Lecture delivered at CNCI, April, 2014

1. ADJUVANT THERAPY IN
MALIGNANCY OF
BODY OF UTERUS
SUJOY DASGUPTA

2. CLASSIFICATION
• Endometrial carcinoma (>90%)
1.Endometrioid Adeno Ca (80%)
Variants-
I. Endometrial Ca with squamous differentiation
II. Viloglandular/ Papillary Ca
III.Secretory Ca
2.Mucinous Ca (5%)
3.Uterine Papillary Serous Ca (UPSC- 4%)
4.Clear cell Ca (<5%)
5.Squamous Ca (Rare)
6.Undifferentiated ca
7.Mixed Ca

3. CLASSIFICATION
• Uterine sarcoma (2-6%)
• Pure Non-epithelial Tx
• Homologous
I. Endometrial Stromal Tx II. Smooth Muscle Tx
a) Benign Tx a) Leiomyosarcoma
b) Endometrial Stromal Sarcoma (ESS) b) Leiomyoma variants
i. Low grade (<10 MF/ 10 hpf) i. Cellular Leiomyoma
ii. High grade (>10 MF/ 10 hpf) ii. Myxoid Leiomyoma
iii. Leiomyoblastoma
c) Uterine Tx Resembling c) Benign Metastatizing Tx
Ovarian Sex Cord Tx i. IV leiomyoamatosis
(UTROSCT) ii. Benign Mets leiomyoma
iii. DPL
• Heterologous
I. Rhabdomyosarcoma
II. Chondrosarcoma
• Osteosarcoma
• Liposarcoma
• Mixed Epithelial- Non-epithelial Tx
A. Malignant Mixed M llerian Tx (MMMT) B. Adeno Sarcomaṻ
i. Homologous (Carcino Sarcoma)
ii. Heterologous

4. ENDOMETRIAL CANCER

5. STAGING and GRADING
FIGO, 1971- CLINICAL STAGING
• Stage I Tumor confined to
the corpus uteri
IA Length of Ut cavity <8 cm
G1, G2, G3
IB Length of Ut cavity >8 cm
G1, G2, G3
• Stage II Involves corpus and
cervix but not beyond uterus
• Stage III Extends outside
uterus but not beyond true
pelvis
• Stage IV Extends outside
true pelvis or obviously
involves bladder and/or
rectal mucosa
IVA To adjacent organs
IVB To distal organs
FIGO PATHOLOGICAL GRADING
G1 5% or less of a non-squamous
or non-morular solid growth
pattern.
G2 6-50% of a non-squamous or
non-morular solid growth
pattern.
G3 More than 50% of a non-
squamous or non-morular solid
growth pattern.
Notes on pathological grading:
(a) Notable nuclear atypia,
inappropriate for the architectural
grade, raises the grade of a grade I
or grade II tumour by one.
(b) In serous adenocarcinoma, clear-
cell adenocarcinoma and
squamous-cell carcinoma, nuclear
grading takes precedence.
(c) Adenocarcinoma with squamous
differentiation is graded according to
the nuclear grade of the glandular
component.

