M. Carmen Martínez Casanova30/10/2014

Chemotherapy

during pregnancy

:

Definition epidemiology

Preclinical and clinical study

Long-term outcome after in utero exposure

Management of cancer in pregnancy by tumor type

International multicenter project: ESMO 2014

Radiation therapy

“gestational cancer”

Pregnancy-related cancer is defined as cancer diagnosed during pregnancy or within a year after delivery

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

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

Specific physiologic changes in thepregnant

Renal excretion of drugs

Increased ordecreased

hepaticfunction

Gastrointestinal absorption orenterohepaticcirculation a

plasma proteinbinding.

Amniotic fluid

3rd compartment

Drugs withmolecular

weight less than600 kDa may

cross theplacenta

Agents thatlipophilic or

remain in theun-ionized statemay cross the

placenta

The teratogenicity of these agents has been demonstrated in animals, Case reports and small studies.

Prospective, randomized trials examining theadverse effects of specific chemotherapeuticagents during pregnancy are not available in

humans for obvious ethical reasons.

(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

placenta will act as a barrier

for

the transfer of most

hemotherapeutic drugs,

reducing fetal exposure

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 was31- 65% of the maternal concentration

and all patients delivered healthy babies

Long-term outcome after in utero exposure tochemotherapy remains a major concern

Aviles et al. examined 84 children educational performance were normal without congenital, neurologic, psychologic, cardiac, cytogenetic abnormalities

or malignancies indicate even better outcome than in

non treated cohorts mf 18.7 y

Van Calsteren et 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).

• 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

Zemlickis D,

Anti-metabolites

Cytarabine 34 leukemia(9 1erT)

brachycephaly, hypoplasia cranial base, four-finger hands andabsent radio; C trisomy mosaicism; 46 chromosomes karyotype; 3 cases of intrauterine death, 5 low birth weight, 4 pancytopenia

5 - FU 53 1er T; 57 2º -3º T

6 IUGR; 1 fetal 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; 5 cases of IUGR

Methotrexate 17 c cancer orrheumaticdisease18 p withleukemia

2 c intra-uterine death, 5c IUGR; 7 aminopterin síndrome, skeletalabnormalities and ambiguous genitalia

Anthracycline antibiotics

Peccatori et al. reported the feasibility and safety of weekly low dose single agent epirubicin after the 1st

trimester in 20 patients with gestational breast cancer.

Concerns exist about safety of daunorubicin and especially idarubicin: cases of

cardiomyopathy, limb deformities and ventricular septal defect in newborns

despite use after the 1st trimester Idarubicin is 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 Adriamycin orEpirubicin and doxorubicinFrédéric Amant,

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

Biologic agents

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

Others Biologic agents

Lapatinib

• Healthy baby after exposure but transplacental transfer

• use of anti-HER2 agents, its use during pregnancy cannot be recommended

Imatinib.

• Teratogenic effects in mice and rats during organogenesis

• 180 p. (9.6%) fetal abnormalities.

Dasatinib and nilotinib.

• limited experience in pregnant,

sunitinib and sorafenib

• No clinical data

bevacizumab

• embryo-fetal developmental toxicity of sunitinib in rats and rabbits

Erlotinib

• In animal models embryo/fetal lethality

During pregnancy the use of TKIs should be avoided,especially during the 1st trimester.

Hormonal therapy

Tamoxifen

can disturb the hormonal environment

and so such treatments should be delayed

Tamoxifen is associated with birth defects including craniofacial malformations and ambiguous genitalia,Goldenhar syndrome(oculoauriculovertebral dysplasia) and fetal death.

Women using tamoxifen should be strongly advised to use active contraception or discontinue its use in case of pregnancy.

