Uterine cancerAhmed Zeeneldin

Associate Prof of Medical OncologyNCI2010

Worldwide incidence and mortality

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ó US: ◦ 40 000 new case/year◦ 8000 death/yearó Incidence to mortality is 5:1ó Sarcoma: 3% of uterine cancers

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NCI-Egypt

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Diagnosis and workupó H&P

◦ Postmenopausal vaginal bleedingó CBCD, Biochemistryó Chest x-rayó Endometrial biopsy:

◦ Epithelial carcinoma◦ Stromal / mesenchymal tumors

ó Suspected cervix involvement:◦ Cervical Bx or MRI

ó CT or MRI: ◦ to show abdominal or pelvic extension

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Endometrial pipette & biopsy

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Disposable, Flexible, 3 mm diameterOffice procedure, no anaesthesiaFalse negatives (FN): 10%FN in symptomatic:

F D&Chystroscopy

Layers of the uterus

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Uterine cancers

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Staging of uterine CAT1=FI (T2=FII) (T3=FIII) (T4=FIVA) N1= FIIIc M1=FIVB

Confined to corpus

A: endometriumor myometriuminner halfB: myometriumouter half

Cervix stroma* but not Outside uterus

Outside UterusA: Serosa, adenxa, cancer cells in ascites or peritoneal washings B: Vagina/parametrium+

Bladder or bowel mucosa

N1: pelvic (3c1)N2: Paraaortic(3c2)

DistantMets

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Endocervical involvement is not considered T2Grade is important: G1: well, G2: moderate, G3: poorly differentiated

TNM Staging 2010Uterine carcinoma

ó T1: Body◦ T1a: endometrium OR ◦ myometrium inner half◦ T1b: myometrium outer half

ó T2: cervical stromaó T3: outside uterus

◦ T3a: Serosa, adenxa, malignant ascites

◦ T3b: parametrium /vagina

ó T4: bladder or bowel mucosa

ó N1: regional LN+◦ N1: pelvic◦ N2 Paraaortic

ó M1: Distant mets

T1 T2 T3 T4 M1

N0 I II III IVA IVB

N+ IIIC IIIC IIIC IIIC IVB

SIMPLIFICATION (FIGO stage)-I: T1 -II: T2-III: T3 OR LN+ -IV: T4 OR M1

TNM Staging 2010Uterine sarcoma

ó T1: uterus◦ T1a: <= 5 cm◦ T1b: > 5 cm

ó T2: invade pelvic tissues◦ T2a: adenexa◦ T2b: other pelvic tisues

ó T3: invade abdominal tissues◦ T3a: One site◦ T3b: multiple sites

ó T4: bladder or bowel mucosa

ó N1: regional LN+

ó M1: Distant mets

T1 T2 T3 T4 M1

N0 I II III IVA IVB

N+ IIIC IIIC IIIC IIIC IVB

SIMPLIFICATION (FIGO stage)-I: T1 -II: T2-III: T3 OR LN+ -IV: T4 OR M1

Treatment of Pure endometrioid cancer

ó According to stage: ◦ (1) disease limited to the corpus, ◦ (2) suspected or gross cervical involvement,

(3) suspected extra-uterine disease.

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T1=FI (T2=FII) (T3=FIII) (T4=FIV)

Confined to corpus

endometrium (T1a=IA)myometrium inner half (T1b=IB)myometrium outer half (T1c=IC)

Cervix but not Outside uterus

Endocervix (T2a=FIIA)Cervical stroma

(T2b=FIIB)

Serosa, adenxa, cancer cells in ascites or

peritoneal washings (T3a=FIIIA)

Vagina (T3b=FIIIB)LN: pelvic or paraaortic

(N1=FIIIB)

Bladder or bowel mucosa

Extrapelvicextension (T4=FIVA)

Distant mets = IVB

Uterine sarcoma

ó Endometrial stromal sarcoma (ESS)ó Leiomyosarcoma (LMS)ó Undifferntiated sarcoma (UDS)

