Management of ovarian cancer

in pregnancy

Charuwan M.D.

Outline Epidemiology Clinical manifestation Investigations Tumor marker Extent of surgery Chemotherapy

Epidemiology In population- based hospital registry

series of malignancies during pregnancy:

- breast

- thyroid- cervix- Hodgkin lymphoma

- ovarian cancer

EpidemiologyLifetime risk of developing ovarian

cancer is 1.4 %0.2 – 2 % of pregnancies are

complicated by adnexal mass

1 – 6 % malignancy

- 1991 – 1999 - N: 4,846,505- 9375 ovarian

masses diagnosed during pregnancy - 87 ovarian cancer (0.93%)

- 115 LMP (1.2%)

Leiserowitz GS et al:Gynecol Oncology2006

Review of publications(1958 – 2007 )

- Mean age 33 years (range 23 – 46 yr)

- FIGO stage I: 59 % stage II: 5 % stage III: 26 % stage IV: 10 %

Palmer J et al:BJOG2009

Clinical manifestations- Prior to the use of U/S:

most adnexal mass remained unrecognized until C/S or symptomatic

Retrospective series:8330 C/S

68 incidental adnexal masses > 5 cm1 malignancy

Dede M, et al:Int J Gynecol Cancer 2007

U/S + Cesarean section

Incidental detection of asymptomatic adnexal mass

Clinical manifestation Nonspecific symptoms:

- abdominal or back pain- constipation- abdominal distension- urinary symptoms

Palpable mass from PV Acute abdominal pain: torsion

U/S- Size > 10 cm + tumor growth

rate > 3.5 cm/week :

Risk of malignancy

Yen CF, et al: Risk analysis of torsion and malignancy for adnexal masses during pregnancy, Fertil Steri 2009.

U/SOvarian mass < 5 cm :

benign(follicular cyst or corpus luteal cyst)

The majority of persistent adnexal mass ≥ 5 cm are dermoid

MRI U/S is inconclusive or insufficient

data Fetus does not expose to ionizing

radiation Soft tissue pathology : - peduncutated myoma

degenerated myoma- endometrioma- massive ovarian edema

CT CT pelvis: fetal ionizing radiation dose

0.035 Gy Fetal radiation exposure < 0.05 Gy: ไม่�เพิ่��ม่

abortion, congenital anomalies, growth restriction or perinatal mortality

Possible increase risk of developing childhood cancer.

Iodinated contrast: transient suppression of the fetal thyroid.

DDxMost common are benign: simple

cyst, hemorrhagic cyst, leiomyomaMost common benign complex mass:

dermoid, endometrioma, hydrosalpinx and cystadenoma

Uncommon: hyperreactio luteinalis, theca lutein cyst and luteoma

DDxAbdominal pain:

- torsion or rupture of ovarian neoplasm

- degeneration of leiomyoma

DiagnosisDefinitive diagnosis bypathologic examination

Tumor marker

Tumor marker in pregnancy Several tumor marker are difficult to

interpret in pregnancy. Oncofetal antigen: AFP, CEA, HCG

and CA – 125 Oncofetal antigens are involved in

biological functions associated with fetal development, differentiation and maturation

Tumor marker in pregnancy The levels are normally elevated

during gestation and fluctuate with gestation age.

They may be abnormally elevated due to abnormal placentation or fetal abnormalities(preeclampsia, Down syndrome, open neural tube defect).

CA 125CA 125 can produce by normal tissues including endometrium

May be elevated during early gestation and immediately following delivery

May be helpful between 15 wk – delivery.

