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ORIGINAL RESEARCH
Accelerated radiotherapy with simultaneous
integrated boost fractionation and
intensity-modulated radiotherapy for advanced
head and neck cancer
Matthew Schwartz, MD, Té Vuong, MD, Olivier Ballivy, MD,
William Parker, MSc, and Horacio Patrocinio, MSc, Montreal, Quebec, Canada
OBJECTIVE: To determine the feasibility and toxicity profile
of accelerated radiotherapy with a simultaneous integrated
boost fractionation scheme with intensity-modulated radiotherapy
(SIB-IMRT) with or without chemotherapy.
STUDY DESIGN AND SETTING: Forty-nine patients with
advanced head and neck cancer underwent SIB-IMRT. Concom-
itant chemotherapy was administered in 29 patients.
RESULTS: Grade 3 acute toxicities included 55% mucositis,
20% odynophagia, 12% nausea, 18% hematologic, and 8% skin.
There were no grade 4 toxicities or treatment-related deaths. With
a median follow-up of 25 months, locoregional control was 83%,
and overall survival was 80%. Of patients with grade 3 late
toxicities, two patients (4% of the total) required a permanent
percutaneous endoscopic gastrostomy tube, and osteonecrosis oc-
curred in one patient (2% of the total).
CONCLUSIONS: SIB-IMRT is a feasible technique that short-
ens the overall treatment time in the radical treatment of patients
with advanced head and neck cancer while maintaining acceptable
rates of acute toxicity in this study. Although the results are
promising, this approach should be considered only in the setting
of a clinical trial.
© 2007 American Academy of Otolaryngology–Head and Neck
Surgery Foundation. All rights reserved.
In patients with locally advanced head and neck cancer,
locoregional control remains a therapeutic challenge. In
recent years, both accelerated radiotherapy and concurrent
chemotherapy have been used to improve outcomes at the
cost of increased toxicity. Intensity-modulated radiation
therapy (IMRT) has the potential to improve the therapeutic
index by achieving a more conformal dose distribution to
the target volumes and better sparing of the normal tissues.
1-3
Several studies have shown the importance of treatment
time in local control for head and neck cancer.
4-6
Withers
et al
6
found that after 4 weeks of continuous once-daily
definitive radiotherapy for squamous cell carcinomas of the
head and neck, greater daily dosage was necessary to pro-
duce the same probability of cell kill. This is thought to be
the result of accelerated repopulation of tumor clonogens in
response to radiotherapy. Accelerated fractionation has
been shown to increase local control in a large multi-insti-
tutional trial (RTOG 90-03) with the use of accelerated
radiotherapy with concomitant boost at the expense of in-
creased acute side effects.
7
Patients treated with the con-
comitant boost fractionation scheme had a 46% rate of
grade 3 acute mucositis vs 25% in patients treated with
standard fractionation. The concomitant boost patients also
had a higher rate (29%) of acute grade 3 pharynx/esophagus
complications, as compared with a rate of 11% in patients
treated with the standard fractionation. The improvement in
local control (54.5% vs 46%, P⫽0.05) was attributed to
decreasing the treatment time.
Similarly, the addition of concurrent chemotherapy to
radiotherapy has increased local control and overall sur-
vival.
8-11
The increase in local control is thought to be due
From the Departments of Radiation Oncology (Drs Schwartz, Vuong,
and Ballivy) and Medical Physics (Mr Parker and Mr Patrocinio), McGill
University Health Center, Montreal, Quebec, Canada.
Presented in part at the 6th International Conference on Head and Neck
Cancer, Washington, DC, August 2004.
Reprint requests: Té Vuong, MD, Montreal General Hospital, Depart-
ment of Radiation Oncology, 1650 Cedar Avenue, Montréal, Québec,
Canada H3G 1A4.
E-mail address: te.vuong@muhc.mcgill.ca.
Otolaryngology–Head and Neck Surgery (2007) 136, 549-555
0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
doi:10.1016/j.otohns.2006.10.044
to the radio-sensitization effects of concurrent cisplatin.
