Effect of Radiotherapy and Chemotherapy on the Risk
of Mucositis during Intensity-Modulated Radiation
Therapy for Oropharyngeal Cancer
Giuseppe Sanguineti, M.D.,*,yMaria Pia Sormani, Ph.D.,zShanthi Marur, M.D.,x
G. Brandon Gunn, M.D.,* Nikhil Rao, M.D.,* Marco Cianchetti, M.D.,*
Francesco Ricchetti, M.D.,yTodd McNutt, Ph.D.,yBinbin Wu, Ph.D.,y
and Arlene Forastiere, M.D.x
Department of *Radiation Oncology, University of Texas Medical Branch, Galveston, TX; Departments ofyRadiation
Oncology and Molecular Radiation Sciences andxOncology, Johns Hopkins University, Baltimore, MD; and Department of
zBiostatistics, University of Genoa, Italy
Received Dec 20, 2010, and in revised form May 18, 2011. Accepted for publication Jun 29, 2011
To define the roles of radio-
therapy and chemotherapy
on the risk of grade 3þ
mucositis during IMRT for
oropharyngeal cancer, 164
consecutive patients treated
with IMRT were selected.
Individual information of the
dose received by the oral
mucosa was extracted as
absolute cumulative DVH,
corrected for the elapsed
treatment days and reported
as weekly DVH. Patients
were seen weekly during
treatment and peak acute
toxicity ? confluent muco-
sitis at any point during the
course of IMRT was consid-
ered the endpoint. On multi-
variate analysis the weekly
Purpose: To define the roles of radiotherapy and chemotherapy on the risk of Grade 3þ muco-
sitis during intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer.
Methods and Materials: 164 consecutive patients treated with IMRT at two institutions in
nonoverlapping treatment eras were selected. All patients were treated with a dose painting
approach, three dose levels, and comprehensive bilateral neck treatment under the supervision
of the same radiation oncologist. Ninety-three patients received concomitant chemotherapy
(cCHT) and 14 received induction chemotherapy (iCHT). Individual information of the dose
received by the oral mucosa (OM) was extracted as absolute cumulative doseevolume histo-
gram (DVH), corrected for the elapsed treatment days and reported as weekly (w) DVH. Patients
were seen weekly during treatment, and peak acute toxicity equal to or greater than confluent
mucositis at any point during the course of IMRT was considered the endpoint.
Results: Overall, 129 patients (78.7%) reached the endpoint. The regions that best discriminated
between patients with/without Grade 3þ mucositis were found at 10.1 Gy/w (V10.1) and 21 cc
(D21), along the x-axis and y-axis of the OM-wDVH, respectively. On multivariate analysis,
D21 (odds ratio [OR] Z 1.016, 95% confidence interval [CI], 1.009e1.023, p < 0.001) and
cCHT (OR Z 4.118, 95% CI, 1.659e10.217, p Z 0.002) were the only independent predictors.
However, V10.1 and D21 were highly correlated (rho Z 0.954, p < 0.001) and mutually inter-
changeable. cCHT would correspond to 88.4 cGy/w to at least 21 cc of OM.
Conclusions: Radiotherapy and chemotherapy act independently in determining acute mucosal
anditisequivalenttoanextra z6.2Gyto21ccofOMover a7-weekcourse.? 2011 ElsevierInc.
Keywords: Intensity-modulated radiation therapy, Chemotherapy, Mucositis
Reprint requests to: Giuseppe Sanguineti, MD, Department of Radia-
tion Oncology and Molecular Radiation Sciences, The Sidney Kimmel
Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway, Suite
1440, Baltimore, MD 21231-2410. Tel: (410) 502-3877; Fax: (410) 502-
1419; E-mail: firstname.lastname@example.org
Conflict of interest: none.
Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e8, 2011
0360-3016/$ - see front matter ? 2011 Elsevier Inc. All rights reserved.
International Journal of
dose to at least 21 cc of oral
mucosa and concomitant
chemotherapy were the only
independent predictors of
Intensity-modulated radiation therapy (IMRT) is currently the
standard approach for oropharyngeal squamous cell carcinoma
(SCC) at most institutions across North America (1). Through
parotid gland underdosing, IMRT has been shown to improve
salivary flow rates, toxicity, and quality of life over conformal
radiotherapy (2e4). However, despite these improvements, the
burden of symptoms that patients experience during a course of
IMRT is still substantial (5), potentially limiting the feasibility of
the treatment itself. One additional concern is that severe acute
morbidity can also lead to late toxicity (“consequential late
However, little is known about the doseevolume response to
radiation of the upper gastrointestinal mucosa (here called ”oral
mucosa,” [OM]). Similarly, although there is a generic acceptance
that cCHT, which is frequently part of the treatment of oropha-
ryngeal SCC, enhances acute mucosal reactions, the only study
that attempted to quantify the effect of chemotherapy in terms of
radiotherapy dosage was inconclusive (7). This lack of knowledge
limits the ability to both identify patients at risk for severe
mucositis and to prevent or minimize this from occurring with
IMRT planning objectives.
