Complex Treatment of Female Genital Tract Neoplasms. Cervical, endometrial and ovarian

cancer

Marcin JędrykaOncogynecologist

Chair of Oncology,

Wroclaw Medical University

Dept. of Oncological GynecologyLower Silesian Cancer Center, Wroclaw

Female genital tract neoplasms:

� Corpus of the uterus: endometrial cancer; sarcoma

� Cervix: cervical cancer

� Adnexa: ovarian cancer and tubal cancer

� Vagina and vulva: vaginal cancer and vulvar cancer

Colposcopy – ectopic epithelium

Colposcopy – ectopy after acetic acid and iodine solution

Colposcopy – HSIL pictures

Colposcopy – invasive cancer

Colposcopy – invasive cancer

Risk of metastases to the lymph nodes in ca. colli uteri

FIGO % pelvic nodes

inolved

% paraortic nodes

involved

Ia1 <1 0

Ia 1-4 <1Ia2 1-4 <1

Ib 10-16 2-4

IIa 25 9-11

IIb 31-40 15-19

III 45-60 30-40

IVa 55-85 40-65

Cervical cancer - treatment

Methods of treatment

100 kobiet jest leczonych: 100 kobiet jest leczonych:

18 - surgery only

58 - chemoradiotherapy only

24 - both methods

( w I stopniu 43 % chorych jest leczonych tylko

chirurgicznie)

Optimal surgery of cervical cancer

� Radical hysterectomy -the type of radicality should be fit o the patient and her disease – keep to the standards but individual attitude is important !

� Always in the aspect of complex traatment – decision making in the team cooperation (radiotherapeutists. oncologists)oncologists)

� After preop evaluation (espacially MRI of the pelvis is valuable)

� Always after discussion of withe the patients and written consent

� Preferably performed in the oncogyn deptarment by oncogynecologist

Radical hysterectomy

1 – cardinal ligaments

2 – sacrouterine

ligaments

3 – round ligaments

4 – infundibulopelvic4 – infundibulopelvic

ligaments

Radical hysterectomy

1 – paravesical fossa

2 – vesical peritoneal

fold

3 – vesicouterine

ligament

4 – pararectal fossa

5 – pouch of Douglas

6 – sacrouterine

ligament

7 – cardinal ligament

Radical hysterectomy

1 – urether

2 – parametrium

Radical hysterectomy

1 – urether

2 – divided round

ligament

Radical hysterectomy

1 – ext. iliac artery

2 – paravesical space

3 – int. iliac artery

4 – pararectal space

Radical hysterectomy

1 – ext. iliac artery

2 – ext. iliac vein

3 – interiliac lymph

nodesnodes

4 – int. iliac artery

Radical hysterectomy

1 – uterine artery

2 – ext. iliac vein

3 – obturator nerve

4 – int. iliac artery

5 – paravesical fossa

6 – pararectal fossa

Radical hysterectomy

3 – bladder

4 – divided

vesicouterine

ligamentligament

5 – urether

6 – divided parametrium

7 – paravesical space

Radical hysterectomy

1 – bladder

2 – left urether

3 – right urether

4 – vagina

5 – uterus

6 – vesicouterine

ligament – internal

part

Radical hysterectomy

1 – left urether

2 – sacrouterine

ligament

3 - rectum3 - rectum

Radical hysterectomy – final specimen

Cervical cancer – methods of treatment

Indications for surgery:* early stages (IA * early stages (IA –– II A)II A)* big fibroids, ovarian tumours, PID in advanced st ages (IIB and * big fibroids, ovarian tumours, PID in advanced st ages (IIB and more) before chemoirradiationmore) before chemoirradiation

Indication for chemoradiotherapy:* advanced stages (IIB – IVA)* early stages after surgery in case of poor progno sis factors* early stages in case of inoperability or lack of consent

radical (therapeutic as alone method)

post-op (as adiuvant therapy)

Radiation of cervical cancer

pre-op (to shrink the tumor – IB2)

�paliative (haemorrhage, bone metastases)

