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Gy. Biomarkers of DNA double-strand breaks (DSB)
recognition and repair were assessed from 10 minutes to
24 hours after irradiation, including the relocalization of
phosphorylated ATM Protein (pATM) as nuclear foci. These
biological results were plotted against the CTCAE grades.
A ROC curve analysis was then performed on patients after
they were merged in two groups: radioresistant (grade <2)
and radiosensitive (grade ≥2).
Results
This study showed that a delay in the nucleoshuttling of
the ATM protein, which is involved in the recognition of
the DSB, was a common feature to patients with
overreaction (OR). The maximal number of pATM foci
between 10 min and 1h post irradiation (pATMmax) was
found to be the parameter with the best correlation with
each OR severity grade, independently of tumor
localization and of the early or late nature of reactions.
When taken as a binary predictive assay with the optimal
cut-off value of 35 pATM foci, pATMmax foci showed
promising predictive performances, with an AUC of 0.97,
a PPV of 99%, a specificity of 92% and a sensitivity of 100%.
Conclusion
The results of these experiments allowed us to identify
pATMmax as a high performance predictive parameter of
post-radiotherapy OR. Additional studies are in progress to
confirm that this radiosensitivity assay reaches the same
performances in any radiotherapy condition to change our
daily clinical practice.
OC-0222 GnRH receptor blockade reduces radiation-
induced bladder toxicity: first evidence in a rat model.
G. Fallara
1
, F. Benigni
1
, C. Cozzarini
2
, B. Noris Chiorda
2
,
C. Sini
3
, L. Perani
4
, A. Spinelli
4
, M. Venturini
4
, A.
Salonia
1
, A. Briganti
1
, F. Montorsi
1
, N. Di Muzio
2
, C.
Fiorino
3
1
Ospedale San Raffaele- Vita-Salute University,
URI/Urology, Milan, Italy
2
Ospedale San Raffaele, Radiotherapy, Milan, Italy
3
Ospedale San Raffaele, Medical Physics, Milan, Italy
4
Ospedale San Raffaele, Experimental Imaging Center,
Milan, Italy
Purpose or Objective
Genitourinary toxicity represents a major side effect in
patients treated with primary, adjuvant or salvage
radiotherapy for prostate cancer (PCa). Many clinical trials
aimed at finding predictive factors of radiation-induced
toxicity analyzed the impact of androgen deprivation
therapy (ADT) with controversial results. However, recent
data on large groups of patients support the hypothesis
that short-term ADT is protective towards radiation
cystitis. Our pilot study is aimed at supporting the putative
beneficial role of a GnRHR antagonist (degarelix) by means
of an animal model that recapitulates many features of
the human pathology.
Material and Methods
Male rats were surgically catheterized and randomly
divided into three groups: radio-treated only (RT, n=4),
radio-treated+degarelix (RT+DGX, n=4) and control (CTRL,
n=2). Rats from RT and RT+DGX group were irradiated with
a single fraction of 20 Gy to the bladder. The RT+DGX
group received the drug (150 µg/kg, sub-cute) once a
week for 3 weeks, starting 1 week prior to irradiation.
Each rat underwent pelvic ultrasound, before and after
(day 6) irradiation, to evaluate bladder wall thickness. At
day 21, cystometry was performed to evaluate bladder
function. Then the animals were sacrificed and their
bladder analysed in H&E and Azan-Mallory trichrome
staining (day 21). One-way ANOVA with Tukey post test
and t-Student were used to assess the statistical
differences.
Results
Our data show that, in RT group, compared to pre-
irradiation baseline, bladder wall thickness increased 1.8-
fold after radiations (0.5±0.2 vs 0.9±0.4 mm, p<0.05),
while no significant differences were found in RT+DGX
group (0.6±0.2 mm). Bladder basal (BP), threshold (TP),
flow (FP), and maximal (MP) pressures as well as AUC/MI
increased significantly in RT group compared to RT+DGX
(BP: 21±6 vs 9.8±0.5; TP: 41±16 vs 15±4; FP: 53±19 vs 24±4;
MP: 83±25 vs 41±3; AUC/MI: 30±10 vs 13±2, cmH2O, all
p<0.01). Also, both micturition volume (MV) and intervals
(MI) were reduced in RT animals and improved after DGX
(MV: 0.4±0.1 vs 1.1±0.3 mL; MI: 174±45 vs 349±116 sec, all
p<0.01). The non-voiding bladder contractions in each
micturition cycle were significantly higher in RT than
RT+DGX group (5.5±2 vs 0.6±0.5, p<0,05). Compared to
CTRL, histopathological analysis confirmed in RT group an
increased mucosal layer (81±25 vs 40±16 µm, p<0.05),
which was instead less pronounced in RT+DGX (63±23 µm).
Finally, the bladder muscle/collagen ratio decreased in RT
rats (0.8±0.1, p<0.01) compared to CTRL (1.3±0.2) and
almost normalized by DGX (1.1±0.2).
Conclusion
In irradiated rats, DGX prevented the urinary functional
impairment and histological subversion of bladder wall.
The differences in terms of both mucosa thickness and
reduced collagen deposition suggest a possible effect by
DGX on inflammation-mediated tissue remodeling. The
presence of GnRH receptors in the bladder urothelium
advocates a local effect with potential applications as
radioprotectors, firstly in high-dose RT for PCa.
Symposium: Paediatric brachytherapy
SP-0223 The AMORE concept and late effects outcome
for paediatric brachytherapy
B. Pieters
1
1
Academic Medical Center P.O. Box, Radiation Oncology,
Amsterdam, The Netherlands
Childhood head and neck rhabdomyosarcomas are often
large tumors at diagnosis. These tumors are usually
located in areas with many vital structures. Radiotherapy
to these tumors will have a high probability for serious late
sequelae because of the sensitivity of normal tissue for
radiation at young age. For these reasons the AMORE
concept was developed in the nineties of last century for
local treatment after the standard chemotherapy courses.
AMORE is the acronym for Ablative surgery, MOld
brachytherapy, and REconstruction. After a macroscopic
radical excision, pulsed-dose rate brachytherapy (32-36 x
1.25 Gy at 2.1hour interval) is applied with a mold
technique. The dose is prescribed on 5 mm from the mold
surface. After brachytherapy the mold is surgically
removed and the defect reconstructed with a free
vascularized flap or a transpositional muscle flap. The
Amsterdam cohort, with AMORE treated patients, was
compared to a similar group of patients from London
treated with only external beam radiotherapy (EBRT) as
the radiation modality. Failure-free survival and overall
survival were 58% and 76%, respectively and not
statistically significant different between the two groups.
Both groups were identically analyzed in a Late Effects
Outpatient Clinic and all possible late effects scored
according to the Common Terminology Criteria for Adverse
Events version 4. The most seen late effect was
musculoskeletal deformities; 60% any grade. The EBRT-
based cohort therapy resulted in more adverse effects
than the AMORE-based cohort. Also grade 3-4 adverse
events were significantly more pronounced in the EBRT-
based cohort. The largest difference in late effects was
found for growth hormone deficiency. The odds ratio was
2.1 for EBRT-based therapy compared to AMORE-based
therapy. In conclusion AMORE, with brachytherapy as
radiation modality, is proven to be equivalent to EBRT
with less late effects.