Management of locally advanced & metastatic prostate cancer

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Management of locally advanced metastatic
prostate cancer

• Dr. Purvish. M. Parikh
• MD, DNB, PhD, FICP
• Professor Head
• Department of Medical Oncology
• Tata Memorial Hospital

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Prostate cancer Epidemiology

• Most commonly diagnosed cancer in men after 50
  Life time risk -30 (microscopic) Risk of
  developing clinical disease -10
• Incidence 36 of all cancers in males
  -316000 new cases diagnosed -Mortality 40000
  deaths

Incidence 4.8 / 100000 pop / year (Chennai)
8.1 / 100000 pop / year
(Mumbai) 32000 new cases in 1999



1 increase in incidence every year
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Natural history
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Locally advanced prostate cancer
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Locally advanced prostate cancer Clinical
staging
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Natural history of clinical T3 prostate cancer

• Prostate cancer is inherently biologically
  heterogenous
• Patients have been staged differently in various
  studies

Johansson et al, JAMA,1997227467-471
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Management options Patterns of care

• Radical prostatectomy 15.8
• External beam radiotherapy 34.3
• Cryosurgery
• Combined modality treatments - 14.3
• Radical prostatectomy ADT
• External beam radiotherapy ADT
• Systemic therapy
• Hormonal therapy 20.2
• Chemotherapy
• No cancer treatment 15.5

Jones et al J Am Coll Surg,1995180545-554
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Results of RP in T3 tumors

• RP alone is unlikely to cure most men with cT3
  disease
• Upto 50 patients are found to have pelvic lymph
  node metastases at staging lymphadenectomy
• RP may have a role in selected patients with
  low/intermediate grade tumors

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Results of EBRT in T3 tumors

• EBRT is less morbid provides good local control
  OS benefit
• Outcomes different in Pre-PSA PSA era
• EBRT alone is unlikely to eradicate most locally
  advanced prostate cancers

Results of conventional EBRT in T3 prostate cancer
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Locally Advanced Prostate CancerModifications in
Radiation Therapy

• Increasing the relative integral dose
• Conformal radiation therapy
  
• Proton beam therapy
  
• Brachytherapy EBRT
  
• Intensity modulated radiation therapy
• Decreasing the volume of tumour prior to RT
• Hormonal therapy
• chemo cytoreduction
• Radiobiologic optimization
• Altered fractionation
  
• Use of radiosensitisers
• Neutron beam therapy

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Locally advanced prostate cancerHormone
Irradiation
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RTOG 92-02
Locally advanced prostate cancer (PC T2c-4) ,PSA
lt150 ng/mL. N 1554
goserelin and flutamide X 2 months
65-70Gy EBRT Prostate, 44-50 Gy EBRT Pelvic
nodes goserelin and flutamide X 2 months
24 months of goserelin (LTAD-RT)
No additional therapy (short-term STAD-RT)
Hanks GE,J Clin Oncol. 2003 Nov 121(21)3972-8.
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RTOG 92-02

• The LTAD-RT arm showed significant improvement in
  all efficacy end points except overall survival
  (OS 80.0 v 78.5 at 5 years, P .73).
• Tumors with Gleason scores of 8 to 10, the
  LTAD-RT arm had significantly better OS (81.0 v
  70.7, P .044).
• There was a small but significant increase in the
  frequency of late radiation grades 3, 4, and 5
  gastrointestinal toxicity ascribed to the LTAD-RT
  arm (2.6 v 1.2 at 5 years, P .037),
• CONCLUSION The RTOG 92-02 trial supports the
  addition of LT adjuvant AD to STAD with RT for
  T2c-4 PC.

