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REVIEW ARTICLE
Measuring side effects after radiotherapy for pharynx cancer
KENNETH JENSEN
Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark
Abstract
Data on side effects after radiotherapy is needed to establish the benefits and drawbacks of new treatments, but side effects
are not quantified as easily as survival or local control. Side effects may be quantified using physical measures.
Unfortunately, only few endpoints exist where a physical measure is obtainable, and the case of a patient-relevant measure is
even rarer. Radiotherapy is often followed by complex symptoms not easily quantifiable by the observer. Quantitative patient
reported side effects can be retrieved using validated questionnaires, but this kind of data is often difficult to interpret and
the correlation with clinically observable or measurable changes not straightforward.
The exploitation of the possibilities of highly conformal radiotherapy and multimodality treatment depends on a better
understanding of the correlation between dose, volume, modifying factors, and side effects. Using pharynx cancer as an
example, the purpose of this article is to summarize the possibilities and limitations of different methods for measurement of
radiotherapy-induced side effects.
A general agreement exists on how to report local
control and survival. A similar agreement does not
exist for the reporting of side effects, as these are not
easily quantified unambiguously. Radiotherapy may
induce changes in organ function and these changes
may produce a physiologic sensation interpreted by
the patient in a patient-specific context and subse-
quently reported by the patient as a symptom.
Organ-specific symptoms thus have a patient-speci-
fic influence on overall measures of health and well-
being. Few side effects are physically measurable,
and the physical measures that do exist are often of
limited relevance to the patient. This trade-off
between patient-relevance and specificity has been
described by Bentzen [1]. An example is radio-
therapy-induced damage of the salivary glands lead-
ing to decreased salivary flow. The degree to which
this is registered as a dry mouth depends on prior
salivary flow, dental status, and mucosal damage. A
dry mouth can seriously impair a patient’s ability to
eat and speak and may have consequential effects for
the patient’s employment, financial possibilities,
social life, and overall quality of life. Sometimes
radiation induces damage to major salivary gland
without giving rise to any clinically significant effects
either because the sub-mucous glands of the oral
cavity have been preserved leading to sufficient
lubrication of the mucous membranes between
meals or because the patient drinks plenty of water
with his meals. In these cases, relatively few sub-
jective symptoms and a limited impact on overall
quality of life will be registered. The cause-effect
relationship is presented in Figure 1, which also
illustrates the patient-relevance and specificity of the
different measures of a side effect.
Radiobiology helps us understand the conse-
quences of radiotherapy for normal tissue. Side
effects can be induced in several ways. A sufficiently
high radiation dose will damage all molecules in the
irradiated cells and lead to acute organ dysfunction.
This is only observed after accidental high-dose
exposure as in acute radiation sickness and possibly
during radiotherapy in the case of damage to saliva
producing cell [2]. Other types of organ dysfunction
are produced by damage to the DNA, which is also
the basis for the therapeutic effects of irradiation.
This kind of effect often only becomes evident when
the cells are replicating. The rate at which side
effects are observed is thus dependent on the cell
turnover of the specific tissues [3]. Late damage is
produced by direct parenchymal cell damage or
by hypoperfusion stemming from endothelial cell
Correspondence: Kenneth Jensen, Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark. E-mail:
Kennethjensen@Dadlnet.Dk
Acta Oncologica, 2007; 46: 10511063
(Received 21 March 2007; accepted 24 May 2007)
ISSN 0284-186X print/ISSN 1651-226X online # 2007 Taylor & Francis
DOI: 10.1080/02841860701481547
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damage and secondarily by replacement of parench-
ymal cells with fibroblasts. These late changes are
observable as atrophy and fibrosis. This chain of
events can lead to severe side effects many years after
radiotherapy that makes long-term follow up im-
portant.
The clinical effects of radiation-induced cell
damage also depend on the organisation of the
tissue: If the function of all sub-volumes in an organ
is a prerequisite for normal organ function, the organ
is said to have a serial organisation. The analogy is an
electric wire: If a segment is missing, the wire does
not conduct electricity. An anatomical example of
this is the spinal cord. If, on the other hand, the
organ has a reserve capacity the function of the organ
depends on the sum of the function of all sub-
volumes. This is called a parallel organisation.
Examples of this are the parotid glands, the lungs,
and the liver. A part of the organ may be damaged
increasing the probability of a degree of side effects
(normal tissue complication probability, NTCP) but
the organ may retain full function or function above
a given threshold. These differences in tissue orga-
nisation are important for radiotherapy planning.
