International Gynecologic Cancer Society

Founded in 1986

Multidisciplinary

Over 1500 members in more than 80 countries

IGCS Mission

• To promote the health and well-being of women with gynaecological cancer across the world

• To improve research into prevention, and early detection, treatment and quality of life of women with gynaecological cancers

• To promote the highest standard of professional care of women with gynaecological malignancies

IGCS Initiatives

• Publishes International Journal of Gynecological Cancer with ESGO

• Meets every two years, rotating among Americas, Asia/Australia/Oceania and Europe/Africa/Middle East with reduced registrations rates for trainees, nurses and persons from less developed countries (Bangkok 2008: only 150$)

IGCS Initiatives (1)

• IGCS Workshop program for Lower-income countries with financial support for up to 10 meetings in 2008.

• Travelling Scholarships in 2007-8: 20 of 5000-10000 $ (Current deadline October 31st).

• Partner in Global Initiative on Women’s Cancer (GLOW)

IGCS Initiatives (2)

www.IGCS.ORG

• Website based tumor boards with expert opinions and voting system.

• On line Journal Clubs with commentaries on controversial topics or papers.

• Off year meetings in other continents than the Biennial meetings: eg Brazil April 2008

IGCS

• Website: www.igcs.org

• Email: adminoffice@igcs.org

• Membership rates based on World Bank country income levels

IGCS Workshop“Gynecologic malignancies”

8-9 September, 2008, Ankara, Turkey

Vesna KesicInstiute of Obstetrics and GynecologyClinical Center of Serbia

Cancer and Pregnancy

Biological uniqueness of cancer in pregnancy is the combination of

• an uncontrolled growth of a malignant tumour• a controlled growth of a feto-placental complex

inside the same body.

The biggest physiological process of human reproduction

and the biggest pathological process which in most cases results in death

are linkedin the battle fought between immortality and destruction

The occurrence of cancer in pregnancyis relatively rare,

about 1 case per 1000 deliveries

Cancer in pregnancy- the cruelest dillema

Does the women lose the baby to save her life

orrisk her life to try to save baby ?

Is the potential life of an unborn child

more important than prolonging a life of a young woman?

Whose lif

e is of g

reater value?

And whose decision is this anyway ?

?

Fetus Mother

Pregnancy

Risk

For women diagnosed with cancerwaiting for 40 weeks

could be a death sentenceparticularly with high-grade, aggressive

or metastatic cancers.

Malignant disease in pregnancycomplicates the management of

both cancer and the pregnancy.

The diagnostic and therapeutic approachis particularly difficult

because it involves two persons:the mother and the baby.

Obstetricians and Oncologists should offer at the same time optimal:

- maternal treatment - fetal well-being

Treatment that may be essentialfor the mother

may be fatal or highly damaging for the baby.

Factors influencing the management of pregnant women diagnosed with cancer

• Stage of cancer and associated prognosis• Age of gestation- fetal viability• Possible adverse effects of treatment on fetus • Risk for mother from delay of therapy• Risk for fetus of premature delivery • Potential need to terminate the pregnancy

Management of cancer in pregnancy

There are not many options and none of them are ideal

To delay treatment until the child can be safely delivered

• For mother this poses the risk that may be hard to quantify• It also means that she will have to care for a very premature baby while coping with the side-effects of cancer treatment

This option is more viable the lower the risk posed by the cancer and the more advanced the pregnancy

First option

To terminate the pregnancy to allow normal treatment to go ahead

• This may be the safest option for the mother’s health• Unacceptable to some mothers

More likely to be considered early in pregnancy

Second option

To treat cancer as effectively as possiblewhile continuing the pregnancy and trying to

minimize the risk for fetus

Third option

Problems in treatment of cancer in pregnancy

• Late diagnosis• Damaging effects of radiotherapy• Consequences of chemotherapy

Cancer in pregnancy if often detected laterbecause the symptoms are masked by other,

usually physiological, body changes

Delay in diagnostics • Presenting symptoms often attributed to pregnancy• Anatomical and physiological changes of pregnancy may compromise the physical examination

• Tumor markers are increased in pregnancy (beta HCG, AFP, CA 125... ) • Imaging techniques or invasive procedures

Difficulties in diagnostics & staging

Some techniques are non-reliable• Cervical cytology• Mammogram• Blood tests- tumor markers

Some techniques are dangerous• Abdominal X-rays• CT• Radioisotope investigations• Cervical conisation

Diagnostic procedures that cansafely be performed in pregnancy:

• Ultrasound•Nuclear magnetic resonance (NMR)

Treatment is often conducted on the basisof incomplete information about the disease !

