Int. J. Radiation Oncology Biol. Phys., Vol. 76, No. 3, Supplement, pp.

S3S9, 2010
Copyright 2010 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/10/$see front matter

doi:10.1016/j.ijrobp.2009.09.040

INTRODUCTORY PAPER

QUANTITATIVE ANALYSES OF NORMAL TISSUE EFFECTS IN THE CLINIC

(QUANTEC): AN INTRODUCTION TO THE SCIENTIFIC ISSUES
SREN M. BENTZEN, PH.D., D.SC.,* LOUIS S. CONSTINE, M.D.,y JOSEPH O. DEASY, PH.D.,z
AVI EISBRUCH, M.D.,x ANDREW JACKSON, PH.D.,k LAWRENCE B. MARKS, M.D.,{
RANDALL K. TEN HAKEN, PH.D.,x AND ELLEN D. YORKE, PH.D.k
From the *Departments of Human Oncology, Medical Physics, Biostatistics and Medical Informatics, University of Wisconsin School of
Medicine and Public Health, Madison, WI; yDepartment of Radiation Oncology, University of Rochester Medical Center, Rochester, NY;
z
Department of Radiation Oncology, Washington University, St. Louis, MO; xDepartment of Radiation Oncology, University of
Michigan, Ann Arbor, MI; kDepartment of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY; {Department of
Radiation Oncology, University of North Carolina at Chapel Hill, NC
Advances in dosevolume/outcome (or normal tissue complication probability, NTCP) modeling since the seminal
Emami paper from 1991 are reviewed. There has been some progress with an increasing number of studies on large
patient samples with three-dimensional dosimetry. Nevertheless, NTCP models are not ideal. Issues related to the
grading of side effects, selection of appropriate statistical methods, testing of internal and external model validity,
and quantification of predictive power and statistical uncertainty, all limit the usefulness of much of the published
literature. Synthesis (meta-analysis) of data from multiple studies is often impossible because of suboptimal primary analysis, insufficient reporting and variations in the models and predictors analyzed. Clinical limitations
to the current knowledge base include the need for more data on the effect of patient-related cofactors, interactions
between dose distribution and cytotoxic or molecular targeted agents, and the effect of dose fractions and overall
treatment time in relation to nonuniform dose distributions. Research priorities for the next 510 years are
proposed. 2010 Elsevier Inc.
QUANTEC, Normal tissue complications, Overview, Modeling.

Modern radiation therapy (RT) techniques generally yield

nonuniform dose distributions in nontarget tissues. The introduction of external beam megavoltage RT in the 1950s
shifted the most important side effects from the skin and subcutaneous tissues to the deeper seated tissues. The ensuing
wide adoption of parallel opposing field techniques led to improvements in target dose homogeneity, but typically led to
whole or partial organ irradiation of the neighboring non-target tissues: a fractional volume of an organ at risk would essentially receive the prescribed target dose. Because of the
limited capabilities to image the tumor extent, most RT fields
included liberal margins.
Computed tomographybased diagnosis and RT planning
in the 1980s and 1990s revolutionized target volume visualization and facilitated multiple-field and three-dimensional
(3D) conformal RT. Conceptual and technological advances
have led to new RT technologies (e.g., intensity-modulated
radiation therapy, rotational or helical delivery, robotic

delivery, and proton therapy). These technologies typically

deliver near-uniform doses to the target volume. However,
the dose distribution in the surrounding normal tissues is
more variable.
Therefore, these new technologies provide the treatment
planner with increased flexibility in determining which regions of normal tissue are to be incidentally irradiated. The
treatment planner needs information to predict the risk of
a normal tissue injury for competing 3D dose distributions,
such that the therapeutic ratio can be optimized. One of the
goals of QUANTEC is to summarize the available 3D
dosevolume/outcome data.
At the same time, increasing use of combined modality
therapy has often increased the burden of early and late toxicities (1). Understanding the tradeoff between an expected
decrease in toxicity resulting from an improved dose distribution, and the possible increase in toxicity with systemic
agents, is an increasingly pertinent, yet poorly researched,
area.

