3. What Other Anti-Cancer Therapy Induces
Remissions Lasting More than a Decade?
Cancer Type Life Expectancy after Relapse
Pancreatic cancer 4 months
Kidney cancer 6-8 months
Stomach cancer 8-10 months
Lung cancer 12-14 months
Colon cancer 24 months
Prostate cancer 160 months!
3
4. TIP Maintains a Low and Stable PSA for
an Average of Ten Years After Relapse
PSA relapse:
Surgery or Hormone
Start TIP
radiation resistance
Average 3 10 years
years or so
4
6. Six Types of Anti-Testosterone Therapy
1. Proscar & Avodart
5-alpha reductase inhibitors
Block DHT synthesis from testosterone
DHT is 5-10 times more potent than testosterone
1. Casodex, Nilutamide & Flutamide
Anti-androgens: Block androgen receptor
Blood testosterone remain normal or rise
6
7. Six Types of Anti-Testosterone Therapy (cont.)
3.Lupron, Trelstar, Eligard, Zoladex, Vantas & Firmagon
LHRH agonists and antagonists
Block testicular production of testosterone
Essentially the same net effect as orchiectomy
though blood testosterone is slightly lower with
Lupron: (van der Sluis, J. Urol. 187:1601, 2012)
4. Estrogens: DES, Estrogen Patches (Vivelle Dot)
Block testicular production of testosterone and
Also sharply increase the levels of sex hormone
binding globulin (SHBG) in the blood. SHGB binds
and inactivates testosterone
7
8. Six Types of Anti-Testosterone Therapy
(cont.)
5. Zytiga (abiraterone), Nizoral (ketoconazole)
Block testosterone synthesis in the cancer cell
Can affect the blood levels of other medications
including statins
6. MDV-3100 (Pending FDA approval)
Blocks the androgen receptor
Estimated to be 20 times more potent than Casodex
8
9. Ascending Levels of TIP Potency
1. Mild—Avodart & Proscar
2. Moderate—Casodex, Nilutamide & Flutamide
(Anti-androgen monotherapy)
3. Stronger—Lupron, Zoladex, Trelstar, Estrogen
4. Even stronger—#1 + #2 + #3
5. Most Potent—Zytiga, MDV-3100 (plus Lupron)
6. Even More Potent?—Zytiga plus Nilutamide or
Zytiga plus MDV-3100?
9
10. Roles for Testosterone Deprivation
Preliminary to radiation to reduce prostate size
Ancillary to radiation (or surgery) to improve cure rates
Intermediate-Risk
High-Risk
PSA-Relapsed disease
As standalone therapy
Intermediate-Risk
PSA-Relapsed disease
Advanced disease
Second-line therapy
Zytiga
Nilutamide
Ketoconazole
10
11. TIP to Shrink the Prostate Gland
Prior to Radiation
Men receiving three months of Casodex and Avodart
had prostate size reduced by an average of 33%
(Merrick, UROLOGY 68:116, 2006)
Men receiving 3 months of TIP before seeds benefited
with reduced
AUA scores lasting up to
3 years after implantation
compared to men not
receiving TIP
(Stone, J. Urol. 183:634,2010)
11
13. TIP with Radiation: Intermediate-Risk
Jones, NEJM 365:107, 2011
4 months of Lupron and Flutamide with radiation
vs. radiation alone:
Cancer death at 10 years: 4% vs. 8%
13
14. TIP with Radiation: High-Risk
1. 4 months Zoladex/Flutamide vs. none (Pilepich, IJROBP 50:1243, 2001)
Cancer death @ 8 years: 23% vs. 31%
2. 36 months of Zoladex vs. none (Bolla, Lancet 2010)
Cancer death @ 10 years: 10% vs. 30%
3. 24 months of Zoladex vs. 4 months of Zoladex plus
Flutamide: (Horwitz, JCO 26:2497, 2008)
Cancer death @ 10 years: 11% vs. 16%
14
15. Observations: TIP Plus Radiation
Long TIP is better than Short TIP
Short TIP is better than no TIP
TIP improves mortality rates to a smaller degree in
Intermediate-Risk as compared to High-Risk
All the TIP/radiation studies cited used low-dose
radiation compared to modern standards. Therefore,
some experts contend that with modern radiation
TIP’s favorable impact on survival may be less
15
16. TIP to Prolong Life with Surgery:
High-Risk or Positive Nodes
Two years of TIP consisting of Zoladex plus
Casodex resulted in surprisingly low relapse rate in
481 men with High-Risk disease (Dorff, JCO 29:2040, 2011)
7.5% relapse rate @ five years (no control arm)
Lifelong TIP is better than TIP at relapse with
positive nodes after surgery (Messing, NEJM, 341:1781, 1999)
Less overall mortality @ 7 years: 15% vs. 40%
16
17. TIP with Radiation for PSA Relapse
Shipley, IJROBP 78:S27, 2010
771 patients with positive margins or PSA relapse after
surgery treated with radiation alone or radiation plus
Casodex 150 mg daily for 2 years
Only difference in side effects was breast growth
Outcome after seven years:
