Dépistage des cancers ovariens

TUMEURS RARES DE L’OVAIRE
et
Emergence de réseaux pour la prise
en charge de tumeurs rares
gynécologiques
Isabelle Ray-Coquard,
Centre Léon Bérard
Vendredi 23 Mars 2012 Paris
Isabelle Ray-Coquard - 2011
Conflicts of interest 2011
• honoraria : Novartis, Sanofi, Roche, Pharmamar, Amgen, GSK,
Vifor, Ratiopharma, J&J, Jansen, Schering
• Advisory board :Novartis, Sanofi, Roche, Pharmamar, Amgen,
GSK, J&J, Jansen, Schering, Merck, MSD
• Consultant : Roche, Novartis, Pharmamar, Bipar, Sanofi,
Millenium, Jansen, Vifor, Amgen, J&J, Pfizer
• Research grant : Novartis, Merck, Millenium, Borinhger, MSD,
Pfizer, Roche,
Isabelle Ray-Coquard - 2012
Incidence & prevalence by sites
Table 3. Incidence and prevalence of rare and common cancers by site in EU27
Incidence
rate per
100,000
Common
Rare
All
Common
Rare
All
Common
Rare
All
Common
Rare
All
Common
Rare
All
Common
Rare
All
Common
Rare
All
Common
Rare
All
Common
Rare
All
Digestive tract
Digestive tract
Digestive tract
Respiratory tract
Respiratory tract
Respiratory tract
Skin
Skin
Skin
Breast
Breast
Breast
Female genital tract
Female genital tract
Female genital tract
Male genital tract
Male genital tract
Male genital tract
Urinary system
Urinary system
Urinary system
Haematopoietic system
Haematopoietic system
Haematopoietic system
All sites
All sites
All sites
76,1
17,2
114,1
31,6
13,6
64,1
61,3
1,5
63,7
47,7
4,9
64,3
9,6
16,1
29,5
40,6
4,3
52,0
25,9
2,5
33,1
11,1
9,6
21,9
309,6
97,1
503,6
Standard
error
0,1
0,1
0,1
0,1
0,0
0,1
0,1
0,0
0,1
0,1
0,0
0,1
0,0
0,0
0,1
0,1
0,0
0,1
0,1
0,0
0,1
0,0
0,0
0,1
0,2
0,1
0,3
Estimated Incidence Prevalence per
incident
distribution
100,000
cases in
(%)
EU27
380 565
67
400,3
86 143
15
50,0
570 236
100
474,6
157 903
49
56,2
68 125
21
60,2
320 391
100
130,0
306 427
96
744,6
7 487
2
14,8
318 615
100
779,7
238 471
74
522,6
24 415
8
56,9
321 429
100
700,1
47 779
32
126,7
80 669
55
176,2
147 597
100
331,7
203 224
78
279,5
21 673
8
93,0
259 868
100
399,6
129 253
78
202,2
12 693
8
18,5
165 457
100
238,7
55 273
50
59,0
48 077
44
62,5
109 721
100
123,9
1 548 036
61
2428,2
485 697
19
797,3
2 518 108
100
3565,4
Standard
error
1,2
0,4
1,4
0,3
0,4
0,6
1,5
0,3
1,5
4,1
0,7
6,3
0,6
0,8
1,1
1,4
0,8
1,6
0,7
0,4
0,8
0,5
0,5
0,7
4,9
2,0
7,2
Estimated Prevalence
prevalent distribution
cases in
(%)
EU27
2 001 514
84
250 005
11
2 373 151
100
280 918
43
300 876
46
649 911
100
3 722 876
95
74 116
2
3 898 655
100
2 612 913
75
284 484
8
3 500 252
100
633 546
38
881 107
53
1 658 589
