ESMO E-learning: Cancer Management During Pregnancy · Crosses the placenta ... Gadolinium crosses the placenta and causes foetal abnormalities in rats, MRI causes heating/cavitation

Cancer management during pregnancy

Stergios Boussios, MD

Resident in Medical

Oncology

Medical School

University of Ioannina,

Greece

George Pentheroudakis, MD PhD

Assistant Professor of Oncology

Medical School


Greece

Nicholas Pavlidis, MD, PhD, FRCP (Edin)Professor in Medical Oncology

School of Medicine,


Greece

An important topic…

1. Involves two people, the mother and the foetus

2. Should aim for optimal maternal treatment and safeguard foetal

well-being (when the two are compatible!)

3. Trend for delaying pregnancy into the later reproductive years:

expected to see more cases of cancer complicating pregnancy

4. Medical, ethical, psychological and religious issues

“Optimal Gold Standards”

1. To try to benefit mother’s life

2. To try to treat curable malignant disease of pregnant women

3. To try to protect foetus and new-born from harmful effects of

cancer treatment

4. To try to retain mother’s reproductive system for future gestations

Occurrence of cancer in pregnancy

� Cancer is the 2nd most common cause of death during the

reproductive years

� The occurrence of cancer in a pregnant woman is relatively rare

(0.07 - 0.1% of all malignant tumours)

� In Europe, yearly 3,000 to 5,000 patients are diagnosed with

cancer during pregnancy

� Annually in USA there are 3,500 cases (about 1 case every 1,000

pregnancies)

Epidemiology

� Incidence of malignant tumours during gestation

Tumour type Incidence*

Breast cancer 1:3,000-10,000

Cervical cancer 1.2:10,000

Hodgkin’s disease 1:1,000-6,000

Melanoma 2.6:1,000

Leukaemia's 1:75,000-100,000

Ovarian cancer 1:10,000-100,000

Colorectal cancer 1:13,000

*Malignant tumours per pregnancies or deliveries

Pavlidis N. Oncologist 2002;7(4):279-287

Chemotherapy safety

When a drug is

administered to the

mother, placental transfer of the drug

could be hazardous

to the foetus

Reprinted from Cardonick E et al. Lancet Oncol 2004;5(5):283-291, with permission from Elsevier

Chemotherapy safety

Reprinted from Cardonick E et al. Lancet Oncol 2004;5(5):283-291, with permission from Elsevier

Chemotherapy during pregnancy

� Most drugs with MW<600 KDa are capable of crossing the placenta.

Chemotherapy agents have a MW of 250-400 KDa

� PK changes in pregnancy: Increased plasma volume, increased

renal clearance of drugs, faster hepatic oxidation, reduced albumin

levels, third space (amniotic fluid)

� In most cases toxic effects were reported when treatment was given

during embryogenesis in the first trimester

� Most of the available data on the teratogenic risks of

chemotherapy are based on case reports and retrospective series.

More data are needed

Effects of chemotherapy by gestational stage

Stage Effect

1st trimester Abortion 20-30%

Malformations 10-25%

2nd and 3rd trimesters IUGR, low birth weight, miscarriage,

premature birth 20-40%

Perinatal period Maternal/foetal myelosuppression,

infections, haemorrhage

Late effects No detrimental effects on physical and

neurocognitive function, gonads or

second tumours

IUGR = intrauterine growth restriction

Potential for abortion/malformations by drug type

High

� Aminopterin

� Methotrexate

� Chlorambucil

� Busulfan

� Cyclophosphamide

� Mustard

� Procarbazine

� Ara-C

� Tamoxifen

Low

� 5FU

� Doxorubicin

� Daunorubicin

� Vinca alkaloids

� Interferon

Unknown

� Taxanes

� Platinum compounds

� Rituximab

� Imatinib

� Trastuzumab

� Other mAbs

Cardonick E et al. Lancet Oncol 2004;5(5):283-291

Long-term follow-up of people exposed to chemotherapy in utero

� Aviles et al. 2001: FU of 84 children for a median of 19 years

� Normal physical, neurological, psychological development

� Normal sexual development-12 became parents

� No increased risk for second tumours

� Nulman et al. 2001: Summary of 111 children followed up for 2-19

years

� Normal physical

� Normal neurological development

Avilés A et al. Clin Lymphoma 2001;2(3):173-177;

Nulman I et al. Br J Cancer 2001;85(11):1611-1618. Review

Supportive care Hormonal therapy

� Ondansentron + metoclopramide:

� Safe during pregnancy (most accumulated data and two prospective

RCTs)

� Erythropoietin:

� Not crossing placenta

� No reported teratogenic effects

� Transfusions preferable?

