Prospective
randomised study comparing three-fraction regimens of High Dose Rate
Brachytherapy for cancer of the cervix stage IIB and IIIB
Dr Wondemagegnhu Tigeneh MD,
M Med Rad (T) (WITS), FC Rad Onc.( SA), PG Dip Palli Medicine
(UCT)1;
Dr. Jeffry
Kotzen MBBCh,
M. Med Rad (T)(WITS) 2,
Prof.
Bernard Donde MBBCh, M
Med Rad (T (WITS)2.
1Oncology
Center, Medical
Faculty, Addis Ababa University, Addis Ababa, Ethiopia.
2Division
of Radiation
Oncology, University of the WITS, Johannesburg, South Africa
Corresponding
author: Dr
Wondemagegnhu Tigeneh,
Oncology Center,
Medical Faculty, Addis Ababa University,
P.O. Box 3819, Addis Ababa,
Ethiopia; Email: tigeneh@yahoo.com
Afr J
Haematol Oncol
2011;2(1):149-156
ABSTRACT
AIM
Limiting the number of high-dose-rate brachytherapy (HDR-BT)
applications from
4 or 3 to 2 fractions has the potential benefit of improving patient
compliance. Two HDR-BT applications of 9
Gy each is most cost effective and resource sparing compared to 3 or 4
insertions.
The aim of this study was to compare
the
treatment results and incidence of bladder and rectal complications
following
radical treatment of carcinoma of cervix with 2, 3 or 4 fractions of
(HDR-BT)
and standard external beam radiotherapy (EBRT).
METHODS
Sixty-six
patients with biopsy proven stage IIB and stage IIIB cancer of
the cervix received EBRT 50 Gy in 25 fractions
and concomitant Cisplatin 80
mg/m2
once
every 3 weeks. The patients were then randomized into
one of
three-fractionation arms of
HDR-BT: (I) 6.5
Gy ´ 4; (II) 8
Gy ´ 3; and
(III) 9 Gy ´ 2. The
biologic effective dose (BED) to organs at risk was used to assess the
complication rates of treatment.
Patients were
evaluated using SOMA/LENT (subjective, objective,
management and analytic/
late effects in normal tissues) scales
during treatment, at 6
weeks
and finally at 6 months. Pap-smears were performed at 6 months to
assess local
control.
RESULTS Fifty-nine
patients completed chemo-radiotherapy and attended follow up for
evaluations at
6 weeks and 6 months. The mean age of the patients was 51.6 years and
the mean
duration of the treatment was 47.2 days. Of the 59 patients who
completed
treatment and had six months follow up, 29 patients were stage IIB and
30 were
stage IIIB. The overall complete response rate for the whole group was
88%. The
response rate was 90% in arm I,
85.7%
in arm II, and 88.8 in arm III, which was not statistically significant
(p=0.463). The influence of the following prognostic factors on local
control
was not statistically significant: stage (IIB vs. IIIB) (p=0.995), age
above
and below 50 years (p=0.532), treatment duration (p=0.6508),
and number of fields used (p=0.603). The adverse effects of
radiation-induced
toxicity depended on age group (p=0.01), number of fields (p=0.001),
and BED Gy3
to organs at risk and were statistically significant (p=0.001). The
rectal,
grade 3 and 4 radiation induced toxicity were observed to be increased
when the
BED Gy3
dose was above 105 Gy3. Similarly,
bladder grade 3 & 4 toxicity
rate were increased with BED Gy3
dose of 120 Gy3
(p=0.001)
CONCLUSION This study
showed that 9 Gy ´ 2
fractionations HDR-BT with concomitant
chemo-radiotherapy was equally effective in short term local control
and had
similar incidence of treatment related complications compared to 6.5 Gy
´ 4 and 8 Gy ´ 3 regimens during 6
months of
follow up.
Keywords: Cancer of cervix; Implant radiotherapy; Brachytherapy; Dose fractionation; Radiotherapy
INTRODUCTION
Carcinoma of the uterine cervix is
the second most common neoplasm in women worldwide and is the most
frequent
cancer among women in Africa, Asia and South America.
