Int. J. Radiation Oncology Biol. Phys., Vol. 48, No. 1, pp.

716, 2000
Copyright 2000 Elsevier Science Inc.
Printed in the USA. All rights reserved
0360-3016/00/$see front matter

PII S0360-3016(00)00663-5

CLINICAL INVESTIGATION

Head and Neck

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
KAREN K. FU, M.D.,* THOMAS F. PAJAK, PH.D., ANDY TROTTI, M.D.,
CHRISTOPHER U. JONES, M.D.,! SHARON A. SPENCER, M.D., THEODORE L. PHILLIPS, M.D.,*
ADAM S. GARDEN, M.D., JOHN A. RIDGE, M.D., PH.D.,# JAY S. COOPER, M.D.,! AND
K. KIAN ANG, M.D., FOR THE RADIATION THERAPY ONCOLOGY GROUP"
*University of California San Francisco, San Francisco, CA; RTOG Statistical Unit, Philadelphia, PA; H. Lee Moffitt Cancer Center
at the University of South Florida, Tampa, FL; University of Alabama at Birmingham, Birmingham, AL; !Radiation Oncology Center,
Sacramento, CA; University of Texas M.D. Anderson Cancer Center, Houston, TX; #Fox Chase Cancer Center, Philadelphia, PA;
!
New York University, New York, NY; "The other institutions that participated in the study are listed in the Appendix.
Purpose: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial.
The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated
fractionation individually against standard fractionation.
Methods and Materials: Patients with locally advanced head and neck cancer were randomly assigned to receive
radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7
weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3)
accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks
including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/
day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment
days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The
median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive.
Results: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had
significantly better local-regional control (p ! 0.045 and p ! 0.050 respectively) than those treated with standard
fractionation. There was also a trend toward improved disease-free survival (p ! 0.067 and p ! 0.054
respectively) although the difference in overall survival was not significant. Patients treated with accelerated
fractionation with split had similar outcome to those treated with standard fractionation. All three altered
fractionation groups had significantly greater acute side effects compared to standard fractionation. However,
there was no significant increase of late effects.
Conclusions: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than
standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.
2000 Elsevier Science Inc.
Head and neck cancer, Fractionation, Radiotherapy, Hyperfractionation, Accelerated fractionation.

INTRODUCTION
The distribution of radiation dose over time, known as
fractionation, is one of the most important factors determining the outcome of radiotherapy. A variety of fractionation
schedules including standard fractionation, hyperfraction-

ation, accelerated fractionation, and their variants have been

used in the radiotherapy of advanced head and neck cancer
(13). In essence, altered fractionation is predicted to improve the therapeutic ratio through a differential response
between tumors and normal tissues to fractionated radiotherapy. Theoretically, with hyperfractionation it is possible

Reprint requests to: Karen K. Fu, M.D., Department of Radiation Oncology, University of California San Francisco, San Francisco, CA 94143-0226. E-mail: fu@radonc17.ucsf.edu
AcknowledgmentsSupported by research grants CA21661,
CA37422, CA32115, and CA06294 from the National Cancer
Institute. Its contents are solely the responsibility of the authors
and do not necessarily represent the official views of the National
Cancer Institute. We wish to acknowledge the dedication and hard

work of the RTOG clinical investigators, statisticians, clinical

research associates, administrative staff, and dosimetrists who
have contributed to the success of this trial. We are grateful for the
valuable contributions of Mr. Brian A. Berkey in the statistical
analysis of the results, Ms. JoAnn Stetz, Ms. Janet Finnegan, and
Ms. Karen Kuhn in data management, and Ms. Elizabeth Martin in
dosimetry and quality assurance review of radiotherapy delivery.
Accepted for publication 3 March 2000.
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to increase the total dose, thereby increasing the probability

