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SandlerPresentation Powered By Docstoc
					            Perspectives and
             Speculations on
           Chemotherapy for
             Prostate Cancer

               Howard Sandler


  Department of Radiation Oncology
The

             University of Michigan
   Disclosure

• Sanofi-Aventis
  – Research funding, DMC
    Prostate Cancer:Epidemiology
• Second most common cancer in men
• ~240,000 new cases will be diagnosed
  annually
• ~27,000 deaths resulting from PC will
  occur annually
• ~7% of diagnosed cases are metastatic
• 5-year survival rates are ~100% for local
  disease
      Prostate Cancer:Risk Factors

• Age: most cases occur in men ≥60 and the
  disease is rare in men ≤40
• Family History: risk increases if a man’s father
  (RR=2.2) or brother (RR=3.4) had prostate cancer
• Ethnicity: 61% more common in African
  Americans and 16% less common in Hispanic-
  Latinos compared with Caucasians
• Diet: a diet high in fat or meat may increase risk,
  while a diet high in fruits and vegetables may
  reduce risk
  “Chemo” in Prostate Cancer 2007

1. Role in HRPCa – Docetaxel + ?
2. Neoadjuvant Therapy
3. Adjuvant Therapy
4. Concurrent Therapy?
PCa:Mortality Risk After RP




              D’Amico et al. N Engl J Med. 2004;351:125
   PCa:Mortality Risk After RP
                       Hazard
    Variable            Ratio           P Value
PSA doubling time
(relative to ≥15 mo)
       <3.0 mo          27.5              <0.001

      3.0-8.9 mo        8.76              <0.001

      9.0-14.9 mo       2.44                0.09
Years from RP to
recurrence              3.53                0.002
      ≤3 vs >3 y
Gleason score
                        2.26                0.002
      ≥8 vs <8
                       Freedland et al. JAMA. 2005;294:433
  Role in HRPC

• TAX 327
• SWOG 9916
        Treatment for HRPC:TAX 327

                                                 Docetaxel (30 mg/m2) +
                                      n=334      Prednisone (5 mg bid)
                                   R                  qw for 6 wk,
                                   A               for up to 5 cycles
                                   N
                                   D
Patients (aged 36-92 y)   N=1006   O n=335       Docetaxel (75 mg/m2) +
                                                 Prednisone (5 mg bid)
with metastatic HRPC               M             q3w for up to 10 cycles
                                   I
                                   Z
                                   E
                                               Mitoxantrone (12 mg/m2) +
                                   D n=337     Prednisone (5 mg bid) q3w
                                                   for up to 10 cycles




                                   Tannock et al. N Engl J Med. 2004;351:1502
                    HRPC:TAX 327 Efficacy
                                    Overall Survival
          100
                                                      Docetaxel q3w (n=335)
                                                      Docetaxel qw (n=334)
           80
                                                      Mitoxantrone (n=337)
Percent




           60
                                                                    HR = 0.76 (P=0.009)
                                                                  Median survival = 18.9 mo
           40            Median survival = 16.5 mo

           20
                                                        HR = 0.91 (P=0.36)
                                                      Median survival = 17.4 mo
            0
                0    3   6    9     12    15    18    21   24    27    30     33
                                         Months

                                                Tannock et al. N Engl J Med. 2004;351:1502
                    HRPC:SWOG 9916
                                        Overall Survival

          100
                                          Hazard Ratio = 0.80 (P=0.02)

           80
Percent




           60
                                                              Docetaxel + estramustine
                                                          (n=338; median survival = 17.5 mo)
           40

                        Mitoxantrone + prednisone
           20       (n=336; median survival = 15.6 mo)


            0
                0                 12                24                36               48
                                                 Months

                                                     Petrylak et al. N Engl J Med. 2004;351:1513.
    HRPC:Novel Agents

   Agent                Target
  Calcitriol   Vitamin D nuclear receptor
Bevacizumab              VEGF
 Satraplatin   Nucleophilic groups in DNA
 Provenge           Immunotherapy
     Novel Agents + Docetaxel in
     HRPC:Rationale for Calcitriol
• Calcitriol is a high-dose oral formulation of 1,25-dihydroxy-
  cholecalciferol that targets the VDR
• VDR overexpression occurs in a wide range of neoplasms,
  and the antiproliferative action of VDR ligands has been
  demonstrated in many common human malignancies,
  including cancers of the prostate, breast, colon, and lung
• Calcitriol has demonstrated antiproliferative and
  proapoptotic activity in preclinical models of multiple cancer
  types, including prostate cancer
• In preclinical models, calcitriol has enhanced the activity of
  multiple anticancer chemotherapy agents
         Docetaxel + Calcitriol in
         HRPC: ASCENT Phase II

