Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 5, pp.

1442–1451, 2006
Copyright © 2006 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/06/$–see front matter

doi:10.1016/j.ijrobp.2005.10.014

CLINICAL INVESTIGATION Normal Tissues

ADVERSE EVENT REPORTING AND DEVELOPMENTS IN RADIATION

BIOLOGY AFTER NORMAL TISSUE INJURY: INTERNATIONAL ATOMIC
ENERGY AGENCY CONSULTATION

YUHCHYAU CHEN, PH.D., M.D.,* ANDY TROTTI, M.D.,† C. NORMAN COLEMAN, M.D.,‡
MITCHELL MACHTAY, M.D.,§ RENE O. MIRIMANOFF, M.D.,储 JOHN HAY, MB. BCHIR.,¶
PETER C. O’BRIEN, M.B., B.S.,# BRAHIM EL-GUEDDARI, M.D.,** JOAO V. SALVAJOLI, M.D.,††
‡‡
AND BRANISLAV JEREMIC, M.D., PH.D.

*Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry,
Rochester, NY; †Division of Radiation Oncology, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL;
‡
Radiation Oncology Sciences Program, National Cancer Institute, Bethesda, MD; §Radiation Oncology at Thomas Jefferson
University Hospital, Philadelphia, PA, and Radiation Therapy Oncology Group; 储Centre Hospitalier Universitaire,
Vaudois, Lausanne, Switzerland, and European Organization for Research and Treatment of Cancer, Brussels, Belgium;
¶
British Columbia Cancer Agency, Vancouver, Canada, and National Cancer Institute of Canada Clinical Trials Group,
Toronto, Ontario, Canada; #Department of Radiation Oncology, Newcastle Mater Hospital, and
Trans-Tasman Radiation Oncology Group, Newcastle, New South Wales, Australia;
**National Institut of Oncology, Rabat, Morocco, and African Radiation Oncology Group, Cape Town, South Africa;
††
Hospital do Cancer—A.C. Camargo, Sao Paulo, Brazil, and Curriculo Radioterapeutica Ibero Latino Americana, Lima, Peru;
‡‡
Applied Radiation Biology and Radiotherapy Section, International Atomic Energy Agency, Vienna, Austria

Purpose: Recent research has enhanced our understanding of radiation injury at the molecular-cellular and
tissue levels; significant strides have occurred in standardization of adverse event reporting in clinical trials. In
response, the International Atomic Energy Agency, through its Division of Human Health and its section for
Applied Radiation Biology and Radiotherapy, organized a consultation meeting in Atlanta (October 2, 2004) to
discuss developments in radiobiology, normal tissue reactions, and adverse event reporting.
Methods and Materials: Representatives from cooperative groups of African Radiation Oncology Group,
Curriculo Radioterapeutica Ibero Latino Americana, European Organization for Research and Treatment of
Cancer, National Cancer Institute of Canada Clinical Trials Group, Radiation Therapy Oncology Group, and
Trans-Tasman Radiation Oncology Group held the meeting discussion.
Results: Representatives of major radiotherapy groups/organizations and prominent leaders in radiotherapy dis-
cussed current understanding of normal tissue radiobiologic effects, the design and implementation of future clinical
and translational projects for normal tissue injury, and the standardization of adverse-event reporting worldwide.
Conclusions: The consensus was to adopt NCI comprehensive adverse event reporting terminology and grading
system (CTCAE v3.0) as the new standard for all cooperative group trials. Future plans included the imple-
mentation of coordinated research projects focusing on normal tissue biomarkers and data collection methods.
© 2006 Elsevier Inc.

IAEA, Radiotherapy, Late effects, Biomarkers, Common toxicity criteria.

INTRODUCTION (1–5), and survivors of nuclear accidents (6), occupational

exposure (7, 8), and exposure from the atomic bomb (9, 10).
Radiation oncologists and researchers have long recognized There has been a great deal of cooperative research activity:
the serious nature of complications from radiation exposure. a number of recent NCI workshops have been held to
Late radiation adverse sequelae is a continuum of acute, address mechanisms of normal tissue injury and their rela-
subacute, and long-term normal tissue effects that have been tionship to wound healing (11), to develop a comprehensive
observed in those receiving therapeutic radiation for cancer scoring system for adverse effects from cancer therapy

Reprint requests to: Yuhchyau Chen, Ph.D., M.D., Department Technical Meeting on Late Normal Tissue Toxicity in Radiother-
of Radiation Oncology, James P. Wilmot Cancer Center, Univer- apy, on Oct 2, 2004, in Atlanta, GA.
sity of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY Acknowledgments—The authors would like to thank Ms. Amy
14642-8647. Tel: (585) 275-5623; Fax: (585) 275-1531; E-mail: Huser for writing and editing assistance.
Yuhchyau_chen@urmc.rochester.edu Received June 2, 2005, and in revised form Oct 3, 2005.
Presented at the International Atomic Energy Agency (IAEA) Accepted for publication Oct 11, 2005.