of tumor control without increasing late complications
through the use of multiple smaller dose fractions. Accelerated fractionation, by shortening the overall treatment
time, should minimize tumor repopulation during treatment
and therefore increase the probability of tumor control for a
similar total dose.
The Radiation Therapy Oncology Group (RTOG) has
conducted several fractionation studies in head and neck
cancer. An initial Phase III trial compared hyperfractionation (1.2 Gy/fraction, twice daily, 5 days/week to 60 Gy in
5 weeks) to conventional fractionation (1.8 2.0 Gy/fraction/day, 5 days/week to 66 73.8 Gy in 6.57 weeks) (4). In
spite of a lower total dose used in the hyperfractionation
arm, there was no significant difference in either localregional control or survival. A subsequent randomized
Phase I/II dose escalation study of hyperfractionation established that total doses up to 81.6 Gy at 1.2 Gy/fraction,
twice daily, can be delivered with acceptable acute side
effects without increasing late effects (57). This trial
showed a trend toward increased local-regional control with
doses !72 Gy. Another Phase I/II trial of two types of
accelerated fractionation schedules established their feasibility and tolerance in a multi-institutional cooperative trial
setting (8). Based on these results, this Phase III randomized
trial was begun in 1991 to test the efficacy of hyperfractionation and these two types of accelerated fractionation
individually against standard fractionation in locally advanced head and neck cancer. The primary endpoint was
local-regional control; the secondary endpoints were disease-free survival and overall survival. The acute and late
adverse effects were also determined. This is the first report
of the outcome of this trial based on data received at the
RTOG Headquarters by August 20, 1999.

METHODS AND MATERIALS

Patients and eligibility criteria
Patients 18 years or older with a Karnofsky performance
score !60 who had previously untreated Stage III or IV but
MO squamous cell carcinoma of the oral cavity, oropharynx, supraglottic larynx, or Stage IIIV carcinoma of the
base of tongue or hypopharynx were eligible. Patients with
a prior (within 5 years) or synchronous malignancy other
than nonmelanoma skin cancer were excluded.
A medical history and physical examination, complete
blood count, chest X-ray, computed tomography, or magnetic resonance imaging of the head and neck, a diagram of
the primary tumor and neck nodes, and a dental evaluation
were required. The disease was staged according to the 1988
classification of the American Joint Committee on Cancer
Staging.
The National Cancer Institute and the participating institutions approved the protocol. A study-specific informed
consent was obtained from all patients.

Volume 48, Number 1, 2000

Treatment
Eligible patients were randomized to receive radiotherapy
delivered using: 1) standard fractionation at 2 Gy/fraction/
day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 6 hours apart, 5
days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated
fractionation with split at 1.6 Gy/fraction, twice daily, 6
hours apart, 5 days/week, to 67.2 Gy/42 fractions/6 weeks
including a 2-week rest after 38.4 Gy; or 4) accelerated
fractionation with concomitant boost at 1.8 Gy/fraction/day,
5 days/week to large field # 1.5 Gy/fraction/day to boost
field given 6 hours after treatment of the large field for the
last 12 treatment days to a total dose of 72 Gy/42 fractions/6
weeks. Additional boost doses not exceeding 5.0 Gy
through reduced fields to persistent primary tumor and/or
clinically positive nodes were allowed. Neck dissection was
allowed for neck nodes $3 cm prior to radiotherapy at the
discretion of the responsible head and neck surgeon and
radiation oncologist.
Radiotherapy was delivered using linear accelerators or
cobalt-60 machines with a source-to-surface or source-toisocenter distance !80 cm. Simulation films and beam
verification port films were required for each treatment field.
A combination of lateral opposing fields, anterior and
lateral wedged fields, or other field arrangements was used
to treat the primary tumor and the lymph nodes in the upper
neck. A single anterior field was used to treat the neck
below the fields for the primary tumor. For patients with
nodes $6 cm, supraclavicular nodes, or pyriform sinus
tumors that were T3 or T4 or with clinically positive nodes,
the anterior field could extend 5 cm inferiorly to include the
upper mediastinum. All fields were treated on each treatment day.
At least two field reductions were recommended for all
four arms. The first field reduction off the spinal cord
occurred at 40 44 Gy for arm 1, 45.6 Gy for arm 2, and
38.4 Gy for arm 3. The second field reduction occurred at
50 60 Gy for arm 1, 50.4 60.0 Gy for arm 2, and 51.2
60.8 Gy for arm 3. A third field reduction at 69.4 Gy was
recommended for arm 2. A minimum 2-cm margin around
the initial tumor volume and positive neck node(s) for the
first field reduction, a minimum of 11.5 cm margin for the
second field reduction, and a minimum 1 cm margin for the
third field reduction were required. For arm 4, the concomitant boost field with a minimum 11.5 cm margin around
the initial tumor volume and positive neck node(s) was
begun at 32.4 Gy. The primary treatment fields were reduced off the spinal cord at 45 Gy.
Follow-up
During treatment, patients were examined weekly. Once
treatment ended, patients were evaluated at 4 weeks, then
every 3 months for the first 11.5 years, every 4 months
from 18 months through 3 years, biannually in years 35,
and annually thereafter.
In addition to tumor status, acute and late (occurring $90
days from start of treatment) normal tissue effects were

