Uterine Cancer Review for

Health Care Professionals

Created by the GOC Nursing Committee:

Joanne Power, Janet Giroux, Nancy Drummond, Heidi

Thomas, Carrie Thornton, Joanne Brodeur and Elisha

Andrews, Joanne Power, Rebecca Sirois

Medical Advisor: Dr. X. Zeng

Updated: November 2019

The slides presented are meant to be used as an

orientation package for health care providers new to

gynecologic oncology; to review the management and

treatment of uterine cancers.

Variation across the country can occur in accordance with

provincial guidelines.

Remember that not all patients are the same and that some

deviation CAN and often does occur.

Uterus Review • Pear-shaped, hollow, and fibro

muscular organ located in a woman’s pelvis between the bladder and rectum

• Varies greatly in size • Made up of 3 sections

– Cervix (lower)

– Corpus (middle)

– Fundus (top) • The inside of the uterus

has two tissue layers

– Endometrium (inner)

– Myometrium (outer)

Cartwright-Alcarese & O’Sullivan, 2010

The walls of the uterus are

composed of muscular

tissue called myometrium

(middle layer).

The superficial (outside

layer) of the uterus is called

the serosa and is

continuous with the pelvic

peritoneum.

• The epithelial membrane

(lining of uterus) is called

the endometrium.

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Serosa

Cartwright-Alcarese & O’Sullivan, 2010

The Role of Estrogen and Progesterone • Estrogen stimulates the uterine lining to proliferate

and grow

• Progesterone inhibits the proliferative growth effects of estrogen, and provides structural support to the endometrium

• With the withdrawal of progesterone at the end of the menstrual cycle, the structural support to this thickened endometrium is weakened, and shedding of the uterine lining occurs (menses)

Landrum, Zuna & Walker, 2012; Redlin Frazier, 2010

Incidence of Endometrial Cancer

• Most common gynecologic cancer

• Estimated that 7300 Canadian women were

diagnosed in 2018, 1150 died from it

• 4th most common cancer in Canadian women, 8th

most common cause of cancer death

• Lifetime risk in Canada is 1 in 38 women

Canadian Cancer Society, 2018

Endometrial Cancer Risk Factors Lifestyle Factors Hormonal and Reproductive

Factors

Age > 50 Early menarche

Obesity (more than 50 pounds over

normal BMI)

Postmenopausal

Never given Birth**

Diet/lack of exercise Late menopause (>55)

Personal Breast/Colon Cancer

History

Endometrial Hyperplasia

Diabetes **

Genetic Factors

Prolonged use of estrogen without

opposing progesterone

Tamoxifen use

Polycystic Ovarian syndrome

Amant Moerman, Neven, Timmerman, Van Limbergen & Vergote, 2005; Burke, 2005;

Creasman & Scott Miller, 2012; Farley-Omerod & Fusco, 2010; Lockwood, 2008; Redlin Frazier, 2010;

Tiffen & Mahon, 2006, Canadian Cancer Soceity; Endometrial Cancer 2019

Lynch II Syndrome (HNPCC)

• An inherited disorder that increases the risk of many

types of cancer, particularly cancers of the colon

(large intestine) and rectum, which are collectively

referred to as colorectal cancer.

• People with Lynch syndrome also have an increased

risk of cancers of the stomach, small intestine, liver,

gallbladder ducts, upper urinary tract, brain, and skin.

Additionally, women with this disorder have a high

risk of cancer of the ovaries and lining of the uterus

(the endometrium).

Ahnen & Axell, 2015

Lynch II Syndrome (HNPCC) “Red Flags”

• Onset of colorectal cancer before age 50

• Onset of endometrial cancer before age 50

• Two or more HNPCC cancers in an

individual or family

Endometrial Cancer Risk Factor: Obesity

• Widely recognized risk factor for endometrial

cancer

• Affects both premenopausal and postmenopausal

risk for endometrial cancer

• Those with high amount of body fat can be up to

10x more likely to develop Uterine Cancer

Farley-Omerod & Fusco, 2010; Redlin Frazier, 2010;, Renehen et al., 2008; Tiffen & Mahon, 2006, CCS, 2019

