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2015v1.0
Proton Therapy
 F I R S T E D I T I O N

Proton Therapy
Indications, Techniques,
and Outcomes
STEVEN J. FRANK, MD
Professor
Radiation Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas

X. RONALD ZHU, PhD

Professor
Radiation Physics
The University of Texas MD Anderson Cancer Center
Houston, Texas
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-899

PROTON THERAPY: INDICATIONS, TECHNIQUES, AND OUTCOMES ISBN: 978-0-323-73349-6

Copyright © 2021 by Elsevier, Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about
the Publisher’s permissions policies and our arrangements with organizations such as the Copyright
Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/
permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical treatment
may become necessary. Practitioners and researchers must always rely on their own experience and
knowledge in evaluating and using any information, methods, compounds or experiments described
herein. Because of rapid advances in the medical sciences, in particular, independent verification
of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is
assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or
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any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Control Number: 2020932479

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Content Development Manager: Ellen Wurm-Cutter
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Publishing Services Manager: Deepthi Unni
Project Manager: Janish Ashwin Paul
Design Direction: Bridget Hoette

Printed in the United States

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 DEDICATION
This book is dedicated to all of our patients and their
loved ones who have entrusted us with their cancer care
with proton therapy.

v
LIST OF CONTRIBUTORS

Houda Bahig, MD Daniel R. Gomez, MD, MBA

Department of Radiation Oncology Department of Radiation Oncology
Division of Radiation Oncology Memorial Sloan Kettering Cancer Center
The University of Texas MD Anderson
David R. Grosshans, MD, PhD
Cancer Center
Departments of Experimental and Radiation
Andrew J. Bishop, MD Oncology
Department of Radiation Oncology Division of Radiation Oncology
Division of Radiation Oncology The University of Texas MD Anderson
The University of Texas MD Anderson Cancer Center
Cancer Center
Archana S. Gautam, MSc
Bouthaina S. Dabaja, MD Department of Radiation Oncology
Department of Radiation Oncology Division of Radiation Oncology
Division of Radiation Oncology The University of Texas MD Anderson
The University of Texas MD Anderson Cancer Center
Cancer Center
G. Brandon Gunn, MD
Joe Y. Chang, MD, PhD Department of Radiation Oncology
Department of Radiation Oncology Division of Radiation Oncology
Division of Radiation Oncology The University of Texas MD Anderson
The University of Texas MD Anderson Cancer Center
Cancer Center
Jillian R. Gunther, MD, PhD
Seungtaek L. Choi, MD Department of Radiation Oncology
Department of Radiation Oncology Division of Radiation Oncology
Division of Radiation Oncology The University of Texas MD Anderson
The University of Texas MD Anderson Cancer Center
Cancer Center
Stephen M. Hahn, MD
Prajnan Das, MD, MS, MPH Division of Radiation Oncology
Department of Radiation Oncology The University of Texas MD Anderson
Division of Radiation Oncology Cancer Center
The University of Texas MD Anderson
Karen E. Hoffman, MD
Cancer Center
Department of Radiation Oncology
Steven J. Frank, MD Division of Radiation Oncology
Department of Radiation Oncology The University of Texas MD Anderson
Division of Radiation Oncology Cancer Center
The University of Texas MD Anderson
Yoshifumi Hojo, PhD
Cancer Center
Department of Radiation Physics
Michael T. Gillin, PhD Division of Radiation Oncology
Department of Radiation Physics The University of Texas MD Anderson
Division of Radiation Oncology Cancer Center
The University of Texas MD Anderson
Cancer Center

vi
LIST OF CONTRIBUTORS vii

Emma B. Holliday, MD Arnold C. Paulino, MD, FACR, FASTRO

Department of Radiation Oncology Department of Radiation Oncology
Division of Radiation Oncology Division of Radiation Oncology
The University of Texas MD Anderson The University of Texas MD Anderson
Cancer Center Cancer Center
Heng Li, PhD Falk Poenisch, PhD
Department of Radiation Oncology and Department of Radiation Physics
Molecular Radiation Sciences Division of Radiation Oncology
Johns Hopkins University The University of Texas MD Anderson
Cancer Center
Yupeng Li, MS
Department of Radiation Physics Narayan Sahoo, PhD
Division of Radiation Oncology Department of Radiation Physics
The University of Texas MD Anderson Division of Radiation Oncology
Cancer Center The University of Texas MD Anderson
Cancer Center
Zhongxing Liao, MD
Department of Radiation Oncology Li Wang, MD, PhD
Division of Radiation Oncology Department of Experimental Radiation
The University of Texas MD Anderson Oncology
Cancer Center Division of Radiation Oncology
The University of Texas MD Anderson
Lillie L. Lin, MD
Cancer Center
Department of Radiation Oncology
Division of Radiation Oncology Wendy A. Woodward, MD, PhD
The University of Texas MD Anderson Department of Radiation Oncology
Cancer Center Division of Radiation Oncology
The University of Texas MD Anderson
Steven H. Lin, MD, PhD
Cancer Center
Department of Radiation Oncology
Division of Radiation Oncology Richard Wu, MS
The University of Texas MD Anderson Department of Radiation Physics
Cancer Center Division of Radiation Oncology
The University of Texas MD Anderson
Radhe Mohan, PhD
Cancer Center
Department of Radiation Physics
Division of Radiation Oncology Xiaodong Zhang, PhD
The University of Texas MD Anderson Department of Radiation Physics
Cancer Center Division of Radiation Oncology
The University of Texas MD Anderson
Quynh-Nhu Nguyen, MD
Cancer Center
Department of Radiation Oncology
Division of Radiation Oncology X. Ronald Zhu, PhD
The University of Texas MD Anderson Department of Radiation Physics
Cancer Center Division of Radiation Oncology
The University of Texas MD Anderson
Matthew Palmer, MBA, BA
Cancer Center
Chief Operating Officer
MD Anderson Proton Therapy Center
The University of Texas MD Anderson
Cancer Center
PREFACE

Proton therapy has been used to treat cancer patients since the early 1950s; however, technologic
advancements in proton therapy delivery with spot scanning and treatment planning systems
are rapidly evolving, making it more accessible for the management of solid tumors. In this first
edition of Proton Therapy: Indications, Techniques, and Outcomes, we aim to communicate the most
up-to-date advancements in radiobiology, indications, literature, management approaches, treat-
ment planning, quality assurance, and outcomes after proton therapy by disease site. Education
and training in proton therapy are more important now than ever before, as systems become
smaller and more cost-effective, resulting in greater access for community hospitals and their
multidisciplinary oncology teams.
The radiobiology of proton therapy and its relative biological effectiveness versus conventional
x-rays (RBE) will continue to be a dynamic field of interest based on the DNA damage and repair
mechanisms in individual tumor cell lines as well as the acute and late effects on normal tissues.
Specifically, multifield optimization intensity-modulated proton therapy (MFO-IMPT) provides
a great opportunity for understanding how best to exploit the linear energy transfer (LET) of
protons at the distal edge of the Bragg peak to our advantage.
Proton therapy quality assurance and management of uncertainties during treatment planning
and treatment delivery will continue to be a hallmark of medical physics. Robust planning,
robust analysis, and robust optimization are important tools during the proton therapy treatment
planning process. Deeper understanding of the variations of stopping power and their effects on
adaptive real-time planning is an exciting opportunity to further advance patient care.
Clinical outcomes by disease site are carefully examined in each clinical chapter, and a special
section on head and neck cases is included that photographically documents the full cycle of
proton therapy care. Finally, the current indications for proton therapy at The University of Texas
MD Anderson Cancer Center are a clarified, as well as opportunities for the advancement of
proton therapy in future indications.
We thank all of the authors and dedicate this first edition of Proton Therapy: Indications,
Techniques, and Outcomes to the late James D. Cox, MD, whose leadership and vision became
a clinical reality in 2006 when the first cancer patient was treated with proton therapy at The
University of Texas MD Anderson Cancer Center.