Radiation Radiation & Casodex
PSA Failure 60% 43%
Metastases 12.6% 7.4%
Overall Survival 86% 91%
17
19. TIP as Standalone Therapy
Intermediate-Risk
Fifteen percent of men in the United States with newly-
diagnosed prostate cancer are treated solely with
primary TIP (Cooperberg, JCO 28:1117, 2010)
Men with Intermediate-Risk and men with large
prostate glands are much more likely to to maintain
long-term remissions when TIP is stopped than men
who are High-Risk (Scholz, Clin. GU Cancer 9:89, 2011)
High-Risk men receiving TIP without surgery or XRT
may have increased mortality compared to men who
have surgery or XRT added to TIP (Solberg, IJROBP 80:55,
2011)
19
20. As Standalone Therapy:
PSA Relapse
Time to androgen independence is the same with
Intermittent TIP and continuous TIP (Klotz, next
slide)
Quality of life is better with intermittent TIP
Men on intermittent TIP have longer holiday
periods when TIP is stopped if they take Proscar
or Avodart (Scholz, J. Urol 175:1673, 2006)
20
21. Intermittent TIP
Klotz, ASCO 2011, abstract #4514
Phase III: 1386 men with PSA-relapsed disease:
690 men intermittent, 696 men on continuous
8 months TIP, restarting TIP triggered when PSA=10.
Results:
No difference in overall survival
IHB: on treatment only 27% of the time
Time to hormone resistance: 10 years
More men died of non-cancerous causes
21
22. TIP as Standalone Therapy in Elderly Men with
Advanced Disease that is Hormone Sensitive:
Studer, JCO 24:1868, 2006
985 patients median age 73 median PSA 16 randomized
between immediate vs. delayed TIP (LHRH alone)
Median time to TIP in delayed group was 7 years
Median PSA was 56 when in delayed group when TIP was
begun
Early TIP reduced prostate cancer mortality, but it was
not statistically significant
TIP reduced cardiovascular mortality to a statistically
significant degree
22
23. TIP as Standalone Therapy in Hormone
Sensitive Advanced Disease
Casodex vs. Orchiectomy (Iverson, Scand J. Urol 30:93, 1995)
376 men, 2/3 with more than five mets. or super-scan
Median survival for orchiectomy was 27 months
Median survival of low-dose Casodex was 19 months
Nilutamide plus Orch. vs. Orch. (Dijkman, J. Urol 158:160, 1997)
457 men with D2 disease
Median survival for orchiectomy was 30 months
Median survival for Nilutamide plus Orch. was 37 mo.
23
24. Intermittent TIP
Advanced Disease
Salonen, J. Urol 187:2074, 2012
Phase III: 852 men locally advanced or metastatic:
Randomized if PSA < 10 after 6 months of Zoladex
274 men intermittent, 280 men continuous
Restart Zoladex if PSA rose to 20 (or to baseline if
lower)
Results: No difference in overall survival
24
25. Anti-Androgen Monotherapy
Less efficacious than Lupron
Shorter off-cycle when used intermittently
Higher PSA nadir than Lupron
Shorter survival with advanced metastatic disease
Milder side effects than Lupron
Less loss of libido and less erectile dysfunction
Does not cause osteoporosis (increases estrogen)
Indicated in select situations:
To reduce prostate size before radiation
Elderly men with less aggressive disease
25
27. Zytiga for Advanced Disease
de Bono, NEJM 364:1995, 2011
Randomized study evaluating men with metastatic
disease previously treated with Taxotere
After one year of therapy:
Placebo Zytiga
PSA Response 6% 29%
PSA Progression 6.6 months 10.2 months
Survival 10.9 months 14.8 months
Side Effects: Generally well tolerated. Occasional liver
problems, some drug interactions
27
28. 50% PSA Decline with Nilutamide
Results after failure of Lupron alone:
72% responded (Nakabayashi, BJU 96:783, 2005)
Results after failure of Lupron & Casodex:
33% responded (Nakabayashi, BJU 96:783, 2005)
29% responded (Kassouf, J.Urol 169:1742, 2002)
50% responded (Desai, Urology 58:1016, 2001)
Potential side effects
Slow light adaptation
1% incidence of interstitial pneumonitis
28
29. Ketoconazole for Men Resistant to
Lupron and Casodex
Scholz, J. Urol 173:1947, 2005
78 patients with a median PSA of 25; 53 bone scan (+)
Response Rates:
Average response time was 14.5 months
Survival was 5 years with > 75% decrease in PSA
Survival was 2 years with < 75% decrease in PSA
Common side effects:
Fatigue and weakness
Stomach and liver problems
Multiple potential drug interactions
29
30. Second Line TIP
Zytiga is clearly superior to the other second line agents.