1 It
is the
most common malignancy among African and European-African females in
South
Africa with a lifetime (1-74 years) risk of 1 in 41 2 and the 2nd
and 5th
most common cancer in Asian
and Caucasian females, respectively
. 2
Over
the past
decade, between 550 and 640 new patients with carcinoma of the cervix
were seen
at Johannesburg Hospital annually .
3
Radiotherapy
(RT) is the cornerstone and the treatment of choice for Fédération International de Gynécologique et Obstétrique (FIGO) stage IIB, IIIA,
IIIB or IVA
carcinoma of the cervix and is an excellent alternative to surgery in
selected
patients with stage IA, IB, or IIA disease. 4-5
RT for
primary
cervical cancer consists of a combination of external beam radiotherapy
(EBRT)
and intracavitory brachytherapy (ICRT), except in stage IA disease
where
brachytherapy alone may be used. 5
The
success of brachytherapy may be attributed to the delivery of a high
radiation
dose to the tumour while sparing the surrounding normal tissues.
4
The
use of high dose rate (HDR) brachytherapy is the result of
technological
developments in the manufacture of high-intensity radioactive sources,
sophisticated
computerised remote after loading devices and treatment planning
software.
Several advantages of HDR brachytherapy, including rigid immobili
In order
to maximise the benefits of HDR-BT while improving patient compliance
and
resource sparing,
various fractionation
regimens have been studied
in different
countries and centres. 7-10
Five-year survival, local
control, and
recurrence rates have not been significantly different and there has
been no
evidence of increased toxicity in the HDR brachytherapy groups.
Limiting
the number of high-dose-rate brachytherapy (HDR-BT) applications from 4
or 3 to
2 fractions has the main potential benefit of improving patient
compliance. Two
HDR-BT applications of 9 Gy each is most cost effective and resource
sparing
compared to 3 or 4 insertions. The aim of this study was to compare the
treatment results and incidence of bladder and rectal complications
following
radical treatment of carcinoma of cervix with 2, 3 or 4 fractions of
(HDR-BT)
and standard external beam radiotherapy (EBRT).
METHODS
Sixty-six
patients with biopsy proven cancer of cervix and FIGO stage IIB
(distal) or
stage IIIB (early) disease were recruited if they met the following
additional
criteria: age above 20 and below 75, performance status ECOG 0 up to 2
and HIV
negative.
Patients were excluded if
they
were unavailable for follow up, had previous hysterectomy or pelvic
radiotherapy, had active systemic disease, or had other malignancy
other than
skin cancer not controlled for five or more years. Ethical approval was
obtained from the committee for research on Human Subjects of the
University of
the Witwatersrand – Johannesburg.
All
patients were treated radically based on departmental protocol and
received
EBRT 50 Gy in 25 fractions at 2 Gy per fraction. Patients
also received concomitant Cisplatin
80 mg/m2 every
three weeks. Patients
were then randomized into one of the three-fractionation arms of HDR.
In arm I,
patients received HDR brachytherapy of 4 fractions of 6.5 Gy each. The
brachytherapy was given once weekly during the last 4 weeks of EBRT
with
concomitant chemotherapy. In arm II, patients received HDR
brachytherapy of 3
fractions of 8 Gy per fraction. The brachytherapy was given during the
last 3
weeks of EBRT with concomitant chemotherapy. In arm III, patients
received HDR
brachytherapy of 2 fractions of 9 Gy per fraction. The brachytherapy
was given
weekly during the last 2 weeks of external beam radiotherapy with
concomitant chemotherapy.
The
departmental treatment field arrangement protocol for EBRT depended on
the
anterior-posterior separation of each patient. Every patient received
either
anterior or posterior fields or anterior, posterior, and two lateral
fields
from either side depending on separation of the patient.
During
treatment, the patients were assessed weekly for side effects. Each HDR
brachytherapy application was evaluated individually. A rigid
intrauterine
tandem (nucleotron 6 cm, 4 cm, or 2 cm in length) and a ring applicator
(nucleotron 3.4 cm, 3.0 cm, or 2.6 cm in diameter) with a rectal shield
were
used. The length of the tandem and the diameter of the ring were
individualised
for each patient. Two radiographs anterior posterior (AP) and lateral
with a
dummy source in the applicator were taken (Figure
1).
|
Figure 1. Lateral and anterior posterior radiographs of applicator in situ |
`
Transparencies
indicating the isodose distributions were placed over the applicator
image on
the screen. This was used to check the isodose distributions. The
rectum and
the bladder points were calculated according to the ICRU 38
recommendations.