In a previous study, using a previously reported definition of
OM (8), we found a significant correlation between the absolute
amount of OM that received 9.5 Gy per week and the need for or
dependence on a feeding tube during and after exclusive IMRT for
oropharyngeal cancer (9). Because we also found in the same
study a correlation between the risk of confluent mucositis and the
use of percutaneous endoscopic gastrostomy (PEG) (9), we
decided to investigate a possible correlation between the risk of
severe mucositis during IMRT and the dose to the OM in a larger
group of patients treated with or without chemotherapy.
Methods and Materials
Patient characteristics: Volumes, dose,
Dosimetric data on all patients treated for oropharyngeal cancer
with IMRT at the University of Texas Medical Branch (UTMB)
from May 2002 to September 2006 and at Johns Hopkins
University (JHU) from August 2007 to October 2010 were
recovered. All patients were treated and evaluated under the
supervision of the same radiation oncologist (G.S.).
As previously reported, during the study period, patients were
treated according to three fractionation schedules: 2.2 Gy daily for
30 fractions in 6 weeks to 66 Gy, 2.0 Gy daily for 35 fractions in 7
weeks to 70 Gy, or 1.3 Gy twice a day for 60 fractions in 6 weeks
to 78 Gy (10, 11).
In all the patients, a dose-painting IMRT approach with three
dose levels was adopted with regard to the planning target volume
(PTV): PTV1, PTV2, and PTV3 identified the volumes containing
gross disease, microscopic disease at high risk, and microscopic
disease at low risk, respectively. The prescription doses to PTV1,
PTV2, and PTV3 according to the three schedules were as
follows: 78, 69, and 60 Gy for hyperfractionated/accelerated
IMRT; 66, 60, and 54 Gy for hypofractionation, and 70, 63, and
58.1 Gy for conventional fractionation, respectively.
At UTMB, treatment was intensified with accelerated hyper-
fractionation rather than with cCHT. At JHU, patients were
generally treated with conventional fractionation and cCHT if
their tumor exceeded T1e2, N0e1; for patients with advanced
and unresectable nodal disease (N3) or T4 primary lesions,
consideration was also made for induction chemotherapy (iCHT).
For patients receiving cCHT, the choice of chemotherapy was
cisplatin 50 mg/m2 on Day 1 and Day 8, repeated every 21 days
for three full cycles. The iCHT included two cycles of taxotere 75
mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2(TPF)
followed by cCHT with cisplatin as outlined above. Patients with
T1e2, N0e1 tumors who were enrolled in a clinical trial received
weekly cetuximab (an epidermal growth factor receptor inhibitor)
for 9 weeks, dasatinib (a tyrosine kinase inhibitor) daily taken
orally for 8 weeks and radiation Weeks 3 to 9.
IMRT: planning procedures
The IMRT approach at UTMB has been detailed in previous
reports (9e12). The gross tumor volume was manually expanded
to clinical target volume (CTV) 1 at the discretion of the treating
radiation oncologist (G.S.). The CTV2 was a further (manual)
expansion of CTV1 to cover for possible microscopic extension
around primary/nodal disease and/or to cover areas at high risk of
containing disease; for CTV3, we typically covered Levels II to IV
on both sides of the neck and Levels IB and V on the side of the
neck with positive lymph nodes. An example of our target
volumes concept has been previously reported (11). PTV1, PTV2,
and PTV3 were obtained by expanding the corresponding CTV1,
CTV2, and CTV3 by 5 millimeters. An identical approach has
also been used at JHU (13).
We considered and contoured the spinal cord (with an isotropic
expansion of 4 millimeters), brain, brainstem, parotid glands,
mandible, larynx (12), OM, (8), and unspecified tissue as organs at
All treatment planning was performed using the Pinnacle3
treatment planning system. Briefly, seven coplanar and non-
opposed gantry angles were used at UTMB and nine at JHU.