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DFS
Overall survival for patients with Gleason scores
8 to 10
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Primary hormone therapy

• RP is often not done in patients with prostate
  cancer due to poor risk for surgery, patient's
  wish, or physician's recommendation.
• N 151 patients with T1b, T1c, T2a, T2b or T3a
  prostate cancer
• Group I received leuprorelin acetate depot, 3.75
  mg monthly
• Group II received LH-RHa with chlormadinone
  acetate (100 mg/day).
• At 12 weeks of treatment, 49 of the patients in
  both groups had a CR.
• Of the patients showing a partial response (PR)
  after 12 weeks of treatment, 25 in Group I and
  52 in Group II improved to CR 1 year later
  (plt0.05).
• Group II showed a longer progression-free
  survival (p lt0.05).
• PFS rates
• T2b- 62 (Group I) and 91 (Group II)
• T3- 43 (Group I) and 73 (Group II)
• Early primary hormone therapy is a reasonable
  treatment option for localized or locally
  advanced prostate cancer patients if radical
  prostatectomy was not scheduled.

Akaza H, Jpn J Clin Oncol. 2000 Mar30(3)131-6.
 
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• Adjuvant flutamide treatment improves DFS but
  does not improve median-term overall survival
  after radical prostatectomy for locally advanced,
  lymph node-negative prostate cancer.(Wirth MP,
  Eur Urol. 2004 Mar45(3)267-70 )

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Management of hormone sensitive metastatic
prostate cancer
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Goals of treatment

• Prolonging survival
• Preventing or delaying symptoms due to disease
  progression
• Improving and maintaining QOL
• Reducing treatment related morbidity.

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Treatment options

• Androgen Deprivation
• Bilateral orchiectomy
• LHRH analogues - Goserilin, Leoprolide etc.,
• Total androgen Blockade e.g..,adding flutamide
• Experimental options
• Intermittent androgen suppression
• Treatment of Local Symptoms
• "Channel" TURP.
• Prostatic Urethral stenting
• External Beam Radiotherapy

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Physiology of androgens
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Questions!

• What are the standard initial treatment options?
• Are antiandrogens as effective as other
  castration therapies?
• Is combined androgen blockade better than
  castration alone
• Is early androgen deprivation therapy better than
  deferred ADT?
• Is intermittent ADT better than continuous ADT?

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What are the standard initial treatment options?

• Orchidectomy
• Simple cost effective
• Quick palliation
• Compliance not a problem
• Nonreversible
• Carries significant psychological burden
• Risk-Surgical complications
• Side effects-Vasoactive symptoms, weight gain,
  mood lability, gynecomastia, fatigue, loss of
  libido, cognitive changes, osteopenia,
  hypercholesterolemia
• LHRH analogues
• Costly
• Risk of tumor flare
• Potentially reversible
• Convenient
• No psychological burden
• Side effects-Vasoactive symptoms, weight gain,
  mood lability, gynecomastia, fatigue, loss of
  libido, cognitive changes, osteopenia,
  hypercholesterolemia
• Diethystilbesterol
• Convenient oral route
• Risk of thrombosis cardiovascular
  complications, edema, dyspnea, cramps

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Single-Therapy Androgen Suppression in Men with
Advanced Prostate Cancer A Systematic Review
and Meta-Analysis

• 24 RCT involving 6600 patients, (1966 - 1998)
• Results
• LHRHa are equivalent to orchiectomy (10 trials,
  n1908, HR- 1.262, 95 CI, 0.915-1.386).
• There was no difference in OS among the LHRH
  analogues
• Leuprolide (hazard ratio, 1.0994 CI, 0.207 to
  5.835)
• Buserelin (hazard ratio, 1.1315 CI, 0.533 to
  2.404)
• Goserelin (hazard ratio, 1.1172 CI, 0.898 to
  1.390).
• Nonsteroidal antiandrogens are associated with
  lower OS( 8 trials, 2717 patients, HR 1.2158 CI,
  0.988 to 1.496).
• Treatment withdrawals are less frequent with
  LHRHa (0 to 4) than with nonsteroidal
  antiandrogens (4 to 10).

Seidenfield et al Annals of Intern Med 2000,
132 7 566-577
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• Conclusions
• Survival after therapy with an LHRH agonist was
  equivalent to that after orchiectomy.
• No evidence shows a difference in effectiveness
  among the LHRH agonists.
• Survival rates may be somewhat lower if a
  nonsteroidal antiandrogen is used as monotherapy.

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Are antiandrogens as effective as other
castration therapies?