From lateral radiograph, the anterior rectal wall was identified with
the help
of a radio-opaque balloon and the posterior wall of bladder was
identified
using an indwelling catheter with contrast material in its balloon.
The pelvic
sidewall reference point was visualised on an anterior-posterior
radiograph
related to a fixed bony structure (acetabulum). This point was intended
to be
representative of the absorbed dose at the distal part of parametrium
and at
the obturator lymph node.
The doses
to critical organs (rectum and bladder) were calculated by measuring
the
distance from the applicator to ICRU reference points from the graph
after
correcting for the magnification factor. The graph was plotted for each
ring
size and tandem length.
By using
packing with each application, an attempt was made to increase the
distance
between the tandem and critical organs. The dose to critical organs was
inversely proportional to the square distance away from the tandem
(Figure 2).
For each HDR application, a calculation was done by measuring the
distance from
the tandem to the organ at risk by using the magnification factor, and
the
graph for the bladder, rectum, and the pelvic sidewall points.
|
Figure
2. Relationship
between the percentage dose
prescribed to point A against distance from applicator, ring size 34
and tandem size 46 (R34IU46), to the ICRU rectum, bladder. |
For each arm, the contribution of point A dose was calculated as per the linear quadratic model (LQM) from both external beam radiotherapy and intracavitary portions of the treatments. The total biologically effective dose (BED) to the tumor was calculated by using an a/b ratio = 10 (Gy10) 4,6 (Table 1). The BED Gy10 can be converted to a linear quadratic effective dose (LQED) for a 2 Gy fraction by dividing the BED dose by 1.2 (the relative effectiveness for a 2 Gy fraction). 11
The median
BED for late responding tissue for arm I patients was 165 Gy3 at point A. With
adequate packing
and good application, the bladder and the rectum would usually receive
60 – 80%
of the prescribed dose to point A. 4,6
If the normal
tissues
received 70% dose, then the 165 Gy3
term would reduce to
about 115
Gy3.
The LQED 6,11
for a 2 Gy fraction to late
responding
tissue can be calculated by dividing the BED by 1.67 (the relative
effectiveness for a 2 Gy fraction to the late responding tissues)
,
115 Gy/1.67 = 69 Gy (Table 2).
Table 1:
BED Gy10
dose to point A for the three HDR
fractionation regimens |
Table
2. BED
Gy3
dose and to late responding tissue for
three fractionation regimens |
In this
study, the treatment outcome and complication were assessed in each arm
using
the following criteria: (1) the local control of the disease by a
Pap-smear at
six months post treatment in each arm; (2) the effect of stage, age,
ring
application and duration of treatment on local control; (3) toxicity in
each
arm; (3) the effect of age and number of fields treated on radiation
induced
toxicity; and (4) the doses to the bladder and rectal reference points
and
their association with radiation induced toxicity. Radiation induced
grade 3
and 4 bladder and rectum effects were assessed using Lent SOMA scale in
each
arm.
All
statistical analysis was performed using the Epi Info program 2002.
Duration of
treatment was measured from the first day of treatment to the end day
of
treatment. Patient age, tumour stage, number of portals and duration of
treatment were used as prognostic factors for the factor analyses of
local
control and adverse effects of RT. Comparisons of categorical variables
were
performed using the Chi-square test, t test and for more than 2
variables,
Analysis Of Variance (ANOVA) test was used. Statistical significance
was
considered with p-values of less than 0.05 or 95% of significance.
RESULTS
Seventy-one
patients were entered in the study. Three patients were excluded due to
active
non-malignant diseases. One patient had active tuberculosis and 2
patients had
severe skin reactions and herpes zoster. A repeat HIV test in the
latter 2
patients confirmed that they were HIV positive.
Two
patients withdrew following the first HDR application. The remaining 66
patients were further analysed.
