Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: Influence of proliferation

Abstract

Based on the assumption that an accelerated proliferation process prevails in tumour cell residues after surgery, the possibility that treatment acceleration would offer a therapeutic advantage in postoperative radiotherapy of locally advanced head and neck cancer was investigated. The value of Tpot in predicting the treatment outcome and in selecting patients for accelerated fractionation was tested. Seventy patients with (T2/N1–N2) or (T3-4/any N) squamous cell carcinoma of the oral cavity, larynx and hypopharynx who underwent radical surgery, were randomized to either (a) accelerated hyperfractionation: 46.2 Gy per 12 days, 1.4 Gy per fraction, three fractions per day with 6 h interfraction interval, treating 6 days per week or (b) Conventional fractionation: 60 Gy per 6 weeks, 2 Gy per fraction, treating 5 days per week. The 3-year locoregional control rate was significantly better in the accelerated hyperfractionation (88±4%) than in the CF (57±9%) group, P=0.01 (and this was confirmed by multivariate analysis), but the difference in survival (60±10% vs 46±9%) was not significant (P=0.29). The favourable influence of a short treatment time was further substantiated by demonstrating the importance of the gap between surgery and radiotherapy and the overall treatment time between surgery and end of radiotherapy. Early mucositis progressed more rapidly and was more severe in the accelerated hyperfractionation group; reflecting a faster rate of dose accumulation. Xerostomia was experienced by all patients with a tendency to be more severe after accelerated hyperfractionation. Fibrosis and oedema also tended to be more frequent after accelerated hyperfractionation and probably represent consequential reactions. Tpot showed a correlation with disease-free survival in a univariate analysis but did not prove to be an independent factor. Moreover, the use of the minimum and corrected P-values did not identify a significant cut-off. Compared to conventional fractionation, accelerated hyperfractionation did not seem to offer a survival advantage in fast tumours though a better local control rate was noted. This limits the use of Tpot as a guide for selecting patients for accelerated hyperfractionation. For slowly growing tumours, tumour control and survival probabilities were not significantly different in the conventional fractionation and accelerated hyperfractionation groups. A rapid tumour growth was associated with a higher risk of distant metastases (P=0.01). In conclusion, tumour cell repopulation seems to be an important determinant of postoperative radiotherapy of locally advanced head and neck cancer despite lack of a definite association between Tpot and treatment outcome. In fast growing tumours accelerated hyperfractionation provided an improved local control but without a survival advantage. To gain a full benefit from treatment acceleration, the surgery-radiotherapy gap and the overall treatment time should not exceed 6 and 10 weeks respectively.
British Journal of Cancer (2002) 86, 517–523. DOI: 10.1038/sj/bjc/6600119 www.bjcancer.com
© 2002 Cancer Research UK

Full text

Accelerated hyperfractionation (AHF) compared to conventional
fractionation (CF) in the postoperative radiotherapy of locally
advanced head and neck cancer: influence of proliferation
HK Awwad*
,1
, M Lotayef
1
, T Shouman
1
, AC Begg
2
, G Wilson
3
, SM Bentzen
4
, H Abd El-Moneim
1
and S Eissa
1
1
Department of Radiotherapy, National Cancer Institute, University of Cairo, Fom El Khalig 11796, Cairo, Egypt;
2
Division of Experimental Therapy, The
Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, The Netherlands;
3
Experimental Oncology, Gray Cancer Institute, Northwood,
Middlesex 2JR, UK;
4
Biostatistics in Oncology, Gray Cancer Institute, Northwood, Middlesex 2JR, UK
Based on the assumption that an accelerated proliferation process prevails in tumour cell residues after surgery, the possibility
that treatment acceleration would offer a therapeutic advantage in postoperative radiotherapy of locally advanced head and
neck cancer was investigated. The value of T
pot
in predicting the treatment outcome and in selecting patients for accelerated
fractionation was tested. Seventy patients with (T2/N1 – N2) or (T3-4/any N) squamous cell carcinoma of the oral cavity,
larynx and hypopharynx who underwent radical surgery, were randomized to either (a) accelerated hyperfractionation:
46.2 Gy per 12 days, 1.4 Gy per fraction, three fractions per day with 6 h interfraction interval, treating 6 days per week or
(b) Conventional fractionation: 60 Gy per 6 weeks, 2 Gy per fraction, treating 5 days per week. The 3-year locoregional