Altered fractionation for head and neck cancer

graded with the RTOG radiation morbidity scoring criteria

(9).
Randomization procedures
Patients were enrolled by telephone call to the RTOG
headquarters. Following confirmation of their eligibility,
patients were stratified by Karnofsky Performance Score
(90 100 vs. 60 80), N-Stage (N% vs. N#), and primary
site (oral cavity versus oropharynx versus hypopharynx and
larynx). The randomization scheme described by Zelen (10)
was used to achieve balance in the treatment assignments
among the institutions.
Quality control
Radiotherapy records of each patient, including simulation and verification port films, total dose, number of fractions, and elapsed treatment days relative to the protocol
prescription were reviewed by the two radiation oncology
study co-chairs (K. K. Fu and K. K. Ang) with the RTOG
staff. Calibration of each institutions equipment was obtained from the Radiological Physics Center at the University of Texas M. D. Anderson Cancer Center. Each institution had their records audited at least once every 3 years as
mandated by the National Cancer Institute.
Statistical analysis
The trial was designed to test whether any of the three
altered fractionation schemes improved local-regional control compared to standard fractionation. Since it involved
the comparison of three experimental treatments to a
single control treatment, the Dunnetts two-sided multiple
test (11) was used to adjust for multiple comparisons. The
sample size was calculated using Bristols modification
(12). The 2-year local-regional control rate was used as the
primary endpoint because local-regional failure after 2 years
was infrequent and the arcsine transformation for the binomial distribution normalized the variable so that Dunnetts
test could be employed. The baseline 2-year local-regional
control rate for standard fractionation based on a previous
RTOG study was 40% (13). The study was designed to
detect a 15% difference. The Type I error rate and the
statistical power were set at 0.05 and 0.80. The sample size
was increased by 20% to allow for patients who were
ineligible, lost to follow-up, or died without local-regional
failure before 2 years. Thus, the targeted sample size for the
study was 1080 patients.
To permit comparisons with other published reports, local-regional control, disease-free survival, and overall survival were estimated with the Kaplan-Meier method (14).
The log-rank statistic was used to test for differences but no
adjustments were made for multiple testing (15). Because
local-regional failure is a cause-specific failure and patients
could die without failing either locally or regionally, we also
performed the cumulative incidence analysis (16) and used
the Grays test to test for differences (17). Since the two
approaches yielded remarkably similar results, only the
results from the first approach are described in this report.

