The document discusses uterine cancer including epidemiology, diagnosis, staging, treatment options for different stages of endometrial and uterine sarcoma, adjuvant therapies, relapse patterns, and hormone replacement therapy considerations after treatment. Staging involves assessing tumor size, depth of invasion, spread to lymph nodes or other organs, and treatment involves surgery with or without radiation and/or chemotherapy depending on stage. Relapse patterns include isolated local recurrence, solitary metastasis, or disseminated metastases which are treated with additional surgery, radiation, chemotherapy, or hormone therapy.

1. Uterine cancer
Ahmed Zeeneldin
Associate Prof of Medical Oncology
NCI
2010

2. Worldwide incidence and mortality
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3. Ahmed Zeeneldin 3

4. — US:
◦ 40 000 new case/year
◦ 8000 death/year
— Incidence to mortality is 5:1
— Sarcoma: 3% of uterine cancers
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5. NCI-Egypt
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6. Diagnosis and workup
— H&P
◦ Postmenopausal vaginal bleeding
— CBCD, Biochemistry
— Chest x-ray
— Endometrial biopsy:
◦ Epithelial carcinoma
◦ Stromal / mesenchymal tumors
— Suspected cervix involvement:
◦ Cervical Bx or MRI
— CT or MRI:
◦ to show abdominal or pelvic extension
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7. Endometrial pipette & biopsy
Disposable, Flexible, 3 mm
diameter
Office procedure,
no anaesthesia
False negatives (FN): 10%
FN in symptomatic:
F D&C
hystroscopy
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8. Layers of the uterus
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9. Uterine cancers
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10. Staging of uterine CA
T1=FI (T2=FII) (T3=FIII) (T4=FIVA) N1= FIIIc M1=FIVB
Confined to Cervix Outside Uterus Bladder or bowel N1: pelvic Distant
corpus stroma* but A: Serosa, adenxa, cancer mucosa (3c1) Mets
not Outside cells in ascites or N2: Paraaortic
A: endometrium uterus peritoneal washings (3c2)
or myometrium B: Vagina/parametrium+
inner half
B: myometrium
outer half
Endocervical involvement is not considered T2
Grade is important: G1: well, G2: moderate, G3: poorly differentiated
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11. TNM Staging 2010
Uterine carcinoma
— T1: Body
◦ T1a: endometrium OR
◦ myometrium inner half
◦ T1b: myometrium outer half
— T2: cervical stroma
— T3: outside uterus
◦ T3a: Serosa, adenxa, malignant
ascites
◦ T3b: parametrium /vagina
— T4: bladder or bowel mucosa
T1 T2 T3 T4 M1
— N1: regional LN+
N0 I II III IVA IVB ◦ N1: pelvic
N+ IIIC IIIC IIIC IIIC IVB ◦ N2 Paraaortic
SIMPLIFICATION (FIGO stage) — M1: Distant mets
-I: T1 -II:T2
-III:T3 OR LN+ -IV:T4 OR M1

12. TNM Staging 2010
Uterine sarcoma
— T1: uterus
◦ T1a: <= 5 cm
◦ T1b: > 5 cm
— T2: invade pelvic tissues
◦ T2a: adenexa
◦ T2b: other pelvic tisues
— T3: invade abdominal tissues
◦ T3a: One site
◦ T3b: multiple sites
T1 T2 T3 T4 M1 — T4: bladder or bowel mucosa
N0 I II III IVA IVB
— N1: regional LN+
N+ IIIC IIIC IIIC IIIC IVB
— M1: Distant mets
SIMPLIFICATION (FIGO stage)
-I: T1 -II:T2
-III:T3 OR LN+ -IV:T4 OR M1

13. Treatment of Pure endometrioid cancer
— According to stage:
◦ (1) disease limited to the corpus,
◦ (2) suspected or gross cervical involvement,
(3) suspected extra-uterine disease.