� GCSF:

� Crosses the placenta

� No teratogenesis in rats or humans

� Use only in absolute need for protracted febrile neutropenia

� Biphosphonates:

� Not recommended bone and renal malformations in animals

Biological effects of ionising radiation

� Deterministic effects: Biological effects due to severe cellular

damage

� Characterised by a «threshold dose» and by severity that increases

with absorbed dose

� Abortion, stillbirth, congenital malformations, mental

retardation, IUGR, low birth weight

� Stochastic effects: Biological effects due to radiation-induced

modifications of cells (mutations)

� No safe «threshold dose» exists

� According to the Linear - No Threshold Model, the probability of

appearance of stochastic effects diminishes with lower absorbed

doses, though the severity does not

� Second cancers during childhood or adult life

Safety of radiodiagnostic procedures: Stochastic effects

� Stewart et al. 1956

� Mac Mahon et al. 1962

� In utero exposure to radiodiagnostic procedures has an increased risk (1.3 - 3.0) of leukaemia or solid tumours, especially when exposure was

during the 1st trimester

� Helmrot et al. 2007

� No increased risk of leukaemia or second tumours in 652 children

irradiated with diagnostic x-ray in utero

� Absolute risk for entire life span: 0.015%/mGy

Stewart et al. 1956;

MacMahon B et al. J Natl Cancer Inst 1962;28(5):1173-1191;

Helmrot E et al. Eur Radiol 2007;17(1):205-209

Radiation dose guidelines: Deterministic effects

Dose Foetus effect

Up to 100 mGy No major effect

>100 to 200 mGy Increased risk

>2000 mGy Malformations in most or abortion

Absorbed dose: 1 Gy = 1 Joule/Kg = 100 cGy or rad

Equivalent dose: 1 Sv = 1 Gy x Wr

Adverse effects of radiation in relation to gestational stages

Recommended staging imaging tests in pregnant women with cancer

� Should be limited to those associated with the lowest exposure to

ionising radiation

� Abdominal plain films, isotope scans, PET scans and CT-scans

should be avoided

� Chest X-ray (lead apron) and abdominal ultrasound can be indicated

and are safe

� Nicklas et al. , Semin Oncol 2000;27:623:

� Gadolinium crosses the placenta and causes foetal abnormalities in

rats, MRI causes heating/cavitation in early embryos

Nicklas AH and Baker ME. Semin Oncol 2000;27(6):623-632

Breast cancer associated with pregnancy (1)

INCIDENCE

� Approximately 1:3,000-10,000 pregnancies (the most common)

� 3% of all breast cancer is associated with pregnancy

� Pregnancy-associated breast cancer is defined as cancer that is

diagnosed during pregnancy or within 1 year postpartum

� Median age: 33 years (23-47)


DIAGNOSIS

� Mammography sensitivity: 68% (due to increased density and

congestion)

� Ultrasonography sensitivity: 93%

� FNA, Open or Core Needle breast biopsy confirms diagnosis

� Pregnant women have a 2.5 - fold higher risk to present with

advanced disease

Breast cancer features in pregnant women (3)

1. Invasive ductal

2. Grade 2-3 60-80%

3. Lymph node involvement 40-75%

4. HR negative 40-80%

5. HER2 overexpression 20-40%

Similar to all non-pregnant

women with breast cancer

<40 years old

With permission of Pentheroudakis G. ESMO 2008; Bonnier P et al. Int J Cancer 1997;72(5):720-727; Colleoni M et al. Ann Oncol 2002;13(2):273-279; Middleton LP et al. Cancer 2003;98(5):1055-1060; Miller KD et al. J Clin Oncol 2005;23(4):792-799; Rodriguez AO et al. Obstet Gynecol 2008;112(1):71-78


MD Anderson (57)Hahn K et al.

Cancer 2006

IEO (20)Peccatori F et al.

Breast Ca Res Treat 2009

FAC Regimen Weekly epirubicin

37 W Gestational age at delivery 35 W

2/57 (4%) Pre-term pregnancies 1/20 (5%)

3/57 (5.3%) Congenital anomalies 1/20 (5%)

70%

77%

Maternal outcome at 38m

DFS

OS

70%

85%

Hahn KM et al. Cancer 2006;107:1219-1226;

Peccatori FA et al. Breast Cancer Res Treat 2009;115(3):591-594


Treatment of cancer during pregnancy: the need for tailored

strategies*

Why weekly?

