Boost RT ou Curiethérapie?

Radiothérapie du cancer du canal anal : Boost RT ou Curiethérapie? G. Créhange Centre GF Leclerc, Dijon Radiothérapie des cancers de
l’anus
Pas de standard ferme sur les techniques
•  RTE avec ou sans boost*
(* photon or electron)
•  RTE avec curiethérapie
•  Curiethérapie ou Electronthérapie
on is
ent of
me paquired
utions
on to a
ry and
distant
domen
nce of
cer inrectal
diated
ticular
erineal
nerally
ates.25
ph nogroin
cussed
finitive
tances
urgical
trol in
rate of
e, and
opiate
and reder or
s skin
lished between 1990 and June 2013. The search terms
included squamous cell carcinoma, anal cancer, anal canal
carcinoma, anal margin cancer, survival, diagnosis, recurrence, surgery, chemotherapy, radiotherapy, chemoradiation, chemo-radiotherapy.
ESMO-­‐ESTRO-­‐ESSO Table 5
Summary of recommendations.
! Patients with anal cancer should be managed, from diagnosis through
initial treatment and subsequent surveillance, by an experienced and
specialised multidisciplinary team.
! Loco-regional control with good quality of life and the avoidance of a
permanent stoma is the primary aim of treatment.
! The optimal total dose of radiation is unknown. Chemoradiation with
at least 45 Gy, infused FU and mitomycin remains the standard
treatment for stage II or higher anal canal tumours and a boost with
15e20 Gy may be applicable, especially if chemotherapy cannot be
safely delivered, leading to cure in the majority of patients.
! Less intensive treatment programs with lower doses of irradiation
may be successfully used in smaller tumours or fragile patients
although evidence from randomised trials is not available.
! Neoadjuvant and adjuvant chemotherapy using cisplatin has not been
shown to improve outcomes (progression-free survival or OS).
! Chemoradiation with 5FU and cisplatin had similar complete
response and overall toxicity when compared with 5FU and MMC but
less haematological toxicity. Any marginal benefit for cisplatin in
terms of haematological toxicity is likely to be outweighed by the
extra resources needed to administer cisplatind two courses of
intravenous treatment with hydration over several hours, compared
with only a single dose of mitomycin.
! Response should be assessed from 6 weeks, but data suggest that the
optimal time to assess complete response may be 26 weeks, rather
than 11 weeks, if surgical salvage is discussed.
! Surveillance/follow-up after completion of chemoradiation treatment
have not been rigorously examined, but should focus on salvage of
local failure (less than 10% will recur after the first three years
following completion of chemoradiation treatment).
! The techniques for surgical salvage in anal cancer are different to that
performed for rectal cancer, are associated with high morbidity, and
require input from multiple surgical teams (e.g. urology and plastic
reconstruction).
Glynne Jones R et al. Radiother Oncol 2014, EJSO 2014 Facteurs pronosDques sur DFS •  N= 305 •  Suivi moyen = 103 mois • 
• 
• 
• 
Pour grosses Tumeurs : seul F pronosDque = RT+/-­‐CT : 70.3% vs 94.9% à 5 ans (p= 0.0083) Durée du Gap < vs > 38j Réponse à la fin de la RT •  F pronosDque sur DFS: •  RT : 71.6% à 5 ans •  RT + Bx : 86.5% (p= 0.07) Deniaud Alexandre, IJROBP 2003 CORS 03 : Rôle du boost curie Volume 85 " Number 3 " 2013
Boost technique for anal cancer patients with node involvement e139
N= 99 Suivi = 71.5 mois OTT <78d vs > 78d N1 vs N2-­‐3 Boost RT vs Boost BT Fig. 1. Overall survival (OS) for whole population (A), OS according to overall treatment time (OTT) (<78 days vs !78 days) (B), OS
according to nodal status (N1 vs N2/N3) (C), and OS according to boost technique: brachytherapy (BCT) versus external beam radiation
therapy (EBRT) (D).
Moureau-­‐Zaboeo L, IJROBP 2013 CORS 03 : Rôle du boost curie Volume 85 " Number 3 " 2013
Boost BT vs RT Boost technique for anal cancer patients with node involvement e141
OTT OTT <78d vs > 78d N1 vs N2-­‐3 N1 vs N2-­‐3 BT vs RT chez N1 Boost RT vs Boost BT Fig. 2. Cumulative rate of local recurrence (CRLR) for whole population according to boost technique (brachytherapy [BCT] vs external
beam radiation therapy [EBRT]) (A), CRLR according to overall treatment time (OTT) (<78 days vs !78 days) (B), CRLR according to
nodal status (N1 vs N2/N3) (C), and CRLR for N1 population according to boost technique (BCT vs EBRT) (D).
Moureau-­‐Zaboeo L, IJROBP 2013 study even in the case of initial perirectal node involvement. First,
a bias in the evaluation of nodal status was possible, but such
a bias should be identical in the BCT and EBRT boost groups. In
this study all the patients were evaluated by a digital rectal
examination and ERUS. The reliability of ERUS for nodal evaluation in anal carcinoma is poorly described in the literature. In
leading to an equivalent uniform dose higher than the prescribed
dose (13). Consequently, a boost dose of 15 to 20 Gy delivered
through BCT could be biologically more efficient than the same
prescribed dose delivered with EBRT.