Pignon et al
11
in a meta-analysis of 10,741 patients in 63
trials found an absolute survival benefit of 4% at 5 years in
favor of the concomitant chemotherapy. This increase in
local control and survival is at the expense of increased rates
of mucositis and hematologic toxicity. A randomized trial
of advanced stage oropharyngeal carcinoma by Calais et
al
10
reported higher rates of grade 3 mucositis (71% vs
39%), hematologic toxicity (12% vs ⬎1%), and weight loss
⬎10% (13% vs 5%) in patients treated with combined
chemotherapy and radiotherapy vs the radiotherapy alone
arm.
Inversely planned IMRT is a novel treatment technique
that uses nonuniform beam fluences to achieve a more
conformal dose delivery to the target and better sparing of
normal tissues. IMRT also allows for the simultaneous
delivery of different doses to different target volumes and
thus represents an ideal technique for the implementation of
a simultaneous integrated boost fractionation scheme. But-
ler et al
12
previously reported the results of a simultaneous
modulated radiation therapy boost technique (SMART) for
head and neck cancer patients. In their study, the primary
targets (consisting of palpable or radiologically visible tu-
mor and involved lymph nodes) received 60 Gy in 25
fractions of 2.4 Gy, while simultaneously the secondary
targets (including all regions at risk for microscopic disease
such as the draining lymph nodes) were treated to a dose of
50 Gy at 2 Gy per fraction. The low neck nodes received
conventional treatment with a direct anterior photon field.
This technique allowed for increased parotid sparing from
the high radiation doses, and the average mean dose to the
contralateral parotid was less than 21 Gy.
Our study was designed to determine the feasibility and
the toxicity profile of accelerated radiotherapy with a simul-
taneous integrated boost fractionation scheme using an in-
tensity-modulated radiotherapy delivery technique (SIB-
IMRT), with or without chemotherapy, in patients with
locally advanced head and neck cancer. Similar to the study
from Butler et al,
12
the IMRT planning was designed to
deliver a dose of 60 Gy in 25 fractions to the gross tumor
volume and a dose of 50 Gy in 25 fractions to the tissues at
risk for microscopic disease while limiting the mean dose
received by the parotids to less than 25 Gy. The overall
treatment time is then shortened from 7 to 5 weeks. This,
together with greater sparing of the critical normal struc-
tures, may improve the therapeutic ratio in these patients. In
addition, from a practical standpoint, this technique is much
simpler by avoiding the need for the addition of electron
fields, field junctioning, or multi-plan techniques to limit the
cord dose to within tolerance.
METHODS AND MATERIALS
General Information
The institutional review board approved the retrospective
chart review for the purposes of this study. Between January
2002 and May 2005, 49 patients with previously untreated
advanced head and neck cancer underwent accelerated ra-
diotherapy using SIB-IMRT at our institution. All patients
were treated with a curative intent and had stage III or IV
disease according to the 1997 American Joint Committee on
Cancer (AJCC) staging classification. The patient charac-
teristics are given in Table 1.
Radiotherapy Protocol
All patients first underwent a planning CT scan in the
treatment position. A thermoplastic mask was used for head
and neck immobilization. The target volumes and organs at
risk (OAR) were delineated on each CT slice for each
patient by the same staff radiation oncologist. The gross
tumor volume (GTV) was defined as the tumor visible by
imaging studies and clinical examination. This included the
primary tumor and metastatic lymph nodes. The clinical
target volume (CTV) was defined as the GTV plus a min-
imum of 5 mm margin for microscopic disease and the
nodal regions at risk for metastatic spread. A margin of 3 to
Table 1
Patient and tumor characteristics
Parameter Value
Age
Range (y) 38-95
Median (y) 61
Sex
Female 16
Male 33
Primary tumor site
Oropharynx
Tumor stage*
T1-2 N0 3
T1-2 N0-1 13
T2-4 N0-3 13
Hypopharynx
Tumor stage*
T2 N0 1
T3 N1 1
Nasopharynx
Tumor stage*
T1-2 N0 2
T2-3 N0-2 3
Unknown primary
Tumor stage*
Tx N1 3
Tx N2-3 6
Larynx
Tumor stage*
T3 N0-2 4
Histology
Squamous cell carcinoma 43
Poorly differentiated carcinoma 6
Concomitant chemotherapy
Yes 29
No 20
*American Joint Committee on Cancer (AJCC), 5
th
edition,
1997.