                                                     Placebo +
                                     R n=125         Docetaxel
                                     A         (36 mg/m2 on day 2 for
                                     N           3 wk of 4-wk cycle)
   Patients (aged 45-92 y)           D
                             N=250
   with chemotherapy-naive           O
       metastatic HRPC               M
                                                      Calcitriol
                                     I
                                               (45 µg weekly on day 1)
                                     Z n=125         + Docetaxel
                                     E          (36 mg/m2 on day 2 for
                                                  3 wk of 4 wk cycle)


• Primary end point: 6-month PSA response
• Secondary end point: Overall survival
                                     Docetaxel + Calcitriol in HRPC
                                     ASCENT
                          1.00
                                                                                         Docetaxel + Calcitriol
                                                                                         Docetaxel + placebo
Probability of survival




                          0.75


                                                  Median Survival
                          0.50
                                       Placebo 16.4 mo (observed)
                                       Calcitriol 23.5 mo (estimated)

                          0.25                         Hazard Ratio (95% CI)
                                       Unadjusted      0.70 (0.48-1.028), P=0.070
                                       Multivariate    0.67 (0.45-0.97), P=0.035
                            0
                                 0      12        24         36         48          60          72         84
                                                                  Weeks
      Docetaxel + Calcitriol in HRPC:
      ASCENT - Adverse Events
                     Grade 3/4 Toxicities (%)
                                     Docetaxel +
                  Docetaxel +
                                      Placebo
                Calcitriol (n=125)
                                      (n=125)
Neutropenia            10               8
Infection               8              13
Fatigue                 8               16
Hyperglycemia           6               12
Leukopenia              4                4
          Docetaxel + Calcitriol in
          HRPC:ASCENT-2

                                           R
                                                         Docetaxel
                                           A n=450
  • Ages ≥18                                              (q3w) +
                                           N            Prednisone
  • Prostate adenocarcinoma     Expected   D                (bid)
  • HRPC                         N=900     O
  • ECOG PS ≤2                             M
                                           I             Calcitriol +
  • No prior chemotherapy                    n=450
                                           Z             Docetaxel
    (except estramustine)                            (weekly for 1st 3 wk
                                           E
                                                       of 4 wk cycles)
                                           D


• Primary end point: Survival
   Novel Agents + Docetaxel in
   HRPC: Bevacizumab

• Bevacizumab demonstrates antiangiogenic
  activity through VEGF blockade
• VEGF expression is increased in both local
  and metastatic prostate cancer and serum
  level correlate with outcome
• Bevacizumab monotherapy active in
  multiple tumor types
          Docetaxel + Estramustine +
          Bevacizumab in HRPC:
          CALGB 90006 Phase II Trial
          Design

                                                   Docetaxel
                                              (70 mg/m2 on day 2) +
       Patients with progressive,                 Estramustine
                                    N=79     (280 mg tid days 1-5) +
       metastatic HRPC with no
       previous cytotoxic therapy                 Bevacizumab
                                               (15 mg/kg on day 2)
                                                       q3w




• End points: PSA response rate, toxicity.

Dexamethasone 8 mg was given bid on days 1-3, and warfarin 2 mg was
Picus et al. ASCO, 2003. Abstract 1578.
encouraged but not required.
           Docetaxel + Estramustine +
           Bevacizumab in HRPC:
           Efficacy and Adverse Events