Moreover, the volume encompassed by BCT should normally
include the gross tumor volume but not systematically perirectal
CORS 03 : Analyse mulDvariée Table 3
Multivariate analysis for 5-y OS, CRLR, CRDR, and CFS for overall population
5-y OS
Factors
Categories HR
Gender
Female
Male
Age
<63 y
!63 y
T stage
T1/T2
T3/T4
N stage
N1
N2/N3
Boost technique BCT
EBRT
OTT
<78 d
!78 d
Anal margin
involvement
3.09
95% CI P value HR
5-y CRDR
95% CI
95% CI P value HR
P value HR
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.5-6.5
.003
2.76
1.06-7.2
.037
-
-
2.14 0.74-6.19
.16
.03
3.77 1.28-11.1
.018
2.23 1.05-4.8
-
5-y CRLR
-
-
-
-
-
P value
-
-
-
-
-
-
-
-
-
-
-
0.47 0.09-2.4
-
95% CI
-
6.31 1.4-28.8
-
5-y CFS
1.02 0.99-1.06
.17
.17
2.55
1.3-5.01
.006
-
-
-
-
.4
-
-
-
-
-
-
-
Abbreviations: BCT Z brachytherapy; CFS Z colostomy-free survival; CI Z confidence interval; CRLR Z cumulated rate of local recurrence;
EBRT Z external beam radiation therapy; HR Z hazard ratio; OS Z overall survival; OTT Z overall treatment time.
Colostomy-­‐FS = Pas d’impact de la technique de boost Moureau-­‐Zaboeo L, IJROBP 2013 Boost curie : Série du CLB t
t
Table 5 Acute and late toxicity
Grade 3
12
3
8
1
2
1
1
Local Control (LC)
•  DT (RT+BT) médiane 63Gy (51-­‐76.7) Grade 3–4
0
0
10
4
0
0
0
Local Control (LC) according to Brachytherapy
dose (< 18 Gy vs > or = 18 Gy)
Table 6 Clinical
outcomes with results of univariate1.0
and multivariate analysis
1.0
t
p
s
i
n
i
t
e
in part
in
as elde
21], tht
5-years advan
MFS
mustC
terms
Overall population
(%)
90.5
e
0.6
text of
T
[22], a
T1–T2 (%) 0.4
79.6
84.9
88.6 0.4 70.1
80.5 Brachytherapy
87.4 do
dose94.8
pean S
S
<18Gy
T3–T4
77.3
75.9
82.0 0.2 68.4
77.7
74.6
84.7
0.2
.
ogy [2
> or = 18Gy
LC0.14
p
0.5
0.13
0.94
0.50
0.006
0.08
obtain
D
0.0
0.0
by RC
Neoadjuvant CT
r
0
50
100
150
200
250
0
50
100
150
200
250
as, the
Yes(%)
81.6
74.9
79.3
69.0
82.4
88.5
76.7
Time (months)
Time (months)
condit
No (%)
72.2 Cancer79.6
81.5 (CSS) 91.8
M
Survival (OS)82.0
Specific Survival
Overall 78.9
according 86.2
data a
to the Local Control
according to Local Control
p
0.85
0.91
0.69
0.71
0.79
0.46
0.047
other8
1.0
1.0
Concomitant CT
differe
0.8
Yes (%)
80.3
84.7
88.8 0.8 76.7
80.6
81.5
91.4
dalitieC
anal ca
a
No (%)
74.0
70.6
77.2
67.1
75.6
84.1
87.6
0.6
0.6
Mo
p
0.16
0.026
0.011
0.54
0.22
0.72
0.15
toricalR
0.4
0.4 –
LC
–
Local Cont
Control
as it is
Local Control
o
Yes (%)
89.5
96.1
90.9 no 96.1
no 94.7 0.2
0.2
least, c
yes
yes
B
No (%)
51.8
55.4
19.8
51.3
70.6
the exp
0.0
p
< 0.0001 < 0.00010.0
< 0.001 < 0.0001 < 0.0001 BRT pe
0
50
100
150
200
250
0
50
100
150
200
250
late evI
BRT dose
Time (months)
Time (months)
py cen
t
< 18 Gy (%)
88.8
91.4
92.5
68.2
88.5
88.0
94.9
ical res
B
(LC) and significant
of LC on some
endpoints
≥ 18 GyFig.
