Chimiothérapie pendant la grossesse

Cancer et grossesse
Prise en charge du cancer du sein
Jean-Yves Pierga
Département d’Oncologie médicale
Laboratoire des Biomarqueurs Circulants (SIRIC)
Institut Curie
Cancer et grossesse
Prise en charge du cancer du sein
Epidémiologie
Pronostic
Traitement
Pharmacologie
Toxicité fœtale et maternelle
Stratégie de prise en charge
Autres cancers
Epidémiologie
Mitrou S. Journal of Advanced Research (2016) 7, 559–563
Epidémiologie
Incidence selon l’âge
Rouzier R et al, 2008
Epidémiologie
Définition
Cancer du sein pendant la grossesse
Fréquence
1 cas / ~ 3000 grossesses soit 300 à 350 cas par an en France
1er cancer associé à la grossesse (col, mélanome)
10% des cancers du sein chez femmes < 45 ans
(pendant la grossesse ou l’année qui suit)*
En augmentation: âge moyen 1ère grossesse = 30 ans
Age médian au diagnostic ~ 34 ans
Age gestionnel median au diagnostic 23 SA
Facteurs de risque
association fortuite,
mais femmes jeunes donc prédisposition BRCA plus fréquente
* Étude de 1993 à 2009 :
16 555 cancers du sein
1 958 âgées de 20-43 ans
117 cas = 6%
âge moyen=33,7 ans
Langer et al, 2014
Registre européen 2008
Contexte physiopathologique
• prolifération cellulaire & hypervascularisation
• état de tolérance immunitaire
• hyper-estrogénie
Bilan d’extension
Mitrou S. Journal of Advanced Research (2016) 7, 559–563
Cancer du sein : radiothérapie
D
o
s
e
50 Gy
. .
. .
10 cm
40 cm
200cGy
15cGy
Terme
Concept°-implantation° ( JO à J9):
loi du tout ou rien
Période foetale (>J41):
RCIU
Anomalies fonctionnelles
Cancers post-nataux
Organogénèse (J10 à 41):
RCIU
Tératogénèse (SNC, oeil, os)
Abdominal shielding of a pregnant uterus during irradiation
of the breast.
Chimiothérapie
• Les agents de chimiothérapie les plus souvent utilisés
pour le cancer du sein et en hématologie sont :
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•
•
•
•
•
•
Anthracyclines
Cyclophosphamide
5-fluorouracil (5-FU) pour le sein
Taxanes cancer du sein , du col utérin et cancer de l’ovaire
Vinca alkaloides pour les pathologies hématologiques
Les sels de platine pour les cancers du col , du sein et de
l’ovaire (Dekrem et al., 2013).
All of these agents have their own specific working mechanism. Cyclophosphamides,
5-FU and platinum agents will interfere directly with the DNA and DNA-replication,
whereas vinca alkaloids and taxanes will inhibit mitosis by disrupting microtubule
function (Wiebe and Sipila, 1994).
Chemotherapy is contraindicated during the first trimester of pregnancy
because of a higher risk of inducing fetal malformations.
The (US) National Toxicology Program monograph reports a prevalence
of malformations of 14% if chemotherapy is given in the first trimester,
declining to 3% if chemotherapy is applied later in Gestation
In comparison, the reported rate of major malformations in the general
population is approximately 3% in the United States and 6.7% in a German
registry
NTP Monogr. 2013;(2):i-214.
Chimiothérapie pendant la grossesse
Même suivi obstétrical - collaboration / obstétricien
Séquentiel standard
Taxol hebdo > Taxotere
Accouchement > 35 SA
Prévention de la prématurité
Arrêt chimio > 3 S
Chimiothérapie pendant la grossesse
Loibl S JAMA Oncol. 2015 Nov;1(8):1145-53
Options thérapeutiques durant la grossesse
Loibl S JAMA Oncol. 2015 Nov;1(8):1145-53
Chimiothérapie pendant la grossesse
Loibl S JAMA Oncol. 2015 Nov;1(8):1145-53
Pharmacologie
The pharmacokinetics of drugs are affected during pregnancy :
• a decreased gastrointestinal motility
• a significant increase in plasma volume and extracellular fluid
• an increased glomerular filtration and tubular function,
• up- or downregulation of hepatic enzymes,
• an increased fat mass and the amniotic fluid which increases the distribution
volume.
•
These changes interfere with drug absorption, distribution, metabolism and
excretion. van Hasselt et al. (2014) have recently shown that this leads to a
decreased plasma volume of certain chemotherapeutic drugs such as
docetaxel and paclitaxel in pregnant women (Bell and Kerr, 2015).
