CURRICULUM VITAE

Name

: Dr. Syafrizal Syafei, SpPD-KHOM

Position

: Medical Staff, Div. Hematology Medical-Oncology,

Department of Internal Medicine, University of Indonesia

Education

1983

: Medical Doctor, University of Indonesia

1990

: Internist Department of Internal Medicine, University of

Indonesia

2000

: Hematologist-Medical Oncologist, Div. Hematology

Medical-Oncology, Department of Internal Medicine,
University of Indonesia

Basic Principle & Administration

of Hormonal & Integrated
Therapy in Cancer
Syafrizal Syafei
Dharmais Cancer Hospital
Hematology-Medical Oncology Division
Dept.of Int. Medicine, Faculty of Medicine
University of Indonesia, Jakarta
Seminar & Workshop The Role of Internist in Cancer Management (ROICAM)
Thursday, April 2nd 2015, Dharmais Cancer Hospital, Jakarta.

Introduction
Hormone-dependent cancers, include of Breast
and Prostate Ca, also Ovary, Uterus and Testicular
Cancer.
Estrogens & Androgens are steroidal sex hormones
derived from cholesterol via production of
androstenedione, and its use to synthesize the
androgens dihydrotestoterone and testoterone.
The enzyme aromatase has an important role in
produce estrogen 17b-estradiol, either from
testoterone itself, or from androstenedione via the
production of intermediate estrone.
Cancer Chemotherapy, Basic Science to the Clinic, Rachel Airley, p 106, Wiley-Blackwell 2009.

Introduction, continue
The link between exposure to male and female
steroidal sex hormones and the risk of
hormone-dependent cancers is well known.
Two major discoveries included that of Beatson
(1896), showed that oophorectomy, improved
prognosis in woman with advanced breast
cancer, and Huggins and Hodges (1935) showed
the same effect of testoterone in prostate ca
who got orchiectomy.

Cancer Chemotherapy, Basic Science to the Clinic, Rachel Airley, p 106, Wiley-Blackwell 2009

Estrogen antagonist
The first significant advance in development of
estrogen receptor blocking agents was the
introduction of Tamoxifen, a non-steroidal
tryphenylethylene, which is acknowledged as the
first selective estrogen receptor modulating agent
(SERM).
Tamoxifen is effective ER antagonist in breast ca,
but it has pronounced partial agonist effect to
endometrium and bone.
Effort to get second generation ER antagonist
with reduced partial agonist, produce fulvestrant.

Estrogen antagonist, continue1

Tamoxifen still continues to be important
hormonal therapy for the prevention and
treatment of breast cancer worldwide.
The US Food and Drug Administration (FDA)
approved for the prevention of premenopausal
breast cancer, the treatment of ductal carcinoma
in situ (DCIS), and the treatment of surgically
resected premenopausal estrogen receptor (ER)
positive breast cancer.

Hormonal Agents,, Tamoxifen, p 278,Matthew P Goetz et al, DeVita, Hellman, & Rosenbergs, Cancer Principles &
Practices of Oncology, 10th edition , 2015, Wolters Kluwer Health

Estrogen antagonist, continue2

The standard daily dose of tamoxifen is 20 mg,
and optimal duration depends on the underlying
clinical setting.
The recommended duration in the prevention
and DCIS is 5 years, recently published prospective studies have demonstrated that for the
adjuvant treatment of invasive breast cancer, a
duration of 10 years compared to 5 years further
reduced the risk of breast cancer mortality and
improved overall survival.

Hormonal Agents, Tamoxifen, p 278, Matthew P Goetz, et al, DeVita, Hellman, & Rosenbergs, Cancer Principles &
Practice of Oncology, 10th edition, 2015, Wolters Kluwer Health

Estrogen antagonist, continue,3

The most common toxicity from tamoxifen is hot
flashes, affecting + 50% of treated women.
Tamoxifen increases the incidence of endometrial cancer in postmenopausal, but not
premenopausal women.
The absolute risk depends on the duration of
administration. For women who receive 10 years
of adjuvant tamoxifen, the cumulative risk is
3,1%, mortality, 0,4% vs 1,6%, mortality 0,2% for
5 years tamoxifen.