• Antiandrogens
• Nonsteroidal (Flutamide,Bicalutamide, Nilutamide)
• Side effects-Gynecomastia, breast pain,
  hepatotoxicity
• Steroidal (Cyproterone acetate)
• Side effects-Hepatotoxicity, edema, weight gain
• Monotherapy with nonsteroidal antiandrogens has
  equivalent survival to orchidectomy but with less
  toxicity (Seidenfield et al. AIM, 2000)
• Steroidal aniandrogens have an inferior TTP as
  compared to LHRHa (Thorpe et al, Eur Uro,1996)

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Is combined androgen blockade better than
castration alone?
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Is combined androgen blockade better than
castration alone?

• N1387 patients (Orch Flutamide group-700,Orch
  Placebo group-687)
• Patients receiving flutamide had greater rates
  of diarrhea and anemia .
• There was no significant difference between the
  two groups in overall survival (P0.14).
• HR for flutamide as compared with placebo was
  0.91 (90 CI- 0.81-1.01).
• Flutamide was not associated with enhanced
  benefit in patients with minimal disease.
• Conclusions The addition of flutamide to
  bilateral orchiectomy does not result in a
  clinically meaningful improvement in survival
  among patients with metastatic prostate cancer.

Eisenberger et al, NEJM,1998,3391036-1042
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Metaanalysis of CAB-1

• 20 trials (6,320 patients).
• The pooled OR for overall survival was
• 1.03 (95 CI0.85 to 1.25) _at_ 1year
• 1.16 (95 CI1.00 to 1.33), _at_ 2 years
• 1.29 (95 CI1.11 to 1.50) _at_ 5 years
• OS was only significant at 5 years.
• PFS was improved only at 1 year follow-up
  (OR1.38)
• Cancer-free survival was improved only at 5 years
  (OR1.22).
• Adverse events occurred more frequently with CAB
  and resulted in drug withdrawal in 10.
• Quality of life was better with orchiectomy alone
  Conclusion
• MAB produces a modest overall and cancer-specific
  survival at 5 years but is associated with
  increased adverse events and reduced quality of
  life.

Schmitt B et al. Cochrane Reviews 1999, Issue 2.

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Metaanalysis of CAB-2

• Metaanalysis of individual patient data
• 27 RCT, n8275 men (Metastatic-88, Locally
  advanced-12
• Results
• 5932 (72) men died 80 deaths attributed to
  prostate cancer.
• 5-year survival was 254 with MAB vs 236 with
  AS alone (2p011).
• The results for cyproterone appeared slightly
  unfavourable to MAB (5-year survival 154 MAB
  vs 181 AS alone 2p004)
• The results for nilutamide and flutamide appeared
  slightly favourable (5-year survival 276 MAB
  vs 247 AS alone 2p0005).
• Non-prostate-cancer deaths accounted for some of
  the apparently adverse effects of cyproterone
  acetate.
• Conclusion
• In advanced prostate cancer, addition of an
  antiandrogen to AS improved the 5-year survival
  by about 2 or 3 (range 0-5. )

PCTC meta-analysis .Lancet 2000, 355
92141491-1498
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Conclusions-CAB

• The findings range from no benefit (17 studies)
  to an estimated 3.7-7 months survival
  improvement(3 studies)
• In metaanalysis, CAB offers a stattistically
  significant but clinically questionable
  improvement in survival over orchidectomy or
  LHRHa monotherapy
• Benefit of CAB is limited to patients taking only
  NSAAs
• Benefit of CAB is seen only after 5 years
• GI (diarrhea, pain) ophthalmologic side effects
  are more with CAB
• CAB results in 1 million per quality adjusted
  life year over orchidectomy alone

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Early versus Late ADT

• 4 trials (n2,167)
• All trials were conducted prior to use of PSA
  testing were heterogenous
• All studies found PFS was consistently better in
  the early intervention group at all time points.

