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Cancer Therapy Vol 6, page 673
Cancer Therapy Vol 6, 673-682, 2008
Conventional versus hyperfractionated
radiotherapy in locally advanced head and neck
cancer
Research Article
Azza Abd El-Naby1, Aly Tawfek2, Hala M. El-Shenshawy1,*, Amal Halim1, Rasha
Hamdy1
1
2
Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Dakhlia, Egypt
Department of ENT, Faculty of Medicine, Mansoura University, Dakhlia, Egypt
__________________________________________________________________________________
*Correspondence: Hala Mohamed El- Shenshawy, Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine,
Mansoura University, Dakhlia, Egypt; Tel: 0020123810407; Fax: 0096672501305; e-mail: [email protected]
Key words: conventional, hyperfractionated radiotherapy, head and neck, locally advanced
Abbreviations: 5-fluorouracil, (5-FU); chemotherapy, (CT); complete response, (CR); conventional fractionated radiotherapy, (CFRT);
European Organization for the Research and Treatment of Cancer, (EORTC); hyperfractionated radiotherapy, (HFRT); karnofsky
performance status, (KPS); partial response, (PR); progressive disease, (PD); radiotherapy, (RT); stationary disease, (SD)
Accepted at the Annual Scientific Meeting of the Radiological Society of North America, 2007 (RSNA-2007), Radiation
oncology section, November 25-November 30, 2007, Chicago-USA.
Received: 19 November 2007; Revised: 14 January 2008
Accepted: 17 January 2008; electronically published: September 2008
Summary
Radiotherapy is often the primary treatment of locally advanced squamous cell head and neck cancer, but the
optimal fractionation schedule has been controversial. The aim of this study was to examine whether, after
preceeding induction chemotherapy, hyperfractionated radiotherapy (HFRT) is superior to conventional
fractionated radiotherapy (CFRT). Patients with locally advanced squamous cell head and neck cancer were treated
with 3 cycles of cisplatin (100 mg/m2 D1) and 5-fluorouracil (1000 mg/m2 D1-4), repeated every 3 weeks. Then
patients were randomized to receive either CFRT at 1.8-2 Gy / fraction / day, 5 day / week to 65- 70 Gy / 33- 35
fractions / 7 weeks or HFRT at 1.2 Gy / fraction, twice daily with a 6-h interfraction interval, 5 days / week to 76.8
Gy / 64 fractions / 7 weeks. All patients in both treatment arms received concomitant chemotherapy in the form of
weekly bolus injection of cisplatin (20mg/m2). Of the 60 patients entered, only 53 patients were evaluable for
outcomes. The primary end points were local control and progression- free survival. Chemotherapy was well
tolerated, the overall response rate after induction chemotherapy was 73.6%, including 13.2% complete response
rate. After completion of radiotherapy, patients treated with HFRT had an overall response rate of 96.2% vs 77.8%
in CFRT (P= 0.037) and complete response rate of 65.4% in HFRT vs 40.7% in CFRT (P=0.013). After a median
follow- up of 28 months, overall survival was 57.7% in HFRT vs 44.4% in CFRT (P= 0.068). The 2-year
progression- free survival was 44% in HFRT vs 23.8% in CFRT (P=0.028). The 2- year locoregional control was
significantly higher in HFRT (58.8%) than those with CFRT (36.4%) (P=0.021). The incidence of local recurrence
rate was 41.2% in HFRT vs 63.6% in CFRT (P=0.019). However, the incidence of distance metastases was 7.7% in
HFRT vs 11.1% in CFRT (P=0.439). Patients treated with HFRT had significantly greater acute side effects
compared to CFRT. However, there was no significant increase of late effects. After induction chemotherapy,
hyperfractionated radiotherapy is more efficaceous than conventional fractionated radiotherapy in locally
advanced squamous cell head and neck cancer. Acute but not late effects are increased, but it is tolerable and
manageable.
mainstay for this group of patients because chemotherapy
alone has only palliative means. Apart from intrinsic
radioresistance and sublethal damage repair of tumor cell
I. Introduction
The prognosis of locally advanced head and neck
cancer is still dismal. Radiation therapy (RT) is the
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El-Naby et al: Conventional versus hyperfractionated radiotherapy in locally advanced head and neck cancer
clonogens, hypoxia and repopulation are also known to be
poor , with median 3-year overall survival and
locoregional control rates of approximately 30% and 40%
respectively (Hoeckel et al, 1996; Withers et al, 1988).