Reprint requests to: Sren M. Bentzen, Ph.D., D.Sc., University

of Wisconsin School of Medicine and Public Health, Department
of Human Oncology, K4/316 Clinical Science Center, 600 Highland
Avenue, Madison, WI 53792. Tel: (608) 265-8572; Fax: (608) 2639947; E-mail: [email protected]

AcknowledgmentThis work was partially supported by NIH grants

CA014520 (S.M.B.), CA85181 (J.O.D.), and CA69579 (L.B.M.),
and a grant from the Lance Armstrong Foundation (L.B.M.).
Received April 8, 2009, and in revised form Sept 1, 2009.
Accepted for publication Sept 2, 2009.

WHY QUANTEC?

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I. J. Radiation Oncology d Biology d Physics

ANALYZING RT-RELATED TOXICITY

Cancer survivorship issues have been gaining prominence,
partly because of the increasing number of cancer survivors;
a tripling in the United States (2) between 1970 and 2001.
This increase is the result of early diagnosis, screening efforts, improved treatments, and an increased incidence of
many cancers. Radiation oncologists have pioneered recording and analysis of late treatment sequelae and the available
literature on late effects is much richer for this modality than
for cytotoxic or surgical treatments. However, toxicity is often underreported, and probably underrecorded, even in the
more rigorous framework of prospective clinical trials (3
5). Clearly, this is a special concern in NTCP (normal tissue
complication probability) modeling studies where the data
analyzed often are retrospectively extracted from charts or
databases.
The US National Cancer Institute Common Terminology
Criteria for Adverse Events (CTCAE) v3.0 is a comprehensive dictionary for recording and grading of side effects of
all major cancer therapies (6). Widespread adoption of a common grading system for adverse events, such as CTCAE,
would improve between-study comparability and is encouraged. However, CTCAE still combines multiple signs and
symptoms into a single grade. Although this may be convenient for routine studies and comparisons of therapies across
studies, it is associated with a loss of specificity in toxicityspecific studies (7). For such studies, including NTCP modeling studies, grades should be atomized (i.e., broken down to
specific signs and symptoms that are likely to reflect specific
radiation pathophysiologies). The SOMA (Subjective, Objective, Management, Analytic) scale explicitly distinguishes
between objective signs and subjective symptoms. For toxicity-specific studies, a SOMAtized scalethat is, a scale
where these components of toxicity are kept separateis
preferable. Grouping several specific toxicities into a single
composite endpoint is likely associated with a loss of statistical resolution (3, 8).
THE EMAMI PAPER AND EARLY NTCP
MODELING
The paper by Emami et al. (9) is the most frequently cited
paper ever published in the International Journal of Radiation Oncology Biology Physics, with 1,062 citations according to the ISI Web of Science (accessed February 3, 2009).
This paper published the tolerance doses for irradiation of
one third, two thirds, or the whole of various organs. Because
high-quality clinical data were scarce, the task force took the
bold approach to establish these doses by a simple consensus
of clinical experience or opinions. In an accompanying paper,
Burman et al. (10) fitted a Lyman model (11) to the Emami
consensus dosevolume data thereby facilitating the use of
Emamis constraints for an arbitrary fraction of a whole organ
uniformly irradiated. Further, Kutcher et al. (12) proposed
a method, a so-called dosevolume histogram (DVH) reduction algorithm, for reducing an arbitrary nonuniform dose
distribution into a partial volume receiving the maximum