Treatment was planned to be delivered by a static-gantry, step-
and-shoot multileaf collimation technique and 6-MV photons.
Whole field IMRT was used. For optimization purposes and
coverage of each PTV, we pursued V95%>99% and V100%>
Sanguineti et al.International Journal of Radiation Oncology ? Biology ? Physics
95%. In addition to primary doseevolume objectives on the cord
þ 4 millimeters (1 cc Dmax: 45 Gy), brainstem (1 cc Dmax: 54
Gy), brain (1 cc Dmax: 60 Gy) and the secondary ones on the
parotid glands (V30<50% of at least one), the mandible (1 cc
Dmax: 70 Gy) and the larynx (1 cc Dmax: 70 Gy), we tried to
limit the dose to the portion of the OM outside any PTV to the
maximum dose of 30 Gy (8). It should be noted that the dos-
eevolume objectives were the same regardless of the fractionation
Patients were seen weekly during treatment, and mucositis was
scored at the time of examination with blinding to dosimetric data.
At UTMB, we used paper-based forms, whereas at JHU the data
were collected and stored in Mosaic (Impac Medical Systems,
INC, Sunnyvale, CA). Examination was usually performed
through transoral inspection of the oral cavity and the visualized
oropharynx. Mucositis was defined according to the Common
Terminology Criteria for Adverse Events v3.0. Peak acute toxicity
of Grade 3 or more at any point during the course of IMRT was
considered the endpoint of this study.
Logistic univariate analysis was performed with the following
clinical variables considered as potential predictors: age, sex,
institution, smoking history, T stage, American Joint Committee on
Cancer stage, T subsite, concomitant systemic treatment (biologic
and/or cytotoxic therapy), cCHT (cytotoxic only) and iCHT.
Selected dosimetric variables, as detailed below, were also consid-
ered. Variables with p values below 0.20 at univariate analysis were
included in a stepwise logistic multivariate analysis assessing the
best predictors unless otherwise specified. Several dosimetric
factors related to the doseevolume histogram (DVH) of the OM
were considered.TheOMwascontoured aspreviously reported(8).
The absolute cumulative DVH of the OM was extracted for each
DVH per week (wDVH), taking into consideration deviations in
dose and overall treatment time compared to the prescription. This
conversion is consistent with the evidence that the weekly dose is
a predictive factor of acute toxicity within a relatively narrow range
of total doses (9). Therefore, the wDVH was considered as a robust
surrogate of a “biologically” corrected DVH, without any other
correction for the difference in dose per fraction and incomplete
repair effects that are generally considered less relevant for acutely
The average wDVH of the OM in patients with and without
confluent mucositis during IMRT were compared through two-
sided t tests to assess the best predictive region of the wDVH.
Receiver operating characteristic (ROC) curves were used to
assess the most predictive doseevolume combinations for the
wDVH of the OM. The nonparametric Spearman’s test was used
to measure the correlation coefficient between selected dosimetric
Selected patient, tumor, and treatment characteristics are given in
Table 1. The median age was 57 years (range, 34e83 years).
Thirty-two patients (19.5%) had N0, 15 (9.1%) had bilateral
lymph nodes, and the remaining 117 (71.3%) had unilateral neck
Twenty-five patients were treated with hyperfractionated/
accelerated radiation therapy to a median dose of 78 Gy (range,
72.8e78 Gy) in 6.1 weeks (range, 5.4e7.6 wks). Eleven patients
were treated with hypofractionation to a median dose of 66 Gy
(range, 59.4e66 Gy) in 6.0 weeks (range, 5.7e6 wks). Finally,
128 patients were treated with conventional fractionation to 70 Gy
(range, 68e74 Gy) over 7.1 weeks (range, 6.6e9.6 weeks).
Regarding systemic treatment, 14 patients received induction
TPF chemotherapy, and of those, 12 also received cCHT. Details
of the cCHT are given in Table 1. 14 patients receiving cisplatin
were switched to carboplatin, AUC 1.5 to 2.0, because of
ototoxicity or nephrotoxicity. For the purpose of the present study,
only patients who received platinum-based cCHT (cisplatin, car-
boplatin alone or with paclitaxel, Table 1, 87 patients) were
considered as having received cCHT. Six patients who received
cetuximab alone or in combination with dasatinib were considered
within the group of patients who underwent concomitant systemic
treatment, but not cCHT.
