ADJUVANT THERAPY IN MALIGNANCY OF BODY OF UTERUS

SUJOY DASGUPTA

CLASSIFICATION• Endometrial carcinoma (>90%)

1.Endometrioid Adeno Ca (80%)Variants- I. Endometrial Ca with squamous differentiationII. Viloglandular/ Papillary CaIII.Secretory Ca

2.Mucinous Ca (5%)3.Uterine Papillary Serous Ca (UPSC- 4%)4.Clear cell Ca (<5%)5.Squamous Ca (Rare)6.Undifferentiated ca7.Mixed Ca

CLASSIFICATION• Uterine sarcoma (2-6%)

• Pure Non-epithelial Tx• HomologousI. Endometrial Stromal Tx II. Smooth Muscle Txa) Benign Tx a) Leiomyosarcomab) 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. Leiomyoblastomac) Uterine Tx Resembling c) Benign Metastatizing TxOvarian Sex Cord Tx i. IV leiomyoamatosis(UTROSCT) ii. Benign Mets leiomyoma iii. DPL• Heterologous I. RhabdomyosarcomaII. Chondrosarcoma• Osteosarcoma• Liposarcoma

• Mixed Epithelial- Non-epithelial TxA. Malignant Mixed Mṻllerian Tx (MMMT) B. Adeno Sarcomai. Homologous (Carcino Sarcoma)ii. Heterologous

ENDOMETRIAL CANCER

STAGING and GRADINGFIGO, 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 GRADINGG1 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.

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 ⁎

uteriIA 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 tumorIIIA⁎ 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 metastasesIVA 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.

ManagementMEDICALLY 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 cm5. 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.

ADJUVANT THERAPYLow 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 only3 monthly x 1 year6 monthly x 2 yearThen yearly

Moderate RiskReduced cure rate by surgery aloneMay or may not be benefited by adjuvant therapyRisk 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 benefitPORTEC 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

High RiskHigh risk of recurrence and lower survival rate without adjuvant therapyRisk of mets to LN- 20-60% (pelvic) and 15-30% (para-aortic)• IIIA, IIIB any G- 1. Pelvic plus vaginal RT2. Selected patients (with good performance status)- Chemotherapy prior to RTGOG trial- doxo + cis- ↑survival rate and ↓ recurrence but ↑toxicityResponse rate 38-76%Progesterone can be added to CT to ↓ toxicity but no survival advantagea) AP- Doxorubicin 50-60 mg/m2 + cisplatin 60-75 mg/m2b) TAP- Paclitaxel + cis + doxo- superior to AP but ↑ neurotoxicityc) PAC- Cis + Doxo + cyclophosphamided) 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

Rationale of Adjuvant TherapyLN involvement is the

MOST IMPORTANT prognostic factor

5 yr survival rate • 90% - if no LN mets• 54%- with LN metsPara-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%

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, 20052. Frumovitz Met al, 20043. Chan JK et al, 20064. Kilgore LC et al, 19955. Homesley HD et al, 1992• Chuang L et al, 1995

"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

Special CasesStage 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 benefitTAH (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.

Management of Recurrence• Surgery- Selected cases with isolated pelvic recurrence

with no evidence of extrapelvic or nodal disease-Exenteration or simple removalLaparotomy for intestinal obstruction• RT- If no previous RT received- EBRT + Brachy• Hormones- may be beneficial- 40-60% responseFor endometrioid Ca onlyMPA 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

UTERINE SARCOMA

STAGING• Stage I- Tx limited to uterusIA- Tx ≤5 cm in greatest dimensionIB- Tx >5 cm in greatest dimension• Stage II- Tx extended outside uterus but limited to true pelvisIIA- Involves adnexaIIB- Other pelvic Tissue• Stage III- Tx infiltrates (not just protrudes) into abdominal tissueIIIA- One site, node negativeIIIB- More than one site, node negativeIIIC- Regional LN Mets• Stage IV- Involves bladder/ bowel mucosa or distant metsIVA- Bladder/ bowel mucosaIVB- Distant mets

Applies to ESS and LeiomyosarcomaCarcinosarcoma- staged like Ca Endometrium

Surgical ManagementExploratory 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

Adjuvant Therapy- Stage I• Low Grade ESS- 1. Obsreve2. Consider Hormone Therapy (Progestin, Aromatase

inhibitors, GnRH agonists)• High Grade ESS- 1. Observe2. Consider RT• Leiomyosarcoma-1. Observe2. Consider Chemo• MMMT-Consider Chemo

Adjuvant Therapy- Stage II• Low Grade ESS- Hormone Therapy + RT • High Grade ESS- RT• Leiomyosarcoma-Chemo1. Single Agent- Dacarbazine, Doxorubicin, Ifosfamide (+Mesna), Epirubicin, Liposomal

Doxorubicin, Vinorelbine, Docetaxel2. Multiagent- Docetaxel + Gemcitabine- Preferred3. Others- Doxo + Ifosfamide/ Dacarbazine4. Gemcitabine + Dacarbazine/ Vinorelbine• MMMT- 1. Only Ifosfamide2. Ifosfamide + Cisplatin- preferred3. Carbo + Pacli- recently tried

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

Adjuvant Therapy- Stage IVB• Combination therapy/ Palliative therapy

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