control rate was significantly better in the accelerated hyperfractionation (88+4%) than in the CF (57+9%) group, P=0.01
(and this was confirmed by multivariate analysis), but the difference in survival (60+10% vs 46+9%) was not significant
(P=0.29). The favourable influence of a short treatment time was further substantiated by demonstrating the importance of
the gap between surgery and radiotherapy and the overall treatment time between surgery and end of radiotherapy. Early
mucositis progressed more rapidly and was more severe in the accelerated hyperfractionation group; reflecting a faster rate of
dose accumulation. Xerostomia was experienced by all patients with a tendency to be more severe after accelerated
hyperfractionation. Fibrosis and oedema also tended to be more frequent after accelerated hyperfractionation and probably
represent consequential reactions. T
pot
showed a correlation with disease-free survival in a univariate analysis but did not
prove to be an independent factor. Moreover, the use of the minimum and corrected P-values did not identify a significant
cut-off. Compared to conventional fractionation, accelerated hyperfractionation did not seem to offer a survival advantage in
fast tumours though a better local control rate was noted. This limits the use of T
pot
as a guide for selecting patients for
accelerated hyperfractionation. For slowly growing tumours, tumour control and survival probabilities were not significantly
different in the conventional fractionation and accelerated hyperfractionation groups. A rapid tumour growth was associated
with a higher risk of distant metastases (P=0.01). In conclusion, tumour cell repopulation seems to be an important
determinant of postoperative radiotherapy of locally advanced head and neck cancer despite lack of a definite association
between T
pot
and treatment outcome. In fast growing tumours accelerated hyperfractionation provided an improved local
control but without a survival advantage. To gain a full benefit from treatment acceleration, the surgery-radiotherapy gap and
the overall treatment time should not exceed 6 and 10 weeks respectively.
British Journal of Cancer (2002) 86, 517 – 523. DOI: 10.1038/sj/bjc/6600119 www.bjcancer.com
ª
2002 Cancer Research UK
Keywords: head and neck cancer; postoperative radiotherapy; accelerated hyperfractionation; proliferation kinetics; predictive factors
Locoregional recurrence due to regrowth of tumour cell residues is
the main cause of failure of surgery for locally advanced head and
neck cancer (HNC). An active proliferation process is expected to
prevail in tumour cell aggregates left in the surgical field in view of
a small cell number, a large growth fraction and possibly also a low
cell loss factor (Awwad et al, 1992; Peters and Withers, 1997; Ang
et al, 2001). The present study aims at testing the possibility of
improving the postoperative radiotherapy results in locally
advanced HNC by applying an accelerated fractionation scheme.
The study also involves measurement of T
s
, LI and T
pot
on the
basis of a combination of flow cytometric (FCM) and immunhis-
tochemistry analysis performed on a single tumour sample
obtained 4 – 6 h after intravenous injection of 5-iodo-2’-deoxyuri-
dine (IdUrd). This combination provides a better estimate of
T
pot
in diploid tumours since FCM alone tends to underestimate
their proliferative activity (Begg et al, 1985; Bennett et al, 1992,
Wilson, 1993). In a postoperative radiotherapy setting the pretreat-
ment T
pot
, may be assumed to be an indicator of the effective
doubling time (T
eff
) prevailing during the course of postoperative
radiotherapy. Accordingly the predictive power of pretreatment
proliferation parameters was tested. In addition, the possibility that
Clinical
Received 4 July 2001; revised 19 November 2001; accepted 5 December
2001
*Correspondence: Dr HK Awwad; E-mail: awwad@internetegypt.com
British Journal of Cancer (2002) 86, 517 – 523
ª
2002 Cancer Research UK All rights reserved 0007 – 0920/02 $25.00
www.bjcancer.com

accelerated fractionation can be more effective than conventional
fractionation in fast growing tumours was examined.
MATERIALS AND METHODS
Patients and tumour characteristics
Patients less than 65 years of age with (T2/N1 – 2) or (T3-4/any N)
squamous cell carcinoma of the oral cavity, larynx and hypophar-
ynx who underwent radical surgery were admitted to the study
provided that: (a) there was no evidence of gross residual disease
or distant metastases; (b) performance status score 42 according
to the WHO scale, 1980; (c) liver, kidney and other vital functions
were within normal. The patient written consent was also required.