Selected patient and tumor characteristics
Base of tongue
Carboplatin þ paclitaxel*
Cetuximab þ dasatinib
Primary tumor site
Abbreviations: AJCC Z American Joint Committee on Cancer;
UTMB Z University of Texas Medical Branch; JHU Z Johns Hopkins
University; iCHT Z induction chemotherapy.
* Considered as having received concomitant chemotherapy.
Volume - ? Number - ? 2011IMRT and chemotherapy on risk of mucositis
A total of 129 patients (78.7%) experienced confluent muco-
sitis during treatment. All patients treated with altered fraction-
ation (and without chemotherapy) reached the endpoint.
The region of the wDVH of OM that best discriminated between
patients with from those without confluent mucositis was found
between 8 and 13 Gy/week along the x axis and 1 to 100 cc along
the y axis, as shown in Fig. 1. When plotting the p value of the
two-sided t test between patients with and without mucositis, the
minimum values were found at 10.1 Gy/week and 21 cc along the
x and y axes, respectively. On the basis of these results, the
fraction of OM receiving at least 10.1 Gy/week and the weekly
dose to at least 21 cc of OM were selected for the analysis.
However, inasmuch as for a conventionally fractionated treat-
ment to 70 Gy, V10.1 might fall outside the upper edge of the
wDVH (it was 0 in 22 of 128 patients treated with conventional
fractionation, 17.2%) and therefore impossible to be used at
planning, we also considered both V8.5 and V9.5 Gy/week as
covariates. All the selected dosimetric variables were highly
correlated (Table 2).
Weekly DVH of OM as predictor of mucositis
A summary of the results of the univariate logistic analysis is
shown in Table 3. The main predictors were D21 and V10.1.
Figure 2 shows the logistic regression curve for D21.
Concomitant chemotherapy was not found to be related to
confluent mucositis on univariate analysis. However, patients who
received chemotherapy had a significantly lower D21 and V10.1
than did the remaining patients (p < 0.001 for both, Mann-
Whitney U test) because altered fractionation was never used in
the context of cCHT. Figure 3 illustrates D21 by fractionation
group and cCHT. Inasmuch as dosimetric factors may have
(two-sided t test) are also illustrated along both the x-axis and the y-axis.
Comparison of weekly doseevolume histogram of patients with and without Grade 3þ mucositis. The corresponding p values
Correlation coefficients among selected dosimetric covariates
Spearman test, rho value. All correlations are significant at the 0.01 level (two-tailed).
Sanguineti et al.International Journal of Radiation Oncology ? Biology ? Physics
masked the effect of cCHTat univariate analysis, it was decided to
include it at multivariate analysis regardless of its initial p value.
At multivariate analysis, cCHT (odds ratio [OR] Z 4.118; 95%
CI, 1.659e10.217; p Z 0.002) and D21 (OR Z 1.016; 95% CI,
1.009e1.023, p < 0.001) were the only independent predictors. If
D21 was replaced by V10.1, the odds ratios for cCHT and V10.1
were 3.711 (95% CI, 1.537e8.958; p Z 0.004) and 1.047 (95%
CI, 1.025e1.070; p < 0.001), respectively. Once included in the
model as dosimetric variables, both V8.5 and V9.5 were also
independent predictors (p Z 0.001 and p < 0.001, respectively).
Figure 4 illustrates the effect of cCHT on the D21emucositis
relationship. No interaction was detected between dosimetric
factors and cCHT.
Summary of the results of the univariate logistic analysis for Grade 3þ mucositis during intensity-modulated radiation
Variable Stratification OR95% CIp value
Base of Tongue
OM volume (cc)
Concomitant systemic treatment
Primary tumor site0.857e5.753
Abbreviations: OR Z odds ratio; CI Z confidence interval; JHU Z Johns Hopkins University; UTMB Z University of Texas Medical Branch;
AJCC Z American Joint Committee on Cancer; SP Z soft palate; PW Z pharyngeal wall; cCHT Z concomitant chemotherapy; iCHT Z induction
mucosa, with 68% confidence intervals.
Plot of the risk of Grade 3 mucositis versus D21 of oral
AF Z altered fractionation; CF Z conventional fractionation) and
concomitant chemotherapy (CHT). None of the patients treated
with AF received concomitant CHT.
Box and whiskers plots of D21 by fractionation.
Volume - ? Number - ? 2011 IMRT and chemotherapy on risk of mucositis
Cutoffs for dosimetric variables
An ROC analysis was performed to find the optimal cutoffs of
dosimetric variables. The results are summarized in Table 4.