Wilt T, et al Cochrane Reviews 2001, Issue 4.
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OS
PFS
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Early versus Late ADT

• The pooled estimate for the difference in OS
  survival favored early ADT but was significant
  only at 10 yrs
• The pooled estimate of prostate cancer specific
  survival at 2, 5, and 10 years favored early
  therapy but were not statistically different.
• The risk differences at 2, 5, and 10 years were
  2.7, 5.8, and 4.6.

Wilt T, et al Cochrane Reviews 2001, Issue 4.
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Timing of ADTConclusions

• The evidence from RCTs is limited by the
• variability in study design,
• stage of cancer and
• subjects enrolled,
• interventions utilized,
• definitions and reporting of outcomes and
• Lack of PSA testing for diagnosis monitoring
• Additional studies are required to evaluate more
  definitively the efficacy and adverse effects of
  early ADT
• In particular trials should evaluate the impact
  of early ADT in patients with rising PSA syndrome

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Timing of ADTConclusions

• Early ADT offers a statistically significant
  benefit in PFS OS
• Early ADT reduces disease progression and
  complications due to progression.
• There was no statistically significant difference
  in prostate cancer specific survival
• Early ADT leads to higher costs
• Treatment is most cost effective when started
  after the onset of symptoms
• Complications due to disease progression are more
  frequent in the deferred treatment group.
• Adverse events due to treatment are more frequent
  in the early treatment group.

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Is intermittent ADT better than continuous ADT?

• Rationale
• Prolonged ADT may cause androgen independence
• Side effects are lesser with intermittent ADT
• No prospective randomized trials
• No guidelines for starting stopping therapy
• No data available on testosterone levels, QOL,
  BMD sexual function
• Two phase III studies are underway

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Management of Hormone Refractory Prostate
Cancer
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Hormone refractory prostate carcinoma

• Definition Disease progression despite
  castrate serum levels of testosterone
• Progression is defined by
• Increase in size of measurable lesions
• Appearance of new measurable lesions
• Increase in PSA gt50 on at least 2 consecutive
  measurements
• Increase in pain associated with new bony lesions
• Duration of response
• Limited or no metastases-5 years
• Metastatic disease-2 years
• Median survival approximately 1 year

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Considerations in the management of HRPC

• Is the patients functionally castrated?
• What are the previous therapies?
• What was the response to previous therapy?
• What was the duration of response
• What is the current pace of the disease?
• Is the disease localized or metastatic at
  recurrence?
• Is the patient symptomatic?
• What are the sites number of metastasis?
• Is there a risk of Pathologic or cord
  compression?
• What are the comorbidities?
• Is the organ function compromised?

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Management Options in HRPC

• Observation
• Withdrawl therapies
• Second line hormonal agents
• Estrogenic compounds-DES, Fosfetrol
• Antiandrogens-Bicalutamide, Flutamide, Nilutamide
• Adrenal suppressants-Ketoconazole,
  Aminoglutethimide
• Glucocorticoids-Prednisone, Dexamethasone,
  Hydrocortisone
• Chemotherapy
• For skeletal metastases
• Bisphosphonates
• External beam radiotherapy
• Bone seeking radiopharmaceuticals-Sumarium153,
  Strontium89
• Adjunctive therapies
• Pain management
• Radiofrequency ablation
• Cryotherapy
• Investigational therapies

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Antiandrogen withdrawl

• Preferred for patients who are using
  antiandrogens or CAB
• Withdrawl responses can be seen with
• Nonsteroidal antiandrogens
• Diethylstilbesterol
• Megestrol acetate
• Estramustine
• Ketoconazole
• Response rates 20
• Decline in PSA level
• Occassional radiographic responses
• Expected timing of response
• Flutamide-4 weeks (Half life of 6 hours)
• Bicalutamide-8 weeks (Half life of 6 days)
• Response duration 4-6 months
• Continuation of LHRHa indefinitely despite
  relapse may be beneficial

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Second line hormonal agents

• For patients who have received monotherapy
  (LHRHa/orchidectomy), addition of an antiandrogen
  is useful.
• Patients may respond differentially to different
  antiandrogens
• No major symtomatic relief
• More beneficial in
• asymptomatic patients
• biochemical failures
• Effects are short lived
• median duration of response- 2-6 months
• Combining second line agents with AA does not
  confer any benefit therefore should be used
  sequentially

