Cancer durante el embarazo

1. M. Carmen Martínez Casanova
30/10/2014
Chemotherapy
duringpregnancy

2. :
Definitionepidemiology
Preclinicaland clinicalstudy
Long-term outcome after in utero exposure
Management of cancer in pregnancy by tumor type
International multicenter project: ESMO 2014
Radiation therapy

3. “gestationalcancer”
Pregnancy-relatedcancer is defined as cancer diagnosed during pregnancy or within a year after delivery

4. Incidence of 1 in 1000–1500 pregnancies,
Málaga 17.289
nacimientos en 2013 (47 diarios)
1: 1.230 embarazos
Baulies C. Dexeus
Delay childbearing, the incidence of is expected to increase

5. Teratogenic exposure in the first 10–14 days after conception will result in an all-or-nothing
phenomenon:

6. Specificphysiologicchangesin thepregnant
Renal excretion of drugs
Increasedordecreasedhepaticfunction
Gastrointestinal absorptionorenterohepaticcirculationa
plasma proteinbinding.
Amnioticfluid
3rd compartment
Drugswithmolecular weightlessthan600 kDamaycrosstheplacenta
Agentsthatlipophilicorremainin theun-ionizedstatemaycrosstheplacenta

7. The teratogenicity of these agents has been demonstrated in animals, Case reportsand small studies.
Prospective, randomizedtrialsexaminingtheadverse effectsof specificchemotherapeuticagentsduringpregnancyare notavailablein humansforobviousethicalreasons.

8. (1) The concentration gradient between the maternal and
fetal circulation,
(2) the placental blood flow
(3) the physicochemical properties of the drugs.
lipid solubility,
ionization constant (pKa),
molecular weight (MW),
protein binding.
Uncharged, low MW (<500 Da), lipid soluble, and
unbound compounds can easily cross the human placenta
Remarkable
P-glycoprotein substrates revealed a limited transfer.
Importance of ATP-binding cassette proteins in the
protection of the fetus from xenobiotics.
Van Calsteren 2010

9. placenta will act as a barrier
for
the transfer of most
hemotherapeutic drugs,
reducing fetal exposure

10. Van Calsteren et al mice and baboon models
maternofetal transfers
not be detected very limited High
taxanes anthracyclines carboplatin
vinblastine cytarabine
cyclophosphamide *Trastuzumab
Marnitz et al. reported the concentration (in vivo) of
cisplatin in the fetomaternal compartment of seven
patients was
31- 65% of the maternal concentration
and all patients delivered healthy babies

11. Long-term outcome after in utero exposure tochemotherapyremainsa majorconcern
Aviles et al. examined 84 children educational performance were normal without congenital, neurologic, psychologic, cardiac, cytogeneticabnormalities
or malignancies indicate even better outcome than in
non treatedcohortsmf18.7 y
Van Calsterenet al. no developmental problems after
a thorough cardiac and neurologic investigation in 10 children. Echocardiographic a normal cardiac function in exposure to cytotoxic drugs, including anthracyclines
(Aviles and neri, 2001; Hahn et al., 2006; Van Calsteren 2010).

12. •1er trimester cyclophosphamide embryopathy.
•Safe during the 2nd and the 3rd
cyclophosphamide
•No apparent adverse during the 2nd or the 3rd trimester
•only 2 cases with malformations after use of busulfan in the 2nd trimester.
busulfan and chlorambucil
•No reports exist of fetal malformations when dacarbazine has been used after the 1st trimester
Dacarbazine
Alkylating agents
Teratogenicity and carcinogenicity in a twin exposed in utero to Cyclophosphamide
ZemlickisD,

