14 / 21
THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part I: The Basics of Brachytherapy
Version 1 - 22/10/2015
Radiobiology of LDR, HDR, PDR and VLDR Brachytherapy
14
Late complications
Late responding normal tissues, at a low α/β ratio of about 3 Gy,
are expected to be more sensitive to increasing dose rate. This
has been confirmed in many studies:
Fontanesi
et al
. found an effect of dose rate on complications in
the re-irradiation of 23 head and neck tumours with iridium 192
(Fontanesi 1989). Sarin
et al.
found, in a population of 289 pa-
tients treated with conservative surgery and irradiation for ear-
ly breast cancer, that higher dose per fraction with EBRT and
higher dose rate with a BT boost adversely affected cosmesis and
contributed to late complications (Sarin 1993).
Mazeron
et al
. found an effect of dose rate in the range of 0.3-0.9
Gy/h on both the probability of local failure and necrosis in 279
T1-2 tumours of the oral cavity treated with a 60-70 Gy iridium
192 implant alone (Mazeron 1991). Pernot
et al
. showed , in a
population of 1134 patients implanted for a squamous cell car-
cinoma in oral cavity or oropharynx , that a dose rate in excess
of > 0.6 Gy/h was associated with an increased rate of compli-
cations (10% if > 60cGy versus 6% if < 60cGy/hr , p =0.006))
(Pernot1997).
In the GEC-ESTRO survey on BT for lip cancer, a significant
dose rate effect was also noted for incidence of post RT lip ulcers
in the dose rate range from <40 to >120 cGy/hr.:2.5% for dose
rates < 40cGy, 6% for 40-80 cGy, 7% for 80-120 cGy/h and 15.2%
for dose rates over 120 cGy/hr.(Van Limbergen presented data)
Similar conclusions were made from the French Cooperative
Study on LDR BT for cervix cancer (Horiot 1989). Bladder
complications G 3-4 were significantly higher at dose rates >
60cGy/hr at the ICRU bladder point: 5.3% versus 0.8 % at <cGy/
hr (p=0.001). The same was noticed for rectal complications G
3-4: 8.5% for > 60cGy/hr at ICRU rectal point versus 2.3% for <
60cGy/hr (p= 0.01)
The IGR randomised trial compared two dose rates (0.4 and 0.8
Gy/h) in a population of 204 patients with T1-2 of the cervix,
treated with a 60 Gy preoperative caesium 137 intracavitary ap-
plication (Haie 1994). They found that the higher dose rate was
associated with an increased prevalence of late effects and surgi-
cal complications. (Fig 5.14)
In conclusion there is an effect of dose rate on local outcome in
the range 30-150 cGy/h. These effects are significantly larger for
late reacting tissue than for local control, certainly for squamous
cell carcinoma, but not for breast or prostate cancer and depend
on the repair capacity and kinetics of the irradiated cells. The
higher the repair capacity, the lower the α/β ratio, the more the
increase in dose rate (as in fraction size in fractionated high dose
rate) will lead to increased cell kill.
In practice it is therefore not advisable to adapt the dose to the
dose rate in the range of 30-100 cGy/h (see practical examples
below). It seems more appropriate to keep the total dose high to
maximise local control, and the dose rate low (40-60 cGy/h) to
minimise late effects.
However, a dose-correction is usually recommended when the
dose rate exceeds 1 Gy/h (Hunter 1994, Leborgne 1996, Lebor-
gne 1999). Such dose rates have been used for gynaecological
treatments given with caesium 137 afterloading equipment. The
clinical gain is a shorter hospital stay but, to compensate for the
higher dose rate, the total dose had to be adapted. Treatment du-
ration usually ranges from 10 to 30 hours with dose rates of 1.5
to 2 Gy.h
-1
. This range of time corresponds to the experimental
conditions described above, in which a differential effect was not
observed between early and late radiation damage models. The
ensuing discussion is thus fully relevant to 1.5 to 2 Gy.h
-1
BT. In
practice, 1.5 to 2 Gy.h
-1
BT is also fractionated. The radiobiologi-
cal interpretation of clinical data should therefore combine dose
rate and dose fractionation parameters. Little differential effect is
expected but the fractionation of the treatment (2 or 3 fractions)
compensates, to some extent, for this lack of relative protection
of late responding normal tissues.
9.3 HDR Clinical data
Dose per fraction is one of the most important parameters of the
therapeutic ratio with high dose rate BT as in external beam ra-
diation therapy (see above). In particular the risk of developing
late injury directly depends on the dose per fraction. This is clin-
ically confirmed by the results of a survey published by Orton
et al
. on HDR BT in carcinoma of the uterine cervix. The rates
of severe complications were 1.28% and 3.44% with doses per
fraction at point A < 7 Gy, and > 7 Gy, respectively (p < 0.001)
(Orton1991).
The main advantage of HDR BT is that it can be delivered in a
few or a limited number of fractions, and that usually this is pos-
sible, like external beam RT in an outpatient setting.
Since the biological effects are predominantly dependent on to-
tal dose and fraction size, smaller doses per fraction will reduce
normal tissue injury, but then a higher number of fractions is re-
quired. Depending on the clinical situation, several fractionation
schedules have been developed.
The best experiences from HDR BT come from clinical situa-
tions where the target can be irradiated to a high effective dose,
while the normal tissues at risk can be spared by applying mod-
Fig 5.14: IGR randomised trial (Haie 1994): Prevalence of Grade 2 or more complications after
preoperative utero-vaginal BT for early cervix cancer at 2 different dose rates 0.4 versus 0.8
Gy/h at the 60 Gy ICRU prescription isodose.