Optimizing anticancer drug treatment in pregnant cancer
patients: pharmacokinetic analysis of gestation-induced
changes for doxorubicin, epirubicin, docetaxel and
paclitaxel
decreased plasma
volume of docetaxel
and paclitaxel in
pregnant women
Van Hasselt Annals of Oncology 25: 2059–2065, 2014
Transplacental transfer of chemotherapeutic agents in
pregnant baboons, from simultaneously collected
maternal and fetal plasma samples
Amant F Lancet 2012; 379: 570–79
Variation in transplacental transfer of tyrosine kinase
inhibitors in the human perfused cotyledon model
The results suggest that TKis cross the placenta at therapeutic level. Particularly,
erlotinib crosses the placenta at a higher rate than gefitinib or imatinib. All of them
have a very low placental uptake. These data may suggest that gefitinib should be
preferred to erlotinib for the treatment of pregnant woman with lung cancer
harboring an EGFRactivating mutation, during the second and third trimesters of
pregnancy.
C Jovelet Annals of Oncology 26: 1500–1504, 2015
Effects of prenatal exposure to cancer treatment on neurocognitive
development
D.C.-M. Vercruysse et al.NeuroToxicology 54 (2016) 11–21
Pronostic fœtal - 1, les études
• Effectifs
129 / étude cas-contrôles (vs 129) prospective multicentrique
~ 400 / étude observationnelle
• Durée de suivi : m = 24 mois++ (80 cas à 7 ans voire 18 ans)
• Type de suivi : cœur, cognition, développement; fertilité, leucémies..
• Majorité des data  anthracyclines
• +/- taxanes
• Pas/peu de données  thérapies ciblées
 Risque = prématurité >> chimio in utero mais indépendant
Amant F et al, NEJM 2015; Amant F et al, Lancet Oncol 2012; Loibl S et al, Lancet Oncol 2012; Murthy et al, BCR 2014
Conséquences pédiatriques des cancers traités pendant la
grossesse
Amant F N ENGL J MED 2015 373;19
Pediatric Outcome after Maternal Cancer Diagnosed during
Pregnancy
Bayley Scales of Infant Development test to assess
the neurocognitive development
Amant F N ENGL J MED 2015 373;19
Pediatric Outcome after Maternal Cancer Diagnosed during
Pregnancy
Amant F N ENGL J MED 2015 373;19
Pediatric Outcome after Maternal Cancer Diagnosed during
Pregnancy
Amant F N ENGL J MED 2015 373;19
Outcomes of children exposed in utero to chemotherapy for
breast cancer
Between 1992 and 2010, 81 pregnant patients with breast cancer were treated in a single-arm,
institutional review board–approved study with 5-fluorouracil, doxorubicin, and cyclophosphamide
(FAC) in the adjuvant or neoadjuvant setting.
Labor and delivery records were reviewed for each patient and neonate.
In addition, the parents or guardians were surveyed regarding the health outcomes of the children
exposed to chemotherapy in utero.
In total, 78% of the women (or next of kin) answered a follow-up survey.
At a median age of 7 years, most of the children exposed to chemotherapy in utero were growing
normally without any significant exposure-related toxicity or health problems.
Three children were born with congenital abnormalities:
one each with Down syndrome
ureteral reflux
clubfoot.
The rate of congenital abnormalities in the cohort was similar to the national average of 3%.
Conclusions: During the second and third trimesters, pregnant women with breast cancer can be
treated with FAC
safely without concerns for serious complications or short-term health concerns for their offspring who
are exposed to
chemotherapy in utero. Continued long-term follow-up of the children in this cohort is required.
Murthy et al. Breast Cancer Research (2014) 16:500
Options thérapeutiques durant la grossesse
Loibl S JAMA Oncol. 2015 Nov;1(8):1145-53
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A limited number of drugs are proven human teratogens and are contraindicated during
pregnancy.
Older-generation alkylators (procarbazine, busulfan, chlorambucil, and nitrogen mustard)
have high teratogenic and abortive potential; whereas anthracyclines and vinca
alkaloids (vinblastine, vincristine) have the lowest.
The antimetabolites aminopterin and methotrexate are teratogenic, whereas cytarabine
has lower fetotoxic potential.
Thalidomide causes phocomelia and CNS dysmorphology at a frequency of 15% to
100%, particularly when taken 27 to 50 days postconception.
Lenalidomide and pomalidomide, the new immunomodulating agents, are also considered
teratogenic based on their effect on rats and on the thalidomide experience in humans
Tretinoin (known as all-trans-retinoic acid [ATRA]) is associated with cardiac, craniofacial,
and neurologic malformations (retinoid embryopathy) in up to 85% of cases, if taken during
the first trimester.
Treatment and prognosis of haematological cancers
Brenner B Lancet 2012; 379: 580–87
Eyre TA et al British Journal of Haematology, 2015, 169, 613–630
Treatment and prognosis of haematological cancers
Brenner B Lancet 2012; 379: 580–87
Cancer du col utérin
Hecking Arch Gynecol Obstet (2016) 293:931–939
Drugs used for the treatment of ovarian and cervical
cancer during pregnancy
Morice P Lancet 2012; 379: 558–69
Conclusion
Une chimiothérapie est possible après le premier
trimestre de la grossesse
Nécessité d’une collaboration étroite entre équipe
obstétricale et oncologique
Manque de données sur les nouvelles générations de
traitement anti-cancéreux: anticorps monoclonaux,
TKI, inhibiteurs de Check point immunitaires