6. SURGICAL STAGING
FIGO, 1988
• IA G1 2 3 No myometrial invasion
• IB G1 2 3 Less than half
myometrial invasion
• IC G1 2 3 More than half
myometrial invasion
• II A G1 2 3 Extension to
endocervical glands
• II B G1 2 3 Extension to cervical
stroma
• IIIA G1 2 3 Positive serosa of the
corpus uteri and/or adnexae and/or
positive peritoneal cytology
• IIIB G1 2 3 Vaginal involvement
• IIIC G1 2 3 Metastases to pelvic
and/or para-aortic lymph nodes#
• IVA G1 2 3 Tumor invasion of
bladder and/or bowel mucosa
• IVB Distant metastases, including⁎
intra-abdominal metastases and/or
inguinal lymph nodes
FIGO, 2008
• Stage I Tumor confined to the corpus⁎
uteri
IA No or less than half myometrial invasion⁎
IB Invasion equal to or more than half of the⁎
myometrium
• Stage II Tumor invades cervical stroma,⁎
but does not extend beyond the uterus⁎⁎
• Stage III Local and/or regional spread of⁎
the tumor
IIIA⁎ Tumor invades the serosa of the corpus uteri
and/or adnexae#
IIIB Vaginal and/or⁎ parametrial involvement#
IIIC Metastases to pelvic and/or para-aortic lymph⁎
nodes#
IIIC1 Positive pelvic nodes⁎
IIIC2 Positive para-aortic lymph nodes with or⁎
without positive pelvic lymph nodes
• Stage IV Tumor invades bladder and/or⁎
bowel mucosa, and/or distant metastases
IVA Tumor invasion of bladder and/or bowel mucosa⁎
IVB Distant metastases, including intra-abdominal⁎
metastases and/or inguinal lymph nodes
• ⁎Either G1, G2, or G3.
• ⁎⁎Endocervical glandular involvement only should
be considered as Stage I and no longer as Stage II.
• #Positive cytology has to be reported separately
without changing the stage.

7. Management
MEDICALLY
CHALLENGED
PATIENTS
• Simple vaginal
hysterectomy
• Whole pelvis
irradiation +
intracavitray
brachytherapy (Like
Ca Cx)
• For elderly, obese
etc- Intracav brachy
only
EXPLORATORY LAPAROTOMY
• POD washings for cytological examination.
• Careful exploration of abdominal cavity.
• If tumour resectable: extra-fascial total abdominal hysterectomy
(Type I) and bilateral salpingo-oophorectomy (TAH, BSO)
• Pelvic lymphadenectomy –
Indications:
1. Grade 3, with or without myometrial invasion.
2. Type of histology (UPSC-Clear cell carcinoma).
3. ≧Stage II disease.
4. Tx >4 cm
5. Preop MRI- myo-invasion >50%
• Indications for Frozen Section:
1. Pre-operative complex atypical hyperplasia.
2. Grades 1 and 2 adenocarcinoma.
Pathologist to assess (frozen section) histological type, grade, depth of
myometrial invasion, and cervical involvement.
If the frozen section indicates more than 50% myometrial invasion, grade 3
or cervical stromal involvement, proceed to pelvic lymphadenectomy.
• Omentectomy is recommended in patients with grade 3 disease
and with clear cell or UPSC tumours.
• Locally advanced stage disease: cytoreductive surgery including
TAH-BSO should be attempted.
• Removal of bulky lymph nodes should be attempted.

8. ADJUVANT THERAPY
Low Risk
Low incidence of recurrence and high cure rate
without any post op therapy
Risk of lymph node involvement- 0%
• IA, IB G1, G2- Observation only
3 monthly x 1 year
6 monthly x 2 year
Then yearly

9. Moderate Risk
Reduced cure rate by surgery alone
May or may not be benefited by adjuvant therapy
Risk of LN involvement 3-6% (pelvic) and 2% (para-aortic)
• IA G3- Vaginal RT by colpostat 6000-7000 cGy in uper vagina (4-6 wk after
Sx)
Reduces risk of vaginal recurrence from 15% to 1-2%
GOG trial- superior to whole pelvis RT
• IB G3- Pelvic RT (EBRT) 4500-5040 cGy, 25# (180cGy)- over 5-6 wk to field
encompassing
upper 1/2 of vagina (Inf)
lower border of L4 (Sup)
1 cm lat to margin of bony pelvis (Lat)
Plus vaginal boost (6000-7000cGy)
GOG trial- Reduces recurrence by 58% but no survival benefit
PORTEC trial- same result
• IC, any G- Pelvic plus vaginal RT
• Stage II, any G- Pelvic plus vaginal RT
• LVSI- Pelvic plus vaginal RT
• If stage I/II but no LN dissection done- Pelvic plus vaginal RT

