthew Hatton
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