(%)1 8 Local control72.2
74.7 impact
81.5
69.7of the secondary
73.6
78.4 consid87.8
Inje
ered (all p < 0.001)
p
0.003
0.045
0.047
0.37
0.002
0.09
0.08
of 78.6
D
LC local control, OS overall survival, CSS cancer-specific survival, DFS disease-free survival, CFS colostomy-free the thr
survival,influenced
NRFS nodalby
relapse-free
survival,
MFS metastases-free
BRT Tournierbrachytherapy 87 %)e
58 survival,
monthsCT
ofchemotherapy,
follow-up), and
the number
of sources
used
5-year
LC
78.6
5-year
OS
80.9
5-year
5-year
CSS 0.8 DFS
85.7 0.6 69.4
LC rate
LC rate
0.8
OS rate
•  BT boost DT médiane 18Gy (10-­‐31.7) •  LDR (72%) / PDR (28%) Late toxicity
Grade 1–2
6
19
64
78
0
8
5
5-year
CFS
79.4
5-years
NRFS
82.1
CSS rate
•  N= 209 •  EBRT DT moyenne 45Gy (36-­‐56) Acute toxicity
Grade 1–2
Skin
102
Diarrhea
138
Anal
132
Rectal
39
Vulvar
15
Vaginal Original
12 article
Urinary
18
Lestrade L et al., Strahlenther Onkol 2014 Boost curie : Série du CLB study of Tournier-Rangeard et al., b
did not report the rate of colostom
two groups of boost technique d
1.0
1.0
(EBRT, 24 patients vs. BRT, 233 p
0.8
0.8
[11]. Chapet et al. reported a globa
late G3–G4 toxicity of 23.4 %, wit
0.6
0.6
221 patients (5.8 %) undergoing c
0.4
0.4
my because of treatment-related t
Brachytherapy Dose
Local Control
<18Gy
[10]. In the study of Papillon et al. [
no
> or = 18Gy
0.2
0.2
yes
G4 late complications were unco
with seven of 221 cases (3.1 %) of c
0.0
0.0
my. These authors underlined the
100
200
250
0
50
150
100
0
50
150
200
250
tance of strictly following the BRT
Time (months)
Time (months)
dure and, in particular, the import
ostomy Free Survival (CFS) according to
Colostomy
Overall Survival (OS) according to th
the
maintaining an intersource spacin
chytherapy dose (< 18 Gy vs > or = 18 Gy) Brachytherapy dose (< 18 Gy vs > or = 18
1 Gy)
Brachytherapy
er than 1.5 cm. These results are
1.0
1.0
to our rates of G3–G4 late toxicity
0.8
0.8
and toxicity-related colostomy (6/
tients, 2.8 %). The results of the p
0.6
0.6
lar subgroup of T3–T4 patients
0.4
0.4
also be discussed: Generally, T4 a
Brachytherapy Dose
Brachytherapy Dose
<18Gy
nal tumors are not considered goo
<18Gy
0.2
0.2
> or = 18Gy
> or = 18Gy
didates for BRT, because of the hi
of toxicity, as they usually requir
0.0
0.0
more needles. In our experience, w
0
50
100
150
200
250
0
50
100
150
200
250
ed five patients with T4 disease, th
Time (months)
Time (months)
ter a major response to RT-CT a
Fig. 2 8 Significant impact of the dose of brachytherapy on some
of the secondary
young patients
(522and
57 years o
Lestrade L eendpoints
t al., Sconsidtrahlenther Onkol 014 CSS rate
MFS rate
CFS rate
OS rate
e
Cancer Specific Survival (CSS) according
to Brachytherapy dose (< 18 Gy vs > or 18 Gy)
ered (all p ≤ 0.04)
Metastases Free Survival (MFS)
according to Local Control
Boost curie : Revue de la lieérature Tableau 1
Études sur la curiethérapie utilisée comme boost dans le traitement des cancers du canal anal.
Étude/Années de traitement
Nombre de
patients/total/
Curiethérapie
Radiothérapie
externe/
Chimioradiothérapie
concomitante
Suivi
médian
(mois)
Réponse
complète
évaluée à
l’issue de la
curiethérapie
(%)
Contrôle local
Survie sans
colostomie
Survie globale
Survie
spécifique
Survie sans
progression
Toxicité
Allal et al., 1993 [9]
1976–1989
125/108
65
71
65,5 % (5 ans)
77 % (5 ans)
61,5 % (5 ans)
31 % de
complications
tardives
252/218
58
93
70 % (5 ans)
Contrôle
locorégional :
65 % (5 ans)
–
68 % (5 ans)
Chapet et al., 2005 [10]
1980–1998
61,5 % (5 ans)
47 % (10 ans)
72,6 % (5 ans)
57,3 % (10 ans)
82,7 % (5 ans)
76,3 % (10 ans)
60 % (5 ans)
47 % (10 ans)
Grade 3 : 15,8 %
Grade 4 : 5,8 %
Tournier-Rangeard et al.,
2007 [11]
1976–2005
286/233
Radiothérapie
externe : 57
Chimioradiothérapie
concomitante : 68
Radiothérapie
externe : 84
Chimioradiothérapie
concomitante : 168
Radiothérapie
externe : 180
Chimioradiothérapie
concomitante : 106
65
–
80,8 % (5 et
10 ans)
Contrôle
locorégional
71 % (5 ans)
71 % (5 ans)
69,5 % (10 ans)
66,4 % à 5 ans
78,1 % (5 ans)
71,3 % (10 ans)
64,8 % (5 ans)
50,7 % (10 ans)
6,3 % de
colostomie ou
amputation
abdominopérinéale pour
toxicités de
grade 3–4
Lestrade et al., 2013 [13]
1992–2009
76/76
(> 70 ans)
70
–
75,8 % (5 ans)
75,8 % (5 ans)
82,8 % (5 ans)
Survie sans
métastase :
89 % (5 ans)
Grade 3 : 14,5 %
Grade 4 : 6,6 %
(chirurgie : 2)
Lestradea
1992–2009
(Lyon-CLB)
209/209
Radiothérapie
externe : 37
Chimioradiothérapie
concomitante : 39
Radiothérapie
externe : 58
Chimioradiothérapie
concomitante : 151
72,8
91,4
78,6 % (5 ans)
80,9 % (5 ans)
85,7 % (5 ans)
82,1 % (5 ans)
Aiguë grade 3 :
11,2 %
Tardive grades
3–4 : 6,3 %
a
79,4 % (5 ans)
Thèse de médecine 2012 ; soumis pour publication.
