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Treatment intensification by induction chemotherapy (ICT) and radiation dose escalation
in locally advanced squamous cell anal canal carcinoma (LAAC): definitive analysis of the Intergroup ACCORD 03 trial.
Abstract
#4033
T. Conroy(1), M. Ducreux (2), C.Lemanski (3), E. François (4), M. Giovannini (5), F. Cvitkovic (6), X. Mirabel (7), O. Bouché (8), C. Montoto-Grillot (9), D. Peiffert (1)
Institut Gustave Roussy – Villejuif ; (3) Centre Val d’Aurelle-Paul Lamarque – Montpellier; (4) Centre Antoine Lacassagne – Nice; (5) Institut Paoli-Calmettes – Marseille; (6) Centre René Huguenin – Saint-Cloud;
(7)
Centre Oscar Lambret – Lille; (8) Hôpital Robert Debré – Reims; (9) Fédération Nationale des Centres de Luttre Contre le Cancer – Paris
France
Intergroup trial : FNCLCC: Fédération Nationale des Centres de Lutte Contre le Cancer, SFRO : Société Française de Radiothérapie Oncologique, FFCD : Fédération Francophone de Cancérologie Digestive
(1) Centre Alexis Vautrin – Nancy;
Backgroun
d
(2)
Trial design : 4 arms study
Patients with larger tumors or clinical N+ locally advanced anal canal carcinoma
cancer have poor local control and higher colostomy rates.
Local relapse remains the first cause of failure.
Pelvic irradiation with concomitant 5-FU and Mitomycin C chemotherapy and
radiation boost is the standard treatment.
Bartelink H et al: J Clin Oncol 1997;5:2040-9
UKCCCR : Lancet 1996;348:1049-54
A 5-FU/Cisplatin regimen delivered as induction and concomitant treatment was
tested in a Phase II trial and achieved promising results :
Perspectives
RT: 45 Gy over 5 weeks
after completion RT-CT :
98%
FUP: 5-FU-Cisplatin
3-year survival
„
Colostomy-free : 73%
„
Relapse-free
„
Tumour-specific : 88%
Actuarial 3-year results (%)
Arm C is the reference
arm
after induction CT : 61%
„
„
Acute toxicity (number gr. 3-4 toxicities) during
induction (ind) and concomitant treatment (cc)
Status of
cases
Local response
„
Concomitant chemoradiotherapy:
delivered vs planned dose of 5-FU
307 patients were enrolled between January 1999 and March 2005
Previous phase II
Study
„
Results
Eligibility
: 70%
Patients’
characteristics
No grade 3-4 bleeding or neurological toxicities
occurred
ƒ Analysis of quality of life data
ƒ Exploratory analysis of colostomy-free
survival per arm
One toxic death occurred in each arm
• Anal canal primary :
Peiffert D et al: Ann Oncol 2001; 12:
397-404
Rationale for the experimental arms :
downstaging
Induction
chemotherapy
Concurrent
chemo and RT
Size after
chemotherapy
Original size
Local boost
Higher dose
Size before
boost
•
•
Follow-up
–
> 50% of T. volume inside the canal
–
Squamous cell carcinoma histologically proven
–
Adequate organ function
B
Primary end
point
Locally advanced clinical stage M0 :
–
T. diameter > 4 cm (T2-4), any N, or
–
T. diameter < 4 cm (T1-2) and N1-3 or usN1
Hb > 11g/dL
–
Neutrophils > 2,000 /µL
–
Platelets > 100,000 /µL
–
Creatinine < 130 µmol/L
Pelvic radiotherapy
•
Age 18 – 80 years and performance status of 0-1
•
Written informed consent
D
%
Log rank:
ns
Conclusions
• This trial analyzed according to the 2 X 2 factorial design, did not detect
any significant benefit of induction chemotherapy with 5-FU and cisplatin
at these doses nor of a radiation dose over 60 Gy on colostomy-free
survival
Treatment delivery
- higher local control
- better functional results
A
Colostomy-free survival :
role of induction chemotherapy
Biology :
–
C
• Oncologic and functional results are good in all the 4 groups
Treatment
Objective
s
•
•
• Results were better than expected in the reference arm C:
77% colostomy-free survival at 3 years
• Full dose of 5-FU during concomitant chemoradiation was not delivered
in 19.3% of the cycles in the induction chemotherapy group vs 9% of the
cycles
in the upfront chemoradiation group
To define the role of induction chemotherapy before definitive chemoradiation
To define the role of higher dose of radiation delivered as a boost after pelvic CRT
Treatment arms (chemotherapy details)
• Radiotherapy doses were delivered respecting the prescribed doses in the
4 arms
Arms A and B: induction chemotherapy then chemoradiation
Induction and concomitant chemotherapy at W1, W5, W9 and W12
Primary end point
•
Colostomy–free survival at 3
years
Secondary end point
•
Disease-free survival
•
Overall survival
•
Cumulative colostomy rate
•
Local-regional failure rate
•
Specific survival
•
Quality of life (EORTC QLQ–
C30)
• All treatments were well tolerated
– 5-FU 800 mg/m2/d continuous infusion on D1 to D4
• Further analysis will be performed to identify a subgroup of patients who
may benefit from the intensification
– Cisplatin 80 mg/m2 at D1
Pelvic irradiation was initiated with chemo starting on W9.