Risks of radiotherapy

Radiotherapy is contraindicated in pregnancyalthough some specialists use it above the

diaphragm with abdominal shieldingparticularly in later stages of pregnancy

Risks of radiotherapy

Therapeutic doses of 5000-6000 cGy expose the fetus to 10 cGy in early pregnancy

and 200 cGy or more in later pregnancy

Doses over 2,5-5 cGy pose high riskfor malformation early in pregnancy

0.05 Gy is limit doses for the risk of malformations.

With 1 Gy the risk is 50%

From conception to days 9/10 Letal effect

Weeks 2-6 Malformation Growth retardation

Weeks 12-16 Mental and growth retardation, microcephaly

Weeks 20-25 to birth Sterility, malignancies, genetic disorders

Likely effects of radiotherapy

Risks of chemotherapy

Almost all drugs cross the placentalbarrier to some extent

As chemotherapeutic drugs workby inhibiting cell division,

they pose a risk to the developing fetus.

Risks of chemotherapy

Chemotherapeutic drugs are associated with:

• Spontaneous abortion• Malformations• Teratogenesis• Mutations• Carcinogenesis• Organ toxicity • Retarded development

Most common drugs reported to induce the malformations

or to exert teratogenic effects

In « Cancer in Pregnancy », Cambridge 1996

Alkylating agents Antimetabolites

Bisulfan AminopterinCyclophosphamide MetotrexateChlorambucil 5-Fluorouracil Cytosine arabinoside

First trimester• Damage is more likely to occur in the 1st trimester.• The rate of chemotherapy –associated fetal malformation is 12,7-17% with singl-drug regimens and up to 25% with combination regimens (general population rate 1-3%)• Low birth weight occurs in around 40%

Second and third trimester• Many drugs pose a relatively low risk• It is preferable to wait until the development of CNS is complete, around 16. weeks

Risks of chemotherapy

Delivery

If a baby is delivered within 2 weeks of the last chemotherapydose, there is a risk of a neutropenic baby being born to aneutropenic mother

Breastfeading

Breast feeding is not advisable for women who have recentlybeen on chemotherapy

Risks of chemotherapy

0.07 - 0.1% of all malignant tumors are diagnosed during or shortly after

the pregnancy

What are the most common cancers complicating pregnancy?

The incidence of malignant tumors in pregnancy

Cervical cancer 0.17%Breast cancer 0.07%Gastric cancer 0.05%Colon cancer 0.02%Ovarian cancer 0.01%

Genital tumous and pregnancy

Cervical cancerOvarian tumors

Endometrial cancerVaginal cancerVulvar cancer

Ries LAG, Eisner MP, Kosay CL et al., eds. SEER Cancer StatisticsReview, 1975-2001. Bethesda, MD: National Cancer Institute.

Available at http://seer.cancer.gov/csr/1975_2001.

Estimated number of cases: 60,000Number of deaths: 30,000

Burden of cervical cancer, Europe, 2002

Ferlay J, et al. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide, Version 2.0 IARC CancerBases No. 5. Lyon, IARC, 2004.

The disease has been detected during the pregnancy or postpartum period

in 1.7 to 3.1%.

In reproductive age ≈10%

Creasman WT et al., 1970

The incidence of invasive cervical cancer in pregnancy is between

0.3 to 1.6 per 1000 pregnancies

The incidence of cervical pre-cancerand invasive cancer in pregnant women

is similar to the incidence in general population

• Pregnant women (4230) 0.17%• Non-pregnant women (107 230) 0.18%

Bokhman JV, 1998.

Screening for invasive cervical cancer should be performed during

the first antenatal examination

Harper DM, Roach MS. J Fam Pract, 1996; 42: 79-83

Normal pregnancy is not a contraindication for taking cervical smear,

nor to colposcopic examination !

Management of abnormal cervical smearduring pregnancy

Abnormal cytology (5%)

Colposcopy

Biopsy

Indications for colposcopy

• Clinically suspicious cervix • Recurrent and otherwise unexplained bleeding • Abnormal cervical smear• The presence of HPV changes in cervical smear

The aim of colposcopic examination during the pregnancy

is to exclude the invasion !