K. K. FU et al.

Data monitoring
A formal RTOG Data Monitoring Committee (DMC)
was in place to oversee the trials progress. They reviewed
the interim analyses after enrolling 30%, 60%, and 100% of
the targeted accrual.
RESULTS
Characteristics of the patients
Between September 30, 1991 and August 1, 1997, 1113
patients were entered. Of these, 28 patients who were subsequently found to be ineligible, 5 who refused protocol
treatment or died before the start of treatment, and 7 who
had inadequate data were excluded. The remaining 1073
patients form the basis of this outcome analysis.
Table 1 shows the pretreatment patient characteristics.
They were well balanced among the treatment groups. Oropharynx was the most common primary site. The overall
Stage was II (tongue base and hypopharynx primaries only)
in 3.4%, III in 28.3%, and IV in 68.3% of the patients.
Treatment and compliance
The median dose (Gy), number of fractions, and overall
time (days) were 70.3, 35, and 50 for standard fractionation,
81.6, 68, and 50 for hyperfractionation, 67.6, 42, 43 for
accelerated fractionation with split, and 72, 42, and 43 for
accelerated fractionation with concomitant boost respectively. Eighty-eight percent of the patients had their treatment delivery scored as in accordance with the protocol or
with minor variations. The radiotherapy delivery was scored
as having major but acceptable deviations in 5.6%, unacceptable major deviations in 1.7%, and incomplete treatment due to disease progression, death, or patient refusal in
4.7% of the patients. There was no significant difference in
compliance among the treatment groups.
Outcome
The median follow-up was 23 months for all analyzable
patients and 41.2 months for surviving patients. Both the
hyperfractionation and the accelerated fractionation with
concomitant boost groups had significantly increased localregional control rate at two years ( p & 0.05 by Dunnetts
test). Results of Kaplan-Meier estimates of local-regional
control, disease-free survival, and overall survival are
shown in Figs. 13. Local-regional control significantly
increased in patients treated with hyperfractionation ( p '
0.045 by log-rank test) or accelerated fractionation with
concomitant boost ( p ' 0.05 by log-rank test) compared to
standard fractionation (Fig. 1). There was a trend toward
improved disease-free survival (Fig. 2) ( p ' 0.067 for
hyperfractionation, and p ' 0.054 for accelerated fractionation with concomitant boost by log-rank test) but no significant difference in overall survival (Fig. 3). Patients treated with
accelerated fractionation with split had similar outcome to
those treated with standard fractionation. Table 2 shows the
2-year local-regional control rate, disease-free survival, and
overall survival for the different treatment groups.

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Volume 48, Number 1, 2000

Table 1. Characteristics of the patients*

Standard
fractionation
(N ' 268)

Hyperfractionation
(N ' 263)

Characteristics
Gender
Male
Female
Race
White
Hispanic
Black
Oriental
Native American
Indian
Filipino
Other
Unknown
Age
&60
!60
Median
Range
Primary site
Oral cavity
Oropharynx
Hypopharynx
Supraglotti
Larynx
KPS
60
70
80
90
100
T-Stage
T1
T2
T3
T4
N-Stage
N0
N1
N2A
N2B
N2C
N3
AJC Stage
Stage II
Stage III
Stage IV

Accelerated
fractionation with split
(N ' 274)

Accelerated
fractionation with
concomitant boost
(N ' 268)

Number of patients (Percent)

199 (74%)
69 (26%)

211 (80%)
52 (20%)

220 (80%)
54 (20%)

224 (84%)
44 (16%)

190 (71%)
17 (6%)
48 (18%)
2 (1%)
1 (1%)
2 (1%)
1 (1%)
0
7 (3%)

177 (67%)
16 (6%)
57 (22%)
4 (2%)
1 (1%)
1 (1%)
0
1 (1%)
6 (2%)

197 (72%)
17 (6%)
50 (18%)
3 (1%)
1 (1%)
2 (1%)
0
0
4 (1%)

191 (71%)
16 (6%)
44 (16%)
1 (1%)
2 (1%)
2 (1%)
0
3 (1%)
9 (3%)

123 (46%)
145 (54%)
60
3086

131 (50%)
132 (50%)
60
3486

120 (44%)
154 (56%)
61
3490

118 (44%)
150 (56%)
61
3188

31 (12%)
159 (59%)
34 (13%)
44 (16%)

26 (9%)
160 (61%)
28 (11%)
49 (19%)

29 (11%)
165 (60%)
40 (15%)
40 (15%)

24 (9%)
165 (62%)
39 (15%)
40 (15%)

17 (6%)
28 (10%)
60 (22%)
120 (45%)
43 (16%)

11 (4%)
31 (12%)
57 (22%)
141 (54%)
23 (9%)

10 (4%)
34 (12%)
63 (23%)
118 (43%)
49 (18%)

11 (4%)
29 (11%)
64 (24%)
116 (43%)
48 (18%)

15 (6%)
77 (29%)
102 (38%)
74 (28%)

14 (5%)
68 (26%)
99 (38%)
82 (31%)

18 (7%)
72 (26%)
108 (39%)
76 (28%)

17 (6%)
71 (26%)
97 (36%)
83 (31%)

62 (23%)
48 (18%)
29 (11%)
48 (18%)
49 (18%)
32 (12%)

60 (23%)
58 (22%)
22 (8%)
49 (19%)
46 (17%)
28 (11%)

62 (23%)
55 (20%)
30 (11%)
59 (22%)
39 (14%)
29 (11%)

55 (21%)
53 (20%)
21 (8%)
49 (18%)
53 (20%)
37 (14%)

11 (4%)
80 (30%)
177 (66%)

11 (4%)
78 (30%)
174 (66%)

7 (3%)
73 (27%)
194 (71%)

9 (3%)
71 (26%)
188 (70%)

* Because of rounding, not all percentages total 100.