100
1 397 655
70
465 225
23
1 997 975
100
1 011 037
85
92 689
8
1 193 504
100
295 022
48
312 462
50
619 550
100
12 141 163
68
3 986 679
22
17 826 767
100
Isabelle Ray-Coquard - 2012
Incidence & survival rates by subgroups
Table A. Incidence, survival and prevalence of cancers in EU27
CATEGORY AND SUBCATEGORIES
EPITHELIAL TUMOURS OF CORPUS UTERI
Adenocarcinoma and variants of corpus uteri
Squamous cell carcinoma and variants of corpus
uteri
Adenoid cystic carcinoma of corpus uteri
Transitional cell carcinoma of corpus uteri
EPITHELIAL TUMOURS OF CERVIX UTERI
Squamous cell carcinoma and variants of cervix
uteri
Adenocarcinoma and variants of cervix uteri
Undifferentiated carcinoma of cervix uteri
MIXED EPITHELIAL AND MESENCHYMAL
TUMOURS OF UTERUS
EPITHELIAL TUMOURS OF OVARY AND
FALLOPIAN TUBE
Adenocarcinoma and variants of ovary
Mucinous adenocarcinoma of ovary
Clear cell adenocarcinoma of ovary
Adenocarcinoma and variants of fallopian tube
NON EPITHELIAL TUMOURS OF OVARY
Mixed epithelial mesenchymal tumors of ovary
Sex cord tumours of ovary
Malignant immature teratomas of ovary
Germ cell tumours of ovary
EPITHELIAL TUMOURS OF VULVA &
VAGINA
Squamous cell carcinoma and variants of vulva
and vagina
Adenocarcinoma and variants of vulva and
vagina
Paget disease of vulva and vagina
Undifferentiated carcinoma of vulva and vagina
Incidence
rate
New
cases
Observed
5-yr survival
Relative
5-yr
survival
Complete
prevalence
Prevalent
Cases
10,42
52 102
69,5
79,5
133,11
665 573
9,54
47 721
71,7
81,3
126,65
633 271
0,12
583
46,1
53,4
0,95
4 745
0,00
7
70,0
74,5
0,29
1 453
0,00
1
0,0
0,0
0,01
31
6,07
30 373
61,9
66,6
106,46
532 319
4,28
21 398
62,8
67,3
76,24
381 213
1,01
5 055
62,2
66,7
15,59
77 945
0,03
125
30,0
34,1
0,32
1 597
0,45
2 228
31,6
37,4
2,59
12 954
9,41
47 036
33,0
37,7
59,78
298 918
5,97
29 849
33,1
37,0
39,13
195 664
0,84
4 225
52,4
58,0
9,56
47 779
0,32
1 617
49,9
53,9
2,55
12 756
0,27
1 337
42,6
47,8
1,98
9 917
0,43
2 166
57,8
62,5
6,69
33 457
0,16
783
15,9
18,2
0,49
2 474
0,13
671
76,1
82,7
1,85
9 271
0,07
338
80,4
83,2
1,50
7 519
0,07
374
83,7
84,5
2,24
11 185
1,91
9 571
47,0
60,9
15,34
76 689
1,50
7 514
46,4
59,6
12,42
62 107
0,08
388
35,3
42,9
0,52
2 623
0,05
255
78,0
98,0
0,47
2 350
0,01
40
26,3
31,5
0,05
236
0,02
118
89,6
90,0
0,86
4 297
0,02
118
89,6
90,0
0,78
3 906
TROPHOBLASTIC TUMOURS OF PLACENTA
Choriocarcinoma of placenta
* ICD-O3 code not available
Isabelle Ray-Coquard - 2012
Rare ovarian cancer
Germ cell tumors
Sex cords stromal tumors
But also:

borderline (serous, mucinous, papillary)

Epithelial: mucinous & clear cell

Sarcoma (angiosarcoma, leiomyosarcoma, SSE, fibrosarcoma)

carcinosarcoma

Small cell carcinoma (< 0,5%)

Metastasis from carcinoma (uterus, breast, colon, Krukenberg)

NHL & leukemia
Germ cell tumors (1)
 Specificities : curable with chemotherapy
 Similar results than testicular lesion =
similar disease?
 Abnormalities of isochromosome 12 [i(12p)]
 Rapid development
 Chemotherapy efficient allow conservative
surgery
LES TUMEURS GERMINALES (2)
 Différents groupes histologiques :
 Les dysgerminomes (45%).
 Les tumeurs non dysgerminomateuses:
– les tumeurs du sac endodermiques (20%)
– les tératomes (grade de maturité) (20%)
– les carcinomes embryonnaires purs (5%)
– les choriocarcinomes purs rares (<5%)
– les tumeurs composites (10%).
LES TUMEURS GERMINALES (3)
 Les marqueurs tumoraux :
Type de tumeur
FP
hCG
LDH
Dysgerminome
-

+
Tumeur sinus endodermique
+
-

Tératome immature

-
-
Carcinome embryonnaire
+
+

Choriocarcinome
-
+

Tumeur mixte



Bonne spécificité mais sensibilité médiocre
Doivent toujours être dosés avant chirurgie d’une masse pelvienne chez
une patiente jeune.
Autres marqueurs:
CA 125, CA 19-9, NSE, Angiotensine, MCSF
LES TUMEURS GERMINALES (4)
facteurs pronostiques
Les facteurs décrits
– la taille tumorale > 10 cm
– le type histologique:sinus endodermique, choriocarcinome
– le grade histologique (tératomes immatures)
– l ’âge > 22 ans
– le PS
– Le stade élevé, et la rupture tumorale
taux de survie à 5 ans <30%
CARE PROCESS RATIONAL
 Rare ovarian
followed:
tumour
treatment
is
established
as
– Surgery is conformed to the ovarian carcinoma
surgery with possibility of conservative approach
– Chemotherapy supported by the evidence based
on testicular germ cell tumors.
– Surgery, chemotherapy and a eventual second look
surgery are strongly interlinked.
 The surgical act, which remains essential can rely on the
chemotherapy efficiency and had to salvage the
reproductive function
LES TUMEURS GERMINALES (5)
chirurgie
• Conservatrice l’immense majorité des cas
• 3 objectifs :
- thérapeutique (ablation de la tumeur)
- diagnostique (histologie)
- détermination du stade d’extension
• Femme jeune + marqueurs non dosés (contexte d’urgence) +
examen extemporané impossible: annexectomie unilatérale
(ré intervention rapide si adénocarcinome)
==> évite des chirurgies mutilantes inutiles si T germinale.
LES TUMEURS GERMINALES (6)
chirurgie
• Au minimum :
– annexectomie unilatérale
– exploration complète (pelvis + toute la cavité abdominale)
– lavage péritonéal et/ou prélèvement de toute ascite
– biopsies péritonéales multiples systématiques
(y compris au niveau de l’épiploon)
– prélèvement de tout élément suspect
• Pas de consensus sur 3 points :
ganglions, ovaire controlatéral, réduction tumorale.
LES TUMEURS GERMINALES (7)
Prise en charge initiale chimio?
 Chimiothérapie
à
base
de
platine
(Williams
1987)
plus
particulièrement depuis 1987 3 ou 4 cycles BEP (Gershenson 1990)
 Selon les stades tumoraux/résidus post op:
– stades II et III : 3 ou 4 cycles de BEP (résidu tumoral)
– stades IV: 4 cycles de BEP
– stades I (70%): * dysgerminome pur Ia et Ib
* tératomes immatures Ia Ib de grade 1
pas de traitement complémentaire ap Xie
tous les autres chimiothérapie ?
 Radiothérapie adjuvante: a priori plus d’indication
GERM CELL TUMOURS
post therapeutic follow-up:
 INTENSIVE (every 2 months the first year)
– Clinical
– Biologic
– CT scans
– Measure of the toxicities due to the chemotherapy
– Assessment of the fertility potential
GERM CELL TUMOURS
Care process of the relapse
 Relapse after treatment without CT:
– Chemotherapy through platinium salts
– +/- supplementary surgical act.
 Additional treatment after CT failure:
– Debulking surgery yes if teratomas
– chemotherapy: protocole depending on the sensibility to
platinium (6 months)
– HD
chemotherapies
(therapeutic
trials
or
individualy
decision)
– VP 16 oral; VAC; ifosfamide, phase I, targeted th? ….
LES TUMEURS DE CORDONS SEXUELS ET DU
STROMA
 Tumeurs stromales ovariennes
– tumeurs de la granulosa (90%)
 forme adulte
 forme juvénile
– tumeurs du groupe fibro-thécome (1- 4 %)
 Les tumeurs stromales de Sertoli et Leydig (2%)
(androblastomes)
 Les tumeurs des cordons sexuels avec tubules
annelés (<1%)
 Gynandroblastomes (<1%)
 Les tumeurs à cellules stéroïdiennes (<1%)
LES TUMEURS DE CORDONS SEXUELS
ET DU STROMA
 7% de tumeurs ovariennes
 La plupart sont fonctionnelles : synthèse de
progestérone, oestrogènes, androgènes,
corticostéroïdes
 Problématique particulière
– diagnostic différentiel?
– critères histologiques de malignité?
– Chirurgie conservatrice ?
– pronostic? Indication de traitement adjuvant?
Mutation of FOXL2 in Granulosa-Cell Tumors of the ovary.
Sohrab P.Shah et al NEJM 2009
Clinical Prognostic Factors in SCT
•
•
•
•
•
Stage
Age
Tumor Size
Bilaterality
Rupture
TUMOR RUPTURE
Preop rupture: 3/12 pts received CT
Intraop rupture: 4/9 pts received CT
Schneider et al, JCO vol 22, n10, 2004
HISTOLOGIC PROGNOSTIC FACTORS IN GCT
•
•
•