Pommier P et al. Cancer Radioth 2013 Boost RT vs BT : CORS-­‐03 714
I. J. Radiation Oncology d Biology d Physics
Volume 80, Number 3, 2011
Table 2. Treatment features
Treatment feature
Neoadjuvant chemotherapy
Yes
No
Concurrent chemotherapy
Yes
No
Field size
of EBRT first course
Small field*
Pelvic field
Pelvic field + inguinal nodes
Mean dose
of EBRT first
course (Gy) (minimum–maximum)
Mean boost
dose (Gy) (minimum–maximum)
Mean overall
treatment timey (days) (minimum–maximum)
Mean gap durationz (days) (minimum–maximum)
EBRT boost
n = 76 (%)
BCT boost
n = 86 (%)
p value
Whole population
n = 162 (%)
7 (9)
69 (91)
10 (12)
76 (88)
0.80
17 (10)
145 (90)
50 (66)
26 (34)
62 (72)
24 (28)
0.39
112 (69)
50 (31)
0.06
5 (7)
41 (54)
30 (39)
45.4 (39.5–50)
11 (13)
31 (36)
44 (51)
44.9 (40–50)
0.10
16 (10)
72 (44)
74 (46)
45.1 (39.5–50)
18.3 (8–25)
17.4 (10–25)
0.07
17.9 (8–25)
82 (45–143)
69 (37–128)
<0.001
75 (37–143)
39 (0–106)
30 (2–89)
0.02
36 (0–106)
Abbreviations: EBRT = external beam radiotherapy; BCT = brachytherapy.
* Small field = field encompassing only anal canal and perirectum.
y
Overall treatment time = time from first day of EBRT first course to last day of boost.
z
Gap = delay between last day of EBRT first course and first day of boost.
chemotherapy during the first treatment step. The regimen based on
Hannoun Levi JM, IJROBP 2011 36 days (range, 0–106).
According
to technical
considerations,
the
Boost RT vs BT : CORS-­‐03 716
I. J. Radiation Oncology d Biology d Physics
Volume 80, Number 3, 2011
Fig. 2. Overall survival for the whole population (A), regarding the overall treatment time < 80 days vs. $80 days (B),
according to the boost technique: brachytherapy (BCT) vs. external-beam radiotherapy (EBRT) (C).
for 4 patients (20%) in the EBRT group vs. 4 patients (57%)
and 3 patients (43%) in the BCT group (p = 0.005). The 5-
Hannoun Levi JM, IJROBP 2011 pects of the boost. To our knowledge, this analysis represents
the first study to explore the question of anal cancer boost
18
Boost RT vs BT : CORS-­‐03 I. J. Radiation Oncology d Biology d Physics
Volume 80, Number 3, 2011
Analyse mulDvariée : Technique Boost curie = seul F pronosDque sur la CFS…(négaDf sur le CLR) Toxicités??? P=0.03 P=0.21 Fig. 3. Cumulative rate of local recurrence for the whole population (A), regarding the boost technique: brachytherapy
(BCT) vs. external-beam radiotherapy (EBRT) (B), regarding the overall treatment time (<80 days vs. $80 days) (C),
and combining boost technique and overall treatment time (D).