Steven J. Frank, MD, FACR, and

X. Ronald Zhu, PhD, FAAPM

viii
 ACKNOWLEDGMENT

We would like to acknowledge Christine F. Wogan, MS, ELS, of MD Anderson’s Division of

Radiation Oncology, for her substantive editorial efforts.

ix
TA B L E O F C O N T E N T S

SECTIO N I Introduction
1. Principles of Radiobiology 2
Li Wang Steven J. Frank

2. Principles of Proton Beam Therapy 14

Radhe Mohan

SECTIO N II Physics and Treatment Planning

3. Clinical Commissioning of Pencil Beam Scanning for Intensity-Modulated Proton
Therapy 26
X. Ronald Zhu Falk Poenisch Narayan Sahoo Michael T. Gillin

4. Immobilization and Simulation 45

Archana S. Gautam Richard Wu X. Ronald Zhu Falk Poenisch

5. Principles of Intensity-Modulated Proton Therapy Treatment Planning 56

Xiaodong Zhang Yupeng Li Heng Li Richard Wu Matthew Palmer

6. Physics Quality Assurance 80

Falk Poenisch Narayan Sahoo Heng Li Yoshifumi Hojo

7. Intensity-Modulated Proton Therapy Patient Treatments 106

Michael T. Gillin Yoshifumi Hojo Narayan Sahoo X. Ronald Zhu

SECTIO N III Disease Sites

8. Proton Radiotherapy for Breast Cancer 116
Wendy A. Woodward Falk Poenisch Karen E. Hoffman

9. Adult Central Nervous System Tumors 126

David R. Grosshans

10. Gastrointestinal 135

Emma B. Holliday Prajnan Das

11. Proton Therapy for Gynecologic Malignancies 145

Lillie L. Lin

12. Proton Therapy for Prostate Cancer 151

Seungtaek L. Choi Quynh-Nhu Nguyen

13. Head and Neck 161

Steven J. Frank G. Brandon Gunn

14. Proton Therapy for Hematologic Malignancies 180

Jillian R. Gunther Bouthaina S. Dabaja

15. Pediatric Considerations for Proton Therapy 186

Arnold C. Paulino

x
TABLE OF CONTENTS xi

16. Proton Therapy and Sarcomas 191

Andrew J. Bishop Stephen M. Hahn

17. Esophagus Cancer 198

Steven H. Lin Heng Li Daniel R. Gomez

18. Lung Cancer 205

Daniel R. Gomez Heng Li Xiaodong Zhang Joe Y. Chang Zhongxing Liao Steven H. Lin

SEC T I O N IV Future Outcomes and Advancements

19. Technological Advancements and Outlook in Proton Therapy 216
X. Ronald Zhu Xiaodong Zhang Matthew Palmer Steven J. Frank

20. Appendix 1: The University of Texas MD Anderson Cancer Center’s

Recommended Proton Therapy Indications 221
1. Recommended Breast Cancer Proton Therapy Indications
2. Recommended Central Nervous System Proton Therapy Indications
3. Recommended Esophagus Cancer Proton Therapy Indications
4. Recommended Gastrointestinal Cancer Proton Therapy Indications
5. Recommended Head and Neck Cancer Proton Therapy Indications
6. Recommended Hematologic Cancer Proton Therapy Indications
7. Recommended Pediatric Cancer Proton Therapy Indications
8. Recommended Prostate Cancer Proton Therapy Indications
9. Recommended Thoracic Cancer Proton Therapy Indications

21. Appendix 2: Head and Neck Clinical Case Scenarios and Outcomes
by Disease Site See Expert Consult ebook
Houda Bahig G. Brandon Gunn Steven J. Frank
 S E C T I O N I
Introduction

1
Principles of Radiobiology
Li Wang ■ Steven J. Frank

Introduction
Radiotherapy is used as one of the major treatment modalities for patients with malignant dis­
eases at different disease stages. Currently, the most common radiation choice for the majority of
cancers is photon (x-ray)-based intensity-modulated external beam radiotherapy. Notably, recent
advances in technology and basic and clinical research have facilitated the safe delivery of more
effective and noninvasive radiotherapy for malignant diseases using charged particles, including
intensity-modulated proton therapy. Proton beams deliver most of their energy at the distal edge
of their range (the Bragg peak), which leads to an increase of th - radiation doses to the clinical
targets and minimization of the irradiation dose to adjacent nmmal tissues. Moreover, photon
beams are categorized as low linear energy transfer (LET), whereas proton beams, especially in
the spread-out Bragg peak (SOBP), which majorly contains pragg peaks, are categorized as high
LET Thus in addition to the physical dose distribution adv.antage, proton therapy also presents
distinct biology advantages compared with photon radiation. Even though the biological features
of tumors and normal tissues after photon radiation have 0(:en e,xtensively studied, the biological
responses of tumors and normal tissues to proton radiation are far from clear. The biological
properties of proton beams that differ significantly from those of photons will be summarized in
this chapter. Particular emphasis is placed on relatiye biological effectiveness (REE), DNA
damage, and repair effects induced by protons, proton beam-induced cell death mechanisms,
the impact of proton beams on tumor imm�responses, and the influence of proton beams on
tumor angiogenesis.

DNA Damage and Repair

DNA DAMAGE
DNA is the critical target of radiation. Photon radiation induces DNA damage by the direct action
of deposing beam energy to DNA. Photon radiation also induces DNA damage by the indirect
action of forming reactive species near the DNA, primarily by turning a water molecule into a free
radical (hydroxyl radicals, OH).1-3 Photon radiation causes many types of DNA damage, including
single-base damage and single-strand breaks (isolated), and clustered base damage and double­
strand breaks (DSBs) (clustered within a few DNA helical turns).4 Most single-strand breaks can
be repaired normally. However, repair is more difficult, and erroneous rejoining of broken ends in
DSBs may result in significant biological consequences. Failure of DNA DSBs repair results in
induction of mutations, chromosome aberrations, cell death, or even possibly in malignant cell
transformation.H It is believed that the complexity of DNA damage is the determining factor for
the consequent cellular response to radiation.
Although photon radiation-related DNA damage and repair researches have been conducted
extensively, the DNA damage and repair as a consequence of proton radiation remain poorly
understood. Similar to that of photon radiation, it has been proven that the indirect effect of

2
1—PRINCIPLES OF RADIOBIOLOGY 3

proton beams plays a major role and causes a large proportion of DNA damage compared with
the direct effect of proton beams. 1,7–9 However, Monte Carlo simulations have indicated that the
average number of DNA damages per cluster tends to increase with the increasing of the radia-
tion beam LET, which implies a higher level of DNA damage complexity induced by proton
beams versus by that caused by photon beams. 1,4 These mathematical model prediction results
have been verified by several other studies by testing DNA plasmids or cell lines. Using DNA
plasmids pBR322 or T7 as testing material, the direct damage effect of proton beams to DNA
was proven to generate more DSB clusters compared with non-DSB clusters compared with
photon beams. 7,10 Similar observations were also demonstrated in cell-based studies. An in-
creased complexity of DNA damages and slower DNA damage repair kinetics were observed in
the human skin fibroblast AG01522 cells at the distal end of the SOBP after proton radiation.11
Other than this, large foci, which represent the DSB clusters, were also found more commonly
in Chinese hamster ovary (CHO) cell lines CHO10B2 and irs-20 after proton radiation com-
pared with photon radiation.12 The more severe DNA damage caused by proton beams were also
proven by another study on the thyroid-stimulating hormone–dependent Fischer rat thyroid
cells.13 The authors found more free-end DNAs 1 hour after proton radiation than photon ra-
diation, which means a more rapid DNA damage repair in the cells exposed to photon beams
than those exposed to proton beams. They further verified their results by finding a higher rate
of micronucleus formation and the presence of larger micronuclei in cells treated by proton beams
than those cells treated with photon beams.13 Persistent DNA damage was also observed in dif-
ferent head and neck cancer cell lines after exposure to proton beams versus exposure to photon
beams.14 However, conflicting results were observed in a study using the DNA plasmid pBR322.
In this study, the authors did not find a difference in the amount of the clustered DNA damage
induced by proton beams compared with photon beams in either the liquid or in the dry samples.4

DNA DAMAGE REPAIR

Because DNA DSBs are the key lesion leading to severe biological consequences in cells exposed
to photon radiation, it is meaningful to study DSB and its processing after cells are exposed to
proton beams. Because the DNA damages induced by proton beams are with higher complexity
than those induced by photon beams, the repair of the damaged DNA caused by proton beams
may be different from the repair of damaged DNA caused by photon beams. Compared with the
extensively studied DNA damage repair mechanisms after photon beam exposure, the study of
DNA damage repair after proton beam radiation is limited, and mechanisms underlying the
DNA damage repair are still to be uncovered.
There are two major distinguished DSB repair pathways15–17(Fig. 1.1): homologous recombi-
nation (HR) and nonhomologous end joining (NHEJ). NHEJ is active throughout the cell cycle
and is the predominant repair pathway for photon radiation–induced DSBs in mammalian cells.
15,18
The roles of HR and NHEJ in DNA damage repair in response to proton versus photon
beams have been studied.15 In this study, the CHO cells AA8, CHO9, UV5, Irs1sf, and XR-C1
with different Rad51 (a protein related to HR15,17) and DNA-PKcs (a protein related to
NHEJ15,17) status were exposed to proton or photon beams. Cell survival and DSB repair were
evaluated after radiation. The authors found that when compared with wild-type cells, Rad-
51-deficient or suppressed cells have a higher proton versus photon radiation response rate;
however, DNA-PKcs-deficient cells have not shown a different response rate to proton versus
photon radiation when compared with wild-type cells. Moreover, delayed DSB repair was also
found in the Rad-51-deficient cells after proton radiation. The authors concluded that HR is
preferentially required for proton beam–induced DSB repair.15 A similar phenomenon was also
found in human lung adenocarcinoma (A549) and human glioblastoma (M059K and M059J)
cells.19 In this study, after blocking DNA-PKcs, a higher level of delayed DSBs repair and a more
4 PROTON THERAPY