Eversion of columnar

epithelium

Physiological metaplasia

Decidual reaction

Decidual polypus

HPV in pregnancy

CIN in Pregnancy

The incidence of CIN in pregnancy

0.25 - 1.1 %

Bokhman VJ, 1989 0.17 %Kashimura M, 1991 0.93 %Ueki M, 1995 0.3 %Chuquai R, 1994 1.15 %Kesic V, 1996 0.73 %

Conization in pregnancy:

• Microinvasion confirmed by biopsy• Cytologic suspicion to microinvasive or invasive cancer• Large High grade lesion • Unsatisfactory colposcopic examination in histologically proven high grade lesion

Management after the histological finding in pregnancy

CIN Microinvasive cancer Invasive cancer

Conization

Postpone further Radicaldiagnostic and hysterectomy therapeutic procedures orfor post-partum period radiotherapy

Targeted biopsy

Conization in pregnancy

Treatment of cervical cancer in pregnancyis affected

• by the stage of the disease• by the age of gestation

The treatment of invasive cervical cancer in pregnancy

should proceed without regard for the fetus, unless the lesion is diagnosed at a stage

close to fetal viability

Treatment of cervical cancer in pregnancyis affected

• by the stage of the disease• by the age of gestation

• mother’s belief regarding pregnancy termination • future childbearing desires

Cervical cancer in pregnancy

I trimester: Immediate treatmentIII trimester: Treatment after Caesarean section

II trimester ? Medical and ethical problem

Stage Ib/ IIa

Cervical cancer in pregnancy

I trimester: Surgery with embryo in uteroIII trimester: Surgery immediately after Caesarean section

II trimester ? Medical and ethical problem

Stage > IIb

Cervical cancer in pregnancy stage > II a

I trimester: Start external irradiation Wait for spontaneous abortionIII trimester: Caesarean section Irradiation immediately after recovery

II trimester ? Medical and ethical problem

Invasive cervical cancer in second trimester

Before 20-24 weeks

Evacuating pregnancy by hysterotomy and immediately after radical hysterectomy

After 24-28 weeks

Waiting for fetal maturity

Delay of treatment for 2-10 weeks

• Stage < IIb• Small tumor

• Gestational age > 20 weeks

van Villet W i sar. Eur J Obst Gynec Reprod Biol, 1998; 79: 153-7

Karolinska hospital, Stochkolm, Sweden

• Period: 1914-1995• 19 475 women with cervical carcinoma • 207 (1%) diagnosed in relation with pregnancy• Mean age 34.3 years (21-47)

Bjorkholm E & Pettersson F. Carcinoma of the uterine cervix and simultaneous pregnancy. Int J Gynec Cancer, 1999; 9 (suppl 1): 116

Karolinska hospital, Stochkolm, SwedenCervical cancer and simultaneous pregnancy

Actuarial survival

1914- 1943: 30.4%1944- 1959: 53.6%1969- 1995: 81.5%

Bjorkholm E & Pettersson F. Carcinoma of the uterine cervix and simultaneous pregnancy. Int J Gynec Cancer, 1999; 9 (suppl 1): 116

Adnexal masses during pregnancy1:1000 deliveries

Most masses are benign

Ovarian cancer 1 per 10.000 – 100.000 births

Ovarian tumors and the pregnancy

Most frequent types of ovarian tumors in pregnancy

Benign cystic teratoma ................. 36%Serous cystadenoma ................ 25%Mucinous cystadenoma ................. 12%Corpus luteum cyst ................. 5.5%Malignant tumors ................ 4%

Malignant ovarian tumors and pregnancy

In non-pregnant woman 20% ovarian tumors are malignant.

In pregnancy this percentage isdecreased to 5% ( 3% - 9.7%)

Histological types:-- Epithelial carcinomas 33-65%-- Germ-cell tumors 17-40%-- Sex cord-stromal tumors 9-13%

Malignant ovarian tumors and pregnancy

• Only 16% of ovarian tumors are detected in the first trimester• 20% diagnosed during SC or after delivery• Almost 25% have an acute presentation (torsion)

If there are no complications, the best timing for surgeryof persistant ovarian mass in pregnancy is between

16 to18 weeks of gestation

If adnexal mass is < 6 cm, unilateral, mobile and asymptomatic:

- observation and repeat U/S at 14 to 16 wks.