The side effect of an organ organized in series is best
predicted by the maximum dose (to a small volume).
The mean or median dose, or the volume receiving
more than a threshold dose, may predict the risk of
side effects of an organ organized in parallel.
Mathematical models have been developed to de-
scribe the correlation between a heterogeneous dose
distribution to an organ and the probability of side
effects, depending on the radiosensitivity and vo-
lume dependency (organisation) of the organ.
Nevertheless, there is not sufficient data to suggest
superiority of one model over another [48]. It
nevertheless seems that these models are needed as
inverse dose optimisation based on single parameter-
constraints often leads to dose plans giving signifi-
cant dose to a significant volume just below the
constraint value. Dose-volume histogram parameters
(DVH) are closely correlated so coincidence often
determines which parameter is significant in the
single reports [9]. The result is dose distributions
with little biological sense, and this approach will
probably not result in an optimal reduced chance of
avoiding morbidity
The purpose of this article is to summarize the
possibilities and limitations of different methods of
measuring side effects after radiotherapy. Pharynx
cancer is used to as an example to illustrate the
challenges.
General methods for measurement of side
effects
Radiotherapy can affect organ function in ways that
are physically measurable as changes of e.g. organ
weight, flow, and biomechanical properties, poten-
tially leading to overall changes in overall well-being
and function. The methods for measuring side
effects must cover this range of consequences in
order to give a comprehensive insight into the side
effects of radiotherapy. Scoring manuals for side
effects have been developed-the most recent being
CTCAE [10]. These manuals contain an abundance
of graded endpoints. They are constructed by
consensus among researchers and clinicians and
are rarely validated against other endpoints. Most
scales are based on an observer based scoring of
symptom intensity or as registration of initiated
treatment of a given side effect. Although grade
III-IV morbidity seems to be the standard unit for
reporting morbidity, irrespective of endpoint and
scoring systems, the different scoring systems have
only limited correlation with each other and cannot
be used interchangeably [11]. Nevertheless, toxicity
should be scored according to generally accepted
scoring systems, preferably CTCAE, as these sys-
tems are the product of consensus between impor-
tant scientific organisations, and as uniformity in the
reporting of side effects strongly increases the value
of data. However, some arguments for not only
registering side effects according to CTCAE are
discussed in the following.
Objective signs
Semi-quantitative objective assessment scales are
available for a variety of endpoints. Several classi-
cal radiobiological endpoints belong to this cate-
gory: Fibrosis, atrophy, and mucositis. Functional
Figure 1. Illustration of the cause effect chain and the trade off
between relevance and specificity of different measures of side
effects.
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endoscopic evaluation of swallowing without
(FEES) or with sensory testing (FEESST) can be
used to evaluate swallowing [1214]. Interpretation
of auditory evoked potentials [15], speech [16],
and cognitive changes [17] are other examples of
semi-quantitative endpoints relevant for research in
side effects after radiotherapy. The WHO and
Karnofsky performance status scales are observer-
based estimations of the function and physical
capabilities of a patient. Both have been shown
to be strong predictors of survival.
Analytical endpoints
Saliva flow is an obvious measure of salivary gland
function. Whole mouth and parotid gland flow are
measured using either stimulated or resting flow
rate. The choice of measure is often based on
concerns regarding reproducibility or resources
rather than the scientific question posed. Regional
assessment of salivary gland function using SPECT
or PET and its correlation with radiation dose is an
interesting research topic [18,19]. Since both sub-
volume and overall organ function can be measured
directly, the dose-volume-effect relationship can
theoretically be described without making any model
assumptions. Swallowing is traditionally assessed
using modified barium swallows (video-fluoroscopy
(VF)). It provides the observer with several possibi-
lities of retrieving quantitative measurements of
speed and range of motion of the structures involved
in the swallowing process as well as a quantitative
estimate of residuals, penetration, and aspiration
[20].
Observer-scored subjective symptoms
Systems for quantitatively scoring subjective and
objective morbidity have been developed and are
continuously evolving: Dische [21], WHO [22],
NCIC-CTG, EORTC/RTOG SOMA-LENT [23
25], CTCAE [10] and DAHANCA [26] are exam-
ples of authors or organisations that have included
subjective symptoms in their scoring systems. As
mentioned above the development of the systems
rests on experience and consensus rather than
validated scales. Yet, they are the cornerstone of
the majority of available knowledge on subjective
side effects after radiotherapy as they are relatively
simple, fast, and cheap to use. The scoring systems
are sensitive enough to detect differences in toxicity
dependent on volume [27], acceleration [28], frac-
tionation [29], and concomitant chemotherapy [11].