Moreover, the last column of Table 4 shows how much dosee
volume would be equivalent to the concomitant administration
of chemotherapy according to the regression model. For example,
cCHT would represent at least 28.5 cc receiving 10.1 cGy/week;
therefore, to meet the doseevolume objective, V10.1 would need
to be maintained at 6.1 cc or less in patients receiving cCHT.
The analysis was rerun on selected patient subgroups to test its
First we selected only 128 patients treated with conventional
fractionation with or without cCHT. Of note, in this subgroup,
cCHT was significant on univariate analysis (OR, 3.832; 95% CI,
1.689e8.694; p < 0.001) along with either D21 or V10.1. At
multivariate analysis, cCHT (OR, 5.135; 95% CI, 2.054e12.83,
p < 0.001) and D21 (OR, 1.014; 95% CI, 1.006e1.021; p < 0.001)
or cCHT (OR, 4.706; 95% CI, 1.931e11.47; p Z 0.001) and V10.1
(OR, 1.038; 95% CI, 1.013e1.064; p Z 0.003) were significant.
Finally, we selected only patients who received cCHT (87
patients). At univariate analysis, both D21 and V10.1 were
significantly correlated with the risk of mucositis (OR, 1.013; 95%
CI, 1.004e1.022; p Z 0.004) and (OR, 1.035; 95% CI,
1.000e1.071, p Z 0.049), respectively.
In the present study, we found a significant correlation between
the risk of confluent mucositis and both the radiation dose to the
OM and the use of cCHT.
Virtually all patients who receive radiotherapy for head-and-
neck SCC experience some degree of mucositis. Severe mucositis
can cause pain, interfere with the patient‘s ability to chew and
swallow, worsen the patient’s quality of life, interfere with the
feasibility of both chemotherapy and radiotherapy, and lead to
excess cost (14e16). Moreover, acute mucositis may predispose to
the development of subacute and late injuries, such as bone
exposure and necrosis or swallowing problems (6).
ineffective. In a recent Cochrane review to assess the effectiveness
of interventions for treating oral mucositis in patients receiving
radiotherapy, only low-level laser treatment was found to be
somewhat effective in reducing the severity of mucositis, although
the evidence behind its use was defined as “unreliable and weak”
(17). Drugs used to prevent or treat mucositis typically fall into
three classes: antimicrobials, growth factors, and radioprotectors.
To date, drugs in all three categories have had little success in
preventing radiation-induced mucositis (18). Consistently, no
protectant is currently recommended by the American Society of
Clinical Oncology for head-and-neck SCC radiotherapy-induced
Another strategy would be to try to limit the dose to the OM at
planning. In an earlier work, we found that IMRT could poten-
tially provide more mucosa sparing than three-dimensional
conformal radiotherapy. We preliminarily found that a maximum
dose of 30 Gy over 7 weeks to the portion of the OM outside any
PTV would be associated with minimal mucosal reactions in the
absence of cCHT (8). In a detailed prospective study, Narayan
et al. confirmed that cumulative point doses up to 32 Gy to the oral
cavity were associated with limited mucosal reactions (20).
However, this would be feasible only on the portion of the mucosa
outside any PTV. In a retrospective analysis of 88 patients with
a variety of head-and-neck SCC, Werbrouck et al. found a positive
correlation between the risk of confluent mucositis and the mean
dose to the oral cavity, but not to the ”mucosa,” defined very
similarly as we did (21). Besides a predictive role of the whole
OM on confluent mucositis, we also identified novel doseevolume
objectives (Table 4) that are potentially useful both at planning (to
try to minimize the exposure of the OM to the high-dose region)
and during treatment (as predictors of patients at risk for severe
acute mucosal reactions). In a partially overlapping patient pop-
ulation, we have previously shown that OM weekly V9.5 also
predicts the need and the dependence on a PEG tube during
exclusive IMRT for oropharyngeal carcinoma (9).
Lee and Eisbruch tried to quantify the radiation dose that
would correspond to cCHT (7). With the use of data from
randomized studies, it has been estimated that cCHT would be
equivalent to three to four additional 2-Gy fractions to the
”mucosa.” However, the estimate is strongly dependent on the
slope of the doseeresponse curve using radiation alone that is
inconsistent in clinical data (7). One problem is that toxicity is not
mucosa by concomitant chemotherapy (CHT).
The risk of Grade 3 mucositis versus D21 of oral
Cutoffs for selected dosimetric variables at ROC analysis and concomitant chemotherapy equivalence
Covariate CutoffSensitivity Specificity AUC95% CIp value Chemotherapy equivalence*
Abbreviations: ROC Z receiver operating characteristic; AUC Z area under the curve; CI Z confidence interval.