Bariatric Surgery Decreases Risk of

Endometrial Cancer

• Bariatric surgery, which results in dramatic weight loss in formerly severely obese women, reduces the risk of endometrial (uterine) cancer by 71% immediately after weight loss and 81% if healthy weight is maintained after surgery

Ward et al., 2014

Unopposed Estrogen Exposure • In an environment of chronically unopposed estrogen

exposure (such as seen in obesity), the endometrial

layer undergoes a progression of abnormal cellular

changes from benign endometrial hyperplasia to

endometrial intraepithelial neoplasia (EIN) and

endometrial adenocarcinoma

• Use of estrogen replacement therapy for menopause

does not increase the risk of endometrial cancer as

long as concurrent progesterone is given.

Redlin Frazier, 2010

Endometrial Cancer Risk Factor

Selective Estrogen Receptor Modulators • Used as both treatment and chemoprevention of breast

cancer

• SERMS: Tamoxifen, Raloxifene

• Although Tamoxifen is an anti-estrogen in breast tissue, it

paradoxically has estrogen-like properties in the

endometrium and increases the risk of endometrial cancer

• It is also associated with thromboembolism and stroke

• It provides protection against bone loss, osteoporosis and

fractures, but does not appear to carry an increased risk of

myocardial infarction

Landrum, Zuna & Walker, 2012

Endometrial Cancer: Risk Reducing Factors

Use of combination oral

contraceptives

Diet modifications (low fat, increase

fruit and vegetable intake)

Multiparity Decrease phyto-estrogen (soy)

intake

Exercise and physical activity Weight control/loss to reflect ideal

BMI of < 25

Tubal Ligation

Genetic counselling and risk

assessment of women at risk

Mirena IUD

Amant et.al, 2005; Farley-Omerod & Fusco, 2010; Redlin Frazier, 2010

Endometrial Cancer: Screening

• No good screening test for endometrial cancer

• The pelvic exam enables the clinician to detect

only an abnormally sized uterus

• Sampling of the endometrium is neither cost-

effective nor indicated in the general population

and is not required before or during HRT (hormone

replacement therapy) in asymptomatic women

Amant et.al, 2005; Burke, 2005; Farley-Omerod & Fusco, 2010; Redlin Frazier, 2010; Tiffen & Mahon,

2006;

Endometrial Cancer: Signs & Symptoms

Post menopausal

women • Post menopausal bleeding (PMB) after menopause is the most common symptom

– About 90% of women diagnosed with endometrial cancer have abnormal uterine bleeding as presenting symptom

Premenopausal

women • Increased menstrual flow and bleeding between periods may be the only symptoms

• Other signs may include: • A yellow, watery vaginal discharge

• Pyometria (accumulation of pus in the uterus)

• Pain in the hypogastric or lumbosacral areas or the pelvis

• Pain during intercourse

• Ascites

• Weight loss

Amant et.al, 2005; Burke, 2005;;Farley-Omerod & Fusco, 2010; Lockwood, 2008; Otto, 2001;

Tiffen & Mahon, 2006; Canadian Cancer Society, 2019

Postmenopausal Bleeding

• Most PMB is caused by benign conditions

– Most common benign causes are endometrial polyps, sub-

mucosal fibroids and atrophy of the endometrium, HRT and

Tamoxifen use

• Cancer and hyperplasia are present in 20%

of women with PMB

• A biopsy should be performed to evaluate the

endometrium in women with abnormal uterine

bleeding after age 40

Amant et.al, 2005; Farley-Omerod & Fusco, 2010; Lockwood, 2008; Singh et al., 2013

Endometrial Cancer Diagnosis

• Ultrasound

(TransVaginal-TVUS) to

look at thickness of

endometrial lining and

localize lesions – An endometrium thicker

than 16 mm in

premenopausal women and

in postmenopausal women

thicker than 5 mm is a

predictor of abnormal

endometrial pathology

• Endometrial biopsy to

sample lining of the

uterus – Most cost effective when the

prevalence of endometrial

cancer is over 15%

– +/- Hysteroscopy/D&C

(Dilatation & Curettage)

• Pathology

• Other Imaging Studies

– MRI, CT scan, Chest x-

ray

Amant et.al, 2005; Farley-Omerod & Fusco, 2010; Lockwood, 2008; Redlin Frazier, 2010;; Tiffen & Mahon, 2006