It is both better tolerated and more effective. If Zytiga
can be obtained, it should be started first
Ketoconazole has the same mechanism of action as
Zytiga so Keto, being a weaker drug, is unlikely to be
effective in Zytiga resistant patients. Keto is more toxic
and less effective than Zytiga so it is only indicated when
Zytiga is unattainable.
Nilutamide is less potent than Zytiga but blocks
testosterone by a different mechanism. Studies need to
be done to see if there is any benefit in adding
Nilutamide to Zytiga when Zytiga stops working
30
34. Arthritis Symptoms are Common,
Particularly in the Hands and Spine
Common anti-inflammatory medications are effective
Celebrex: Has an anticancer effect also (Pruthi, BJU 93:275,
2004)
Motrin, Advil, Ibuprofin are short acting (3-6 hours)
Aleve, Naprosyn are long acting (8-12 hours)
Potential side effects include:
Stomach ulcers
Reversible reduction in kidney function (increased
creatinine noted on blood test)
Arthritis from TIP improves after TIP is stopped and
normal testosterone is restored (Intermittent Therapy)
34
35. Osteoporosis and Fractures
Smith, Cancer 93:789,2003
33% of all hip fractures are in men. Mortality is high
QCT is more sensitive than DEXA for measuring
density
Median time from
starting TIP to any
fracture is 22 months.
After 5 years of TIP, 38%
of untreated men will
have developed a bone
fracture (mostly spine) 35
36. Preventing Bone Fractures
in Men Taking TIP
Calcium 1200mg/day
Evening administration increases effectiveness
Vitamin D 1000 IU/day
Need to check blood levels after 3 months
Bisphosphonates
Oral: Fosamax, Actonel, Boniva
Intravenous: Aredia, Zometa
Denosumab: Xgeva and Prolia
Monthly dosing delays bone mets (Smith, Lancet 2011)
36
37. Change in Bone Density while on TIP:
Treatment Outcome Relative to Placebo
Treatment Difference in Reference
Bone Density
Fosamax 70 mg +5.1% after Greenspan, Ann. Int.
Med.
weekly 1 year 146:416, 2007
Zometa 4 mg IV +7.8% after Smith J. Urol
169:2008, 2003
Q 3 mo. 1 year
Prolia 60 mg IM + 4.7% after Smith, NEJM
361:745, 2009
Q 6 months 1 year
37
38. Side Effects of Bone Medications
Brief chills and muscle aches (with non-oral agents)
More common during 1st treatment; less thereafter
Decadron administration sharply curtails chills and
aches
Stomach and esophageal ulcers
Only with oral medications
Osteonecrosis of the jaw
Closely associated with bigger lifetime dosage of the
non-oral agents
Slowly reverses when treatment is stopped
38
40. Loss of Libido
Loss of libido with Lupron is age dependent:
Over age 70: 90% of men, over 60: 80%, over 50: 70%
Casodex alone: about 50%
“Hey, feet off the table please.”
Proscar/Avodart: 20%
Men can still perform
with Viagra (Scholz, J. Urol
161:1914, 1999)
Regular Cialis should be
administered to prevent
erectile atrophy (Mulhall)
40
41. Breast Tenderness and Enlargement
Much more common with anti-androgen monotherapy
Enlargement is preventable, but not reversible!