1442
 IAEA 2005 radiation normal tissue injury report ● Y. CHEN et al. 1443

called Common Terminology Criteria for Adverse Events tumors have been observed (10, 16). Although a relatively
version 3.0 (CTCAE v3.0) (12), and to review the state-of- rare event, radiation-induced cancer has been reported in
the-science in mechanisms of radiation injury (13). In ad- survivors of cancer therapy, as well as in survivors of
dition, a Late Effects of Normal Tissue (LENT V) meeting atomic radiation from atomic bombing, occupational expo-
was held in May 2004 in Rochester, NY, with the proceed- sure, or nuclear accidents (17). Second malignancy was also
ings forthcoming from the journal Radiotherapy & Oncol- reported in individuals who received radiation for benign
ogy. Furthermore, a Working Group for the Office of Sci- conditions such as thymic gland enlargement in infants,
ence and Technology Policy of the White House has ankylosing spondylitis of spine, tinea capitis in children,
summarized the state-of-the-science in developing radiation and others (18).
countermeasures (14). In general, the effects of radiation on humans have been
The section for Applied Radiation Biology and Radio- studied by three groups of researchers. The first group
therapy of the Division of Human Health (Nuclear Appli- investigates the environmental impact of chronic, low-dose
cations and Human Health) at the International Atomic radiation lower than 1 Gy. These studies have been sup-
Energy Agency is addressing a number of critical issues in ported by the National Institutes of Health, Department of
the field of radiation oncology worldwide. Recognizing the Energy, and National Aeronautics and Space Administra-
challenges of adverse events occurring from radiation ther- tion. The second group studies high-dose, single-dose, or
apy (RT), radiation accidents, and terrorism, Applied Radi- fractionated radiation in the range generally higher than 10
ation Biology and Radiotherapy/Nuclear Applications and Gy and up to 100 Gy. These studies have been performed by
Human Health/International Atomic Energy Agency orga- the radiation oncology and biology communities supported
nized a technical meeting in Atlanta, on Oct. 2, 2004, with by the National Cancer Institute and other funding agencies.
the aim of assembling representatives of major radiotherapy Single-dose exposure, as may occur in a nuclear attack or
groups and organizations to discuss the current status and accident, has been of interest to the Department of Defense
the problem of adverse event reporting in radiation oncol- and the Armed Forces Radiobiology Research Institute. The
ogy. This assembly had an initial task of both evaluating terrorist attack in New York City and the Pentagon on Sept
current aspects of adverse events reporting in the various 11, 2001, heightened concern regarding radiologic/nuclear
cooperative group settings and providing insight into cur- terrorism via an improvised nuclear device, a dirty bomb, or
rent thinking on the biologic premises of adverse events environmental contamination with radioisotopes for radia-
after RT. In particular, long-term consequences on normal tion researchers and pertinent government agencies. Re-
tissues were emphasized after RT alone and in combination search in this scenario deals with a radiation dose range of
with drug treatment, including chemotherapy, sensitizers, 1–10 Gy, which was termed moderate-dose radiation (13).
and bioprotective agents. It was also envisaged that this Furthermore, with the recent implementation of intensity-
meeting could lead to a number of improvements in clinical modulated radiotherapy, moderate-dose radiation is increas-
adverse event reporting, which may be applicable world- ingly relevant to clinical radiation therapy for cancer. The
wide. Finally, new biomarkers for radiation normal tissue ability to focus and shape the radiation through multibeam,
injury, application of agents for mitigating radiation inju- multiplanar, and arc beams has led to more tissues receiving
ries, as well as assays for radiation biodosimetry were all low or moderate radiation doses, compared with the more
discussed as both necessary to refine cancer therapy and conventional, three-dimensional conformal approaches.
mitigate radiation effects. Relevant observations on the limitations of intensity-mod-
ulated radiotherapy include that it may produce a signifi-
cantly higher whole-body dose (19), and that, although the
THE BIOLOGIC BASIS OF NORMAL TISSUE
incidence of radiation inducible cancer is low (approxi-
EFFECTS OF RADIATION
mately 1%), intensity-modulated radiotherapy may lead to a
Normal tissue injury from radiation doubling of radiation-induced cancers (20). Indeed, second-
The improvements in cancer curability, long-term sur- ary cancers tend to occur at the margins of the field (ap-
vival, and organ preservation after radiation treatment, as proximately 6 Gy) (21). The consequences of large-volume,
well as improvements in combined modality therapy have moderate-dose radiation normal tissue exposure, via treat-
resulted in many cancer patients living with the late, adverse ment or accident, needs to be closely studied and monitored.
effects. Long-term follow-up of these individuals reveals
progressive fibrosis and functional impairment of organs Biomarkers and mechanisms of normal tissue injury
along with associated comorbidities such as decreased tis- Research on biomarkers for radiation injury has revealed
sue compliance, accelerated senescence of organs, the de- information vital to the understanding of molecular targets
cline of endocrine function, infertility, cardiac dysfunction, and cellular pathways of radiation, starting with initial in-
joint stiffness, myelopathy, neurocognitive impairment, and juries and continuing through the perpetual normal tissue
others (15). Apart from the tissue and organ structural late effects. Not only do biomarkers reveal mechanisms of
damage, radiation DNA damage may cause malignant trans- radiation injuries, but they may also serve as potential tools
formation of normal cells in the form of mutagenesis and for dose estimation (i.e., biodosimetry), which is critical for
carcinogenesis. Both hematopoietic malignancy and solid managing acute radiation damage by facilitating the identi-
1444 I. J. Radiation Oncology ● Biology ● Physics Volume 64, Number 5, 2006