DSB
ATM/ATR

rH2AX

RNF8

MDC1

RNF168

BRCA1 53BP1

CtIP RIF1

Ku 70–80

RAD51 DNA-PKcs
Fig. 1.1 Double-strand break (DSB) repair
pathways ATM, Ataxia-Telangiesctasia mu-
tated; ATR, ataxia telangiectasia and Rad3 re-
lated; HR, homologous recombination; NHEJ,
HR NHEJ nonhomologous end joining.

profound radio response was observed after cells were exposed to photon versus proton beams. On
the other hand, depleting RAD51 led to an enhanced response of A549 cells to proton beams. The
authors claimed a preference of HR versus NHEJ in proton beam–induced DSB repair.19 On the
contrary, conflicting results were reported by others.12 In one study, the authors compared the DSB
repair of the DNA-PKcs wild-type CHO cell line CHO10B2 with its derived radiosensitive
mutant cell line, the DNA-PKcs-deficient cell line irs-20 after cells were exposed to photon and
proton beams.12 Irs-20 cells presented more persistent DSBs compared with CHO10B cells after
cells were exposed to both photon and proton beams. A dependence on the DNA-PKcs in repair-
ing DSBs caused by both proton and photon beams was verified.12 In another study involving the
DNA-PKcs wild-type CHO cell line CHO10B2, Ku80-mutated CHO mutant cell XRS-5,
DNA-PKcs null V3 cells, Rad51D-mutated 51D1 cells, and 14 cell lines derived from V3 cells
with complementary human DNA PKcs containing amino acid substitutions at specific positions,
the cell responses to proton beams versus photon beams were not correlated with the status of
DNA-PKcs or RAD51; thus, no preferential DSB repair pathway of HR or NHEJ was observed
in proton beam–induced DSB repair.18 Other than the previously mentioned, a study using cervi-
cal cancer HeLa cells claimed that the higher cell response rate of proton beams versus photon
beams in the SOBP is in an Artemis protein–dependent manner. Because Artemis protein is a
member of the NHEJ pathway, this result reflects the dependency of the repair of proton beam–
induced DSBs on NHEJ.20 Some other studies also demonstrated the preference of the NHEJ
pathway in the repair of DSBs induced by proton beams.21,22 This evidence includes the activation
of Ataxia-Telangiesctasia mutated (ATM, contributing to NHEJ23) and DNA-PKcs but not
ataxia telangiectasia and Rad3 related (ATR) by proton beams in human lung adenocarcinoma
A549 cells21 and the induction of ATM by proton beams in human prostate cancer PC3 cells.22
1—PRINCIPLES OF RADIOBIOLOGY 5

Taken together, the overall DNA damage caused by proton is different than that of photon
beams, at least to a certain extent. However, the repair mechanisms of the DSBs induced by
proton beams are still unclear. Future studies specifically investigating the DNA repair pathways
of proton beams will translate the findings into biology-based rationales of treatment selection
between proton- and photon-based radiation and the combination of therapies that targeted
specific signal pathways.

Cell Death
One of the severe consequences of the failure of DNA damage repair induced by radiation is cell
death. The mechanisms of photon radiation–induced cell death are intensively studied. Photon
radiation is known to kill cancer cells via apoptosis, necrosis, autophagy, mitotic catastrophe,
and senescence.24–28 However, the mechanisms by which proton radiation induces cell death are
unclear.

CELL MITOTIC CATASTROPHE

Extensive evidence demonstrated that mitotic catastrophe is the major mechanism of cell death
in solid tumors in response to photon radiotherapy.24,26 However, the role of cell mitotic catas-
trophe in response to proton beam radiation is unclear. We uncovered that mitotic catastrophe
was the dominant mechanism of cell death in both human papillomavirus (HPV)–related and
HPV-unrelated human head and neck squamous carcinoma cells after proton beam radiation at
4, 24, 48, and 72 hours after radiation (Fig. 1.2). Moreover, the results demonstrated that com-
pared with photon beams, a 4-Gy dose of proton radiation led to a higher level of mitotic catas-
trophe in these cells. The more pronounced cell mitotic catastrophe induced by proton beams
versus photon beams suggests that combining therapy targeting the DNA damage repair pathway
may promote cell death differently after proton radiation compared with photon radiation.

CELL SENESCENCE
With emerging evidence, cellular senescence is increasingly being recognized as one of the most
important mechanisms in photon radiation–induced tumor suppression.26,29,30 Similar to that
observed in photon radiation, we found that senescence was also a major type of cell death
induced by a 4-Gy dose of proton beam radiation in HPV-related and HPV-unrelated human
head and neck squamous carcinoma cells at 4 and 6 days after exposure (Fig. 1.3). More impor-
tantly, compared with photon beams, proton beams led to a higher proportion of cells undergoing
senescence in these cell lines. Based on the above facts, the role of combination treatment that
interferes with cell senescence pathways may influence cell responses to proton beams versus
photon beams differently and warrants further investigation.

CELL APOPTOSIS
Apoptosis plays a modest role in the response of many solid tumors to photon irradiation. To
date, little is known about cell apoptosis after they are exposed to proton radiation. The study
result from one group31 indicated that compared with photon beams, proton beams led to a
greater level of cell apoptosis at 48 hours after radiation in H460 and A549.21,31 Similarly, a study
(16 in DNA damage literature) using patient-derived glioma stem cells to compare proton beam
with photon beam irradiation indicated that proton beams induce more cell apoptosis and lead
to more cell apoptosis–related caspase-3 activation and poly(adenosine diphosphate [ADP]-
ribose) polymerase (PARP) cleavage. Other than the higher incidence of cell apoptosis after
6 PROTON THERAPY

Control XRT PRT Control XRT PRT

DAPI

γ-Tubulin

Merge

A B
SqCC/Y1
100 Control 100 HN5
P all < .001
XRT
Percentage of mitotic

80 80 *P < .05
catastrophe cells

PRT *
* *
60 60 *
* * *
40 40 * * *

20 20

0 0
4h 24 h 48 h 72 h 4h 24 h 48 h 72 h

DAPI

γ-Tubulin

Merge

C D
100 100
UPCI-SCC-154 UMSCC-47
Percentage of mitotic

80 P all < .05 80 *P < .05

catastrophe cells

* *
* * * *
60 60 *
* *
40 40 * *

20 20

0 0
4h 24 h 48 h 72 h 4h 24 h 48 h 72 h
Time after 4 Gy irradiation (hours)

Fig. 1.2 Mitotic catastrophe in head and neck squamous cell carcinoma cell lines after exposure to photon
(XRT) versus proton (PRT) irradiation. Two human papillomavirus (HPV)–negative cell lines (SqCC/Y1, panel
A; and HN5, panel B) and two HPV-positive cell lines (UPCI-SCC-154, panel C; UMSCC-47, panel D) were
tested. Cells were fixed, permeabilized, blocked, and incubated with anti-g-tubulin (primary antibody) and
Texas Red (secondary antibody) to visualize immunoreactivity; DNA was stained with 4’,6-diamidino-2-
phenylindole. Immunoreactions were visualized with a Leica Microsystem at 3100 magnification.
1—PRINCIPLES OF RADIOBIOLOGY 7