13. Anti-metabolites
Cytarabine
34 leukemia
(9 1erT)
brachycephaly, hypoplasia cranial base, four-finger hands and
absentradio; C trisomy mosaicism; 46 chromosomes karyotype; 3 cases of intrauterine death, 5 low birth weight, 4 pancytopenia
5 -FU
53 1er T;
57 2º -3ºT
6 IUGR;1fetal death and 1 neonatal death; Down s.; 2 congenital anomalies (club foot and congenital bilateral ureteral reflux)
6-Mercaptopurine
49 c(29 1ºT)
2 c of intra-uterine death; 5cases of IUGR
Methotrexate
17 c cancer or
rheumaticdisease
18 p withleukemia
2 c intra-uterinedeath, 5c IUGR; 7 aminopterinsíndrome, skeletalabnormalitiesand ambiguousgenitalia

14. Anthracyclineantibiotics
Peccatoriet al.reported the feasibility and safety of weekly low dose single agent epirubicinafter the 1st trimester in 20 patients with gestational breast cancer.
Concerns exist about safety of daunorubicinand especially idarubicin: cases of cardiomyopathy, limb deformities and ventricular septal defect in newborns despite use after the 1st trimester Idarubicinis more lipophilic compared to other anthracyclines, and thus placental transfer is more likely to occur .
No adverse outcomes for the use after the 1st trimester for AdriamycinorEpirubicinand doxorubicin
FrédéricAmant,

15. Vinca alkaloids
•Less potent teratogens than the antimetabolites.
•Normal neonatal outcomes have been reported with use after the 1st trimester
Taxanes
•40 cases only one case of pyloric stenosis (Mir et al.)
•appears feasible during the 2nd and 3rd trimesters of pregnancy
Platinum-based agents
•60 cases 2nd and 3rd trimester and except for one case of ventriculomegaly during the 2nd trimester no fetal malformations were reported.
•Two cases of fetal exposure to cisplatin during the 1st trimester : microphthalmos , Cleft palate and tracheoesophageal fistula
•use of platinum agents is feasible during the second and third trimester

16. Biologicagents
TRASTUZUMAB
•Oligohydramnios or anhydramnios 8/14 patients, neonatal deaths in four cases, transient respiratory or renal failure in three
•Linked to the duration of exposure.
•In the first trimester no congenital malformations
Rituximab
•3/7p CD19B cells were decreased or undetectable at birth or shortly after.Reversible within 3-6 months

17. OthersBiologicagents
Lapatinib
•Healthybabyafterexposurebuttransplacentaltransfer
•use of anti-HER2 agents, its use during pregnancy cannotbe recommended
Imatinib.
•Teratogeniceffects in mice and rats during organogenesis
•180 p. (9.6%) fetal abnormalities.
Dasatiniband nilotinib.
•limitedexperiencein pregnant,
sunitiniband sorafenib
•No clinicaldata
bevacizumab
•embryo-fetal developmental toxicity of sunitinibin rats and rabbits
Erlotinib
•In animal models embryo/fetal lethality
During pregnancy the use of TKIs should be avoided,
especially during the 1st trimester.

18. Hormonal therapyTamoxifen
can disturb the hormonal environment
and so such treatments should be delayed
Tamoxifenis associated with birth defects including craniofacial malformations and ambiguous genitalia,Goldenharsyndrome(oculoauriculovertebraldysplasia) and fetal death.
Women using tamoxifen should be strongly advised to use active contraception or discontinue its use in case of pregnancy.

19. Otheragents
•Medlock et al. in animal models, G-CSF crosses the placenta and stimulates fetal granulopoiesis.
•There have been reported cases of G-CSF use after the 1st trimester with normal outcomes
•May be considered for the management of febrile neutropenia in pregnant women.
G-CSF
•Animal studies unfavorable effects on the fetus, mainly in the skeleton
•In humans case reports and small studies. 50 cases not anomalies to the embryo or fetus,
•Infants should be monitored for hypocalcemia
•should be avoided during pregnancy.
Bisphosphonate
•Be safe during pregnancy in prospective trials and can be used during pregnancy].
The antiemeticsmetoclopramide and ondasentron
•can be the analgesic and antipyretic of choice during all phases of pregnancy
Acetaminophen
Corticoids:
methylprednisolone or hydrocortisone is preferred over dexa/betamethasone
glucocorticoids are metabolized in the placenta, so relatively little crosses intothefetal compartment