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Treatment of uterine sarcoma

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Adjuvant treatment of ESS

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HORMONE THERAPY(ESS only)•Megestrol acetate•Aromatase inhibitors (category 2B)•Tamoxifen (category 2B)•Medroxyprogesterone acetate•GnRH analogs (category 2B)

Adjuvant treatment of LMS, UDS

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Chemotherapeutic agents (single or combinations)•Doxorubicin•Gemcitabine/docetaxel•Other single agent options (category 2B): Dacarbazine, paclitaxel•gemcitabine, ifosfamide, docetaxel, epirubicin, liposomal doxorubicin

Treatment of endometrial carcinoma

Surg RT Chemo

Local’zd I uterus Yes* Adj RT may(G3 or IB/C)

Adj CT may(G3 + IC/IB)

II cervix Yes * ORà

adjRT in allRT then Surg

Adj CT in G3

extraut IIIA abdomen Yes adj RT Adj CT in G3

IIIBIVA

Pelvisvag/param/bladd/rectm

May after RT RT may

mets IVB mets yes May Palliative CTOR hormonal T

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* If surgery is not feasible à RT

HYSTERECTOMYó TH/BSO: Total hysterectomy + bilateral salpingo-oophorectomyó RH: Radical hysterectomyó Pathologic assessment to include:

◦ Nodesñ Level of nodal involvement (pelvic, common iliac, para-aortic)

◦ Peritoneal cytology◦ Uterusñ Ratio of depth of myometrial/stromal invasion to myometrial thicknessñ Cervical stromal or glandular involvementñ Tumor sizeñ Tumor location (fundus vs lower uterine segment/cervix)ñ Histologic subtype with gradeñ Lymphovascular space invasionñ Consider mismatch repair analysis to identify genetic problems

◦ Fallopian tubes/ovaries

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Disease Limited to the Corpusstage Ió If medically operable:

◦ Surgeryñ TH/BSO + Pelvic & PA LNDñ inspection and palpation of diaphragm, liver, omentum,

and pelvic and bowel peritoneal surfaces)

ó If medically inoperable:◦ RT

ó Adjuvant:◦ RT for high grade◦ +Chemo for IC/IB G3

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T1=FI

Confined to corpus

endometrium (T1a=IA)myometrium inner half (T1b=IB)myometrium outer half (T1c=IC)

Stage I

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Incompletely resected

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Cervical Involvement (stage II)ó If medically operable:

◦ Surgery: RH/BSO + Pelvic&PA LNDOR◦ RT --> surgery (TH/BSO + PA LND)

ó If medically inoperable:◦ RTó Adjuvant:

◦ RT in stage II◦ +Chemo for G3

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(T2=FII)

Cervix but not Outside uterus

•Endocervix (T2a=FIIA)•Cervical stroma(T2b=FIIB)

Gross or suspected cervical involvement (stage II)

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Extra-uterine Disease: III-IVó Intra-abdominal : IIIA

(ascites, omental, nodal, ovarian, or peritoneal involvement):◦ Surgery: TH/BSO + Pelvic and PA LND +

maximum debulking◦ Adjuvant:ñ RTñ +chemo for G3

ó Extrauterine pelvic : IIIB-IVA(vaginal, bladder, bowel/rectal, or parametrial involvement): ◦ RT and brachytherapy +/- surgery and

chemotherapy.ó Distant mets: IVB (liver, lung)

◦ TH/BSO +/- RT, hormonal therapy, or chemotherapy

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(T4=FIV)

Bladder or bowel mucosaExtrapelvic extension

(T4=FIVA)

Distant mets = IVB

(T3=FIII)

Serosa, adenxa, cancer cells in ascites or

peritoneal washings (T3a=FIIIA)

Vagina (T3b=FIIIB)LN: pelvic or paraaortic

(N1=FIIIB)

Stage III& IV

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Adjuvant Therapyó Types:

◦ RT: stage IC and above◦ Chemo: IC & G3

ó Indications◦ Grade 3 (regardless of the stage): RT + Chemo◦ Deeper invasion; > ½ of myometrium (regardless of grade)

stage IC: RT◦ LN+, stage IIIB: chemo or RT◦ Others:ñ Ageñ LVIñ Tumor volumeñ Involvement of lower uterine segment:

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No adjuvant RTó IA G1-2 : observationó IB G1 : observation

◦ (NB: IA G3: vag BT)◦ (NB: IB G3: vag BT)◦ (NB: IB G2: observation or vag BT

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Adjuvant RTó Uterine-confined disease:

◦ RT: ñ significantly decreased locoregional recurrence,

paticularliy in the vaginañ it did not increase OS or decrease metsñ Type: EB vs Brachytherapyñ whole pelvic RT & vag brachytherapy are equally effectiveñ Vag brachyteherapy is less toxic

ó Extrauterine disease:ó Adjuvant therapy

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Adjuvant RT vs Chemo: GOG 122ó Randall et al., J Clin Oncol. 2006 Jan

1;24(1):36-44.ó Compared

◦ Whole Abdominal RT (WAI) &◦ Chemo AP: doxorubicin A, Cisplatin Pñ 7 cycles: D 60mg/sm, P 50 mg/sm q 3wñ 8th: only P

ó Stage III and IV

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Adjuvant RT vs Chemo

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Adjuvant RT vs Chemo: PFS

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Adjuvant RT vs Chemo: OS

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AP vs AP+paclitaxeló Homesley et al, Gynecol Oncol 2008;108:S2ó GOG 184ó AP+paclitaxel increased toxicityó No benefit

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Systemic therapy in endometrial ca

ó Used in:◦ Recurrent◦ Metastatic or◦ High-risk diseaseó Types:

◦ Hormonal: endometroid histology onlyñ Aromatase inhibitorsñ Progestational agentsñ tamoxifen

◦ Chemo

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Chemotherapy in endometrial caó (Multi-agent chemotherapy regimens preferred, if

tolerated)◦ Cisplatin/doxorubicin (category 1 adjuvant)◦ Cisplatin/doxorubicin/paclitaxel(category 1 metastatic)◦ Ifosfamide plus paclitaxel(category1for carcinosarcoma)◦ Carboplatin◦ Carboplatin/paclitaxel◦ Cisplatin◦ Doxorubicin◦ Paclitaxel◦ Cisplatin/ifosfamide(forc arcinosarcoma)◦ Ifosfamide (forcarcinosarcoma)

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Relapse ó Isolated locaoregional recurrenceó Solitary metastasisó Disseminated metastases

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Isolated locoregional recurrenceó No prior RT to the site:

◦ RT or ◦ Surgery then RT +/- chemoó Prior RT to the site:

◦ Surgery +/- RT +/- chemo or◦ Hormonal therapy or ◦ chemotherapy

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Disseminated metastasesó Asymptomatic or low grade (G1):

◦ Hormonal therapy à progression à chemo à progression àBSC

ó Symptomatic or high grade (G2,3) or large volume:◦ Chemo and or RT à progression àBSC

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Solitary metastasisó Resectable:ó Surgery +/- RT à progression (as

disseminated)ó Irresectable: as disseminated

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Hormone Replacement Therapy for Endometrial Cancersó Follows TH or RH/BSOó Early menopasue:

◦ hot flashes, ◦ mood lability, ◦ Vaginal dryness, ◦ pelvic soft tissue atrophy, ◦ osteoporosis, and ◦ an increased risk of cardiovascular disease.