550 Otolaryngology–Head and Neck Surgery, Vol 136, No 4, April 2007
5 mm was added around the GTV and CTV to account for
uncertainties in setup and organ motion and to obtain the
planning target volume (PTV). We have previously reported
that these margins are effective in preventing significant
deviation from the prescribed dose in these patients.
13
The
CT images and structure sets were then transferred to a
commercially available inverse treatment planning system
(CORVUS, V.5.0, NOMOS Corp) to generate IMRT plans.
The prescription dose was 60 Gy in 25 fractions to the GTV
and 50 Gy in 25 fractions to the CTV. The treatment goals
were to provide adequate coverage of the target volume
while not exceeding the tolerance of the spinal cord and
minimizing the dose to the parotids, larynx, esophagus, and
mandible. The treatment goals were the following: 99% of
CTV to receive ⱖ49.5 Gy; 99% of GTV to receive ⱖ59.4
Gy; 95% of the CTV to receive ⱖ50 Gy; 95% of the GTV
to receive ⱖ60 Gy; ⬎1 cc of the CTV to receive ⬎110% of
the dose prescribed. The dose constraints to the organs at
risk (OAR) were the following: spinal cord maximum dose
to1cc⬍50 Gy; brain stem maximum dose ⬍60 Gy,
mandible maximum dose ⬍70 Gy, dose to 50% of the
parotids volume ⬍30 Gy, and larynx mean dose ⬍35 Gy.
We also attempted to keep the volume of tissue receiving
⬎110% of the prescribed dose to ⬍1 cc. The IMRT was
delivered with six MV photon beams and a dynamic se-
quencing multileaf collimator.
Before treatment, a qualified medical physicist carried
out patient specific quality assurance. This included an
absolute dose measurement within an ionization chamber in
a water-equivalent phantom. A relative film measurement of
the spatial dose distribution in the coronal plane was also
performed. During treatment, weekly portal imaging was
performed to verify isocenter alignment. If the patients lost
more than 5% of their body weight or had a difference in
any setup parameter of ⬎1 cm, they underwent repeat CT
simulation and were re-planned if necessary to ensure proper
coverage of the target and avoidance of organs at risk.
Chemotherapy Protocol
Twenty-nine patients with good performance status and no
major comorbidities were administered concomitant chemo-
therapy consisting of cisplatin 100 mg/m
2
/day on weeks 1
and 5. Twenty patients with unknown primary (n ⫽9) and
T1-2 N0 oropharynx (n ⫽3) and nasopharynx (n ⫽2)
cancer received radiation alone as well those (n ⫽6) with
severe liver disease or poor kidney function. Percutaneous
gastrostomy tubes were routinely placed before treatment
for those patients who received chemotherapy. Patient mon-
itoring during treatment was performed weekly and con-
sisted of a focused history and physical examination, patient
weight, and CBC test results.
Follow-up
Patients were seen in follow-up every month for the first 2
years after treatment, then every 3 months until 3 years, then
yearly. At each follow-up, each patient received a focused
history and physical examination. Imaging studies were re-
peated 3 months after the end of treatment and then yearly.
Toxicity Evaluation
Acute and late normal tissue effects were graded according
to the Radiation Therapy Oncology Group (RTOG) radia-
tion morbidity scoring criteria.
RESULTS
Dose-volume histogram analysis showed that the average
mean doses delivered to the GTV and CTV were 62.8 Gy
and 54.2 Gy, respectively. The average doses to 95% of the
GTV and CTV (D
95
) were 59.8 Gy and 49.1 Gy, respec-
tively. The average maximal dose to the spinal cord was
45.7 Gy and the dose to a volume of 1 cc was kept below 50
Gy in all patients. The average mean doses to the ipsilateral
and contralateral parotids were 25.1 Gy and 23 Gy, respec-
tively. The average mean dose to the larynx was 28.8 Gy.
The average GTV volume was 89.1 cc (median, 64.3 cc)
and the average CTV volume was 570.6 cc (median, 517.6
cc). The average ratio of GTV/CTV volumes was 0.18
(maximum, 1.53; minimum, 0.03; median, 0.12). There was
no correlation between GTV volume or the GTV/CTV ratio
and the incidence of long-term toxicity (the two patients
who required chronic PEG use had ratios of 0.059 and
0.037, respectively, and both had GTV volumes less than
the median).
