Hormonal Therapies

DR Awatif Abousahmeen
Radiation oncologist
INTRODUCTION

It has long been recognized that tumors derived from

hormone-dependent tissues , such as the breast,
endometrium , and testes, are themselves dependent on
the same hormones.
This is demonstrated by the remissions observed in
premenopausal breast cancer following ovariectomy
(surgical removal of the ovaries) and in prostatic cancer
following orchidectomy (surgical removal of the testes)
Cont
Hormonal treatments play a large role in the treatment of
these tumors. While not curative, they may provide
excellent palliation of symptoms in selected patients, some
times for many years.
 As with all treatments, tumor response and toxic side
effects should be carefully monitored and treatment
changed→ if progression occurs or side effects exceed the
benefits.
BREAST CANCER
The management of patients with breast cancer involves
surgery, radiotherapy, drug therapy, or a combination of
these treatments.
the most common cytotoxic chemotherapy regimen for
both adjuvant use and metastatic disease was a
combination of cyclophosphamide, methotrexate, and
fluorouracil.
anthracycline-containing regimens are now
increasingly used and are regarded as standard therapy
unless contraindicated (e.g., in cardiac disease).
Cont
In metastatic disease, the chemotherapy regimen chosen
reflects whether the patient has previously received
adjuvant treatment and also the presence of any
comorbidity.
 cyclophosphamide, methotrexate, and fluorouracil or
an anthracycline-containing regimen is the standard
initial therapy for metastatic breast disease.
The choice of adjuvant treatment is determined by→
the risk of recurrence, the estrogen-receptor status of the
primary tumor, and menopausal status.
History of hormonal therapy
Oophorectomy – 1896
 surgeon George Beatson found he could extend the lives of women
with metastatic breast cancer by surgically removing their ovaries
Tamoxifen – 1966
 initially developed as a fertility treatment
 first used in breast cancer in 1971
Aromatase inhibitors - early 1990s
 anastrazole (Arimidex)
 letrozole (Femara)
 exemestane (Aromasin)
Hormones&Hormone Antagonists
Least toxic of anticancer drugs
Highly selective
Breast, endometrial, prostate cancers
 6categories
 Estrogen
 Antiestrogen
 Aromatase inhibitors
 Androgens-Progestins
 Antiandrogen
 Gonadotropin-releasing hormone analogs
Hormone receptor positive breast cancer

Breast cancer with receptors to the 2 female hormones

– oestrogen and progesterone - on its cells
75% of all breast cancers
Testing for oestrogen receptors
ER positive ER negative
Menopause
When the ovaries stop producing eggs and menstrual periods
end
Average age is 51 years (range 45 – 55)
Definitions Peri-menopause (transition) – periods become
irregular/ less frequent, can last several years
Menopause – no periods for 12 months
Post-menopause – the time after menopause
Sources of oestrogen
 Before menopause - ovaries
 After menopause - subcutaneous fat, liver, muscle
Options for anti-hormone therapy
Pre-menopausal women
 Tamoxifen
 Inhibition of estrogen production from the ovaries
 temporary - monthly zoladex injections

 permanent - surgical oophorectomy

Post-menopausal women
 Tamoxifen
 Aromatase inhibitors
 How do hormone therapies work?

Tamoxifen
Aromatase stops
inhibitors oestrogen
decrease attaching to
production of breast cancer
oestrogen cells

Without oestrogen breast cancer cells are not

stimulated to grow
Hormonal Therapy
Selective EstrogenReceptor Modulators(SERMs)
 Tamoxfen
 Raloxifen
 Torimefene
 Anti Estrogens
 Fulvestrant
 Aromatase Inhibitors
 Letrozole
 Anastrazole
 Exemestane
Cont
LHRH Agonists
 Leuprolide
 Goserlin
 Progestins
 Megestrol acetate
 Medroxyprogesterone acetate

Ovarian Function Suppression

1-Oopherectomy
2-Rt ablation
3-LHRHagonists
Selective Estrogen Receptor Modulators (SERMs)
Tamoxifen : Non steroidal antiestrogen