     • Outcomes
          –53% partial response rate (n=17)
          –>50% PSA decline in 65% (n=20)
     • Adverse events
          –No major bleeds
          –One patient died of mesenteric vein
           thrombosis
Picus et al. ASCO, 2003. Abstract 1578.
          –One patient had a deep vein thrombosis
          –One patient had a stroke
           Novel Docetaxel-Based
           Combinations for HRPC:
           Phase II Studies
     Study           N               Regimen                PSA Decline >50%
  Goodin et                        Docetaxel +
                     40                                              66%
  al1                              Vinorelbine
                                  Docetaxel +
  Marur et al2       18                                              77%
                                  Capecitabine
  Borner et
                     37      Docetaxel + Gefitinib                   46%
  al3
  Thakkar et                      Docetaxel +
                     29                                              32%
  al4                             Gemcitabine

1. Goodin et al. Cancer Chemother Pharmacol. 2005;56:199; 2. Marur et al. ASCO, 2006.
Abstract 4634;
3. Borner et al. ASCO, 2006. Abstract 258; 4. Thakkar et al. ASCO, 2006. Abstract
14501.
    Ongoing Trials in HRPC:
    Docetaxel + ?

                                                     End
Study    Phase    Patients         Treatment        Points

                 Metastatic   Docetaxel + Placebo
CALGB
          III     HRPC                vs            OS*
 90401                            Docetaxel +       PFS
                 (656/1020)      Bevacizumab

                                 Docetaxel +
SWOG             Metastatic     Prednisone vs       OS*
S0421             HRPC
          III                    Docetaxel +
DAHRT
                                Prednisone +        PFS*
 Trial            (10/930)
                                 Atrasentan
   Novel Agents in HRPC:
   Rationale for Satraplatin

• Satraplatin is an oral platinum analog
• Satraplatin + prednisone as first-line
  therapy in HRPC significantly
  prolonged PFS compared with
  prednisone alone (small randomized
  phase II)
   Neoadjuvant Trials

• Generally preRP
• Rationale unclear
        Neoadjuvant Phase II Studies
   Study     N       Regimen          Efficacy            Toxicities
Hussain et   21      Docetaxel       CR=52%              Grade 3/4:
al1               70 mg/m2 day 1     PR=48%         Neutropenia 38%
                         +          ORR=100%        Deep vein thrombosis
                   Estramustine                     10%
                  280 mg tid days                   Hyperglycemia 5%
                        1-3                         Myalgia/arthralgia 5%
                  q3w followed by                   Line sepsis 5%
                     RP or RT

Dreicer et   29      Docetaxel      PSA decline     Granulocytopenia 14%
al2                   40 mg/m2         >50%         Diarrhea 7%
                  qw for 6 weeks     in 24% of      Constipation 4%
                  followed by RP      subjects      Neuropathic pain 4%
                                                    Hypocalcemia 4%


                                         1. Hussain et al. Urology. 2003;61:774.
                                         2. Dreicer et al. Urology. 2004;63:1138.
           Neoadjuvant Phase II Studies
   Study      N       Regimen            Efficacy             Toxicities
Ryan et al1   23    Vinblastine +        5-Year         Nocturia 70%
                    Estramustine        PFS=34%         Urinary stricture 4%
                     followed by                        Proctitis/diarrhea 9%
                   Estramustine +
                        3D-RT



Febbo et      19      Docetaxel       PSA decline       Infection 5%
al2                    36 mg/m2          >50%           Cough 5%
                        qw for         in 58% of        Hypernatremia 5%
                   up to 6 months       subjects        Hypokalemia 5%
                   followed by RP
                                                        Syncope 5%




                                1. Ryan et al. Urology. 2004;64:90.
                                2. Febbo et al. Clin Cancer Res. 2005;11:5233.
            High-Risk Localized Prostate
            Cancer:
            Neoadjuvant Docetaxel Phase
            II Studies (cont’d)
    Study         N         Regimen            Efficacy            Toxicities
 McKenzie et      54     Docetaxel +      PSA ≤ 0.5 µg/L Unacceptable Toxicity
 al1                     nilutamide + in 48% of subjects 15%*
                          buserelin                        Docetaxel qw:
                         followed by                       Acute GU toxicity 6%
                       buserelin + RT
                                                           Hypersensitivity 2%
                                                           Fatigue 2%
                                                           Docetaxel q3w:
  Garzotto et    22       Docetaxel     Subjects with PSA Febrile neutropenia
                                                           Primary toxicity:
  al2                      36 mg/m 2
                                          reduction 95% 2% neutropenia
*        Unacceptable toxicity +                           Neutropenia 2%
                             qw was defined as > grade 3 nonhematologic
                        Mitoxantrone
 (except nausea/vomiting, tearing,                         Other GU effects:
                                           Average PSA Acute sidetoxicity 2%
 short-term fatigue, and 2-5 mg/m  2
                          easily controlled diarrhea), grade 4 thrombocytopenia,
                                          reduction 41% hyperglycemia,
 grade 4 neutropenia for 12-16 weeks
                       followed by RP                      nausea, neuropathy,
 lasting >7 days, febrile neutropenia, or RT-related toxicity.
                                                           and thrombosis
1. McKenzie et al. ASCO, 2006. Oral presentation. Abstract 4631.
2. Garzotto et al. Urol Oncol. 2006;24:254.
    Ongoing Neoadjuvant Trials