Survival in patients with locally advanced head and neck
cancer is determined by locoregional outcome, with a
probability of less than 30% long- term tumor control
despite optimal treatment with surgery and/ or
conventional radiotherapy. In less advanced tumor stages,
the probability of survival is up to 60%. In these cases, the
results are influenced by locoregional recurrences and
second tumors. The accumulated knowledge on tumor
biology has resulted the investigators to modify
conventional treatment modalities with the intention of
achieving better local control bettering order to improve
the survival rates (Galiana et al, 2002).
A number of strategies have been explored during the
last two decades to improve the outcome in locally
advanced head and neck cancer (Stuschike et al, 1997; Fu
et al, 2000). New fractionations in radiotherapy on head
and neck cancer have emerged as a treatment of choice to
increase local control of this disease. Altered fractionation
is predicted to improve the therapeutic ratio through a
differential response between tumors and normal tissues to
fractionated radiotherapy. Hyperfractionated radiotherapy
is probably the best studied form of altered classical
fractionation of 2 Gy as a single daily fraction, and
consists of administering two or more small fractions
every day to reduce the repopulation of tumor cells
between two consecutive fractions. The overall treatment
time is not increased. Hyperfractionation has been
considered as the most promising and tempting alternative
to standard fractionation (Horiot et al, 1992; Hall, 1994;
Stuschike et al, 1997).
Retrospective studies of patients treated with
accelerated fractionation and hyperfractionation have
demonstrated an improvement in disease control of about
20%, as compared with historical controls treated with
conventional daily radiation, without an increase in longterm toxicity. A prospective randomized trial by the
European Organization for the Research and Treatment of
Cancer (EORTC) showed an increase of 20% in the rate of
locoregional control of oropharyngeal carcinoma at five
years and an improvement of 14% in survival after
treatment with 8050cGy of radiation in hyperfractionated
doses as compared with rates achieved with once-daily
radiotherapy (total doses, 7000 cGy), without any increase
in acute or chronic toxic effects (Horiot et al, 1992; ElSayed and Nelson,1996).
Even the most effective radiotherapy regimens result
in local control rates not exceeding 50-70% and diseasefree survival rates not more than 30-40%. This
circumstance has stimulated the investigation of
treatments combining radiotherapy and chemotherapy.
Several review articles have explored the different
chemotherapeutic agents and RT schemes of these
treatment programs (El-Sayed and Nelson, 1996). The
combination of RT and chemotherapy (CT) is another
promising approach investigated to improve results in
advanced head and neck cancer. Induction or neoadjuvant
chemotherapy performed before definitive RT was widely
used and easily given. It results in a high response rate as
it reduces the tumor mass facilitating its elimination by
radiation. Synchronous or concurrent chemotherapy
results in the delivery of RT and CT on the same days,
typically CT is given for one or more days at the initiation
of RT and then repeated in the same fashion several weeks
later (Ang, 2007). By adding systemic drugs to radiation,
both the tumor lesions within the irradiated field and
micrometastases outside the irradiated area are exposed to
the drugs' cytotoxic action. In addition, chemotherapeutic
drugs may make tumor cell clonogens undergoing
irradiation more susceptable to killing by ionizing
radiation.
This
radiosensitizing
property
of
chemotherapeutic agents constitutes the major rationale
for concurrent chemoradiotherapy (Perez et al, 2004).
The activity of cisplatin in head and neck squamous
cell carcinoma was already documented in an early period
(Knox et al, 1986). Some experimental studies showed
synergism between RT and the drug in vitro (Zamboglou
et al, 1989). The simultaneous administration of RT and
CT with cisplatin and 5-fluorouracil (5-FU) proved
feasible and highly effective in terms of objective
response. The combination of 5-FU and cisplatin remains
the best-studied and most active drug regimen. One
advantage of this drug combination is that both agents are
radiosensitizers (Douple, 1988). 5-FU is an S-phase
specific agent with a short half- life (<10 min), making it
particularly suitable for administration as continuous
infusion, which enhances cell kill by increasing the
exposure of dividing cells (Lockich et al, 1981). Addition
of concomitant chemotherapy to either hyperfractionated
or conventional fractionated RT could be a good option,
since such a method of combining two treatment
modalities seems to be the most promising approach, as
demonstrated in meta-analyses and recent randomized
studies (Lockich et al, 1981; Brizel et al, 1998; Pignon et
al, 2000; Domenge et al, 2000).
