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Management of locally advanced & metastatic prostate cancer


Management of locally advanced & metastatic prostate cancer Dr. Purvish. M. Parikh MD, DNB, PhD, FICP Professor & Head Department of Medical Oncology – PowerPoint PPT presentation

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Title: Management of locally advanced & metastatic prostate cancer

Management of locally advanced metastatic
prostate cancer
  • Dr. Purvish. M. Parikh
  • MD, DNB, PhD, FICP
  • Professor Head
  • Department of Medical Oncology
  • Tata Memorial Hospital

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

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
Locally advanced prostate cancer
Locally advanced prostate cancer Clinical
Natural history of clinical T3 prostate cancer
  • Prostate cancer is inherently biologically
  • Patients have been staged differently in various

Johansson et al, JAMA,1997227467-471
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
Results of RP in T3 tumors
  • RP alone is unlikely to cure most men with cT3
  • 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

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
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

Locally advanced prostate cancerHormone
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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.
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.

Overall survival for patients with Gleason scores
8 to 10
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
  • 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.
  • 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 )

Management of hormone sensitive metastatic
prostate cancer
Goals of treatment
  • Prolonging survival
  • Preventing or delaying symptoms due to disease
  • Improving and maintaining QOL
  • Reducing treatment related morbidity.

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

Physiology of androgens
  • 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?

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,
  • 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,
  • Diethystilbesterol
  • Convenient oral route
  • Risk of thrombosis cardiovascular
    complications, edema, dyspnea, cramps

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
  • Leuprolide (hazard ratio, 1.0994 CI, 0.207 to
  • Buserelin (hazard ratio, 1.1315 CI, 0.533 to
  • Goserelin (hazard ratio, 1.1172 CI, 0.898 to
  • 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
  • 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.

Are antiandrogens as effective as other
castration therapies?
  • Antiandrogens
  • Nonsteroidal (Flutamide,Bicalutamide, Nilutamide)
  • Side effects-Gynecomastia, breast pain,
  • 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)

Is combined androgen blockade better than
castration alone?
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
  • Cancer-free survival was improved only at 5 years
  • Adverse events occurred more frequently with CAB
    and resulted in drug withdrawal in 10.
  • Quality of life was better with orchiectomy alone
  • MAB produces a modest overall and cancer-specific
    survival at 5 years but is associated with
    increased adverse events and reduced quality of

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

Metaanalysis of CAB-2
  • Metaanalysis of individual patient data
  • 27 RCT, n8275 men (Metastatic-88, Locally
  • 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
  • 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
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  • 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
  • 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

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.
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.
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

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.

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

Management of Hormone Refractory Prostate
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
  • 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
  • Is the patient symptomatic?
  • What are the sites number of metastasis?
  • Is there a risk of Pathologic or cord
  • What are the comorbidities?
  • Is the organ function compromised?

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

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

Second line hormonal agents
  • For patients who have received monotherapy
    (LHRHa/orchidectomy), addition of an antiandrogen
    is useful.
  • Patients may respond differentially to different
  • 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

Role of chemotherapy
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

Chemotherapy regimens in HRPC
Role of Docetaxel
Grade 3 or 4 neutropenic fevers, nausea and
vomiting , and cardiovascular events were more
common among patients receiving docetaxel and
Petrylak et al NEJM, 351151513-1520
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Role of Docetaxel-2
Tannock et al NEJM, 351151502-1513
Tannock et al NEJM, 351151502-1513
Tannock et al NEJM, 351151502-1513
  • Goal of chemotherapy for hormone refractory
    prostate cancer mainly to relieve symptoms
  • Modest survival advantages have now been shown
    with some regiments

  • Incidence of bone metastases 6575
  • Classification osteolytic, osteoblastic, or
  • 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
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
  • Reduce bone-resorbing cytokine production
  • Inhibit tumor-cell invasion and adhesion to bone
  • Induce apoptosis in tumor-cell lines
  • May inhibit tumor-cell secretion of growth
    factors that stimulate osteoblasts
  • Inhibit number and activity of osteoblasts

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
Time to first skeletal-related event (SRE)
Saad et al, JNCI,2002941458-1468
Skeletal morbidity rate
Saad et al, JNCI,2002941458-1468
Change in composite pain score
Saad et al, JNCI,2002941458-1468
Palliative measures
  • External beam RT (Local/Hemibody irradiation)
  • Painful bony metastases,
  • Spinal cord/nerve root compression
  • Radio isotopes (Strontium-89 and Sumarium-153,
  • ? -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

Newer agents
  • Satraplatin
  • 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