Study    Phase Patients    Treatment     End Points
CALGB     III    Stage        RP vs      Recurrence
 90203          T1-T3a     Docetaxel +
                                           Safety
                 high-    estramustine
                risk PC         RP
   Adjuvant Rx

• Rationale is clear
         Adjuvant Rx Following PSA
         Relapse: Phase II Trial Design

    Patients
(aged 49-78y)
   with PSA                  Estramustine
                                                             Bicalutamide
  progression          (10 mg/kg in 3 divided qd
                N=62                                         (50 mg qd) +
 following RP              doses) days 1-5 +
                                                           Goserelin acetate
     and/or                   Docetaxel
                                                            (10.8 mg q12w
radiotherapy               (70 mg/m2) day 2
                                                               for 15 mo)
     with no                q3w for 4 cycles
  metastases




• Primary end point: Response rate
• Secondary end point: Time to progression


                                         Taplin et al. J Clin Oncol. 2006;24:5408.
Adjuvant Rx for PSA Relapse




            Taplin et al. J Clin Oncol. 2006;24:5408.
   Adjuvant Rx: Adverse Events
                               % of Patients
                                  (n=62)
Grade 3/4 neutropenia                     61
Infection (non–life
                                             8
threatening)
Deep vein
                                             5
thromboses
Cerebrovascular
                                             2
event
                      Taplin et al. J Clin Oncol. 2006;24:5408
   Adjuvant Docetaxel
• Multicenter phase II
• “High risk post op” = >50% risk of
  recurrence, no RT allowed
  – 77 cases, 2002-2003
  – 65% +SV, 38% +LN, 50% +SM
• 6 cycles of docetaxel 35/m2 d1,8,15
• 3 toxic deaths (GI bleed, cardiac,
  pulmonary)
                          Kibel et al. J Urol. 2007;177:1777
Adjuvant Docetaxel




    40 patients with undetectable PSA
            Ongoing Adjuvant Trials:TAX 3501


                                                             Leuprolide
 • Ages ≥ 18            R     Observation      Progression
 • No bone              A                                    Leuprolide +
   metastases           N                                    Docetaxel
 • ECOG ≤ 1             D
 • ≤ 90 days     N=2172 O
   post-RP                     Leuprolide
                        M
 • No prior RT
                        I
 • No prior
                        Z
   systemic
   therapy              E     Leuprolide +
                        D     Docetaxel


• Primary end point: Progression-free survival
• Secondary end points: Overall survival, metastases-free
survival
          Ongoing Adjuvant Trials: SWOG 9921

                                      SED!
                            CL
    • RP within 120 days prior
                                     O
                                      R
    • Stage T1-T3, N0, M0                      Androgen Deprivation
                                      A
    • Considered operable for cure                (bicalutamide +
                                      N
       And ≥1 of the following:                      goserelin)
                                      D
    • Gleason's sum ≥8
                                      O
    • pT3b or pT4 or N1
                                      M
    • Gleason's sum 7 and + margin             Androgen Deprivation +
                                      I           Mitoxantrone +
    • Pre-op PSA of >15 ng/mL
                                      Z             Prednisone
    • Biopsy Gleason >7
                                      E
    • PSA >10 ng/mL + Gleason >6



• Primary end point: Overall survival
• Secondary end point: Disease-free survival
            Ongoing Adjuvant Trials: RTOG 0521