Post-op indication for irradiation

� metastases to lymph nodes

� parametria infiltration

� surgical margins are infiltrated � surgical margins are infiltrated

� metastases to adnexa

� uterine corpus infiltration

Grading G2/G3, LVSI,

Currently the standard treatment

means chemoirradiation

- FIGO IIB - IVA

- Post-op adiuvant treatment

- radiotherapy (tele- and brachyterapy)

- chemotherapy: cisplatin: 40 mg/m2 every week; 6 cycles

(combined with teletherapy)

Addition of chemotherapy gives the 10-15% improval of

ENDOMETRIAL HYPERPLASIA WITHOUT ATYPIA

� Exagerrated proliferation of endometrium due to estrogen stimulation

� Hyperplasia of glands and stromaHyperplasia of glands and stroma

� Divided acc. to histopathological exam:simple, complex

� Treatment: progestins

ENDOMETRIAL HYPERPLASIA WITH ATYPIA

* Precursor of endometrioid cancer of

endometrium

� * Due to spontaneus single mutations (K-Ras, Ki 67) of endometrial glandsRas, Ki 67) of endometrial glands* Divided acc. to histopathological exam:

simple and complex

� * Treatment: simple hysterectomy

Cancer of endometrium – type I

� ENDOMETRIOID CARCINOMA- Adenocarcinoma (typical)- Secretory (variant)- Ciliated cell (variant)- villoglandular (variant)- villoglandular (variant)- Adenocarcinoma with squamous

differentiated („adenoacanthoma”)

� ADENOCARCINOMA MUCINOSUM (<9%)

Cancer of endometrium – type II

Nonendometrioid carcinoma:

� Serous papillary carcinoma,

� Clear cell carcinoma

Endometrial cancer.5-y OS concerning GRADING:

� G1 80-85%

� G2 74-78%

� G3 50-64%

Endometrial cancer.5-y OS concerning STAGING

� FIGO I - 83%

� FIGO II - 73%

FIGO III - 52%� FIGO III - 52%

� FIGO IV - 27%

Endometrial cancer.Prognostic factors

� Histologic type

� Grading (G)

� Staging (FIGO, TNM)

� Myometrium infiltration

� Lymph vessels infiltration � Lymph vessels infiltration

� Cervix infiltration

� Lymph node metastases

� Receptors (ER, PR)

� Molecular biology and gene expression of p53, bcl2, MSI, PTEN

Methods of endometrial cancer treatment

� Surgery only

� Radiotherapy: tele + brachy

� Surgery + radiotherapy

� Surgery + radiotherapy and adiuvant � Surgery + radiotherapy and adiuvant

systemic treatment (chemotherapy,

hormonotherapy)

� Radiotherapy and subsequent surgery

Surgery of endometrial cancer

� Qualification:

� Histologically prooved endometrial

cancer

� Qualification of internal doctor and

anaesthetist: OBESITY, HYPERTENSION,

DIABETES, ASTHMA

Surgery of endometrial cancer

� Stage I: simple hysterectomy with

bilateral salpingooophorectomy

(abdominal, laparoscopical, robotic)

Surgery of endometrial cancer

� Stage II and III: radical hysterectomy

with bilateral salpingoophorectomy

(dependent on technical aspects –

obesity, patient's performance status and

health ability for longer operation)health ability for longer operation)

Surgery of endometrial cancer

� Surgical and histological

assessement of disease spread:

� Hysterectomy alone is not enaugh

� Full FIGO staging is mandatory� Full FIGO staging is mandatory

� Retroperitoneal lymph nodes

assessemnet… (systematic lympadenectomy

vs biopsy vs SN)

Surgery of endometrial cancer. When systematic lympadenectomy (pelvic and paraortal)?

� Stage IC - IIIB

� Myometrial infiltration > 50% or tu. > 2 cm id diameter

� IIIC – lymph nodes infiltrated ! Bulky nodes !

