Progress in the Treatment of Locally Advanced Prostate Cancer

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Progress in the Treatment of Locally Advanced
Prostate Cancer

• Robert Share MD
• Radiation Oncologist
• Tinley Cancer Care Center

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Prostate Cancer in the United States in 2002

• Approx. 189,000 diagnosed --1 case every 3
  minutes
• 30,200 men died --1 death every 17 minutes

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Prostate Cancer Risk

• 1/6 lifetime risk
• Risk doubles if close relative has prostate
  cancer
• Five-fold increase if two relatives diagnosed
  with prostate cancer
• 97 risk if three close relatives have the
  diagnosis

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Prostate Cancer Risk cont.

• Birth 39 y/o 1 in 10,000
• 40 59 1 in 45
• 60 79 1 in 7

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Prostate Cancer Mortality
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Diagnosis

• PSA
• Digital Rectal Exam (DRE)
• Symptoms

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Prostate Cancer Risk Factors

• T-Stage
• T1c--Not palpable
• T2a--Nodule
• T2b--Nodule ½ single
• T2c--Nodules in both lobes
• T3--Extraprostatic spread

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Prostate Cancer T-Stage
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Prostate Cancer Risks cont.

• PSA level 0 to infinity
• Gleasons Score A number that describes the
  potential for a prostate cancer to grow locally
  and to spread to distant sites.
• 2-6
• 7
• 8-10

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Prostate Cancer Risk Categories

• Low Risk
• -PSA
• Gleason Score
• Intermediate Risk
• -PSA 10ng/ml and
• Gleason Score 7, T2b-T2c
• High Risk
• -PSA 20ng/ml
• Gleason Score 8-10, T3

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Treatment Options

• Watchful Waiting
• Radical Prostatectomy
• External Beam Radiation Therapy (EBRT)
• Prostate Seed Implant (PSI)
• EBRT PSI
• Androgen Suppression

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Radical Prostatectomy Outcomes

• Freedland, et. al. Pre-op PSA PSA Free
  Survival--6yr
• Normal 78 10 to 20ng/ml 50
• 20ng/ml 30
• Age adjusted

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Radiotherapy vs. Surgery

• Risk Group RT Sx
• Low 92 98 pNS
• Intermediate 81 77 pNS
• High 53 51 pNS
• DAmico, et.al. Int. J. Radiat. Oncol. Biol.
  Phys. 1997.

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Radiation Therapy Treatment
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Goals of Radiation Therapy

• Sterilize gross and microscopic cancerous tissue
• Minimize damage to non-cancer bearing tissues

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Dose Response Data

• Is more better?

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p
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Freedom from Failure by PSAUpdate 2002
PSA PSA 10 ng/ml
78 Gy
78 Gy
70 Gy
70 Gy
p 0.46
p 0.012
2002
Pollack IJROBP 2002
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High Risk Prostate Cancer

• Roadblocks to Survival
• 1. Persistent local/regional disease
• 2. Presence of occult metastases

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Androgen Supression Therapy

• Testosterone promotes cell proliferation and
  growth
• Absence of testosterone leads to increase in
  prostate cell death
• Decrease in number of cancer cells targeted by
  radiation
• Potential elimination of micrometastases

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Prostate Hormone Pathways
Hypothalamus
x
GNRH
CRF
LHRH Agonists
x
Anterior Pituitary
DES
Testes
Adrenal
x
x
Cholesterol
Orchiectomy
Aminoglutethimide Sprironolactone
Testosterone
Testosterone
(600ng/dl)
(50ng/dl)
Testosterone
5-alpha Reductase
Dihydrotestosterone
x
Flutamide Biclutamide
Prostate
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Androgen Suppression Therapy (AST) for Prostate
Cancer

• 1988-Zagars et. al. 15yr. Follow-up
• 78 pts. Bulky (T3,T4) tumors
• Randomized to RT alone vs. RT DES
• DFS 63 vs. 35
• OS No difference

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AST for Prostate Ca. cont.

• RTOG 85-31, 1987
• 945 patients, T3 or LN (), 10yr. follow-up
• Randomized to RT AST vs. AST at relapse
• Survival 49 vs. 39
• Local Failure 23 vs. 38
• Distant Failure 24 vs. 39
• Death from prostate ca. 16 vs. 39

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AST for Prostate Ca. cont.

• RTOG 86-10
• 456 patients, Bulky (5x5cm, T2b-T3) or LN
• Arm 1 AST x 2 months RT AST
• Arm 2 RT alone (70Gy)
• Local Failure 32 vs. 43
• Distant Failure 35 vs. 46
• Disease-free Survival 22 vs. 8
• Overall Survival 51 vs. 41 (NS)

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AST for Prostate Ca. cont.