The aim of this study was as follows: (a) to analyse
and compare locoregional control, progression-free
survival and overall survival in both conventional
fractionated radiotherapy arm and hyperfractionated
radiotherapy arm. (b) to determine and compare the acute
and late adverse effects in both treatment arms and (c) to
determine variations in treatment outcome per arm in a
variety of head neck sub-sites and T and N stages.
II. Materials & Methods
Between June 2004 and June 2006, 60 patients with locally
advanced squamous cell carcinoma of the head and neck who
attended to Clinical Oncology and Nuclear Medicine
Department, Mansoura University Hospital, were randomly
assigned in this prospective study.
A. Eligibility criteria
Eligibility criteria included patients of either sex older than
18 years, hisitologically proved squamous cell carcinoma of the
head and neck, karnofsky performance status (KPS) ! 60, locally
advanced non metastatic stage III, IV (according to UICC/ AJCC
stage classification for head and neck cancer) and no evidence of
coexistent synchronous or previous malignant disease, previous
head and neck radiotherapy, previous chemotherapy or previous
surgery except biopsy only.
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Cancer Therapy Vol 6, page 675
Treatment fields were verified by simulator before starting
treatment and weekly during treatment to ensure reproducibility.
All patients were instructed to meticulous oral hygiene and
change their eating habits. During RT, the patients were
examined for acute toxicity every week. Toxicity of RT
developing within 90 days from the beginning of RT (acute
toxicity) was assessed according to RTOG and EORTC criteria
(Perez et al, 1992). RT toxicity developing after 90 days
(chronic/ late toxicity) was graded with the same scale for late
sequelae and evaluated every 6 months. Mucositis was treated by
saline mouth washes, pain management, antimicrobials
(antibiotics, antivirals and antifungal) and maintaining nutritional
intake.
B. Pretreatment evaluation
Pretreatment evaluation included complete history,
physical examination, head and neck examination including
mirror and panendoscopic examination, histopathologic
examination of the primary tumor or cervical lymph nodes,
complete blood count (WBC count !3.5"109/L, platelets
!100"109/L, hemoglobin !10g/dL), blood chemistry including
liver function tests (serum bilirubin #1.5 mg/dL), and kidney
function test (serum creatinine #1.5mg/dL), computed
tomography and or magnetic resonance imaging of the head and
neck to define the extent of the disease and metastatic workup
including chest x-ray and imaging of liver by ultrasound or
computed tomography in all patients. Bone scan was not
routinely performed and was restricted to those with bone pain or
elevated serum alkaline phosphatase. Dental care was applied to
each eligible patients before therapy.
D. Post-treatment evaluation
Response was assessed six weeks after completion of
radiotherapy by clinical examination, endoscopic examination,
and CT and/or MRI of head and neck. Criteria for response were
as follows: complete response (CR) was defined as complete
regression of all evidence of tumor. Partial response (PR) was
defined as an estimated decrease in tumor size of 50% or more.
Stationary disease (SD) was defined as < 50% decrease in tumor
size or < 25% increase in pretreatment tumor size. Progressive
disease (PD) was defined as > 25% increase in pretreatment
tumor size.
Re-evaluation was done at 3 months interval during the
first two years of follow- up unless any manifestations of
progression were developed. Chest radiography and
ultrasonography of the liver were performed every year.
C. Treatment schedule
Induction chemotherapy consisting of 3 cycles of cisplatin
100mg/m2 IV on day 1 and 5-fluorouracil 1000mg/m2 on days 1
through 4 by continous infusion, to be repeated every 3 weeks.
All patients had prehydration with intravenous fluids for one day
prior to chemotherapy. Cisplatin was administered as an infusion
over one to two hours and 5- fluorouracil was administered as
continous infusion. Antiemetics prophylaxis was routinely given,
IV dexamethasone 10-20mg and diphenylhydramine 50mg IV
were given prior to chemotherapy. The dose of cisplatin was
decreased by 25% if serum creatinine level was elevated 1.5 to 2
times above the baseline values and by 50% if serum creatinine
level were elevated 2 to 2.5 times above baseline. If creatinine
levels were elevated more than 2.5 times the baseline value, no
further cisplatin was given to that patient. Reassessment of
response was performed at the end of the 3 cycles of
chemotherapy.
Radiotherapy began within 3 weeks of completion of the
last cycle of induction chemotherapy and after re-assessment of
response (primary tumor as well as lymph nodes) by clinical
examination, endoscopic examination and CT and/or MRI.
