la chemioterapia in - project & communication

Claudio Zamagni Bologna 28 novembre 2014

Claudio Zamagni

Oncologia Medica

Istituto Addarii

Azienda Ospedaliero-Universitaria di Bologna

Policlinico S.Orsola-Malpighi

Chirurgia in gravidanza

Bologna 28-29 Novembre 2014

La chemioterapia in

gravidanza


Annual Incidence of Cancer during Pregnancy or Lactation, proportions per year per 100,000 pregnancies

Stensheim, H. et al. J Clin Oncol; 2009; 27:45-51


MSKCC series 1992-2007

Murphy CG et al, Cancer 2011


Cancer Chemotherapy During Pregnancy: Study Types


Pharmacokinetic Parameters in Pregnant vs Control Patients

Van Calsteren K et al Acta Obstet Gynecol 2010


Reduced Chemotherapy Exposure in Pregnancy

Van Calsteren K et al Acta Obstet Gynecol 2010

3: breast C

9: NHL

21: Ovarian C


Relative Cisplatin Concentration in Umbilical Cord Blood and Amniotic Fluid

at the Time of Caesarean Section

Marnitz S et al Oncology 2010


Transplacental Transfer of Chemotherapy

Amant F et al Lancet 2012


The Placental Barrier and the main ABC Drug Efflux Transporters

ABC: ATP- Binding Cassette superfamily:

membrane proteins that transport a

variety of substrate

Staud S et al. Journal of Drug Targetting 2012


ABC Transporters in the Placenta

Transporter Encoding Placent Function

name gene localization

P-glycoprotein ABCB1/ MDR1 Apical Fetus protection by efflux of

substrates from SCT to mother

BCRP ABCG2 Apical as P-GP + survival factor during the formation of

placental syncytium; protects trophoblast against

cytokine-induced apoptosis; vectorial transport of

sulphate conjugates from fetus to mother

MRP1 ABCC1 Basolateral Transport of endogenous substrates

(leukotrienes; reduced glutathione) to

fetus; vectorial transport of

sulphate conjugates from mother to

fetus

MRP2 ABCC2 Apical as P-GP

BCRP: Breast Cancer Resistance Protein

MRP: Multidrug Resistance-associated Proteins


La chemioterapia in gravidanza può

danneggiare il feto?


Crucial Periods in Prenatal Development

Moore P The Developing Human, 1998

Bars indicate highly (purple) and less (green) sensitive period


Chemotherapeutic Agents with > 100 Reported Conceptuses

5-Fluorouracil 179

Cisplatin 105

Cyclophosphamide 419

Cytarabin 168

Daunorubicin 108

Doxorubicin 430

Imatinib 157

Vincristine 228


Number of Reported Conceptuses for Agents Used During Pregnancy in Breast and Gynaecologic

Cancers

Carboplatin 17

Cisplatin 105

Cyclophosphamide 419

Docetaxel 21

Doxorubicin 430

Paclitaxel 38


Major Malformations Following Cancer Chemotherapy Use During Pregnancy, by Agent and Trimester Exposed


Major Malformations Rate Following Cancer Chemotherapy Use During Pregnancy,

All Agents

Overall 5% (62/1,156)*

First tr. 14% (41/303)

Second/Third tr. 3%** (21/826)

*Time of exposure not specified in 27 cases

**The prevalence of major congenital malformations in the general population of the United States is 3%


Rate of Spontaneous Abortion Following Cancer Chemotherapy Use During Pregnancy,

All Agents

First tr. 13%* (42/327)

Second/Third tr. 2%** (20/836)

*Spontaneous fetal loss at < 22 weeks of gestation ; the result is similar to that observed in healthy women

**The prevalence of stillbirth (late spontaneous fetal death ≥22 weeks of gestation) in the general population of

the United States is 0.3-0.4%; the apparent increase is mainly due to agents used to treat leukemia (it’s

possible that mother’s disease may influence the rate of stillbirth)


Pregnancy Complications Rate Following Cancer Chemotherapy Use During Pregnancy

Abnormally low levels of amniotic fluid

(olygohydramnios/anhydramnios)

All Agents 3% (33/1,118)*

Trastuzumab 74% (14/19)

Spontaneous Preterm Birth 9% (97/1,118)**

(< 37 weeks of gestation)

*The prevalence of ogohydr./anhydramnios) in the general population of the United States is 2.4-4%

** The prevalence of spontaneous Preterm Birth in the general population of the United States is 12%


Advers Effects on Newborn Weight and Health Following Cancer Chemotherapy Use

During Pregnancy

Small for Gestational Age Infants 8% (89/1,118)*

(<10th percentile)

Transient myelosuppression 4.1% (46/1,118)

Cardiotoxicity inconclusive data

*Mainly in haematological cancers


Advers Effects on Infant Growth and Development Following Cancer

Chemotherapy Use During Pregnancy

Few studies have conducted evaluation beyond the second year of life

(up to 20 years)

No effects on general health and growth

No increase in auditory, neurological or cardiac morbidity

Data limited and adverse effects may not be apparent until later in life

Amant et al, Lancet Oncol 2012

Aviles et al, Int J Cancer 2012


La chemioterapia in gravidanza incide

negativamente sulla prognosi della

madre?


Clinicopathologic variables of Pregnant vs Non-Pregnant Breast Cancer Patients

56.5

Amant F et al J Clin Oncol 2013


Prognosis of Pregnant vs Nonpregnant Breast Cancer Patients

Amant F et al J Clin Oncol 2013


MSKCC series 1992-2007

Murphy CG et al, Cancer 2011


Pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies

Azim HA et al Eur J Cancer 2011

Meta-analysis

performed on published

data rather than on

individual patients data

No information on ER

and HER2 status


Breast Cancer During Pregnancy General Recommendations

To treat as closely as possible according to general recommendations for

non-pregnant women

Prefer sequential regimen due to lower toxicity but equal efficacy

e.g. EC-Paclitaxel weekly or Paclitaxel weekly – EC

Dose according to acutal weight – avoid underdosing

Supportive treatment as indicated

Observe pregnancy closely – Biometry once a cycle

Treat within a multidisciplinary team including obstetricians, perinatologist,

neonatologist

Include the patients in public available registries

Loibl S, Addarii Lecture 2013


Cervical and Ovarian Cancer During Pregnancy General Recommendations

Pregnancy does not have a deleterious effect on the prognosis of cervical or

ovarian cancers

When neoadjuvant chemotherapy is indicated administer chemotherapy as

closely as possible according to general recommendations for non-pregnant

women

Dose according to actual weight – avoid underdosing

Supportive treatment as indicated

Observe pregnancy closely – Biometry once a cycle

Treat within a multidisciplinary team including obstetricians, perinatologist,

neonatologist

Include the patients in public available registries

Morice P et al Lancet 2012


MM 36 anni

ECOGRAFIA

cT2N0

27a 30a

BIOPSIA

CDI, G3,

RE 5%, RPg 5%,

KI67 73%, HER2 1+ PARTO

40a

INTERVENTO

CDI, Gx,

RE 0%, RPg 0%,

KI67 37%, HER2 0

ypT1aN0

18 giorni

dopo il parto

1° ciclo di

TAXOLO

38 giorni

dopo il parto

32a

EC EC

38a 35a

EC

Epirubicina: 90 mg/mq

Ciclofosfamide:600 mg/mq

AUTORISCONTRO

Nodulo mammario

24a Sett. grav.

la chemioterapia in - project & communication

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