Postoperative radiotherapy schedules and techniques
Postoperative radiotherapy was planned to be commenced 3 – 8
weeks after surgery. The sealed envelope method was used as a
simple randomization procedure. Accordingly patients were
assigned to one of the two following schedules:
(a) Conventional fractionation (CF). A total dose of 60 Gy was
given in 30 fractions (2 Gy per fraction) in 6 weeks treating 5
days per week.
(b) Accelerated hyperfractionation (AHF). A three fractions per day
regimen was adopted with an interfraction interval of 6 h at
least. A dose per fraction of 1.4 Gy was used (4.2 Gy day
71
),
with a total dose of 46.2 Gy per 33 fractions per 12 days,
treating 6 days per week.
Standard postoperative radiotherapy techniques (Awwad et al, 1992)
were applied using a Philips 6 MV linear accelerator, a Varian simu-
lator and a Multidata computer treatment planning system. Custom-
made plastic shells for head and neck immobilization were applied
during treatment. The dose to the primary tumour site was
prescribed according to the ICRU 50 reference point, while for neck
nodes the reference was set at a depth of 0.5 cm below the skin. All
portals were treated during each radiation fraction. Wherever possi-
ble the spinal cord was shielded after 40 – 45 Gy and the volume of
the irradiated parotid salivary glands minimized.
Cell proliferation kinetics studies
Two hundred mg of IdUrd dissolved in 10 ml saline were injected
intravenously as a bolus 4 – 6 h before start of surgery. The time of
sampling used in the subsequent relative movement calculation was
taken as the interval between drug injection and the time of liga-
tion of the main arterial trunks. The surgical specimen was
examined conjointly with the pathologist. Multiple 0.5 – 1 cm
3
pieces were taken from representative non-degenerating parts of
the tumour. One or more pieces were then fixed in 10% formal
saline and then embedded in paraffin for immunohistochemistry
(IHC). The remaining pieces were processed for FCM.
The procedures for IdUrd staining and FCM analysis used are
those described by Begg et al (1988) and by Wilson et al (1988).
For immunohistochemistry 5 mm sections were mounted on
poly-l-lysine coated slides. One section was stained with haematox-
ylin and eosin while other adjacent sections were
immunohistochemically stained for IdUrd (Bennett et al, 1992;
Wilson, 1993). For cell counting, high power fields (640 objec-
tive610 eyepiece) were captured and labelling was scored in a
minimum of 1000 cells. The average LI was calculated as the total
number of IdUrd-labelled cells divided by the total number of
scored tumour cells. This was then corrected for cell division taking
place during the time between injection and tumour sampling. For
this the FCM LI data were used as described by Begg et al, 1985.
The duration of the S-phase (T
s
) was derived from the FCM data
using the relative movement analysis (Begg et al, 1985). The poten-
tial doubling time (T
pot
) was then calculated using the relationship
T
pot
=l(Ts/LI), where lwas assumed to be unity.
RESULTS
Out of 88 consecutive patients witth locally advanced HNC who
survived radical surgery during the period November 1995 and
October 1997, 70 patients satisfied the eligbility criteria and were
admitted to the trial and randomized to either CF (39 patients)
or AHF (31 patients). Five patients (four in the CF and one in
the AHF group) refused to complete the prescribed treatment
due to personal and social factors i.e. an overall compliance of
93%. The representation of different clinicopathological parameters
did not differ significantly in the two therapeutic groups as listed
in Table 1.