Endometrial Biopsy/Pipelle

Image retrieved June 4, 2015 from http://www.nlm.nih.gov/medlineplus/ency/imagepages/17059.htm

Diagnostic Tests for Uterine Abnormalities

Endometrial Hyperplasia

• An overgrowth of the endometrial lining of the uterus as a result of stimulation of the endometrium

• Typically presents clinically as abnormal bleeding

• Hyperplasia with atypia is a complex pattern with overcrowding of the glands; the presence of atypical cells indicates high risk for the progression to endometrial cancer

– Endometrial hyperplasia with atypia is considered a precursor state to endometrial cancer

Farley-Omerod & Fusco, 2010; Lockwood, 2008

• The scientific explanation for the low incidence rates for endometrial hyperplasia is that it is a lesion that is usually unrecognized and asymptomatic until cancer develops

• Women with cellular atypia is considered to be premalignant; whereas those without atypia are benign. Hysterectomy is the standard of treatment when atypia is present

• Patients with hyperplasia should be treated with progestins or hysterectomy if atypical cells are associated with the hyperplasic cells – Patient’s age, fertility plans & need for contraception, comorbidities and

personal preferences play an important role in the management of these lesions

Endometrial Hyperplasia

Farley-Omerod & Fusco, 2010; Landrum, Zuna & Walker, 2012; Lockwood, 2008

Uterine Cancers: Classification

● The primary types of uterine cancers are endometrioid

carcinoma, adenocarcinoma, sarcomas, mucinous

carcinoma, serous carcinoma, and clear cell carcinoma

● More than 95% are endometrial adenocarcinomas and

less than 5% are sarcomas ● Endometriod makes up 75-80%

● Serous makes up roughly 10%

● Clear cell roughly 5%

● Sarcoma roughly 2-5%

Otto, 2001, WHO 2014

Endometrial Cancer

• Neoplasm that occurs within the lining

of the uterus

• Arises from the glandular component of

the endometrial mucosa

• Divided into 2 subtypes (Type I and

Type II)

Amant et.al, 2005 ; Brown, 2008 ;Farley-Omerod & Fusco, 2010;

Lockwood, 2008; Redlin Frazier, 2010; Tiffen & Mahon, 2006;

Endometrial Cancer Subtypes

Type I

• Well or moderately

differentiated estrogen

dependent subtypes that tend

to have a better prognosis

(tends to be diagnosed early

stage and has a better

prognosis). Prolonged

exposure to estrogen

Type II • Aggressive, non-estrogen

dependent subtypes such as

clear cell and serous which

has a poorer prognosis related

histologically to a higher grade

or poorer differentiation and is

more often diagnosed at a late

stage, it has a propensity for

metastases or because it is a

non-endometrioid subtype

Amant et.al, 2005 ; Brown, 2008 ;Farley-Omerod & Fusco, 2010;

Lockwood, 2008; Redlin Frazier, 2010; Tiffen & Mahon, 2006;

Endometrial Cancer

• Morbidity and mortality increases with age and

stage, making early diagnosis a priority in order

to achieve better outcomes

Redlin Frazier, 2010

Endometrial Cancer: Grading

• The grade of the tumour signifies how closely

the tumour resembles the tissue of origin

• In endometrial cancer, the tumor grows in a

solid fashion, whereas the normal tissue grows

in a glandular fashion

Lockwood, 2008

Endometrial Cancer Grading Grade Differentiation % of Tumour Showing

a Solid Growth Pattern

I Well differentiated 5% or less

II Moderately differentiated 6% - 50%

III Poorly differentiated > 50%

Lockwood, 2008

Endometrial Cancer Staging

Stage Extent of Uterine Involvement

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

II Tumor invades cervical stroma, but does not extend beyond the uterus

III Local and/or regional spread of the tumor

IIIA Tumor invades the serosa of the corpus uteri and/or

adnexae

IIIB Vaginal involvement and/or parametrial involvement

IIIC Metastases to pelvic and/or para‐aortic lymph nodes

IIIC1 Positive pelvic nodes

IIIC2 Positive para‐aortic nodes +/- positive pelvic nodes

IV Tumor invades bladder and/or bowel mucosa, and/or distant metastases

IVA Tumor invasion of bladder and/or bowel mucosa

IVB Distant metastasis, including intra‐abdominal metastases

and/or inguinal nodes) Amant et al., 2018

Endometrial Cancer • Endometrial cancer is surgically staged

– Histological assessment of the hysterectomy specimen remains the

gold standard

• Workup for biopsy proven Endometrial Cancer

includes a clinical examination. Other diagnostic

tests may include Transvaginal Ultrasound, Chest

X-ray, CT, MRI.