Sites of failure
The primary site was the most common location of treatment failure. The 2-year local (primary site) failure rates
were 43.7%, 37.8%, 43.0%, and 36.9% and the 2-year nodal
failure rates were 32.1%, 26.6%, 30.8%, and 33.3% for the
standard fractionation, hyperfractionation, accelerated fractionation with split, and accelerated fractionation with concomitant boost respectively. The incidence of distant me-

tastasis at 2 years was 17.8%, 16.8%, 18.0%, and 16.6%

respectively.
Adverse effects
Tables 3 and 4 show the site and grade of worst acute and
late adverse effects by treatment group. The incidence of
Grade 3 or worse acute and late effects was 35.0% and
26.8% for standard fractionation, 54.5% and 28.0% for

Altered fractionation for head and neck cancer

Fig. 1. Kaplan-Meier estimates of the duration of local-regional

control of disease.

hyperfractionation, 50.4% and 27.6% for accelerated fractionation with split, and 58.8% and 37.2% for accelerated
fractionation with concomitant boost. As expected, the most
common sites of acute side effects were the mucous membranes and the pharynx. The most common sites of Grade 3
or worse late effects were the pharynx and the salivary
gland. Compared to the standard fractionation group, all
three altered fractionation groups had significantly increased Grade 3 or worse acute side effects ( p & 0.0001
for hyperfractionation, p ' 0.0002 for accelerated fractionation with split, and p & 0.0001 for accelerated fractionation with concomitant boost). However, only the accelerated fractionation with concomitant boost group had

K. K. FU et al.

11

Fig. 2. Kaplan-Meier estimates of disease-free survival.

significantly increased Grade 3 or worse late effects ( p '

0.011). Because the RTOG defines late effects as those
noted $90 days from the start of radiotherapy, some of
these late effects were actually prolonged acute effects. As
shown in Table 5, there was no significant difference in the
frequency of Grade 3 or worse late effects reported at 6 24
months after treatment start among the different treatment
groups.
DISCUSSION
This is the largest randomized trial of altered fractionation in the radiotherapy of locally advanced head and
neck cancer ever conducted. Our results suggest that both

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Fig. 3. Kaplan-Meier estimates of overall survival.

total dose and treatment duration (or overall time) are

important in the outcome of radiotherapy. Local-regional
control was significantly increased by an increase of the

Volume 48, Number 1, 2000

total dose without changing the overall time using hyperfractionation or by a shortening of the overall time
while maintaining the same total dose using accelerated
fractionation with concomitant boost.
In contrast to historical comparisons (18 22), accelerated fractionation with split was not shown to improve
local-regional control in this randomized trial. Any potential gain with accelerated fractionation may have been
negated by the interruption of treatment during the split
and a slightly lower total dose than standard fractionation. It is also interesting that in successive RTOG
randomized trials in head and neck cancer, the 2-year
local-regional control rate has improved over time from
29% in the late 1970s (4) to 40% in the late 1980s (13)
to 46% in the current trial.
In addition to this RTOG trial, hyperfractionation has
also been shown to improve the outcome of radiotherapy
for head and neck cancer in four other randomized trials
(2326). The trial with the longest follow-up conducted
by the European Organization for Research and Treatment of Cancer (EORTC) showed that an increase of total
dose from 70 Gy with standard fractionation to 80.5 Gy
with hyperfractionation led to an increase of local control
of intermediate-stage (T2-3, N0-1) oropharyngeal carcinoma (excluding the base of tongue) without an increase
of late complications. Similar results are seen in this
RTOG trial even though it included patients with base of
tongue carcinoma and other head and neck primary sites
and more advanced stages of disease.
Results of randomized trials of accelerated fractionation
are less consistent (2731). A variety of accelerated schedules have been studied. In general, local control increased
with a shortening of the overall time by 12 weeks while
maintaining a similar total dose to standard fractionation
(27, 29, 31). However, no improvement was seen when a
lower total dose than the standard fractionation was used
(32). Late effects increased significantly with a thrice daily
schedule or delivery of !14 Gy per week without a reduction of total dose (29, 33, 34). In this RTOG trial, shortening
the overall time using a concomitant boost technique also
increased local-regional control. Our results and others support the hypothesis that tumor repopulation during radiotherapy is a major cause of treatment failure in head and
neck cancer.
In this RTOG trial, all three altered fractionation
schedules resulted in increased acute toxicity compared