Early normal tissue reactions
Acute skin reactions were generally mild and comparable in both
therapeutic groups. In the CF-arm, acute mucositis developed gradu-
ally reaching its peak during the fourth week. In the AHF-arm,
mucositis progressed rapidly from the beginning of the second week
to reach its peak during the third week. In both arms complete disap-
pearance of acute mucositis was noted by 8 – 10 weeks. Both objective
and functional reactions tended to be significantly more severe in the
Clinical
Table 1 Clinicopathological and proliferation characteristics of patients in
the two therapeutic groups
CF AF P
Age (year) 0.37
Range 25—65 29—65
Median 50 50
Sex (male : female) 32 : 7 24 : 7 0.63
82 : 18% 77 : 23%
Anatomical site 0.24
Oral cavity 14 (36%) 14 (45%)
Larynx 20 (51%) 10 (32%)
Hypopharynx 5 (13%) 7 (23%)
TN-category
T2 5 (13%) 3 (10%) 0.91
T3 22 (56%) 18 (58%)
T4 12 (31%) 10 (32%)
N0 25 (64%) 16 (52%) 0.15
N1-2 14 (36%) 15 (48%)
Histological grade
G1 15 (38%) 13 (42%) 0.82
G2 20 (51%) 16 (52%)
G3 4 (10%) 2 (6.0%)
Performance status 0.93
1 23 (59%) 13 (42%)
2 16 (41%) 18 (58%)
HB G % 0.60
Range 9.2—16 9—17
Median 12.5 12.8
Surgical margin 0.86
Adequate 20 (51%) 16 (52%)
Inadequate 17 (49%) 15 (48%)
Surgery-RT interval 0.41
Range 16—152 16—99
Median 47 43
Proliferation parameters
Frequency of aneuploidy 46% 42%
Median T
s
(h) 12.2 11.8 0.68
Median LI (%) 10.1 12.1 0.26
Median T
pot
(day) 4.3 3.6 0.40
Accelerated vs conventional fractionation
HK Awwad et al
518
British Journal of Cancer (2002) 86(4), 517 – 523
ª
2002 Cancer Research UK

AHF arm (Table 2). Overall, the G2 objective mucosal reaction
(patchy mucositis) and G2 functional mucositis (moderate irritation)
were the most common mucositis grades in both arms. Generally and
in both treatment groups acute mucosal reactions did not seriously
interfere with patients feeding with no weight loss nor need for tube
feeding or hospitalizations for fluid or nutritional support. Simple
analgesics were sufficient to relieve local pain.
Late normal tissue reactions
All patients suffered some degree of late xerostomia (expressed as
dryness of mouth and difficulty in mastication and swallowing)
which persisted for 2 years at least. There was a tendency, though
statistically insignificant, for xerostomia to be more severe in the
AHF than in the CF group (G2 and G3 xerostomia: 33 and 42%
respectively in AHF and 39 and 13% respectively in CF, P=0.17).
The same trend was noted for G2 and three lymphoedema
(CF=10%, AHF=16%) and G2 and G3 subcutaneous fibrosis
(CF=13%, AHF 26%), (P=0.7). There was only one incidence of
transient myelopathy (L’hermitte syndrome) in the AHF group
which was expressed 3 months after the end of treatment and
recovered within 6 months. In this patient, the dose to the cervical
spinal cord was estimated to be 42 Gy.
Loco-regional control
Loco-regional recurrence was observed in 15 out of the 70 rando-
mized patients (three in the AHF and 12 in the CF groups). Using
Kaplan – Meier (product limit) estimate, the 3-year locoregional
control rate was 72+6%. Four factors were shown to influence
the loco-regional control rate significantly: gender (P=0.04), perfor-
mance status (P=0.01), the overall treatment time (P=0.005) and
radiotherapy schedule (P=0.01) (Table 3). AHF was associated with
a higher loco-regional control rate (88+8%) than CF (57+9%),
(P=0.01) (Figure 1). Using the Cox’s proportional hazards model,
the influence of the radiotherapy schedule on the loco-regional
control was examined after adjusting for the distribution in the
CF and AHF arms of all other variables listed in Table 3. After this
adjustment, AHF remained superior to CF; the risk ratio for type
of radiation treatment was 3.86 with a 95% confidence interval
of 1.87 and 9.36 and a P-value of 0.0001.
Survival
During the first 3 years, there were 30 deaths (17 in the CF and 13
in the AHF group) among the 70 randomized patients. According
to the Kaplan – Meier estimate, the overall 3-year disease-free survi-
val in the entire series amounted to 55+6%. The
clinicopathological factors that significantly influenced survival
included gender, primary site, performance status, and inadequacy
of the surgical margin (Table 3). The survival rates in the AHF and
CF groups did not differ significantly (P=0.29).