� Allow close monitoring of pregnancy

� Low peak plasma concentration resulting in

� Lower toxicity (more safe)1

� Possible lower placental transfer & foetal exposure2

� Easy interruption in case of toxicity

� Efficacy of weekly regimens is established outside pregnancy3

*Azim HA and Peccatori FA. J Clin Oncol 2010;28(18):e302-e303;1. Norton L et al. Oncologist 2005;10(6):370-381;2. Zucchetti M. Personal communication;3. Ellis MJ et al. J Clin Oncol 2011;29(17):2342-2349


� Foetal outcome (chemo vs. no chemo)

� Median birth weight at delivery: 2760 gm (vs. 2810)

� Median gestational age at delivery: W37 (vs. W38)

� Median HB level post-partum: 16 g/dl

� European Registry on BC during pregnancy

Total number of patients 315

Treated with chemotherpay 121 (51%)

Treated with anthracycline-based regimens 95 (78%)

AC/EC 71

FEC 20

Single agent epirubicin/doxorubicin 4

Loibl S et al. Proc SABCS 2010;Abstract S6-S2


Long-term effects of in utero exposure to doxorubicin-based regimens

Median FU Number Late effects

Doxorubicin-based

regimens

(leukemia/lymphoma)18 Y 89 None

FAC (CI Doxo) 6 Y 18 None

Avilés A et al. Ann Oncol 2006;17(2):286-288;

Hahn KM et al. Cancer 2006;107:1219-1226


Long-term effects of in utero exposure to weekly epirubicin (n=30)

Age 0-1 Age 2-3 Age 4-5 Age 6-7 Age 8

No 5 10 9 3 3

Normal development!

Updated Peccatori F et al. Breast Cancer Res Treat 2009;115(3):591-594


Taxanes in gestational breast cancer

NumberBreast cancer

Other2713

RegimenPaclitaxelDocetaxel

Both

21163

Neonatal outcomeGestational age at delivery

Foetal weightMedian FU 18 m

W 362400 g

No anomalies reported

Mir O et al. Ann Oncol 2010;21(2):425-426


Transplacental transfer of chemotherapy in baboon models

Van Calsteren V et al. Gynecol Oncol 2010;119:594-600;

Van Calsteren V et al. Int J Gynecol Cancer 2010;20:1456-1464


CMF in pregnancy

� CMF: Normal outcome in 2nd, 3rd trimester exposure (25 cases)1

� CMF < “Anthracyclines” < “Anthra + Taxanes”2

� MTX used in induction of abortion3

� 1st trimester exposure = highly teratogenic4

AVOID during PREGNANCY 1st trimester

1. Azim HA Jr et al: Cancer Treat Rev 2010;36(2):101-109;2. Bedard PL and Cardoso F. Ann Oncol 2008;19(suppl 5):v122-v127;3. Say L et al. Cochrane Database Syst Rev 2005;(1):CD003037;4. Aebi S and Loibl L. Recent Results Cancer Res 2008;178:45-55. Review


HER2 plays a pivotal role in the development

of different foetal organs

LUNG KIDNEY INTESTINE SKIN

Patel NV et al. Am J Respirol Mol Biol 2000;22(4):432-440; Courtesy of Kokai Y et al. Proc Natl Acad Sci U S A 1987;84(23):8498-8501


TRASTUZUMAB IN GESTATIONAL BREAST CANCER

Number of cases (2005-2011) 17

Setting

In combination with Chemotherapy Hormonal therapy Alone

4 2 11

Time Preconception to 3rd trimester

Pregnancy

Anhydramnios 10/17 (59%)

Ectopic pregnancy/abortion 2/17 (12%)

PROM 1/17 (6%)

IUGR 1/17 (6%)

Baby

Respiratory failure 6/17 (35%)

Renal failure 3/17 (18%)

Death 4/17 (23,5%)

Premature 1/17 (6%)

IUGR = intrauterine growth restriction, PRO = premature rupture membranes

Trastuzumab and the amniotic fluid


� Anhydramnios

� Trastuzumab blocks HER-2 expressed in foetal kidney

� It interferes with VEGF signalling responsible for amniotic fluid

production and reabsorption

Sekar R and Stone PR. Obstet Gynacol 2007;110(2 Pt 2):507-510;