Out of 60 patients, only 56 patients completed 3 cycles of
induction chemotherapy. All 56 patients were randomly assigned
into two treatment arms. Arm I (n=28 patients) treated by
conventional fractionated radiotherapy (CFRT) to total dose of
65-70 Gy, 1.8-2 Gy / fraction, one fraction / day, 5 days / week.
Arm II (n= 28 patients) treated by hyperfractionated radiotherapy
(HFRT) to total dose of 76.8 Gy, 1.2 Gy / fraction, 2 fractions /
day with 6- h interval between fractions, 5 days / week. All
patients in the two treatment arms received concomitant
chemotherapy in the form of weekly bolus injection of cisplatin
(20mg/m2).
The primary tumor and draining lymphatic system were
irradiated in most patients by two parallel- opposed lateral fields.
In the initial lateral fields: arm I received 45 Gy (1.8 Gy /
fraction / day, 5 days / week) , however, arm II received 43.2 Gy
(1.2 Gy / fraction, 2 fractions / day, 5 days / week) after that
these initial fields were reduced for spinal cord shielding. Further
reductions were made whenever possible to limit the volume of
tissues receiving high- dose RT. Patients were treated by 6 MV
photons of a linear accelerator or Cobalt-60 teletherapy device
with the centres of the fields marked on the shell. Electron beam
irradiation was used to boost the dose to the posterior cervical
lymph node chains and to the selected lymph node region as
indicated. However, the supraclavicular nodes and nodes in the
lower part of the neck were treated with the use of a single
anterior field with midline blocking to prevent spinal cord
overlap. Anterior lower neck field doses were prescribed at depth
of 3 cm with a total dose of 50 Gy (2 Gy / fraction / day, 5 days
/week). The inferior border of the lateral fields and the superior
border of anterior lower neck field coincided on the skin.
E. Endpoints
The primary endpoints were to analyse and compare
locoregional control and acute and late adverse effects in both
treatment arms. The secondary endpoints were to analyse and
compare progression-free survival and overall survival in both
treatment arms.
F. Statistical methods
Pretreatment characteristics of both treatment arms were
compared using the Chi- square test. Overall survival and
progression- free survival were calculated using the KaplanMeier method. Responses were compared using the Chi- square
test. Mann- Whitney U test used to compare the median
responses, survival and progression- free survival in both
treatment groups. Confidence intervals (CIs) were calculated
using Cox's proportional hazard model.
Prognostic factors related to response, survival and
progression- free survival were assessed using Cox proportional
hazards regression model.
Informed consent was obtained from all patients, and
ethical committee approval was received by our participating
center.
The randomization scheme was a permuted block design
with an equal probability of assignment to either treatment arms.
Patients were stratified by primary site of disease and stage of
disease and were then randomized to receive one of the two
treatments planned in the trial.
III. Results
A. Patient's characteristics
All sixty patients with locally advanced squamous
cell carcinoma of the head and neck received induction
chemotherapy but only 56 patients completed their 3
cycles of chemotherapy. These patients were randomly
assigned into two treatment arms, either CFRT arm or
HFRT arm with 28 patients in each treatment arm. In
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El-Naby et al: Conventional versus hyperfractionated radiotherapy in locally advanced head and neck cancer
CFRT arm, only 27 patients completed their treatment as
one patient died from tumor 2 weeks from beginning of
RT. While in HFRT arm, only 26 patients completed their
protocol as the remaining 2 patients died during the course
of RT (one patient died from hepatitis and the other died
from local disease). Only 53 patients out of 60 patients
were analyzable for outcome. The median follow-up of all
eligible patients were 28 months (range 12-34 months).
Table 1 shows the pre-treatment patients
characteristics. They were well balanced among the both
treatment groups. The nasopharynx was the most common
primary site. All patients were stage III (43.4%) and stage
IV (56.6%). The median age was 57 years, ranging from
20 to 80 years.
B. Response
The overall response rate after induction
chemotherapy was 73.6% (95% CI: 0.617 to 0.855),
including 13.2% complete response rate, 60.4% partial
response rate and 26.4% stable disease. However, the
overall response rate in all evaluable patients 6 weeks after
the completion of concomitant chemoradiotherapy were
Table 1. Patients Characteristics
Character
Age(years):
<60
!60
Sex:
Male
Female
Smoking:
Smoker
Non smoker
KPS:
60
70
80
90
Site:
Oral cavity
Maxillary sinus
Nasopharynx
Oropharynx
Hypopharynx
Larynx
Grade
I
II
III
Undifferentiated
T-stage
T2
T3
T4
N-stage:
N0
N1
N2
N3
AJC stage:
III
IV
Hemoglobin
concentration:
! 12 g/dl
< 12 g/dl
Total
No.