Tamoxifen: Inexpensive and effective but estrogenic
activity suggests a blood clot risk (Staiman, Urology 50:929, 1997)
Aromitase inhibitors: Lower estrogen, so no risk of clots
Femara
(Smith, Cancer 95:1864, 2002)
Arimidex
(Santen, Cancer 92:2095, 2001)
Prophylactic radiation
(Widmark, Urology 61:145, 2003)
41
42. Hot Flashes
Depo-Provera® shot 400 mg
91% improved; 46% total resolution
(Langenstoer, J. Urol 174-642, 2005)
Vivelle Dot® 0.1 mg estrogen patch
83% improved; 42% had breast swelling
(Gerber Urology 55:97 2000)
Effexor® 12.5 mg twice a day (Quella, J. Urol 162:98, 1999)
63% of men had more than 50% decrease in hot flashes
Acupuncture 30’ twice weekly for two weeks then weekly
for ten weeks (Frisk, E. Urol 55:156, 2009)
78% of men improved; benefit maintained for 9 months
42
43. Mood Swings
Normally, testosterone dampens
emotional response in men
Low testosterone can cause:
Moodiness, Depression & Anger
Sadness & Crying
Euphoria & Joy
Men’s reaction to their increased emotionality varies
For men who feel out of control or are depressed, small
doses of Zoloft, Effexor, Celexa etc. are very effective
43
45. Anemia: Low Red Blood Cells
Symptoms: Fatigue, short of breath, fast heart rate
Lab: Low hemoglobin (Hgb. < 10)
Potential Causes:
Low testosterone
Cancer invading marrow
Chemotherapy
Radiation
Diagnosis & Treatment:
Check B12, thyroid and iron levels*
Subcutaneous injection of Aranesp, Procrit or Epogen
Blood transfusion
*Iron is rarely of value and may be deleterious 45
47. Situational or Hormonally Induced
Depression May Respond to
Medication
Common antidepressants are safe enough to be
prescribed by a family doctor or an oncologist
If mood fails to improve within 30-60 days consider
consultation with a psychiatrist as new agents and
combinations of agents may be more effective
Commonly prescribed antidepressants are:
Celexa, Zoloft, Lexapro, Effexor, Cymbalta,
Paxil, Wellbutrin and Prozac
47
48. Mental Testing of Cognitive Effects
Compared to Healthy Normal People
Combination TIP (Higano, J. Urol 170:188, 2003)
Decreased spatial ability; improved verbal memory
Lupron vs. Climera® patches (Beer, J. Urol 175:130, 2006)
Lupron decreased immediate and delayed verbal memory
compared to controls. Mental function was slowed
Estrogen patches improved verbal memory performance
Various Types of TIP for 1.8 years (Joly, J. Urol 176:2443, 2006)
Lower energy, worse bladder control, less sexual function
Results of cognitive testing and patient-reported mental
function were similar to controls
48
49. Metformin Lowers Insulin
TIP is associated with weight
gain, fat accumulation and
increased insulin (Basaria,
Cancer 106:581, 2006)
Elevated insulin associated with
increased risk of prostate cancer
recurrence (Lehrer, The Prostate
50:1, 2002)
Diabetics taking Metfomin are
44% less likely to be diagnosed
with prostate cancer (Wright,
Cancer Cause Control
20:1617,2009)
49
51. Some Retrospective Studies Have
Implicated TIP as Exacerbating Heart
Disease
Certainly TIP is associated with weight gain and weight
gain can lead to insulin resistance and accelerated
atherosclerosis.
However, retrospective trials evaluating cardiovascular
events have problems:
TIP is often selected for weaker, more feeble men
TIP prolongs life placing men at risk for cardiovascular
events for a longer period of time
Additionally, there are some reasons to consider that
lower testosterone would improve survival
Women outlive men by an average of 4 years
Also, recall the results of the randomized Studer trial (slide
#22) that showed reduced cardiovascular mortality
51
52. What About Testosterone Causing Heart Problems?
Basaria, NEJM 363:109, 2010
Trial Design:
209 men mean age 74 and testosterone averaging 243 were
randomized to testosterone gel vs. placebo
Many had previous HTN, diabetes, obesity and high cholesterol
Results:
With treatment, testosterone increased to 574 in the treated men
Higher testosterone did improve strength and energy levels
Hemoglobin levels increased in the testosterone group
Unanticipated Toxicity:
Within 6 months of starting the trial 9 men in the testo group had
serious cardiovascular events: 3 heart attacks, 3 hospitalizations
for chest pain or heart failure, two men with fainting spells and
one stroke. The trial was stopped early
In the placebo group only one man suffered a fainting spell
52
53. Meta-Analysis: TIP and Heart Disease
The Final Word on this Hot Topic!
Nguyen, JAMA 306:2359, 2011
Analysis of 4100 patients evaluated in 8 randomized
prospective trials comparing men receiving TIP vs.
those not receiving TIP
Cardiovascular mortality was found to be equivalent in
both groups
Prostate cancer specific and overall mortality was
reduced in the groups receiving TIP
Practically every published study implicating TIP as a
possible cause for heart disease is retrospective
53
54. TIP and Heart Disease
The Pros and the Cons:
The “Con”
Men who are overweight are prone to insulin
resistance, higher blood sugar levels should think twice
before starting TIP
The “Pro”
Men on TIP develop a mild anemia, i.e., lower
hemoglobin levels. This puts less strain on the heart
and slightly lowers the risk of heart attacks and strokes
Bottom Line, “Whether taking TIP or not—Keep your
weight under control!”
54
55. Conclusions
Testosterone blockade has powerful anti-cancer
effects
Treatment with TIP needs to be individualized:
Insufficient treatment of men with High-Risk can lead
to increased mortality from prostate cancer
Over-aggressive treatment in Low or Intermediate-Risk
incurs unnecessary side effects without prolonging life
Mechanisms for reducing side effects include:
Intermittent therapy
Anti-androgen monotherapy
Supportive medications, diet and exercise
Men taking TIP who have major heart problems and
are overweight are probably chancing an exacerbation
of their heart problems
55
