Guidelines for management of Endometrial

Carcinoma
Dr Veena P
Additional Professor
Dept of OG, JIPMER
8th July 2017
 Incidence

• The incidence of endometrial cancer is low in India

• The highest being observed in Delhi (ASR=4.3) and Bangalore (ASR=4.2) while in
Mumbai it is 2.8 per 100,000 vs 25.1 per 100,000 in western world*
• Incidence is steadily increasing more so in urban, affluent Indian women
• Changing life style – more westernization
• Changing fertility preferences

*Ganesh Balasubramanian, S Sushama, B Rasika, et al. Hospital-based Study of Endometrial Cancer Survival
in Mumbai, India. Asian Pacific J Cancer Prev, 2013. 14 (2), 977-980
 Early
menarche &
Late
menopause
Tamoxifen HRT

Risk
factors
Obesity,
Lynch II
DM, HTN

Nulliparity &
PCOS
 Tamoxifen
• In standard doses used in adjuvant treatment of breast cancer, it is known to cause
endometrial hyperplasia and polyps, invasive endometrial carcinoma and uterine sarcoma
• Causes sub-epithelial stromal hypertrophy, which gives a false impression of thick
endometrium on ultrasonography  Poor correlation between endometrial thickness and
abnormal pathology  so evaluate only women with AUB
• Risk of developing endometrial carcinoma is estimated to be only 1.26 for 1000 patient
years after 5 years of tamoxifen intake
• ATLAS  ACOG  tamoxifen use may be extended to 10 years

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of estrogen receptor-positive
breast cancer: ATLAS, a randomized trial. The Lancet, Volume 381, 2013
 Protective factors
• Oral contraceptive pills: 1 year of use confers 30-50% reduced risk
• Risk reduction is up to 10-20 yrs
• Progestin component has chemo protective role
• Progesterone IUCDs confers long term protection
• Earlier age of menopause
• Smoking
 Type I tumors
• 80% of endometrial carcinomas
• Estrogen-dependent
• Usually preceded by atypical
complex endometrial hyperplasia
• Tumors of endometrioid histology
that are grade 1 or 2, mucinous
carcinoma
• Favorable prognosis
Type II tumors
• 10 to 20% of endometrial carcinomas, but
account for more than 50% of all endometrial
cancer deaths
• Not clearly associated with estrogen stimulation
• A precursor lesion is rarely identified
• Include grade 3 endometrioid tumors, serous,
clear cell, undifferentiated, MMMTs
• Poor prognosis – behave like ovarian cancers
 Clinical scenarios
1. 55 year old obese woman, P2L2, known DM & HTN, presented with PMB.
EB is reported as Endometrioid Adeno Ca Gr 2
2. 35 year old nulliparous woman undergoing treatment for infertility, presented with HMB
and found to have Endometrioid Adeno Ca Gr 1 on EB
3. 65 year old k/c/o CAD, uncontrolled HTN and DM diagnosed to have Endometrioid
Adeno Ca on EB done for PMB
4. 50 year old, TAH BSO done for HMB  found to have endometrial Ca on final HPR
5. Post surgical staging for endometrial cancer, woman develops menopausal symptoms
6. A woman treated for early endometrial cancer with surgery alone presents with vaginal
bleeding after 14 months of surgery
1. 55 year old Obese woman, P2L2, known diabetic and hypertensive,
presented with PMB  EB is reported as Endometrioid Adeno Ca Gr 2
 Outline
• Initial evaluation
• Surgical staging
• MIS
• Vaginal hysterectomy
• Risk stratification
• Adjuvant therapy
• Follow up
Initial evaluation of endometrial cancer (NCCN 2017 and ESMO-ESGO-
ESTRO 2015)
Recommended Optional