SqCC/Y1 HN5 UPCI-SCC-154 UMSCC-47

Control

XRT

PRT

A
50 SqCC/Y1 50 HN5
Control P all < .001 P all < .001
40 XRT 40
PRT
30 30

20 20
Percentage of senescent cells

10 10

0 0
4 days 6 days 4 days 6 days
50 UPCI-SCC-154 50 UMSCC-47

40 P all < .01 40 P all < .01

30 30

20 20

10 10

0 0
4 days 6 days 4 days 6 days
Time after 4 Gy irradiation (days)
Fig. 1.3 Senescence in head and neck squamous cell carcinoma cell lines after exposure to photon (XRT)
versus proton (PRT) irradiation. Two human papillomavirus (HPV)–negative cell lines (SqCC/Y1 and HN5) and
two HPV-positive cell lines (UPCI-SCC-154 and UMSCC-47) were stained with senescence-associated
b-galactosidase (SA-b-gal) and analyzed 4 days and 6 days later. (A) Photographs of senescent cells at
6 days after irradiation. Cells were photographed with an optic microscope at 320 magnification. Cells stain-
ing positive for SA-b-gal show blue cytoplasmic staining.
8 PROTON THERAPY

proton beam versus photon beam radiation, studies from other groups also revealed the time
point differences of the cell apoptosis occurrence between photon versus proton beam radiation.
One group from Italy32 exposed the prostate adenocarcinoma cell line PC3 to photon and proton
beams. They found that the peak of PC3 cells undergoing apoptosis was reached at 8 hours after
proton irradiation compared with 48 hours for photon irradiation. Differently, a study from
Germany on HeLa cells indicated that during the maximum observation time of 48 hours, the
proportion of apoptotic cells induced by proton beams increased with time.33 Other than the
above direct evidence of cell apoptosis induced by proton beams, indirect evidence of cell
apoptosis–related signal pathway changes were also generated. One study21 demonstrated sig-
nificantly more upregulation of proapoptotic gene, Bax, and downregulation of antiapoptotic
gene, Bcl-2, at 12 hours after lung cancer A549 cells were exposed to proton beams compared
with those cells exposed to photon beams. However, our study in HPV-related and HPV-
unrelated human head and neck squamous carcinoma cells showed a different result (Fig. 1.4A).
Both photon and proton beams only induced limited cell apoptosis, and no difference was ob-
served in the proportion of proton beam–induced cell apoptosis versus that induced by photon
beams. Because both proton beams and photon beams can cause DNA damage and DNA dam-
age is a major pathway by which radiation causes apoptosis, strategies to target apoptosis pathway
to enhance proton beam or photon beam–induced tumor cell apoptosis may be another effective
strategy for enhancing the antitumor activity of radiation.

CELL NECROSIS
Necrosis typically occurs after a large dose of photon radiation,27,34 but it has also been observed
in cancer cell lines and patient tumor tissue–derived cancer cells after a single 4-Gy or 6-Gy
dose of photon irradiation.35 Comparing the proportion of cells undergoing necrosis in four
HPV-related and HPV-unrelated human head and neck squamous carcinoma cell lines after a
single 4-Gy dose of proton or photon beam radiation, we found that proton and photon beams
only led to significantly increased necrosis in one HPV-unrelated cell line 48 hours after radia-
tion, and no differences were found between proton versus photon beams (Fig. 1.4B). Mecha-
nistic studies of tumor necrosis have identified several molecular targets that mediate necrosis
after treatment.34–36 Interfering with those molecular targets may be another new approach to
promote both proton and photon beam–induced necrotic cell death and may be a potential to
enhance radiosensitivity.34,35
In summary, mitotic catastrophe and senescence are the major types of cell death induced by
both photon and proton beams, and proton beams kill more cells by either mechanism than
photon beams. Individual cancer patients with different gene mutation statuses may derive dif-
ferent levels of benefit from targeted therapy that interferes with different cell death–related
pathways according to whether the radiotherapy is photon or proton based. Further mechanistic
and in vivo studies may open a new avenue of improving tumor control with proton or photon
radiation and lead to novel, individually optimized combination treatment plans consisting of
molecular-targeted therapy combined with proton or photon beams for cancer patients with
tumors of different biological features.

Relative Biological Effectiveness

Proton therapy has shown promise to protect normal tissues in the treatment of malignant dis-
eases such as pediatric cancers,37 central nervous system and skull base tumors,38–40 ocular mela-
noma,41,42 and head and neck cancers that are near critical structures43–45 and are difficult to treat
with surgery or conventional photon radiation.46,47 However, because of variations in the RBE of
protons in different types of cells or tissues,48,49 whether the dosimetric advantages of proton
1—PRINCIPLES OF RADIOBIOLOGY 9

12 SqCC/Y1 12 HN5
10 Control 10
XRT P all > .05
8 PRT 8
6 P < .05 6
Percentage of apoptotic cells

4 4
2 2
0 0
4h 24 h 48 h 4h 24 h 48 h
12 UPCI-SCC-154 12 UMSCC-47
10 10
P all > .05 P all > .05
8 8
6 6
4 4
2 2
0 0
4h 24 h 48 h 4h 24 h 48 h
A Time after 4 Gy irradiation (hours)

60 SqCC/Y1 60 HN5
P < .001
50 Control 50
XRT P < .05
P all > .05
40 PRT 40
30 30
20 20
Percentage of necrotic cells

10 10
0 0
4h 24 h 48 h 4h 24 h 48 h
60 UPCI-SCC-154 60 UMSCC-47
50 50
P all > .05 P all > .05
40 40
30 30
20 20
10 10
0 0
4h 24 h 48 h 4h 24 h 48 h
B Time after 4 Gy irradiation (hours)
Fig. 1.4 Necrosis and apoptosis in head and neck squamous cell carcinoma cell lines after photon (XRT) or
proton (PRT) irradiation. Two human papillomavirus (HPV)–negative cell lines (SqCC/Y1 and HN5) and two HPV-
positive cell lines (UPCI-SCC-154 and UMSCC-47) were subjected to terminal deoxy-nucleotidyltransferase
(TdT) dYTP nick-end labeling (TUNEL) and incubated with fluorescein isothiocyanate (FITC)-conjugated
annexin V and propidium iodide and analyzed by BD Accuri C6. Percentages of necrotic or apoptotic
cells were quantified with FlowJo V10 software. (A) Quantification of apoptotic cells. (B) Quantification of
necrotic cells.
10  PROTON THERAPY

Th1 Increased Tumor Radiation

cytokines expression
increase of vascular
adhesion
Th2
molecules
cytokines
(ICAM-1)
decrease
Dying tumor
Calreticulin
cells
translocation
Cytokines
Release of
release
DAMPs
(IL-10, IL-2,
Activation MHC1
Tumor TNFβ and
of ACP ATP
antigens others)
HMGB1 Reduced
release IL-12

T cell Reduced Th1 Regulatory T

Cytokines PD-L1
activation response cell response

Immunoactivation Abscopal tumor attack Immunosuppression

Fig. 1.5 Immune response changes after x-ray-based radiation. ATP, Adenosine triphosphate; DAMP,
damage-associated molecular pattern; HMGB1, high mobility group box-1; IL, interleukin; PD-L1, pro-
grammed death-ligand 1. (Summarized based on Diegeler S, Hellweg CE. Intercellular communication of
tumor cells and immune cells after exposure to different ionizing radiation qualities. Front Immunol.
2017;8:664 and Ebner DK, Tinganelli W, Helm A, et al. The immunoregulatory potential of particle radiation
in cancer therapy. Front Immunol. 2017;8:99.)

beams can be translated into demonstrable clinical benefits of normal tissue protection and tumor
control for these cancers remains unclear.
Currently, clinical use of proton beams is based largely on the experiences that are derived from
photon beam radiation. However, the difference in the energy deposition patterns of photon beams
and proton beams means that equal doses of proton or photon beam radiation do not produce equal
biological effects; one type of radiation may be more effective at killing cells than the other one. The
RBE of proton beams is defined as the ratio of the doses required for photon versus proton beams
radiation to produce the same level of biological effectiveness, such as cell killing or DNA dam-
age.50,51 The RBE of proton beams has been recognized as variable values. The RBE is determined
by a number of physical and biological factors, such as proton beam energy, depth, radiation dose,
radiation fraction size, radiation fraction number, cell or tissue types, and the end points.47,52–57 The
advantages of proton versus photon beams only can be presented in the case of accurately assured
higher/equal target volume dose and lowered surrounding normal tissue dose in proton radiation.
Therefore an accurate proton beam RBE is required in proton beam radiation.
In current clinical practice, the RBE of proton therapy has been assumed to be 1.1 regard-
less of tumor type, beam energy, and treatment planning differences.49 This RBE value was
mainly derived from preclinical experiments with normal cells or early-reacting normal tissues
rather than cancer cells or tumor xenografts.53–55 Moreover, these experiments also demon-
strated a big range of RBE at the middle of SOBP (ranging from 0.9 to 2.1 for in vitro ex-
periments and from 0.7 to 1.6 for in vivo experiments).52 Thus, use of this constant RBE
without considering differences in tumor biology or the effects of fractionation increases the
1—PRINCIPLES OF RADIOBIOLOGY 11

extent of clinical dose uncertainties for tumor and normal tissues associated with proton
therapy, the nature and extent of which are largely unknown but are crucial to the safe and
effective use of proton therapy.
More importantly, emerging evidence has established the increased RBE values in regions of
high LET at the distal falloff of most proton beams, which are normally located within the target
volume.58–60 Thus, special attention should bring in treatment planning of proton beam radiation
to avoid locating organs at risk to the distal portion of SOBP, which might induce normal tissue
complications at the distal field edges. Furthermore, because in vivo study also found a trend that
late-responding tissues may have higher RBE values compared with early-responding tissues,61
more attention should be placed on the observation of late normal tissue response in those
patients who accepted proton beam radiation in the clinical setting.
In summary, because of the uncertainties of the RBE in proton beam radiation, more studies
on the clinically relevant dose range in the response of different normal tissues or tumor types in
animals are needed.