Twenty-two
patients were recruited to Arm I; twenty-three to arm II and twenty-one
to arm
III. Sixty-six patients completed the prescribed dose of radiotherapy
but only
fifty-nine had the six-week and the six-month prescribed evaluation and
Pap-smear, and were further evaluated. Of these, thirty-nine (59%) were
stage
IIB (distal) and twenty-seven (41%) stage IIIB (early). All
66
patients
received HDR and 59 received concomitant cisplatin 80 mg/m2
every three weeks. The reasons for not receiving
chemotherapy (n=7) were low creatinine clearance in four patients, two
could
not receive chemotherapy for logistical reasons and one patient
absconded. Of
the seven patients, three were in arm I, two were in arm II and two
were in arm
III. The only chemotherapy-related side effect noted was mild to
moderate
nausea and vomiting. Further
analysis included only those 59 patients who completed the prescribed
dose of
chemoradiotherapy and attended the six week and six month assessments
and Pap
smears.
Twenty-nine
patients were aged 31-50 years and 30 were aged 51-75 years. There was
no
statistical significant difference between the mean ages in the three
arms with
p value of 0.995. There were no statistically significant differences
between
the three arms in terms of stage distribution and the number of
chemotherapy
cycles given (p=0.678 and 0.532 respectively).
The mean
time to completion of treatment was 46.4 days with a range of 35-58
days. The
duration of treatment was similar in the three arms with p value of
0.651.
The overall
complete response rate for the whole group was 88%. The response rate
was 90%
in arm I,
85.7% in arm II, and 88.8
in
arm III, which was not statistically significant (p=0.463). The number
of
fields used did not affect local control (p
= 0.603) nor did the duration of treatment (p
= 0.402).
In terms of
adverse effects of radiation, although the numbers of patients in each
age
group were nearly equal, of the 12 patients who developed grade 3 and 4
bladder
and rectal toxicity, eight patients were below the age of 50 (p
< 0.001). The BED to the rectum and
bladder ICRU reference point was calculated from both EBRT and
intracavitory
HDR brachytherapy. Patients treated with two fields EBRT in addition to
the HDR
brachytherapy had an increased chance of grade 3 and 4 toxicity
compared to
those treated with four fields (p
=
0.001). In our study the incidence of grade 3 & 4 rectum and
bladder
radiation induced toxicity were observed on the patients who had above
BED Gy3
dose of 105 and 120
respectively to the rectal and bladder
referral
points.
DISCUSSION
Despite
screening programs, cervical carcinoma remains a major health problem
throughout the world. Until recently, pelvic radiation has been the
standard
therapy for advanced disease with overall five-year survival rates of
50%.
Recently, 5 randomized trials demonstrated a significant survival
advantage for
the concomitant administration of radiotherapy and Cisplatin-based
chemotherapy. 5
Radiation
therapy to cancer of the cervix is delivered with EBRT and BT. It is an
alternative to surgery in stage I, IIA, and IVA and comparable survival
and
tumour control with either modality have been reported.
8 Several
prognostic factors, including tumour stage, volume, age of patient,
performance
status, and presence of metastatic pelvic, para-aortic lymph nodes,
have been
shown to affect the therapeutic outcome. 11
Patients
with extensive loco regional disease have a high rate of local relapse
if
treated surgically. For this reason, patients with stage IIB, III, and
IVA
tumours are treated with radiotherapy, which results in five-year
survival rate
of 65, 40, and less than 20 percent, respectively. 12
In previous
years, different studies have shown that HDR brachytherapy with
concomitant
chemo-radiotherapy is safe and effective in management of locally
advanced
cervical cancer. Patel et al (1992) 7
studied 412 patients
diagnosed
with stage III cancer of the cervix treated with EBRT. More recently at
the end
of 2001 a study done in Albert Einstein College of Medicine 10
showed that 2 fractions
of HDR brachytherapy of
9 Gy each with concomitant EBRT to the pelvis provided similar local
control
without increasing toxicity. In the current study, the local control
rate based
on 6 month clinical findings and Pap-smear result did not show any
statistically significant differences when comparing the 3
brachytherapy
fractionation regimens.
According
to a univariate analysis done in Brazil, the overall treatment time
with cohort
value of 50 days was a statistically significant factor for five years
actuarial local control rate (84% versus 53%, p = 0.008). 11 The
over-all treatment duration has
been reported by several authors to be of prognostic significance in
patients
with cervical cancer treated by radiation therapy.