fication of those who received low-, moderate-, or high-dose The application of this methodology using peripheral blood
exposure, thereby providing complementary measures in specimens had to overcome the splenic filtering effect of
predicting potential long-term sequelae of radiation acci- some species such as rat and human. After refining staining
dents or of cancer treatment. protocols and calibration of the flow-cytometry, researchers
Markers for genotoxicity. The biologic effects of radia- have developed a high throughput, automated analysis of
tion result principally from damage to DNA, either by direct MN-RET using a small quantity (2 mL) of peripheral blood
action of radiation or through the indirect pathways involv- samples (31). The advantage of this method is that it is an
ing free radicals. Accidental radiation exposure may be in vivo assay without the need for ex vivo cultures, and is
immediate or protracted, and partial body exposure might rapid, sensitive, objective, and is potentially applicable to
be a common consequence of the detonation of an impro- multi-center analyses for population-based, large-scale mea-
vised nuclear device. The possibility of radiologic/nuclear surements after radiation exposure. In a pilot study of cancer
terrorism has brought attention to the critical need for rapid patients exposed to radiation or chemotherapy for cancer
and accurate biodosimetry. The traditional radiation bi- treatment, MN-RET has demonstrated its potential utility to
omarker for genotoxicity is based on chromosome aberra- assess bone marrow genotoxicity, as well as rapid biodo-
tions using a cytogenetic method of lymphocyte karyotyp- simetry in the event of accidental or occupational exposure
ing. This method manually scores cultured lymphocytes to radiation (31).
expanded ex vivo by plant mitogens such as phytohemag- Cytokine markers for normal tissue injury. What is
glutinin and subsequently blocked in metaphase. Cytoge- emerging from the advances in molecular and cellular bi-
neticists specializing in karyotyping are necessary for this ology is a remarkable opportunity to understand the mech-
methodology because they score the frequency of dicen- anisms of radiation normal tissue injury, which serves as the
trics, acentrics, ring chromosomes, and translocations. Di- basis for the comprehensive grading system for the adverse
centric scoring has been applied to radiation biodosimetry effects of cancer treatment (32). Although clinical manifes-
given the advantage of zero background in nonirradiated in- tation of radiation normal tissue injury has traditionally
dividuals. The International Atomic Energy Agency (IAEA) been grouped temporally into early and late effects, using a
has endorsed cytogenetic measurement for biologic dosime- relatively arbitrary dividing time line of 90 days after ther-
try and radiation genotoxicity and detailed the methodology apy, research in the past two decades emphasizes that nor-
and the scoring criteria (22). This methodology is time mal tissue injury is a dynamic and progressive process
consuming, requires lymphocyte ex vivo cultures, and has without a cutoff time point separating acute radiation
been applied to dose estimation after exposure to both low effects from late effects. These events start from energy
linear energy transfer radiation and high linear energy trans- deposition through molecular change of DNA damage,
fer radiation (23, 24). Automated or semiautomated systems radiation-inducible processes, changes in cytokine mi-
have been developed and some are commercialized in im- lieu, changes in cell-to-cell interaction, the influx of
proving throughput of analyses, but at the expense of less inflammatory cells, to the induction of reparative and
accuracy (25, 26). restorative processes. These events lead to gradual tissue
Subsequently, a cytokinesis-blocked micronucleus assay loss or destruction, and impaired organ function.
has been applied to population-based monitoring of genetic Radiation triggers an interaction between the damaged
damage, screening of chemicals for genotoxic potential, or cells and their microenvironment through chemokines, in-
prediction of radiation sensitivity (27, 28). Micronuclei are flammatory cytokines, fibrotic cytokines, and other humoral
fragments of chromosomes (or an entire chromosome) that factors (33, 34). The effect of radiation on normal soft tissue
are not incorporated in the cell division process after DNA has been compared with a dynamic spectrum of injury,
damage or damage to the spindle apparatus. Very low levels repair, inflammation, and compensatory responses (35).
of micronuclei are present in nonirradiated individuals or Both the basic science research and clinical data suggest
samples. A cytokinesis-blocked micronucleus assay scores that changes in local and systemic cytokine expression are
binucleated lymphocytes containing micronuclei after ex an integral part of the ongoing development of radiation-
vivo culture with expansion by plant mitogens, with cyto- related inflammation and fibrogenesis. These humoral fac-
kinesis blocking after one cell cycle progression. The tors modulate the host-immune response to radiation injury
method is adaptable to many laboratories and does not by mediating cell-to-cell interaction, recruitment of immune
require the expertise of a specialized cytogeneticist (29). cells to participate in radiation inflammatory reaction, and a
Automated scoring of micronuclei in binucleated human lym- chronic but progressive process of tissue hypoxia, perpetual
phocytes has also been reported (30). tissue damage, and long-term fibrosis (36).
A newer method in development is based on genotoxicity Radiation exposure induces a cascade of responses by
assessment, which scores micronucleated reticulocytes upregulating the expression of genes with various cytokine
(MN-RET). MN-RET analysis is an in vivo assay of DNA functions (37). Radiation injury to lung has been exten-
damage to cells involved in erythropoiesis and traditionally sively investigated in animal research models. Key cytokine
requires biopsy of the bone marrow. MN-RET is a Food and mediators of injury have been identified, including chemo-
Drug Administration–approved method for genotoxicity kines and adhesion molecules such as monocyte chemotac-
testing of food and chemical agents using animal models. tic protein 1, intercellular adhesion molecule-1, and inter-
 IAEA 2005 radiation normal tissue injury report ● Y. CHEN et al. 1445