Patient-assessed symptoms and quality of life
Several patient-administered, well-validated ques-
tionnaires for cancer patients exist. Fortunately,
head and neck cancer is almost as popular among
quality of life researchers as it is among radio-
biologists: Several head and neck cancer as well as
symptom-specific questionnaires are available. Ex-
amples are presented in Table I. As for observer-
assessed morbidity, the key issue is to pick a well-
validated measurement tool that is well known to the
scientific community, and as for observer-assessed
morbidity, it is also the case that two methods for
measurement should not be expected to produce
comparable scores just because the name of their
scales might be identical [30].
Table I. Important available tools for retrieving patient-reported morbidity data.
Name of first author and questionnaire Population/symptom Items Scales
Aaronson, EORTC-C30 [105] Cancer patients 30 9
Cella, FACT-G [77] Cancer patients 28 5
Chang, Edmonton Symptom Assessment System [106] Palliative care patients 10
Bjordal, EORTC H&N35 [76] Head and neck cancer patients 35 7
D’Antonio, FACT-H&N, Head and neck
radiotherapy Questionnaire [107]
Head and neck cancer patients 22 6
Hassan, UW-QOL University of Washington
Head and neck Cancer [108]
Head and neck cancer patients * 9
Terrel, Head and Neck Cancer-Specific QoL
(HNQoL) [109]
Head and neck cancer patients 37 4
Henson, Xerostomia Related QoL XeQoLS [110] Xerostomia in head and neck cancer
patients treated with radiotherapy
15
Chen, M. D. Anderson dysphagia Inventory
(MADI) [111]
Dysphagia in head and neck cancer patients 20 4
McHorney, SWAL-QoL and SWAL-CARE [112] Quality of life and quality of care in dysphagia
patients of both benign and malignant aetiology
4415 102
Taylor, Neck dissection impairment index (NDII) [113] Quality of life after neck dissection 10
*35 possible answers for each scale.
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Specific side effects after radiotherapy for
pharynx cancer
Reduction in quality of life and three different side
effects will be mentioned to illustrate the methodo-
logical difficulties of measuring side effects: Swal-
lowing problems are mentioned as an example where
no agreement exists on the relevant endpoint, the
organ at risk, or the preferred objective analytical
method. Dry mouth is mentioned as an example of a
side effect with a relatively simple analytical end-
point and a well-defined organ at risk. Finally, dental
problems may be objectively well defined, but no
analytical endpoints exist and its causal relation with
radiotherapy is insufficiently described.
Dysphagia
Dysphagia is the sensation in a patient of having
problems with eating and swallowing. It is not
reported to be as intense or frequent as xerostomia,
but it might be of greater importance for health [31].
Dysphagia prolongs or prohibits the intake of normal
meals. It thereby impacts on the social life of the
patients. Since the patients tend to eat less and to
limit the variation of food, they are at risk of
becoming under- and malnourished. Some patients
become dependent on a feeding tube, some of them
even for life. Part of the function of the swallowing
reflex is to prevent aspiration, i.e. the entry of liquid
and food into the airways. Aspiration puts the patient
at risk for repetitive pneumonias and perhaps even
death [32]. However, little is known about the
clinical importance of aspiration. It is a frequent
finding in long-time survivors but it often goes
unnoticed [3335]. During combined modality
treatment where chemotherapy intensifies the effects
of radiotherapy, dysphagia is often described as the
dose-limiting side effect [32,36].
Swallowing is a complex process that involves
many structures. The food is chewed in the mouth
where it is also mixed with saliva to form a bolus.
The bolus is swallowed consciously when the tongue
is pressed up- and backwards to initiate a row of
reflexes. The soft palate is moved cranially closing
the nasopharynx. Then the base of the tongue and
posterior pharyngeal wall (the upper pharyngeal
constrictor) is moved together to propel the bolus
downwards. This pushes the epiglottis down- and
backwards. Simultaneously, the larynx moves cra-
nially and the vocal cords close to protect the
airways. The upper oesophageal sphincter is relaxed,
and the lower part of the pharyngeal constrictor
presses the bolus into the oesophagus. The bolus
then passes through the oesophagus by a peristaltic
movement of involuntary muscles. This is a carefully
orchestrated process depending on connective tissue,
muscles, motor, and sensory nerves. All of these
structures can be damaged by radiotherapy, and
many objective changes have been identified after
radiotherapy: Reduced range of motion and de-
creased speed of movement of the tongue, the base
of the tongue, the posterior pharyngeal wall, larynx,
the vocal cords, and the upper oesophageal sphinc-
ter. Also, compromise of composite measures of
swallowing have been described: Velopharyngeal
incompetence, delayed swallowing reflex, reduced
OPSE (oropharyngeal swallowing efficiency), pyri-
form sinus and valecular residuals, premature leak-
age and reduced sensitivity [3741].