� Grading G3� Grading G3

� Type II cancer (serous or clear cell)

� ca. adenosquamosous

Endometrial cancerPercentage of lymp nodes involvement in stage I in comparison with myometrial invasion and Grading (n=621, metastases in 144 pts. -22%)

Depth of

myometrial infiltration

GRADING

G1 G2 G3

Inner 1/3 of

myometrium

3% 5% 9%

2/3 depth of

myometrium

0% 9% 4%

Full thickness of

myometrium

11% 19% 34%

Creasman WT, Morrow CP, Bundy BN et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987; 60:2035-41

Endometrial carcinomaProbability of lymph nodes metastases depending on FIGO stage and gradingin stage I (metaanalysis, Kreienberg 2005)

STAGE Pelvic (%) Paraortal (%)

FIGO Ia, b G1 3 2

FIGO Ib G2,3 9 4-6

FIGO Ic G1-3 18 16

FIGO II 29-41 16-30

FIGO III 66 33

FIGO IV 44

Indications for adiuvant treatment of Indications for adiuvant treatment of endometrial cancer (after surgery)endometrial cancer (after surgery)

Risk factors of relapse in Risk factors of relapse in endometrial cancerendometrial cancer

Age (> 60y (> 60y ptspts. . oftenoften moremore advancedadvanced, , withwith G3 andG3 and

M > 50%)M > 50%)

�� Carcinoma Carcinoma cellscells inin lymphaticlymphatic vesselsvessels (LVSI) (LVSI) ––independent independent riskrisk and and predictivepredictive factorfactor of of metastasesmetastases to to Carcinoma Carcinoma cellscells inin lymphaticlymphatic vesselsvessels (LVSI) (LVSI) ––

independent independent riskrisk and and predictivepredictive factorfactor of of metastasesmetastases to to thethe pelvicpelvic lymphlymph nodesnodes, ,

�� RetroperitonealRetroperitoneal lymphlymph nodesnodes metastasesmetastases

Risk factors of relapse in Risk factors of relapse in endometrial cancerendometrial cancer

�� myometrial infiltration > ½ depth;myometrial infiltration > ½ depth;

�� grading = G2, G3;grading = G2, G3;

�� cervical infiltration;cervical infiltration;

�� parametrial infiltration;parametrial infiltration;

�� adnexal metastases;adnexal metastases;

�� cancer cells in peritoneal cytology;cancer cells in peritoneal cytology;

�� type II cancer: type II cancer: ca clarocellulareca clarocellulare, ,

ca serosum;ca serosum;

Radiotherapy of endometrial cancer

Low risk group Low risk group (I(I °°°°°°°°AA--G1,2)G1,2)•• Surgical treatment is Surgical treatment is

sufficeint sufficeint

Intermediate risk group (I °°°°A-G3, I°°°°B-G1,2)

* Surgical treatment following by brachytherapy only sufficeint sufficeint

•• No need for irradiationNo need for irradiationby brachytherapy only allows to cure 90% of pts.

Radiotherapy of endometrial cancer

High Risk Group. Stage IB G3 and II and III

� Both tele- and brachy therapy is recomended after the surgery

� Such combined treatment allows to treat more sufficientmore sufficient

� In high risk factors such as G3, lymph nodes metastases, distant organs metastases chemotherapy should be introduced before irradiation

Brachytherapy in oncogynecology

- input of irradiation source in the proximity of cured tissue

- different applicators – ovoids, uterine cavity probes, vaginalprobes

− after-loading methods;(LDR; cezium): 2 or 3 applications of probe to the uterine(LDR; cezium): 2 or 3 applications of probe to the uterinecavity and ovoids to the fornices of vagina; single applicationtime: approx. 6 – 8 hrs, repeated after 5-7 days

− (HDR; irydium): 4 to 6 applications lasting severalminutes in ambulatory conditions

Teletherapy in oncogynecology

Accelerators – megavolt energy therapy ensures the proper dose of tumor irradiation

preserving the skin and critical organs (such as bladder or rectum)

Irradiation scheme: total time: 4-5 weeks, each day (5 days in a week) fraction lasts several

minutes kilka minut - totally 20 – 25 fractions.