* Computed from the ratio of the odds ratio at multivariate analysis.
Sanguineti et al. International Journal of Radiation Oncology ? Biology ? Physics
uniformly reported and scored (22). Even when these factors are
considered and accounted for, reported rates still vary consider-
ably. In Radiation Therapy Oncology Group Trial 9003, the
incidence of confluent mucositis or worse mucosal toxicity within
the concomitant boost technique arm was only 41% (23), whereas
it was almost twofold (35 of 43 patients, 81.4%) in the first report
of this approach from the M.D. Anderson Cancer Center (24).
Although it has been reported that toxicity may be underestimated
in trials (22) where compliance may be lower than planned (25),
such inconsistency hampers the detection of a doseeresponse
curve for acute mucositis. Usually tumors of the oral cavity/
oropharynx have increased rates of mucositis compared with those
of the laryngopharynx (15, 16, 26), although this seems to result
from the accessibility to evaluation and scoring rather than from
a radiobiologic difference (26). For this reason we selected for the
present study only tumors arising from the oropharynx.
Additional problems are the individuation of a region of
interest representing the OM and the extraction of the dosimetric
data for each patient. Regarding the former, although other options
are available (2, 27), we decided to include in our definition of
OM the mucosa of the oral cavity, oropharynx, and hypopharynx,
as previously reported and discussed (8). We believe that
a comprehensive definition better accounts for a volume effect. In
the two-dimension era, Bentzen et al. found a significant dose-
earea effect for mucositis, with a significant increase in incidence
and severity with increasing field size (26). Regarding the latter,
the extraction of individual dosimetric data has been possible only
since the implementation of three-dimensional planning and thus
only recently. Because the rate of mucositis is strongly dependent
on overall treatment time (28), we corrected the OM DVH by the
elapsed treatment time. However, it should be noted that D21 at
planning (based on the planned rather than the actual treatment
time) was already significant on univariate analysis (OR, 1.011;
95% CI, 1002e1019; p Z 0.011). Considering the OR of D21
given in Table 3 after correction for the actual treatment time, we
conclude that both dosimetric data at planning and subsequent
adjustment for elapsed treatment time contributed to the results.
Finally, we found that cCHT significantly increases the risk of
severe mucositis. Vera-Llonch et al. in a community-based cross
sectional survey found that cCHT increases the risk of severe
mucositis, as per provider assessment and without a specific scale,
by 3.3 times over RT alone (range,1.4e8.0) (16). Using the
Common Terminology Criteria 2.0 definition, we found an OR
value slightly higher (OR Z 4.1), particularly for patients treated
with conventional fractionation (OR Z 5.1). Elting et al. reported
a detrimental effect on any mucositis grade of cCHT over
conventional fractionation with radiation therapy alone even
higher (OR Z 7.8) (15). Of note, two studies that used patient-
reported outcomes did not find a negative effect of cCHT on
acute toxicity domains (29, 30). Whether the perception of
mucositis intensity during CHT is blurred by other symptoms or it
cannot be discriminated because it is already beyond a given
threshold is unclear and deserves future study.
This study also shows that in the context of cCHT it is very
difficult to achieve a dosimetric sparing of the OM at planning
(Table 4) and it certainly does not support treatment acceleration
in the setting of cCHT.
In the present study we did not attempt to differentiate between
the mucosal effects of cisplatin and carboplatin alone or in
combination with a taxane because of the scarcityof patients in the
latter subgroup. Regarding the fractionation of cisplatin, on the
basis of the results of a recent study that did not find a significant
difference in the rates of confluent mucositis after unfractionated
(100 mg/m2every 3 weeks) and fractionated (20 mg on Days 1e5
and Days 29e33) cisplatin delivered with conventional fraction-
ation and radiation therapy (31), we believe that the present results
can be reasonably applied to either fractionation setting.