20. Management of cancer in pregnancy by tumor type
Theincidenceof malignanciesin pregnantwomendoesnotseemtodifferfromthatof non-pregnantwomenof thesameage
mujer no embarazada
mujer embarazada

21. Importantissues
For fetal protection, chemotherapy is contraindicated until 10 weeks’ gestation. With a safety period of 4 weeks, chemotherapy can start from 14 weeks’ gestation
A 3 week interval should be left between the last cycle of chemotherapy and the delivery
Chemotherapy should not be administered after 35 weeks since spontaneous labourbecomes more likely risk of neutropaeniaat the time of delivery
Multidisciplinaryteam; should be performed as in a high-risk obstetric unit
term delivery (P37 weeks) should be aimed for
Vaginal delivery -> lower risk of therapy delay due to lower maternal morbidity
the placenta should be analysed histopathologically

22. EPIDEMIOLOGY
1 in 3000 pregnanciesisassociatedwithcáncer
3% of breast cancers are diagnosed duringpregnancy
Due to the physiological changesbreast cancer diagnosis may be delayed from 2 to 18 months
Breastcáncer
in pregnancy

23. Histopathologicfeatures
Breastcáncer
in pregnancy
•Riskfactorsare similar to those for age-adjusted breast cancer
•Between 60% and 80% (ER) and (PR) negative
•HER2 positivity in 42% vs(39%) in nonpregnant( Resultsare inconclusive)
•Delayed: 65% -90% stage II and III, increase the risk of nodal involvement andmore metastasespooreroutcomes
•Increase in mammary stem cells that are highly responsive to steroid signallingdespite the absence of hormone receptors is unknown

24. Treatment
Surgery with axillary lymph node dissection (ALND) can be
performed during all trimesters of pregnancy with minimal
risk to the fetus .
Chemotherapy during the first trimester should be postponed.
Dosage based on actual height and weight of the patient
Anthracycline based regimens remain the best choice for
adjuvant therapy
Since the safety of taxanes is less documented, it remains the
second best choice for patients previously exposed to
anthracyclines or with contraindication to anthracyclines
Trastuzumab should be avoided during pregnancy.
Breast cáncer
in pregnancy
Termination of
pregnancy does not
seem to improve
maternal outcome
Anthracyclines and
taxanes have a high
molecular weight, a high
protein binding capacity,
are substrates of ATP-binding
cassette
transporters such as P-glycoprotein,
and result in
a low fetal exposure

25. Cervical cancer
Second most common solid tumor encountered during pregnancy
Squamous (80-90%)
Prognosis does not seem to be influenced by pregnancy
10 years earlier than in non-pregnant women 70% stage(Ia-IIa)

26. Cervical cancer
Pre-invasivelesion: Colposcopy/6-8t weeks and definite treatment delayed until after delivery.
IA1: ,conizationduring the second trimester is sufficient
i)Stage > IA1 or positive margins < 12 weeks’ gestation ii) locally advanced and iii) small cell histological subtype, poorly differentiated squamous or adenocarcinoma or disease progression:
-Platinum based neoadjuvantchemotherapy 2nd and 3rd T
-CarboplatinePaclitaxel2-4 C untilfetal maturity
Cesariandelivery is often advocated

27. 8% of allcancersdiagnosedduringpregnancy
Melanoma
most frequently metastasizing to the placenta
28 c.asesdacarbazine-based 2nd and 3rd tr, 1 case minor fetal malformation (syndactyly) and 1 fetal death
No conclusions can be drawn for rate of secondary malignancies in the newborns
adjuvant treatment regimens with high dose interferon have not been studied and are Not routinely recommended
Only women diagnosed with melanoma in pregnancy had a worse prognosis than non- pregnant women