• CA-125 is a potential tumour marker

Amant et.al, 2005; Brown, 2008; Farley-Omerod & Fusco, 2010; Lockwood, 2008;

Treatment for Endometrial Cancer

• Surgery

– Hysterectomy

– Lymphadenectomy

• Radiation Therapy

• Chemotherapy

Redlin Frazier, 2010

Hormone Therapy

• Hormone therapy with Progestin may be considered in certain cases of grade 1 when there is no invasive disease and patient wants fertility preservation

• The use of progestin-secreting IUD has been utilized in cases where surgical morbidity prevents traditional treatment

Montz, Bristow, Bovicelli, Tomacruz & Kurman, 2002; Redlin Frazier, 2010

Endometrial Cancer

Surgical Management • Depends on the stage and grade of the cancer; considers

the usual spread pattern of endometrial cancer to the lymph nodes nearest to the uterus

• Surgery includes Total Hysterectomy and Bilateral Salpingo-Oophorectomy (TH BSO) +\- surgical staging – Approach may be abdominal or minimally invasive

– Removal of the adnexa at time of surgery is thought to be important given that approximately 5% of endometrial cancers have metastatic disease to the ovaries and/or fallopian tubes

– Removal of the upper vagina does not appear to decrease vault recurrences

• Pelvic +/- para aortic lymph node dissection may be done depending on grade and/or histology of endometrial biopsy

Creasman & Scott Miller, 2012; Redlin Frazier, 2010

Role of Lymphadenectomy • Sentinel lymph node mapping in patients with apparent early

stage disease may be considered

• Pelvic lymphadenectomy, with or without paraaortic

lymphadenectomy, plays an important role in the surgical

staging of endometrial cancer, and thus provides more accurate

prognostic information

• The therapeutic role of lymphadenectomy and its ability to

modify adjuvant therapy continues to evolve

– Impacts the addition or deletion of radiation/chemotherapy

postoperatively

– Need to discuss the pros/cons of lymph node dissection and

potential for complications in the future

Creasman & Scott Miller, 2012; Hacker, 2000, NCCN, 2019

Pathologist Review • Measures the depth of myometrial invasion in

relationship to myometrial thickness and the size

and location of the tumour and then makes a

determination as to the extent of disease

• Examines the specimen(s) microscopically and

the histologic subtype, grade and presence of

lymphovascular space invasion

Redlin Frazier, 2010

Poor Prognostic Features

• Papillary Serous, Clear Cell Histology

• Grade 3 (poorly differentiated)

• More advanced stage

• Myometrial invasion > 50%

• Positive pelvic lymph node(s)

• Positive para-aortic lymph node(s)

(highest risk feature)

Carcinosarcoma • Uterine carcinosarcomas, or formerly referred to as

Malignant Mixed Müllerian tumours (MMMTs), are highly

aggressive cancers with a 5-yr survival rate reported as 18-

39%

• Usually arise in women older than 65 and commonly

present at an advanced stage

• Considered a high-risk variant of endometrial

adenocarcinoma because carcinosarcomas share

similarities in epidemiology, risk factors, and clinical

behavior more closely with endometrial carcinoma as

opposed to uterine sarcomas. Dulko, 2010; Lockwood, 2008; McMeekin, 2012; Penson & Powell, 2014

Carcinosarcoma

• Uterine carcinosarcoma displays both epithelial and

stromal differentiation and is further subdivided into

homologous and heterologous subtypes based on the

sarcomatous component

• Recently, carcinosarcomas have been treated more as a

carcinoma rather than sarcoma

• Uterine carcinosarcoma tends to spread by local extension

to pelvic structures, but may metastasize with the manner

of spread being mainly through the lymphatic system rather

than through the blood

Dulko, 2010; Lockwood, 2008; McMeekin, 2012

Adjuvant Treatment

• The need for adjuvant treatment is determined

by the final pathology report

• Adjuvant treatment may include:

– External beam radiotherapy

– Brachytherapy

– Chemotherapy

– Hormonal therapy

Redlin Frazier, 2010

GOG Criteria for Determining Adjuvant

Radiotherapy Treatment in Stage I or II

1. Patients who are age 70 or older and any 1 of the

following risk factors:

– Tumour grade 2 or 3

– Outer third myometrial invasion

– Presence of lymphovascular space involvement.