Histologic pattern
Degree of cellular atypia
Mitotic activity
Ki 67 over expression
Mutation of chromosome
6, 12, 22 ?
Controversial
 c-myc, p21-ras, c-erB2 and p53
no
 FOXL2 not expressed or underexpressed in juvenile aggressive GCT
yes?
PRINCIPE DE LA CHIRURGIE INITIALE
• Surgery as Primary Treatment:
 Total abdominal hysterectomy and bilateral
salpingo-oophorectomy
+ complete Surgical Staging
• Complete exploration of the cavity
• Cytologic evaluation
• Omentectomy
• Peritoneal biopsies
 Place of Fertility-Sparing Surgery?
 Lymph nodes dissection?
Chirurgie conservatrice ?
• SEER database of 326 pts (01/1992 to 12/2001)
• 134 young patients (<50 years) with stage I
• 97% and 94% survival at 5 and 10 years
• 71 pts (54%) had conservative uterine-sparing surgery
• No outcome difference between women undergoing
standard vs. conservative surgery (97% vs. 98%)
Zhang et al. Gynecol Oncol, 2007
Place du curage ganglionnaire
RISQUE DE RECHUTE TCG
AUTHORS
Nb cases
Nb rec.
%
Schwartz
37
6
16
Stenwig
118
24
21.2
Evans
118
22
18.6
34
3
8.6
Kim
Chan
83
20
24
Ray-Coquard
70
19
27
460
94
20
Total
SURVIE APRES RECHUTE
AUTHORS
Schwartz
Interval
Survival
1-9 yrs
19%
Panckratz
13%
Stenwig
1-22 yrs
13%
Evans
1-23 yrs
27%
Chimiotherapie
Advanced /Recurrent
Sex-cord Stromal Tumors
Author
CT
N.
RR
Gersherson
1987
CAP
8
63%
Pectasides
1992
CAP
10
60%
Uygun
2003
CAP
9
44%
Colombo
1986
PVB
11
82%
Zambetti
1990
PVB
7
66%
Pecorelli
1999
PVB
38
61%
Gersherson
1996
BEP
6
83%
Homsley
1999
BEP
57
61%
Sex cords TUMORS
Care process of the relapse
Relapse after treatment without CT:
– Supplementary surgical act.
– Chemotherapy with platinium salts
Additional treatment after CT failure:
– Debulking surgery
– chemotherapy: protocole depending on the sensibility
to platinium (6 months)
– VP 16 oral, VAC, Docetaxel – GEM, phase I, targeted
th? ….
Vorinostat in Stage IV GCT
Histone Deacetylase (HDAC) Inhibitor
Response after 11 months of treatment. Prior treatment included BEP,
doxorubicin, tamoxifen, carboplatin, leuprolide, topotecan, paclitaxel, ….
Rubin et al, Clin Cancer Res December 1, 2006
Bevacizumab & TSC
Ovarian small cell carcinoma
• Very underestimated tumors
• Histogenesis? Classification?
• High calcium level (para endocrine)
– Young adult (median age 24 years)
– hypercalcemia in 2/3 of pts
– stage > Ia for more 50% of patients
– Poor prognostic (60% of Ia relapsed and died)
– Prognostic factors : age > 30 y, calcium level, size < 10
cm, only small cells
• Pulmonary form
– As SCPC
– Oldest patients
• Treatment: complete surgery, HD chemotherapy &
pelvic radiation
Mucinous ovarian carcinoma
•
•
•
•
•
•
Rare epithelial tumor: < 5%
Young patients (median age 58 y)
From borderline mucinous tumor
Low grade, localized disease (75%)
Ras mutation (50%)
Specificities:
– Advanced disease rare
– Differential diagnosis
– Standard chemotherapy very disapointing
CLINICAL PRESENTATION AND SENSITIVITY TO PLATIN-BASED CHEMOTHERAPY
(CT) OF MUCINOUS ADVANCED EPITHELIAL OVARIAN CARCINOMA: THE GINECOGROUP EXPERIENCE
Response rate
(% of evaluable patients)
Serous
Mucinous
(N=342)
(N=51)
Response
(complete + partial)
277 (81%)
20 (67%)
Stable disease
36 (10%)
1 (3%)
Progression
29 (9%)
9 (30%)
p
0.0001
Progressive disease during chemotherapy was observed
in 40% of pts with stage IV mucinous EOC.
J Alexandre for the GINECO-Group, France.
Progression-Free Survival
Overall Survival
Fonction de survie cum ulée
Fonction de survie cum ulée
1
1
Serous
Mucinous
0,8
0,8
0,6
0,6
0,4
0,4
0,2
0,2
0
0
12
24
36
48
60
72
0
84 0
Mucinous
36
serous
mucinous
Progression Free Survival
Serous
24
48
60
overall survival
(months)
months
Progressionmonths
Free Survival (months)
serous
12
mucinous
Overall survival
Median (CI95%)
Log rank
Median (CI95%)
Log rank
17.5 (16.2-19.1)
0.002
47.2 (43.1-52.2)
<0.0001
11.4 (6.9-14.2)
21.6 (13.5-32.1)
72
84
A GCIG Intergroup multicentre trial of open label carboplatin and paclitaxel +/bevacizumab compared with oxaliplatin and capecitabine +/- bevacizumab as first
line chemotherapy in patients with mucinous Epithelial Ovarian Cancer (mEOC)
The mEOC Study is a multi-national collaboration
with the Gynecologic Oncology Group (GOG), USA.
RATIONALE


