ENDOMETRIAL CANCER Uterine cancer is the 4th most common cancer among women in the

UK (2010), accounting for 2.5% of all new cases of cancer in females In 2010, 8,288 women in the UK were diagnosed with uterine cancer.

In 2011, there were 1,930 deaths from uterine cancer in the UK

RISK FACTORS FOR ENDOMETRIAL CARCINOMA

Obesity Polycystic ovary syndrome Endometrial hyperplasia Hypertension nulliparity early menarche late menopause diabetes Tomoxifin

THE EFFECTS OF TAMOXIFEN TREATMENT ON THE ENDOMETRIUMDaniel Y et al et al Fertility & sterility 1996, 65(6):1083-1089

Meta analysisRESULTS:

Tamoxifen treatment is associated with, with a 1.3 to 7.5 relative risk of developing endometrial carcinoma.

Incidence of polyp formation is 1 in 2000 and endometrial Ca is 1;4000

CONCLUSIONS: The results of Tamoxifen treatment in breast carcinoma

override the risk of developing endometrial carcinoma. Any vaginal bleeding in women treated with Tamoxifen

should be investigated carefully and promptly.

ENDOMETRIAL CARCINOMA SYMPTOMS

The most common sign of endometrial cancer is abnormal vaginal bleeding.

• In a woman who is still having menstrual periods,abnormal bleeding is defined as bleedingbetween menstrual periods or heavy irregularmenstrual bleeding.

• In a postmenopausal woman, any vaginalbleeding is considered abnormal, even if it is onlyone drop of blood. This is especially true inwomen who are not taking postmenopausalhormone therapy

DIAGNOSIS OF ENDOMETRIAL CARCINOMA

History

Histology (Pipelle biopsy or curetting) +/-Hysteroscopy

Trans vaginal ultra sound

MRI

CT

HISTORY

Endometrial cancer may be found in 1% to 25%(typically quoted as 10%) of women with unexpected PMB, depending on age and risk factors

More than 90% of cases occur in women older than 50 years, and abnormal bleeding is the most common presenting symptom

THE ACCURCY OF ENDOMETRIAL SAMPLINING IN THE DIAGNOSIS OF ENDOMETRIAL CAECINOMA

Paul F et al . American cancer society 2000

Met analysis 39 studies compared Endometrial sampling to D&C 7914 patients included in the studies Peri and postmenopausal women were included

FINDING In both peri and post menopausal the detection rate was

99.6% in post menopausal and 91% in peri menopausal The sensitivity of sampling was 81% The specificity of sampling was greater than 98%

U/S IN DIAGNOSIS OF ENDOMETRIAL CANCER Multi Centre Involved 1168 patients with PMB All patients had endometrial thickness assessment before D&C

FINDING In women with atrophic endometrium the mean endometrial thickness

(±SD) was 3.9 ± 2.5 mm. The corresponding figures for women with endometrial cancer were 21.1 ± 11.8 mm

.No malignant endometrium was thinner than 5 mm In 30 women (2.8%) it was not possible to measure the thickness of the

endometrium; one of these women had endometrial cancer The probability of excluding endometrial abnormality was 5.5% when

the endometrial thickness was ≤4 mm (95% confidence limit)

SONOGRAPHIC STANDARDS FOR EVALUATINGA WOMAN WITH PMB?

A. The sonogram should be interpreted as abnormal if the double thickness of theendometrium is greater than 5 mm. This conclusion is based on 2 importantobservations:

B. Nearly nearly all patients with proven endometrial cancer had anendometrial thickness of greater than 5 mm

C. Meta-analysis of 85 published studies that included 5892 womenshowed that an endometrial thickness of greater than 5 mm identified96% of endometrial cancer.

D. Non-diagnostic finding is reported if the endometrium cannot be visualized in itsentirety. This observation, is found in approximately 5% to 10% of patients

E. The sonographic findings are abnormal if a focal endometrial abnormality is detected

F. The sonographic findings are abnormal if the margins of the endometrium are indistinct. Endometrial cancer often expands the endometrial cavity and, in addition to thickening, may result in an indistinct appearance of the endometrial lining

COMPARISON BETWEEN U/S,CT,MRI IN DIAGNOSIS OF MYOMETRIAL INVATION IN ENDOMETRIAL CARCINOMA

META-ANALYSIS::• Six studies met the inclusion criteria for CT; 16, for US; and 25, for MR

imaging. • Summary receiver operating characteristic analysis showed no significant

differences in the overall performance of CT, US, and MR imaging. In the assessment of myometrial invasion.

