Rare Solid Cancers: An Introduction - Slide 8 - I. Ray-Coquard - Rare female genital cancersPresentation Transcript
RARE GYNECOLOGICAL CANCERS Isabelle Ray-Coquard MD, PhD Centre Léon Bérard Lyon, France Stresa, March 2011
Rare Gynecological cancer:
Vulva and vagina
There are six potential sites for gynecologic cancer, each with a distinctive anatomy and histology. The cancer can be traced to a derivative cell. Ovary epithelial neoplasms include the common varieties of adenocarcinomas and also give rise to a rich variety of germ cell neoplasms. The uterine wall undergoes dramatic proliferative change monthly in its glandular epithelium during the menstrual cycle, gives rise to adenocarcinomas. The cervix has a simple columnar epithelium and changes to a stratified squamous epithelium, which gives rise to squamous cell cancers. The fallopian tube is lined by ciliated columnar epithelium and tends to give rise mainly to serous adenocarcinomas. Syncytiotrophoblast gives rise to choriocarcinoma, gestational trophoblast tumors.
Rare ovarian cancers
Germ cell tumors and sex cords tumors
Invasive Border line tumors (serous, mucinous, papillary)
All members of polycomb group (PCb) of genes inolved in the histones methylation
Endometrial stromal sarcoma Treatment Algorithm F Amant, Lancet 2009
Endometrial stromal sarcoma Hormonal therapy options F Amant, Lancet 10 & Fayette et al, ASCO 06
2) Rare ovarian cancers
Mostly Sex cords and germ cell
Few data from literature
Only retrospective studies
The most important series : 200 patients over 15 years
Information come from data concerning other localizations, clinical situations or hystology:
TESTICULAR GERM CELL TUMOURS
NO DEFINITE NOR CONSENSUAL DATA
PRINCIPLE OF INITIAL SURGERY
Surgery must delineated :
The staging of the disease
The initial therapeutic act.
Specific issues :
The first step is often done by non oncologist specialists
The place of fertility-sparing surgery
The role for re staging
The benefit from systematic lymph node dissection
At least :
Complete exploration (pelvis + abdominal cavity)
Peritoneal waching +/- cytology
Systematic peritoneal biopsy (omentum)
Resection of all suspect events
Major point is fertility sparing surgery
No consensus on 3 points :
nodes, contrrolateral ovary, debulking surgery.
GERM CELL TUMOURS
GERM CELL TUMOURS
Platinum based chemotherapy (Williams 1987) especially since 1987 3 or 4 cycles of BEP (Gershenson 1990)
Depending on the tumour stages/postoperative residue:
stages II and III : 3 or 4 cycles BEP (residual tumor)
stage IV: 4 cycles BEP
stades I (70%): * pure dysgerminoma Ia and Ib
* immature teratomas Ia Ib grade 1
no supplementary treatment after surgery
Adjuvant radiotherapy : in general no more indication
SEX CORD AND STROMA TUMOURS
Ovarian stromal tumours
Granulosa cell tumours
Tumours of the fibro-thecoma group
Sertoli and Leydig Stromal tumours (androblastomas)
Steroid cell tumours
SEX CORD AND STROMA TUMOURS
8% of ovarian tumours
Most of them are secretories : synthesis of progesterone, oestrogens, androgens, corticosteroids ….
Differential diagnosis ?
Malignancy histologic criterias?
Prognosis? And so indication of adjuvant treatment
Relapse risk for GCT
AUTHORS Nb cases Nb rec. %
Schwartz 37 6 16
Stenwig 118 24 21.2
Evans 118 22 18.6
Kim 34 3 8.6
Chan 83 20 24
Ray-Coquard 70 19 27
Total 460 94 25%
Survival after relapse
AUTHORS Interval Survival
Schwartz 1-9 yrs 19%
Stenwig 1-22 yrs 13%
Evans 1-23 yrs 27%
Clinical Prognostic Factors in SCT
Preop rupture: 3/12 pts received CT Intraop rupture: 4/9 pts received CT TUMOR RUPTURE Schneider et al, JCO vol 22, n10, 2004
HISTOLOGIC PROGNOSTIC FACTORS IN GCT
Degree of cellular atypia
Ki 67 exp
Mutation of chromosome 6, 12, 22 ?
c-myc, p21-ras, c-erB2 and p53
FOXL2 not expressed or under- expressed in juvenile aggressive GCT
Controversial no yes?