FACTORIAL TRIAL DESIGN (332 patients)
mEOC FIGO stages II–IV OR recurrent stage I No
previous chemotherapy; >18yrs; PS=0-2
Patients with mucinous epithelial ovarian cancer (mEOC) are
currently treated with carboplatin + paclitaxel chemotherapy.
However this treatment is not as effective in treating mEOC, as
it is in treating other forms of ovarian cancer. Because mEOC
shares molecular similarities with mucinous tumours of the
gastrointestinal (GI) tract, it is thought that the chemotherapy
agents (oxaliplatin + capecitabine) used to treat these GI
tumours may be effective in treating mEOC.
A trial evaluating bevacizumab in ovarian cancer is already
underway (ICON-7 & GOG 218), so it is appropriate to examine
this therapy specifically in patients with mucinous tumours.
Furthermore the results of chemotherapy and bevacizumab
have been positive in mucinous large bowel tumours. It is
reasonable to incorporate anti-VEGF therapy in the mEOC
study.
Randomise
83 patients
Carboplatin AUC 5/6*
Paclitaxel 175mg/m2
6 x 21-day cycles
83 patients
Oxaliplatin 130 mg/m2
Capecitabine 850mg/m2 bd
6 x 21-day cycles
Clinical assessment every 6 weeks for 36 weeks
Telephone call at week 3 between every 6-week visit
PRIMARY OBJECTIVE