28. 1 in 1000 to1 in 6000 pregnancieswitha media 32 y
Hodgkin’slymphoma
When diagnosed early in pregnancy,->pregnancy termination
Diagnosed in the 1st trimester and preservation of pregnancy is the aim, a “watch and wait” approach until the 2nd trimester is preferred
Forpatientsdiagnosedin the2nd and the3rd trimester, thegoldstandard regimenABVD (doxorubicin, bleomycin, vinblastin, dacarbazine) can be safelyadministered
Prognosis forpregnantpatientswithHL doesnotseemtobe inferior tothatof nonpregnantpatients

29. Leukemiaand lymphomaare thesecondmostfrequentmalignancies, aftermelanoma, thatmetastasizetotheplacenta orthefetus
Prognosis for pregnant patients with NHL does not seem to be inferior to that of non-pregnant patients
Rituximab is not indicated as it may increase the risk of neonatal infections (suppressing the B-cell component of the newborns)
Diagnosis made during the 1st trimester, chemotherapy should be initiated.

30. 14 cases per 100,000pregnancies
Surgery should be offered during the 2nd trimester of pregnancy.
Thyroidcancer
•Follicular or early stage papillary thyroid cancers are candidates for delayed surgical intervention.

31. Ovariancancer
Bilateral alpingooophorectomyafter the 7th w. gestation, when the trophoblastassumes the hormone production-
For advanced stage termination of pregnancy
and complete surgical debulkingis recommended.
If preservation of pregnancy is the aim, hysterectomy may be performed post- partum. Platinum-based chemotherapy during the 2nd and the 3rd
For non-epithelial ovarian cancer the use of BEP (bleomycinetoposide, cisplatin); EP (etoposide, cisplatin); and PVB (cisplatin,
vinblastin, bleomycin) have been reported with no major adverse fetal effects.

32. one case per 13,000 pregnancies
colorectalcancer
diagnosis is delayed
85% below the peritoneal reflection .
Endoscopy only when there is a strong indication. MRI , transrectal ultrasound (CEA)to monitor the response to treatment
First half of the pregnancy surgery adjuvant chemotherapy(or radiotherapy) is needed it can be offered post-partum.
20 weeks of gestation, surgery should be delayed until a viable fetus is delivered (28 -30 weeks)
5-FU with oxaliplatinwas used after the 1st trimester without adverse effect on the fetus

33. Lungcancer
Lessthan 50 cases have been reported in the literature with very poor
prognosis for the patients
Eight patients were treated with systemic therapies during the course of gestation with normal fetal outcome and no evidence of fetal or placental metastases.
Whether gestational lung cancer represents a more aggres-sivedisease entity is still not clear. The available evidence doesnotestablish a distinct biologic behavior of lung cancer duringpregnancy.
Predominantly of adenocarcinomatypeaccounted for the majority of histological diagnosis (77– 87%)and almost all patients presented with advanced disease.
The regimens used were basedon cisplatin or carboplatin combinations with vinorelbine, gem-citabine, etoposide or taxanes [

34. K. Van Calsteren
Frederic Amant

35. UniversityHospital Gasthuisbergin Leuven, Belgium international multicenter project
Initiated in 2005 (INCIP)
(Belgium, the netherlandsand the Czech republic)
International Network for Cancer, Infertility and Pregnancy registry
1011 p. 21 countries (I. 897) .
management modalities
the maternal and fetal outcome
pharmacological study and their transplacentalpassage
effects neurological development

37. outcome
birthweight was below the 10th p 14.9% not related to a specific type of cancer
24.2% Prematurity was common iatrogenic preterm delivery should be avoided
No increasedincidence of congenital malformations after in utero exposure to chemotherapy in the 2nd or 3rd trimester of pregnancy
Not associated with increased CNS, cardiac or auditory morbidity, or with impairments to general health and growth compared with the general population
ESMO 2014
“Fear about the risks of chemotherapy administration should not be a reason to terminate a pregnancy, delay cancer treatment for the mother, or to deliver a baby prematurely”

