This document discusses hormone therapy for prostate cancer. It begins by providing global and Indian statistics on prostate cancer incidence and mortality. It then describes the roles of testosterone and dihydrotestosterone in prostate growth and cancer. Hormone therapy aims to suppress androgen production and is used in metastatic, locally advanced and some early-stage prostate cancers. Common hormone therapies include surgical castration, LHRH agonists and antagonists, antiandrogens, and androgen synthesis inhibitors. The document discusses the use, mechanisms, and side effects of these various hormone therapy options in detail.

1. Hormone therapy in
prostate cancer
Dr Deepika Malik
Resident Radiotherapy

2. World wide burden.
Prostate cancer
 fourth most common cancer in the world.
 second most common cancer in men.
 Incidence rates are highest in Australia/New Zealand
and Northern America (ASR 111.6 and 97.2 per 100,000,
respectively )but remain low in Asian populations with
estimated rates of 10.5 and 4.5 in Eastern and South-
Central Asia.
 With an estimated 307,000 deaths in 2012, prostate
cancer is the fifth leading cause of death from cancer in
men (6.6% of the total men deaths.)

3. Indian figures.
Prostate cancer
 second most common cancer among males in large
Indian cities like Delhi, Kolkatta, Pune and
Thiruvananthapuram
 Third leading site of cancer in cities like Bangalore and
Mumbai
 Among the top ten leading sites of cancers in the rest of
the population based cancer registries (PBCRs) of India.

4.  Prostate -male sex accessory gland that
surrounds the urethra and contributes
secretions to the ejaculate.

5.  Testosterone production is regulated by
luteinizing hormone (LH) and luteinizing
hormone-releasing hormone (LHRH).
 The hypothalamus releases LHRH, which
stimulates the release of LH from the
pituitary gland.
 LH acts on specific cells in the testes to
produce the majority of testosterone in
the body. Most of the remaining
androgens are produced by the adrenal
glands.

6.  The prostate requires androgenic hormones and an intact
androgen receptor for normal growth and development.
 The major circulating androgenic hormone is Testosterone ,
5α-reductase
 Testosterone 5α-dihydrotestosterone (DHT)
inside the prostatic stroma

7. Dihydrotestosterone
 is a more potent androgen than testosterone
 binds to intracellular androgen receptor and
activates the expression of selected target genes.
 Which then bring about a response
-stimulation of cell division
- inhibition of apoptosis
- cellular differentiation.

8.  Androgens , especially DHT promote the growth of both
normal and cancerous prostate cells.
 This forms the basis of hormone therapy a.k.a androgen
suppression or androgen deprivation therapy.

10. When to give hormonal
therapy in prostate cancer?
 The NCCN Guidelines incorporate a risk stratification
scheme that uses a minimum of stage, grade, and PSA
to assign patients to risk groups.

 Risk groups are used to select the appropriate
treatment options.

12. •Gland architecture is examined
•Rated from 1 to 5
•2 different specimens examined.
•Score for each added.

13. Prostate Specific Antigen
 Normally present in blood of healthy men at very low
levels ( < 4 ng/ml)
 Glycoprotein enzyme, which liquifies semen and allows
sperms to swim freely in semen.
 Raised in prostate cancer
 Nonspecific- also raised in BPH, prostatitis

14. Very Low:
 • T1c
 • Gleason score 6
 • PSA <10 ng/mL
 • Fewer than 3
prostate biopsy cores
positive50% cancer in
any core
 • PSA density <0.15
ng/mL/g
Low:
• T1-T2a
• Gleason score 6
• PSA <10 ng/mL
HORMONAL THERAPY NOT
INDICATED

15. Intermediate:
• T2b-T2c or
• Gleason score 7 or
• PSA 10-20 ng/mL
High:
• T3a or
• Gleason
score 8-10 or
• PSA >20 ng/mL
neoadjuvant 2 month
concurrent
+/- adjuvant 2 month
- neoadjuvant 2 month
concurrent
adjuvant 24-36 months
Very High:
• T3b-T4
• Primary
Gleason pattern
5

16. Metastatic
ADT is the gold standard for
patients Who present with
metastasis at presentation.

17. Hormone therapy in prostate cancer
 As primary systemic therapy in metastatic
prostate cancer
 Neoadjuvant/ concomittant/ adjuvant in
combination with radiation for localised
or locally advanced prostate cancer.