Volume 76, Number 3, Supplement, 2010

dose, effectively allowing the extrapolation of Emamis constraints to any dose distribution. The mathematical method
amounted to a common formula for taking a generalized
mean, although this was not recognized at the time. This
Lyman-Kutcher-Burman model, combining Lymans model
with the Kutcher-Burman DVH reduction scheme, remains
the most widely used NTCP model. Although the model
claims no deep mechanistic validity, its mathematical form
is sufficiently flexible to allow representation of various
dosevolume dependencies. Within the structural resolution
of current datasets, the Lyman-Kutcher-Burman model can
typically not be rejected as a good fit of the data, although
it is not always the best model considered. Probabilistic
models, studied in groundbreaking papers in the 1980s by
Schultheiss (13) and Withers (14), introduced concepts like
serial and parallel tissue organization and functional subunits and became conceptually influential but have played
a relatively modest role in actual data analyses except for
The Relative Seriality Model (15), that has found some use
in analyzing clinical data.
SMALL ANIMAL MODELS AND LIMITATIONS TO
A DVH-BASED APPROACH
DVH-based analyses inherently assume that organ function is uniformly distributed within an organ. Experimental
animal studies of the volume effect have produced important
proof-of-principle insights that question this assumption.
However, these have had relatively little impact on clinical
NTCP modeling so far. In 1995, Travis et al. (16, 17) reported that partial organ irradiation of a volume of the mouse
lung base was more likely to cause radiation pneumonitis
than irradiating an identical volume of the apex or, even
more pronounced, the middle regions of the lung. Because
the histological damage in the lung did not vary with location, this finding has been interpreted as a result of variation
in the functional importance of different lung regions. However, some of the demonstrated effect may have also resulted
from inadvertent inclusion of the central airways/vessels
within the computed tomographydefined lung. Attempts at
modeling location effects in human lung have only been tried
relatively recently, with mixed results (see the paper by
Marks et al. in this issue). Location effects have also been
demonstrated in partial volume irradiation of the parotid
gland (18), probably reflecting damage to the excretory ducts,
blood vessels, and nerves. Another example where DVHbased analysis for the organ at risk may not be adequate is
lung, where irradiation of the heart in addition to the lung
has been shown in experimental animals to affect the risk
of radiation induced pneumonitis as assessed by respiratory
rate (19).
Hopewell and Trott (20) analyzed experimental dosevolume data and concluded that Volume, as such, is not the relevant criterion, since critical, radiosensitive structures are not
homogeneously distributed within organs. Work by Trott
et al. (21) in 1995 documented a volume effect for functional
damage after irradiation of the rat rectum but found no

QUANTEC: scientific issues d S. M. BENTZEN et al.

significant influence of volume on structural damage to the

rectal wall. The theme of different radiation pathogenesis
for different rectal side effects, and therefore varying radiobiological properties, has only relatively recently been systematically analyzed in patients by the group at the Netherlands
Kanker Instituut (22).
Extensive studies by van der Kogel in the late 1980s showing that the probabilistic model did not correctly predict the
probability of spinal cord injury after irradiation of two geometrically separated 4-mm segments of rat cervical spinal
cord undoubtedly discouraged further exploration of this
model in the analysis of clinical datasets (23). Van der Kogels studies were subsequently expanded into an elegant,
systematic study of dosevolume effects in the rat spinal
cord, ending with the sobering conclusion that not any of
the 14 mathematical models, tried by the authors, could fit
all the data (24).
PROGRESS ON ALL FRONTS SINCE 1991
Much has changed since 1991 (Table 1). Many, mainly retrospective, clinical studies have been published on dosevolume-outcome analysis of clinical data. The QUANTEC
review identified >70 papers on radiation pneumonitis alone.
Some of these studies are very large (e.g., a study of rectal effects in 1,132 patients by Fiorini et al.) (25). There are quantitative analyses of dosevolume-outcome relationships for
>30 organs and tissues. More than a dozen mathematical
dose volume models have been proposed.
One class of NTCP models reduces the 3D dose matrix to
a scalar, often thought of as an effective volume or an effective dose received by a defined reference volume. This scalar
is subsequently related to the incidence or risk of normal tissue toxicity through a sigmoid link function, typically a logistic or probit relationship. This model building strategy is
similar to the one used originally by Lyman (11) and it
may be reasonable classifying these as generalized Lyman
models. The push from cell-killing based models towards
heuristic models has been strengthened by novel insights
into radiation pathogenesis of late effects (26) and an increased appreciation of the role of anatomical and physiological factors in normal tissue dysfunction.
Other modeling approaches have been used such as principal component analysis (27), contiguous (or cluster) damage
model (28), and data mining to build multivariate models
(29). Further approaches include the use of artificial neural
networks (30) and support vector machines (31) as classifiers
of patients with respect to the development of side effects.
These methods are complementary to more traditional modeling and will undoubtedly be further explored in the coming
years.
THE QUANTEC INITIATIVE
It was on this background that the QUANTEC Steering
Committee was formed. Stimulated by a proposal from the
Science Council of the American Association of Physicists
in Medicine to revise and update the Emami guidelines, the

