Endometrial cancer case presentation

Radosaw Mdry, Janina Markowska

Uniwersytet Medyczny im. K. Marcinkowskiego w Poznaniu 2010

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Epidemiology
Endometrial cancer (EC) remains the most common gynecologic malignancy in the United States. The newly diagnosed EC increased in US from 35,000 (1987) to 41,200 (2006) The number of deaths rose from 2900 to 7350, a 153% increase

Risk factors
postmenopausal status body mass index (BMI) >25 kg/m2 or more
>30 pounds over ideal weight >50 pounds over ideal weight

unopposed exogenous estrogen nulliparous late menopause diabetes mellitus hypertension complex atypical hyperplasia tamoxifen

3x 10 x 9.5 x 2x 2.4 x 2.8 x 1.5 x 29 x 3x

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Risk reduction factors

normal weight physically active pregnancy oral contraceptives 0.5 smoking decreases the risk of endometrial cancer progestins even when administered in combination with estrogen replacement.

Epidemiology is important, however

only half of patients present with identifiable risk factors. The other half appear to be at low risk:
they are thin or of average weight, have no history of exogenous estrogen exposure, are perimenopausal (20%-25%), or are younger than 40 years (5%).

Diagnostic approach
Endometrial cancer presents with abnormal uterine bleeding in 90% of patients
Endometrial cancer is found in approximately 10% of patients with postmenopausal bleeding (PMB).

Pap smear:
25% of patients with atypical endometrial cells on Pap smear have an underlying EC. the presence of benign endometrial cells on Pap smear is associated with EC in 6% of patients.

Abnormal endometrial thickness in TVUS

(< 5mm, HRT < 7mm, tamoxifen < 8mm)
Karlsson B, Granberg S, Wikland M, et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleedinga Nordic multicenter study. Am J Obstet Gynecol. 1995;172(5):1488-1494
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Diagnosis
The criterion standard for EC diagnosis is dilation and curettage, a procedure performed in the operating suite with the patient under regional or general anesthesia

Screening
Screening for EC using transvaginal ultrasonography in asymptomatic postmenopausal women has a poor PPV (9%) and is not recommended.
Langer RD, Pierce JJ, OHanlan KA, et al, Postmenopausal Estrogen/Progestin Interventions Trial. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. N Engl J Med. 1997

Treatment overview
The cornerstone of curative therapy for patients with EC is surgical treatment
including complete hysterectomy, removal of remaining adnexal structures, and appropriate surgical staging.

External pelvic radiotherapy and/or vaginal brachytherapy is used postoperatively for patients with tumor characteristics that predict:
a high risk of local recurrence and a poor prognosis

Treatment overview
A prospective GOG study showing a survival benefit for stage III or IV patients who received systemic chemotherapy vs those who received whole abdominal radiotherapy with a pelvic boost. Palliative hormonal therapy or chemotherapy can be used in patients with liver and extra-abdominal metastases Primary external beam radiotherapy and/or intrauterine brachytherapy can be used to treat medically inoperable patients.
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Primary surgical treatment

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Survival is heavily dependent on surgical stage

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Preoperative evaluation
Evaluation for systemic disease is typically limited to:
physiacal exam transvaginal ultrasound chest radiography and laboratory evaluations performed in preparation for surgery.

Pelvic CT is of limited value and is indicated only when there is suspicion of extrapelvic disease.
If imaging is necessary, such as for medically inoperable patients, pelvic magnetic resonance imaging (MRI) is superior to computed tomography for visualizing the uterus and surrounding tissues.

Baseline cancer antigen levels can be useful for predicting extrauterine spread
but are not sufficiently sensitive to replace surgical staging.
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Surgical treatment - lymphadenectomy

Pelvic and para-aortic lymph node dissection are crucial to surgical staging for patients with EC Lymphadenectomy is used as a:
staging, therapeutic, and diagnostic tool.

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Surgical treatment - lymphadenectomy

As a staging tool, it can be used to accurately define the extent of disease spread and determine the prognosis of the patient, thus facilitating comparative evaluations.

A therapeutic role for both pelvic and para-aortic lymphadenectomy has been suggested by retrospective investigations.
As a diagnostic tool, lymphadenectomy can be used to determine the need for and extent of postoperative treatment.
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New stage IA

New stage IB

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NCCN

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Case 1
She was admitted to hospital because newly diagnosed EC Age 72 BMI 35.3 (156 cm/ 86 kg) Hypertension from 10 years Diabetes from 1 year Cholecystectomy 1998 Partial thyroidectomy 2000 Family history
Father: lung cancer Mother sister: melanoma

abnormal uterine bleeding in April 2009 (after 24 years) D & C Adenocarcinoma G1 (11.05.2009)

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Case 1
PE normal uterus transvaginal us: small fibroids and endometrium 6mm normal X-ray abdominal US no changes abdominal CT not done

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Case 1

TAH, BSO, abdominal washing (16.06.2009) No palpable nodes in pelvic and paraaortic area Final histology:
Adenocarcinoma endometrioides endometrii G1 CIN1 Invasion in uterus less than of myometrium Cancer in uterus less than 2 cm in diameter