Forty-five (91.8%) of 49 patients completed treatment
within 40 days (mean, 36 days; median, 36 days; range, 31
to 48 days). Of the four patients whose treatments lasted
longer than 40 days, two patients who received chemother-
apy had acute grade 3 mucositis and hematologic toxicities
and the other two patients who did not receive chemother-
apy had grade 3 nausea and vomiting and hematologic
toxicities for which their treatments were delayed by 9, 11,
6, and 12 days beyond the mean number of days, respec-
tively. Three of these patients had a complete response;
however, one of the four patients has had a recurrence in the
neck nodes.
Acute RTOG toxicities were defined as those that occurred
within 3 months of starting radiation treatments (Table 2).
Grade 3 acute toxicities included: mucositis (27 patients),
odynophagia/dysphagia (10 patients), nausea and/or vom-
iting (6 patients), hematologic (9 patients), and skin desqua-
mation (4 patients). The patients with skin and odynopha-
gia/dysphagia toxicities were analyzed with respect to
patient-related, treatment-related, or disease-related factors
that may account for the toxicity, but there were no consis-
tently identifiable factors. No patients had grade 4 toxicity
and there were no treatment related deaths.
Late toxicities were defined as those persisting longer than
3 months or beginning after 3 months from the start of treat-
ment, and included two (4%) patients who required chronic
PEG tube use, and osteonecrosis in one (2%) patient. Both
551Schwartz et al Accelerated radiotherapy with simultaneous . . .
patients with chronic PEG dependence received concomitant
chemotherapy and had acute odynophagia/dysphagia. The os-
teonecrosis has completely resolved without surgical interven-
tion. No patients had grade 3 or higher late xerostomia, and 12
(25%) of 49 patients had grade 2 late xerostomia.
There was a higher incidence of acute grade 3 nausea
and/or vomiting, greater than 10% weight loss, and grade 3
hematologic toxicities in those patients who received che-
motherapy concomitantly with radiotherapy (Table 3).
With a median follow-up of 25 months (range, 3 to 53
months) for all patients and a median follow-up for surviving
patients of 29 months, the 3-year actuarial locoregional control
was achieved in 41 (83%) of 49 patients, and the 3-year
actuarial overall survival was 80%. Of the eight patients that
failed locoregionally, four had primary and nodal failures, one
failed in the lymph nodes and had distant failure, and three
patients failed locally alone. Seven of the eight patients had
in-field failures and there was a marginal miss on one patient.
Four patients have developed distant metastases: one patient
with a stage IVa nasopharyngeal cancer developed bone and
liver metastases, one patient with a stage IV base of tongue
cancer has developed lung metastases, another patient with
stage III tonsil cancer developed liver and bone metastases, and
one patient with stage III unknown primary cancer developed
liver metastases.
DISCUSSION
The simultaneous integrated boost fractionation scheme
with the use of intensity modulated radiation therapy (SIB-
IMRT) was designed to decrease the treatment time with
better sparing of the critical normal tissues.
The addition of chemotherapy may allow for increase in
local control and overall survival in these patients, but likely
at the expense of increased toxicity. As shown in Table 3,
we found a higher incidence of grade 3 acute toxicities of
nausea and/or vomiting, greater than 10% weight loss, and
hematologic toxicities in patients who received concomitant
chemotherapy and radiotherapy. Amosson et al
14
reported
in abstract form, a 47.3% rate of acute grade 3 mucositis and
21.8% rate of grade 3 or 4 pharyngitis with the SMART
boost technique. They reported that the patients with con-
current chemotherapy had higher rates of toxicity and this
treatment was not tolerable. In our series, the rate of acute
grade 3 mucositis in our patients who received SIB-IMRT
with or without concomitant chemotherapy was 58% and
45%, respectively, but remained below the 70% observed in
the Gortec and Brizel trials (Table 4) when chemotherapy
was given concurrently. An important factor in the morbid-
ity of mucositis is likely the volume of tissue that receives
60 Gy. Although it is difficult to quantify, patients with
small focal areas of confluent mucositis seem to do better
than those with larger areas. Further studies that emphasize
the volume of normal mucosa irradiated are necessary to
explore this issue.