Hannoun Levi JM, IJROBP 2011 Boost dose to primary tumour (PTV3)
4 cm). was
The applicator
and dose
distributionstients
are presented
The EQD2 for
external radiotherapy
calculated
using
had received external 3D conformal radiotherapy. In
EBT boost
n = 30 (51%)
in Fig. 2. HDR brachytherapy was carried out with fixed
EBT boost dose the linear quadratic
8.5 Gy (5.4–18)
model. The EQD2
forwithout
one 3D-based
1.8 Gy dose
frac-planning. two
of the
geometry
The number
of patients, chemoradiotherapy was preceded by
HDR boost
n = 29 (49%)
needles and the length of the loading were decided
accord- tumour excision; in one patient, the tumour
non-radical
HDR fraction size tion of EBT was
5 Gy1.72
n = 3 Gy. The mean EQD2 in patients treated
to palpation and proctoscopy. The number of needles
n = 26calculated toingbe
by EBT alone6 Gy
was
50.2 Gy (range 43–
was a circumferential T3 cancer. In the fourth patient, no
used and the length of the loading in each needle are preNumber of fractions
1–2 (1, n = 5; 2, n = 24)
60.5 Gy). The4–7
dose
was
the intumour
predisposing factors could be found. One patient needed
Table 2. site and at
Number of needles
(median
5) same at sented
Length loaded (cm)
4–7 (median
5) anal canal. In patients treated by
the opposite wall
of the
dilatation for anal stricture following radiotherapy. This paTotal treatment time (EBT); days
43 (31–79)
K. Saarilahti et al. / Radiotherapy and Oncology 87 (2008) 383–390
Chemotherapy
and HDR 27
the
total EQD2 was calculated
as the sum of
tient was
also treated by external 3D conformal radiotherTime from EBT to EBT
HDR; days
(12–41)
All patients were scheduled to receive concomitant
che-
Boost curie HDR 387
EQD2EBT and EQD2HDR. The total EQD2
at with
themitomycin
opposite
motherapy
(10 site
mg/m on days
1 and
29)aand
apy
for
circumferential T3 tumour.
fluorouracil (1 g/m2) on days 1–4 and days 29–32, given as
of the anal canal (DFR 0.2) was 44.8 Gy (range 44–45 Gy)
Grade 2–3 late skin toxicityTable
was3observed in 4 patients,
continuous infusion.
Acute radiation-related
adverse
and at the tumour site (DFR 0.8) 56.5 Gy (range 50.5–
all of who were treated by external
radiotherapy. One
pa- effects in patients treated by
IMRT cystitis.
and in patients treated by normal 3D CRT
58 Gy).
tient developed grade 3 radiation
of EQD2
the treatment-related
acute and late
It could be calculated thatScoring
the mean
to anal canal
Adverse effect
IMRT
3D CRT
P
toxicities
(N = 20)
(n = 39)
opposite to the tumour was significantly lower in patients
Loco-regional tumour control
Acute treated
treatment-related
toxicity (toxicity during the
treated by EBT + HDR than in patients
by EBT alone
After chemoradiotherapy, the
loco-regional tumour conDiarrhoea
treatment
andvariance).
up to three
months following the treatment)
(44.8 Gy vs. 50.2 Gy; P < 0.01,
analysis of
In con0
5
0.05
trol was assessed by clinical Grade
examination,
proctoscopy 7
scored
according
to the
RTOG acute radiation morbidity
trast, the mean EQD2 at thewas
tumour
site
was higher
in paGrade 1–2
22
NS
including biopsies from any suspicious
tissue and CT/MRI. 13
[8]Gy,
during
the treatment. The worst score for
Gradefollowing
3–4
12
0.004
tients treated by EBT + HDR scoring
(56.5 Gysystem
vs. 50.2
P < 0.01).
The loco-regional tumour control
chemoradio- 0
each patientproctitis
was reported.
For evaluation of the late morThe occurrence of radiation-induced
was registherapy of anal cancer between
1992mucosa
and 2003
has been
Perianal
and skin
bidity
(treatment-related
toxicity
>3 months after the end
tered during follow-up visits.
When
the probability of
P
published previously [20]. AfterGrade
2003,
1–2IMRT was adopted 4
7
NS
of the
treatment),
RTOG/EORTC
late radiation morbidgrade 2 radiation proctitis was
calculated
as a the
function
of
Grade 3–4
32
NS
as the standard external radiotherapy
for anal cancer at 16
ity scoring
used. The occurrence of late
total dose, a correlation between
EQD2scheme
at the [8]
analwas
canal
our institution. There is not enough
data
yet
to
calculate
Female genitalia
proctitis
andradiation
possible other
late adverse events were regisopposite to the tumour (DFR
0.2) and
proctitis
definitive local control or survivalGrade
statistics.
3–4 The preliminary 1(/15)
8(/23)
.04
tered during
every
visit. Only patients with a folwas observed (Fig. 3.). In contrast,
the EQD2
at follow-up
the tumour
data, however, have not shown any differences in tumour
low-up
time
of
at
least
12
months
without
salvage
Haematological
site (DFR 0.8) did not correlate with the occurrence of radicontrol following IMRT as compared to conventional 3D con(nadir/mean)
resection
were included in the analysis
ation proctitis. Patients that abdominoperineal
had received a boost
dose with
formal radiotherapy. Local control
was achieved in all 20 117
Haemoglobin
114
NS
reactions.