Other agents

• 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/betamethasoneglucocorticoids are metabolized in the placenta, so relatively little crosses into thefetal compartment

Management of cancer in pregnancy by tumor type

The incidence of malignanciesin pregnant women does notseem to differ from that of non-pregnant women of thesame age

mujer no embarazada

mujer embarazada

Important issues

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 neutropaenia at 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

EPIDEMIOLOGY

1 in 3000 pregnancies isassociated with cáncer

3% of breast cancers are diagnosed during pregnancy

Due to the physiological changes breast cancer diagnosis may be delayed from 2 to 18 months

Breast cáncer

in pregnancy

Histopathologic features

Breast cáncer

in pregnancy

• Risk factors are similar to those for age-adjusted breast cancer• Between 60% and 80% (ER) and (PR) negative• HER2 positivity in 42% vs (39%) in nonpregnant ( Results are

inconclusive)• Delayed: 65% - 90% stage II and III, increase the risk of nodal

involvement and more metastases poorer outcomes• Increase in mammary stem cells that are highly responsive to

steroid signalling despite the absence of hormone receptors is unknown

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 patientAnthracycline based regimens remain the best choice for adjuvant therapySince the safety of taxanes is less documented, it remains the second best choice for patients previously exposed toanthracyclines or with contraindication to anthracyclinesTrastuzumab 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 highprotein binding capacity, are substrates of ATP-binding cassette transporters such as P-glycoprotein, and result in a low fetal exposure

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)

Cervical cancer

Pre-invasive lesion : Colposcopy /6-8t weeks and definite treatment delayed until after delivery .IA1: , conization during the second trimester is sufficienti) 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 neoadjuvant chemotherapy 2nd and 3rd T - CarboplatinePaclitaxel 2-4 C until fetal maturity

Cesarian delivery is often advocated

8% of all cancers diagnosed during pregnancy

Melanoma

most frequently metastasizing to the placenta

28 c.ases dacarbazine-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

1 in 1000 to 1 in 6000 pregnancies with a media 32 y

Hodgkin’s

lymphoma

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

For patients diagnosed in the 2nd and the 3rd trimester, thegold standard regimen ABVD (doxorubicin, bleomycin, vinblastin, dacarbazine) can be safely administered

Prognosis for pregnant patients with HL does not seem to be inferior to that of nonpregnant patients

Leukemia and lymphoma are the second most frequent malignancies, after melanoma, that metastasize to the placenta or the fetus

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.

14 cases per 100,000 pregnancies

Surgery should be offered during the 2nd trimester of pregnancy.

Thyroid cancer

• Follicular or early stage papillary thyroid cancers are candidates for delayed surgical intervention.

Ovarian cancer

Bilateral alpingooophorectomy after the 7th w. gestation, when the trophoblast assumes the hormone production-

For advanced stage termination of pregnancyand complete surgical debulking is 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 (bleomycin etoposide, cisplatin); EP (etoposide, cisplatin); and PVB (cisplatin,

vinblastin, bleomycin) have been reported with no major adverse fetal effects.

one case per 13,000 pregnancies

colorectal cancer

diagnosis is delayed85% 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 oxaliplatin was used after the 1st trimester without adverse effect on

the fetus

Lung cancer

Less than 50 cases have been reported in the literature with very poorprognosis 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-sive disease entity is still not clear. The available evidence doesnot establish a distinct biologic behavior of lung cancer duringpregnancy.

Predominantly of adenocarcinomatype accounted 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 [

K. Van Calsteren

Frederic Amant

University Hospital Gasthuisberg in Leuven, Belgium international multicenter project

Initiated in 2005 (INCIP)

(Belgium, the netherlands and 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 transplacental

passage

effects neurological development

outcomebirthweight 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 increased incidence 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”

Radiation therapy

The reduction of the field size and modification of energy minimize the fetal exposure exposure of 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 cancerradiotherapy is incompatible with preservation of fetal life

..

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

“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?”

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.

Highly teratogenic .- dose dependent, gestational age, the radiation field and the fractionation.

1. Implantation period: all-or-nothing effect (embryonic death or normal development)

2. Up to 8 weeks of gestation: growth and mental retardation > 0.05 Gy

3. Up to 16 weeks of gestation: microcephaly and mental retardation (0.06 and 0.31 Gy)

4. ↑ risk of carcinogenesis during childhood and adolescence for those exposed to radiation during gestation

Fetal radiation doses from common imaging tests

Imaging test Typical fetal radiation dose

(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

(

MRI can be used at the 1.5 T or lower

magnetic fieldstrengths

Gadolinium throughthe placental barrier

Reports withoutadverse effects

(US) has

no documented adverse effects on

the fetus

(PET/CT) highradiation dose

Contrast agents gadobenatedimeglumine (US Food and Drug Administration) andgadoterate meglumine(European Medicines Agency)

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 physiologic changes in 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 for disease recurrence.