The standard swallowing examination is the mod-
ified barium swallow (video-fluoroscopy (VF)). It
provides the observer with the possibility of retriev-
ing quantitative measurements of speed and range of
motion of the structures involved in the swallowing
process as well as a quantitative estimate of residuals,
penetration and aspiration [20].
Functional endoscopic evaluation of swallowing
(FEES) without or with sensory testing (FEESST)
can also be used [1214]. It does not produce direct
information on the oropharyngeal phase of swallow-
ing but this can be assessed indirectly. Furthermore,
the method gives information on the sensitivity of
the throat and aspiration of saliva. It is cheaper than
VF and does not expose the patient to ionising
radiation [14,20]. The output of the examination is
unfortunately only semi-quantitative measures.
Only few researchers have tried to correlate
tumour dose with dysphagia. Smith et al. [42] report
from a non-randomized study in 27 patients treated
with 60 or 74.4 Gy tumour dose concomitant with
chemotherapy. They found more penetration/ as-
piration and more frequent long-term tube depen-
dency with 74.4 Gy than with 60 Gy. A study by Wu
[39] has been presented including FEES data that
failed to show a correlation between tumour dose
and dysphagia.
The organ at risk for the development of dyspha-
gia is a matter of debate. No single organ or specific
dysfunction has been shown to determine the overall
swallowing process and the ability for protection of
airways. Eisbruch [43] has presented a study of 26
patients receiving chemo-radiation. Videoflouro-
scopy (VF) abnormalities were seen in all phases of
the swallows. Based on significant oedema on CT
scans the pharyngeal constrictor, supraglottic larynx,
and glottic larynx were identified as the dysphagia-/
aspiration-related structures. A continuation of this
study has been conducted, and the results of an
IMRT protocol aimed at sparing the dysphagia-
related structures have been presented by Feng
[44]. Even after deliberately reducing radiation
dose to the dysphagia-related structures, dose was
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still predictive of changes on the VF. The relation
between dose to organs at risk and swallowing
function has also been described in an abstract
from ASTRO 2005: Simmons et al. [45] presented
data on 27 patients. Patient-reported diet, swallow-
ing, and speech data showed a significant correlation
with doses to the aryepiglottic fold, false vocal cords,
and lateral pharyngeal walls at the level of the false
cords. Levendag et al. presented data on subjective
swallowing in 77 head and neck cancer patients at
ESTRO 2006 [46]. Mean doses of potential organs
at risk were used in the analysis, and doses to the
upper and median pharyngeal constrictors signifi-
cantly correlated with the side effects reported in
quality of life questionnaires. Jensen et al. have
investigated the dependency on dose to critical
structures of the upper aerodigestive tract of answers
to the swallowing-related scales in the EORTC
H&N35 questionnaire as well as of the result of a
FEES. Dose-volume parameters of especially the
supraglottic region were predictive of swallowing
dysfunction [33].
Even though relevant endpoints have been chosen
for these studies, there is no agreement as to which
organ should be spared. This can be explained by the
diversity in examination methods and endpoints.
Further studies are needed that take into account the
effect of primary tumour site. Ideally, the function of
sub-structures (e.g. the ary-region) should be eval-
uated and compared with doses to these volumes,
and models should be constructed to predict overall
changes, e.g. aspiration, weight loss, normality of
diet or dysphagia based on dose-volume parameters
of the sub-structures and their function.
It is believed that dysphagia can be partially
avoided or treated with exercises [47,48]. Little
evidence supports this belief [49] however. The
exercise strategy has the advantage as compared
with an organ-sparing strategy that it does not
influence radiotherapy planning and specifically
does not introduce a risk of underdosage of the
tumour. At Aarhus University Hospital a study has
been initiated of prophylactic swallowing exercises
(ClinicalTrials.gov Identifier: NCT00332865).