feron-inducible protein 10, which are involved in the early sures, the general term “radioprotector” has been defined as
extravasation of and migration of these inflammatory and follows (51): radiation protection/prophylaxis agents are ad-
immune cells to the site of radiation injury (38, 39). Inflam- ministered before exposure (e.g., amifostine or Tempol);
matory cytokines such as tumor necrosis factor, interleukin radiation mitigators are given after exposure to reduce the
(IL)-6, and IL-1 are involved in the inflammatory process of effect of exposure: this might be a decorporation agent (e.g.,
radiation response, whereas fibrotic cytokines such as trans- Prussian Blue for cesium) or one that decreases tissue
forming growth factor (TGF)-␤1, basic fibroblast growth uptake (e.g., KI for radioactive iodine), or an agent that
factor (bFGF), and platelet-derived growth factor (PDGF) reduces renal injury (e.g., the ACE inhibitors or AII inhib-
are involved in the progressive fibrosis of tissue (37, 40). itors) (52, 53); therapeutics are agents that treat existing in-
Investigations in humans have found an increase of IL-6 and jury, such as superoxide dismutase or pentoxifylline (49, 50).
TGF-␤ in the bronchoalveolar lavage fluid of the irradiated To effectively develop countermeasures requires under-
chest regions of cancer patients but not in the nonirradiated standing of the relationship between molecular mechanisms
chest regions (41). At the systemic level, the circulating and the appropriate clinical applications, and this necessi-
levels of soluble intracellular adhesion molecule (42), IL-1 tates a range of model systems as well as expertise in
(43, 44), IL-6 (56), and TGF-␤ (45) have all been found to pharmaceutical development (54). Recent research has
be associated with radiation pneumonitis in cancer patients demonstrated novel molecular targets for radiation counter-
receiving thoracic radiotherapy. measures. Some examples are the TGF-␤ pathway (55–57),
Molecular markers of radiation-inducible genes. A num- tumor suppressor gene p53 pathway (58, 59), and the cer-
ber of cancer patients receiving radiotherapy have demon- amide pathway (60). It is beyond the scope of this article to
strated a genetically determined normal tissue radiosensi- provide detailed discussion of these targets, but a few gen-
tivity. With the advent of reverse transcription polymerase eral points are worth considering.
chain reaction and cDNA microarray hybridization tech-
1. The radiation dose in the experiment must be consid-
niques, it has become possible to detect radiation-induced
ered. Large single-dose radiation (⬎10 Gy) is often used
mRNA biomarkers with high sensitivity. Human peripheral
to help define a potential mechanism of action in the
blood lymphocytes have been irradiated ex vivo and assayed
animal research model; however, fractionated radiation
for radiation-inducible genes using molecular techniques.
may have quite different cellular or organ targets and
Many upregulated genes in irradiated peripheral blood lym-
different tissue effects (59).
phocytes have been identified, among which are the stress
2. Mechanisms for radiation countermeasures may be tis-
response genes, cell cycle genes, DNA repair genes, and genes
sue specific (59).
involved in apoptotic pathways. Some of the molecular mark-
3. Cells responsible for chronic injury may not have been
ers for radiation injury have shown promise: GADD45A,
irradiated but rather are recruited into irradiated tissue
CDKN1A (CIP/WAF1), DDB2, MDM2, TRAIL receptor 2,
(inflammatory effect) (61, 62).
DRAL (FHL2), cyclin G, and cyclin protein gene (46, 47).
4. Timing of intervention is critical. Development of post-
Among these, GADD45A, CDKN1A, and DDB2 were found
exposure countermeasures will be of tremendous value
to be increased in the whole blood extract after total body (in
for accidental or intentional exposure and are of partic-
vivo) radiation of cancer patients (48). The translation of
ular interest.
these molecular markers into clinical tools for predicting
5. Radiologic/nuclear terrorism countermeasures need not
radiation late injury, as well as for application to radiation
be concerned with tumor protection in that the popula-
biodosimetry is under investigation.
tion needing treatments are the exposed individuals and
the first-responders. Radiation exposure, toxicity, and
Drug development: radioprotectors and mitigating agents
clinical performance degradation will be the limiting
Remarkable observations have found that some late ef-
factors.
fects may be reversible and postexposure intervention may
be possible (49, 50). There are new opportunities for the
radiation biology and oncology fields to support counter- EVOLUTION OF CLINICAL RADIATION
measure research and development through the National TOXICITY SCORING SYSTEMS
Institutes of Health. The research community now has a
unique opportunity to help develop medical countermea- All the major radiotherapy clinical trial cooperative
sures that reduce the long-term burden of cancer for oncol- groups worldwide have used some kind of radiation toxicity
ogy patients as well as to conduct clinical trials of radiation scoring system for reporting adverse events, but a number of
protectors, mitigators, and therapeutics that could be different systems have been applied over the years. Histor-
broadly applicable to the general population. Radiobiolo- ically, the lack of a standardized toxicity terminology and
gists and radiation oncologists thus have both a responsi- grading system has been problematic in comparing treat-
bility and a broad opportunity in basic and clinical radiation ment-related toxicity in published clinical studies (63).
research. Given the complexity of this effort, collaborative Standardizing the scoring system and reporting of compli-
programs are necessary. cations will allow clinicians to objectively evaluate and
To help standardize terminology for radiation countermea- monitor radiation toxicities. There have been a number of
1446 I. J. Radiation Oncology ● Biology ● Physics Volume 64, Number 5, 2006