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Role of chemotherapy
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Role of chemotherapy in HRPC

• Until 1990, chemotherapy was considered to have
  no role in the management of HRPC
• Active agents
• Taxanes-Docetaxel, Paclitaxel
• Mitoxantone
• Estramustine
• Adriamycin
• Vinorelbine
• Carboplatin
• Mitoxantrone is FDA approved for use in HRPC for
  palliation. It does not confer a survival benefit

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Chemotherapy regimens in HRPC
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Role of Docetaxel
P0.02
Plt0.001
Plt0.001
P0.30
Grade 3 or 4 neutropenic fevers, nausea and
vomiting , and cardiovascular events were more
common among patients receiving docetaxel and
estramustine.
Petrylak et al NEJM, 351151513-1520
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Role of Docetaxel-2
Plt0.001
P0.01
P0.005
Tannock et al NEJM, 351151502-1513
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Tannock et al NEJM, 351151502-1513
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Tannock et al NEJM, 351151502-1513
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Conclusions

• Goal of chemotherapy for hormone refractory
  prostate cancer mainly to relieve symptoms
• Modest survival advantages have now been shown
  with some regiments

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Bisphosphonates

• Incidence of bone metastases 6575
• Classification osteolytic, osteoblastic, or
  combination/mixed
• Etiology activation of osteoclasts and
  osteoblasts by soluble mediators released by
  prostate tumor cells metastasized to bone
• Treatment with a LHRHa decreases BMD and
  increases the risk of fracture in men with
  prostate cancer.
• Pamidronate has been shown to prevent bone loss
  in this group of patients.

Smith et al NEJM, 2001,34513948-955
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Rationale for using bisphosphonates

• Preferentially bind to bone surfaces undergoing
  active remodeling
• Inhibit osteoclast maturation and suppress
  osteoclast function
• Inhibit osteoclast recruitment to site of bone
  resorption
• Reduce bone-resorbing cytokine production
• Inhibit tumor-cell invasion and adhesion to bone
  matrix
• Induce apoptosis in tumor-cell lines
• May inhibit tumor-cell secretion of growth
  factors that stimulate osteoblasts
• Inhibit number and activity of osteoblasts

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Role of bisphosphonates

• Randomized, double-blind placebo-controlled trial
  
• Randomization to
• Intravenous Zolendronic acid 4 mg (n214)
• Intravenous Zolendronic acid 8 mg (n221)
• Placebo (n208)

Saad et al, JNCI,2002941458-1468
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Time to first skeletal-related event (SRE)
Saad et al, JNCI,2002941458-1468
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Skeletal morbidity rate
Saad et al, JNCI,2002941458-1468
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Change in composite pain score
Saad et al, JNCI,2002941458-1468
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Palliative measures

• External beam RT (Local/Hemibody irradiation)
• Painful bony metastases,
• Spinal cord/nerve root compression
• Radio isotopes (Strontium-89 and Sumarium-153,
  Rhenium-188)
• ? -emitting isotopes which can improve bone pain
  
• Administered as a single dose
• Response rate 35-89
• Duration of response-3-12 months
• Flare can occur in upto 23 of patients
• More effective in combination with EBRT(Porter
  etal , IJROBP,1993)
• Anticholinergics
• Limited TURP for obstruction
• Radiofrequency ablation
• Cryosurgery
• Chemoembolization

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Newer agents

• Satraplatin
• PC-SPECS
• Panzem (2-methoxyestradiol)
• Calcitriol
• Tyrosine kinase inhibitors
• Imatinib,
• Gefitinib
• Thalidomide
• Bortezomib
• VEGF inhibition-
• Bevacizumab,
• SU-5416
• Flavopiridol
• GM-CSF

• Exisulind
• Trastuzumab
• Epothilone B analog
• BMS-247550
• Somatostatin Analogue
• sms-D70
• Rhenium-188
• Endothelin-A Receptor Blockade
• Atrasentan
• Antisense Oligonucleotides
• ISIS 3521
• ISIS 5132
• Gene therapy