Pant S et al. J Clin Oncol 2008;26(9):1567-1569


Facts about tamoxifen

� Pregnancy is possible on tamoxifen

� Moreover, currently used in induction of ovulation and licensed in

the UK for managing infertility

� Preclinical models have shown that it causes ambiguous genitalia

and ++ genital cancers in off springs

Barthelmes L and Gateley CA. Breast 2004;13(6):446-51. Review


Biphosphonates

� Concerns

� Preclinical models: Skeletal deformities, genital defects

� Maternal hypocalcaemia: Affects uterine contraction

� However

� A systematic review of literature till 09-2008

� 52 patients exposed (mainly osteoporosis): Normal outcomes

Patlas N et al. Teratology 1999;60(2):68-73;

Ornoy A et al. Reprod Toxicol 2006;21(4):446-457;

Djokanovic N et al. J Obstet Gynaecol Can 2008;30(6):505-507


� Recommendations of an international consensus meeting

� Surgery:

� Breast conserving surgery or mastectomy

� Sentinel procedure or axillary dissection

� (Neo-) Adjuvant chemotherapy

� From 14 weeks on

� Currently used cytotoxic drugs are allowed

Diagnosis of breast cancer in pregnancy

Before term (before 37 weeks)Near term (37 weeks)*

Delivery at ≥37 weeks

Staging and treatment

Amant F et al. Eur J Cancer 2010;46(18):3158-3168


Number 12

Median age (range) 38 (33-42)

Clinical stage T1N0 (7); T2N0 (5)

Median gestational age at SLN

(range)

17w (5-33w)

SLN outcome 10 –ve; 2 +ve

At 32 months of FU

• Patient

• Babies

No axillary recurrence

Normal development

Gentilini O et al. Eur J Nucl Med Mol Imaging 2010;37:78-83


� Recommendations of an

international consensus meeting

“…The Panel encountered scarce literature data on the outcome of

children whose mothers were given therapeutic irradiation during BCP…”

“…However, based on data on long term outcome of pregnant atomic bomb

survivors and based on theoretical assumptions, the Panel accepts radiotherapy as a relatively safe

treatment option during the first and second trimester of pregnancy.

The Panel states that better clinical data are needed”

Before term (before 37 weeks)

Diagnosis of breast cancer in pregnancy

Near term (37 weeks)*

Delivery at ≥37 weeks

Staging and treatment

� Surgery:

� Breast conserving surgery or mastectomy

� Sentinel procedure or axillary dissection

� (Neo-) Adjuvant chemotherapy

� From 14 weeks on

� Currently used cytotoxic drugs are allowed

No chemotherapy after 35 weeksSchedule delivery ≥37 weeks

Chemo-delivery interval of 3 weeks

Amant F et al. Eur J Cancer 2010;46(18):3158-3168

Do patients with GBC have worse prognosis compared

to matched controls ?


Limitations:

� Small-sized (lack of power)

� Multi-institutional

� Lack of matching according to stage – therapy

� Scarce information regarding pathological features

Around 30 published case-control trials with conflicting results!


Unpublished data

Recent studies… (1)

Prognosis of Women With Primary Breast Cancer Diagnosed During Pregnancy: Results From an International Collaborative Study

� Two international multicenter cohort studies collaborated in this initiative

� Aim of the study � Estimation of the prognostic impact of pregnancy when

breast cancer is diagnosed

� Results� 447 women with BCP registered, of whom 311 were eligible for this analysis.

� 240 (77.2%) of 311 patients were included prospectively

� These 311 patients were compared with 865 women with breast cancer who were not

pregnant (ratio 1:2.78)

� The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19

(95% CI, 0.73 to 1.93; P = .51) for OS

� Treatment� Pregnant patients � Administration of taxanes to 95 (47.03%) with adjuvant chemotherapy

and to 69 (71.13%) with neoadjuvant chemotherapy

� Nonpregnant patients � Administration of taxanes to 168 (30.88%) with adjuvant

chemotherapy and to 79 (77.45%) with neoadjuvant chemotherapy

� Conclusion� Similar survival for patients between pregnant and non pregnant patients with breast cancer

Amant F et al. J Clin Oncol 2013;31(20):2532-2539


Prognosis of Pregnancy-associated Breast Cancer: A Meta-analysis of 30 Studies

� Comprehensive analysis of all published studies that addressed the prognosis of pregnancy-associated breast cancer

� The primary and secondary end-points were overall and disease-free survival

� Overall survival

� Significantly worse OS compared to breast cancer controls (pHR: 1.44; 95% CI [1.27–1.63])

� Disease free survival

� Significant risk of relapse compared to controls (pHR: 1.60; 95% CI [1.19–2.16])

� Conclusions

1. Poorer prognosis because diagnosis is delayed in new mothers

2. Pregnancy has an independent effect on prognosis via influencing the biology of breast cancer

3. Breast cancer arising postpartum was significantly associated with poor OS

4. The trend was not as substantial in patients diagnosed during pregnancy

5. Poorer overall survival is particularly obvious in patients diagnosed in the 1-year post-partum period than those diagnosed during pregnancy

Azim HA Jr et al. Cancer Treat Rev 2012;38(7):834-842


Treatment of Breast Cancer During Pregnancy: An Observational Study.