2. Patients 50 years of age or older and any 2 of the risk

factors described above.

3. Patients of any age and all 3 factors described

above.

Keys et al., 2004; Kupets & Le, 2013

Radiation Therapy

• Radiation therapy has been the

mainstay of adjuvant therapy for

endometrial cancer – Adjuvant radiotherapy following primary surgery

significantly improves pelvic tumour control, but has no

measurable impact on overall survival

– Vault Brachytherapy is being recommended more often

for lower stage disease and for all high stage disease.

Creasman & Scott Miller, 2012; Lockwood, 2008, NCCN 2019

Radiation Therapy

• Treatment may include external beam radiation therapy and/or brachytherapy (intravaginal)

• For patients who are at high risk for

recurrence, radiation therapy is used to improve loco-regional control

• Radiation therapy utilization has

been widely variable

Lockwood, 2008; Redlin Frazier, 2010

Radiation Side Effects • Depending on area

that is irradiated, may

include:

– Skin Changes

– Bowel Changes

– Urinary Changes

– Vaginal Changes

– Fatigue

– Psychological

Lockwood, 2008; Smith & McLaughlin, 2012; Redlin Frazier, 2010

Brachytherapy • Health Care professionals should not underestimate the

physiologic and psychological effects of intravaginal radiation therapy

• Women who receive this treatment should be counselled carefully prior to treatment with a mindfulness that it may be humiliating, disturbing and in some cases of previous sexual abuse, an exceptionally difficult treatment to undergo

• Any woman receiving pelvic radiation (external or internal) needs to be advised/taught to use vaginal dilators to maintain vaginal patency and to prevent agglutination

Miles et al., 2012; Redlin Frazier, 2010

PORTEC 3 Treatment

• Consists of 5 weeks of external beam radiation of

48Gy in 25 fractions with Concurrent Cisplatin at

50mg/m2 on week 1 and 4. Followed by a 2 week

break from treatment and then 4 cycles of Carboplatin

and Paclitaxel.

• This protocol shows better distant recurrence control

vs local control

• Better overall survival vs RT alone (79% vs 70%)

• Better failure free survival vs RT alone (69% vs 58%)

de Boer, et al. 2018

Chemotherapy

• The role of chemotherapy in the treatment of

endometrial cancer is complex and evolving

– Was traditionally reserved for patients with recurrent or

disseminated cancer

• Systemic therapy may be used

– In cases of initial advanced disease

• Advanced and high-risk early-stage

– At the time of relapse

Amant, et.al, 2005; Creasman & Scott Miller, 2012; Lockwood, 2008; Redlin Frazier, 2010

Chemotherapy

• These therapies are often provided in the outpatient setting

• See next slides for common agents and side effects

• Incidence and severity of any of these side effects is largely dependent of the patient’s characteristics such as diagnosis, stage, performance status, comorbidities and individual treatment regimen – agent, dosage and schedule

• Nurses have an essential role in teaching, monitoring and managing side effects related to gynecologic cancer treatments

Hydzik & O’Connor, 2010

Clinical Trials

• Provide novel treatments that show promise in treatment of endometrial cancer

• Available clinical trials should always be presented as an option to eligible patients

Combination of Chemotherapy Agents

• Studies have found the combination of Cisplatin or

Carboplatin with other agents (Doxorubicin,

Taxanes—Paclitaxel) to have significant activity in

endometrial cancer treatments

• Combining two or more active agents has been an

important strategy (Phase III studies) – Better response rates when agents are combined compared to used

alone

Creasman & Scott Miller, 2012

Paclitaxel • Often given in combination with Carboplatin

• Has potential for hypersensitivity reactions, patients need to be premedicated

with steroids

• Indicated for patients with ovarian cancers, cervical cancers and endometrial

cancers.