The primary aim of this trial is to determine whether
chemotherapy with oxaliplatin + capecitabine improves the
survival of patients with mucinous ovarian cancer, compared to
standard chemotherapy with carboplatin + paclitaxel. In addition,
we aim to determine whether Bevacizumab improves overall
survival of patients with mucinous epithelial ovarian cancer.
SECONDARY OBJECTIVES





Progression free survival
Response rate
Toxicity
Quality of life measured by FACT-O TOI, FACT/GOG-NTX
Subscale and EQ-5D QoL questionnaires
Translational research
CURRENT STATUS



Interest from sites in UK, Denmark, Finland, Sweden,
Norway, France, Italy & Germany.
MHRA & MREC approved in UK, NCRI approved trial.
8 Sites open in the UK
mEOC Flyer – June 2010
83 patients
83 patients
Carboplatin AUC 5/6*
Paclitaxel 175mg/m2
6 x 21-day cycles
Oxaliplatin 130 mg/m2
Capecitabine 850mg/m2 bd
6 x 21-day cycles
Bevacizumab 15mg/kg given
every 3 weeks for 5 or 6
cycles
Bevacizumab 15mg/kg given
every 3 weeks for 5 or 6
cycles
ELIGIBILITY CRITERIASummarised
Inclusion Criteria:
• Histological diagnosis of mucinous ovarian carcinoma
• FIGO stage II-IV
• Aged 18 or above
• Life expectancy >3 months
• No previous chemotherapy or radiotherapy
• Recurrent stage I
• ECOG performance status 0, 1 and 2
• Adequate haematological, renal and hepatic function
• Adequate neurological function (sensory & motor  grade 1)
• Urine dipstick for proteinuria <2+
• Adequate coagulation parameters
Exclusion Criteria:
• Histological diagnosis of non-mucinous ovarian carcinoma
• Previous history of malignancy except cervical carcinoma in situ,
and basal cell carcinoma of the skin
• Concurrent uncontrolled medical condition
• Previous chemotherapy, radiotherapy or any investigational
treatment for ovarian or rectal cancer.
• Symptoms or history of peripheral neuropathy
• Previous history of malabsorption or other conditions preventing
oral treatment
• Clinically significant cardiac disease, including M.I. in last 12
months
• Previous CVA, TIA or SAH in last 6 months
• Non healing wound, ulcer or bone fracture
• Surgery or significant traumatic injury within 4 weeks of first
planned dose of bevacizumab
• Uncontrolled hypertension
• History/evidence of thrombotic/haemorrhagic disorders
Bevacizumab 15mg/kg given every 3 weeks for 12 cycles
Clinical assessment every 6 weeks for 36 weeks
CONTACT: Rachel Slade, Trial Coordinator
[email protected] +44 (0) 20 7679 9857
CT scans are carried out post cycle 3 of chemo, 1 month after
completion of cycle 6, then 3 monthly for Year 1
Follow up: 3 monthly years 1-2, 6 monthly years 3-5
*The carboplatin dose depends on the method used to obtain GFR. If
GFR has been estimated, AUC=6, if GFR has been measured, AUC=5
Chief Investigator- Prof Martin Gore
Royal Marsden Hospital, London
Conducted by the Cancer Research UK & UCL Cancer Trials
Centre
RÉSUMÉ
 Ce que nous savons:
– Tumeurs curables même à la rechute pour certaines
– Sujets jeunes, fonction ovarienne à respecter
– Efficacité de la chimiothérapie en fonction histo++++
– Prise en charge initiale svt inadéquat (trop/pas assez)
 Ce que nous ne savons pas:
– Facteurs pronostiques & biologie moléculaire
– Diagnostic différentiel
– Geste chirurgical agressif pour qui?
– Chimiothérapie adjuvante pour qui?
– Alternatives thérapeutiques ?
OBSERVATOIRE NATIONAL
DES TUMEURS MALIGNES RARES DE L’OVAIRE :
http://ovaire-rare.org
Clinical study inclusion
01/07/2008
01/03/2008
01/11/2007
01/07/2007
250
01/03/2007
01/11/2006
50
01/07/2006
01/03/2006
100
01/11/2005
01/07/2005
01/03/2005
01/11/2004
01/07/2004
01/03/2004
01/11/2003
01/07/2003
01/03/2003
01/11/2002
01/07/2002
01/03/2002