Radiation-induced xerostomia is an important factor in a
patient’s quality of life after treatment. Approximately 75%
of patients in our study had no significant late salivary
toxicity. Eisbruch et al
2
showed that by limiting the mean
parotid dose to 26 Gy or less with the use of 3-dimensional
conformal radiotherapy, a substantial preservation of the
parotid function is possible. The mean dose to each parotid
in our study was less than 26 Gy. The low rate of late
salivary toxicity seen in our study is likely due to the use of
the IMRT as it has been shown to decrease late salivary
toxicity as compared with conventional techniques.
In our study, we took special care to limit the doses to the
spinal cord and mandible, and although the median fol-
low-up is short, we found no cases of radiation myelititis,
and only one case of osteonecrosis of the mandible. In
Table 3
Frequency of grade 3 or higher acute radiation
morbidity (RTOG scoring criteria)
Type
Received
chemotherapy
No
chemotherapy
Mucositis 18/29 (58%) 9/20 (45%)
Odynophagia/
dysphagia 6/29 (20%) 4/20 (20%)
Nausea and/or
vomiting 5/29 (17%) 1/20 (5%)
Skin desquamation 3/29 (10%) 1/20 (5%)
Hematologic 7/29 (24%) 2/20 (10%)
Salivary gland 0/29 1/20 (5%)
Weight loss ⬎10% 7/29 (24%) 3/20 (15%)
Table 2
Acute radiation morbidity (RTOG scoring criteria)
Type
Number of
patients Grade
Mucositis 0 0
6 (12%) 1
16 (32%) 2
27 (55%) 3
Odynophagia/dysphagia 20 (40%) 0
7 (14%) 1
12 (24%) 2
10 (20%) 3
Nausea and/or vomiting 19 (38%) 0
8 (16%) 1
16 (23%) 2
6 (13%) 3
Skin desquamation 1 (3%) 0
15 (30%) 1
29 (59%) 2
4 (8%) 3
Hematologic 9 (18%) ⱖ3
Salivary gland 24 (49%) 0
18 (36%) 1
6 (12%) 2
1 (3%) 3
Weight loss ⬎10% 11 (22%)
552 Otolaryngology–Head and Neck Surgery, Vol 136, No 4, April 2007
addition, the inverse treatment planning used allowed pro-
tection of the brain stem and optic nerves in cases, such as
the nasopharynx cancers, where the target volume is near
these structures. We had no cases of optic neuritis or cranial
neuropathies as a result of radiation.
Acute skin toxicity is an important dose-limiting side
effect of the IMRT for head and neck cancer patients. In our
series, we had only four (8%) patients with grade 3 acute
skin toxicity. Lee et al
15
showed that taking the skin into
consideration as a sensitive structure during inverse plan-
ning, it was possible to decrease the dose to a tolerable
level. Our low rate of acute skin toxicity can likely be
attributed to the fact that we gave special attention to keep-
ing the target volumes at a distance of at least 5 mm from
the skin surface in order to minimize the dose delivered to
the skin. As seen in Table 4, our rate of grade 3 acute skin
toxicity is lower than the accelerated fractionation with
concomitant boost arm of the RTOG 90-03 protocol.
7
This
emphasizes the fact that proper target volume delineation
with IMRT can significantly spare the skin leading to more
tolerable treatment regimens.
With altered fractionation, severe dysphagia can be an
important late complication lowering the therapeutic ratio.
The addition of concurrent chemotherapy to accelerated
radiotherapy may increase the incidence of late dysphagia.
In our series, we had only two (4%) patients who required
chronic PEG tube. In a phase I/II trial of accelerated radio-
therapy plus concurrent paclitaxel, Bucci et al
16
reported a
9% rate of severe esophageal strictures that required per-
manent gastrostomy. Our 4% incidence of pharyngeal com-
plications is less than the 15% seen in the accelerated
fractionation with concomitant boost arm of the RTOG
90-03 study.