Arms C and D: upfront chemoradiation:
Boost irradiation : techniques and doses
Concomitant chemotherapy at W1 and W5
Colostomy-free survival :
role of higher dose of the boost
# 281 patients
– 5-FU 800 mg/m2/d continuous infusion D1 to D4
– Cisplatin 80 mg/m2 at D1
Pelvic irradiation was initiated on W1 at D1
Acknowledgments :
Treatment arms (radiotherapy details)
1. Large pelvic field with superior border at L5/S1 junction
• Box technique or 3-field technique
• Inguinal fields when indicated
• 45 Gy in 25 fractions of 1.80 Gy / 5 W
The patients and their families
%
Mireille Hirsch, Elisabeth Luporsi, Monique Maire
Log rank:
p:0.067
Induction chemotherapy:
delivered vs planned dose of
5-FU
2. Short gap 8 – 21 days
3. Reduction for boost irradiation
Hypothesis, sample size and statistics
Arms A and C: 15 Gy
Arms B and D: 20-25 Gy
All investigators
Pr Peiffert, Pr Conroy, Dr Kaminsky, Dr Tournier-Rangeard -Centre Alexis Vautrin Nancy; Pr Gérard, Pr Mornex, Dr Romestaing, Dr
Chapet, Dr Ardiet - Centre Hospitalier de Lyon-Sud Lyon; Pr Ducreux, Dr Lusinchi, Dr Villing, Dr Deutsch, Dr Malka, Dr Boige Institut Gustave Roussy Villejuif; Dr François, Dr Hannoun-Lévy, Dr Thomas - Centre Antoine Lacassagne Nice; Dr Lemanski, Dr
Senesse, Dr Jacquot, Dr Azria - Centre Val d'Aurelle Montpellier; Dr Giovannini, Pr Seitz, Dr Magnin, Dr Viret - Institut PaoliCalmettes Marseille; Pr Adenis, Dr Mirabel - Centre Oscar Lambret Lille; Dr Martel, Dr Carrie, Dr Desseigne, Dr Montbarbon - Centre
Léon Bérard Lyon; Pr Hennequin, Dr Bleichner-Hennequin - Hôpital Saint-Louis Paris; Dr Etienne, Dr Lamezec - Clinique
Armoricaine Saint-Brieuc; Dr Ollivier, Dr Jacob, Dr Vie - Centre François Baclesse Caen ;Pr Guimbaud, Pr Bugat, Dr Delors, Dr
Rives - Institut Claudius Regaud Toulouse; Dr Goineau, Dr Atlani, Dr Denis - Hôpital Pasteur Colmar; Pr Mahé - Centre René
Gauducheau Nantes; Pr Bouché - CHU Robert Debré Reims; Dr Sobhani, Dr Aparicio - Hôpital Bichat Paris; Dr Cvitkovic - Centre
René Huguenin Saint-Cloud; Dr Paillot, Pr Michel - CHU Charles Nicolle Rouen; Dr Seng, Dr Hamidou - Centre Henri Becquerel
Rouen; Pr Piedbois, Dr Sobhani - CHU Henri Mondor Créteil; Dr Zawadi - Centre Hospitalier Départemental La Roche-sur-Yon; Dr
Leloup - Hôpital La Source Orléans; Pr Seitz, Dr Paoli - CHU La Timone Marseille; Pr Rixe, Dr Pourel-Hôpital Claude Bernard Metz;
Dr Huchet, Dr Laporte - Hôpital Georges Pompidou Paris; Dr Nasca - Institut Jean Godinot Reims; Dr Noirclerc - Centre Hospitalier
du Hasenrein Mulhouse; Pr Raoul - Centre Eugène Marquis Rennes; Dr Borel - Centre Paul Strauss Strasbourg; Dr Platini - Hôpital
Bon-Secours Metz; Dr Saidi - Hôpital Clarac Fort-de-France; Dr Albin - Clinique Pasteur Evreux; Dr Soulié - Centre Paul Papin
Angers; Dr Cailleux - Clinique Fleming Tours.
• Brachytherapy LDR delivered on reference isodose
•
Hypothesis: induction chemotherapy or a higher dose of RT would increase
colostomy-free survival from 70% to 85%
• External beam irradiation: 1.8 to 2.0 Gy per fraction
•
Number of pts= 288: assumed a constant accrual rate of 60 patients per year, a 5year duration of inclusion inclusion was expected
•
2 x 2 factorial design
•
Data were analyzed according to intention to treat
0
6
This study was supported by grants from the
Ligue Nationale Contre le Cancer and Clinical
Research Program (PHRC 1997) from the
French Ministry of Health
© Centre Alexis Vautrin – mai 2009
• alpha= 5%, beta= 10%, unilateral test