Immune Response
Accumulated evidence has demonstrated that photon beam radiation not only can control tumor
by local tumor irradiation but can also influence tumor growth by the effects of photon radiation
on the activation and suppression of the immune system (Fig. 1.5).62–64 To avoid the immunosup-
pression effect and to enhance the immunoactivation effect of photon radiation, the impact of
photon radiation on the immune system is under extensive study currently to investigate the pos-
sibility of radiation and immune therapy combination to improve cancer treatment outcomes.

IMMUNOACTIVATION EFFECT OF PHOTON AND PROTON BEAMS

It has been demonstrated that photon radiation can influence tumor immune response through
different mechanisms, which include direct effects and indirect effects. Photon beams can directly
influence both immune cells and tumor cells to impact the tumor suppression effect of radiation.
One of the important mechanisms of the activation of tumor immunity by photon radiation is
that photon beams can turn tumor cells into in situ vaccine to facilitate tumor cell immune rec-
ognition by inducing the expression of different molecules on the surface of the tumor cells, in-
creased expression of adhesion molecules, death receptors, stress-induced ligands, and immune
cell stimulatory molecules.65–71
The direct damage caused by photon beams in tumor cells can lead to an increased expression
of major histocompatibility complex I, which can facilitate the immune cells to recognize the
tumor cells and initiate immune response to the tumor cells.62,72 The important factor of photon
beam–related immune activation is the presence of damage-associated molecular patterns
(DAMPs) in tumor cells after irradiation. Calreticulin (CRT), adenosine triphosphate, high
mobility group box-1 (HMGB1), and type I interferons are major factors in the DAMPs.27,73,74
Photon beam radiation can induce the translocation of CRT to the tumor cell surface.65,67 CRT
is a critical molecule that is involved in immune recognition to increase sensitivity of tumor cells
to T cell killing.65,75 A similar phenomenon was also observed after different types of tumor cells
were exposed to proton beams.65,67 When human prostate cancer cells (LNCaP), human breast
cancer cells (MDA-MB-231), human lung cancer cells (H1703), and chordoma cells ( JHC7)
were exposed to 200-MeV proton beams or photon beams of a dose of 8 Gy irradiation, increased
expression of surface molecules that are involved in immune recognition, such as HLA-ABC,
CEA, MUC-1, and ICAM-1, was observed after both photon and proton beam exposure; an
increased cell-surface CRT expression and cytotoxic T lymphocytes–mediated tumor cell lysis
was demonstrated.67 However, unlike those of photon beams, the changes of other members in
DAMPs in tumor cells after exposure to proton beams were absent and need to be uncovered.
Another random document with
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The Holy Virgin’s Descent into Hell. (XII. century.)
In spite of the prohibition of the Church, apocryphal
literature reached Russia from Byzantium by way of Bulgaria,
and not only spread all over Russia as a possession of the
people, but even crept into ecclesiastical literature, serving
frequently the same purpose as the writings of the Church
Fathers. These apocryphal productions, of which there is a
very large number, held sway over the people from the twelfth
to the seventeenth century, and even now form the
background of many popular tales and songs, especially of
those of the “wandering people” and beggars. One of the
most beautiful stories of this kind is The Holy Virgin’s Descent
into Hell, the Russian manuscript of which goes back to the
twelfth century. Similar stories were also current in Italy,
where there were colonies of Bulgarian Manicheans, who
were most active in disseminating them. Dante was, no doubt,
acquainted with them when he wrote his Divine Comedy.
The Holy Virgin wished to see the torments of the souls, and She
spoke to Michael, the archistrategos: “Tell me all things that are upon
earth!” And Michael said to Her: “As you say, Blessed One: I shall tell
you all things.” And the Holy Virgin said to him: “How many torments
are there, that the Christian race is suffering?” And the
archistrategos said to Her: “Uncountable are the torments!” And the
Blessed One spoke to him: “Show me, in heaven and upon earth!”
Then the archistrategos ordered the angels to come from the
south, and Hell was opened. And She saw those that were suffering
in Hell, and there was a great number of men and women, and there
was much weeping. And the Blessed One asked the archistrategos:
“Who are these?” And the archistrategos said: “These are they who
did not believe in the Father and the Son and the Holy Ghost, but
forgot God and believed in things which God has created for our
sakes; they called everything God: the sun and the moon, the earth
and water, beasts and reptiles. They changed Troyán, Khors, Velés,
Perún[100] to gods, and believed in evil spirits. They are even now
held in evil darkness, therefore they suffer such torments.”
And She saw in another place a great darkness. Said the Holy
Lady: “What is this darkness, and who are those who dwell therein?”
Spoke the archistrategos: “Many souls dwell in this place.” Spoke the
Holy Virgin: “Let the darkness be dispersed that I may see the
torment.” And the angels who watched over the torment answered:
“We have been enjoined not to let them see light until the coming of
your blessed Son who is brighter than seven suns.” And the Holy
Virgin was saddened, and She raised Her eyes to the angels and
looked at the invisible throne of Her Father and spoke: “In the name
of the Father and the Son and the Holy Ghost! Let the darkness be
taken off that I may see this torment.”
And the darkness was lifted, and seven heavens were seen, and
there dwelt there a great multitude of men and women, and there
was loud weeping and a mighty noise. When the Holy Virgin saw
them, She spoke to them, weeping tears: “What have you done,
wretched and unworthy people, and what has brought you here?”
There was no voice, nor an answer from them. And the watching
angels spoke: “Wherefore do you not speak?” And the tormented
said: “Blessed One! We have not seen light for a long time, and we
cannot look up.” The Holy Virgin looking at them wept bitterly. And
the tormented, seeing Her, said: “How is it, Holy Virgin, you have
visited us? Your blessed Son came upon earth and did not ask for
us, nor Abraham the patriarch, nor Moses the prophet, nor John the
Baptist, nor Paul the apostle, the Lord’s favourite. But you, Holy
Virgin and intercessor, you are a protection for the Christian
people.”... Then spoke the Holy Virgin to Michael the archistrategos:
“What is their sin?” And Michael said: “These are they who did not
believe in the Father and the Son and the Holy Ghost, nor in you,
Holy Virgin! They did not want to proclaim your name, nor that from
you was born our Lord Jesus Christ who, having come in the flesh,
has sanctified the earth through baptism: it is for this that they are
tormented here.” Weeping again, the Holy Virgin spoke to them:
“Wherefore do you live in error? Do you not know that all creation
honours my name?” When the Holy Virgin said this, darkness fell
again upon them.
The archistrategos spoke to Her: “Whither, Blessed One, do you
want to go now? To the south, or to the north?” The Blessed One
spoke: “Let us go out to the south!” And there came the cherubim
and the seraphim and four hundred angels, and took the Holy Virgin
to the south where there was a river of fire. There was a multitude of
men and women there, and they stood in the river, some to their
waists, some to their shoulders, some to their necks and some
above their heads. Seeing this, the Holy Virgin wept aloud and asked
the archistrategos: “Who are they that are immerged up to their
waists in the fire?” And the archistrategos said to Her: “They are
those who have been cursed by their fathers and mothers,—for this
the cursed ones suffer torment here.” And the Holy Virgin said: “And
those who are in the fiery flame up to their necks, who are they?”
The angel said to Her: “They are those who have eaten human flesh,
—for this they are tormented here.” And the Holy One said: “Those
who are immerged in the fiery flame above their heads, who are
they?” And the archistrategos spoke: “Those are they, Lady, who
holding the cross have sworn falsely.”... The Holy One spoke to the
archistrategos: “I beg you this one thing, let me also enter, that I may
suffer together with the Christians, for they have called themselves
the children of my Son.” And the archistrategos said: “Rest yourself
in paradise!” And the Holy One said: “I beg you, move the hosts of
the seven heavens and all the host of the angels that we may pray
for the sinners, and God may accept our prayer and have mercy
upon them. I beg you, order the angelic host to carry me to the
heavenly height and to take me before the invisible Father!”
The archistrategos so ordered, and there appeared the cherubim
and seraphim and carried the Blessed One to the heavenly height,
and put Her down at the throne of the invisible Father. She raised
Her hands to Her blessed Son and said: “Have mercy, O Master,
upon the sinners, for I have seen them, and I could not endure: let
me be tormented together with the Christians!” And there came a
voice to Her and said: “How can I have mercy upon them? I see the
nails in my Son’s hands.” And She said: “Master! I do not pray for the
infidel Jews, but for the Christians I ask Thy forgiveness!” And a
voice came to Her: “I see how they have had no mercy upon my
children, so I can have no mercy upon them.”
Spoke again the Holy One: “Have mercy, O Master, upon the
sinners,—the creation of Thine own hands, who proclaim Thy name
over the whole earth and even in their torments, and who in all
places say: “Most Holy Lady, Mother of God, aid us!” Then the Lord
spoke to Her: “Hear, Holy Mother of God! There is not a man who
does not praise Thy name. I will not abandon them, neither in
heaven, nor upon earth.” And the Holy Virgin said: “Where is Moses,
the prophet? Where are all the prophets? And you, fathers, who
have never committed a sin? Where is Paul, God’s favourite? Where
is the Sunday, the pride of the Christian? And where is the power of
the worshipful cross through which Adam and Eve were delivered
from their curse?” Then Michael the archistrategos and all the angels
spoke: “Have mercy, O Master, upon the sinners!” And Moses wept
loud and said: “Have mercy upon them, O Lord! For I have given
them Thy Law!” And John wept and said: “Have mercy, O Master! I
preached Thy gospel to them.” And Paul wept and said: “Have
mercy, O Master! For I carried Thine epistles to the churches.”
And those that were in the darkness heard of this, and they all
wept with one voice and said: “Have mercy upon us, Son of God!
Have mercy upon us, King of all eternity!” And the Master said: “Hear
all! I have planted paradise, and created man according to my
image, and made him lord over paradise, and gave him eternal life.
But they have disobeyed me and sinned in their selfishness and
delivered themselves to death.... You became Christians only in
words, and did not keep my commands; for this you find yourselves
now in the fire everlasting, and I ought not to have mercy upon you!
But to-day, through the goodness of my Father who sent me to you,
and through the intercession of my Mother who wept much for you,
and through Michael, the archistrategos of the gospel, and through
the multitude of my martyrs who have laboured much in your behalf,
I give you from Good Thursday to the holy Pentecost, day and night,
for a rest, and you praise the Father and the Son and the Holy
Ghost!” And they all answered: “Glory be to Thy goodness! Glory to
the Father and the Son and the Holy Ghost, now and for ever!”