Hormonal Agents, Tamoxifen, p 278, Matthew P Goetz et al, DeVita, Hellman & Rosenbergs, Cancer Principles &
Practices of Oncology, 10th edition, 2015, Wolters Kluwer Health

Estrogen antagonist, continue,4

Tamoxifen predisposes patients to thromboembolic phenomena, especially if used with
concomittant chemotherapy.
An uncommon effect from tamoxifen is retinal
toxicity. This drug can also increase the risk of
cataracts. However, no difference in the rate
vision-threatening ocular toxicity has been seen
among prospectively treated tamoxifen patients.
Depression has also been described, but the
association with tamoxifen is not clear.

Hormonal Agents, Tamoxifen, p 278, Matthew P Goetz et al, DeVita, Hellman & Rosenbergs, Cancer Principles &
Practice of Oncology, 10th edition, 2015, Wolters Kluwer Health

The aromatase inhibitors

Aromatase inhibitors and inactivators block the
aromatization of androgens.
This is the final step in estrogen synthesis, by
conversion of androstenedione to estrone, though
aromatase may also directly conversion of testoterone
to estradiol.
Aromatase inhibitors have been classified in a number
of different ways, including first, second, and third
generation, steroidal and non-steroidal, reversible
(ionic binding) and irreversible ( suicide inhibitor,
covalent binding).

Hormonal Agents, Aromatase Inhibitors, p 282, Matthew P Goetz et L, DeVita, Hellman & Rosenbergs, Principles & Practice
of Oncology, 10th edition, 2015, Wolters Kluwer Health

The aromatase inhibitors, cont1

The non nonsteroidal aromatase inhibitors
include aminoglutethimide (first generation),
rogletimide and fadrozole (second generation)
and anastrozole, letrozole, and vorozole (third
generation).
The steroidal aromatase inhibitors include
formestane (second generation), and
exemestane (third generation)

The aromatase inhibitors,cont 2

First generation of aromatase inhibitor is
aminoglutethimide, but this agent actually is not
specific to aromatase , but it has total ablation of
adrenal steroids by also inhibiting the conversion of
cholesterol to pregnenolone
Second generation is fadrozole, and the third
generation are anastrozole and letrozole.
Aromatase inactivators are steroidal compounds that
are analogues to androstenedione , and able to bind to
substrate binding site irreversible, leading to
degradation of the enzyme.

The aromatase inhibitors,..cont 3

This group includes formestane and exemestane,
where exemestane has proved to be useful in
patients showing disease progression with
tamoxifen.
Aromatase inhibitors and inactivators are
contraindicated in pre-menopausal women, in
absence of ovarian blockade with gonadotropin
releasing hormone (GnRH) analogues.

Letrozole & Anastrozole

Both letrozole and anastrozole have been extensively
studied in the metastatic and adjuvant setting.
When compared to tamoxifen, both letrozole and
anastrozole showed superior response rates and
progression-free survival in the metastatic setting.
In adjuvant setting , 2 trials have been showed
superiority in terms of relapse-free survivals of both
anastrozole and letrozole.
Recently anastrozole has been compared to placebo in
womwn at an increases risk of developing breast
cancer, and was showed to significantly reduce of
invasive breast cancer.

Hormonal Agents, Letrozole & Anastrozole, p 283, Matthew P Goetz et al, DeVita, Hellman & Rosenbergs, Cancer Principles &
Practice of Oncology, 10th edition, 2015, Wolters Kluwer Health

Letrozole & Anastrozole, ..cont 1

The side effects of both anastrozole and letrozole are
similar, and include arthralgias and myalgias in up to 50%
patients.
Both letrozole and anastrozole are related with a higher
rate of bone fracture, compared with tamoxifen.
When offering anastrozole for extended periods of time to
patients with early breast cancer, attention to bone health
is important, and bone density should be monitored in all
patients.
Bisphosphonates prevent aromatase inhibitor-induced
bone loss, reduce bone recurrences and prolong overall
survival.

Hormonal Agents, Letrozole & Anastrozole, p 283, Matthew P Goetz, DeVita, Hellman & Rosenbergs, Cancer Principles & Practice of
Oncology, 10th edition, 2015, Wolters Kluwer Health

Exemestane
Exemestane has a steroidal structure, and classified as a
type 1 aromatase inhibitor, also known as an aromatase
inactivator, because it irreversibly binds with and
permanently inactivates the enzyme.
Exemestane has been compared to tamoxifen in both the
metastatic and adjuvant settings.
In the setting of tamoxifen-refractory metastatic breast
cancer, exemestane is superior to megesterol acetate.
In the adjuvant setting, exemestane compared 2 to 3
years of tamoxifen, showed exemestane is superior in
disease free and overall survival in ER positive subtype.