efforts to integrate the various systems into a single common conduct, and coordinate research in Europe on the treatment
language. From a historical perspective, phase III studies from of cancer and related problems in a multidisciplinary and
the Radiation Therapy Oncology Group (RTOG) of the United multinational effort. The current database includes more
States have included planned analyses of short- and long-term than 100,000 patients, and more than 27,000 patients are
effects from irradiation since the early 1970s. In 1982, Na- still in follow-up. The organization comprises 20 disease
tional Cancer Institute Cancer Therapy Evaluation Program sites or special focus groups, of which the radiotherapy
of the United States developed the original Common Tox- group is one of the largest, with approximately 1000 pa-
icity Criteria (CTC version 1.0) in an effort to standardize tients entered per year. The radiotherapy group performs
toxicity reporting; however, the CTC was geared more primarily large randomized trials, integrating radiotherapy
toward drug rather than radiotherapy toxicity profiles. At with surgery and chemotherapy or hormone therapy in
approximately the same time, RTOG developed its own common cancers, and it is also active in innovative phase
criteria for acute toxicity and collaborated with the EORTC I-II studies to integrate new modalities or new drugs with
to develop the joint RTOG/European Organization for Re- radiation.
search and Treatment of Cancer (EORTC) criteria for late The EORTC has used a number of different late effect
toxicities. It was recognized that standardizing the reporting grading systems over the past 10 years; in the early 1990s,
system of treatment-related toxicity among different coop- it used the RTOG/EORTC late effects system, in the mid-
erative groups was necessary for the objective comparison 1990s, the Subjective Objective Management and Analysis-
of adverse event data. There are several radiotherapy coop- LENT, and, the most recently the CTCAE v3.0 system. The
erative groups worldwide with various expertise in incor- EORTC worked in close cooperation with the RTOG to elab-
porating radiation toxicity scoring into their clinical studies. orate upon the Subjective Objective Managment and Anal-
Nonetheless, the difficulties involved in efforts to standard- ysis-LENT system in the mid-1990s, and participated in the
ize toxicity scoring and reporting have been a common recent RTOG/NCI CTCAE v3.0 initiative (St. Petersburg,
theme among large cooperative groups. The current state of Florida, April 2002).
toxicity reporting and some historical perspective are briefly
described. National Cancer Institute of Canada Clinical Trials
Group (NCIC CTG)
African Radiation Oncology Group The NCIC CTG was founded in 1980. Since then more
African Radiation Oncology Group was founded in 1997 than 40,000 patients have been entered into approximately
by the group of African Regional Agreement (AFRA) 300 trials. In 1990, the NCIC CTG adapted the then current
project coordinators involved in the program (RAF 6014) National Cancer Institute Common Toxicity Criteria to in-
representing 22 African countries. This young organization corporate toxicities unique to radiation therapy and biologic
strongly supported by the IAEA has not yet conducted agents. This adaptation was evaluated and used for subse-
research in formal clinical trials, but some individual Afri- quent NCIC CTG initiated trials (64). When the CTG par-
can Radiation Oncology Group sites are participating in ticipated in international trials led by another group, the
clinical research projects conducted by the IAEA in disease sponsoring group’s toxicity criteria was used.
sites involving nasopharyngeal carcinoma, cervical cancer, Since 2003, the NCIC has used CTCAE v3.0. for all new
and cancer of the esophagus. protocols. Protocols activated or developed before April
2003 continue to use the adapted NCIC system. It is antici-
Circulo de Radioterapeutas Ibero Latino Americanos pated that all future trials, regardless of sponsor, will use the
The Circulo de Radioterapeutas Ibero Latino Americanos CTCAE v3.0 criteria or subsequent amendments to them.
(CRILA) was founded in 1971. CRILA does not conduct
clinical trials but some members are active in an IAEA RTOG
cervical cancer clinical project. CRILA conducts a scientific Since its inception in 1971, the RTOG has conducted
meeting once every 2 years. One of the goals is to set the approximately 300 protocols and accrued approximately
stage for the new model to report adverse effects through 60,000 patients to clinical trials. In the late 1990s, the
various activities, nationally and internationally, and also in RTOG became a research base for the NCI’s Community
Latin American regional meetings supported by IAEA. It is Clinical Oncology Program. This not only allowed commu-
expected that Asociacion Ibero Latino Americana de Tera- nity researchers to access the RTOG general portfolio of
pia Radiante en Oncologia, recently formed from CRILA trials, but also spearheaded interests in new clinical trials in
and Grupo Latino Americana Curietherapie, will emphasize which toxicity would be a primary endpoint. Phase III
adverse events reporting. RTOG studies designed in the early 1970s used ad hoc
terminology but included planned analyses of short- and
EORTC long-term effects of irradiation. Clinical trials conducted
The EORTC is one of the largest cancer clinical research since the mid-1980s have collected toxicity data and ana-
organizations in the world. It enrolls more than 6000 new lyzed it using RTOG acute and RTOG/EORTC late toxicity
patients per year in approximately 110 clinical trials among scales developed in 1984.
450 institutions. The goal of the EORTC is to develop, In 1982, NCI Cancer Therapy Evaluation Program devel-
 IAEA 2005 radiation normal tissue injury report ● Y. CHEN et al. 1447