FOOTNOTES:

[99] The slope of the mountain near Kíev, where to-day is the
suburb of Podól.
[100] Pagan divinities. For Troyán, see note on p. 82; Khors,
the god of the sun (cf. note on p. 93); Velés, the god of
abundance (cf. note on p. 83); Perún, the god of thunder (see p.
70).
 Daniel the Prisoner. (XIII. century.)
For some unknown reason Daniel had been imprisoned in
an island in the Lake of Lach, in the Government of Olónetsk.
He seems to have belonged to the druzhína of Yarosláv
Vsévolodovich of Pereyáslavl, who died in 1247 as Grand
Prince of Vladímir. That is all that is known about the life of
this layman, one of the few in the old period whose writing
has come down to our times. The begging letter which he
addressed to the Prince is composed of incorrectly quoted
biblical passages and popular saws and proverbs; many of
these he drew from an ancient collection, The Bee, in which
moral subjects are arranged in chapters. In their turn, Daniel’s
saws have largely entered into the composition of a very
popular collection of the same kind, The Emerald.

LETTER TO PRINCE YAROSLÁV VSÉVOLODOVICH

We will blare forth, O brothers, on the reasoning of our mind, as on

a trumpet forged of gold. We will strike the silver organs, and will
proclaim our wisdom, and will strike the thoughts of our mind, playing
on the God-inspired reeds, that our soul-saving thoughts might weep
loud. Arise, my glory! Arise, psalter and cymbals, that I may unfold
my meaning in proverbs, and that I may announce my glory in
words.... Knowing, O lord, your good disposition, I take refuge in
your customary kindness, for the Holy Writ says: Ask and you shall
receive. David has said: There is no speech nor language, where
their voice is not heard. Neither will we be silent, but will speak out to
our master, the most gracious Yarosláv Vsévolodovich.
Prince my lord! Remember me in your reign, for I, your slave, and
son of your slave, see all men warmed by your mercy as by the sun;
only I alone walk in darkness, deprived of the light from your eyes,
like the grass growing behind a wall, upon which neither the sun
shineth nor the rain falleth. So, my lord, incline your ears to the
words of my lips, and deliver me from all my sorrow.
 Prince my lord! All get their fill from the abundance of your house;
but I alone thirst for your mercy, like a stag for a spring of water. I
was like a tree that stands in the road and that all passers-by strike;
—even thus I am insulted by all, for I am not protected by the terror
of your wrath, as by a firm palisade.
Prince my lord! The rich man is known everywhere, even in a
strange city, while the poor man walketh unseen in his own. The rich
man speaketh and all are silent, and his words are elated to the
clouds; but let the poor man speak out, and all will call out to him, for
the discourse of those is honoured whose garments are bright. But
you, my lord, look not at my outer garb, but consider my inner
thoughts, for my apparel is scanty, and I am young in years, but old
in mind, and I have soared in thought like an eagle in the air.
Prince my lord! Let me behold your fair face and form. Your lips
drop honey; your utterances are like paradise with its fruit; your
hands are filled with gold of Tharsos; your cheeks are a vessel of
spices; your throat is like a lily dropping myrrh—your mercy; your
look is as the choice Lebanon; your eyes are like a well of living
water; your belly is like an heap of wheat, feeding many; your head
riseth above my head....
Prince my lord! Look not at me as a wolf at a lamb; but look at me
as a mother at her babe. Look, O lord, at the birds of the air, that
neither plough, nor sow, nor gather into granaries, but rely upon
God’s kindness. Let not your hand be closed against giving alms to
the needy. For it is written: Give to him who asketh of you, open to
him who knocketh, that you may not forfeit the kingdom of heaven.
For it is also written: Confide your sorrow to the Lord, and He will
nurture you until eternity. Deprive not the needy wise man of his
bread, but extol him to the clouds, like pure gold in a dirty vessel; but
the silly rich man is like a silken pillow-case stuffed full of straw.
Prince my lord! Though I am not a valiant man in war, yet am I
strong in words, and I cull the sweetness of words, mixing them, as
sea-water in a leather bottle, and wind them and adorn them with
cunning parables, and I am glib of speech and ... my lips are
pleasing, like a stream of the river rapids.
 Prince my lord! As an oak is strong by the multitude of its roots,
thus is our city under your domination. The helmsman is the head of
the vessel, and you, Prince, are the head of your people. I have seen
an army without a prince;—you might say: a big beast without its
head. Men are the heads of women, and princes—of men, and God
—of the prince. As the pillow-case that is adorned with silk makes a
pleasant appearance, even thus you, our Prince, are glorified and
honoured in many lands through the multitude of your men. As the
net does not hold the water, but keeps a multitude of fish, even thus
you, our Prince, keep not the wealth, but distribute it among the
strong, making them brave, for you will gain gold and cities through
them. Hezekiah, the King of the Jews, boasted before the
messengers of the King of Babylon, when he showed them the
treasure of his gold. But they answered: “Our kings are richer than
you, not with the treasure of gold, but with a multitude of brave and
wise men.” (For men will gain gold, but gold will not gain men.) Water
is the mother of the fish, and you are Prince of your people. Spring
adorns the earth with flowers, and you, Prince, adorn us with your
mercy. The sun alone warms with its rays, and you, Prince, adorn
and revive with your mercy.
Prince my lord! I have been in great distress, and have suffered
under the yoke of work: I have experienced all that is evil. Rather
would I see my foot in bast shoes in your house than in crimson
boots in the court of a boyár. Rather would I serve you in homespun
than in purple in the court of a boyár. Improper is a golden ring in the
nose of a swine, and a good garment upon a peasant. Even if a
kettle were to have golden rings in its handles, its bottom would not
escape blackness and burning. Even thus a peasant: let him be ever
so haughty and insolent, he will not escape his blemish, the name of
a peasant. Rather would I drink water in your house, than mead in
the court of a boyár; rather would I receive a roasted sparrow from
your hand than a shoulder of mutton from the hand of a bad master.
Often has my bread, earned by work, tasted as wormwood in my
mouth, and my drink I have mingled with tears. Serving a good
master, you gain your liberty in the end, but serving a bad master,
you only gain an increase of your labour. Solomon has said: Better is
one wise man than ten brave men without understanding; better is
one clever man than ten rulers of cities. Daniel has said: A brave
man, O Prince, you will easily acquire, but a wise man is dear; for
the counsel of the wise is good, and their armies are strong, and
their cities safe. The armies of others are strong, but without
understanding, and they suffer defeat. Many, arming themselves
against large cities, start out from smaller towns; as Svyatosláv, the
son of Ólga, said on his way to Constantinople to his small druzhína:
“We do not know, O brothers, whether the city is to be taken by us,
or whether we are to perish from the city: for if God is with us, who is
against us?”...
Not the sea draweth the ships, but the winds; even thus you, O
Prince, fall not yourself into grieving, but counsellors lead you into it.
Not the fire causeth the iron to be heated, but the blowing of the
bellows. A wise man is not generally valiant in war, but strong in
counsel; so it is good to gather wise men around you. It is good to
pasture horses in a fertile field (and to fight for a good prince). Often
armies perish through lack of order. If the armies are strongly placed,
they will, though they be defeated, make a good running fight; thus
Svyatopólk, who was guilty of killing his brothers, was so fortified,
that Yarosláv barely overcame him at night. Similarly Bonyák the
Scurfy through cunning routed the Hungarians at Gálich: when the
latter fortified themselves behind ramparts, the first scattered like
hunting men over the land; thus they routed the Hungarians, and
badly defeated them.
Prince my lord! I have not been brought up in Athens, nor have I
studied with the philosophers, but I have pored over books, like a
bee over all kinds of flowers: from them have I gathered sweetness
of speech, mingling wisdom with it, as sea-water in a leather bottle....
 Serapión, Bishop of Vladímir. (XIII. century.)
Serapión had been abbot of the monastery of the Grottoes
in Kíev, and in 1274 he was made bishop of Vladímir and
Súzdal. He died in 1275. We have five of his sermons, which
are distinguished for a certain simple, stern eloquence. The
thirteenth century produced very few writers, and Serapión’s
sermons have an additional interest because they contain
references to the Tartar invasion.