• contrast-enhanced MR imaging performed significantly better than did non enhanced MR imaging or US (P < .002) or CT

CONCLUSION: Although US, CT, or MR imaging can be used in the pre treatment evaluation of endometrial cancer, contrast-enhanced MR imaging offers “one-stop” examination with the highest efficacy.

TRANSVAGINAL ULTRASONOGRAPHY OF THE ENDOMETRIUM IN WOMEN WITH POSTMENOPAUSAL BLEEDING

Bengt Karlsson. AJOG, 172;5;1995

Multi Centre Involved 1168 patients with PMB All patients had endometrial thickness assessment before D&C

FINDING In women with atrophic endometrium the mean endometrial

thickness (±SD) was 3.9 ± 2.5 mm. The corresponding figures for women with endometrial cancer were 21.1 ± 11.8 mm

.No malignant endometrium was thinner than 5 mm In 30 women (2.8%) it was not possible to measure the thickness of

the endometrium; one of these women had endometrial cancer The 95% confidence limit for the probability of excluding

endometrial abnormality was 5.5% when the endometrial thickness was ≤4 mm as measured by transvaginal ultrasonography.

THE ACCURCY OF ENDOMETRIAL SAMPLINING IN THE DIAGNOSIS OF ENDOMETRIAL CAECINOMA

Paul F et al . American cancer society 2000

THE ACCURCY OF ENDOMETRIAL SAMPLINING IN THE DIAGNOSIS OF ENDOMETRIAL CAECINOMA

Paul F et al . American cancer society 2000

Met analysis 39 studies compared Endometrial sampling to D&C 7914 patients included in the studies Peri and postmenopausal women were included

FINDING In both peri and post menopausal the detection rate was

99.6% in post menopausal and 91% in peri menopausal The sensitivity of sampling was 81% The specificity of sampling was greater than 98%

SONOGRAPHIC STANDARDS FOR EVALUATINGA WOMAN WITH PMB?

SONOGRAPHIC STANDARDS FOR EVALUATINGA WOMAN WITH PMB?

A. The sonogram should be interpreted as abnormal if the double thicknessof the endometrium is greater than 5 mm. This conclusion is based on 2important observations:

B. Nearly all patients with proven endometrial cancer had anendometrial thickness of greater than 5 mm

C. Meta-analysis of 85 published studies that included 5892women showed that an endometrial thickness of greater than5 mm identified 96% of endometrial cancer.

D. The sonogram should be interpreted as non-diagnostic if the endometriumcannot be visualized in its entirety. This observation, found inapproximately 5% to 10% of patients

E. The sonographic findings are abnormal if a focal endometrial abnormality is detected

F. The sonographic findings are abnormal if the margins of the endometrium are indistinct. Endometrial cancer often expands the endometrial cavity and, in addition to thickening, may result in an 8indistinct appearance of the endometrial lining

deep myometrial invasion (arrow) in the posterior myometrial

wall

Superficial invasion (arrow)wall

COMPARISON BETWEEN U/S,CT,MRI IN DIAGNOSIS OF MYOMETRIAL INVATION IN ENDOMETRIAL CARCINOMA

META-ANALYSIS::• Six studies met the inclusion criteria for CT; 16, for US; and 25, for

MR imaging. • Summary receiver operating characteristic analysis showed no

significant differences in the overall performance of CT, US, and MR imaging. In the assessment of myometrial invasion.

• contrast-enhanced MR imaging performed significantly better than did non enhanced MR imaging or US (P < .002) or CT

CONCLUSION: Although US, CT, or MR imaging can be used in the pre treatment evaluation of endometrial cancer, contrast-enhanced MR imaging offers “one-stop” examination with the highest efficacy.

REVISED FIGO STAGING OF ENDOMETRIAL CANCER2009

STAGE 1 (T1, N0,M0) The cancer is only growing in the body of the uterus. Itmay also be growing into the glands of the cervix, butis not growing into the cervical stroma.