oped the original Common Toxicity Criteria (CTC) in an this method of analysis, acknowledging that other methods
effort to standardize toxicity in chemotherapy trials. This of analysis may provide a more accurate indication of the
system has been used to supplement the RTOG systems prevalence of a given effect (70, 71). Exploring the issue of
when chemotherapy is administered. In the 1980s and early the most appropriate analyses of longitudinal toxicity data
1990s, the RTOG primarily conducted fractionation studies remains a priority for TROG, particularly since this may
or utilized minimal chemotherapy. Acute toxicity was lim- provide a better understanding of the pathophysiology of,
ited and generally resolved within 4 weeks of treatment. The and relationship between, acute and late effects (35, 72).
“90-day rule” was created to help distinguish acute from TROG also sees the ability to store and retrieve three-
late effects: toxicity that occurs within 90 days from the dimensional planning data electronically to be a fundamen-
start of radiotherapy would be analyzed using the acute tal pre-requisite for the evaluation of dose-volume relation-
morbidity scale; events that occur beyond 90 days from the ships as they apply to toxicity.
start of radiotherapy would be recorded using the RTOG/
EORTC late morbidity scale. It was recognized that the
decision to use 90 days as the cutoff was somewhat arbitrary
and that some “acute” toxicities (e.g., radiation pneumoni- CTCAE: EVOLUTION OF A COMPREHENSIVE
tis) may not manifest until the “late” period. DICTIONARY FOR ALL MODALITIES
In 1998, the NCI developed CTC version 2 (CTC v2.0) in
The National Cancer Institute (NCI) Common Toxicity
collaboration with the RTOG, and it included acute toxicity
Criteria system (CTC v1.0) was first created in 1983 to aid
related to radiotherapy. CTC v2.0 quickly replaced the
in the recognition and grading of adverse effects of chemo-
RTOG acute radiotherapy morbidity scales in most studies,
therapy. It was updated and expanded in 1998 (CTC v2.0)
whereas RTOG/EORTC late toxicity scales continued to be
but remained focused on acute effects (73). In June 2003,
mandatory for most studies. In late 2003, the CTCAE v3.0,
the NCI announced the third revision of the CTC, relabeled
including all acute and late effects was developed, dropping
the “90-day rule.” This was finalized and published online CTCAE v3.0 (65). The principal changes, compared with
(65). All RTOG protocols activated in 2004 use solely the version 2.0, are the inclusion of a full set of late effects
CTCAE v3.0 for assessment of all toxicities. The CTC v2.0 criteria, expansion of criteria for surgical effects, and better
acute toxicity scales and the RTOG/EORTC late toxicity anatomic site specificity (12). CTCAE v3.0 represents the
scales are still used for “legacy trials” activated before 2004. first comprehensive multimodality grading system for re-
In the future, it may be possible to “map” toxicities as porting both acute and late effects in oncology, and it is the
scored by the older toxicity systems onto the newer CTCAE required grading tool for all NCI-funded clinical trials. The
v3.0 system. CTCAE v3.0 has been adopted by the pharmaceutical in-
dustry, and it has been mapped to function alongside other
Trans-Tasman Radiation Oncology Group standard regulatory dictionaries (e.g., MedDRA: Medical
Since its inception in 1989, Trans-Tasman Radiation On- Dictionary for Regulatory Activities). Overall, the new
cology Group (TROG) has accrued more than 5000 patients CTCAE v3.0 contains more than 1000 sites and organ-
to clinical trials in Australia and New Zealand. Early on, specific terms, most with four grades, for approximately
TROG recognized the importance of appropriate assess- 4000 recognizable forms of symptoms and tissue injury.
ment, recording, and reporting of acute and late effects
during its altered fractionation schedules in the treatment of
head-and-neck cancer (66, 67). These initial trials used the Surgical late effects are now included
Dische toxicity scoring system (68). This experience stim- The CTCAE v3.0 is organized into 28 organ systems
ulated the development of operating procedures that in- (e.g., gastrointestinal, genitourinary) that may be used for
cluded guidelines on toxicity scoring and recording for all any injury regardless of modality, although some are clearly
clinical trials developed by TROG. The guidelines have designed to describe surgical injury (e.g., flap failure). The
evolved initially using the RTOG/EORTC acute and late CTCAE v3.0 contains many new terms that are applicable
toxicity scoring systems and later included LENT-Subjec- to surgery, but in general, it is not practical to capture all of
tive Objective Management and Analysis (69). All proto- the acute and expected events associated with surgery in the
cols developed during or after 2004 will use the CTCAE immediate postoperative period. Per NCI guidance, only the
v3.0 as the toxicity scoring system. TROG is investigating unintended severe and life-threatening (Grades 3– 4) conse-
possible methods to evaluate the reliability of toxicity re- quences of surgery should be the focus of surgical reporting.
porting using CTCAE v3.0 at an intra- and interclinician Reportable events are the unintended consequences of the
level, given the large number of terminology categories. surgery, but not the surgery itself. For example, hospital-
In 2004, TROG added recommendations to its operating ization for neck dissection is not an adverse event, but
procedures for the analysis and publication of late toxicity reoperation for bleeding or chyle leak would be a gradable
endpoints. These now state that “an actuarial approach and reportable adverse event. The functional outcome or
should be used in the analysis of rates of late toxicity.” prolonged impact of surgery may be collected according to
Several TROG trials with late toxicity endpoints have used the protocol-specific guidance.
1448 I. J. Radiation Oncology ● Biology ● Physics Volume 64, Number 5, 2006