18. Duration of neoadjuvant ADT
 3 trials
 The Canadian Urologic Oncology Group (CUOG) study
- randomized 361 patients to either 3 or 8 months of
neoadjuvant AST plus radiotherapy .
- no difference in 5-year overall survival or freedom from
failure
-positive biopsies extracted 24 to 30 months after
radiotherapy, were also not significantly different (14% vs. 9%,
respectively; p = 0.34).

19.  the Trans-Tasman Radiation Oncology group,TROG
96.01
-three-arm study with a radiotherapy-alone control
group .
-The other two arms were 3 and 6 months of
neoadjuvant AST.
-An improvement in local control and biochemical
disease-free survival was seen in both AST arms (52% to
56%) over the control arm (38%; p <0.005), although the
benefit seemed to be more pronounced in the 6-month
arm.
-Prostate cancer “specific mortality was slightly less
in the 6-month” (6%) but not the 3-month arm (8%) as
compared to the control arm (9%).

20.  Irish Clinical Oncology Research Group,
- compared 4 to 8 months of Neoadj ADT with EBRT
- no significant difference in overall survival or
biochemical control.

21.  The largest study, TROG 96.01 showed advantage to
longer duration Neoadj AST
 Other 2 trials did not show any difference
 RTOG – 9910 , compared 8 and 28 weeks of neoadj AST.
- over 1500 patients accrued
- results are eagerly anticipated
- until then available evidence remains conflicted.

22. Duration of Adjuvant
Hormonal Therapy
 the Quebec L-101 trial randomized 161 intermediate-risk patients
into 3 arms
- radiotherapy alone,
- 3-months of neoadjuvant AST and radiotherapy
- -10 -months of neoadjuvant, concurrent, and adjuvant AST
with radiotherapy
Although the two experimental arms had superior 7-year PSA control
rates over the control arm, there was no difference between the
two AST arms (69% vs. 66%; p = 0.6;).

23.  Laverdiere's L-200 study, subsequent confirmatory trial
-296 intermediate-risk patients were randomized to
either of the two experimental arms of L-101.
-After a median follow-up of 3.7 years, the 5-year
biochemical control was identical in both arms at 70%

24.  for intermediate-risk patients, short-term AST (3 to 4
months of neoadjuvant and concurrent) appears to be
sufficient,
 for high-risk patients, the addition of long-term (>2
years) adjuvant AST appears to confer improved
outcomes.

25. History-
 The scientist Charles Huggins first
established this over 75 years ago in
work that led to his winning the Nobel
Prize
 Huggins found that Bilateral
orchiectomy could slow the growth of
the disease

26. modalities
 Surgical castration
 Medical castration
LHRH agonists
LHRH antagonists
Antiandrogens
Androgen synthesis inhibitors
Estrogens

27. Surgical castration
 The surgical removal of the testicles was the
earliest form of hormone therapy for prostate
cancer
 In 1941, Huggins and Hodges first treated
men with prostate cancer with either
orchiectomy (or estrogen).
 They monitored changes in prostate size and
observed that improvements in acid and
alkaline phosphatases were associated with
cancer-related symptom relief.


28.  Bilateral orchidectomy rapidly reduces circulating androgens
to castrate levels ( < 50 ng/dl)
 Limitations—
-many patients find it psychologically unacceptable
-some are not surgical candidates owing to
advanced age.

29.  Orchidectomy is preferred initial treatment in patients
with impending spinal cord compression or ureteral
obstruction.

30. LHRH Agonists (analogs)
 synthetic proteins
 structurally similar to LHRH and bind to the LHRH receptor in
the pituitary gland
 (Intermittent pulsed LHRH ---- sustained FSH, LH release)
 High dose and continuous I/V LHRH agonist, inhibits
gonadotrophin release due to receptor down regulation.