Hormonal Agents, Exemestane, p 284, Matthew P Goetz et al, DeVita, Hellman & Rosenbergs, Cancer Principles & Practice of
Oncology, 10th edition, 2015, Wolters Kluwer Health

Exemestane, ..continue 1
Exemestane has side effects, including arthralgias
and myalgias, look similar to other aromatase
inhibitors.
Risk of bone fractures, also the same with other
aromatase inhibitors.
Exemestane has weak androgenic properties,
such weight gain and acne.
Exemestane is administered once daily via oral
with recommended dose 25 mg.

Hormonal Agents, Exemestane, p 284, Matthew P Goetz et al, DiVita, Hellman & Rosenbergs, Cancer Principles &
Practice of Oncology, 10th edition, 2015, Wolters Kluwer Health

Anti-androgens
Anti-androgens inhibit the AR and include the
steroidal androgen analogue cyproterone acetate
and the non-steroidal compound bicalutamide,
flutamide and nilutamide .
The major aplication, like endocrine therapy, is in
the treatment locally advanced prostate ca.
The more modern non-steroidal anti-androgens
show more specificity to the AR expressed in
prostate tumor cells.
This is in contrast to cyproterone acetate, cause its
prosgeterogenic effect suppresses whole body
testoterone leading to loss of sexual function.

Anti-androgens,
Androgen Receptor (AR), signalling is necessary for
the development of prostate ca.
Androgens exert their biological effects through AR.
Androgen deprivation therapy for prostate was
describe over 50 years ago, and remains the
mainstay of systemic therapy.
Although the mechanisms by which prostate cancer
cells change androgen sensitivity are unclear, it is
believed that the ca cells must either bypass or
adapt the AR-mediated cell growth pathway to
survive in a low androgen microenvironment during
androgen ablation therapy.

Systemic Treatment of Prostate Cancer, Alan Horwich, p 1, Oxford Oncology Library, 2010

Endocrine Therapy for Prostate Ca

Endocrine therapy manipulates the
hypothalamus-pituitary axis, the stimulatory,
inhibitory, and feedback processes involved in
the production of the gonadotropin leutinizing
hormone (LH) and follicle stimulating hormone
(FSH), which bring about a decrease in the
production of testicular-derived testoterone.
These agents includes estrogen agonist, GnRH
agonist and GnRH antagonist.

Endocrine Therapy,continue 1
The estrogen agonists such as diethylstilbestrol are
still used rarely, but are administered parenterally
to avoid cardiovascular toxicity.
The GnRH agonists, which include goserelin,
leuprorelin, buserelin and triptorelin, stimulate the
production of LH and FSH, initially increasing the
production of testoterone, and long term treatment
with high concentration, will lead to down-regulation of GnRH-receptors and inhibition of LH
release, then inhibiting production testoterone.

Endocrine Therapy,continue 2
GnRH antagonists are undergoing development as a
means of achieving a rapid fall in LH and FSH, and
therefore androgen production, but without the risk
of tumor flare.
The first of this novel class agents is abarelix, who
get FDA approval in 2004 for the treatment of
advanced symptomatic prostate ca.

Inhibitor of Androgen Biosynthesis

Abiraterone is a potent, selective, and irreversible
inhibitor of CYP17-hydroxylase and C-17,20,lyase
activities, both essential steps in androgen biosynthesis
by adrenal glands, testes, and within prostate ca cells.
Continuous CYP17 inhibition results in raised levels of
ACTH, which increases steroid levels upstream of CYP17
and induces a syndrome of secondary mineralocorticoid excess. These adverse effect are best avoided by
coadministration of steroids.
A phase III study of abiraterone vs placebo in patients
previously treated by docetaxel, showed a significant
improvement in OS in favor abiraterone from 10,9 to
14,8 months.

Clinical Pharmacology of Anti-Cancer Agents, ESMO Handbook Series, ESMO Press 2012

Conclusion
Hormonal and Endocrine therapy for Breast Cancer has
important role in the treatment, both premenopausal
and postmenopausal, and also metastatic breast
cancer patients.
In Prostate Cancer hormonal therapy and Endocrine
Therapy also has important role, even with patient
also getting chemotherapy.
Risk of thromboembolic and bone fracture must always
managed properly.
Patients with comorbidities, like Hypertension,
Diabetes Mellitus, Liver problem must be in good
controlled.

Thank you for your attention