Distant metastases
Eight patients (11%) developed distant metastases (four in each
treatment group). The risk of distant metastases significantly corre-
lated with the anatomical tumour site (P=0.006). Five out of the 12
patients (42%) with hypopharyngeal cancer developed metastases
while the incidence was 2 out of 30 (7%) in patients with laryngeal
cancer and 1 out of 28 (4%) in oral cancer. The other variables did
not seem to influence the risk of metastases.
Influence of treatment times
For the whole group, the surgery-radiotherapy interval did not seem
to influence the locoregional control or the survival rates (Table 3).
However, within the two fractionation groups the best local control
result was that of the AHF when started within 6 weeks of surgery.
This benefit was, however, insignificant when the treatment gap was
46 weeks (Table 4). Moreover, the length of the gap did not seem
to influence the locoregional control results of the CF group. The
gap length did not affect the survival of all patients or of patients
in either treatment arm. In contrast, an overall treatment time (time
between surgery and the end of radiotherapy) longer than 10 weeks
had a significantly unfavourable effect on the locoregional control
for all patients (Table 3) (P=0.005). It is interesting to note that
patients in the long and short overall treatment times groups were
similar in respect to their clinicopathological characteristics (data
not shown). No effect was, however, observed on the disease-free
survival when the entire group of patients was analyzed. However,
when the AHF and CF patients were analyzed separately, the best
locoregional control (P=0.0005) and survival (P=0.01) results were
obtained in the AHF patients when treated over 10 weeks or less.
This benefit associated with AHF was, however, lost when the over-
all treatment time was extended to more than 10 weeks. In the CF
group both locoregional control and survival were not influenced
by the overall treatment time.
Proliferation studies
The proliferation parameters (ploidy, T
s
LI, and T
pot
) are compar-
able in the two treatment groups (Table 1). There were no
significant differences between different clinicopathological cate-
gories as regards these parameters. (data not shown).
Overall, 44% (31 out of 70) of tumours were aneuploid. The
proliferation parameters of diploid and aneuploid tumours did
not seem to differ significantly (LI=11.5+5.4%, for diploid and
11.7+5.5% for aneuploid tumours, P=0.9, T
pot
=4.4+3.1 d for
diploid and 5.1+3.1 d for aneuploid tumours, P=0.4).
Ploidy and the length of T
s
did not seem to influence the treat-
ment end-results (data not shown). Local control did not also
correlate with the LI or T
pot
but there was a significant correlation
between T
pot
and survival (P=0.05) (Table 5). Applying the Cox’s
proportional hazards model, T
pot
did not prove to be an indepen-
dent prognostic factor after adjusting for the other
clinicopathological and treatment factors (risk ratio of 0.95 with
a 95% confidence interval of 0.78 and 1.09, P=0.49).
In an attempt to identify optimum cut-off points for different
proliferation parameters that best predict treatment results the
corrected minimum P-value method was applied (Altman et al,
1994). First the cut-off point was systematically varied to find
out the points with the least Pvalue (P
min
) according to the log
rank test. This is then adjusted to find out a corrected P-value
(P
cor
):
Pcor ¼jð¼Þ½¼ ÿð1=¼Þloge½ð1ÿeÞ2=e2þ4jð¼Þ=¼ð1Þ
where jdenotes the probability density function and = is the (1-
P
min
/2) quantile of the standard normal distribution. Applying this
approach, a minimum P-value could be identified for locoregional
Clinical
Table 2 Early mucosal reactions (WHO scoring system)
Treatment
CF (%) AF (%) Total % P-value
Objective mucosal reactions
G
1
: erythema 13 (33) 3 (10) 16 (23) 0.04
G
2
: patchy mucositis 23 (59) 23 (74) 46 (66)
G
3
: mild confluent mucositis 3 (8) 5 (16) 8 (11)
G
4
: moderate confluent mucositis – – –
Functional mucosal reactions
G
1
: mild irritation 11 (28) 1 (3) 12 (17) 0.007
G
2
: moderate irritation 24 (62) 23 (74) 47 (67)
G
3
liquid diet only 4 (10) 7 (23) 11 (16)
Accelerated vs conventional fractionation
HK Awwad et al
519
ª
2002 Cancer Research UK British Journal of Cancer (2002) 86(4), 517 – 523

control in relation to the LI and for survival in relation to the LI
and T
pot
, but none of them attained a significant level (P40.05)
after correction using equation 1 (Table 6).