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Hormone Replacement Therapy for Endometrial Cancersó Controversial

◦ Beneficial or detrimental to uterine CA:ñ In normal women: + endometrial cañ In endometrial ca: no + in relapse

◦ + breast canceró Can be used individualy in low risk

patientsó 6-12 months after adjuvant therapyó Raloxifene can be used

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Progestens as alternative to surgeryó Indications:

◦ young women who desire fertility preservation with either ñ atypical endometrial hyperplasia or ñ grade 1 endometrial hyperplasia; or

◦ women who are very poor surgical candidates.ó Agents:

◦ medroxyprogesterone acetate (MPA 200mg/d PO) or

◦ Megestrol acetateó How:

◦ Progestins plus repeated D&C

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Treatment of Relapsed or Metastatic Diseaseó Surgery: surgery and or RTó RT: suregry, re-RT, hormonal therapy, CTh

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Hormonal Therapy in metastatic uterine caó Indications:

◦ Endometrioid histologies only◦ Asymptiomatic

ó contraindications:◦ papillary serous, clear cell, or carcinosarcoma

ó Agents:◦ Progestational agents: Mainly MPA 200mg/d PO ◦ Tamoxifen and aromatase inhibitors can be used

ó Predictors of response:◦ well-differentiated tumors, ◦ a long disease-free interval, and ◦ the location and extent of extrapelvic (particularly

pulmonary) metastases.

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Progestins in Met Uterine caó Thigpen et al, J Clin Oncol

1999;17(6):1736-1744.ó RCT between PO:óMPA: LD 200 mg/dóMPA: HD 1000 mg/d

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Progestins in Met Uterine ca

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Progestins in Met Uterine ca

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Progestins in Met Uterine ca

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Progestins in Met Uterine ca

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Arzoxifene (SERM)in met uterine ca

ó Burkeet al, Gynecol Oncol 2003;90(2 Pt 2):S40-46.ó RR 28%

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Tamoxifen in met uterine ca: GOG studyó Thigpen et al, J Clin Oncol 2001;19(2):364-367.ó RR 10% (CR 4%)ó PFS: 1.9 mó OS: 8.8 mó Conclusion: Not to be used

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Chemotherapy for Metastatic and Recurrent Diseaseó Indications:

◦ Symptomatic, ◦ Grade 2-3, or ◦ large-volume disseminated metastases◦ Failure of hormonal therapyó Single-agent: RR 20-35%ó Cisplatin, carboplatin, paclitaxel, and

doxorubicin.

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Cis-doxo +/- pacli: RCTó GOG: Fleming et al, J Clin Oncol. 2004 Jun 1;22(11):2159-66.

ó Cis 50, doxo 60 (45) mg/sm D1 q3wó Cis 50, doxo 45 D1, pacli 160 mg/sm D2 +GCSF

q3w

Cis-doxo Cis-doxo-pacli

N 135 135

RR 34 57% (S)

PFS 5 m 8 m (S)

OS 12 m 15 m (S)

G2-3 Neurotxicity 5 39%

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Pacli-carbo:ó 1. Sovak et al, Int J Gynecol Cancer. 2007 Jan-Feb;17(1):197-203.ó 2. Pectasides D et al, Gynecol Oncol. 2008 May;109(2):250-4.

Sovak Pectasides

N 85Failed 1st line

47De no vo, or failed

RR (CR) 43 (5)% 62 (21)%

PFS 5.3m 15 m

OS 13.2 m 25 m

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Aggressive uterine epithelial CAsó Include:

◦ Papillary Serous Carcinomas, ◦ Clear Cell Carcinomas, and◦ Carcinosarcomas (MMTs)

ó Characters:◦ All are high grade (g3) and aggressive◦ Mimic ovarian Ca

ó Treatment as Ovarian ca◦ TAH/BSAO+Pelvic & PA LND + staging◦ Adjuvant: individiulaized

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Aggressive uterine epithelial CAsó Surgery:

◦ TAH/BSAO+ Pelvic & PA LND + stagingó Adjuvant:

◦ Stage IA:ñ Observationñ chemotherapy, or ñ Tumor-directed RT.