The cause-effect relationship between different
measures of swallowing dysfunction and selected
contributing factors is illustrated in Figure 2. The
figure does not provide a full explanation of the
swallowing process but is intended to be illustrative of
the fact that specificity of the endpoint must decrease
as more factors may explain an endpoint Similar
figures can be constructed for all endpoints.
Dry mouth
The subjective feeling of dryness of the mouth,
xerostomia, has been pointed out by the patients as
the most frequent and bothering side effect after
radiotherapy for head and neck cancer [50]. Xer-
ostomia can lead to problems with speaking for
longer periods without sipping water. Saliva facil-
itates chewing and bolus formation of the food, and
flavours must be dissolved in fluid before they can be
Figure 2. Illustration of a cause-effect chain and different approaches to measuring side effects. Swallowing as an example.
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tasted. Patients with xerostomia often have problems
sleeping because of dry mucous membranes, espe-
cially if they have to breath through the mouth, e.g.
during a cold. The same is often a hindrance to
strenuous physical activity. Saliva physically flushes
the teeth and possesses pH-buffering as well as anti-
microbial activities. Saliva is therefore important for
dental status [51].
Parotid gland sparing has been an important
argument for introducing IMRT in many depart-
ments of radiotherapy. Important clinical results
have been published demonstrating high local con-
trol rates and preserved parotid function at the same
time [52,53]. Several authors have contributed with
data to establish a dose-volume dependency of the
parotid. A mean dose to these structures below 26
30 Gy seems to result in a low probability of
xerostomia [18,5457]. The parotid gland is a
good example of a well-defined structure (the gland)
with a well defined endpoint (saliva production),
making it an ideal test case for volume sparing. As
suggested in the introduction, a mean dose below a
fixed threshold will probably not be the perfect
conbstraint for xerostomia. Mean doses as a single
constraint parameter are counter-intuitive because
a very high dose to a small area will affect the
parameter more than is biologically reasonable
cells can only be killed once. At the same time,
glandular structures treated to low doses are capable
of compensatory hypertrophy. Treatment of xeros-
tomia is often very difficult, and most patients must
substitute saliva with either water or artificial saliva.
If some salivary function is preserved after radical
radiotherapy, salivary secretion can be stimulated
with drugs, acidic candy, or chewing gum [58].
Acupuncture has been tested, but with no proven
benefit [59]. Furthermore, xerostomia can partially
be prevented using amifostine, a radioprotectant
with a relative specificity to normal tissues, but
with a high degree of acute side effects [60].
Several relevant endpoints of salivary gland func-
tions exist. Saliva flow can be measured as whole
mouth flow, either by having the patient spitting in a
pre-weighted cup, by placing a pre-weighted cotton
cloth in the mouth, by suction, and by draining [61].
This will collect saliva from the macroscopic salivary
glands and from the sub-mucous glands. Alterna-
tively, saliva can be collected more gland-specific by
placing collecting tubes over the orifices of the
parotids [62] or sublingual/ submandibular glands
[63]. Gland-specific flow measurements are essential
for establishing dose-volume-effect relationships, as
other measures will depend on several variables. The
salivary glands are stimulated by a nervous signal.
This can be stimulated by a parasympathomimetic
agent such as pilocarpine, by having the patients
chewing on taste-less paraffin, or by applying a sour
substance on the tongue [64]. Irrespective of mea-
surement methods, the inter- and intra-subject
variations are high, especially for un-stimulated
flow [61,65]. Comparing different methods of sti-
mulation, Ericson [66] found only a moderate
correlation. An abstract by Duran [67] reports that
by stimulating saliva flow with 2% citric acid,
applied to the tongue every 30 seconds, the saliva
flow was maximally stimulated after 2 minutes, and
this could be maintained. This is in contrast to the
varied peak effect of pharmacological substances.
Whole-mouth saliva flow is probably more relevant
to the patient than gland-specific flow. Unstimulated
whole-mouth saliva flow is used as the objective
endpoint for xerostomia in CTCAE 3.0. Unstimu-
lated flow probably determines the sensation of dry
mouth during sleep and speech as the unstimulated
mucous saliva lubricates the mucous membranes
between meals. The parotid glands produce more
serous saliva, when stimulated, which enables chew-
ing and initiates digestion. This could indicate that
stimulated parotid flow is less important for the
sensation of xerostomia, since the patients will be
able to compensate for the lack of parotids function
by drinking during meals. The available data only
partly supports this simplistic correlation between
salivary gland function and xerostomia. Both whole
mouth and parotid saliva flow have been correlated
with xerostomia [55,6871]. Radiotherapy dose to
the parotid and submandibular gland have been
correlated with flow as well as xerostomia [57,69
71]. Of special interest is the study by Eisbruch [71].