Survival of patients with short T
pot
did not significantly differ in
the CF and AHF groups i.e. T
pot
could not predict a survival bene-
fit from AHF (Table 7). However, locoregional control was
significantly better in the AHF than in the CF group in fast
tumours (P=0.01). For slowly growing tumours both the tumour
control and survival probabilities were not significantly different
in the CF and AHF groups (Table 7).
Rapid tumour growth (indicated by a high LI and a short T
pot
)
was associated with a significant increase in the incidence of distant
metastases, P=0.01 (Table 5).
DISCUSSION
According to current evidence-based concepts, postoperative radio-
therapy of locally advanced HNC is still based on careful clinical
observations (level IV evidence) rather than on randomized clinical
trials (level I or II evidence). Search for an optimum postoperative
radiotherapy dose in presence of high risk factors has been made. A
randomized study identified an optimum dose of 57.5 – 63 Gy and
demonstrated that a dose escalation beyond 63 Gy did not seem to
improve the therapeutic ratio (Peters et al, 1993).
Compared with radical radiotherapy for HNC, very few studies
tested the therapeutic advantages of accelerated radiotherapy in the
postoperative radiotherapy of high-risk patients. A notable example
is the conjoint prospective randomized study reported by Ang et al
(1999) where a concomitant boost regimen (63 Gy in 5 weeks) was
compared with CF to the same total dose but given over 7 weeks.
Interim results pointed out a trend for better local control and
survival at the expense of more severe acute reactions but without
an apparent increase in late morbidity. For high risk patients, the
present study demonstrated that AHF can significantly improve
the locoregional control rate though without a significant survival
advantage. The favourable influence of a short treatment time was
Clinical
Table 3 The 3 year locoregional control and disease-free survival according to
clinicopathological factors using the Kaplan – Meier (product limit) estimate
Loco-regional control Disease-free survival
Estimated+SE P-value Estimated+SE P-value
Overall 0.72+0.06 0.55+0.06
Sex
Male (20%)
a
0.78+0.06 0.55+0.07
Female (80%)
a
0.46+0.16 0.03 0.31+0.13 0.01
Age (years)
450 0.66+0.09 0.40+0.09
450 0.79+0.08 0.36 0.55+0.11 0.31
Anatomical site
Oral cavity (40%)
a
0.66+0.10 0.46+0.11
Larynx (43%)
a
0.79+0.08 0.62+0.11
Hypopharynx (17%)
a
0.73+0.1 0.45 0.13+0.11 0.0007
Histological grade
I (26%)
a
0.75+0.12 0.59+0.13
II—III (74%)
a
0.71+0.07 0.68 0.42+0.08 0.46
T-stage
T
2
(11%)
a
0.83+0.15 0.72+0.16
T
3
(57%)
a
0.75%+0.07 0.62+0.09
T
4
(32%)
a
0.63+0.12 0.61 0.21+0.09 0.03
N-stage
N
0
(59%)
a
0.79+0.07 0.54+0.09
N
1
—N
2
(41%)
a
0.63+0.10 0.17 0.38+0.10 0.18
Performance status score
1 (51%)
a
0.81+0.13 0.75+0.13
2 (41%)
a
0.41+0.16 0.01 0.37+0.15 0.01
HB (g%)
412.5 (20%)
a
0.66+0.13 0.53+0.14
412.5 (80%)
a
0.61+0.17 0.79 0.61+0.17 0.32
Surgical margin
Adequate (59%)
a
0.80+0.07 0.56+0.10
Inadequate (41%)
a
0.64+0.10 0.23 0.37+0.10 0.05
RT-surgery interval
46 weeks (50%)
a
0.79+0.08 0.55+0.10
46 weeks (50%)
a
0.66+0.08 0.33 0.41+0.08 0.58
Overall time
b
410 weeks (57%) 0.92+0.05 0.60
410 weeks (43%) 0.55+0.05 0.005 0.44 0.22
RT schedule
CF 0.57+0.09 0.46+0.09
AF 0.88+0.04 0.01 0.60+0.10 0.29
a
Representation of the category as a per cent of all patients. The representation of all clinico-
pathological factors did not significantly differ in both groups.
b
Overall time=time between
surgery and end of radiotherapy.