EBT (n = 19) were compared of
tolate
those
having received it by
patients treated by IMRT; duringWhite
the follow-up,
blood cells three local 2.78
3.4
NS
HDR brachytherapy (n = 20). Nine cases of grade P2 radiafailures were observed. In the Neutrophils
39 patients treated by 3D 1.69
1.44
NS
Follow-up
of7the
patients
tion proctitis (23% overall) were
observed,
in the
external
conformal radiotherapy, 3 primary
failures and seven local 158
Trombocytes
162
NS
After
the patients
were followed
up follow-up
radiotherapy group and two in
thechemoradiotherapy,
HDR group (loading
recurrences
during the
time were
Unplanned
gaps observed. The 2
19
0.004
in number
the Department
of 5Oncology
HelsinkiinUniversity
lengths 4 and 6 centimetres,
of needles
and 6, of the
treatment gap
difference
local control isCause
not of
statistically
significant
Hospital
at three-month
for the
first two
respectively). The differenceCentral
did not,
however,
reach sta- intervals
Diarrhoea
7
(P = 0.54,
log-rank
test). It must
be noted, however, that 0
years
and at
six-month
intervals
for
three
addiDermal
or
mucosal
eruption
1
7
tistical significance (P = 0.065,
Fisher’s
exact
test). No
rec- thereafter
the mean follow-up time in the patients treated by IMRT
3
tional years (until five years post-treatment).
In addition,
is 19 months
(range 3–38) and Haematological
81 months (range 32–124) 1
Infection
0
2
rectoscopy was performed 1–2 months
following
chemorain patients treated by conventional radiotherapy.
diotherapy
and
every
six months
thereafter
until five years
g. 2. (a) HDR applicator in place, (b) Isodoses (%), 4 needles loaded.
The rectal tube
drawn
schematically
(smaller circle),
(c) The respective
ase and total dose distribution after EBT by IMRT with HDR boost (above). Doses are expressed in grays.
post-treatment in the Department of Gastrointestinal Surused for comparing changes in blood cell counts. Thus, if
gery of the same hospital. Biopsies were performed on any
there had been any difference in blood counts following
suspicious tissue observed in rectoscopies.
chemotherapy, the role of the radiotherapy technique
Discussion
have been
to be the cause. In the number
The results of the present might
study suggest
thatspeculated
IMRT results
Statistical analysis
of
unplanned
gaps
due
to
acute
in Statistical
fewer acute
> grade 2 gastrointestinal (P = 0.004) and chemoradiotherapy-related
NCSS 2000 statistical software (NCSS
Software,
adverse
effects,
significant
dermal
reactions
in the female
genital
area (Pa= 0.04)
due difference was observed
Kaysville, UT, USA) was used for statistical calculations.
(P = .004)
to the benefit
of IMRT group. The comparison of
to
chemoradiotherapy
compared
to
conventional
3D
confor2
Frequency tables were analyzed using either v or Fisher’s
acute toxicity
presented
in Table 3.
mal radiotherapy.
Patients treated
by IMRT is
had
significantly
exact test. For analysis of haematological
toxicity, onefewer
unplanned
gaps during the radiotherapy course
way ANOVA was used. All P values are
two-tailed.
ComparTreatment-related late toxicity
= 0.004).
isons of local control and survival (P
rates
between groups
In
order
to compare
thetreatotal doses received by patients
The
EQD2
at
the
tumour
site
was
higher
in patients
were done using the log-rank test.
treated
by EBT
thoseretreated by EBT combined with
ted by combined HDR and IMRT.
In only
contrast,
thetodose
HDR, of
the the
biologically
effective
ceived by the opposite wall
anal canal
was doses (BED) were calculated.
Since intreatment
HDR brachytherapy
the dose given to normal tissues
significantly lower in the combined
group. Radio2
1X6Gy ou 2X5Gy ProcRRs G2+ 7 (Boost BT) vs 2 (boost RT) (p= 0.065) SaarhilaD Radiother Oncol 2008 ACT I (UKCCCR) : Mind the Gap! •  ACT I, Phase III •  N=577 •  Boost EBRT (15Gy) •  Boost Ir192 (25Gy) •  Effets du boost •  Effets du Gap Morbidité / Tox tardive Ulcères / Radionécroses Boost vs no boost : 0 vs 8% (p= 0.03) EBRT vs BT : 6% vs 14% (p= 0.003) Glynne Jones R, IJROBP 2011 ment as per protocol, the median OTT was 2.9 months
(range, 1.2–6.2 months).
There was no significant difference in the OTT between
the two treatment arms but, as anticipated, patients who
received the 40 Gy/20 fraction regimen had a shorter OTT
than the two primary schedules by approximately 25 days
(Table 4). Table 2 indicates no association between OTT
and any outcome. Figure 1B suggests those patients, in
both RT alone and CMT groups, where OTT was less than
2 months had a lower risk of locoregional relapse than other
patients. This effect persists after adjusting for baseline
than 2 months is small (n = 38).
Late/persistent morbidity
Among good responders, there were no reports of late ulcers/radionecrosis in those patients who were not boosted,
whereas the boosted reported 8% morbidity (p = 0.03). Furthermore, there were more reports of ulcers/radionecrosis for
the subgroup who received boost by implant (14%) compared with the EBRT boost subgroup (6%; p = 0.003). There
was no consistent pattern to the late morbidity other than the
incidence of necrosis/bleeding after implantation.