T1=FI (T2=FII) (T3=FIII) (T4=FIV)
Confined to corpus Cervix but not Serosa, adenxa, cancer Bladder or bowel
Outside uterus cells in ascites or mucosa
endometrium (T1a=IA) Endocervix (T2a=FIIA) peritoneal washings Extrapelvic
myometrium inner half (T1b=IB) Cervical stroma (T3a=FIIIA) extension (T4=FIVA)
myometrium outer half (T1c=IC) (T2b=FIIB) Vagina (T3b=FIIIB)
LN: pelvic or paraaortic Distant mets = IVB
(N1=FIIIB)
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14. Uterine sarcoma
— Endometrial stromal sarcoma (ESS)
— Leiomyosarcoma (LMS)
— Undifferntiated sarcoma (UDS)
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15. Treatment of uterine sarcoma
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16. Adjuvant treatment of ESS
HORMONE THERAPY(ESS only)
•Megestrol acetate
•Aromatase inhibitors (category 2B)
•Tamoxifen (category 2B)
•Medroxyprogesterone acetate
•GnRH analogs (category 2B)
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17. Adjuvant treatment of LMS, UDS
Chemotherapeutic agents (single or combinations)
•Doxorubicin
•Gemcitabine/docetaxel
•Other single agent options (category 2B): Dacarbazine, paclitaxel
•gemcitabine, ifosfamide, docetaxel, epirubicin, liposomal
doxorubicin
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18. Treatment of endometrial carcinoma
Surg RT Chemo
Local’zd I uterus Yes* Adj RT may Adj CT may
(G3 or IB/C) (G3 + IC/IB)
II cervix Yes * adjRT in all Adj CT in G3
ORà RT then Surg
extraut IIIA abdomen Yes adj RT Adj CT in G3
IIIB Pelvis May after RT RT may
IVA vag/param
/bladd/rectm
mets IVB mets yes May Palliative CT
OR hormonal T
* If surgery is not feasible à RT
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19. HYSTERECTOMY
— TH/BSO: Total hysterectomy + bilateral salpingo-oophorectomy
— RH: Radical hysterectomy
— Pathologic assessment to include:
◦ Nodes
– Level of nodal involvement (pelvic, common iliac, para-aortic)
◦ Peritoneal cytology
◦ Uterus
– Ratio of depth of myometrial/stromal invasion to myometrial thickness
– Cervical stromal or glandular involvement
– Tumor size
– Tumor location (fundus vs lower uterine segment/cervix)
– Histologic subtype with grade
– Lymphovascular space invasion
– Consider mismatch repair analysis to identify genetic problems
◦ Fallopian tubes/ovaries
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20. Disease Limited to the Corpus
stage I T1=FI
Confined to corpus
— If medically operable: endometrium (T1a=IA)
◦ Surgery myometrium inner half (T1b=IB)
myometrium outer half (T1c=IC)
– TH/BSO + Pelvic & PA LND
– inspection and palpation of diaphragm, liver, omentum,
and pelvic and bowel peritoneal surfaces)
— If medically inoperable:
◦ RT
— Adjuvant:
◦ RT for high grade
◦ +Chemo for IC/IB G3
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21. Stage I
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22. Incompletely resected
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23. Cervical Involvement (stage II)
(T2=FII)
— If medically operable:
Cervix but not Outside
◦ Surgery: RH/BSO + Pelvic&PA LND uterus
•Endocervix (T2a=FIIA)
OR •Cervical stroma
(T2b=FIIB)
◦ RT --> surgery (TH/BSO + PA LND)
— If medically inoperable:
◦ RT
— Adjuvant:
◦ RT in stage II
◦ +Chemo for G3
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24. Gross or suspected cervical
involvement (stage II)
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25. Extra-uterine Disease: III-IV
— Intra-abdominal : IIIA
(ascites, omental, nodal, ovarian, or (T3=FIII)
peritoneal involvement):
◦ Surgery: TH/BSO + Pelvic and PA LND + Serosa, adenxa, cancer
maximum debulking cells in ascites or
peritoneal washings
◦ Adjuvant: (T3a=FIIIA)
– RT Vagina (T3b=FIIIB)
– +chemo for G3 LN: pelvic or paraaortic
(N1=FIIIB)
— Extrauterine pelvic : IIIB-IVA
(vaginal, bladder, bowel/rectal, or
parametrial involvement): (T4=FIV)
◦ RT and brachytherapy +/- surgery and Bladder or bowel mucosa
chemotherapy. Extrapelvic extension
— Distant mets: IVB (liver, lung) (T4=FIVA)
◦ TH/BSO +/- RT, hormonal therapy, or Distant mets = IVB
chemotherapy
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26. Stage III& IV
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27. Adjuvant Therapy
— Types:
◦ RT: stage IC and above
◦ Chemo: IC & G3
— 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:
– Age
– LVI
– Tumor volume
– Involvement of lower uterine segment:
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28. No adjuvant RT
— IA G1-2 : observation
— IB G1 : observation
◦ (NB: IA G3: vag BT)
◦ (NB: IB G3: vag BT)
◦ (NB: IB G2: observation or vag BT
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29. Adjuvant RT
— Uterine-confined disease:
◦ RT:
– significantly decreased locoregional recurrence,
paticularliy in the vagina
– it did not increase OS or decrease mets
– Type: EB vs Brachytherapy
– whole pelvic RT & vag brachytherapy are equally effective
– Vag brachyteherapy is less toxic
— Extrauterine disease:
— Adjuvant therapy
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30. Adjuvant RT vs Chemo: GOG 122
— Randall et al., J Clin Oncol. 2006 Jan
1;24(1):36-44.