A SERMON ON OMENS

The Lord’s blessing be with you!

You have heard, brothers, what the Lord Himself has said in the
gospel: in the last years there will be signs in the sun, in the moon,
and in the stars, and earthquakes in many places, and famine. What
had been foretold by the Lord then, is now fulfilled in our days.[101]
We have seen many times the sun perished, the moon darkened,
and the stars disturbed, and lately we have seen with our own eyes
the quaking of the earth. The earth, firm and immovable from the
beginning by the order of God, is in motion to-day, trembling on
account of our sins, being unable to bear our lawlessness. We did
not obey the gospel, did not obey the apostles, nor the prophets, nor
the great luminaries, I mean Basil and Gregory the theologues, John
Chrysostom, and the other holy fathers, by whom the faith was
confirmed, the heretics repelled, and God made known to all the
nations. They have taught us without interruption, but we are living in
lawlessness.
It is for this that God is punishing us with signs and earthquakes.
He does not speak with His lips, but chastises with deeds. God has
punished us with everything, but has not dispelled our evil habits:
now He shakes the earth and makes it tremble: He wants to shake
off our lawlessness and sins from the earth like leaves from a tree. If
any should say that there have been earthquakes before, I shall not
deny it. But what happened to us afterwards? Did we not have
famine, and plague, and many wars? But we did not repent, until
finally there came upon us a ruthless nation, at the instigation of
God, and laid waste our land, and took into captivity whole cities,
destroyed our holy churches, slew our fathers and brothers, violated
our mothers and sisters. Now, my brothers, having experienced that,
let us pray to our Lord, and make confession, lest we incur a greater
wrath of the Lord, and bring down upon us a greater punishment
than the first.
Much is still waiting for our repentance and for our conversion. If
we turn away from corrupt and ruthless judgments, if we do away
with bloody usury and all rapacity, thefts, robbery, blasphemy, lies,
calumny, oaths, and denunciations, and other satanic deeds,—if we
do away with all that, I know well that good things will come to us in
this life and in the future life. For He Himself hath said: Turn to me,
and I will turn to you. Keep away from everything, and I will withhold
your punishment. When will we, at last, turn away from our sins? Let
us spare ourselves and our children! At what time have we seen so
many sudden deaths? Many were taken away before they could care
for their houses; many lay down well in the evening and never arose
again. Have fear, I pray you, of this sudden parting! If we wander in
the will of the Lord, God will comfort us with many a comfort, will
cherish us as His sons, will take away from us earthly sorrow, will
give us a peaceful exit into the future life, where we shall enjoy
gladness, and endless happiness with those who do the will of the
Lord.
I have told you much, my brothers and children, but I see our
punishments will not be diminished, nor changed. Many take no
heed, as if they weened themselves to be immortal. I am afraid that
the word of God will come to pass with them: If I had not spoken to
them, they would not have sinned; but now they have no excuse for
their sin. And I repeat to you, if we do not change, we shall have no
excuse before the Lord. I, your sinful pastor, have done the
command of God in transmitting His word to you.
 FOOTNOTES:

[101] These disturbances of nature are mentioned in the

Chronicle under the year 1230.
 The Zadónshchina. (XIV. century.)
The Zadónshchina, i. e., The Exploits beyond the Don, has
come down in two versions, and is an interesting poetical
account of the battle at Kulikóvo (1380). The Word of Ígor’s
Armament had taken a strong hold on the author, who seems
to have been a certain Sofóniya of Ryazán. Not only are there
many parallels in the two poems, but whole passages are
bodily taken from the older text, with corruption of some
phrases, the meaning of which was not clear to the author of
the Zadónshchina.

THE ZADÓNSHCHINA

Let us go, O brothers, into the midnight country, the lot of Japheth,
[102] the son of Noah, from whom has risen the most glorious Russia;
let us there ascend the Kíev mountains, and look by the smooth
Dnieper over the whole Russian land, and hence to the Eastern land,
the lot of Shem, the son of Noah, from whom were born the Chinese,
[103] the pagan Tartars, the Mussulmans. They had defeated the race