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QUANTEC group was formed from a loose network of researchers with a longstanding interest in dosevolume modeling. The Steering Committee defined three aims for
QUANTEC.
(1) To provide a critical overview of the current state of
knowledge on quantitative doseresponse and dosevolume relationships for clinically relevant normal-tissue
endpoints
(2) To produce practical guidance allowing the clinician to
reasonably (though not necessarily precisely) categorize
toxicity risk based on dosevolume parameters or model
results
(3) To identify future research avenues that would help improve risk estimation or mitigation of early and late side
effects of radiation therapy
A kickoff workshop with 57 invited participants from
North America and Europe was held in Madison, Wisconsin,
in October 2007 with generous financial support from the
American Association of Physicists in Medicine and the
Board of the American Society for Therapeutic Radiation
Oncology. The main deliverable from the workshop was
the formation of a number of working groups charged with
producing organ site-specific overviews of quantitative
dosevolume relationships as well as groups producing
vision papers on future research avenues in the field. The results of these efforts are partly presented in this issue of the
International Journal of Radiation Biology and Physics,
again made possible with generous support from American
Society for Therapeutic Radiation Oncology.
Although overall progress has been real and substantial,
research in the past two decades has also defined limitations
to our current methods and the resulting knowledge. One of
the main lessons from the literature overviews is that more
uniform and comprehensive reporting would be a huge
help when trying to combine data from multiple studies
(see the paper by Jackson in this issue). Current best estimates of dosevolume parameters can in many situations
be based on empirical data, in contrast to the consensus
values proposed by Emami et al. However, there is still
a lack of proper estimation of the uncertainty in these parameters in most cases. Clinically, the literature on patient-related
risk factors is scattered and often inconsistent from one study
to the next. When patient- or treatment-related risk factors parameters are not listed as significant in a given paper, it is often not clear whether the factor has been tested or not.
Therapeutically, RT is combined with drugs in more and
more indications. Although calculating the risk associated
with the RT dose distribution alone may provide some guidance, it cannot generally be assumed that giving a drug together with radiation will even preserve the ranking of
competing radiotherapy RT plans (32). The increased use
of hypofractionation, and the use of an increasing number
of beam orientations (e.g., rotational delivery), results in a relatively large volume of normal tissue receiving a low total
dose and dose per fraction. The available dosevolume/outcome data may not be applicable in this setting. There has

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Table 1. Dose-volume relationships ca. 1990 and 2009+

ca. 1990
Treatment usually with parallel opposing fields or box
techniquesthree-dimensional conformal radiation therapy
gaining ground clinically in some centers
Radiation therapy typically delivered as single modality spectrum
of toxicities relatively well-characterized
Conventional fractionation dominatesclinical trials of
hyperfractionation and accelerated fractionation
Authors search for a safe dosevolume constraint
Early interest in normal tissue complication probability modeling
Lyman model most widely used
Analysis often based on groups of patients
Lack of consistency in contouring organs at risk among
investigators
Models often applied with parameters from the literatureno
adjustment for patient or treatment characteristics
Toxicity underscored and underreported in most studies
A lack of quantitative, evidence-based dosevolume constraints
Emami et al. develops a ground-breaking set of consensus
constraints for partial organ irradiation