31. leuprolide
 Leuprolide acetate-
 Leuprolide depot-
- leuprolide acetate in coated pellets; coating
- dissolves at slow rate to allow sustained levels
- intramuscularly
- 7.5 mg every 28 days
- 22.5 mg every 12 weeks
- 30 mg every 16 weeks
 Leuprolide mini osmotic pump- delivers 120 microgm
daily for 12months.

32.  Goserelin implant
3.6 mg every 28 days
10.8 mg every 12 weeks
 Triptorelin depot
3.75 mg every 28 days
11.25 mg every 84 days.

33. Tumor flare
 most common side effect of LHRH agonists
 Disease flare up during the first week of therapy
 Hot flashes, erectile impotence, decreased libido,
injection site reactions
 Caused by initial induction of FSH and LH by LHRH
agonists –--- inreased testosterone production
 Manifests as exacerbation of disesase related symptoms,
esp bone pains and urinary symptoms
 Resloves after 2 weeks
 To tackle this : antiandroen is initiated before
administration of LHRH agonist and continued for 2-3
weeks

34. LHRH Antagonists
 Bind irreversibly to LHRH recerptors in pituitary , thus
reducing testosterone to castrate levels.
 Major advantage over LHRH agonists–--
castrate levels of testosterone reached within 7 days
( compared to 28 days with antagonists) ; ---- no tumor
flare and no need for antiandrogens.

35.  Degerelix
 recently approved by FDA for advanced prostate cancer
 Available as 40 mg/ml and 20 mg/ml vials for
subcutaneous injections
 Starting dose – 240 mg , followed by 80 mg every 28
days

36. estrogen
 Although estrogens are also able to inhibit androgen
production by the testicles, they are seldom used today
in the treatment of prostate cancer because of
their side effects.

37. Antiandrogens.
 Bind to androgen receptor in prostate cells – inhibit
androgen uptake by prostate cancer cells ----- growth of
cancer cells is retarded
 they are used in combination with orchiectomy or an
LHRH agonist.

38. Flutamide
 750 mg/day perorally in 3 divided doses ( 250 mg TDS)
Bicalutamide
 50 mg OD
Nilutamide
 300 mg OD for 1 month , then 150 mg OD

39. Adverse effects of antiandrogens-
 Gynecomastia, hot flashes, GI disturbances, liver
function abnormalitites, breast tenderness

40. Androgen synthesis inhibitors
 Inhibit androgen synthesis in testes and adrenals
 block testosterone production by inhibiting
an enzyme called CYP17. (produces testosterone
from cholesterol).
 Three androgen synthesis inhibitors are approved in the
United States. – ketoconazole, aminoglutathemide,
abireterone acetate

41. Ketoconazole
 Imidazole antifungal
 400 mg TDS orally
 a/e- GI intolerance, hypoadrenalism
 strong inhibitor of CYP A1 and CYP 3A4 , therfore
contraindicated with midazolam, traizolam ( commonly
used in prostate cancer patients)
 Absorption requires gastric acidity , so should not be
given with H2 blockers, PPI’s

42. Toxicities of ADT
 Fatigue
 weight gain
 osteoporosis
 depression
 decreased cognitive function
 erectile dysfunction
 loss of libido
 Gynecomastia
 Anemia
 decreased high-density lipoprotein
 hot flashes

43.  In a recent study of 50,613 men with prostate cancer
compiled from a linked database of Surveillance
Epidemiology and End Results (SEER) and Medicare, the
addition of AST significantly increased the risk of any
fracture from 12.6% to 19.4%; fractures requiring
hospitalization similarly increased from 2.37% to 5.19%

44. chemoprevention
 5 α reductase inhibitors have been shown to decrease
risk of prostate cancer
 Inhibit 5α-reductase , such that testosterone does not
convert to its more active form DHT
 Finesteride , Dutasteride
 American Society of clinical oncology and American
Urological Association recommend that asymptomatic
men with PSA less than 3 ng/ml may benefit .
 Risk of developing high grade prostate cancer

45. Take home message
 Hormone therapy is an integral part of managing
prostate cancer
 For metastatic cases – hormone therapy is the Gold
standard
 For early cases – hormone therapy is given as per risk
stratification
 Chemoprevention- with risk of developing high grade
prostate cancer.

46. Thank you.