CA 125 level: 1,000 – 10,000 Suggest cancer

75 – 150 could be pregnancy or ovarian cancer

Alpha - fetoproteinDuring pregnancy,

- AFP expressed as multiples of median (MoM) because these value are easy to derive, more stable and allow for interlaboratory variation

Abnormal MSAFP > 2 – 2.5 MoM > 9 MoM should concern for germ cell

tumor if absence of fetal abdominal defect or anencephaly

Alpha – fetoprotein

High MSAFP levels(often > 1000 ng/ml)

- EST- Embryonal carcinoma- Mixed tumor

MSAFP < 500 ng/ml : NTD

Lactate dehydrogenaseLDH is not elevated in normal pregnancy

LDH can elevate in severe preeclampsia and HELLP syndrome

LDH is a reliable marker for diagnosis and FU in pregnancy

Inhibin AInhibin A is made in the

developing placenta:

Inhibin A may be measure for screening Down syndrome (average 2 fold higher)

Early pregnancy

Sonographer should evaluate ovaries ifabnormal serum down screening test

Ovarian tumor in pregnancy

Epithelial ovarian tumor 50 % LMP LMP in pregnancy may exhibit

atypical characteristics suggestive of invasive cancer:

- nuclear enlargement- multifocal microinvasion

Informed pathologist + pathologist skill

Germ cell tumor3/4 of germ cell tumor in

pregnancy: dysgeminomaDysgeminoma are bilateral:

10 – 15%, other germ cell tumor are almost always unilateral

Sex cord- stromal tumors50% granulosa cell tumor1/3 sertoli leydig cell tumorMost of these tumor: unilateral20 % presented with intraperitoneal

hemorrhage and/or hemorrhagic shock

10 – 15 % of stromal tumor secrete androgen and produce virilization

Management

ManagementInterdisciplinary consultation:

- MFM- Gyne -

oncology- Pediatrics- Pathology

I/C for surgeryPersist into second trimesterTumor size > 10 cmSolid or mixed solid and cystic

highly suspicious for malignancy

For early stage and to prevent adnexal torsion, rupture or obstruction of labor

Time to surgery Early second trimester

- Organogenesis is complete: minimizing risk of drug induced teratogenesis- Risk of pregnancy loss is low.- Cystectomy or oophorectomy does not affect progesterone concentration- Almost all functional cyst resolved.- Spontaneous pregnancy losses due to intrinsic fetal abnormalities occur in first trimester

Surgical Approach

Laparoscopy with adnexal mass during pregnancy

Laparoscopy may decrease uterine blood by increasing intraabdominal pressure

- Fetal hypotension, hypoxia

- Uterine perforation by trocar or Veress needle

- Fetal acidosis by CO2 absorption

Surgical approach

Adequate midline incision: minimize need to manipulate gravid uterus

Ascites collection or peritoneal washing

Carefully inspected and palpated contralateral adnexal mass

Preop imaging/intraop. finding suggested benign

Suspected malignancy: frozen sectioncystectomy / USO

Surgical approach- Resection of the contralateral

ovary is not required unless bilateral disease is identified:

This decision must await the frozen section

Surgical approachAll suspicious lesions should be

biopsied.Early stage: considered adequate

surgical stagingAdvance stage: debulking tumor

LMP: adequate surgery

Extent of surgery Clinical judgementBalancing the extent of surgery/expected benefit

It is rare that removal of gravid uterus is required.

Return for secondary cytoreduction following chemotherapy and successful completion of the pregnancy.

Termination of pregnancySome woman diagnosed with ovarian cancer in early pregnancy may choose to undergo TOP.

Early stageT he goal of initial surgery sho

uld be to completely resect all r esidual disease, without disturbi

ng the pregnancy

Early stageChemotherapy

- Stage IA,IB with G2, 3

- Stage IC, II with any grade- Clear cell

Early stage No residual tumor 271 nonpregnant

women:- Cisplatin/observe- Immediate Cisplatin+P32/Cisplatin at the time of

relapseDelay chemotherapyUntil after delivery

No difference of OS

Bolis G: Ann Oncol 1995

Early stageGross residual tumor:

- possibly should not delay chemotherapy > 6 – 8 wks after surgery

Chemotherapy

Chemotherapy during pregnancyRare eventIf indicated: prefer in the second or early third trimester.

Chemotherapy Category D Chemotherapy preferentially kill

rapidly proliferating cells fetus

The risk of spontaneous abortion, fetal death and major malformation depend on drug agent and gestational age.