Table 2. 2-Year local-regional control, disease-free survival, and overall survival by treatment

2-Year endpoints

Standard
fractionation
(N ' 268)

Hyperfractionation
(N ' 263)

Accelerated
fractionation with split
(N ' 274)

Accelerated
fractionation with
concomitant boost
(N ' 268)

Local-regional control
Disease-free survival
Overall survival

46.0%
31.7%
46.1%

54.4%
37.6%
54.5%

47.5%
33.2%
46.2%

54.5%
39.3%
50.9%

Altered fractionation for head and neck cancer

K. K. FU et al.

13

Table 3. Worst acute adverse effects of radiotherapy

Standard
fractionation
(N ' 268)
Organ/Tissue
Skin

Mucous membrane

Salivary gland
Pharynx/Esophagus

Larynx

Upper gastrointestinal
Subcutaneous
Ear
Spinal cord
Bone
Joint
Other
Maximum toxicity
per patient

Grade
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade3
Grade1
Grade2
Grade1
Grade2
Grade1
Grade1
Grade1
Grade2
Grade3
Grade1
Grade2
Grade3
Grade1
Grade2
Grade3
Grade4

Hyperfractionation
(N ' 263)

Accelerated
fractionation with split
(N ' 274)

Accelerated
fractionation with
concomitant
boost (N ' 268)

Number of patients (Percent)

93 (35)
131 (49)
20 (7)
0 (0)
33 (12)
146 (54)
67 (25)
0 (0)
57 (21)
179 (67)
58 (22)
117 (44)
30 (11)
0 (0)
76 (28)
45 (17)
9 (3)
0 (0)
27 (10)
21 (8)
4 (2)
21 (8)
3 (1)
6 (2)
1 (1)
0 (0)
1 (1)
2 (1)
0 (0)
0 (0)
8 (3)
6 (2)
2 (1)
12 (5)
154 (57)
94 (35)
0 (0)

to standard fractionation. However, only the accelerated

fractionation with concomitant boost group had significantly increased late effects. Because the RTOG used 90
days from treatment start as a cutoff date for scoring
acute and late effects, any acute adverse effects lasting
$90 days would have been reported as late effects. Some
of these late effects were actually prolonged acute effects. In fact, most of the late effects resolved with time
and there was no significant difference in the frequency
of reported late effects at 6 24 months after treatment
start among the treatment groups.
At the present time, the major limitation of altered fractionation radiotherapy or combined radiotherapy and chemotherapy for head and neck cancer is increased acute reaction,
primarily acute mucositis (35, 36). Several toxicity antagonists
are under active investigation (37). In the future, some of these
agents may decrease the acute and late effects of cancer ther-

76 (29)
138 (52)
29 (11)
1 (1)
27 (10)
111 (42)
109 (41)
1 (1)
60 (23)
170 (64)
40 (15)
112 (42)
68 (26)
0 (0)
58 (22)
57 (22)
16 (6)
0 (0)
25 (9)
37 (14)
3 (1)
24 (9)
11 (4)
5 (2)
2 (1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
6 (2)
12 (5)
3 (1)
9 (3)
102 (39)
142 (54)
2 (1)