%
CFRT
No.
%
HFRT
No.
%
31
22
61.5
38.5
15
12
55.6
44.4
16
10
61.5
38.5
0.76
0.87
40
13
75.5
24.5
19
8
70.4
29.6
21
5
80.8
19.2
0.56
0.34
32
21
60.4
39.6
16
11
59.3
40.7
16
10
61.5
38.5
0.93
0.81
2
1
26
24
3.8
1.9
49.1
45.3
0
0
14
13
0
0
51.9
48.1
2
1
12
11
7.7
3.8
46.2
42.3
0.34
0.64
0.81
0.79
7
3
20
3
10
10
13.2
5.7
37.7
5.7
18.9
18.9
4
1
11
2
3
6
14.8
3.7
40.7
7.4
11.1
22.2
3
2
9
1
7
4
11.5
7.7
34.6
3.8
26.9
15.4
0.75
0.53
0.72
0.94
0.23
0.51
14
11
10
18
26.4
20.8
18.9
34
9
3
6
9
33.3
11.1
22.2
34.6
5
8
4
9
19.2
30.8
15.4
33.3
0.46
0.17
0.52
0.96
8
35
10
15.1
66
18.9
8
16
3
29.6
59.3
11.1
0
19
7
0
73.1
26.9
0.14
0.31
0.22
13
13
21
6
24.5
24.5
39.6
11.3
7
7
9
4
25.9
25.9
33.3
14.8
6
6
12
2
23.1
23.1
46.2
7.7
0.96
0.96
0.73
0.41
23
30
43.4
56.6
13
14
48.1
51.9
10
16
38.5
61.5
0.51
0.59
15
38
28.3
71.7
9
18
33.3
66.7
6
20
23.1
76.9
0.49
0.52
676
P-Value
Cancer Therapy Vol 6, page 677
77.8% (95% CI: 0.621 to 0.935) in CFRT arm versus
96.2% (95% CI: 0.889 to 1.035) in HFRT arm (P= 0.037),
including 40.7% complete response rate in CFRT vs
65.4% in HFRT (P= 0.013) and 37% partial response rate
in CFRT vs 30.8% in HFRT (P= 0.433). However, 11.1%
had stable disease in CFRT vs 3.8% in HFRT and 11.1%
had progressive disease in CFRT vs 0% in HFRT (Table
2).
grade 3 or worse late side effects as mucositis (P=0.026),
xerostomia (P=0.032) and dysphagia (P=0.045), according
to the RTOG that defines late effects as toxicity noted > 90
days from the start of radiotherapy. However, these late
effects were actually prolonged acute effects. Table 5 had
shown that globally there was no significant difference in
frequency of grade 3 or worse late effects reported at 6-24
months after start of radiotherapy among the two treatment
groups.
C. Toxicity and treatment compliance
D. Survival
Tables 3 and 4 show the site and grade of acute and
late adverse effects by treatment groups. The most
common sites of grade 3 or worse acute side effects were
the mucous membranes and the pharynx. However, the
most common sites of grade 3 or worse late effects were
the mucous membranes, the pharynx and the salivary
gland.
Compared
to
conventional
fractionated
radiotherapy, the hyperfractionated radiotherapy had
significantly increased grade 3 or worse acute side effects
as mucositis (P=0.034), dysphagia (P=0.042) and neck
edema (P=0.049). However, it had significantly increased
The median local recurrence free survival was 15
months (ranging from 4-34 months) in the CFRT group
versus 25 months (ranging from 7-34 months) in the
HFRT group. Hyperfractionated radiotherapy arm had
significantly increased locoregional control rate at two
years (58.9%) compared with CFRT arm (36.4%)
(P=0.021). Results of Kaplan- Meier estimates of localregional control in both treatment groups are shown in
Figure 1.
Table 2. Response after radiation therapy in both treatment groups
CFRT Arm
No.
%
11
40.7
HFRT Arm
No.
%
17
65.4
P Value
Response
Complete response
Partial response
10
37
8
30.8
0.433
Stationary disease
3
11.1
1
3.8
0.159
Progressive disease
3
11.1
0
0
0.081
Overall response
21
77.7
25
96.2
0.037
0.013
Table 3. Acute adverse effects of radiation therapy reported within 90 days after start of radiotherapy in both treatment
groups.