• Potential side effects:

– Alopecia -Neutrophil nadir—Day 10-12

– Mucositis -Platelet nadir—Day 8-9

– Myelosuppresion -Cardiovascular—hypotension, bradycardia,

– Myalgia, arthralgia hypertension

– Peripheral neuropathy -Injection site reactions—erythema, tenderness,

– Visual disturbances skin discoloration, swelling—extravasation

– Ototoxicity hazard irritant

– Diarrhea -Elderly patients have more myelosuppression,

– Nausea, vomiting neuropathy and cardiovascular toxicities

Carboplatin • Usually infused over 60 minutes.

• Often given in combination with Taxol.

– Taxol should be given before Carboplatin to increase efficiency and

limit myelosuppression.

• Indicated for patients with ovarian cancers, cervical cancers and

endometrial cancers.

Side effects: -↓Na, ↓Mg, ↓Ca, ↓K

-Vomiting

-↑ Creatinine

-↑liver function

–Myleosupression (Neutropenia/thrombrocytopenia)

–Neuropathies

–Ototoxicity

–Potential allergic reaction (typically in 2nd line)

Cisplatin • Pre-treatment hydration VERY important

before Cisplatin.

• Compatible with NS (normal saline)

Side effects:

- Significant nausea and vomiting

– Myelosuppression

– Nephrotoxicity

– ↓Mg

– Neurotoxicity and autotoxicity

Hypersensitivity Reactions • An exaggerated or inappropriate immune response that may

be localized or systemic, occurring during or within hours of a

drug administration – Medical emergency as can result in respiratory failure, cardiovascular collapse

and possibly death

– Certain classes of chemotherapy agents are more commonly associated with

hypersensitivity reactions including the taxanes and platinum compounds

• Can be prevented with (prophylaxis of anaphylaxis) – Corticosteroids (Dexamethasone)

– H₁ Blockers (antihistamines such as Diphenhydramine [Benadryl])

– H₂ Blockers (Ranitidine)

– Longer infusion time

Holmes Gobel, 2005; Hydzik & O’Connor, 2010; Myers, 2001; Polovich, White & Kelleher, 2005;

Winkeljohn, 2006

Hypersensitivity Reaction Clinical Manifestations of HSR &

Anaphylaxis • Uneasiness or agitation • Tightness in chest • Shortness of breath (dyspnea), with or

without wheezing (stridor/bronchospasms), 🡫 O₂ sat

• Hypotension • Tachycardia • Urticaria (hives) or rash and/or itching • Flushing • Periorbital or facial edema

(angioedema) • Lightheadedness or dizziness • Abdominal cramping, diarrhea,

nausea, vomiting • *Back pain—Paclitaxel HSR is

believed to be d/t cremophor vehicle

Hydzik & O’Connor, 2010; Otto, 2001; Polovich, Whitford & Olsen, 2009; Young & Markman, 2000

Image retrieved on April 13, 2015 from:

http://synergyhw.blogspot.ca/2013/01/magnesium-part-3-wrath-of-histamine.html

Doxorubicin

• Anthracycline and Anti-tumour Antibiotic

• Myelosuppression

• Increase in Liver Function Tests

• Nausea & Vomiting

• Skin Changes/Radiation Recall

• Skin Hyperpigmentation

• Mucositis or Esophagitis

• Diarrhea

• Alopecia

• Vein Discolouration

• Red urine

• Cardiac Toxicity – Maximum lifetime dose 550 mg/m²

• Potent vesicant – Extravasation may lead to tissue necrosis

Hydzik & O’Connor, 2010; Smith & McLaughlin, 2012;

Gemcitabine

• Antimetobolite • Myelosuppression

• Increase Liver Function Tests

• Diarrhea

• Flu-like Symptoms

– Muscle pain, fever, headache, chills,

fatigue, nausea and poor appetite

• Rash

• May experience alopecia

• Mucositis

• Edema

Hydzik & O’Connor, 2010; Smith & McLaughlin, 2012

Hormonal Therapy • Progestins have been the cornerstone of hormonal treatment

of metastatic endometrial cancer, and response is related to

the presence of steroid-hormone receptors

• Used with the aim of prolonging progression-free interval

• Used in patients with hormone-dependent Type I tumours

• Types of hormone therapy include progestins and aromatase

inhibitors

– i.e. Provera and Megestrol Acetate (Megace)