� 447 patients were registered, 413 of whom had early breast cancer

� Primary endpoint � foetal health for up to 4 weeks after delivery

� Birth weight was affected by chemotherapy exposure after adjustment for gestational age (p=0.018), but not by number of chemotherapy cycles (p=0.71)

� 40 (10%) of 386 infants had side-effects, malformations, or new-born complications

� More common in infants born before the 37th week of gestation (p=0.0002)

� Adverse events were more common in those who received chemotherapy in utero

compared with those who were not exposed (p=0.00045)

� Median disease-free survival for women with early breast cancer

� 70.6 months in women starting chemotherapy during pregnancy

� 94.4 months in women starting chemotherapy after delivery

� Delay of cancer treatment did not significantly affect disease-free survival for mothers with early breast cancer

� Preterm birth was strongly associated with adverse events.

Loibl S et al. Lancet Oncol 2012;13(9):887-896


� Elective systemic therapy in pregnancy: Summary

Consider

weekly

application


How safe is pregnancy after breast cancer?

Practical guidelines

(despite controversies)

� Patients with early stage

disease (stage I-II), a delay of

at least 2 years is necessary

� Patients with stage III should

be deferring pregnancy for at

least 5-years

� Patients with stage IV should

not consider conception at all

Author YearNo. of cases

RR of death

Ives 2006 123 0.59

Blakely 2004 47 0.71

Mueller 2003 438 0.54

Vellentgas 1999 53 0.80

Kroman 2008 465 0.73

Von Schoulz 1995 50 0.48

Sankila 1994 91 0.20

Pregnancy safety after breast cancer (27)

Practical guidelines

(despite controversies)

� Patients with early stage

disease (stage I-II), a delay of

at least 2 years is necessary

� Patients with stage III should

be deferring pregnancy for at

least 5-years

� Patients with stage IV should

not consider conception at all

Time to pregnancy RR of death

2-3 years 0.49

3-4 years 0.30

4-5 years 0.19

Mueller BA et al. Cancer 2003;98(6):1131-1140

Conclusions

� Treatment during pregnancy is feasible, but

� It is safe to consider pregnancy in women with history of

successfully treated BC. According to our results, counselling

against pregnancy in these patients is not justified

� Caution should be made as the data used for analysis is not

individual patient data, but rather, abstracted data

“Though the narrowness of today might reassure us that an

intervention is safe, it is only with the wisdom of time that the full

consequences of our actions are revealed”

Goodman A. New Engl J Med 2010;362(11):e37

Cervical carcinoma associated with pregnancy (1)

Incidence

� One of the most common malignancy during pregnancy

(1: 1,000-10,000)

� Incidence varies from 0.02% - 0.9%

� The incidence recently declines due to effective screening

Diagnosis

� Pregnant women have a 3.1- fold higher chance of early detection

(stage I) due to frequent obstetrical examinations

� Colposcopy and colposcopy-directed biopsy can be safely

performed in women with abnormal Pap smear


STAGE 0 (CIN)

� Conservative management

� Use colposcopy every 6-8 weeks (or colposcopical bx)

� Delay treatment postpartum

� 25% of lesions can regress spontaneously

� Avoid cone bx or conisation. Abortion rates 17%

� Avoid conisation. Abortion rate 33%

Management – pregnancy preserving

SURGERY – literature


� IA1

� Conisation1

� IA2

� Simple trachelectomy + lymphadenectomy2

� IB1, IB2

� Conisation + lymphadenectomy3,4

� Vaginal radical trachelectomy + lymphadenectomy5,6

� Abdominal radical trachelectomy + lymphadenectomy7-9

With permission of Pavlidis N. ESMO 2012;1. Robova H et al. Eur J Gynecol Oncol 2005;26(6):611-614;2. Ben-Arie A et al. Obstet Gynecol 2004;104(5 Pt 2):1129-1131;3. Van Calsteren K et al. Acta Obstet Gynecol Scand 2008;87(2):250-253;4. Marnitz S et al. Fertil Sterili 2009;92(5):1748.e1-e4; Herod, JJO, IJOG, 2010, own case;5. van de Nieuwenhof HP et al. Int J Gynecol Cancer 2008;18(6):1381-1385;6. Iwami N et al. Int J Clin Oncol 2011;16(6):737-740;7. Ungár L et al. Obstet Gynecol 2006;108(3 Pt 2):811-814;8. Abu-Rustum N et al. Gynecol Oncol 2009;116(1):151-152;9. Mandic A et al. Am J Obstet Gynecol 2009;201(2):e6-e8