Organ /Tissue
Skin toxicity
(dermatitis)
Mucous membrane
(mucositis)
Salivary gland
(xerostomia)
Pharynx /Eosphagus
(dysphagia)
Subcutaneous tissue
(neck edema)
Taste sensation
(dysgeusia)
Weight loss
Grade
1
2
3
4
1
2
3
4
1
2
1
2
3
1
2
1
2
1
2
CFRT Arm
No.
%
18
66.7
9
33.3
0
0
0
0
6
22.2
15
55.6
6
22.2
0
0
7
25.9
16
59.3
8
29.6
13
48.1
4
14.8
10
37
0
0
23
85.2
2
7.4
20
74
4
14.8
677
HFRT Arm
No.
%
11
42.3
13
50
1
3.8
1
3.8
2
7.6
12
46.2
11
42.3
1
3.8
6
23.1
17
65.4
1
3.8
17
65.4
7
26.9
12
46.2
1
3.8
20
76.9
5
19.2
13
50
10
38.5
P Value
0.221
0.034
0.89
0.042
0.049
0.14
0.05
El-Naby et al: Conventional versus hyperfractionated radiotherapy in locally advanced head and neck cancer
Table 4. Late adverse effects of radiation therapy reported after 90 days after start of radiotherapy in both treatment
groups.
Organ / Tissue
Mucous membrane
Grade
1
2
3
4
1
2
1
2
3
4
Salivary gland
Pharynx /Esophagus
Subcutaneous tissue
Pharyngo-tracheal fistula
1
2
3
4
1
2
3
4
Laryngeal edema
Temporal lobe necrosis
CFRT Arm
No.
%
2
7.4
9
33.3
0
0
0
0
3
11.1
4
14.8
6
22.2
4
14.8
1
3.7
0
0
8
29.6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
HFRT Arm
No.
%
7
26.9
9
34.6
3
11.5
0
0
6
23.1
10
38.4
3
11.5
9
34.6
2
7.7
0
0
7
26.9
0
0
0
0
0
0
1
3.8
0
0
0
0
0
0
1
3.8
1
3.8
P Value
0.026
0.032
0.045
0.81
0.39
0.39
0.39
Table 5. Frequency of Grade 3 or worse late effects at various times after start of radiotherapy in both treatment groups.
Time after start of
radiotherapy(months)
6
CFRT Arm
No.
%
3
11.1
HFRT Arm
No.
%
4
15.4
P Value
12
2
7.4
4
15.4
0.085
18
2
7.4
3
11.5
0.238
24
1
3.7
2
7.7
0.481
Figure 1. Cumulative probability of local-regional free survival in both treatment groups.
678
0.572
Cancer Therapy Vol 6, page 679
Progression includes the following events: local,
regional, loco-regional and distant failure. The median
progression-free survival was 9 months, ranging from 2-34
months in CFRT vs 19 months, ranging from 3-34 months
in HFRT (P=0.031). In addition, there was improved 2year progression-free survival in HFRT 44 % vs 23.8% in
CFRT, with statistically significant difference (P=0.028),
(Figure 2).
At a median follow-up of 28 months of all analyzed
patients, the median overall survival in CFRT was 19
months, ranging from 5-34 months vs 25 months, ranging
from 7-34 months in HFRT, with no statistically
significant difference (P=0.061). The 2-year overall
survival in CFRT arm was 44.4% vs 57.7% in HFRT, with
no statistically significant difference (P=0.068), (Figure
3). Table 6 shows 2-year local-regional control rate,
progression-free survival and overall survival for the two
treatment groups.
Figure 2. Cumulative probability of progression free survival in both treatment groups.
Figure 3. Cumulative probability of overall survival in both treatment groups.
Table 6. 2-year locoregional control, progression-free survival and overall survival in both treatment groups.
CFRT Arm
No.
%
4/11
36.4
HFRT Arm
No.
%
10/17 58.9
P Value
2-Year endpoints
Locoregional Control
Progression-free survival
5/21
23.8
11/25
44
0.028
Overall survival
12/27
44.4
15/26
57.7
0.068
679
0.021
El-Naby et al: Conventional versus hyperfractionated radiotherapy in locally advanced head and neck cancer
2003). It is possible that induction chemotherapy may
have a role in increasing survival rates for squamous cell
carcinoma of the head and neck patients and appropriate
randomized trials testing this hypothesis need to be
conducted (Cohen et al, 2004).