121 (44)
113 (41)
8 (3)
0 (0)
25 (9)
118 (43)
109 (40)
3 (1)
60 (22)
175 (64)
36 (13)
128 (47)
59 (22)
0 (0)
67 (24)
49 (18)
10 (4)
2 (1)
24 (9)
35 (13)
2 (1)
41 (15)
5 (2)
10 (4)
1 (1)
2 (1)
0 (0)
2 (1)
2 (1)
0 (0)
13 (5)
7 (3)
1 (1)
20 (7)
113 (41)
133 (49)
5 (2)

80 (30)
148 (55)
29 (11)
0 (0)
30 (11)
104 (39)
122 (46)
1 (1)
50 (19)
193 (72)
30 (11)
122 (46)
78 (29)
1 (1)
59 (22)
67 (25)
19 (7)
0 (0)
20 (7)
43 (16)
6 (2)
34 (13)
7 (3)
14 (5)
5 (2)
0 (0)
0 (0)
3 (1)
0 (0)
1 (1)
8 (3)
10 (4)
1 (1)
11 (4)
95 (36)
155 (58)
2 (1)

apy. The therapeutic ratio may also be improved by using

conformal and intensity-modulated radiotherapy. These modern radiotherapy techniques have the capability of improving
tumor target coverage while minimizing the dose to and volume of the surrounding normal tissues irradiated (38 40).
Their routine use in the treatment of head and neck cancer is
anticipated in the near future.
Although both hyperfractionation and accelerated fractionation with concomitant boost resulted in a gain in localregional control and disease-free survival, the overall survival did not change significantly in this analysis. Clearly,
additional treatment modifiers are needed to further improve
the prognosis of patients with locally advanced head and
neck cancer. Data in the literature suggest that chemotherapy given concurrently with radiotherapy improves the results over radiotherapy alone for locally advanced head and
neck cancer (36, 41 43). However, the optimal chemother-

14

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Volume 48, Number 1, 2000

Table 4. Worst late adverse effects reported $90 days from treatment start
Standard
fractionation
(N ' 254)
Organ/Tissue
Skin

Mucous membrane

Salivary gland

Pharynx/Esophagus

Larynx

Upper gastrointestinal
Subcutaneous

Ear
Spinal cord
Brain
Bone

Joint
Other

Maximum toxicity
per patient

Grade
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade3
Grade4
Grade1
Grade1
Grade2
Grade3
Grade4
Grade5
Grade1
Grade2
Grade3
Grade1
Grade2
Grade1
Grade2
Grade1
Grade2
Grade3
Grade4
Grade1
Grade2
Grade3
Grade1
Grade2
Grade3
Grade4
Grade5
Grade1
Grade2
Grade3
Grade4
Grade5

Hyperfractionation
(N ' 253)

Accelerated
fractionation with split
(N ' 261)

Accelerated
fractionation with
concomitant boost
(N ' 261)

Number of patients (Percent)

108 (43)
36 (14)
3 (1)
5 (2)
62 (24)
71 (28)
4 (2)
7 (3)
39 (15)
158 (62)
14 (6)
0 (0)
62 (24)
40 (16)
21 (8)
5 (2)
65 (26)
37 (15)
8 (3)
1 (1)
0 (0)
74 (29)
60 (24)
18 (7)
1 (1)
0 (0)
16 (6)
10 (4)
3 (1)
6 (2)
0 (0)
1 (1)
1 (1)
1 (1)
3 (1)
0 (0)
4 (2)
12 (5)
11 (4)
3 (1)
12 (5)
11 (4)
7 (3)
0 (0)
1 (1)
27 (11)
126 (50)
48 (19)
19 (8)
1 (1)

apy regimen to be combined with radiotherapy remains to

be determined. More recently, Phase II studies of biological
agents such as the antibody against epidermal growth factor
receptor C225 also suggest a potential advantage for head

111 (44)
56 (22)
3 (1)
4 (2)
59 (23)
94 (37)
9 (3)
10 (4)
46 (18)
154 (61)
18 (7)
0 (0)
62 (25)
63 (25)
28 (11)
4 (2)
70 (28)
40 (16)
11 (4)
5 (2)
0 (0)
56 (22)
84 (33)
19 (8)
4 (2)
0 (0)
26 (10)
16 (6)
2 (1)
5 (2)
1 (1)
3 (1)
0 (0)
2 (1)
1 (1)
3 (1)
4 (2)
16 (6)
13 (5)
6 (2)
15 (6)
10 (4)
4 (2)
0 (0)
0 (0)
19 (8)
141 (56)
48 (19)
23 (9)
0 (0)