2008 RESULTS
Expected inclusions
200
150
Série1
Observed inlusions
Série2
Observed inclusions
0
• In 2008, 172 patients with GCT or SCT were included
in the prospective study.
• Controversial results & Some improvement
trails…
– Complete concordance of pathological diagnosis
between initial and second opinion : 67%
– Initial surgery not always optimal, sometime « exotic »
– Non exhaustivity of all french cases
2009, 2nd step : National rare gynecologic
cancer network
• Optimizing the recruitment with systematic expert pathological
review on real time (< 10 days) to help initial pathologist and
oncologists.
• Extention with other French institutions to other rare gynecological
tumors (borderline, carcinosarcoma, mucinous, clear cell, small cell
carcinoma…)
• Elaboration of a cancer network organisation with all French expert
centers for these rare gynecological tumors to organize the patient
management at the national level (financial support by French NCI,
2010)
Ministère de la Santé
et des sports
APPEL A PROJETS 2010
INCa – DHOS
Labellisation de Centres experts
nationaux
pour cancers rares de l’adulte
Dossier de candidature
Mesure 23 plan cancer:
Labéliser centres de référence pour cancer rare (vocation nationale +
équipe de recherche reconnue)
 réseau régional et filière de soins
Soutenir démarche qualité de la prof anatomo pathologique
Tumeurs concernées
• 1) Les tumeurs malignes du stroma et des cordons sexuels
et les tumeurs malignes germinales
• 2) Les tumeurs épithéliales rares malignes (mucineuses, à
cellules claires) et borderline avec implants ou bien posant
des problèmes d’interprétation au gynéco pathologiste du
centre de référence régional.
• 3) les cancers à petites cellules avec hypercalcémie et les
tumeurs endocrines sur strume ovarienne
• 4) Les autres catégories de tumeurs rares, comme les
tumeurs mixtes malignes müllériennes.
Objectifs – soins
 Augmentation du nombre de patientes dont la prise en charge
s’effectue via les RCP de recours dédiées lors de la prise en charge
initiale, post opératoire ou lors de la prise en charge secondaire
 Augmentation du nombre de patientes bénéficiant d’une double
lecture
 Mise à disposition du diagnostic moléculaire dans les centres experts
nationaux.
 Organisation de la formation des soignants pour la prise en charge des
tumeurs rares de l’ovaire.
 Organisation de l’information des patients et leur famille, via le site
Internet dédié et la création du comité de patientes mise en place 2011
 Mise à jour et suivi des référentiels de bonne pratiques médicales
Objectifs - recherche
 Augmentation du nombre de patients inclus dans les études de
recherche clinique par an,
 Développement de chimiothérapies et thérapies ciblées guidées par la
pharmaco génomique et les altérations génétiques de la tumeur.
 Suivi de la prise en charge des patientes atteintes de tumeurs rares de
l’ovaire et suivi des pratiques médicales en conformité avec les
recommandations de pratiques cliniques et les avis proposés par les
RCP de recours regionales ou nationale.
 Surveillance épidémiologique (dans le cadre du site internet dédié) et
suivi de ces cancers rares.
agreement and
Financial
support by
INCA 2010
Coordonator : I Ray-Coquard
List of regional experts centers
AP - HOPITAUX DE PARIS
E Pujade-Lauraine /
MC Vacher-Lavenu
A Cortez
C Genestie
MA Le Frère-Belda
F Walker
INSTITUT GUSTAVE ROUSSY
Centre Oscar Lambret
E Leblanc / I Farré
P Pautier / P Duvillard
Centre Henri Becquerel
H Sevestre (CHU)
M Baron / JC Sabourin (CHU)
Institut Jean Godinot
H Curé / C Garbar Centre Alexis Vautrin
B Weber / A Leroux
Centre François Baclesse
F Joly / C Blanc-Fournier