Our results show activity and relatively low toxicity
of a combined therapy consisting of cisplatin and 5- FU
followed by concomitant chemoradiotherapy in the form
of either CFRT or HFRT with cisplatin as radiosensitizer
in both treatment groups. It was noted, however, that 6-8
weeks after treatment completion, a significant advantage
of the HFRT arm over the CFRT arm was already present.
The overall response at the completion of radiotherapy
was 96.2 % in HFRT vs 77.7 % in CFRT with 65.4% CR
in HFRT vs 40.7% in CFRT. Such a response rate has
been seen in previous studies including induction
cisplatin- fluorouracil regimens (Paccagnella et al, 1994;
Lefebvre et al, 1996; Posner et al, 2000).
Locoregional control represents the major endpoint
of any curative radiotherapy. This randomized trial
demonstrates a significant 2-year locoregional control rate
benefit of a hyperfractionated radiotherapy regimen over a
conventional regimen in locally advanced head and neck
cancers. These findings had been seen in many large
randomized trials that had compared hyperfractionated RT
with conventional fractionated RT (Pinto et al, 1991;
Horiot et al, 1992; Cummings et al, 1996; El-Sayed and
Nelson, 1996; Fu et al, 2000; Jeremic et al, 2000; Galiana
et al, 2002; Orecchia et al, 2002). In the EORTC trial
(Horiot et al, 1997), 356 patients were randomized to
receive 70 Gy in 35 fractions of 2 Gy/fraction in the CFRT
arm versus 80.5 Gy in 70 fractions of 1.15 Gy delivered
twice-a-day (6-h interfraction interval) in the HFRT arm,
both over 7 weeks. The locoregional control was
significantly higher in the twice-a-day arm (56% vs 38%;
P=0.01).
However, it was a trend in favour of
hyperfractionated radiotherapy, especially for the most
unfavourable T and N combinations. In our study we
found that the locoregional control benefit of HFRT is of a
larger magnitude in patients with unfavourable prognosis
factors. Similar conclusions were reached with the
EORTC hyperfractionation trial (Horiot et al, 1997).
However, standard fractionation already reaches rather
high control rates in the more favourable clinical
presentations. Conversely, patients with large primaries
and / or involved nodes do recur more often and sooner
with the conventional regimen. Such conclusions were
reported with EORTC trial (Horiot et al, 1997).
Neoadjuvant chemotherapy followed by concomitant
chemoradiotherapy resulted in reduction of tumor lesions
as well as eradication of micrometastases outside the
irradiated field, this resulted in high local control and low
incidence of both local failure and distant metastases.
Moreover, in hyperfractionated irradiation, the overall
treatment time is reduced with respect to the increased
total dose (76.8 Gy /7 weeks). This lead to increase in
locoregional control, as the hypothesis that tumor
repopulation during therapy is a major cause of treatment
failure. Our findings go ahead with EORTC trial (Horiot et
al, 1997), in which patients with locally advanced head
E. Pattern of treatment failure
The primary site was the most common location of
treatment failure. The 2-year locoregional failure rates
were 63.6% in CFRT vs 41.1% in HFRT, (P=0.019).
However, the incidence of distance metastases at 2-years
was 11.1% in CFRT vs 7.7% in HFRT (P=0.439).
F. Prognostic factors with treatment
outcomes
On multivariate analysis for locoregional control, T
category (T4 vs T2, T3; P=0.003) and tumor site (oral
cavity or oropharynx vs all other sites; P=0.001) were
significant independent adverse prognostic factors for
locoregional control. On other hand, the HFRT arm was
confirmed as an independent factor of good prognosis for
locoregional control (P=0.03). However, on multivariate
analysis for progression- free survival, T category (T4 vs
T2, T3; P=0.001) and N–category (N2-N3 vs N0,N1;
P=0.045), sex (male vs female; P=0.024) and smoker
patients (P=0.033) had independent adverse prognostic
impact on progression-free survival. Whilst, HFRT was
associated with good prognosis for progression- free
survival (P=0.04). In addition, on multivariate analysis for
survival, sex (P=0.03), poor performance status (P=0.03),
T4 (P=0.01), N2-N3 category (P=0.004) and stage IV
(P=0.008) were independent factors associated with poor
prognosis for survival.