38. Radiationtherapy
The reduction of the field size and modification of energy minimize the fetal exposure exposureof less than 0.1 Gy( malformations occurred)
Irradiation during the 3rd t. should beavoided( small uterus and the irradiated .
During the first, or early in the second trimester If the patient is motivated to conserve her breast and it is appropriate,
In patients diagnosed 2º o 3ºT RT could well be postponeduntil after delivery.
For cervical cancer
radiotherapy is incompatible with preservation of fetal life

39. ..
Neuropsychological, behavioral and general health outcomes for those exposed to radiotherapy were within normal ranges. One child revealed a severe cognitive delay, however other pregnancy-related complications are confounding factors, they report.
Impact of radiotherapy on the children of women with cancer.
ESMO 2014

40. “We aim to add to the body of evidence that sentinel node biopsy is feasible during pregnancy and should be considered an option.”
Sentinel node biopsy safe for pregnant women with cancer
97 women with breast cancer who underwent sentinel node biopsy., their cancer recurred in the same or other breast
Peccatori:
“Axillary staging in early breast cancer is a changing paradigm. In non-pregnant patients, sentinel node biopsy is an effective staging procedure that holds equivalent results to axillary lymph node dissection even in patients with up to three positive sentinel nodes, if post operative systemic treatment is adequate. Furthermore, hand sentinel node biopsy is associated with improved arm motility, decreased armpit pain and numbness and shorter hospital stay.
Why should we deny this procedure to pregnant breast cancer patients?”

41. Unplanned pregnancy during cancer treatment
Pregnancy for women who became pregnant during cancer diagnosis or during treatment.
The INCIP database 3.23% (29/897) became pregnant after cancer diagnosis or during treatment.
“It is vital for doctors and patients to discuss contraception during cancer diagnosis and cancer treatment”
Although fertility issues are not the focus of attention at this time, it is necessary to provide advice about contraception.
Importance about contraception during cancer diagnosis and cancer treatment.

42. Highly teratogenic.-dose dependent, gestational age, the radiation field and the fractionation.
1.Implantationperiod: all-or-nothingeffect(embryonicdeath or normal development)
2.Up to 8 weeks of gestation: growth and mental retardation > 0.05 Gy
3.Up to 16 weeks of gestation: microcephalyand mental retardation (0.06 and 0.31 Gy)
4.↑risk of carcinogenesis during childhood and adolescence for those exposed to radiation during gestation
Fetal radiationdoses fromcommonimagingtests
Imagingtest
Typicalfetal radiationdose(mGy)
Chest X-ray
<0.01
Abdominal X-ray
1.4
CT of the head
<0.005
CT of the chest
0.06
CT of the abdomen
8.0
CT of the pelvis
9.4
Mammography (bilateral)
<0.01
99mTc bone scintigram
3.3

44. (
MRI can be usedat the1.5 T orlowermagneticfieldstrengths
Gadoliniumthroughtheplacentalbarrier
Reportswithoutadverse effects
(US) has
no documented adverse effects on the fetus
(PET/CT) highradiationdose
Contrast agents gadobenate
dimeglumine(US Food and Drug Administration) and
gadoteratemeglumine(European Medicines Agency)

45. A multidisciplinary approach is mandatory.
Patients should be informed in detail about the risks and benefits of treatment. Their beliefs and wishes should be acknowledged.
The treatment of pregnant patients should take into consideration the physiologicchangesin pregnancy.
Many diagnostic radiographic procedures do not cause harm to the fetus when used with proper shielding.
Open or laparoscopic surgery may be safe in experienced hands.
Systemic chemotherapy should not be started during the first trimester if at all possible.
Most chemotherapeutic agents are safe during the 2nd and the 3rd trimester.
No robust data exist about targeted therapies.
The dosage should be the same as for non-pregnant patients based on actual height and weight of the patient.
Radiation therapy should preferably be given post-partum.
Termination of pregnancy may be considered in case of need for immediate treatment.
No difference in prognosis has been shown after termination of pregnancy.
Differences at the survival rates between pregnant and non-pregnant cancer patients may exist.
No evidence exists that subsequent pregnancies increase the risk fordiseaserecurrence.