The present study has some limitations. First we considered as
endpoint only the peak toxicity during treatment. We may have
missed some “late” events, even if this is unlikely. In a study from
the M.D. Anderson Cancer Center, only 6 of 204 patients (2.9%)
experienced a higher grade (Grade 3) of mucositis after comple-
tion of radiation therapy, and all cases occurred among patients
who received adjuvant CHT after radiation therapy (15). Adjuvant
chemotherapy was not delivered in our study. More importantly,
we do not have information on the duration of severe mucositis
after treatment completion because patients typically return for
follow-up examination 4 to 8 weeks after completion and not on
a weekly basis, which would be needed to most accurately
determine the duration of mucositis (32). Although we consider
the avoidance of confluent mucositis to be a reasonable and useful
endpoint, we cannot exclude that some of the patients had this
severity of mucositis only for a limited time and thus with limited
Second, although the present data prove the principle, they
should be considered potentially applicable only to patients
treated with the same approach (i.e., oropharyngeal SCC treated
with IMRT), where targets and OARs are defined and contoured as
previously described. The next step will be to apply these prin-
ciples at planning to limit as much as possible the amount of OM
that is exposed to 9.5 to 10 Gy per week and to validate this
approach in a prospective cohort of patients.
Finally, the incidence of mucositis has been reported to vary not
only by treatment but also in relation to various patient character-
istics, although the data are scattered and inconsistent (16, 27). Not
surprisingly, of those tested here, only sex showed a trend (p Z
was not significant at multivariate analysis. Owing to the current
prevalence of human papillomaviruserelated tumors, the oropha-
ryngeal cancer population identifies a group of patients that may
in terms of age, comorbidity, and social habits (33). Although this
interpretation of our results.
In conclusion, the present analysis of a relatively homogeneous
group of patients treated with IMRT for oropharyngeal SCC
identifies both cCHT and the amount of OM exposed to 10.1 Gy/
week as independent predictors of the development of confluent
mucositis during IMRT. These data warrant prospective imple-
mentation and validation as a potential strategy to limit acute
toxicity and to identify patients at risk for more aggressive
prophylactic interventions, such as PEG placement.
1. Gregoire V, De Neve W, Eisbruch A, et al. Intensity-modulated
radiation therapy for head and neck carcinoma. Oncologist 2007;12:
2. Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of
accelerated hypofractionated intensity-modulated radiation therapy for
early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol
Biol Phys 2010;76:1333e1338.
Volume - ? Number - ? 2011IMRT and chemotherapy on risk of mucositis
3. Nutting C, A’Hern R, Rogers MS, et al. First results of a phase III
multicenter randomized controlled trial of intensity modulated (IMRT)
versus conventional radiotherapy (RT) in head and neck cancer
(PARSPORT: ISRCTN48243537; CRUK/03/005). J Clin Oncol
(Meeting Abstracts) 2009;27:LBA6006.
4. Fang FM, Chien CY, Tsai WL, et al. Quality of life and survival
outcome for patients with nasopharyngeal carcinoma receiving three-
dimensional conformal radiotherapy vs. intensity-modulated radio-
therapy: A longitudinal study. Int J Radiat Oncol Biol Phys 2008;72:
5. Rosenthal DI, Mendoza TR, Chambers MS, et al. Measuring head and
neck cancer symptom burden: The development and validation of the
M. D. Anderson symptom inventory, head and neck module. Head
6. Denham JW, Peters LJ, Johansen J, et al. Do acute mucosal reactions
lead to consequential late reactions in patients with head and neck
cancer? Radiother Oncol 1999;52:157e164.
7. Lee IH, Eisbruch A. Mucositis versus tumor control: The therapeutic
index of adding chemotherapy to irradiation of head and neck cancer.
Int J Radiat Oncol Biol Phys 2009;75:1060e1063.
8. Sanguineti G, Endres EJ, Gunn BG, et al. Is there a “mucosa-sparing”
benefit of IMRT for head-and-neck cancer? Int J Radiat Oncol Biol
9. Sanguineti G, Gunn GB, Parker BC, et al. Weekly dose-volume
parameters of mucosa and constrictor muscles predict the use of
percutaneous endoscopic gastrostomy during exclusive intensity-
modulated radiotherapy for oropharyngeal cancer. Int J Radiat
Oncol Biol Phys 2011;79:52e59.
10. Gunn GB, Endres EJ, Parker B, et al. A phase I/II study of altered
fractionated IMRT alone for intermediate T-stage oropharyngeal
carcinoma. Strahlenther Onkol 2010;186:489e495.
11. Sanguineti G, Gunn GB, Endres EJ, et al. Patterns of locoregional
failure after exclusive IMRT for oropharyngeal carcinoma. Int J
Radiat Oncol Biol Phys 2008;72:737e746.
12. Sanguineti G, Adapala P, Endres EJ, et al. Dosimetric predictors of
laryngeal edema. Int J Radiat Oncol Biol Phys 2007;68:741e749.