STAGE 1A ( T1a, N0,M0) The cancer has grown to less than 50% ofmyometrium

STAGE 1B (T1b,N0,M0) The cancer has grown to more than 50% ofmyometrium

STAGE II (T2, N0, M0) The cancer has spread from the body of the uterus and is growing into the cervix.

REVISED FIGO STAGING OF ENDOMETRIAL CANCER2009 cont.

Stage III (T3, N0, M0) Either the cancer has spread outside of the uterus or into nearby tissues in the pelvic area.

Stage IIIA (T3a, N0, M0): The cancer has spread to the outer surface of the uterine serosa and/or to the fallopian tubes or ovaries

Stage IIIB (T3b, N0, M0): The cancer has spread to the vagina or parametrium.

Stage IIIC Metastases to pelvic and/or para-aortic lymph nodesStage IIIC1 (T1 to T3, N1, M0): The cancer is growing in the body of the uterus. It may have spread to some nearby tissues. The cancer has spread to pelvic lymph nodes but not to para aortic lymph nodesStage IIIC2 (T1 to T3, N2, M0): The cancer is growing in the body of the uterus. It may have spread to some nearby tissues. The cancer has spread to peri-aortic lymph nodes with or without positive pelvic lymph nodes

Stage IV The cancer invade mucosa of the urinary bladder and/or the rectum, and/or to distant organs, such as the bones, omentum or lungs.

Stage IVA (T4, any N, M0): The cancer has spread to the mucosa of the rectum or urinary bladder. but has not spread to distant sites.

Stage IVB (any T, any N, M1): The cancer has spread to distant lymph nodes, the upper abdomen, the omentum, or to organs away from the uterus, such as the bones, omentum, or lungs

REVISED FIGO STAGING OF ENDOMETRIAL CANCER2009 cont.

ENDOMETRIAL CANCER RISK FACTORS

STAGE

GRADE

VASCULAR SPACE INVASION

MYOMETRIAL INVASION

PERTONEAL CYTOLOGY & LYMPHADENECTOMY UNCLEAR

HISTOLOGICAL SUBTYPES ( SEROUS PAPILLARY/ CLEAR CELL) AGE

5 YEAR RELATIVE SURVIVAL RATES BY FIGO

IV-B

II

1-B

III-A

1-A

III-B

Stage

III-C

5 year survival rate

IV-A

88%

75%

69%

17%

47%

50%

58%

15%

ALL STAGES OF ENDOMETRIAL CANCER

TAH + Radiotherapy before or after surgery

Increase Morbidity Does it improve rate of recurrence ?

The early low risk : Stage 1a Grade 1 - 2 , No special sub type , no risk factors

The early intermediate risk : stage 1a Grade 3 stage 1b Grade 1 to 2 regardless of risk factors

The early –high risk: Stage 1b Grade 3Stage 2 any grade

The ‘advanced Stage 3 (treatment combined chemotherapy Carbo +/- Paciltaxel + pelvic RT+ Vaginal Brachytherapy )

Metastatic

ENDOMETRIAL CANCER MANAGEMENT SPECTRUM

5 year survival 80-90% Risk of local and regional relapse too low to justify treatment Risk of relapse 5-10 %

STAGE 1a The cancer has grown to less than 50% of myometrium

STAGE 1a The cancer has grown to less than 50% of myometrium but grade 3 or subtypes

STAGE 1b The cancer has grown to more than 50% of myometrium STAGE 1b The cancer has grown to more than 50% of myometriumSTAGE 2 The cancer has spread from the body of the uterus and is growing into the cervix

TREATMENT : TAH +BSO 3 monthly review for 2 years Discharge at 5 years

Max survival rate 50%

ENDOMETRIAL CANCER MANAGEMENT SPECTRUM

The early intermediate risk

INCLUDES ; stage 1a Grade 3 stage 1b Grade 1 to 3 regardless of risk factors

IS TREATMENT BY SURGERY AND RADIOTHERAPY OR RADIOTHERAPY ALONE ?