— Compared
◦ Whole Abdominal RT (WAI) &
◦ Chemo AP: doxorubicin A, Cisplatin P
– 7 cycles: D 60mg/sm, P 50 mg/sm q 3w
– 8th: only P
— Stage III and IV
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31. Adjuvant RT vs Chemo
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32. Adjuvant RT vs Chemo: PFS
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33. Adjuvant RT vs Chemo: OS
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34. AP vs AP+paclitaxel
— Homesley et al, Gynecol Oncol 2008;108:S2
— GOG 184
— AP+paclitaxel increased toxicity
— No benefit
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35. Systemic therapy in endometrial ca
— Used in:
◦ Recurrent
◦ Metastatic or
◦ High-risk disease
— Types:
◦ Hormonal: endometroid histology only
– Aromatase inhibitors
– Progestational agents
– tamoxifen
◦ Chemo
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36. Chemotherapy in endometrial ca
— (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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37. Relapse
— Isolated locaoregional recurrence
— Solitary metastasis
— Disseminated metastases
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38. Isolated locoregional recurrence
— No prior RT to the site:
◦ RT or
◦ Surgery then RT +/- chemo
— Prior RT to the site:
◦ Surgery +/- RT +/- chemo or
◦ Hormonal therapy or
◦ chemotherapy
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39. Disseminated metastases
— Asymptomatic or low grade (G1):
◦ Hormonal therapy à progression à chemo
à progression àBSC
— Symptomatic or high grade (G2,3) or
large volume:
◦ Chemo and or RT à progression àBSC
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40. Solitary metastasis
— Resectable:
— Surgery +/- RT à progression (as
disseminated)
— Irresectable: as disseminated
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41. Hormone Replacement Therapy for
Endometrial Cancers
— Follows TH or RH/BSO
— Early menopasue:
◦ hot flashes,
◦ mood lability,
◦ Vaginal dryness,
◦ pelvic soft tissue atrophy,
◦ osteoporosis, and
◦ an increased risk of cardiovascular disease.
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42. Hormone Replacement Therapy for
Endometrial Cancers
— Controversial
◦ Beneficial or detrimental to uterine CA:
– In normal women: + endometrial ca
– In endometrial ca: no + in relapse
◦ + breast cancer
— Can be used individualy in low risk
patients
— 6-12 months after adjuvant therapy
— Raloxifene can be used
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43. Progestens as alternative to surgery
— Indications:
◦ young women who desire fertility preservation
with either
– atypical endometrial hyperplasia or
– grade 1 endometrial hyperplasia; or
◦ women who are very poor surgical candidates.
— Agents:
◦ medroxyprogesterone acetate (MPA 200mg/d
PO) or
◦ Megestrol acetate
— How:
◦ Progestins plus repeated D&C
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44. Treatment of Relapsed or Metastatic
Disease
— Surgery: surgery and or RT
— RT: suregry, re-RT, hormonal therapy, CTh
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45. Hormonal Therapy in metastatic
uterine ca
— Indications:
◦ Endometrioid histologies only
◦ Asymptiomatic
— contraindications:
◦ papillary serous, clear cell, or carcinosarcoma
— Agents:
◦ Progestational agents: Mainly MPA 200mg/d PO
◦ Tamoxifen and aromatase inhibitors can be used
— 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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46. Progestins in Met Uterine ca
— Thigpen et al, J Clin Oncol
1999;17(6):1736-1744.
— RCT between PO:
— MPA: LD 200 mg/d
— MPA: HD 1000 mg/d
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47. Progestins in Met Uterine ca
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48. Progestins in Met Uterine ca
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49. Progestins in Met Uterine ca
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50. Progestins in Met Uterine ca
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51. Arzoxifene (SERM)in met uterine ca
— Burkeet al, Gynecol Oncol 2003;90(2 Pt
2):S40-46.
— RR 28%
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52. Tamoxifen in met uterine ca: GOG
study
— Thigpen et al, J Clin Oncol 2001;19(2):364-367.