Accelerated vs conventional fractionation
HK Awwad et al
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British Journal of Cancer (2002) 86(4), 517 – 523
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2002 Cancer Research UK

further substantiated by the demonstration that the best locoregio-
nal control and disease-free survival rates were obtained in the
AHF arm when the treatment was given within less than 6 weeks
after surgery and when the overall treatment time did not exceed
10 weeks (Table 4). However, the therapeutic benefit of AHF rela-
tive to CF was masked when the surgery-radiotherapy gap exceeded
6 weeks and also when the overall treatment time was longer than
10 weeks. It seems therefore that the potential therapeutic benefit
of an accelerated treatment can be counterbalanced by a long
gap between surgery and radiotherapy. It is interesting to note that
the surgery-radiotherapy gap and the overall treatment time did
not seem to influence the outcome of treatment in the CF group.
This suggests that the length of the actual radiation treatment time
is more significant than the surgery-radiotherapy gap probably due
to occurrence of an accelerated repopulation process during the
actual postoperative radiation treatment time similar to that
thought to occur during radical radiotherapy of HNC (Withers
et al, 1988).
In case of radical radiotherapy of HNC, the influence of
pretreatment tumour proliferation parameters on the treatment
outcome is a controversial issue (Awwad et al, 1992; Lochin et
al, 1992; Bourhis et al, 1993; Eschwege et al, 1997; Zackrisson et
al, 1997; Høyer et al, 1998). A multicenter analysis of 476 patients
in which 11 centres participating failed to demonstrate an associa-
tion (Begg et al, 1999). Such negative results do not support the
notion that T
pot
can predict repopulation taking place during radi-
cal radiotherapy. Nevertheless, there is strong evidence that, in a
radical radiotherapy setting, shortening of the treatment time
improves the treatment outcome This is in keeping with the
concept that repopulation is a strong determinant of this outcome
(Horiot et al, 1997; Saunders et al, 1997; Withers et al, 1988). In
the present postoperative radiotherapy study, we set out to test
the potential value of tumour proliferation parameters to predict
the overall treatment results. The possibility of their use as a guide
for selecting patients for accelerated treatment was subsequently
tested. Since FCM tends to underestimate the proliferative activity
of diploid tumours (Bennett et al, 1992; Wilson, 1993; Høyer et al,
1998) it was combined with measurement of the LI using immuno-
histochemistry. Nevertheless, none of the proliferation parameters
proved to be an independent predictor of treatment outcome.
Despite lack of a definite association between T
pot
and treatment
outcome in the present postoperative radiotherapy setting, treat-
ment acceleration was associated with a better locoregional
control. As in radical radiotherapy, repopulation seems, therefore,
to be an important determinant of treatment outcome in post-
Clinical
Table 5 Tumour proliferation characteristics and treatment outcome (Kaplan – Meier product limit estimate)
Local control Disease-free survival Distant metastases
Estimate+s.e. P-value Estimate+s.e. P-value Incidence (%) P-value
LI
510.94% 0.61+0.10 0.58+0.11 1/35 (2.9)
510.94% 0.46+0.09 0.19 0.46+0.09 0.19 7/34 (21) 0.01
T
pot
53.95 days 0.76+0.09 0.42+0.09 7/33 (21)
53.95 days 0.70+0.09 0.51 0.65+0.09 0.05 1/36 (2.8) 0.01
Table 6 Corrected P-values for cell proliferation parameters for which a
cut-off point with a minimum P-value40.05 could be identified according
to the log-rank test
Cut-off Minimum Corrected
point P-value P-value
Survival
T
pot
3.88 day 0.050 0.462
LI 10.01% 0.034 0.361
Locoregional control
LI 9.3% 0.02 0.251
Table 4 Influence of the treatment times on treatment outcome using
the Kaplan – Meier (product limit) estimate (estimate+s.e.)