He reports that dose to the oral cavity was the best
predictor of xerostomia indicating an important role
of the lubricating saliva from the submucous glands.
However, this could not be confirmed in a subse-
quent study by Jellema [55].
Dental problems
It is well known that dental problems increase after
radiotherapy for head and neck cancer. It is often
mentioned, but poorly examined. Head and neck
cancer is most often seen in patients above 60 years
of age, in smokers, and in patients with a relatively
poor socioeconomic status. The same parameters
define those at greatest risk for dental problems,
even before treatment [31]. Dental problems after
radiotherapy are related to salivary gland dysfunc-
tion [51]. Few findings support a direct adverse
effect of radiotherapy on the dental tissues [72,73],
but periodontal attachment loss has been shown to
be more pronounced in the treated side compared
with the untreated side in case of unilateral treat-
ment fields [73]. A direct measurement method for
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dental status is not available. Objective assessment
is, however, performed in the routine pre-therapeu-
tic evaluation, as dental status is important for the
risk of developing osteoradionecrosis. The overall
changes in dental status can be scored according to
CTCAE 3.0.
Reduced quality of life
The WHO has defined quality of life (and health) as
‘‘a state of complete physical, mental and social well-
being, and not merely the absence of disease’’. Two
lessons can be learned from this very general
statement: 1) A strict definition is difficult and
maybe even impossible to make. Quality of life is a
concept open to individual interpretation in a con-
text that varies with experience, age, gender, and
culture. 2) Quality of life is multidimensional. Apart
from physical, mental, and social well-being, dimen-
sions such as existential and spiritual well-being
could be added [74].
Overall, health related QoL in pharynx cancer
patients is, to a large extent, determined by the
above-mentioned and other symptoms and their
consequences: The treatment may have an effect
on smell, taste, appearance, speech, sexuality, mo-
bility of head, neck and arms, breathing, pain, mood,
and social interaction. Locally advanced uncon-
trolled disease gives rise to further symptoms but
the description of these lies beyond the scope of the
present paper.
Quality of life can be examined with in-depth
interviews of a limited number of patients, and a
qualitative description of a problem can be given as
is for instance the case for acute dysphagia as
described by Larsson [75]. To produce a feasible
quantitative description, the aim must be simplified.
A common way of achieving this is questionnaires.
Important themes for a questionnaire must be
identified by careful study of the literature and
interviews with patients and professionals from
multiple disciplines. The endpoints that the re-
searcher wants to elucidate (constructs) must be
phrased as questions (items). The most important
questions are selected by presenting the question-
naire draft to large patient groups. Items that are too
identical to others or touch on a problem too rarely
encountered are then deleted. Items can be grouped
together to form a scale in order to increase the
validity of the answer by asking the questions in
different ways, asking about many symptoms of the
same construct, different degrees of the symptoms,
or several dimensions of the construct. Scales can be
constructed based on the statistical behaviour of the
items (factor analysis) or based on the constructs
(clinical ‘‘common sense’’). The questionnaire is
tested again. The purpose of the second test is to
confirm the scale validity and to examine if the
questionnaire is sensitive to differences between
patients with e.g. different tumour load and sensitive
to changes over time with e.g. tumour progression. If
the questionnaire is to be used in a population that
differs with respect to age, types of encountered
problems, cultural background and, not least lan-
guage, the questionnaire must be retested and
perhaps adapted. This is obviously a lengthy and
costly process. The result should, nevertheless, be a
valid and reliable questionnaire that can measure
what was hitherto immeasurable or measurable with
poorer sensitivity or specificity.
One of the endpoints of the questionnaire is often
overall (health-related) quality of life. This quantity
is defined in the EORTC questionnaire by two
questions asking the patients to rate overall health
and overall quality of life. No definitions are given to
the patients, and the score represents the normalized
mean of these two questions [76]. Other systems use
mean score of all (un-related) items of the ques-
tionnaire as a measure of overall quality of life [77]
or head and neck specific quality of life [78]. The
interpretation of these scores does not seem to
be easier than the ‘‘undefined’’ score of EORTC.
The more composite the endpoint is, the harder does
it seem to define it, and the more is it dependent on
other factors than the ones studied [79] (Figures 1
and 2). For instance, differences over time or
between cancer survivors and the overall population
might not be significant for several important overall
endpoints [80]. The absence of expected differences
has to do with coping, or response shift, i.e. changes
in values and expectations as well as re-conceptua-
lization [81]. Nevertheless, a side effect that the
patient has gotten used to is still a side effect.