ChemotherapyFirst 4 wks: all or none phenomenon(either pregnancy loss or no adverse effect)

4 wk – first trimester(organogenesis): risk of fetal malformation

Chemotherapy and breastfeeding

Immune suppressionImpaired growthAssociation with carcinogenesis

American Academy of Pediatrics

Chemotherapy Counselling Immediate/delay chemotherapy Ethical consideration

- patient autonomy- concept of beneficence- nonmalfeasance

Limited data, uncommon clinical problem in pregnancy.Less data on long-term outcomes in offspring

Epithelial ovarian cancerPlatinum and taxane:Limited data

Platinum derivatives during pregnancy Systematic review: 43 pregnancies - 3 IUGR

- 3 Preterm birth- 2 Oligohydramnios- 1 Polyhydramnios

- 1 Ventriculomegaly- 1 Microphthamus

Chemotherapy and breastfeedingEpithelial group:

- Cisplatin is transferred into breast milk (WHO)- Carboplatin: no data- Paclitaxel is lipophilic: potential to be concentrated in breast milk.

TaxaneFew case reports: short term safety but long term outcomes have not been reported.

ICON study: single agent carboplatin

Chemotherapy 217 pregnant women(1983 - 1995)

- congenital abnormalities 18- chromosomal abnormalities 2- still birth 4- spontaneous abortion 15

Multiagent > single agent (25% vs 10%)

Chemotherapy

Second and third trimesterfetal malformation 1.3%IUGRPrematurityLow birth weight

Fetal toxicities: BM suppression, ototoxicity

50 %

Chemotherapy> 35 wks or 3 wks before

delivery: should be avoided- transient myelosuppression- potential bleeding- sepsis- death at the time of delivery

Chemotherapy in EOC Single agent platinum during

pregnancy, followed by PT regimen postpartum.

At least in theory, this approach should be feasible without compromising maternal survival.

Summary of EOC- Surgery :

O ptimal surgical cytoreduction to the e xtent possible consistent with maternal an

d fetal safety. - Chemotherapy is indicated:

- carboplatin during pregnancy

- a fter delivery: PT regimen

Germ cell tumor• Maximal surgical cytoreduction is usually

undertaken initially. • A djuvant chemotherapy is recommended

to reduce the risk of recurrence

S tage IA dysgerminomasS tage I grade I immature teratomas

Except

Germ cell tumorBEP regimenEtoposide: IUGR, neonatal BM

suppression but there are no report of fetal malformations

Germ cell tumor Reports suggest that delaying

chemotherapy increase risk of recurrence.

Chemotherapy should be delayed until afterfirst trimester, but not longer

Chemotherapy and breastfeeding Germ cell tumor: BEP or PVB

- Etoposide is excreted into breastmilk- Cisplatin is C/I by WHO

Summary of Germ cell tumorSurgery:

maximal surgical cytoreduction.

Chemotherapy should be delayed at least until completi

on of the first trimester of pregnancy.

Sex cord stromal tumorSlow progressive.Suggest surgery alone during pregnancy

Chemotherapy can be deferred to postpartum

ChemotherapyReference Cell type GA at

treatChemo

Outcome

Henderson CE,(1993)King LA (1991)Malfetano JH (1990)Tomlinson MW(1997)Malone JM (1986)Kim DS (1989)Metz SA (1989)Weed JC (1979)Hobelt D (1994)

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Preterm(36)Preterm(36)TermE C/S (34)E C/S (32)TermTermPreterm(33)Term

Timing of deliveryEarly delivery to avoid fetal exposure to chemotherapy is reasonable if lung maturity can be documented and GA ≥ 34 wks.

PrognosisNo evidence that pregnancy

worsen prognosis than nonpregnancy matched for histology, stage and grade.

75 % pregnant women are early stage

5 yr survival : 72 – 90 %

Adnexal mass in C/S

• Should be removed: complete surgical removal is preferred over aspiration and cytologic evaluation.

• Frozen section: if available

Summary and recommendations Most adnexal massed in pregnant

women are benign and asymtomatic. Suggested surgery:

- persist into second trimester- > 10 cm - solid or mixed solid-cystic

Multidisciplinary consultation: balancing maternal and fetus risk

Summary and recommendations

Extent of surgery: clinical judgement + balancing the extent of surgery/expected benefit.

When chemotherapy is indicated: started after first trimester and should be avoided 3 wks before delivery

Thank you for your attention