• Clinical history and examination • CA-125 (optional), MRI, CECT in

• General assessment and inventory of suspected extra uterine disease
comorbidities • Cervix biopsy or MRI to r/o cervical
• Pelvic USG involvement
• Histopathology of endometrial biopsy • FDG PET-CT ([18F] 2-Fluoro-2
• CBC including platelets deoxy-D-glucose–positron emission
tomography) in suspected distant
• LFT & RFT
metastases
• Chest X-ray
• Genetic counseling
 Hereditary cancer (Lynch II or hereditary non polyposis colorectal cancer
syndrome (HNPCC))
• <5% of endometrial cancer
• Autosomal Dominant disorder (Germ line mutation in mismatch repair genes (MMR),
MLH1, MSH2 & MSH6 and Micro-satellite instability (MSI))
• Increased risk of colorectal, endometrial, ovarian, gastric, ureter & skin cancer
• 40-60% life time risk of endometrial and colorectal cancer
• Cancer tends to occur in pre-menopausal age (47 yrs vs 60 yrs)
• Genetic counseling and germline testing  women <50 years at diagnosis, those with
mismatch repair (MMR) gene abnormalities and in those with a significant family history
of endometrial cancer and colorectal cancer
Treatment
 Surgical Staging  FIGO 2009
• Stage I- Tumor confined to corpus uteri
• IA- No or <50% of myometrial invasion
• IB- >50% of myometrial invasion, cervical glandular involvement
• Stage II- Tumor invades cervical stroma, but does not extend beyond the uterus
• Stage III- Local &/or regional spread of tumor
• IIIA- Serosa of uterus &/or adnexa
• IIIB- Vaginal &/or parametrial involvement
• IIIC- Pelvic (IIIC1) &/ or Para-aortic LN (IIIC2)
• Stage IV- Bladder &/or Bowel mucosa (IVA) &/or distant mets (IVB)

Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium [published
erratum appears in Int J Gynaecol Obstet 2010;108:176]. Int J Gynaecol Obstet 2009;105:103–4
 Surgical treatment
Stage I
• Includes abdominal exploration, peritoneal cytology, type 1 hysterectomy, bilateral
salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy
• Omentectomy in type 2 tumors
• Indications for pelvic and para-aortic lymph node dissection
• Tumor histology clear cell, serous, squamous, or grade 2-3 endometrioid
• Myometrial invasion > 50%
• Isthmus-cervix extension
• Tumor size > 2 cm
• Extra-uterine disease
“Extent of surgery should be adapted to
the medical condition of the patient”
 Surgical treatment
• Stage II
• Radical hysterectomy with BSO and retroperitoneal lymphadenectomy
• ESMO-ESGO-ESTRO 2015: no need of radical hysterectomy* (Level 4 evidence, Strength of
recommendation: B)

• Stage III
• Operable: Maximal surgical cytoreduction with a good performance status
• Inoperable: (stage 3B): Primary radiation  Extra-fascial hysterectomy
• Stage IV
• IV A: Anterior and posterior pelvic exenteration
• IV B: Systemic therapeutic approach with palliative surgery

*Takano M, Ochi H, Takei Y et al. Surgery for endometrial cancers with suspected cervical involvement:
is radical hysterectomy needed (a GOTIC study)? Br J Cancer 2013; 109: 1760–1765
 MIS

• Minimally invasive surgery is recommended in the surgical management of low- and

intermediate risk endometrial cancer
• It can be considered in the management of high-risk endometrial cancer
• Standard surgical approach for comprehensive surgical staging

Colombo et al. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer. Annals of Oncology 0: 1–26,
2015
 Vaginal hysterectomy

• In selected patients who are

• extremely obese
• have a poor medical status
• for patients with extensive uterovaginal prolapse
• Disadvantages: bilateral salpingo-oophorectomy often is technically difficult and
abdominal exploration and lymph node sampling cannot be performed
• Suitable for patients with low grade IA disease
 Risk stratification

Stage I can be subdivided into following risk categories

• Low risk: Stage IA, G1 and G2, LVSI negative
• Intermediate risk:
• Low intermediate: Stage IB, G1 and G2, LVSI negative
• High intermediate: Stage IA, G3, + LVSI
Stage 1A or B, G1 & G2, LVSI+
• High risk: Stage IB G3 with endometrioid type, LVSI+
“ALL TYPE 2 TUMORS  HIGH RISK”