Comparison of endpoints
Endpoints can be compared with respect to response
rates, tolerability, and resources. This is not provided
in the present paper. Tools can also be compared if a
gold standard exists. It is hard to argue that the gold
standard for subjective endpoints must be the
patient-assessed side effect. If a difference between
patient groups is hypothesized, the sensitivity of
different methods of morbidity assessment to detect
this difference can be examined.
Stephens et al. [82] compared physician ratings
with patient-assessed symptoms using the Rotter-
dam Symptom Checklist in two randomized con-
trolled trials. Physicians tended to underestimate
symptoms, but the degree of underestimation varied
greatly between symptoms and between studies
(treatment modality), but did not vary with the
Measuring side effects 1057
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number of patients seen per centre, indicating that
training was not the reason for underestimation. An
interesting finding was that concordance decreased
as patient-reported symptom intensity increased.
The comparison of toxicity between treatment
arms was, nevertheless, consistent irrespective of
data collection method. Basch [83] compared clin-
ician and patient rating using an adapted form of
the CTCAE in an out-patient population. Again,
there was a tendency for physicians to underes-
timate symptoms, especially more subjective, unob-
servable endpoints. No patient or observer variables
were associated with the disagreement.
Using different scoring systems has yielded similar
results: Answers to the EORTC H&N35 have been
compared with equivalent endpoints of the DA-
HANCA scoring system in 116 recurrence-free
head and neck cancer survivors attending follow up
[84]. The clinicians severely underestimated the
complaints, especially regarding xerostomia. The
questionnaire endpoints, but not the observer-based
scores, were sensitive to the detrimental effects of
smoking [85]. Of note is that patient-assessed
physical function using questions resembling the
WHO performance status (PS) was more closely
associated with observer-assessed (and patient-as-
sessed) toxicity than PS. Meirovitz [86] compared
the RTOG/EORTC xerostomia scores with patient-
assessed xerostomia in 38 patients using a xerosto-
mia questionnaire and found no correlation but a
severe underestimation of xerostomia by the obser-
vers. Bjordal has also found an underestimation of
frequency and intensity of symptoms in head and
neck cancer patients in a cross sectional study [87].
Homsi found a 10-fold increase in the number of
reported symptoms in a population of palliative
patients using a checklist compared to open-ended
questions [88]. Movsas analyzed the results of a
randomized study with amifostine in lung cancer
patients treated with chemo-radiotherapy [89]. The
observer-based scoring of side effects was sensitive
enough to detect the acute toxicity of amifostine, but
not reduced dysphagia. On the other hand, patient-
assessed swallowing diaries showed a significant
effect of amifostine at week 8 and the pain item of
the EORTC C30 form were improved at week 6.
Whether this can be translated into a clinical benefit
is another question, but it proves that sensitivity to
detect treatment effects can be increased if the
proper tool is chosen.
Studies on other endpoints have been performed
using observer- and patient-based systems. Objective
assessment of cognitive function and sedation, using
Mini Mental State Examination and Alertness/Seda-
tion scale, were not correlated with self-reported
cognitive function symptoms of the EORTC ques-
tionnaire in 29 palliative patients [90]. Patient-
reported swallowing problems have been compared
with FEES findings, dental problems with a dental
examination, and xerostomia with saliva flow in 35
pharynx cancer survivors [31]. A significant correla-
tion for all endpoints was found, but patient-
reported toxicity only predicted observable morbid-
ity with a sensitivity of 0.600.83, a specificity of
0.430.81, a positive predictive value of 0.280.81
and a negative predictive value of 0.460.94. Thus,
also these results were very variable. In a chemother-
apy trial of prostate cancer, Fromme [91] compared
clinician-reported treatment-related adverse effects
on CTC-NCI with increasing (10 points) symp-
toms on the EORTC C30 questionnaire and found a
sensitivity of 2483% and a specificity of 992%,
again using QoL as the gold standard.
Patient-reported QoL has been analyzed as a
predictor for local control and survival in head and
neck cancer. Endpoints as fatigue [92] and cognitive
function [93] have been statistically significant, and
superior to physician-assessed overall physical func-
tion (Karnofsky performance scale and WHO per-
formance status (PS).