Staging: pT1b / (old FIGO FIGO IB ) new FIGO IA

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FIGO
The published data suggest that adjuvant radiotherapy is not indicated in the presence of low or intermediate risk stage 1 disease. This would certainly include
a) all G1 tumours without serosal involvement, and G2 < 50% myometrial invasion Staging classifications and clinical practice guidelines of gynaecologic cancers FIGO 2009

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NCCN

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PROTEC 1
Patients with EC FIGO I (grade 1 with deep [50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After TAH, BSO without lymphadenectomy, 715 patients Randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints
Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Creutzberg C. et all. Lancet 2000
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PROTEC 1
5-year locoregional recurrence rates were: 4% in the radiotherapy group vs 14% in the control group (p<0.001) 5-year overall survival rates were similar in the two groups: 81% radiotherapy vs 85% (p=0.31)
Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=037). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<00001).
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Case 1

Follow up without adjuvant radiotherapy

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Case 2
She was admitted to hospital because of abdominal pain and abnormal endometrium in transvaginal us (08.06.2009) Age 51 2,0,0 BMI 21.9 (164 cm/ 59 kg) Partial conisation of cervix 2005 Family history
Father: panceratic cancer Mother sister: genital cancer

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Case 2
PE normal Transvaginal us:
abnormal uterus with endometrium 1,98 mm (last period in may 2009) tumor in right side (3,78 x 2,78 cm)

normal X-ray abdominal US no changes abdominal CT no changes CA125 65,49 IU/ml

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Case 2

09-06-2009 D & C Primary histology:

Adenocarcinoma endometrioides endometrii

12-06-2009 open surgery: Metastases tumors in all abdomen: left tube, right ovary, omentum, on the liver, on surface of bowel TAH, BSO, OM, tumorectomy of all metastses abdominal Residual 0 cm Final histology:

Adenocarcinoma endometrioides endometrii G2 (superficialis myometrii) Metastases in all biopsies

Staging: pT3b / FIGO IV B ER 90% positive / PR 90% positive

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Case 2
Decision to start chemotherapy - AP

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Chemotherapy vs WAI
Study compare:
whole-abdominal irradiation (WAI) and doxorubicin-cisplatin (AP) chemotherapy in women with stage III or IV EC (residual <2 cm)

The hazard ratio for progression adjusted for stage was 0.71 favoring AP (95% CI, 0.55 to 0.91; P < .01). At 60 months, 50% of patients receiving AP were predicted to be alive and disease free when adjusting for stage compared with 38% of patients receiving WAI. Greater acute toxicity was seen with AP. Treatment probably contributed to the deaths of eight patients (4%) on the AP arm and five patients (2%) on the WAI arm.
Randall ME et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006 31

Chemotherapy vs WAI

Randall ME et al. JCO 2006

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Treatment failures
Most treatment failures in patients with EC are the result of unrecognized occult extrauterine dissemination at the time of primary treatment. Traditional therapy (modality-based) for high-risk EC is external beam radiotherapy, frequently supplemented with vaginal brachytherapy.
The modality-based approach improve local control but not survival in early-stage disease

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Predictive factors
The Mayo Clinic team has identified independent pathologic risk factors predictive of the 4 routes of metastatic spread.
Depth of myometrial invasion predicted hematogenous dissemination; positive lymph nodes and cervical stromal invasion predicted lymphatic recurrence; grade 3 histology or lymphovascular space involvement or both were correlated with vaginal recurrence; stage IV disease or combinations of nonendometrioid histology, cervical stromal invasion, positive lymph nodes, and positive peritoneal cytology were predictive of peritoneal failures
Mariani A, et all Hematogenous dissemination in corpus cancer. Gynecol Oncol. 2001 Mariani A, et all. Stage IIIC endometrioid corpus cancer includes distinct subgroups. Gynecol Oncol. 2002;. Mariani A, Predictors of lymphatic failure in endometrial cancer. Gynecol Oncol. 2002 Mariani A, et all Predictors of vaginal relapse in stage I endometrial cancer. Gynecol Oncol. 2005 34

High-risk endometrial cancer subgroups

Mariani A et all. High-risk endometrial cancer subgroups: candidates for target-based adjuvant therapy. Gynecol Oncol. 2004
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Disease-based therapy in postoperatinve treatment of EC

The presence of tumor characteristics predictive of occult metastatic spread suggests the need to administer postoperative therapy targeted at the site identified as high risk.
patients at risk of vaginal recurrence - vaginal brachytherapy, lymphati recurrence - external beam radiotherapy, hematogenous recurrence - systemic chemotherapy. abdominal recurrence - systemic chemotherapy

Tumor characteristics predictive of multiple sites of recurrence (eg, vaginal and hematogenous) should be targeted with multimodality therapy (eg, vaginal brachytherapy and systemic chemotherapy).
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Old and new options

Mariani A et all. High-risk endometrial cancer subgroups: candidates for target-based adjuvant 37 therapy. Gynecol Oncol. 2004;