Colombo et al. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer. Annals of Oncology 0: 1–26, 2015
 Adjuvant treatment

Low risk Observation

Stage I Intermediate risk Observation or vaginal brachytherapy*

High risk EBRT*

*If negative prognostic factors (age>60 years, LVSI and tumor size>2 cm)  EBRT and
add chemotherapy if LVSI+ in type 1 and in all type 2 tumors

Colombo et al. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer. Annals of Oncology 0: 1–26, 2015
 EBRT and Vaginal brachytherapy

Stage II
If grade 1–2 tumour, myometrial invasion<50%, negative LVSI
and complete surgical staging: Vaginal brachytherapy alone

Chemotherapy (Doxorubicin, Platins and Taxols)

Sequential radiotherapy
Stage III–IV

If metastatic disease (IV B): chemotherapy & RT for palliative

treatment
 Follow-up after treatment
• History and physical examination remain the most effective methods of follow-up in
patients treated for endometrial cancer
• Patients should be examined every 3 to 4 months during the first 2 years and every 6
months till 5th year and yearly thereafter for life
• Chest x-ray every 12 months
• CECT/PET– only if clinically s/o disease recurrence
• There is insufficient evidence for routine use of Pap smear or routine CECT to diagnose
asymptomatic recurrences

The overall 5-year survival rate  76%

2. 35 year old nulliparous woman presented with HMB and found to
have Endometrioid Adeno Ca Gr 1
 Fertility preservation
Indications:
• A well-differentiated, grade 1, endometrioid endometrial carcinoma
• No myometrial invasion
• No extra-uterine involvement (no synchronous ovarian tumor or metastases, no
suspicious retroperitoneal nodes)
• Strong desire for fertility preservation
• No contraindications for medical management
• Patient understands and accepts that data on cancer-related and pregnancy-related
outcomes are limited (informed consent)
Erkanli S, Ayhan A. Fertility-sparing therapy in young women with endometrial cancer: 2010 update. Int J Gynecol
Cancer 2010;20:1170–87
 Fertility sparing treatment
Strategies:
• Progestogens, antiestrogens, GnRHas and aromatase inhibitors
• High dose medroxy progesterone acetate (600 mg/day orally) and megesterol acetate
(160-320 mg/day orally)
• Side-effects: thrombus formation, mood alterations, headaches, weight gain and breast
pain and/or tenderness
• LNG IUS with or without GnRH analogues

“Women opting for conservative management should be aware that hormonal

therapy is not the standard form of management and regular follow up is essential”
 Fertility sparing treatment (contd….)
Follow up:
• Endometrial sampling 3 monthly  to assess the response to treatment
• Response to treatment  73–81%, but not absolute
• In case of complete response, conception must be encouraged and referral to a fertility
clinic is recommended
• Pregnancy rates of 40% and subsequent live birth rates up to 47%
• Recurrence rates  18–40%
• The biggest concern: disease progression while on treatment or after initial response to
medical treatment

Gotlieb WH, Beiner ME, Shalmon B, et al. Outcome of fertility-sparing treatment with progestins in young patients with
endometrial cancer. Obstetrics and Gynecology. Oct 2003;102(4):718–25.
3. 65 year old k/c/o CAD, uncontrolled HTN and DM diagnosed to have
endometrioid adeno ca on EB done for PMB
 Medically unfit patients

• Preoperative assessment of metastatic disease with imaging, measurement of serum CA

125, or both may be clinically important for pre-op staging of disease
• Staging among these patients should be done according to 1971 FIGO clinical staging
• In early stage disease: definitive RT can be given with curative intent
• In advanced stage disease  RT or hormone treatment can be considered