Adverse events no longer predesignated modality oncology clinical trials, as well as to serve as a
as “acute” or “late” model for multiple disease sites in oncology.
The previous rules about predesignation of clinical trial To address the importance of standardizing data collec-
events as “acute” or “late” are no longer used in CTCAE tion for CTCAE v3.0 users, the AERO Committee will
v3.0. The use of the RTOG Late Morbidity Scoring tool has explore the development of a protocol disease site–specific
been eliminated in future trials, and thus the “90-day rule” collection of essential safety terms and endpoints to guide
has been dropped. Modern multimodality management in- patient screening at the clinical encounter. Future AERO
volving the interactions of sequential and concurrent mo- initiatives will focus on the display and interpretation of
dalities makes it increasingly difficult to designate an effect adverse event and safety data in publications. The AERO
as an acute, subacute, or late phase injury. Designation of general initiatives were endorsed by the IAEA Technical
acute vs. late is a determination of the investigator upon Committee meeting in October 2004. The IAEA Technical
review and interpretation of the aggregate trial data. Committee believes the development of international ad-
verse event reporting standards is critical to improving the
Data generation and collection and reporting quality of clinical trial data and to facilitate comparison of
not addressed by CTCAE v3.0 acute and late safety profiles among international coopera-
The CTCAE v3.0 does not address patient screening or tive groups and clinical outcome studies. The Committee
methods of data collection. This aspect is currently deter- intends to play an important role in the international devel-
mined by a protocol-specific schedule of evaluations and opment and dissemination of safety reporting standards via
group-specific customs. Protocols may differ substantially critical review, feedback, adoption, or endorsement.
in the terms and elements required for data collection. There
is no standard approach for screening and collecting patient
MEETING CONCLUSIONS
information from the clinical encounter. It may range from
abstracting the clinical record after the encounter (“passive Radiobiology, molecular events, and mechanisms of ra-
data collection”) to a detailed assessment using pre-defined diation injury serve as the common basis for the clinical
templates and structured interviews (“active”). Although manifestation of signs and symptoms resulting from thera-
formal studies are lacking, variations in screening consis- peutic radiation, accidental exposure, nuclear accidents, or
tency and intensity likely affect the completeness and qual- radiation terrorism. It is now recognized that a comprehen-
ity of adverse event data. sive scoring system for normal tissue injury is an essential
Electronic methods to facilitate AE data collection may tool for evaluation, reporting, and management of radiation-
promote more uniform data collection and reporting prac- induced injuries from either intentional or accidental expo-
tices. The NCI has recently begun the development of a sure. The significance of such clinical scoring criteria is
software program to guide the user in the AE data collection exemplified by the incident that occurred at the Instituto
and reporting process. Features will include electronic ac- Oncológico Nacional of Panama, where cancer patients
cess to all elements of CTCAE v3.0 dictionary, terminology undergoing radiotherapy for malignancy in the pelvic region
search functions, protocol-specific adverse-event lists and were unintentionally overexposed to excess radiation due to
templates, patient-specific safety history, generation of various technical errors. Bowel complications alerted clini-
source data documentation, serious AE reporting, upload cians to the potential overdosage, which led to the investi-
to the NCI Adverse Event Expedited Reporting System gation of the error by technical factors, estimated physiologic
(AdEERs) system, and direct electronic submission of AE doses by physicists, and intervention with colostomies. Al-
data to other relevant parties (e.g., sponsor, principal investi- though many died from bowel complications, colostomies
gator, Data and Safety Monitoring Board (DSMB), institu- prolonged the lives of many (75). Thus an objective scoring
tional review board). This product will begin beta testing in system provides timely recognition of radiation injury,
2005 (CTIS, Inc., Rockville, MD). which may allow prompt intervention to avoid serious con-
sequences.
Adverse event reporting standards working group formed With support from the global cooperative groups engaged
The development of AE reporting standards is the focus in cancer radiotherapy, the IAEA meeting has defined future
of the recently created Adverse Events Reporting in Oncol- short-term and long-term goals for standardized reporting of
ogy (AERO) Working Group. This ad hoc international normal tissue effects among the global cooperative groups.
clinical trials interest group includes 25 representatives of a Immediate goals achieved on site included agreement on the
wide variety of multidisciplinary research and practice or- following: identification of adverse events (effects) with an
ganizations. The group first convened in May 2004 to create emphasis on late effects as critical endpoints in RT studies,
recommendations for safety reporting standards for cancer particularly phase III studies (69); endorsement of a single
oncology trials. An initial publication focusing on head standardized dictionary (CTCAE v3.0) containing adverse
and neck cancer will be developed in partnership with the event terminology and grading criteria; support for the
CONSORT organization for reporting standards in clinical concept of uniform disease-specific templates of AE terms;
trials (74). This initiative is intended to create the principles the importance of reporting of long-term follow-up and
for the publication of safety data in multiagent and multi- standardized reporting of late effects in phase III radiother-
 IAEA 2005 radiation normal tissue injury report ● Y. CHEN et al. 1449