Management – pregnancy preserving

NEOADJUVANT CHEMOTHERAPY


� IB1 (>2 cm), IB2

� Postpone surgery/delivery

� Regimen:1

� Carboplatin 6 AUC + paclitaxel 175 mg/m2 every 3 weeks

� Cisplatin 75 mg/m2 + paclitaxel 175 mg/m2 every 3 weeks

� Other: Cytostatics, interval� Cisplatin 75 mg/m2 + doxorubicin 35 mg/m2 every 2 weeks *

� Cisplatin 75 mg/m2 + paclitaxel 175 mg/m2 every 2 weeks *

� Cisplatin 75 mg/m2 every 10 days

� Cisplatin 50 mg/m2 + vincristine 1 mg/m2 every 3 weeks

With permission of Pavlidis N. ESMO 2012;1. Amant F et al. Int J Gynecol Cancer 2009;19(suppl_1):S1-S12


STAGE II, III, IV

� Therapeutic abortion or watchful waiting (if 3rd trimester pregnancy)

� If foetus viable preoperative caesarean section

� Radical hysterectomy or Radiotherapy: treatments of choice

� Neoadjuvant chemotherapy (buys time for waiting?)

� Radical trachelectomy + laparoscopic LN dissection for fertility

preservation in selected patients

Prognosis of cervical carcinoma associated with pregnancy (6)

� No difference in maternal

survival between pregnant and

non-pregnant women1

� More frequent local relapses in

women who had a vaginal

delivery in comparison to those

who had caesarean section

(p=0.04)2

� No difference found3

InvestigatorNo. of

pregnant patients

5-year OS

Tarushim 28 72%

Van der

Vange44 80%

Sood 93 79%

Jones 161 82%

1. Jones WB et al. Cancer 1996;77(8):1479-1488; Zemlickis D et al. 1991;9(11):1956-1961;2. Sood AK et al. Obstet Gynecol 2000;95(6 Pt 1):832-838;3. van der Vange N et al. Obstet Gynecol 1995;85(6):1022-1026


Zemlickis D et al. J Clin Oncol 1991;9(11):1956-1961. Reprinted with permission. © (1991) American Society of Clinical Oncology.All rights reserved

Ovarian cancer (1)

� Incidence 4-5 / 100,000

� 2-5% of pregnancies are complicated by ovarian mass (25,000 pt)

� 90% of cases regress spontaneously till 12th week of pregnancy1

� Ovarian malignancy is usually diagnosed at early stage (60-80% in

stage I)

� Ultrasound CA 125, AFP, HCG, CEA

� Histopathology:

� 50-60% epithelial tumours

� 25-40% germ cell tumours

� 5-10% sex cord tumours

1. Giuntoli RL 2nd et al. Clin Obstet Gynecol 2006;49(3):492-505; Bernhard LM et al. Obstet Gynecol 1999;93(4):585-589

Ovarian cancer-management (2)

� IA, G1 / borderline tumours

� Adnexectomy, omentectomy, peritoneal washings, bs

� Post-delivery restaging

� IA, G2, G3, IB, IC, IIA

� Lymphadenectomy (till 20th week of pregnancy)

� Postpone lymphadenectomy and radical surgery after delivery

� Adjuvant chemotherapy

� IIB and higher

� Radical surgery + termination of pregnancy1

� Cytoreductive surgery + chemotherapy + surgery during pregnancy2

� Cytoreductive surgery + chemotherapy during pregnancy + restaging

after delivery3

1. Tewari K et al. Gynecol Oncol 1997;66(3):531-534;2. Machado F et al. Gynecol Oncol 2007;105(2):446-450;3. Picone O et al. Gynecol Oncol 2004;94(2):600-604

Ovarian cancer-management (3)