— RR 10% (CR 4%)
— PFS: 1.9 m
— OS: 8.8 m
— Conclusion: Not to be used
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53. Chemotherapy for Metastatic and
Recurrent Disease
— Indications:
◦ Symptomatic,
◦ Grade 2-3, or
◦ large-volume disseminated metastases
◦ Failure of hormonal therapy
— Single-agent: RR 20-35%
— Cisplatin, carboplatin, paclitaxel, and
doxorubicin.
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54. Cis-doxo +/- pacli: RCT
— GOG: Fleming et al, J Clin Oncol. 2004 Jun 1;22(11):2159-66.
— Cis 50, doxo 60 (45) mg/sm D1 q3w
— 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 5m 8 m (S)
OS 12 m 15 m (S)
G2-3 Neurotxicity 5 39%
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55. Pacli-carbo:
— 1. Sovak et al, Int J Gynecol Cancer. 2007 Jan-Feb;17(1):197-203.
— 2. Pectasides D et al, Gynecol Oncol. 2008 May;109(2):250-4.
Sovak Pectasides
N 85 47
Failed 1st line De 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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56. Aggressive uterine epithelial CAs
— Include:
◦ Papillary Serous Carcinomas,
◦ Clear Cell Carcinomas, and
◦ Carcinosarcomas (MMTs)
— Characters:
◦ All are high grade (g3) and aggressive
◦ Mimic ovarian Ca
— Treatment as Ovarian ca
◦ TAH/BSAO+Pelvic & PA LND + staging
◦ Adjuvant: individiulaized
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57. Aggressive uterine epithelial CAs
— Surgery:
◦ TAH/BSAO+ Pelvic & PA LND + staging
— Adjuvant:
◦ Stage IA:
– Observation
– chemotherapy, or
– Tumor-directed RT.
◦ Stage IB-II (also adequately debulked III and IV)
– Chemotherapy +/- tumor-directed RT, or
– Whole abdominopelvic RT +/- vaginal brachytherapy
◦ Inadequately debulked atage III and IV:
– Chemotherapy
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58. Ahmed Zeeneldin 58

59. Chemotherapy
— Papillary Serous Carcinomas, Clear Cell
Carcinomas:
◦ Ovarian like: paltinum-taxane
— Carcinosarcomas (MMTs):
◦ Ifosfamide is the most active
◦ Ifosfamide-paclitaxel (category A)
◦ Ifosfamide-cisplatin
◦ Carboplatin-paclitaxel is also active
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60. Carcinosarcoma, Adjuvant
— 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
— Stage I, II
Ifofamide- cisplatin
65
2y- and 8y-PFS 69, 54%
2y- , 5y- and 8-y OS 82, 62, 52%
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61. Metastatic carcinosarcoma
— 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
— 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)
Neuropathy 8 30%
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62. Metastatic carcinosarcoma
REVIEW
— Powell et al, J Clin Oncol. 2010 ;28(5):2727-2731.
◦ Ifo 1.6gm/sm D1-3+ pali 135 mg/sm D1+ GCSF
— Stage III, IV and recurrent
Ifoffamide - Ifoffamide- paclitaxel
cisplatin
RR
PFS
OS
toxicity More Less
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63. Uterine Sarcomas
— Endometrial stromal sarcoma (ESS): low grade
— Undifferentiated sarcoma (high-grade undifferentiated
sarcoma (HGUD) or Pure heterologous sarcoma
— Leiomyosarcoma (LMS)
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64. Treatment
— If medically operable:
◦ Surgery: TH/BSO +/- LND
— 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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65. Low-Grade ESS
(adjuvant treatment)
— If medically operable:
◦ Surgery: TH/BSO +/- LND
◦ Adjuvant:
– Stage I and II:
– Observation
– Stage III and IV:
– Hormonal therapy:
– Megestrol acetate, medroxyprogesterone,
– Tamoxifen, GnRH analogs, AI
– RT may be added (decrease recurrences but no OS advantage)
— Inoperable or Recurrent
– Hormonal therapy:
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66. Leiomyosarcoma and High-Grade
Undifferentiated Sarcoma
— Non-metastatic disease:
◦ Surgery: TH/BSO +/- LND
◦ Adjuvant:
– RT controversial and individualized
– Cth: may be considered due to high risk of systemic
relapse
– Stage I and II completely resected:
– Observe
– RT +/- brachtherapy
– Cth: doxorubicin
— Metastatic /advanced disease:
– Single-agent dacarbazine, docetaxel, liposomal
doxorubicin, epirubicin, gemcitabine, ifosfamide, and
paclitaxel
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67. SYSTEMIC THERAPYFOR UTERINE SARCOMA
— 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)
— 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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