WHAT DO WE NOW• 5 year survival 80-90% overall survival• Relapse rate 4-8% • Relapses: local regional 4-7% Distant metastases 7-17%• Salvage of vaginal recurrence high is 40-80% in unirradiated • Salvage of extra vaginal pelvic relapse is low 20-30% lower in

irradiated patients 5%

In the early intermediate risk group (stage 1b grade 1-2 and stage 1a grade 3 and histological subtypes )SHOULD WE GIVE RADIOTHERAPY?

In the early high risk cases (stage 1b grade 3 & stage 2 any grade)

HOW MUCH SHOULD WE TREAT ?

Does chemotherapy help?

Is there place for lymphadenectomy ?

THE DILEMA

INTERMIDIATE RISK GROUP stage 1a Grade 3

stage 1b Grade 1 to 3 regardless of risk factors

PORTEC 1 (2000) studded patients with intermediate risk stage (1b grade 1-2 andstage 1a grade 3 and histological subtypes) who underwent TAH +BSO withoutlymphadenectomy randomised to pelvic radiotherapy or no radiotherapy

FINDING Showed that EBRT provides A higher significant improvement in local control ( 20% Vs 5 %), But without a survival advantage. The majority (75%) of locoregional ( vaginal and/or pelvic) recurrence were

located in the vagina, Treatment for vaginal recurrence was effective with a 5 year survival of 70% Where as the outcome after pelvic and distal relapses were poor. EBRT was associated with a 26% risk of side effects mainly gastrointestinal

toxicity. CONCLUSION EBRT has become limited to patients at relative risk of recurrence.

And the risk factors for this are:-1. grade 3 2. age over 60y 3 deep myometrial invasion

Fifteen-Year Radiotherapy Outcomes of the Randomized PORTEC-1 Trial for Endometrial Carcinoma

Fig. 1 Probability of locoregional (vaginal and/or pelvic) relapse for patients assigned to postoperative radiotherapy (RT) or no additional treatment (NAT) for the total group (left) and for patients with high-intermediate-risk (HIR) features (right).

Carien L et al ;International Journal of Radiation Oncology*Biology*Physics, Volume 81, Issue 4, 2011, e631 - e638

TAH

EXTERNAL RADIATION

VAGINAL BRACHYTHERAPYrandomly assigned patients with stage I endometrial cancer who did not undergo lymph node dissection to undergo vaginal brachytherapy (VBT) or external-beam radiation therapy (EBRT), with prevention of vaginal recurrence as the primary outcomeCONCLUSION : patients with high risk factors confirmed that EBRT could safely besubstituted by VBT with less toxicity and better quality of life . However for high riskintermediate (stage 1B +/_ hisatological subtypes grade 3 stage 2 &3) EBRT and VBTcontinues to be the most effective adjuvant treatment for pelvic and vaginal control

PORTEC 2INTERMIDIATE RISK GROUP

stage 1a Grade 3 stage 1b Grade 1 to 3 regardless of risk factors

TAH

VBT

EBRT

INTERMIDIATE RISK GROUP stage 1a Grade 3

stage 1b Grade 1 to 3 regardless of risk factors

+ ChemotherapyNSGO-EC-9501 STUDY which randomised phase II study on adjuvant treatmentwith radiotherapy +/_ Chemotherapy in early high risk stages of endometrialcarcinoma CONCLUDED that radiotherapy with chemotherapy treatment wasbetter than radiotherapy alone

RTOG 9708 STUDY which studded adjuvant post operative irradiation combinedwith chemotherapy following surgery for patients with intermediate high riskpatients with endometrial carcinoma CONCLUDED that regional control isexcellent following combined modality treatment in all patients suggestingadditive effect of chemotherapy and radiation. Distant metastases continued tooccur in more advanced stage patients