10. High Risk
High risk of recurrence and lower survival rate without adjuvant therapy
Risk of mets to LN- 20-60% (pelvic) and 15-30% (para-aortic)
• IIIA, IIIB any G-
1. Pelvic plus vaginal RT
2. Selected patients (with good performance status)- Chemotherapy prior to RT
GOG trial- doxo + cis- ↑survival rate and ↓ recurrence but ↑toxicity
Response rate 38-76%
Progesterone can be added to CT to ↓ toxicity but no survival advantage
a) AP- Doxorubicin 50-60 mg/m2 + cisplatin 60-75 mg/m2
b) TAP- Paclitaxel + cis + doxo- superior to AP but ↑ neurotoxicity
c) PAC- Cis + Doxo + cyclophosphamide
d) Paclitaxel + Cis/ Carboplatin
• IIIC-
• Pelvic plus vaginal RT
• Extended Field Radiation- to include entire pelvis, para-aortic and common iliac
LN
Specially include para-aortic area (not more than 4500 cGy) if 2 of common/≧
external iliac LN are involved
• IVA, IVB - Chemo, Progesteron, Palliative RT

11. Rationale of Adjuvant Therapy
LN involvement is the
MOST IMPORTANT
prognostic factor
5 yr survival rate
• 90% - if no LN mets
• 54%- with LN mets
Para-aortic LN is
involved in 50-60%
cases with positive
pelvic LN mets
Condition Chance of LN mets
Stage IA, Grade 1,2 Nearly 0%
Stage IB, Grade 1,2 <5%
Stage IB, Grade 3 15%
Stage IC, Grade 1,2 15%
Stage IC, Grade 3 40%
Tx size <2 cm 4%
Tx size >2 cm 15%
Tx filling the Endo
Cavity
35%
Stage II 15%
Adnexal mets 32%

12. Should we do routine Lymphadenectomy?
• Pre-op and intra-op assessment of ''Risk factors" are inaccurate1
• Routine LN dissection improves survival1,2
• If >20 LN removed in any stage, 5 yr disease free survival increases to 87%
compared to 75% if only one LN dissected3
• If LN dissection done and LN is not involved- PELVIC RT CAN BE AVOIDED- as
RT can prevent loco-regional recurrence only without improving survival
• Even with post-op pelvic RT, lyphadenectomy improves disease free interval4
• No increase in surgical morbidity except more blood loss and more OT time but
no significant risk of transfusion5
• Complication rates related to age, weight and other risk factors
• Risk overweighs benefits6
• More cost-effective than wait for frozen sections
• But should be avoided in medically morbid patients or when adequate exposure
is not possible
1. Eltrabakkh GH et al, 2005
2. Frumovitz Met al, 2004
3. Chan JK et al, 2006
4. Kilgore LC et al, 1995
5. Homesley HD et al, 1992
• Chuang L et al, 1995

13. "Adequate Lymphadenectomy"
• Kilgore eta al, 1995- University of
Alabama- Median number of LN to be
removed= 11
• Chuang L et al, 1995- LN areas are
divided into 10 zones (Rt and Lt- para-
aortic, common/ external iliac, hypogastric,
obturator)- ate least 3 zones should be
removed- including para-aortic from one
side and one pelvic from each side

14. Special Cases
Stage II Cancer
• Like Ca Cx- Radical hysterectomy
+ pelvic and para-aortic
lymphadenectomy
5 yr survival rate- 90-94%
• Alternative- Whole pelvic RT +
Brachy f/b completion TAH
+BSO (after 6 wk) as RT is not as
effective in treating corpus cancer as
Cx Ca
5 yr survival rate 82%
• RT alone- for moribund pt- survival
rate 50%
Stage III and IV Cancer
• Surgery- Tx debulking is of benefit
TAH (except in bulky parametrial ds) + BSO +
remove LN (at least enlarged) + Partial
Omentectomy + remove any gross Tx
• Post op RT
 Goff BA et al, 1994- 47 cases- median
survival 18 mth vs 8 mth
 Chi DS et al, 1997- 55 cases- median
survival 31 mth (residual ds <2cm) vs
12 mth (residual ds >2 cm) vs 3 mth
(no Sx done)
 Lambrou NC, 2004- Optimal
cytoreduction possible in 72% cases
 Bristow RE, 203- LN debulking had
disease free-survival of 37.5 mth vs
8.8 mth
UPSC
• Stages I & II:
• Mid-line vertical incision→.TAH-BSO-Omentectomy-pelvic lymphadenectomy.
• Platinum-based chemotherapy for all stages (as for ovarian cancer).
• If stage IB, IC, II- vaginal vault brachytherapy.
• If only TAH-BSO (No surgical staging) individualise adjuvant treatment.
• Stage III: Surgery as in stage I & II and adjuvant platinum based chemotherapy (6
cycles), followed by pelvic/ Whole Abdomen radiotherapy. (See page 47).
• Stage IV: Debulking surgery followed by chemotherapy where appropriate.