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
Fertility sparing surgery ?
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%
Brown 2008 CbT 11 81%
Chemotherapy in advanced /recurrent sex-cord stromal tumors
Vorinostat in Stage IV GGCT 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
Summary for rare ovarian cancers
What we support with some evidence:
Surgery is the cornerstone of treatment: consider fertility-preserving surgery in young pts
Postoperative chemotherapy for stage II-IV , recurrences,
Repeat surgical resections, whenever feasible, for recurrent diseases
What we would like to know:
Differential histological diagnosis
Radical or conservative surgery, and adjuvant treatment for which patients?
Biological search for new targeted treatment but for which targets?
STEERING COMMITTEE : Pierre Biron, Hervé Curé, Jean-Pierre Droz, Pierre Duvillard, Jean Paul Guastalla, Jean-Pierre Lotz, Pierre Méeus, Laurent Mignot, Eric Pujade Lauraine, Isabelle Ray-Coquard, Daniel Raudrant, Véronique Trillet Lenoir, Isabelle Treilleux, Chistophe Tournigand.
2002: Ovarian rare malignant tumours national website observatory Private access Public access
RATIONAL for a dedicated Website
With health care professionals:
To homogeneously manage treatment of adult ovarian rare tumour
To put the different expert knowledge at the physicians disposal (on-line expert advice).
To include patients with germ cell or sex cords tumors on the prospective databasis
To systematically confirm the histological diagnosis with centralized expert review
To perform molecular analysis of these rare ovarian cancer with all available tumor samples
For the public:
To keep inform the public with the available scientific data
To inform patients about new therapeutic options
The website on rare malignant tumours of the ovary elaborated by the GINECO group can be visited on internet: http://www.ovaire-rare.org
Shortly, each physician, identified by his registration number at the national Medical Association, will register online, then be given a confidential password for connecting to the database .
He will then be able to include patients with germ cell or sex cords tumors and/or enter information concerning his patients on the on-line expert advice forum.
The physician will then have access to on-line expert advice through the website.
Clinical study inclusion
In 2008, 172 patients with GCT or SCT were included in the prospective study.
Granulosa cell tumor small cell carcinoma, clear cell carc
Sertoli Leydig Fibrotecoma (begnin T)
Juvenile granulosa Dysgerminoma
Unclassified sex cord T. Synovialosarcoma (with translocation)
Dysgerminoma indifferentied Carcinoma
Teratoma malignant neurectodermic tumor NOW
37% non agreement Centralized review diagnosis (n=67) Ray-Coquard et al, ESMO 2008
After 4 years, the use of the website is effective and enables to recruit patients.
Histological discrepancies between initial diagnosis and second opinion suggest that this tool is useful for including patients in the clinical trial.
The website provides very interesting data for a better knowledge of these rare tumors and will possibly help improve medical practice.
Controversial results & Some improvement trails…
Complete concordance of pathological diagnosis between initial and second opinion : 67%
Initial surgery not always optimal, sometime « exotic »
Non all French cases are reported
2009, 2 nd 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.
Extension with other French institutions to other rare gynaecological tumors (borderline, mucinous, clear cell, small cell carcinoma…)
Elaboration of a cancer network organisation with all French expert centres for these rare gynaecological tumors to organize the patient management at the national level (financial support by French NCI, 2010)
Ministère de la Santé et des sports Call for proposal 2010 INCa – DHOS Approval for national referent cancer center dedicated to rare cancers
Measure 23 of national cancer plan :
Approval for referent cancer rare centers
Regional network and organized care management
pathologists and experts review
Objectives for gynecological projet - care
To increase the number of patients with rare gynecological disease where medical strategy of care is decided in dedicated regional multidisplinary staff at the time of the initial and first relapse management
To increase the number of tumor samples with systematic second opinion by expert pathologists
Availability of molecular diagnosis for all patients (ex: FOXL2 mutational status for SCT).