Amant, et.al, 2005; Creasman & Scott Miller, 2012; Lockwood, 2008; Tsoref & Oza, 2011

Oral Hormonal Therapies • Progestin

– Medroxyprogesterone acetate (Provera®)

– Megestrol Acetate (Megace®)

• The precise mechanism by which Megace® produces its antineoplastic effects against endometrial carcinoma is unknown at the present time

• Generally, these drugs work by slowing the growth of endometrial cancer cells

• Side effects can include – Hot flashes – Night sweats – Weight gain (from fluid retention

and ↑appetite) – Worsening of depression – For women with diabetes,

progestins can cause increased blood sugar levels

– Rarely, serious blood clots can happen

Creasman & Scott Miller, 2012; Polovich, Whitford & Olsen, 2009; Redlin Frazier, 2010

Immunotherapy • In September 2019 the US Food and Drug

Administration (FDA), the Australian Therapeutic

Goods Administration (TGA), and Health Canada

(HC) simultaneously approved a new two-drug

combination for the treatment of advanced

endometrial carcinoma.

• The approvals were granted to lenvatinib in

combination with pembrolizumab for the treatment of

patients with advanced endometrial carcinoma. All

three approvals were conditional and will require

further evidence of efficacy.

Follow-up • Weight loss, pain and vaginal bleeding can suggest recurrent

disease, which mostly occurs during the first 2-3 years after

primary treatment

• Retrospective data suggest that there is no difference in

survival between symptomatic and asymptomatic

recurrences or between women with recurrences detected

during routine follow-up visits

– Psychological benefit for most patients (reassured)

Amant, et.al, 2005; Creasman & Scott Miller, 2012; Redlin Frazier, 2010

Follow-Up

• Follow up includes a speculum exam with a bimanual

pelvic-rectal exam

• Women need to be counselled to contact their

healthcare team in case of vaginal bleeding

– Surveillance assessments and questions includes:

pelvic, leg or back pain, vaginal bleeding, urinary

changes, changes in bowel habits

• Surveillance should focus on detection of potentially

curable vaginal recurrences

Creasman & Scott Miller, 2012

UTERINE SARCOMAS

Uterine Sarcoma • Rare type of uterine cancer that forms in the connective or

stromal tissues of the uterus

– Group of aggressive and rare cancers that originate from

mesenchymal tissue

• Embryonic mesoderm from which blood vessels, lymphatic

vessels and connective tissue arise

• Two main types of sarcoma

– Leiomyosarcoma

– Endometrial stromal sarcoma (low or high grade)

Dulko, 2010; Lockwood, 2008; McMeekin, 2012; Smith & McLaughlin, 2012

Diagnosis of Sarcomas and

Clinical Presentation • Diagnosis is made following histologic evaluation of the

tumour

• Often found incidentally at the time of a hysterectomy or

myomectomy

• Symptoms include postmenopausal or abnormal vaginal

bleeding, uterine cramping, uterine enlargement and

possible malodorous vaginal discharge

– An enlarged uterus is palpated in about 50% of patients with uterine

sarcomas, and tumour may be seen protruding from the cervix

particularly in women with carcinosarcoma

Amant et al., 2009; Dulko, 2010; Lockwood, 2008; McMeekin, 2012; Tropé et al, 2012

Uterine Leiomyosarcoma (LMS)

• Most common uterine sarcoma

• Uterine LMS arises within the uterine smooth muscle;

therefore, biopsy of the malignant tissue is difficult and many

lesions are found only at final pathology

• Rapidly enlarging mass (sometimes thought to be fibroids)

should be a red flag

• Median age at diagnosis is in the early 50s, with most cases

occurring in women aged 30-50 years

• Risk factors for the development of uterine LMS are not well known

Dulko, 2010; Lockwood, 2008; McMeekin, 2012; Smith & McLaughlin, 2012;