IS THERE A PLACE FOR LYMPHADENECTOMY ?EFFECTIVE OF SYSTEMIC PELVIC LYMPHADENECTOMY IN ENDOMETRIAL

CANCER ( MRC ASTEC TRIAL) A RANDOMISED TRIAL

Kitchener et al. Lancet ;2009,373(9658):125-136 85 centres 1480 patients with proven endometrial carcinoma Randomised into

standard TAH + BSO + peritoneal washing + palpation of para aortic lymph nodes Or TAH + BSO + peritoneal washing + palpation of para aortic lymph nodes +

lymphadenectomy Primary outcome was overall survival Median follow up was 37 monthsFINDINGS:-• 191 women died. (88 in standard surgery and 103 in lymphadenectomy group) therefor • Hazard ration of 1.16 in favour of standered surgery and absolute difference in 5 year

survival of 1%• 251 women had recurrent disease. (107 in standard surgery and 144 in Lymphadenectomy

group)CONCLUSION: the results show no evidence of benefit in terms of overall or recurrence-free survival for

pelvic lymphadenectomy in women with early endometrial carcinoma Lymphadenectomy can not be recommended as routine procedure for therapeutic purposes

IS THERE A PLACE FOR LYMPHADENECTOMY ?

FOR STAGING ONLY

CONCLUSION

STAGE 1A grade I & II TAH + BSO

STAGE 1B & 2 TAH + BSO + RADIO-CHEMO

STAGE 3 & 4 CHEMOTHERAY & RADIOTHERAPY

• The PORTEC-2 trial randomly assigned patients with stage I endometrial cancer who did not undergo lymph node dissection to undergo vaginal brachytherapy (VBT) or external-beam radiation therapy (EBRT), with prevention of vaginal recurrence as the primary outcome.[10] At 5 years, there was no difference in the rates of vaginal recurrence, locoregional recurrence, progression-free survival or overall survival (OS) (84.8% [95% confidence interval—CI—, 79.3–90.3] vs. 79.6% [95% CI, 71.2–88.0] for VBT and EBRT, respectively; P = .57). There were significantly fewer gastrointestinal toxic effects in the VBT group, making VBT the preferred option for adjuvant treatment of patients with stage I disease

• INTERPRETATIONVBT is effective in ensuring vaginal control with fewer gastrointestinal toxic effects than EBRT)( external beam radiotherapy). VBT should be the adjuvant treatment of choice for patients with endometrial Ca of high intermediate risk

• PORTEC 1 Showed that EBRT provides a higher significant improvement in local control ( 20% Vs 5 %), but without a survival advantage. The majority (75%) of locoregional ( vaginal and/or pelvic) recurrence were located in the vagina, and treatment for vaginal recurrence was effective with a 5 year survival of 70% where as the outcome after pelvic and distal relapses were poor. EBRT was associated with a 26% risk of side effects mainly gastrointestinal toxicity. As a result EBRT has become limited to patients at relative risk of recurrence. And the risk factors for this are:-

• 1. grade 3 2. age over 60y. 3 deep myometrial invasion. • PORTEC 2 patients with HIR factors confirmed that EBRT could safely be subsituted by VBT with less toxicity and better

quality of life . However for high risk intermediate ( stage 1B +/_ hisatological subtypes grade 3 atage 2 &3 EBRT continues to be the most effective adjuvent treatment for pelvic control

• PORTEC 1 (2000) studded patients with intermediate risk stage(1b grade 1-2 and stage 1a grade 3 and histological subtypes) who underwentTAH +BSO without lymphadenectomy randomised to pelvicradiotherapy or no radiotherapy

• FINDING 5 year locoregional recurrence rate were 4% in the radiotherapy

group and 14% in no radiotherapy group 5 year survival rate were similar in the two groups (81% RT vs 85%

no RT Treatment related complication was 25% in RT Vs 6% in no RT 2 year survival after vaginal recurrence in RD group was 79% in

contrast to 21% in no RT CONCLUSION: Postoperative radiotherapy in stage-1

endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion

Stage Description

IA Tumor is confined to the uterus with less than half myometrial invasion

IB Tumor is confined to the uterus with more than half myometrial invasion

II Tumor involves the uterus and the cervical stroma

IIIA Tumor invades serosa or adnexa

IIIB Vaginal and/or parametrial involvement

IIIC1 Pelvic lymph node involvement

IIIC2 Para-aortic lymph node involvement, with or without pelvic node involvement

IVA Tumor invades bladder mucosa and/or bowel mucosa

IVB Distant metastases including abdominal metastases and/or inguinal lymph nodes

Endometrial carcinoma is surgically staged using the FIGO cancer stagingsystem. The 2010 FIGO staging]