114 (44)
35 (13)
2 (1)
3 (1)
62 (24)
65 (25)
7 (3)
12 (5)
63 (24)
139 (53)
17 (7)
1 (1)
53 (20)
50 (19)
25 (10)
2 (1)
65 (25)
31 (12)
7 (3)
3 (1)
1 (1)
67 (26)
80 (31)
7 (3)
1 (1)
1 (1)
16 (6)
10 (4)
1 (1)
10 (4)
2 (1)
4 (2)
0 (0)
2 (1)
2 (1)
1 (1)
4 (2)
22 (8)
12 (5)
3 (1)
15 (6)
10 (4)
6 (2)
1 (1)
0 (0)
42 (16)
128 (50)
52 (20)
19 (7)
1 (1)

107 (41)
52 (20)
4 (2)
4 (2)
82 (31)
66 (25)
15 (5)
14 (5)
43 (16)
147 (56)
26 (10)
0 (0)
59 (23)
61 (23)
37 (14)
3 (1)
65 (25)
58 (22)
9 (3)
1 (1)
0 (0)
72 (28)
72 (28)
9 (3)
3 (1)
0 (0)
23 (9)
9 (3)
2 (1)
10 (4)
1 (1)
5 (2)
0 (0)
4 (2)
2 (1)
0 (0)
1 (1)
22 (8)
12 (5)
5 (2)
18 (7)
15 (6)
0 (0)
0 (0)
1 (1)
19 (7)
116 (44)
75 (29)
21 (8)
1 (1)

and neck cancer (44). Future studies are needed to determine whether these chemical and biological modifiers will
further improve the outcome of altered fractionation radiotherapy.

Altered fractionation for head and neck cancer

K. K. FU et al.

15

Table 5. Frequency of Grade 3 or worse late effects at various times after treatment start

Time after
treatment start
(months)
6
12
18
24

Standard
fractionation

Hyperfractionation

Accelerated
fractionation with split

Accelerated
fractionation with
concomitant boost

Number of patients/Number of patients at risk (Percent)

26/248 (10)
21/191 (11)
7/145 (5)
7/111 (6)

35/247 (14)
25/187 (13)
20/160 (13)
17/135 (13)

22/254 (9)
15/198 (8)
14/146 (10)
9/116 (8)

32/249 (13)
20/196 (10)
9/150 (6)
10/128 (8)

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APPENDIX
The following Radiation Therapy Oncology Group institutions and their affiliates contributed to this study:
H. Lee Moffitt Cancer Center at the University of South
Florida; Radiological Associates of Sacramento; University of
Alabama at Birmingham Medical Center; University of California San Francisco; University of TexasM.D. Anderson
Cancer Center; Fox Chase Cancer Center; New York University Hospital; McGill University; Medical College of Wisconsin; Washington University; Montefiore Medical Center; University of Western Ontario; Akron City Hospital; SUNY
Health Science Center/Brooklyn; Wayne State University;
University of Pennsylvania Medical Center; Dartmouth Hitchcock Medical Center; Albert Einstein Medical Center; University of Puerto Rico/Med Sciences Ca; Emory University Af-

filiated Hospitals; University of Alberta; Thomas Jefferson

University Hospital; University of Rochester; LDS Hospital;
Loyola University Medical Center; Johns Hopkins Hospital;
University of Miami; Hamilton Regional Cancer Centre; Mayo
Clinic; University of Kentucky Hospital; South Jersey Oncology Group CCOP; Wake Forest University Baptist Medical
Center; Kansas City CCOP; South Nevada Cancer Research
Foundation CCOP; North Shore University Hospital CCOP;
University of California Davis Medical Center; Greenville,
South Carolina CCOP; West Michigan Cancer Center CCOP;
Atlanta Regional CCOP; Dayton CCOP; Main Line Health
CCOP; Christiana Care Health Services, Inc.; Columbia River
CCOP; Upstate Carolina CCOP; James Haley Veterans Hospital.