of Japheth on the river Kayála.[104] And ever since, the Russian land
has been unhappy, and from the battle of the Kálka[105] up to
Mamáy’s defeat it has been covered with grief and sorrow, weeping
and lamenting its children. The Prince and the boyárs, and all the
brave men who had left all their homes, and wealth, and wives,
children, and cattle, having received honour and glory of this world,
have laid down their heads for the Russian land and the Christian
faith.
Let us come together, brothers and friends, sons of Russia! Let us
join word to word! Let us make the Russian land merry, and cast
sorrow on the eastern regions that are to the lot of Shem! Let us sing
about the victory over the heathen Mamáy, and an eulogy to the
Grand Prince Dmítri Ivánovich and his brother,[106] Prince Vladímir
Andréevich!... We shall sing as things have happened, and will not
race in thought, but will mention the times of the first years; we will
praise the wise Boyán,[107] the famous musician in Kíev town. That
wise Boyán put his golden fingers on the living strings, sang the
glory of the Russian princes, to the first Prince Rúrik, Ígor Rúrikovich
and Svyatosláv, Yaropólk, Vladímir Svyatoslávich, Yarosláv
Vladímirovich, praising them with songs and melodious musical
words.—But I shall mention Sofóniya of Ryazán, and shall praise in
songs and musical words the Prince Dmítri Ivánovich and his
brother, Prince Vladímir Andréevich, for their bravery and zeal was
for the Russian land and the Christian faith. For this, Grand Prince
Dmítri Ivánovich and his brother, Prince Vladímir Andréevich,
sharpened their hearts in bravery, arose in their strength, and
remembered their ancestor, Prince Vladímir of Kíev, the tsar of
Russia.
O lark, joy of beautiful days! Fly to the blue clouds, look towards
the strong city of Moscow, sing the glory of Grand Prince Dmítri
Andréevich! They have risen like falcons from the Russian land
against the fields of the Pólovtses. The horses neigh at the Moskvá;
the drums are beaten at the Kolómna; the trumpets blare at
Serpukhóv; the glory resounds over the whole Russian land.
Wonderfully the standards stand at the great Don; the embroidered
flags flutter in the wind; the gilded coats of mail glisten. The bells are
tolled in the vyéche[108] of Nóvgorod the Great. The men of
Nóvgorod stand in front of St. Sophia, and speak as follows: “We
shall not get in time to the aid of Grand Prince Dmítri Ivánovich.”
Then they flew together like eagles from the whole midnight country.
They were not eagles that flew together, but posádniks[109] that went
out with 7000 men from Nóvgorod the Great to Grand Prince Dmítri
Ivánovich and to his brother Vladímir Andréevich.
All the Russian princes came to the aid of Grand Prince Dmítri
Ivánovich, and they spoke as follows: “Lord Grand Prince! Already
do the pagan Tartars encroach upon our fields, and take away our
patrimony. They stand between the Don and Dnieper, on the river
Mechá.[110] But we, lord, will go beyond the swift river Don, will gain
glory in all the lands, will be an object of conversation for the old
men, and a memory for the young.”
Thus spoke Grand Prince Dmítri Ivánovich to his brothers, the
Russian princes: “My dear brothers, Russian princes! We are of the
same descent, from Grand Prince Iván Danílovich.[111] So far we
brothers have not been insulted either by falcon, or vulture, or white
gerfalcon, or this dog, pagan Mamáy.”
Nightingale! If you could only sing the glory of these two brothers,
Ólgerd’s sons,[112] Andréy of Pólotsk and Dmítri of Bryansk, for they
were born in Lithuania on a shield of the vanguard, swaddled under
trumpets, raised under helmets, fed at the point of the spear, and
given drink with the sharp sword. Spoke Andréy to his brother Dmítri:
“We are two brothers, sons of Ólgerd, grandchildren of Gedemín,
great-grandchildren of Skoldimér. Let us mount our swift steeds, let
us drink, O brother, with our helmets the water from the swift Don, let
us try our tempered swords.”
And Dmítri spoke to him: “Brother Andréy! We will not spare our
lives for the Russian land and Christian faith, and to avenge the
insult to Grand Prince Dmítri Ivánovich. Already, O brother, there is a
din and thunder in the famous city of Moscow. But, brother, it is not a
din or thunder: it is the noise made by the mighty army of Grand
Prince Dmítri Ivánovich and his brother Prince Vladímir Andréevich;
the brave fellows thunder with their gilded helmets and crimson
shields. Saddle, brother Andréy, your good swift steeds, for mine are
ready, having been saddled before. We will ride out, brother, into the
clear field, and will review our armies, as many brave men of
Lithuania as there are with us, but there are with us of the brave men
of Lithuania seven thousand mailed soldiers.”
Already there have arisen strong winds from the sea; they have
wafted a great cloud to the mouth of the Dnieper, against the
Russian land; bloody clouds have issued from it, and blue lightnings
flash through them. There will be a mighty din and thunder between
the Don and the Dnieper, and bodies of men will fall on the field of
Kulikóvo, and blood will flow on the river Nepryádva, for the carts
have already creaked between the Don and Dnieper, and the pagan
Tartars march against the Russian land. Grey wolves howl: they wish
at the river Mechá to invade the Russian land. Those are not grey
wolves: the infidel Tartars have come; they wish to cross the country
in war, and to conquer the Russian land. The geese have cackled
and the swans have flapped their wings,—pagan Mamáy has come
against the Russian land and has brought his generals....
What is that din and thunder so early before daybreak? Prince
Vladímir Andréevich has reviewed his army and is leading it to the
great Don. And he says to his brother, Grand Prince Dmítri
Ivánovich: “Slacken not, brother, against the pagan Tartars, for the
infidels are already in the Russian land, and are taking away our
patrimony!”...
The falcons and gerfalcons have swiftly flown across the Don, and
have swooped down on the many flocks of swans: the Russian
princes have attacked the Tartar might, and they strike with their
steel lances against the Tartar armour; the tempered swords thunder
against the Tartar helmets on the field of Kulikóvo, on the river
Nepryádva. Black is the earth under the hoofs, but they had sowed
the field with Tartar bones, and the earth was watered with their
blood, and mighty armies passed by and trampled down hills and
fields, and the rivers, springs and lakes were turbid. They uttered
mighty cries in the Russian land ... and they vanquished the Tartar
horde on the field of Kulikóvo, on the river Nepryádva.
On that field mighty clouds encountered, and in them lightnings
frequently flashed, and terrible thunders clapped: it is the Russian
brave warriors who were engaging the pagan Tartars for the great
insult, and their mighty gilded armour glistened, and the Russian
princes thundered with their tempered swords against the Tartar
helmets....
At that time neither soldiers nor shepherds called in the field near
the Don, in the land of Ryazán, but only ravens croaked for the sake
of the bodies of the dead, so that it was a terror and a pity to hear:
for the grass was watered with blood, and the trees were bent to the
ground with sorrow, and the birds sang pitiful songs. All princesses
and wives of the boyárs and generals wept for the slain. Fedósya,
the wife of Mikúla Vasílevich,[113] and Mary, the wife of Dmítri, wept
early in the morning at Moscow, standing on the city wall, and spoke
as follows: “Don, Don, you are a swift river, and have cut through
stone walls, and flow through the land of the Pólovtses! Bring back
my beloved one to me!”...
All over the Russian land there spread joy and merriment: the
Russian glory was borne through the land, but shame and
destruction came on the pagan Tartars, evil Mussulmans.... The
Grand Prince by his own bravery and with his druzhína vanquished
pagan Mamáy for the sake of the Russian land and the Christian
faith. The pagans deposited their own arms under the Russian
swords, and the trumpets were not sounded, their voices were silent.
Mamáy galloped away from his druzhína, howled like a grey wolf,
and ran away to the city of Khafest....[114]

FOOTNOTES:

[102] The Byzantine chronographers generally begin their

accounts with Noah; so does Néstor, who follows those sources.
[103] The original has a word derived from Khin, which seems
to be identical with “China,” and is used in general for Asiatics.
[104] See pp. 75 and 89.
[105] The battle with the Tartars at the river Kálka took place in
1224.
[106] Vladímir Andréevich was the cousin of Dmítri Donskóy,
the son of Iván II.
[107] In the text the word is boyarin, i. e., “boyár,” evidently a
corruption of Boyán, which is one of the proofs of the
Zadónshchina being a later imitation of the Word of Ígor’s
Armament.
[108] Popular assembly of Nóvgorod.
[109] Burgomasters or governors of Nóvgorod.
[110] Tributary of the Don.
[111] Iván Kalitá, 1328-1340.
 [112] These Lithuanian Princes had acknowledged the
sovereignty of Moscow.
 Afanási Nikítin. (XV. century.)
Nikítin set out about 1468 for India, whence he returned in
1474. He wrote out an account of his many adventures, which
is interesting for its sober though rather one-sided narration. It
stands alone in the old Russian literature as the writing of a
layman bent on a commercial enterprise. His Travel to India
has been translated by Count Wielhorsky for the Hakluyt
Society.

TRAVEL TO INDIA

I, poor sinner, brought a stallion to the land of India; with God’s

help I reached Junir all well, but it cost me a hundred roubles.
The winter began from Trinity day, and we wintered at Junir and
lived there two months; but day and night for four months there is but
rain and dirt. At this time of the year the people till the ground, sow
wheat, tuturegan (?), peas, and all sorts of vegetables. Wine is kept
in large skins (?) of Indian goats....
Horses are fed on peas; also on kichiris, boiled with sugar and oil;
early in the morning they get shishenivo. Horses are not born in that
country, but oxen and buffaloes; and these are used for riding,
conveying goods, and every other purpose.
Junir stands on a stony island; no human hand built it—God made
the town. A narrow road, which it takes a day to ascend, admitting of
only one man at a time, leads up a hill to it.
In the winter, the people put on the fata, and wear it around the
waist, on the shoulders, and on their head; but the princes and
nobles put trowsers on, a shirt and a caftan, wearing a fata on the
shoulders, another as a belt round the waist, and a third round their
head.
O God, true God, merciful God, gracious God!
 At Junir the Khan took away my horse, and having heard that I
was no Mahommedan, but a Russian, he said: “I will give thee the
horse and a thousand pieces of gold, if thou wilt embrace our faith,
the Mahommedan faith; and if thou wilt not embrace our
Mahommedan faith, I shall keep the horse and take a thousand
pieces of gold upon thy head.” He gave me four days to consider,
and all this occurred during the fast of the Assumption of our Lady,
on the eve of our Saviour’s day (18th of August).
And the Lord took pity upon me because of His holy festival, and
did not withdraw His mercy from me, His simple servant, and allowed
me not to perish at Junir among the infidels. On the eve of our
Saviour’s day there came a man from Khorassan, Khozaiocha
Mahmet, and I implored him to pity me. He repaired to the Khan into
the town, and praying him delivered me from being converted, and
took from him my horse. Such was the Lord’s wonderful mercy on
the Saviour’s day.
Now, Christian brethren of Russia, whoever of you wishes to go to
the Indian country may leave his faith in Russia, confess Mahomet,
and then proceed to the land of Hindostan. Those Mussulman dogs
have lied to me, saying I should find plenty of our goods; but there is
nothing for our country. All goods for the land of Mussulmans, as
pepper and colours, and these are cheap.
The rulers and the nobles in the land of India are all
Khorassanians. The Hindoos walk all on foot and walk fast. They are
all naked and bare-footed, and carry a shield in one hand and a
sword in the other. Some of the servants are armed with straight
bows and arrows.
Elephants are greatly used in battle. The men on foot are sent
first, the Khorassanians being mounted in full armour, man as well as
horse. Large scythes are attached to the trunks and tusks of the
elephants, and the animals are clad in ornamental plates of steel.
They carry a citadel, and in the citadel twelve men in armour with
guns and arrows.
There is a place Shikhbaludin Peratyr, a bazaar Aladinand, and a
fair once a year, where people from all parts of India assemble and