Neoadjuvant / adjuvant chemotherapy

� Epithelial ovarian tumours

� Paclitaxel 175 mg/m2 + carboplatin 6 AUC

� Paclitaxel 175 mg/m2 + cisplatin 75 mg/m2

� Non-epithelial ovarian tumours

� 1st choice: Paclitaxel + carboplatin

� 2nd choice: Bleomycin, etoposide ?, Cisplatin1

� Alternative: Cisplatin + bleomycin

1. Amant F et al. Int J Gynecol Cancer 2009;19(suppl_1):S1-S12

Ovarian cancer (4)

Prognosis

� Similar prognosis to non-pregnant population (histology and stage

matched)

� Prognosis is quite favourable since most ovarian cancers are of low

grade and stage

� 5-year survival rate: 60-75%

Melanoma associated with pregnancy (1)

� 30 – 35% of melanomas in women occur during child-bearing years

� The real incidence of melanomas during pregnancy is unknown

� The estimated incidence of melanomas in pregnancy is from 2.8 – 5

cases / 100,000 pregnancies

� Swedish Cancer Registry 1973-1984: Melanoma was the most

common tumour of pregnant women (25% of total)

� Superficial spreading and nodular melanomas1

� Diagnosis: Excisional biopsy safe

1. Lens MB and Dawes M. Br J Dermatol 2004;150(2):179-185


Management

� Wide local excision with 1-2 cm margins under general or regional

anaesthesia

� Stage I-II: ELND or SLNB (avoid the methylene blue dye) probably

safe. Survival benefit has not been proven (MSLT-1 trial)

� Stage III-IV: Therapeutic lymph node dissection should be

performed, as well as resection of satellite, in-transit or isolated

metastases


Effect of pregnancy on melanoma

� Mortality 50%!1

� 5 controlled studies failed to show inferior survival of pregnant

women with melanoma compared to matched non-pregnant patients

� 10-year OS of 85% vs. 82% for >500 pregnant women vs. 5000

non-pregnant women with melanoma2

1. Pack GT and Scharnagel IM. Cancer 1951;4(2):324-334;2. Lens MB et al. J Clin Oncol 2004;22(21):4369-4375

OR

GI malignancies associated with pregnancy (1)

� Colorectal cancer: 350 cases reported

� Gastric cancer: Very rare, 150 cases reported

� Pancreatic cancer: Exceedingly rare

� Hepatoma: Exceedingly rare, 45 cases reported

GI cancers in pregnancy

Management of localized colorectal cancer after first 24 weeks of gestation

� Watch-and-wait till delivery in week 32-34 and surgery

� Pregnancy termination and surgery

� Attempt surgery and continuation of pregnancy

� RT only possible after pregnancy termination or post partum

OR

GI malignancies associated with pregnancy (2)

� Termination of pregnancy and chemotherapy during 1st trimester

� Chemotherapy in 2nd and 3rd trimesters safe

� Only case reports on bevacizumab, cetuximab, erlotinib,

oxaliplatin

� Pre-eclampsia is caused by high levels of VEGF inhibitors

Advanced disease

Lymphoma associated with pregnancy (1)

� Hodgkin lymphoma : 1 :1,000 – 1: 3,000 deliveries

� Non- Hodgkin lymphoma : 1: 5,000 deliveries

Is immediate treatment necessary?

� During 1st trimester pregnancy termination might be considered

because of higher risk of congenital anomalies

� Starting from 2nd trimester combination chemotherapy is feasible

and safe

� Patients close to term are good candidates to delivery anticipation

Hodgkin lymphoma during pregnancy: Treatment

Lymphoma associated with pregnancy (2)

With permission of Pentheroudakis G. ESMO 2008

Systemic treatment of Hodgkin lymphoma during pregnancy (3)


Prognosis of Hodgkin lymphoma during pregnancy (4)

Does pregnancy affects prognosis?

� In a review of 112 pregnancies among 374 women of childbearing

age with HL, pregnancy did not exacerbate HL and did not affect

the outcome1

� A review of 21 pregnant women among 155 patients with HL

confirmed that survival is similar despite a slightly higher incidence

of advanced stage in pregnant patients2

1. Barry RM et al. Am J Obstet Gynecol 1962;84:445-4542. Gobbi PG et al. Haematologica 1984;69(3):336-341

Non-Hodgkin lymphoma during pregnancy (5)

Different approaches according to pathology subtypes!

� Watchful waiting is safe in most indolent lymphoma patients

� (low grade follicular lymphoma, marginal zone lymphoma, lymphocytic

lymphoma)

� But most pregnant patients with non-Hodgkin lymphomas have

aggressive histology !