Clinique Armoricaine de Radiologie
AC Hardy-Bessard
CHU Hôpital Civil
JE Kurtz / G Averous
Centre Eugène Marquis / CHU Rennes
J Leveque / S Henno
Centre Georges François Leclerc
L Favier / L Arnould
CHR La Source
J Meunier / C Bonneau
Centre Catherine de Sienne
A Lortholary / A Dubois (IHP)
CHU Hôpital Jean Minjoz
E Kalbacher / MP Algros
CHU de Poitiers
C Nadeau / O Renaud
CHU Lyon -La Croix Rousse
M Devouassoux
CENTRE LEON BERARD
I Ray-Coquard / I Treilleux
CHU Dupuytren
S Lavau-Denes / V Fermeaux
Centre Jean Perrin
C Pomel / F Penault-Llorca
Institut Bergonié
A Floquet / G Mac Grogan
Groupe Hospitalier Sud Réunion
M Boukerrou
CHU Hôpital Michalon
F Sergent
Centre Val d'Aurelle
M Fabbro/ MC Chateau
Centre Claudius Regaud
D Querleu / E Mery
Institut Paoli Calmettes
M Provensal / E Charafe-Jauffret
C Charpin (CHU)
Example of dedicated CPG’s for
mucinous ovarian cancer
ALIENOR : A multi-centre, randomized, open label, phase II trial of
Bevacizumab plus weekly Paclitaxel then Bevacizumab monotherapy in
maintenance versus observation in patients with relapsed ovarian sexcord stromal tumours
•
INCLUSION CRITERIA: Histological diagnosis of ovarian SCST previously
treated with platinum-based chemotherapy.
•
PRIMARY ENDPOINT: The non-progression rate after 6 months of
combination or standard chemotherapy.
•
SECONDARY ENDPOINTS:
–
Progression free survival
–
Overall Survival
–
Objective Response Rate and duration of response
–
Safety profiles of the association of Paclitaxel and Bevacizumab and the
safety profile of Bevacizumab monotherapy.
•
ANCILLARY STUDY:
–
Plasma biomarkers, circulating endothelial cells , functional MRI
•
STATISTICAL CONSIDERATIONS:
–
A maximum sample size of 60 patients (30/ arm) will be included
–
A Bayesian approach will be used with 2 interim analyses planned after the
inclusion of 6 and 8 patients per arm.
•
LENGTH STUDY:
–
Patients will be enrolled over 24 month period
–
duration of patient follow-up will 18 months from start of treatment
SCT after at least one
line of chemotherapy
randomisation
W Paclitaxel +
Bevacizumab
until
progression or
intolerance
W Paclitaxel
alone until
progression or
intolerance
Progression
Bevacizumab
Since 2011, activity from French Ovarian
cancer network
• 661 registered centers (private, public), & 26
outside French territory
• > 317 pathologists
• 24 regional referent centers & 3 national centers
• 28 referents pathologists organized in network
• 676 patients since 2002
• 291 new patients en 2011
– 227 for initial management, 64 in relapse
2011 – multidiciplinary decision from Experts
Régional centers (CER) or National centers (CEN)
Multidiscipli N of cases
nary staff discussed in CER
291
81
N of cases discussed in
CER
& CEN
N of cases
discussed only in
CEN
No MS
120
76
14
2011 – second opinion by Experts pathologist
from regional or national expert centers
2011
TOTAL
Second opinion
No SO
ND
total
291
155
80
56
From CER
From national
90
201
29
126
49
31
12
44
2011 – second opinion asked by initial pathologists
And not by the regional or national centers
total
total
Rhônes-Alpes, IDF*, Aquitaine, PACA, Pays
de la Loire
447
path-init SO by Path not SO by
is expert other one
ref
expert
path
125
112
204
204
ND
SO by
expert
path
118
118
conclusions
• Tumeurs ovaires/gynécologiques rares = même
problématique que tous les autres cancers rares:
– Rares, svt curables, peu alternatives thérapeutiques …
– Bons arguments pour travailler ensemble :
• Organisation du diagnostic
• Organisation des soins
• Organisation des connaissances & de l’information
• Organisation de la recherche clinique et fondamentale
– Niveau international indispensable : GCIG?, world
gyneco network?