Gap between surgery and postoperative radiotherapy
CF AHF P-value
Locoregional control
46 weeks 0.59+0.15 1.00+0.0 0.02
46 weeks 0.56+0.12 0.78+0.11 0.20
P-value 0.84 0.10
Disease-free survival
46 weeks 0.44+0.14 0.66+0.17 0.16
46 weeks 0.48+0.12 0.35+0.13 0.91
P-value 0.81 0.27
Overall treatment time
CF AHF P-value
Locoregional control
410 weeks 0.41+0.30 1.00+0.0 0.0005
410 weeks 0.59+0.10 0.34+0.25 0.45
P-value 0.61 0.001
Disease-free survival
410 weeks 0.22+0.19 0.55+0.13 0.01
410 weeks 0.50+0.10 0.17+0.15 0.17
P-value 0.18 0.005
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Local control
AHF
CF
P
=0.01
0 10 20 30 40 50 60 70
Duration in months
Number at risk 0 12 m 24 m 36 m 60 m
CF 39 24 11 8 3
A
H 31 27 16 10 5
Figure 1 Locoregional control in the accelerated hyperfractionation
(AHF) and conventional fractionation (CF) groups using the Kaplan – Meier
(product limit) estimate.
Accelerated vs conventional fractionation
HK Awwad et al
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2002 Cancer Research UK British Journal of Cancer (2002) 86(4), 517 – 523

operative radiotherapy. This is further supported by the aforemen-
tioned influence of surgery-radiotherapy gap and the overall
treatment time.
As expected, the treatment results of slow tumours did not
significantly differ in the AHF and CF groups. AHF did not seem
to provide a survival benefit to fast tumors but may offer a better
local control (Table 7). This suggests the need for additional treat-
ment (such as concomitant chemoradiotherapy) in order to
improve survival of patients with fast growing tumours particularly
since the risk of distant metastases was shown, in the present study,
to be associated with a rapid tumour growth as indicated by a
short T
pot
>.
At present, the median values of the proliferation parameter are
usually selected as cut-off points to identify risk groups. This
approach is associated with a considerable loss of information.
The minimum P-value approach has been proposed as a means
of reducing (though not completely eliminating) the risk of miss-
ing a significant association (Altman et al, 1994). Since this
approach is associated with a marked increase in type 1 error rate
and may thus give false positive associations, a correction factor
similar to that given by equation 1 has to be applied. In the
present study none of the three cut-off points with minimum P-
value 40.05 according to the log rank test, proved to have a
significant corrected P-value although minimum P-values as low
as 0.027 are observed (Table 6). This is in accordance with the
observation that none of the proliferation parameters proved to
be an independent predictor of the treatment outcome when using
standard statistical procedures based on the median values as cut-
off points. The potential validity and use of such an approach is
currently further tested using the clinical material of the present
and other studies.
Compared with CF, AHF involves a faster rate of dose delivery,
which might interfere with the regenerative response (Thames et
al, 1990; Trotti et al, 1998). This can account for the early and
rapid development of acute mucositis and its greater severity in
case of treatment acceleration. However, the severity of early
mucosal reactions did not generally interfere with completion of
the prescribed treatment. The frequency of late reactions (fibrosis
and oedema) is expected to be lower in the AHF group due to a
smaller fraction size and total dose. However, the incidence of
oedema and fibrosis was apparently higher in the AHF though
the difference is not statistically significant. One interpretation
would be that some late reactions are in fact consequential reac-
tions that are driven mainly by mechanisms related to epithelial
injury (Denham et al, 2000). Such reactions are then expected
to be less influenced by the fraction size and to be influenced
by the overall treatment time. Moreover, the surgical trauma
might induce a proliferative response in the connective tissue
and blood vessels and thus render their reactions more similar
to that of early reacting tissues (Tibbs, 1997). All patients suffered
from some degree of late xerostomia, which persisted for 2 years
at least. There was a tendency, though statistically insignificant for
xerostomia to be more severe in the AHF group (P=0.16). In view
of the possibility that the volume of the parotid gland included
within the high dose region can differ widely in different patients,
this small difference is difficult to interpret on a radiobiological
basis.
In conclusion treatment acceleration can provide better local
control in the postoperative radiotherapy of locally advanced
HNC suggesting that repopulation is an important determi-
nant of treatment outcome. T
pot
did not prove to be a
good indicator of repopulation and this limits its use in
selecting patients for AHF. To gain a full benefit from treat-
ment acceleration, the surgery-radiotherapy gap and the overall
treatment time should not exceed 6 and 10 weeks respec-
tively.
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