7
Functional organ preservation is likely to be
an important concept when altered fractionation and che-
motherapy is used. Kotz et al
17
reported on 12 patients with
advanced head and neck cancer treated with chemoradiation
and found that all of these patients had changes in their
swallowing physiology after treatment. The most com-
monly affected mechanism of swallowing was the tongue
base to posterior wall contact. Figure 1 shows an example of
a patient in our series treated with SIB-IMRT and chemo-
therapy with a grade 3 late pharyngeal toxicity. The high
dose region clearly encompasses the previous structures and
may account for this patient’s toxicity. In our series, there
was a correlation between acute and late dysphagia. The use
of concomitant chemotherapy is possibly a risk factor for
severe dysphagia; however, we found a similar rate of grade
3 odynophagia/dysphagia in those patients who received
concomitant chemotherapy vs radiation alone (20% vs 20%)
(Table 3).
As only eight of our patients have failed locoregion-
ally, the tumor control rate appears encouraging with this
accelerated fractionation scheme delivery technique.
However, we acknowledge that we have a heterogeneous
group of patients and that longer follow-up is needed to
determine the impact of this treatment regimen on normal
tissues. It remains that the role of chemotherapy in ad-
dition to altered fractionation is not established. This
question was addressed by the RTOG 0129 study but the
results are pending.
IMRT is a more complex treatment planning technique
than conventional techniques. However, its use allows for
comprehensive irradiation of both the upper and lower neck
within the same treatment fields and thus eliminates the
need for matching with a low anterior field to treat the lower
neck region. The need for electron fields to adequately cover
lymph nodes located in the posterior triangle is obviated.
Therefore, with this technique, the actual treatment time on
the machine is reduced.
Although SIB-IMRT with or without chemotherapy is an
intensive treatment, we believe our regimen has the poten-
tial to increase the therapeutic ratio by increasing tumor
control with toxicity similar to that of conventional treat-
ments. The reduction in dose to the organs at risk has
resulted in a treatment regimen that is well tolerated by our
patients as demonstrated by the fact that 92% of the patients
in this study completed their radiotherapy within 40 days.
Bentzen et al
18
and Khalil et al
19
reviewed the data from
2566 patients participating in altered fractionation trials and
found that 25% of these patients had delays in treatment of
Table 4
Comparative acute toxicities of selected series
GORTEC
10
RTOG 90-03
7
Brizel
20
McGill
Toxicity Chemoradiation
vs RT Alone*
Accelerated fractionation
with concomitant
boost vs Standard RT*
Hyperfractionated
RT ⫹CTX‡ vs
RT Alone*
Accelerated fractionation
with SIB-IMRT† ⫹CTX‡
vs RT Alone
Mucositis Grades 3&4 71% vs 39% 46% vs 25% 77% vs 77% 18/29 (58%) vs 9/20 (45%)
Skin Grade 3 21% vs 11% 11% vs 7% 3/29 (10%) vs 1/20 (5%)
Heme Grade 3 12% vs ⬍1% 7/29 (24%) vs 2/20 (10%)
Weight loss 13% vs 5% 7/29 (24%) vs 3/20 (15%)
⬎10% body mass
*RT, Radiation Therapy.
†SIB-IMRT, Simultaneous Integrated Boost & Intensity Modulated Radiation Therapy.
‡CTX, Chemotherapy.
553Schwartz et al Accelerated radiotherapy with simultaneous . . .
6 days or more. They found that the patients treated with
conventional fractionation had lower compliance to the pre-
scribed treatment. The corresponding delay in treatment
was estimated to decrease the tumor control probability by
at least 10%.
Our technique has additional advantages in terms of
the economic and practical savings with decreasing the
number of fractions from 35 to 25. Butler et al
12
found
that the use of their SMART boost radiotherapy tech-
nique was less expensive than either conventional frac-
tionation ($1600 less) or accelerated fractionation ($2400
less). SIB-IMRT can save the patients the inconvenience
of an additional 2 weeks of treatment, which would have
a significant impact for patients who are older, have
multiple comorbid diseases, or have to travel great dis-
tances for their treatments.
In conclusion, accelerated radiotherapy with SIB-
IMRT, with or without chemotherapy, is a feasible treat-
ment modality for patients with locally advanced head
and neck cancer that allows shortening of the overall
treatment time. Acute toxicity appears to be acceptable
when compared with other trials of altered fractionation
and chemoradiation but longer follow-up data is neces-
sary to monitor unwarranted toxicities, and this type of
fractionation should be carefully tested in the context of
clinical trials only.
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