ACT I : Boost RT vs BT Table 3. Hazard ratios (99% CI) for treatment effect,* by boost type, amongst good responders
Boost type
n
Iridium implant
(p value)
External beam
(p value)
Interaction: boost !
treatment p value
135
289
424
Time to first
locoregional relapsey
Anal cancer
deaths
Overall survival
Relapse-free survival
Non-anal cancer deaths
0.23 (0.09–0.59)
(<0.001)
0.52 (0.32–0.83)
<0.001
0.05
0.41 (0.17–0.97)
0.008
0.78 (0.47–1.32)
0.23
0.10
0.54 (0.30–0.96)
0.006
0.92 (0.64–1.33)
0.56
0.06
0.50 (0.29–0.87)
0.001
0.71 (0.50–1.00)
0.010
0.21
0.69 (0.31–1.54)
0.24
1.09 (0.64–1.84)
0.69
0.26
* Expressed as combined modality treatment vs. radiotherapy alone.
Time to first local relapse analyses are based on 134 iridium implant patients and 289 external beam patients.
y
Glynne Jones IJROBP 2011 ACT II
? Cisplatin better than MMC
? Maintenance therapy beneficial
ACT II - Radiotherapy
•  50.4 Gy in 28 fractions in total (1.8Gy/#)
•  2 phase treatment – no gaps *
* Constantinous et al, 1997: Trend towards improved 5 year survival
when treatment completed within 40 days (86% vs 60%, p=0.14).
ACT II – Phase 1
•  Large ant/post POP
–  include all macroscopic disease
–  include both inguino-femoral regions
•  Prone
•  3060 cGy in 17 fractions
–  Hu et al, 1999: 30-34Gy vs 50.4Gy for presumed microscopic
residual disease following excision biopsy; no difference in
local control.
–  Newman et al, 1992: 62 pts with no clinical or radiological
evidence of groin nodes – only 5 relapsed at this site – all
salvaged by groin dissection
ACT II – Phase 2
• 
• 
• 
• 
Planned simultaneously with phase 1.
Simulator or CT planning.
1980 cGy in 11# (1.8Gy/#).
All visible tumour marked using radioopaque marker (with rectal contrast in
orthogonal films).
•  3 or 4 field plan.
ACT II – Phase 2
RTOG 98-11 : Volumes de RT
N0
N+
T3T4 ou T2
avec résidu à
45 Gy
PTV 2.5 cm
margin
Ajani J et al. JAMA200
ACCORD 03
T2>4cm ou T3-4, N0-3,
u T1 ou T2< 4 cm et N1-3
ou USN1
u 
Peiffert et al., ESTRO
2008
A
FUP
FUP
5FU 800 mg/m² à J1-4
FUP
FUP
Pelvic irr 45 Gy
Boost
15 Gy
CDDP 80 mg/m² à J1
R
A
B
FUP
FUP
FUP
FUP
Pelvic irr 45 Gy
N
Boost
20-25 Gy
D
O
M
C
FUP
FUP
Pelvic irr 45 Gy
D
FUP
FUP
Pelvic irr 45 Gy
Boost
15 Gy
Boost
20-25 Gy
ACCORD 03
Analyse Définitive
•  307 patients
•  T1T2 (22%)
•  T > 4 cm (52%)
•  Fin des inclusions = March 2005
•  Date de point = 01 / 01 / 2008
•  Analyse en intention de traiter:
–  AB Vs CD = impact de chimio d’induction
–  AC Vs BD = impact de la dose du boost
ACCORD 03
CT Induction Vs sans Induction
Colostomy
free survival AB
Survie
sans colostomie
ABvs
VsCDCD
100
90
80
70
60
AB
50
CD
40
30
20
10
0
0
12
24
36
Mois
48
60
ACCORD 03
Complément 15 Gy Vs 20-25 Gy
Survie
sans colostomie
AC Vs BDAC versus BD
Colostomy
free survival
100
90
80
70
60
50
40
30
20
10
0
AC
BD
0
12
24
36
mois
48
60
ACCORD 03
Résultats Actuariels à 3 ans (%)
A
B
C
D
S. sans Colostomie
83
85
86
80
Controle Local
80
96
90
87
S. Sans Evénement
70
78
67
68
S. Spécifique
79
88.5
89
79
Assessment of genital
tract inAvailable
females online
for at www.sciencedirect.com
CIN/VIN
Assessment by
geriatrician
Until the mid-1980s radical surgery was the corn
of treatment. However, following publications fr
ScienceDirect
CIN, cervical intraepithelial neoplasia; VIN, vulval intraepithelial
1970s on combined modality therapy, surgery as
neoplasia.