been little discussionand no consensuson how models or

dosevolume constraints should be adjusted if the fractionation scheme changes significantly. One study did adjust
the individual bins in the dosevolume histogram for dose
per fraction (33), but the fits obtained with a/b = 3 Gy, 10
Gy, or infinity ( = physical dose) were not statistically different for that given treatment fractionation scheme. However,
the model may not be valid without correction if a significantly different fractionation scheme is used.
MODEL VALIDATION AND DATA ANALYSIS
On the model side, there is a need for improved data analytical methods and a more critical appraisal of the various dimensions of model validity.
Face validity
The first screen when judging a model fit to a set of data is
face validity. Is the probability of a side effect a nondecreasing function of dose, dose per fraction, and volume, given
that two of these three variables are held constant? If the
model includes patient characteristics, such as age, smoking
history, or comorbidity, is the effect estimated using the
model consistent with published clinical data? Are confidence intervals or standard errors of the estimates reasonable
in view of the analyzed sample size and the number of events
actually recorded?
Internal validity
Internal validity relates to whether the model actually provides a reasonable representation of the data to which it is fitted. To this end, a graphical representation of the fit to the

2009+
Widespread use of conformal techniques, including intensitymodulated radiation therapy, often resulting in highly nonuniform
dose distribution in organs at risk with large volumes receiving
low doses
Many curative cases receiving combined modality therapymany
regimens are very toxic leading to problems with compliance
Conventional fractionation dominatesclinical trials of
hypofractionation in progress
Increasing appreciation of the risk-benefit tradeoff in an individual
patienta monotonic increase in toxicity risk with increasing
dose/increasing volume
Change from more models to more dataLyman model still
widely used, but new modeling strategies are being pursued
Analysis of individual patient level data
Lack of consistency in contouring organs at risk among
investigators
Statistical estimation of model parametersoften with adjustment
for significant patient or treatment characteristics
Toxicity underscored and underreported in most studiesdespite
attempts to define dictionaries for toxicity reporting such as
Common Terminology Criteria for Adverse Events
A lack of quantitative, evidence-based dose-volume constraints
the QUANTEC group initiates a series of systematic literature
reviews

data may be informative. This may be supplemented with

a formal goodness of fit statistics, such as the chi-square
test. The null hypothesis being tested is that the discrepancy
between the observed toxicity incidence data and the data expected under the fitted model can be explained by chance
alone. A test p value <0.05 means that the null hypothesis
can be rejected at the 5% significance level (i.e., the model
does not fit the data). A nonsignificant p value, however,
may not be very informative as typical NTCP model fits to
clinical data sets yield a relatively low statistical power of
goodness of fit statistics. In other words, two alternative
mathematical models may be quite divergent without either
one of them being rejected based on the goodness of fit test.
The log-likelihood may also be used for comparing the fit
of competing models to a data set; again, studies have shown
that competing models tend to produce very similar log-likelihood values for a given data set (34). For nested models
(i.e., models that differ by the inclusion of one additional parameter), the difference in log-likelihood forms the basis for
the likelihood ratio test, a robust test for the statistical significance of adding this parameter. For non-nested models the
Akaike Information Criterion has been used by some authors,
see for example Tucker (34).
Some authors look at NTCP models as classifiers (i.e., as
a way to separate patients who do or do not develop a given
toxicity). This leads to a standard predictive testing framework, where sensitivity, specificity, and negative and positive predictive values can be estimated. The area under the
curve of the receiver operating characteristic curve can be
used as a figure of merit for comparing alternative models.
Note, however, that a model reliably identifying subgroups
of patients with, say, a 10% and a 40% risk of toxicity would

QUANTEC: scientific issues d S. M. BENTZEN et al.