� High rate of Burkitt‘s lymphoma with poor outcome

� High incidence of breast, uterine, cervical and ovarian involvement

Systemic treatment of non-Hodgkin lymphoma during pregnancy (6)


Systemic treatment of non-Hodgkin lymphoma during pregnancy (7)

Rituximab during pregnancy

Azim HA Jr et al. Expert Rev Clin Immunol 2010;6(6):821-826

Leukemia during pregnancy: Treatment (1)

� During 1st trimester pregnancy termination might be considered

because of higher risk of congenital anomalies

� Starting from 2nd trimester combination chemotherapy is feasible,

with some caveats

� Patients close to term are good candidates to delivery anticipation

ALL and pregnancy (2)

Treatment and outcome

No patients (up to 2010) 21

Drugs

Doxorubicin / Epirubicin 7

Daunorubicin – based 2

Idarubicin – based 2

Others 10

Gestational age of 1st exposure 15 – 35 weeks

Gestational age at delivery 28 – 38 weeks

Foetal outcomePremature 3

IUFD 2

AML and pregnancy (3)

Treatment and outcome

No patients (up to 2010) 64

Drugs Cytarabine - based

Gestational age of 1st exposure 15 - 34 weeks

Gestational age at delivery 28 - 41

Foetal outcome

IUFD 4

IUGR 3

Premature 8

Pancytopenia 3

Fetal distress 3

Maternal – fetal death 2

Congenital anomalies 5

CML during pregnancy (4)

� Imatinib during 1st trimester has a considerable risk of congenital

anomalies and spontaneous abortion

But

� Several uneventful pregnancies reported

� Interferon-alpha can be safely administered throughout the course

of pregnancy

� Shift from Imatinib to IFN (or nothing) before conceiving?

CML during pregnancy (5)

CML pregnant patients treated with imatinib

No patients / pregnancies 36/38

Time of 1st exposure

1st trimester stop after pregnancy: 23

1st trimester continued to 2nd or 3rd: 11

2nd trimester 2

3rd trimester 2

Pregnancy complicationsSpontaneous abortion 3

Premature delivery 1

Foetal adverse events

Hypospadias 2

Pyloric stenosis 1

Meningocele 1

Post – natal foetal death 1

Normal fetal outcomeLess than 1 year 22

More than 1 year 11

� In general, all cytotoxic, hormonal

and targeted therapies are

contraindicated during

breastfeeding

� Not recommended until at least 2-4

weeks after the completion of

chemotherapy

� “Milk rejection sign”: Denial of

lactating infant to nurse from the

carcinomatous breast

Breastfeeding

Pentheroudakis G and Pavlidis N. Eur J Cancer 2006;42(2):126-140

Placental – foetal metastasis

Cases with foetal involvement by tumour type (out of 98 cases)

Incidence of placental involvement by tumour type

Tumour type No. with placental

involvement (%)

Melanoma 25 (28%)

Breast cancer 14 (16%)

Lung cancer 11 (12%)

Leukemias 10 (10%)

GI cancers 9 (10%)

Sarcomas 8 (9%)

Lymphomas 7 (8%)

Head-neck cancer 3 (3%)

Ovarian cancer 2 (2%)

CUP 2 (2%)

Cervical cancer 1 (1%)

Adrenal cancer 1 (1%)

Lakshminarayana P et al. J Med Case Rep 2007;1:21. © 2007 Lakshminarayana et al; licensee BioMed Central Ltd,with permission under the Creative Commons Attribution License

Recommendations

1. The placenta should be submitted to macroscopic and

histopathologic examination

2. Cytologic examination should be performed in both maternal and

umbilical cord blood

3. Neonates should be clinically examined for palpable skin lesions,

organomegaly or other masses. Follow-up of the healthy baby

every six months for two years with physical examination, chest x-

ray and liver function tests

Principles of systemic anticancer treatment in pregnant women

� Medical oncologists should treat the pregnant mother and should

protect the foetus (if the two are compatible)

� Systemic treatment is generally not allowed during the period of

organogenesis (1st trimester)

� Systemic treatment (Chemotherapy) is safer to administer during

the 2nd and 3rd trimester of pregnancy, though increased rates of

some toxic effects should be discussed with the patient and family

� Endocrine treatment should be avoided

� No sufficient evidence is available on the safety/efficacy profile of

small-molecule inhibitors and monoclonal antibodies. They

should generally be withheld

The administration of systemic anticancer therapy

should follow certain important rules:

Documents

ESMO E-learning: Cancer Management During Pregnancy · Crosses the placenta ... Gadolinium crosses the placenta and causes foetal abnormalities in rats, MRI causes heating/cavitation