If adnexal mass is > 6 cm, solid or of complexappearance, bilateral or persists into 2nd trimester:

- laparotomy.

Management of ovarian mass in pregnancy

Prognosis of ovarian cancer in pregnancy

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%

Extra-genital tumous and pregnancy

Breast cancerCancer of the colon

Gastric cancerMelanoma

Thyroid cancerBladder cancerBrain tumors

Tumors of the hypophysisHemoblastosisLiver tumors

…

…

36.0Belaruss38.8Russia

44.3Romania

46.2Bulgaria

52.1Macedonija

58.9B & H

58.9Slovenia

62.2Croatia

64.1Serbia

91.9France

92.0Belgium

Incidence of Breast cancer in Europe(sr per 100,000 women)

Globocan 2002

Breast cancer has been detected during the pregnancy or postpartum period

in 3% of cases

In reproductive age ≈14%

Breast cancer

• 3% of breast cancers is associated with pregnancy• In the reproductive period patients, breast cancer associated with pregnancy in 14% cases

• The incidence of breast cancer in pregnancy is 0,03 (1: 3000-1:10 000 pregnancies)

- Mammography sensitivity: 68% (due to increased density )- Ultrasonography sensitivity: 93%- Open breast biopsy (FNA ±) confirms diagnosis

Pregnant woman has 2.5 - fold higher risk to present with advanced disease

Diagnosis of Breast Cancer in Pregnancy

Breast cancer in pregnancy

• Delay in starting the treatment is not recommended• Mastectomy with axillar lymph node dissection does not jeoparadise pregnancy• Conservative surgery ?• Chemotherapy can be administered in pregnancy• There is no concensus regarding radiotherapy

Survival is equal as in non-pregnant patients if the stage of the disease is considered

Breast cancer in pregnancy

• Overall survival is worse, because the disease is detected in advanced stages

• In 7% pregnant patients with breast cancer, the treatment starts within one month after diagnosis

Breast cancer in pregnancy

• Later pregnancies do not influence free and overall survival

• Next pregnancy should not be planned at least for 2 years after the treatment of breast cancer

Cancer in pregnancy: common obstetrical, oncological and ethical problems

• Are malignant tumors influencing pregnancy ?• Is pregnancy influencing the course of malignancy ?

• How to manage the pregnancy ?• Is metastasing to the placenta and fetus possible ?

• Does pregnancy increase the risk for the development of malignancy ?• Is it necessary to limit the fertility after treatment of' malignant tumor?

How frequently does maternal cancermetastasize to either placenta or fetus?

• Transfer of fetal cells into the maternal circulation is common and occurs throughout gestation.

• In contrast, transfer of maternal cells (red, white blood cells, platelets) to the fetus is a relatively rare event.

• Tumor cells can rarely involve the products of conception, most likely through the hematogenous route.

• The most common tumor metastasizing to the placenta or fetus is malignant melanoma (almost 30%).

The facts we know:

Placenta

Estimated incidence of placental involvement by cancer cells: very rare

Fetus

Estimated incidence of fetal involvement by cancer cells: 25% of the cases with placental involvement

The patient, her partner and her doctor are required

to take a difficult decision without always a clear answer

(rights of the fetus ≠ rights of the mother)

When should therapeutic abortionbe recommended?

Therapeutic abortion- general considerations

- Absence of guidelines.- Final decision is not always easy- Issue becomes more important when cancer diagnosis is made during the first trimester

Most important parameters are: - the stage- the indication for treatment - the curability of the disease.

Recommendations for therapeutic abortion during the first trimester

1. Primary aggressive breast cancer

2. Advanced breast cancer

3. Stage III-IV aggressive NHL or

Hodgkin’s disease

4. Acute leukemia

Treatment of cancer in pregnancy requires:

• Evidence-based medicine built on the data related to treatment associated risks• Multidisciplinary approach• The art of communication with the patient• High dose of humanity

1. Try to benefit mother’s life2. Try to treat curable malignant disease of pregnant women3. Try to protect fetus and newborn from harmful effects of cancer treatment4. Try to retain intact mother’s reproductive system for future gestations

4 optimal gold standards to be considered

Obstetrician

Gynecologist

Patient

Radiotherapist

Neonatologist

Medical oncologist