ACOG PRACTICE BULLETIN on Endometrial carcinoma, Number 149, April 2015

4. 50 year old, TAH BSO done for HMB, found to have Endometrial ca on final
HPR
 Suboptimal surgery
These women should have their risk of extra-uterine disease and potential for disease
recurrence evaluated based on
• Age
Individualize treatment plans and decision for repeat
• Histologic cell type
surgery for the sole purpose of staging
• Uterine tumor features*

*grade, depth of myometrial invasion, presence of LVSI, and tumor size

5. Post surgical staging for endometrial cancer, woman develops menopausal
symptoms
 Estrogen therapy post treatment
• Disease confined to uterus
 No evidence that estrogen therapy after apparently successful treatment of
endometrial cancer increases the risk for cancer recurrence
• Disease beyond uterus
 Avoid systemic estrogen
 Symptomatic relief of hot flashes: medroxyprogesterone acetate, 10 mg orally daily
or 150 mg intramuscularly every 3 months, or non-hormonal agents such as
Peroxotine, Bellergal, clonidine, and venlafaxine

ACOG PRACTICE BULLETIN on Endometrial carcinoma, Number 149, April 2015

6. A woman treated for early endometrial cancer with surgery alone presents
with vaginal bleeding after 14 months of surgery
 Recurrences

• About 1/4th of patients treated for early endometrial cancer develop recurrent disease
• More than half of the recurrences develop within 2 years and about 3/4th occur within 3
years of initial treatment
• Asymptomatic, vaginal bleeding, pelvic pain, hemoptysis, anorexia, nausea & vomiting,
seizures, jaundice
 Treatment of recurrence

• For central pelvic recurrence, the treatment of choice is surgery or radiation therapy,
while for lateral pelvic recurrences it is radiation therapy + chemotherapy
• High rates of local control: complete response (CR) and a 5-year survival of 50%
• Hormonal therapy or cytotoxic chemotherapy
• Hormonal therapy is recommended for endometrioid histologies with ER/PR +ve
and involves mainly the use of progestational agents, tamoxifen and aromatase
inhibitors
• Cytotoxic chemotherapy: anthracyclines, platins and taxanes  most active
agents. The standard of care is six cycles of 3-weekly carboplatin and paclitaxel
 Targeted therapy

• PI3Kinase/mTOR and angiogenesis inhibitors are the most promising classes of drugs
to investigate in advanced/recurrent endometrial cancer and further biomarker-driven
studies are warranted
• Studies are under way and as of now, none of these agents has been approved for
clinical use
 Summary of Recommendations and Conclusions
Level A (based on good and consistent scientific evidence)
• Office EB is reliable and accurate
• Routine preoperative assessment with imaging is not necessary
• The initial management  comprehensive surgical staging (total hysterectomy, BSO,
and pelvic and para-aortic lymphadenectomy, and the collection of peritoneal cytology)
• MIS  standard surgical approach for comprehensive surgical staging
• Adjuvant radiation increases RFS but does not increase OS
• Chemotherapy for advanced endometrial cancer improves patient outcomes
• Vaginal brachytherapy is enough in intermediate risk disease
 Summary of Recommendations and Conclusions

Level B (based on limited or inconsistent scientific evidence)

• Routine screening for endometrial cancer in asymptomatic tamoxifen users is not
recommended
• In women with advanced disease, chemotherapy with paclitaxel and carboplatin is as
effective as other regimens (doxorubicin based) reported in the literature and has less
toxicity
• In cases of ovarian preservation, salpingectomy is recommended
 Summary of Recommendations and Conclusions

Level C (based on consensus and expert opinion)

• Patients with low-grade disease seem to be at low risk of lymph node metastases and
may not require a systematic lymphadenectomy
• Vaginal hysterectomy may be an appropriate treatment for early-stage endometrioid
endometrial cancer in select patients who are at high risk of surgical morbidity
• Chemotherapy and radiation therapy used in combination may offer superior outcomes
compared with single-modality treatment
• In premenopausal women ovarian conservation at the time of hysterectomy can be
considered  should be individualized
References
Thanks for listening
Any questions??
 Levels of Evidence
and
Grades of Recommendation