apy studies; recognition that additional resources are needed meeting was the reality that the study of radiation injury
to achieve these goals. Intermediate goals included the and, indeed, the long-term consequences of cancer treat-
following: discussion of these IAEA-driven recommenda- ment, is costly. Although it can be relatively inexpensive to
tions within respective groups/bodies (it was left at the study overall survival as an endpoint in clinical trials, it is
discretion of the participants to suggest preferable time to somewhat expensive to study surrogate endpoints of cancer
obtain feedback information) and development of a Coor- treatment efficacy, and it is vastly more complicated and
dinated Research Project to assist developing countries to expensive to study toxicity, particularly late toxicity. To
achieve the goals of clinical trial participation and adopting improve outcome and quality of life for patients who un-
the standard terminology and grading system from the NCI- dergo cancer treatment, the ultimate goal of research in
CTC system. Finally, long-term goals included the follow- biomarkers and mitigating agents is to reduce radiation-
ing: refinement of available scoring systems (e.g., CTCAE induced acute and late toxicity. This effort involves the
v3.0); adaptation of the terminology and grading system creation and refinement of effective toxicity scoring systems
from the NCI CTC system to the routine clinical practice in and reporting methods, the prediction of genetic or conse-
both developed and developing countries; and endorsement quential organ injuries, and the selection of appropriate
of proposals and standards consistent with the CONSORT individuals for interventions to mitigate the negative effects
statement on “reporting of harms in medicine.” Future plans of radiation and combined modality treatment. At this time,
also include the implementation of coordinated research there is no substitute for the rigorous basic research and
projects focusing on normal tissue biomarkers and AE data prolonged, large clinical trials that, together, will produce
collection methods. accurate clinical parameters that allow for the determination
Finally, another important issue discussed at this IAEA of the molecular mechanisms of tissue injury.

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