Another measurement of sensitivity is to assess if
the measurement tool can be used for establishing
dose-volume effect correlations in radiotherapy. As
mentioned above observer-scored endpoints have
been correlated with all the important parameters
of radiobiology. The dose-volume effect correlation
for swallowing problems has been examined, and the
authors [33] were able to correlate dose and volume
parameters of several potential organs at risk to both
patient-assessed swallowing problems and objective
changes assessed by endoscopy (FEES), but not to
observer-assessed dysphagia.
Sensitivity to the detection of a beneficial or
harmful effect is one measure of the quality of an
endpoint, but do quality of life studies impact on the
interpretation of study results? This question has not
been addressed in head and neck cancer, but reports
have evaluated the results of studies in breast cancer
[94], prostate cancer [95], and surgical oncology
[96]. The general conclusions are that after well-
performed studies, quality of life data has an impact
on decision making after studies without proven
survival benefit of one arm. Furthermore, quality of
life data often adds to the knowledge of side effects
and improves the quality of information that can be
offered to future patients.
Conclusion and recommendations
To evaluate the therapeutic gain of a certain treat-
ment, knowledge of both sides of the coin must be
collected. Local control and survival as well as side
1058 K. Jensen
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effects must be quantified in clinical studies. Not
only must the relevant endpoints of morbidity be
quantified and registered, but the data must also be
analysed and presented in a relevant manner. Ac-
tuarial analysis has been suggested to be the method
of choice for analysing and reporting late effects
[97,98]. It is certainly to be preferred to simple
frequencies of late effects, but some endpoints, such
as acute toxicity and late xerostomia are at least
partially reversible, and therefore not suited for
actuarial analysis [99102]. Items that must be
discussed before toxicity data is collected are men-
tioned in Table II.
The correlation between physiologic changes,
symptoms, and a detrimental effect on quality of
life is substantiated by the literature for many end-
points, but a measurement of one of the terms of the
cause-effect chain cannot be replaced by quantifying
another term without loosing specificity or sensitiv-
ity. If a treatment or prevention is aimed at inducing
a certain physiologic effect in the patient that can be
measured, this measurement should be carried out,
as it will establish the proof of principle with the
greatest specificity and sensitivity. For quantifying
subjective symptoms, validated quality of life ques-
tionnaires exist that includes questions on most side
effects. Evidence is available that quality of life data
has impact on the interpretation of trial results and
other data is available showing that the data can be
retrieved without insurmountable problems e.g.
using touch screens in the patient waiting areas
[103,104]. Therefore, physician-based scoring of
subjective symptoms can only be justified by argu-
ments of resources since it lacks specificity and
sensitivity.
In order to gain the full benefit of the possibilities
of more conformal radiotherapy, more specific
morbidity data must be collected with the best
available methods to gain information on dose and
volume dependency. At the same time, radiotherapy
is more often combined in multimodality treatments.
Each modality has its unique morbidity profile and
Table II. Questions to ask before selecting methods for measuring side effects.
What
k Analytical endpoints
j Use if feasible and available
j Must be relevant to
Physiology
Patient
j Use analytical endpoint to evaluate organ specific prevention or treatment until principles have been established*
k Subjective endpoints
j Use patient assessed data if feasible
j Use validated questionnaires
k Objective endpoint
j Use accepted scoring criteria’s
When
k Register baseline toxicity
k Time points during and after the treatment course must be relevant in order to determine
j Expected peak intensity
j Duration of side effect
k Follow up time must be sufficient to establish long term time trend (recovery, progression)
m Who
k Patients should register subjective symptoms
k Trained and motivated doctors or nurses should register the remaining data
m How
k Well planned logistics
j Unambiguous measures and forms
j Reminders for missing data
j Electronic forms to avoid typing errors
E.g. patient registered data retrieved using touch screens
k Central database for research and quality assurance
k Analyse and report using accepted statistics
j Actuarial analysis or other analysis taking patients at risk and follow up time into account
j Report measure of cumulated toxicity
Patients finishing at planned time, finishing planned number of treatments etc.
Over all measure of quality of life
Weight loss
Numbers of grade 34 toxicity at any given time
*Measure parotid flow to show that parotid sparing below a certain threshold dose results in increased salivary flow before examining effects
on xerostomia.
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new side effects will arise as a consequence of the
combination of modalities. This poses new demands
for methods that assess the overall strain on the
patient and at the same time is adaptable and
sensitive enough to allow registration of unexpected
specific toxicities. All information must be collected
prospectively and interpreted in the light of duration,
progression, or reversibility. These challenges raise a
number of important scientific and logistical ques-
tions that await an answer.
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