Uterine Leiomyosarcoma (LMS) • LMS is usually

described as a large,

inhomogeneous, oval-

shaped mass with an

area of central

necrosis

• Symptoms

– Pain

– Heavy Vaginal Bleeding

– Presence of a Pelvic

Mass

• 50% of women present with

Stage 1 disease, which means

that the tumour is confined to the

uterus

• No adjuvant therapy has been

shown to be effective in

prolonging survival

– As with other high-risk uterine

cancers, it has been managed

postoperatively by radiation therapy

or chemotherapy

McMeekin, 2012; Smith & McLaughlin, 2012

Endometrial Stromal Sarcoma (ESS)

• Endometrial stromal sarcoma is a heterogeneous

histopathologic entity that is considered less aggressive

and has a better outcome than other uterine sarcomas

• ESS account for 7-15% of all uterine sarcomas

• ESS is malignant with as many as 30% of women with low-

grade ESS having extra uterine disease at presentation

• Most common symptom is irregular vaginal bleeding

• Standard management is surgery

Dulko, 2010; Lockwood, 2008; McMeekin, 2012

Endometrial Stromal Sarcoma (ESS) • Begins in connective tissue cells

• ESS is divided into 2 subtypes:

– Low-grade

– High-grade

• ESS tumours have usually an slow growing clinical course with

an 80-100% 5-yr survival, but approximately 37-60% of

patients eventually recur and 15-25% of women die of the

disease

• The most powerful predictor of clinical outcome whether

measured in terms of survival, number of relapses, or time to

first relapse is surgical stage

Dulko, 2010; Lockwood, 2008; McMeekin, 2012

Staging of Uterine Sarcomas

I A Tumor limited to uterus < 5 cm

I B Tumor limited to uterus > 5 cm

II A Tumor extends to the pelvis, adnexal

involvement

II B Tumor extends to extra-uterine pelvic tissue

III A Tumor invades abdominal tissues, one site

III B Tumor invades abdominal tissues, more than

one site

III C Metastasis to pelvic and/or para-aortic lymph

nodes

IV A Tumor invades bladder and/or rectum

IV B Distant metastasis

Treatment of Sarcomas

• Standard treatment for sarcomas involves surgical resection

of the tumour (exploratory laparotomy)

• Usually involves hysterectomy and bilateral salpingo-

oophorectomy +/- lymph node dissection

• CT scan is done to determine local resectability and to rule

out extra uterine spread in suspected sarcomas

• If extra uterine disease is known or suspected, a CXR or CT

scan is warranted to rule out pulmonary metastasis

Amant et al., 2009; Dulko, 2010; Lockwood, 2008; McMeekin, 2012; Smith & McLaughlin, 2012; Tropé et al.,

2012

Adjuvant Treatment

• Role of radiation therapy is controversial, no studies

have shown a survival benefit associated with post-

operative radiation therapy

• Therapy may reduce the rate of local recurrences, it

has no significant impact on overall survival as most

patients with recurrent disease have distant failures

• Useful in palliative setting to distant sites, bone/brain

Amant, 2009; Dulko, 2010; Lockwood, 2008; Smith & McLaughlin, 2012; Tropé et al., 2012;

Adjuvant Treatment • Most common chemotherapy regimens used include:

– Docetaxol and gemcitabine

– Doxorubicin, cisplatin, and ifosfamide

– Paclitaxel and carboplatin

• No prospective study has shown an improvement in

survival outcomes for treatment with chemotherapy

• Available clinical trials should always be presented as

an option to eligible patients

Gockley et al., 2014; McMeekin, 2012

Ifosfamide

• Alkylating agent

• Key points to remember

– Maintain high fluid intake

– Administered with Mesna

• For the prevention of urinary tract toxicity (hemorrhagic cystitis)

• Side Effects

– Myelosuppression

– N&V

– Alopecia

– Hemorrhagic cystitis

– Neurotoxicity

Hydzik & O’Connor, 2010; Polovich, Whitford & Olsen, 2009

Recurrent Disease • The treatment of recurrent sarcoma often requires the use of

multiple therapeutic modalities

– Rare cases of resectable, isolated pulmonary metastases may occur

• Enrolment into clinical trials is strongly recommended to

facilitate the identification of new active agents for these

malignancies

• In women with poorer performance status or multiple co-

morbidities, palliative measures and supportive care should

be the mainstay of treatment

Dulko, 2010; Smith & McLaughlin, 2012

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