To delineate and to implement standardized pathological report.
To delineate a national & specific multidisciplinary staff dedicated to exceptional situations or used of specific drugs (via the website).
To organize national dedicated workshops and continuing medical education.
To organize and diffuse information for patients, families, with support of patients advocacy groups
To elaborate, diffuse and maintain clinical practices guidelines dedicated to rare gynecologic cancers
Objectives - research
To increase the number of included patients in dedicated clinical trials
International (MEoc trial (GCIG-MRC)) or national (beva & SCT)
To develop tumor banking for all these patients (all included patients signed an informed consent) to delineate specific biologic research.
To develop treatment strategies and targeted treatments based on pharmaco genomic and tumoral genetic alterations.
Epidemiological survey of such diseases.
Evaluation of medical practices concerning rare cancer with comparison of such practices to clinical guidelines and experts advices.
New strategies & new targets Today, more than 250 tumors samples and clinical data for GCT & SCT are available & dedicated to determine new targets ….
List of regional experts centers CHU Hôpital Civil Institut Bergonié Centre Jean Perrin Centre Georges François Leclerc Centre Eugène Marquis Clinique Armoricaine de Radiologie CHU La Source Institut Jean Godinot CHU Hôpital Jean Minjoz AP-HP Hôpitaux de Paris Institut Gustave Roussy CRLC Val d'Aurelle CHU Dupuytren Centre Alexis Vautrin Centre Claudius Regaud Centre Henri Becquerel Centre François Baclesse Centre Catherine de Sienne CHU de Poitiers Institut Paoli Calmettes Groupe Hospitalier Sud Réunion CHU Hôpital Michalon CHU La Croix Rousse Centre Léon Bérard
Approval and Financial support by INCA 2010
Example of dedicated CPG’s for mucinous ovarian cancer
3) Management & improvements for gestational trophoblastic disease
French Trophoblastic Disease Reference Center Lyon Sud University Hospital
Gestational Trophoblastic Neoplasia:
invasive moles and choriocarcinomas
National Cancer Institute (INCa) funding
Coordinating center in Lyon
Regional centers in each of the 22 french regions
Network of 8 reference pathologists
INCa – HAS validated guidelines
ObGyn and Medical Oncologists collaboration
Prof. François GOLFIER, MD, PhD – French Trophoblastic Disease Reference Center
Registration of patients to the trophoblastic disease reference center email@example.com, firstname.lastname@example.org [email_address] Internet (mole-chorio.com) Prof. François GOLFIER, MD, PhD – French Trophoblastic Disease Reference Center
Rare Gynecologic cancers = same problematic than all other rare cancers:
Absence of knowledge, curability, few therapeutic options, no dedicated clinical trials….
Sufficient arguments to work all together :
For diagnosis and molecular tools
Strategy of management
Exchanges on local experiences concerning organization of care
Organization and delineation of research (clinical and biologic)
International cooperation need : Europe - GCIG
Specificity of rare gynecological cancers
Σ of rare cancers > to Σ of frequent cancers ?
All vulvar cancers are to be considered as rare cancers?
Gestational diseases represented more than 5% of rare gynecological cancers?
Survival data are better for all rare gynecological cancer than frequent tumors ?
Low grade endometrial stromal cancer were really sensible to chemotherapy ?
Sex cords ovarian cancers
Most frequent rare ovarian cancers
Fertility sparing surgery is mandatory for all localized stage
Standard chemotherapy is BEP regimen
Histological diagnosis and prognosis are relatively easy to be define for such cancers
Evidence for the use of targeted treatment for such cancers