most likely be clinically useful, but if the latter group is labeled as responders there would still be a 60% false-positive rate. In this case a binned comparison of observed and
expected toxicity may be more informative (35). Cross-validation techniques have been suggested for NTCP modeling
(29), but have so far not been widely applied.
External validity
External validity addresses how well the model explains
the variability in response seen in an independent dataset,
preferably from another institution. Multivariate NTCP
models are often overfitted in the sense that they include
too many parameters relative to the number of events analyzed. This may result in strongly correlated parameter estimates and, although such a model may pass the test for
internal validity with flying colors, it often has poor external
validity. Differences between institutions in the scoring of reactions, in patient demographics, in the burden of comorbidities as well as in treatment characteristics may all contribute
to a reduced predictive power of a model when tested in an
independent dataset. Relatively little research has been performed on external validity of NTCP models. Bradley et al.
(36) applied a radiation pneumonitis model fitted to data
from 219 Washington University patients to an independent
series of radiation pneumonitis data from 129 patients enrolled in the Radiation Therapy Oncology Group 93-11 trial
and concluded that the model performed poorly in the new
dataset. A model fitted to the two datasets combined was
found to give an odds ratio of approximately two between
the 33% of all patients with the riskiest plans and the 33%
of patients with the safest plans, but much of the variability
is still unexplained. Similar problems with generalizabilty
are seen in studies applying different models on the same dataset: as an example, Tsougos et al. (37) found that six published models predicted an incidence of Grade 3+ radiation
pneumonitis ranging from 4% to 21% in a group of 47 patients.
One issue is that various dosevolume metrics often are
strongly correlated within a given dataset (38). This may
lead to problems with multicollinearity, which, although it
may not affect the internal validity of the model, can lead
to reduced generalizability. This becomes particularly relevant for extrapolation in dosevolume space (i.e., if a model
derived on basis of similar dose plans is applied to a very
different dose distribution) (39).
Clinical utility
Dosevolume constraints are used in routine dose planning
as an integral part of the informal optimization of therapeutic
ratio that inverse planning entails. Acceptable dose distributions are identified from a assessment of the risk:benefit ratio
in an individual patientoften on the basis of clinical experience rather than on numerical estimates from dosevolume
models. Population constraints are very important in this context but can obviously not stand alone. Careful consideration
should be given not only to the numerical value of these constraints but also to their statistical uncertainty. Using these

S7

values directly in doseplan optimization should be done

with great caution.
The fact that dosevolume constraints or NTCP models are
used in clinical practice does not in itself prove that they improve cancer care from an evidence-based medicine perspective. Ultimately, the clinical utility of NTCP modeling should
be tested in randomized controlled trials. Phase I/II dose escalation trials in patients with nonsmall-cell lung cancer,
where the individual patient is assigned a dose based on an
NTCP estimate (40), have been completed or are in progress
for example at University of Wisconsin (41), University of
Michigan (42), and the Maastricht Radiation Oncology clinic
in the Netherlands (43). The goal is to test these strategies in
randomized Phase III trials. This could potentially provide an
evidence base for risk adaptive radiotherapy for nonsmallcell lung cancer based on NTCP modeling.
RESEARCH PRIORITIES: BEYOND QUANTEC
Important research priorities, identified above as well as in
the QUANTEC thematic and organ-site reviews, include the
following.
A. Development of tools and strategies for prospective
recording of specific pathologies after RT alone or combined with drugs
B. Wider application of methods adjusting for censoring
when analyzing late effects
C. Quantification of the influence of physiologic factors and
comorbidities on the expression of toxicities
D. The continued development of robust normal tissue endpoints including patient reported outcomes to further our
understanding of the relationship between toxicity and
quality of life
E. Development of methods for synthesizing results across
studies with appropriate estimation of prediction uncertainty
F. Establishment of large continually growing data bases
with full access to the 3D dose matrix and linkage with
biomarkers and clinical outcome
G. Prospective testing of model performance in independent
datasets, preferably from clinical trials
H. Improved understanding of the interaction between dose
distribution on one hand and dose per fraction or administration of other modalities on the other
I. Developing strategies for testing the clinical utility of
NTCP models.
J. Development of methods for recording actual delivered
dose in an individual patient after fractionated radiotherapy.
K. Additional studies that use molecular and functional imaging as an intermediary between local damage and
organ-level signs and symptoms.
Adjustment for dose distribution remains a major challenge in clinical radiation research. A systematic effort, capable of winning competitive research funding, is required to
take this field to the next stage.

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