IV. Discussion
In most patients with advanced head and neck cancer,
conventional radiotherapy does not result in long- term
locoregional control of the tumor, and this failure
ultimately proves fatal (Jeremic et al 2000). One of the
ways to improve the therapeutic ratio is through
modification of dose fractionation. Two types of altered
fractionation regimens were predicted to offer therapeutic
advantage: hyperfractionated and accelerated fractionation
schedules. The main rationale of hyperfractionation is to
increase the total doses through the use of multiple smaller
dose fractions (1.1-1.2 Gy/ fraction) without increasing the
overall treatment time, that allows to increase the
probability of tumor control within the tolerance of late –
responding normal tissues. The rationale for accelerated
fractionation is that reduction in overall treatment time
reduces the opportunity for tumor cell regeneration during
treatment and therefore increases the probability of tumor
control for a similar total dose. This improved tumor
control would lead to a therapeutic gain because overall
treatment time has little influence on the probability of late
normal tissue injury, when the fraction size is not
increased and the interval between dose fractions is
sufficient for cellular repair to approach completion
(Galiana et al, 2002).
The combination of radiotherapy and chemotherapy
is another promising approach investigated to improve
results in advanced head and neck cancer. Induction
chemotherapy and concomitant chemoradiotherapy might
have complementary effects on overall disease control,
with the former leading to a reduction of distant disease
and the latter enhancing locoregional control (Haraf et al
680
Cancer Therapy Vol 6, page 681
and neck cancer recur more often and sooner with
conventional regimen than those with hyperfractionated
one.
The improvement in locoregional control was
responsible for better progression- free survival in HFRT
arm than those in CFRT arm. These findings are in
agreement with the finding of Adelstein and colleagues in
2002; Galiana and colleagues in 2002 and Olmi and
colleagues in 2003.
The improvement in locoregional control was
responsible for improved 2-year overall survival in the
HFRT arm than those of CFRT arm, however it did not
reach to a statistically significant level. Our findings
coincide with many studies (Horiot et al, 1997; Fu et al,
2000; Galiana et al, 2002).
In our study, hyperfractionated schedules resulted in
increased acute toxicity more than standard fractionation
which go ahead with RTOG trial (Fu et al, 2000). The
most common sites of grade 3 acute reactions were the
mucous membrane and the pharynx, which was in
accordance with other studies (Pinto et al, 1991;
Antognoni et al, 1996; Horiot et al, 1997; Fu et al, 2000).
In this study, grade 2 acute reactions were observed in the
subcutaneous tissues and weight loss of patients in the
HFRT group compared with those in the CFRT group.
However Antognoni et al, 1996 reported greater
proportion of mild complication of skin and salivary
glands in patients treated with hyperfractionated
radiotherapy but found no difference in other normal
tissues. In Krstevska and Crvenkova, 2006, grade 2 acute
reactions were observed in the skin and the larynx of
patients in the hyperfractionated group compared with
those in the conventional group.
As regard late adverse effects, the most common sites
of grade 3 late side effects were observed in the mucous
membrane, the pharynx and the salivary gland, which go
ahead with many studies (Pinto et al, 1991; Antognoni et
al, 1996; Horiot et al, 1997; Fu et al, 2000), who reported
that the most common sites of grade 3 late side effects
were in pharynx and salivary gland. In addittion Krstevska
and Crvenkova, 2006 reported that the most common sites
of grade 3 late effects were in the mucous membrane. In
our study, we 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 our study, most of the late effects
(reported >90 days) 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 two
treatment groups. These findings coincide with many
studies (Horiot et al, 1997; Fu et al, 2000; Olmi etal, 2003;
Hehr et al, 2004).
At present time, the major limitation of
hyperfractionated radiotherapy or combined radiotherapy
and chemotherapy for head and neck is increased acute
reaction primarily acute mucositis (Kaanders et al, 1992;
Brizel, 1998). Several toxicity antagonists are under active
investigation (Trotti, 2001). In the future, some of these
agents may decrease the acute and late effects of cancer
therapy. The therapeutic ratio may also be improved by
conformal and intensity- modulated radiotherapy, which
have the capability of the high-dose tumor target coverage
while minimizing the dose to the volume of the
surrounding normal tissues irradiated
V. Conclusion
After induction chemotherapy, hyperfractionated
radiotherapy seems to be more efficacious than
conventional fractionated radiotherapy in locally advanced
squamous cell carcinoma of the head and neck, by
increasing significantly the progression-free survival and
locoregional control. This improvement did not translate
into a statistically significant overall survival
improvement. However, HFRT was associated with
significantly increased acute toxicity, but late toxicity was
not significantly increased and it was tolerable and
manageable.
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