:Antagonistic
Breast and :Agonistic
blood vessels Uterus,
bone, liver,
pituitary
Tamoxifen(Nolvadex)
 The gold standard of treatment in the adjuvant setup is
tamoxifen.
 is a non steroidal estrogen antagonist that is used as a first line
anti-estrogen
 Adjuvant Tamoxifen has been used for treating breast cancer
since 1970s
 is presently the preferred choice of adjuvant hormonal treatment
for all women with estrogen-receptor-positive breast cancer.
 Treatment with tamoxifen leads to delays the growth of
metastases and increases survival also lowers the risk of tumor
formation in the other breast.
Tamoxfen
DOSE:10-20mg bd
Standard hormonal
treatment in breast cancer
Adverse effects:
Hot flushes , vaginal
discharge and bleeding,
menstrual irregularities,
venous
thromboembolism,
endometrial hyperplasia,
rarely endometrial cancer
Benefits of anti-hormone therapy
5 yrs of anti-hormone therapy reduces the risk of:
 breast cancer coming back somewhere else in the body
(metastases / secondaries)
 breast cancer returning in the same breast
 a new breast cancer in the opposite breast
 death from breast cancer

The benefits of anti-hormone therapy last well beyond

the 5 years you take tablets
 Benefits of anti-hormone therapy
Tamoxifen (compared to no hormonal therapy)
 12% reduction in risk of breast cancer coming back
 9% reduction in risk of death from breast cancer

Aromatase Inhibitors (compared to tamoxifen)

 Further 3% reduction in risk of breast cancer coming
back
 Same reduction in risk of death from breast cancer
 All three aromatase inhibitors equivalent efficacy
When to start hormonal therapy

 4-6 weeks after surgery

 After chemotherapy
 During or after radiotherapy
Duration of hormone therapy
At least 5 years
Tamoxifen 10 yrs better than 5 yrs Further reduction
in breast cancer recurrence and death
Especially if large cancer, node positive, high grade

Tamoxifen 5 yrs - AI 5 yrs better than Tamoxifen 5 yrs

Aromatase Inhibitor 5 yrs No data for safety beyond
5 years
Trials completed and results awaited
Side Effects of anti-hormone therapy
Many healthy tissues benefit from oestrogen
 vagina, brain, skin and bones

Menopausal symptoms can occur when:

 oestrogen is blocked from entering healthy tissue by
tamoxifen
 oestrogen levels are reduced by aromatase inhibitors
Tamoxifen side effects
Common
hot flushes (up to 80%, severe in 30%)
vaginal discharge, sexual dysfunction, irregular periods

Less common
dry skin, weight gain, mood change

Rare
Blood clots (venous thrombosis) (DVT / PE, 3 in 100)
 Risks - smoking, surgery, previous blood clots, obesity

cancer of the womb (uterus) (4 in 100) women > 50yrs; longer duration on treatment

cataracts
Anti Estrogens
 Fulvestrant
 Steroidal antiestrogen.
 Considerably higher affinity for Estrogen receptor than
tamoxifen.
 Promotes accelerated ER turnover
 Suppression of ER protein levels
 Inhibition of ER dimerization
 Reduced a huttling of the ER from the cytoplasm to the
nucleus.
conti
An intramuscular injection (500mg loading dose on days
1,14, and 29 of the first month, then maintenance dosing
monthly at day 28,+_3days).

Although originally approved as a monthly intramuscular

injection(250 mg per month),use of the higher dose was
proven to be more effective in subsequent trials and is now
the preferred schedule

 (ref. final overall survival: Fulvestrant 500mg vs 250mg in the randomized CONFIRM trial,2014)
Aromatase Inhibitors
Nonsteroidal (type 2) Steroidal(type 1) Generation
Aminoglutethmide - First (nonselective)

Fadrozole Formestane Second (selective)

Anastrozole(Arimidex) 1mg Exemestane(Aromasin) Third (super selective)

Letrozole(Femara) 25mg Dose (25 mg daily)
Aromatase Inhibitors
 Anastrozole(Arimidex ) is given orally 1 mg/day
 used in postmenopausal women who are unable to take
tamoxifen because of a high risk of thromboembolism or
endometrial abnormalities.
 is recommended for a 5-year duration of treatment only.
 The drug should be used cautiously in women who are
susceptible to osteoporosis, and bone mineral density
should be assessed before and after treatment when
necessary.
 S/E:- vaginal dryness, hot flashes ,rash
Letrozole
 Letrozole (Femara) a nonsteroidal aromatase inhibitor
 It is also used in postmenopausal women with localized
hormone-receptor-positive breast cancer.
 Dose :2.5mg bd orally
S/E:-hot flashes, nausea, vomiting, sometimes weight
gain.
Aromatase Inhibitor Side Effects
Common
 hot flushes
 muscle and joint pains and joint stiffness
 vaginal dryness, sexual dysfunction