mary therapeutic option has generally been abando
EJSO 40 (2014) 1165e1176
www.ejso.com
Still today, smaller lesions (<2 cm in dia
Combinations of 5-Fluorouracil (5FU)-based CRT and
involving the anal margin and not poorly differe
Review
other cytotoxic agents
(mainly mitomycin C [MMC])
may be treated by primary surgery in the form of
have been
established as the standard
of care,
leading to
Anal cancer:
ESMO-ESSO-ESTRO
clinical
practice
excision provided adequate margins (>5 mm) can
*
complete
regression
in 80%e90%
of patients,
guidelines
for tumour
diagnosis,
treatment
and follow-up
tained without compromising sphincter function [
with locoregional failures of about 15%. A multidisciLocal excision has not been shown to be efficaci
a
b
c
R. Glynne-Jones
, P.J. Nilsson
, C. Aschele
, V. Goh dradiation
,
plinary approach
is mandatory,
involving
small tumours in the anal canal and is contra-in
D. Peiffert e, A. Cervantes f, D. Arnold g,*
Although more extensive and poorly differentiated
a
Table
4 Treatment, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom
Centre for
Cancer
b
have a greater risk of being lymph node positiv
Department
of Molecular
Medicine treatment.
and Surgery, Karolinska Instituet and Center for Surgical
Stage
and site-based
Gastroenterology, Karolinska University Hospital, Stockholm, Sweden
important to do proper clinical and radiological
c
Medical
Oncology and Hematology, Felettino Hospital, La Spezia, Italy
Anal
canal
d
also of smaller lesions in order to rule out the pres
Division of Imaging Sciences & Biomedical Engineering, King’s College London, London, United Kingdom
e
Surgery (radical
or local
generally
contraindicated
Radiotherapy
Department,
Centre excision)
Alexis Vautrin,
Vandoeuvre-l!
es-Nancy, France as primary
positive nodes as this
a contra indication
to loc4
f
1172of Valencia, Valencia, Spain
R. is
Glynne-Jones
et al. / EJSO
Department treatment
of Hematology
and Medical Oncology, INCLIVA, University
option
g
sion. Piece-meal resections render assessment of re
Klinik f€ur Tumorbiologie, Freiburg, Germany
STAGE l:
-standard
dose
radiotherapy
(RT),
infused
margins in the specimen impossible and should
Accepted 8 July 2014
5FUonline
and mitomycin
(stage group
Available
- - fractionation
schedule.
Curative
performed.brachytherapy as a single
under-represented in randomised studies)
In case
inadequate
margins or as
R1-resection
-low dose RT, infused
FU and mitomycin
d
modality
is not recommended,
butofmay
be applicable
a
(no data from randomised studies)
after a resection or
of volume
“anal tags” or “h
m
following
response sometimes
to CRT. Double-plane,
ll - lllis a rare cancer
-standard
RT,boost
FU
and
arcinoma of theSTAGE
anus (SCCA)
but its dose
incidence
isinfused
increasing
throughout
the world, and is particularly
rhoids”)
a
further
local
excision
may
be
considere
mmunodeficiency virus positive (HIVþ) mitomycin
population. A(evidence
multidisciplinary
approach
is mandatory
(involving radiation
from multiple
w
implants
may
be necessary,
depending
on the extent of the
adequate
staging and clinical assessment provid
oncologists, surgeons, radiologists and pathologists).
usually spreads in a loco-regional manner within
and
randomisedSCCA
studies)
al. Lymph node
involvement
is observed
in 30%e40%
of casesbut
whilerisk
systemic
spreadnecrosis
is uncommon and radiation proctitis. Comm
tumour,
late
STAGE
lV at diagnosis-5-FU
and cisplatin,
carboplatin/taxol,
resection
can be achieved. However, it is recomm
lvic metastases recorded in 5%e8% at onset,
and
rates
of
metastatic
progression
after
primary
treatment
between
or possibly irinotecan/cetuximab
that
all
undergone
a local resection, th
ir
puterised
3-dimensional
image-based
treatment
planning,
is strongly associated with human papilloma virus (HPV, types
16e18) infection.
The primary aim of treatment
is patients having
loco-regional Anal
controlmargin
and preservation of anal function, with the best possible quality of life. Treatment dramatically
tivedistribution.
of resection margin, should be discussed by an
m
should and
allow
optimal
dose
rcinomas of the lower rectum. Combinations of 5FU-based chemoradiation
other cytotoxic
agents (mitomycin
C)
priate
multidisciplinary
team
(MDT)
to
facilitate
de
STAGE
l,
well
-Local
excision
(re-excision
or
chemoradiation
d as the standard of care, leading to complete tumour regression in 80%e90% of patients with locoregional failures in
b
if involved/close
differentiated:
There is an accepted
role for surgical salvage.
Assessment andmargins)
treatment should be carried out in specialisedregarding
centres
re-excision or definitive CRT.
er of patients as
early asll-lll
possible in the clinical
diagnosis.
date,
the limited
from only 6 randomised trials
STAGE
-standard
dose To
RT,
infused
5FUevidence
and mitomycin
w
Until the introduction of definitive CRT, abdomi
Treatment
of thesiteelderly
arity of the cancer,
and the
history depending
on the predominant
of origin, (the anal
STAGE
lV different behaviour/natural
-5-FU and cisplatin,
or carboplatin/taxol
r above the dentate line) provide scanty direction for any individual oncologist. Here we aim to provide guidelines
neal excision (APE) was recommended for al
dical, radiation and surgical oncologists in the practical management of this unusual cancer.
. All rights reserved.
R