◦ Stage IB-II (also adequately debulked III and IV)ñ Chemotherapy +/- tumor-directed RT, or ñ Whole abdominopelvic RT +/- vaginal brachytherapy

◦ Inadequately debulked atage III and IV:ñ Chemotherapy

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Chemotherapyó Papillary Serous Carcinomas, Clear Cell

Carcinomas:◦ Ovarian like: paltinum-taxaneó Carcinosarcomas (MMTs):

◦ Ifosfamide is the most active◦ Ifosfamide-paclitaxel (category A)◦ Ifosfamide-cisplatin◦ Carboplatin-paclitaxel is also active

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Carcinosarcoma, Adjuvant ó Sutton et al, Gynecol Oncol. 2005 Mar;96(3):630-4.

◦ Ifo 1.5 gm/sm D1-5 vs◦ Ifo 1.6gm/sm D1-5+ cispaltin 20 mg/sm D1-5

ó Stage I, II

Ifofamide- cisplatin

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2y- and 8y-PFS 69, 54%

2y- , 5y- and 8-y OS 82, 62, 52%

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Metastatic carcinosarcomaó Homesley et al, J Clin Oncol. 2007 Feb 10;25(5):526-31.

◦ Ifo 2 gm/sm D1-3 vs◦ Ifo 1.6gm/sm D1-3+ pali 135 mg/sm D1+ GCSF

ó Stage III, IV and recurrent

Ifoffamide Ifoffamide- paclitaxel

91 88

RR 29 45%

PFS 3.6 5.8 m (S)

OS 8.4 13.5 m (S)

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Metastatic carcinosarcomaREVIEWó Powell et al, J Clin Oncol. 2010 ;28(5):2727-2731.

◦ Ifo 1.6gm/sm D1-3+ pali 135 mg/sm D1+ GCSF

ó Stage III, IV and recurrent

Ifoffamide -cisplatin

Ifoffamide- paclitaxel

RR

PFS

OS

toxicity More Less

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Uterine Sarcomasó Endometrial stromal sarcoma (ESS): low gradeó Undifferentiated sarcoma (high-grade undifferentiated

sarcoma (HGUD) or Pure heterologous sarcomaó Leiomyosarcoma (LMS)

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Treatment ó If medically operable:

◦ Surgery: TH/BSO +/- LNDó If medically inoperable:

◦ 1) pelvic RT (with or without brachytherapy) and chemotherapy;

◦ 2) chemotherapy; or ◦ 3) hormone therapy (but only for low-grade

ESS).

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Low-Grade ESS (adjuvant treatment)ó If medically operable:

◦ Surgery: TH/BSO +/- LND◦ Adjuvant: ñ Stage I and II: ñ Observationñ Stage III and IV:ñ Hormonal therapy:ñ Megestrol acetate, medroxyprogesterone, ñ Tamoxifen, GnRH analogs, AIñ RT may be added (decrease recurrences but no OS advantage)

ó Inoperable or Recurrentñ Hormonal therapy:

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Leiomyosarcoma and High-Grade Undifferentiated Sarcomaó Non-metastatic disease:

◦ Surgery: TH/BSO +/- LND◦ Adjuvant: ñ RT controversial and individualizedñ Cth: may be considered due to high risk of systemic

relapseñ Stage I and II completely resected:ñ Observeñ RT +/- brachtherapyñ Cth: doxorubicin

ó Metastatic /advanced disease: ñ Single-agent dacarbazine, docetaxel, liposomal

doxorubicin, epirubicin, gemcitabine, ifosfamide, and paclitaxel

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SYSTEMIC THERAPYFOR UTERINE SARCOMA

ó CHEMOTHERAPYREGIMENS◦ single agents or in combination, as clinically appropriate:◦ Doxorubicin (most active single agent for LMS)◦ Gemcitabine/docetaxel◦ Single-agent dacarbazine, docetaxel, epirubicin,

gemcitabine, ifosfamide, liposomal doxorubicin paclitaxel , TEMPZOLAMIDE and could also be considered (category 2B)

ó HORMONE THERAPY(Low-grade ESS only)◦ Megestrol acetate◦ Aromatase inhibitors (category 2B)◦ Tamoxifen (category 2B)◦ Medroxyprogesterone acetate◦ GnRH analogs (category 2B)

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