12-13 The
American Brachytherapy
Society (ABS) 14-15 recommends
keeping the total treatment duration to less than 8 weeks, because
prolongation
of total treatment duration can adversely affect local control and
survival. 12-13
In this study, the duration of
treatment did not influence local
control,
one possible reason is that the follow up time is too short to assess
definitively the local control as only response was assessed at 6
months. A
study done by Robson Ferrigno and colleagues showed that
patient’s age with
cohort value of fifty years did not influence the actuarial local
control (p
= 0.99).
11
In
addition to that, this study has shown that local
control did
not have any dependency on age group of the patient, duration of
treatment or
number of fields whether two (AP-PA) or four fields (AP-PA and 2
Laterals). The
main reason why this study differs from others may be small number of
patients
and very short follow up period.
A
retrospective study done in Japan showed that
concurrent chemo-radiotherapy using
HDR-ICBT is feasible and efficacious for patients with loco regionally
advanced
uterine cervical cancer.
8
They
demonstrated that those patients who received a cumulative rectal BED
of more
than 100 Gy3
had significantly higher incidences of
proctitis than
those who received less than 100 Gy3
(p
=
0.013). The median BED values at the ICRU 38 rectal reference
point was 94.1 Gy3
(range: 78.3 – 116.1 Gy3).
The low
rectal BED value may have favourably affected the incidence of severe
rectal
complications. 11
Similarly,
a study done in Brazil 11 found
that the 5
years actuarial incidence of
late complications depends on total BED dose to the organ at risk.
A
significant correlation was found between the dose calculated and
measured at
the rectal point defined by the ICRU and the incidence of late rectal
complications. Using the linear quadratic model, they established a
threshold
value for the possibility of developing late rectal complication of 110
Gy3,
which is unrelated to the number of HDR fractions but rather to the
total dose
delivered to the rectal point by the combination of EBRT and HDR
brachytherapy.
Thus,
keeping the biologically effective
dose below
110 Gy3
at the defined ICRU rectal point will minimize the
risk of
late rectal toxicity. The
late rectal damage is a function of
total
biological effective dose to ICRU rectal point and not of the number of
HDR BRT
fractions. 11
In general,
there is more variability in the rectal dose reports. As in some
series, the
point for calculation of the rectal dose is pre-determined and others
take into
account several points along the anterior rectal wall. Nevertheless,
the
different series do show a correlation between rectal dose and
complications.
In spite of the variations in the way the rectal doses are calculated,
a
cumulative dose of 75 Gy can result in a 10% incidence of
proctosigmoiditis.
With higher rectal doses, the incidence of proctosigmoiditis also
increases. 16 The
optimisation of HDR brachytherapy can be further improved with 3D
imaging using
CT or MRI to increase the dose delivery to the adjacent normal tissues.
The rate
of radiation induced grade 3 and 4 bladder and rectal toxicity
increased in
those patients who received EBRT in two fields versus four fields.
Among 12
patients who developed grade 3 and 4 radiation induced toxicity, seven
of them
were stage IIIB and the remaining five patients were stage IIB.
CONCLUSION
HDR
brachytherapy in combination with megavoltage teletherapy appears to be
safe
and effective treatment modality in the treatment of cervical
carcinoma. In our
current study, we have proven that EBRT with concurrent chemotherapy
and two
insertions of 9 Gy each HDR application was feasible with an acceptable
complication rate and equivalent local control rate when compared with
6.5 Gy,
4 fractions and 8 Gy, 3 fractions.
Careful
attention to radiotherapy technique, planning, patient positioning, and
number
of portals will minimise both acute and long-term toxicity.
Limitations
of this study included limited time frame, limited number of patients,
and 2-D
treatment planning.
ACKNOWLEDGEMENTS
Special
thanks to Mr. Grume Taye Zeleke (bio-statistician) for statistical
analysis,
Prof
Debby and Mr. Nhlakanipho
Mdletshe
(medical physicist) for calculating and plotting graph distances from
the
source versus dose to the rectum, bladder, and pelvic sidewall points.
I would
like to acknowledge the support I received from fellow registrars,
nurses, and
radiographers in the department.
Finally,
thanks to my wife, Fantu Mulugeta, for her enthusiastic support and
understanding during all those four academic years.
FOOTNOTES
Conflicts
of interest: The authors declare
no competing
conflicts of interest
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