13. Ricchetti F, Wu BB, McNutt T, et al. Volumetric change of selected
organs at risk during IMRT for oropharyngeal cancer. Int J Radiat
Oncol Biol Phys 2011;80:161e168.
14. Trotti A. Toxicity in head and neck cancer: A review of trends and
issues. Int J Radiat Oncol Biol Phys 2000;47:1e12.
15. Elting LS, Cooksley CD, Chambers MS, et al. Risk, outcomes, and
costs of radiation-induced oral mucositis among patients with head-
and-neck malignancies. Int J Radiat Oncol Biol Phys 2007;68:
16. Vera-Llonch M, Oster G, Hagiwara M, et al. Oral mucositis in patients
undergoing radiation treatment for head and neck carcinoma. Cancer
17. Clarkson JE, Worthington HV, Eden OB. Interventions for preventing
oral mucositis for patients with cancer receiving treatment. Cochrane
Database Syst Rev 2003;CD000978.
18. Garden AS, Chambers MS. Head and neck radiation and mucositis.
Curr Opin Support Palliat Care 2007;1:30e34.
19. Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of
Clinical Oncology 2008 clinical practice guideline update: Use of
chemotherapy and radiation therapy protectants. J Clin Oncol 2009;
20. Narayan S, Lehmann J, Coleman MA, et al. Prospective evaluation to
establish a dose response for clinical oral mucositis in patients
undergoing head-and-neck conformal radiotherapy. Int J Radiat Oncol
Biol Phys 2008;72:756e762.
21. Werbrouck J, De Ruyck K, Duprez F, et al. Acute normal tissue
reactions in head-and-neck cancer patients treated with IMRT: Influ-
ence of dose and association with genetic polymorphisms in DNA
DSB repair genes. Int J Radiat Oncol Biol Phys 2009;73:1187e1195.
22. Bentzen SM, Trotti A. Evaluation of early and late toxicities in che-
moradiation trials. J Clin Oncol 2007;25:4096e4103.
23. Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group
(RTOG) phase III randomized study to compare hyperfractionation and
two variants of accelerated fractionation to standard fractionation
radiotherapy for head and neck squamous cell carcinomas: First report
of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7e16.
24. Ang KK, Peters LJ, Weber RS, et al. Concomitant boost radiotherapy
schedules in the treatment of carcinoma of the oropharynx and
nasopharynx. Int J Radiat Oncol Biol Phys 1990;19:1339e1345.
25. Khalil AA, Bentzen SM, Bernier J, et al. Compliance to the prescribed
dose and overall treatment time in five randomized clinical trials of
altered fractionation in radiotherapy for head-and-neck carcinomas.
Int J Radiat Oncol Biol Phys 2003;55:568e575.
26. Bentzen SM, Saunders MI, Dische S, et al. Radiotherapy-related early
morbidity in head and neck cancer: Quantitative clinical radiobiology
as deduced from the CHART trial. Radiother Oncol 2001;60:
27. Werbrouck BF, Pauwels WJ, De Bleecker JL. A case of 5-fluorouracil-
induced peripheral neuropathy. Clin Toxicol 2008;46:264e266.
28. Kaanders JH, van der Kogel AJ, Ang KK. Altered fractionation:
Limited by mucosal reactions? Radiother Oncol 1999;50:247e260.
29. Elting LS, Keefe DM, Sonis ST, et al. Patient-reported measurements
of oral mucositis in head and neck cancer patients treated with
radiotherapy with or without chemotherapy: Demonstration of
increased frequency, severity, resistance to palliation, and impact on
quality of life. Cancer 2008;113:2704e2713.
30. Epstein JB, Beaumont JL, Gwede CK, et al. Longitudinal evaluation
of the oral mucositis weekly questionnaire-head and neck cancer: A
31. Rades D, Kronemann S, Meyners T, et al. Comparison of four
cisplatin-based radiochemotherapy regimens for nonmetastatic stage
III/IV squamous cell carcinoma of the head and neck. Int J Radiat
Oncol Biol Phys 2011;80:1037e1044.
32. Sanguineti G, Richetti A, Bignardi M, et al. Accelerated versus
conventional fractionated postoperative radiotherapy for advanced
head and neck cancer: Results of a multicenter Phase III study. Int J
Radiat Oncol Biol Phys 2005;61:762e771.
33. Fakhry C, Gillison ML. Clinical implications of human papillomavirus
in head and neck cancers. J Clin Oncol 2006;24:2606e2611.
Sanguineti et al.International Journal of Radiation Oncology ? Biology ? Physics