15. Management of Recurrence
• Surgery- Selected cases with isolated pelvic recurrence
with no evidence of extrapelvic or nodal disease-
Exenteration or simple removal
Laparotomy for intestinal obstruction
• RT- If no previous RT received- EBRT + Brachy
• Hormones- may be beneficial- 40-60% response
For endometrioid Ca only
MPA 50-100 mg TDS oral or 1 g/wk IM- continue for 2-3
months- if good response- continue at lower dose- if
poor response- consider chemo
Tamoxifen- 20 mg BD- if progestin is contraindicated
• Chemo- Mainly palliative- survival not improved bt >12
mth

16. UTERINE SARCOMA

17. STAGING
• Stage I- Tx limited to uterus
IA- Tx ≤5 cm in greatest dimension
IB- Tx >5 cm in greatest dimension
• Stage II- Tx extended outside uterus but limited to true pelvis
IIA- Involves adnexa
IIB- Other pelvic Tissue
• Stage III- Tx infiltrates (not just protrudes) into abdominal tissue
IIIA- One site, node negative
IIIB- More than one site, node negative
IIIC- Regional LN Mets
• Stage IV- Involves bladder/ bowel mucosa or distant mets
IVA- Bladder/ bowel mucosa
IVB- Distant mets
Applies to ESS and Leiomyosarcoma
Carcinosarcoma- staged like Ca Endometrium

18. Surgical Management
Exploratory
Laparotomy
• Explore organs
• TAH + BSO
• Lymphadenectomy
for ESS, MMMT (not
needed in
leiomyosarcoma)
• Omentectomy in
MMMT
• Resection of other
mets, if possible
Special Case
• Medically Unfit
-Non-surgical therapy,
as indicated
• Extrauterine ds-
Neoadjuvant Chemo/
RT → Consider Sx →
Adjuvant therapy

19. Adjuvant Therapy- Stage I
• Low Grade ESS-
1. Obsreve
2. Consider Hormone Therapy (Progestin, Aromatase
inhibitors, GnRH agonists)
• High Grade ESS-
1. Observe
2. Consider RT
• Leiomyosarcoma-
1. Observe
2. Consider Chemo
• MMMT-
Consider Chemo

20. Adjuvant Therapy- Stage II
• Low Grade ESS-
Hormone Therapy + RT
• High Grade ESS-
RT
• Leiomyosarcoma-
Chemo
1. Single Agent- Dacarbazine, Doxorubicin, Ifosfamide (+Mesna), Epirubicin, Liposomal
Doxorubicin, Vinorelbine, Docetaxel
2. Multiagent- Docetaxel + Gemcitabine- Preferred
3. Others- Doxo + Ifosfamide/ Dacarbazine
4. Gemcitabine + Dacarbazine/ Vinorelbine
• MMMT-
1. Only Ifosfamide
2. Ifosfamide + Cisplatin- preferred
3. Carbo + Pacli- recently tried

21. Adjuvant Therapy- Stage III, IVA
• ESS
RT + hormones (for low grade ESS)
• Leiomyosarcoma-
Chemo + Tx targetted RT
• MMMT-
Chemo + RT

22. Adjuvant Therapy- Stage IVB
• Combination therapy/ Palliative therapy

23. THANK YOU