• RTOG 92-02
• 1520 patients, T2b-T4
• Arm 1 4 months AST prior to RT
• Arm 2 Same as Arm 1, plus 2 years AST
• Disease Free Survival 34 vs. 54
• Local Failure 13 vs. 6
• Distant Failure 17 vs. 11
• Death from prostate ca. 13 vs. 8 (p.07)
• Overall Survival 79 vs. 78

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AST for Prostate Ca. cont.

• RTOG 92-02 cont.
• Subgroup analysis Gleason 8-10
• Overall Survival 69 vs. 80
• Disease-free Survival 78 vs. 90
• Both statistically significant.

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AST for Prostate Ca. cont.

• EORTC (Bolla)
• Long Term AST (3 years) RT vs. RT alone
• 415 patients, T3, T4 or high-grade T1, T2
• Local Control 97 vs. 79
• Distant Failure 25 vs. 56
• Disease Free Survival 75 vs. 40
• Overall Survival 78 vs. 62

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AST for Prostate Ca. cont.

• RTOG 94-13 Pelvic RT and AST
• 1294 patients, T2C-T4 or 15 risk LNs
• Median PSA22.8ng/ml, Gleason 7-10 (72)
• Treatment Options
• 1. Whole Pelvis RT (WPRT) AST
• 2. Prostate Only RT AST
• Note AST started 2 months prior to RT and
  continued through RT.

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AST for Prostate Ca. cont.

• RTOG 94-13 cont.
• Results
• Progression Free Survival
• --WPRT AST 61
• --All others 48
• Overall Survival
• --WPRT AST 88
• --All others 82
• Not significant

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AST for Prostate Ca. cont.

• DAmico Study Short Term AST and RT
• 206 patients, (T2a,T2b58)
• Gleason 774, Median PSA11ng/ml
• Arm 1 RT only
• Arm 2 RT plus 6 months of AST

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AST for Prostate Ca. cont.

• DAmico Study cont.
• Results
• Failure Free Survival 57 vs. 82
• Overall Survival 78 vs. 88

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AST for Prostate Ca. cont.

• Consequences of Androgen Suppression
• Erectile dysfunction and loss of sexual interest
• Gynecomastia and breast pain
• Loss of muscle mass and physical vitality
• Liver toxicity
• Osteoporosis

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Individualized AST

• Case 1
• 72 year-old gentleman
• PSA 6.2ng/ml
• Gleason score (33)
• T2c
• Prostate only radiation
• 4 months AST

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Individualized AST

• Case 2
• 70 year-old gentleman
• PSA 5.0 ng/ml
• Gleason score (43)
• T1c
• Prostate only RT
• 6 months AST

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Individualized AST

• Case 3
• 65 year-old gentleman
• PSA 12 ng/ml
• Gleason score (43)
• T2a
• Whole pelvis RT plus prostate boost
• 6 months AST

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Individualized AST

• Case 4
• 75 year-old gentleman
• PSA 9 ng/ml
• Gleason score (44)
• T2b
• Whole pelvis RT plus prostate boost
• 24 months AST

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Future Directions

• RTOG -0521 A Phase III Protocol of Androgen
  Suppression (AS) and 3DCRT/IMRT vs. AS and
  3D/IMRT Followed by Chemotherapy with Docetaxel
  and Prednisone for Localized, High-Risk Prostate
  Cancer
• Hormone Suppression and Radiation Therapy for 6
  months with/without Docetaxel for High Risk
  Prostate Cancer

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Future Directions

• Phase II Study of Neoadjuvant Paclitaxel,
  Estramustine, Carboplatin, and Androgen Ablation
  Followed by Radiotherapy in Patients with
  Poor-Prognosis Locally Advanced Prostate Cancer
• CSP 553 Chemotherapy After Prostatectomy (CAP)
  for High Risk Prostate Carcinoma A Phase III
  Randomized Study

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Future Directions

• Phase III Randomized Study of Adjuvant Androgen
  Deprivation Therapy with or without Mitoxantrone
  and Prednisone after Radical Prostatectomy in
  Patients with High-Risk Adenocarcinoma of the
  Prostate
• Study of Peri-Operative Docetaxel plus
  Laparscopic Radical Prostatectomy in Prostate
  Cancer Patients

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Conclusions

• Mortality rate of prostate cancer is declining.
• Early stage disease may be adequately treated
  with local modalities alone, either radiation or
  surgery.
• Locally advanced disease requires high doses of
  radiation for local control..
• Androgen Suppression Therapy required in locally
  advanced prostate cancer to improve local control
  and decrease distant metastases.
• Systemic chemotherapy and AST likely treatment in
  the future for high-risk patients.

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