Irradiation field: pelvis and sometimes paraortal area to the level of L1/L2 Irradiation field: pelvis and sometimes paraortal area to the level of L1/L2

Ovarian cancerOvarian cancer

��Surgical treatment is the primary choice in Surgical treatment is the primary choice in ovarian cancer patientsovarian cancer patientsovarian cancer patientsovarian cancer patients

��Real assessment of disease spread often Real assessment of disease spread often can be done earlier then during the can be done earlier then during the operationoperation

guzki otrzewnej krezki jelita cienkiego (materiał włas ny)guzki otrzewnej krezki jelita cienkiego (materiał włas ny)

Ovarian cancer surgeryOvarian cancer surgery

��IA IA G1G1

the only situation when reproductive possibilities can be the only situation when reproductive possibilities can be preserved (Adnexectomy, staging procedure including lymph preserved (Adnexectomy, staging procedure including lymph

nodes sampling)nodes sampling) and no adiuvant chemo is demandedand no adiuvant chemo is demanded

In all other cases (almost all of the patients)In all other cases (almost all of the patients)

��Optimal, primary cytoreduction =Optimal, primary cytoreduction =

No residual tumor masses after surgeryNo residual tumor masses after surgery

In case of advanced ovarian cancerIn case of advanced ovarian cancer

in case of inoperabilityin case of inoperability

�� Interval, debulking surgeryInterval, debulking surgery

�� Explorative laparotomy/laparoscopyExplorative laparotomy/laparoscopy�� Explorative laparotomy/laparoscopyExplorative laparotomy/laparoscopy

�� Secondary cytreduction after neoadiuvant Secondary cytreduction after neoadiuvant chemotherapychemotherapy

OtherOther typestypes of operations of operations inin ovarianovarian cancercancerpatientspatients::

�� secondsecond--looklook procedureprocedure

�� cytoreductioncytoreduction of of persistentpersistent diseasedisease

�� SecondarySecondary debulkingdebulking surgerysurgery of of relapsesrelapses

�� PaliativePaliative surgerysurgery

Chemotherapy of ovarian cancer

* Adiuvant after optimal, primary debulking

•Adiuvant after non optimal primary surgery before second

cytoreduction

•Neoadiuvant therapy – before the ateempt of primary•Neoadiuvant therapy – before the ateempt of primary

cytoreduction

•Secondary - in case of relapse

•Paliative – in case of dissemintaed porogression

Ovarian cancerChemo agents

* Cisplatin (DDP) * Ifosfamide (IFX)* Karboplatin (CBDCA) * Etoposide (VP 16)* Ciclophosphamide (CTX) * Gemcytabine (GCB)* Doxorubicine (DOX) * Liposomal DOX* Mitom ycin (MTC)* Mitom ycin (MTC)* Melfalan (MPL) * Metotreksat (MTX)* Paclitaxel (PCL) * Mitoxantron (MTZ)* Docetaksel (DCL)

* Topotekan (TPT)

Chemo in ovarian cancer – multidrugregime

Response rate (CR/pCR) 70-80% (40-50%/20-30%)

Overall survivall 5 ys ~ 35-40%Overall survival 10 ys ~ 20-25%Overall survival 10 ys ~ 20-25%

* Multidrug, first line regime = PCL + DDP = GOLDEN STANDARD* No of cycles – 6 (every 3 week)

2nd line treatment

* Primary response to DDP chemotherapy : PFS > 6 mths- attempt of secondary cytoreduction- CHEMO (DDP/CBDCA + PCL)

* Primary response to DDP chemotherapy : PFS < 6 mths- attempt of secondary cytoreduction- CHEMO: lipo-DOX / TPT / GCB / IFX / VP 16 – choicedependet on patients’ status and costs

Time to progression or PFS (progression free survival)⇓⇓⇓⇓

The most important factor of efficacy of CHEMO II o

Relapse after CTH I o Probability of RR-CTH II o

< 6/ 10%

2nd line treatment

< 6/12 10%

- 12/12 29%

- 18/12 63%

> 18/12 94%

* Blackledge et al. BJC 1989

Follow-up after ovca treatment

- Gynecological examination – every 3 mths

- Ca 125 – every 3 mths

- Chest X-ray - once a year

- Ultrasound or CT assessement of pelvis and abdomen – once a year

- PET-CT in suspition of progression when USG, CT ora MRI are not clear

Thank you