Less common weight gain, mood change

Rare
 osteoporosis, fractures
 cardiovascular risk
 elevated cholesterol
Toxicity management
 Hot flushes
 Usually self limiting and respond well to placebos
 Best managed by life style changes.
 Vaginal bleeding:
 Routine work up indicated.
 Watch out for an endometrial Ca in post menopausal
females.
 Osteoporosis
 Calcium supplements, vitmin D and bisphosphonates
LHRH Analogues
Analogue that activates the GnRH receptor resulting in→
increased secretion of FSH and LH
After their initial stimulating action -”flare” effect-
eventually causes a paradoxical and sustained drop in
gonadotropin secretion

“downregulation” (observed after about 10 days)

Progestins
Megestrol acetate
Medroxyproesteron acetate
 Powerful anti androgenic and anti estrogenic effects
 Significantly lowers the expression of the androgen
receptor (AR) and the Estrogen receptor (ER) in the body
The anti neoplastic action of progestins on carcinoma of
the breast is effected by
 Modifying the action of other steroid hormones and
 By exerting a direct cytotoxic effect on tumor cells
Goserelin (Zoladex)
For breast or prostate cancer, a 3.6-mg acetate implant
(Zoladex) is administered every 28 days into the anterior
abdominal wall by subcutaneous injection
A longer-acting version (Zoladex LA™) containing 10.8 mg
of the acetate is licensed for prostate cancer and can be
administered every 12 weeks.
Side effects : common with agonist analogs of LH-RH
 transient changes in blood pressure
 paraesthesia and, rarely, hypercalcemia
leuprolide
 used for the treatment of advanced prostate cancer,
leuprorelin is administered every 4 weeks by
 subcutaneous or intramuscular injection as a 3.75-mg
microsphere formulation (Prostap SR™)
 Triptorelin
 Used to treat advanced prostate cancer and endometriosis,
this drug is administered
 in the form of a 3-mg aqueous copolymer microsphere
suspension (Decapeptyl SR™) by intramuscular injection
every 4weeks.
ANTI-ANDROGENS
Anti-androgen agents are divided into two families based
on their structures(steroidal or nonsteroidal).
 steroidal agent:- is cyproterone acetate (Cyprostat® or
Androcur®).
 Nonsteroidal anti-androgens:-such as flutamide
(Drogenil™), bicalutamide(Casodex™), and nilutamide
(Anandron™)
Conti
 Cyproterone acetate (Cyprostat™ or Androcur™)
 is the main steroidal anti-androgen in clinical use today
 is licensed in the U.K. for the treatment of prostate cancer
 and is given orally for the tumor flare that occurs initially
with gonadorelin therapy.
 it can be used for longterm palliative therapy
 side effects: most serious S/E of this agent is direct
hepatotoxicity
 careful monitoring is necessary with liver function tests
before and after treatment
Flutamide (Drogenil™ or Eulexin™), the first non steroidal
anti-androgen. Given orally, flutamide is licensed in the
U.K. for use in advanced prostate cancer, Palliative effect in
metastatic Prostatic Ca after orchidectomy
 although it should not be given to patients with cardiac
disease or hepatic impairment.
 S/E One of the most common S/E is
 gynecomastia
 Nausea, vomiting, diarrhea ,increased appetite, insomnia,
and tiredness can also be significant
 Bicalutamide (Casodex™) is a non steroidal peripherally
active anti-androgen
 for the treatment of prostate cancer.
 is well absorbed orally with a half-life of 5 to 7 days.
 It selectively blocks peripheral androgen receptors.
 Side effects include jaundice, cholestasis, hematuria, dry
skin, pruritus, dyspepsia, hirsutism, nausea, vomiting,
diarrhea, hot flashes, alopecia, decreased libido, breast
tenderness, gynecomastia, depression, asthenia, and
abdominal pain.