     Patients with localized,           R
                                             LHRH + AA (8 wk)
          high-risk PC:                 A
       STRATIFIED BY                          RT + LHRH + AA
                                        N
   • Gleason ≥9, PSA ≤150,
                                        D
     and any T stage            N=600
   • Gleason 8, PSA <20,                O
     and ≥T2                            M
   • Gleason 8, PSA                     I
     ≥20-150, any T stage               Z     LHRH + AA (8 wk)
   • Gleason 7, PSA                     E      RT + LHRH + AA
     ≥20-150, any T stage               D    LHRH + Docetaxel +
                                                 Prednisone

• Primary end point: Overall survival
• Secondary end points: Local control, DFS
• Current accrual = 176
     Concurrent RT and Chemo
• Ben-Josef IJROBP 49:699,2001 (Zelefsky,
  Kim, Kumar…)
  – 18 pts, locally advanced
  – Estramustine-etoposide, concurrent
    esstramustine daily plus 3DCRT (no pelvic RT)
  – Local control by biopsy 71%
   Concurrent RT and Chemo

UMCC 2006.066: Salvage Radiation
 Therapy And Docetaxel For
 Biochemical Failure After Radical
 Prostatectomy
       Concurrent RT and Chemo


                            Compare observed
              Salvage RT
Biochemical                 4-yr FFP
              with weekly
Failure                     Vs.
              docetaxel
after RP                    Predicted from
              20 mg/m2
                            Stephenson, et al



    N=44
  New RTOG Concept

• High Risk PCa
  – Balogh - Calgary
  – RT plus concurrent bevacizumab
  – Phase I approach
   Summary

• Lots going on (i.e., immunotherapy)
• Limited data on cytotoxics and RT
• Role of targeted therapy unclear
  – Targets identified, but toxicity is a
    concern
  – Need more studies on RT with targeted
    interventions
Other slides
          Treatment for HRPC:
          SWOG 9916 Phase III Trial
          Design
                                                          Docetaxel
                                      R             (60 mg/m2 on day 2) +
                                      A n=338           Estramustine
                                      N            (280 mg tid on days 1-5)
                                                              q3w
                                      D               for up to 12 cycles
                              N=674   O
    Patients (aged 43-88 y)
    with metastatic HRPC              M
                                                        Mitoxantrone
                                      I
                                                    (12 mg/m2 on day 1) +
                                      Z n=336             Prednisone
                                      E                    (5 mg bid)
                                      D                       q3w
                                                      for up to 12 cycles
• Primary end point: Overall survival
• Secondary end points: Time to progression, PSA response, progression-
  free survival
 Dexamethasone 20 mg PO tid starting the night before docetaxel. An
 amendment added daily warfarin 2 mg plus aspirin 325 mg to the
 estramustine group.
Petrylak et al. N Engl J Med. 2004;351:1513.
           Treatment for HRPC:
           SWOG 9916 Efficacy

                                   Overall Survival



                                                        Hazard Ratio = 0.80 (P=0.02)

                                                        Docetaxel + estramustine
                                                    (n=338; median survival=17.5 mo)

                    Mitoxantrone + prednisone
                 (n=336; median survival=15.6 mo)



                                         Months

Petrylak et al. N Engl J Med. 2004;351:1513.
           Novel Agents for the
           Treatment of HRPC:
           Phase II/III Studies
                                             PSA Decline       TTP-PSA
   Agents + Regimen (n)                       ≥50% (%)          (Days)
   Placebo (104)                                                  71
   Atrasentan 2.5 mg/d (95)                        NA           141*
   Atrasentan 10 mg/d (89)                                      155*
   Bevacizumab 10 mg/kg q2w (15)                   0              57
   Calcitriol 8-12 µg q Mon-Weds +
   Dexamethasone 4 mg q Sun-Weds                  18               28
   (43)
   Ixabepilone 35 mg/m2 q3w (47)
                                                  48              132
   Ixabepilone 35 mg/m2 day 2 +
    estramustine phosphate 280 mg
   tid
*                                                 69              156
         Compared with placebo, log-rank test of Kaplan-Meier curves,
    days 1-5 q3w (45)
 P<0.05.
Carducci et al. J Clin Oncol. 2003;21:679.
Reese et al. Prostate J. 2001;3:65.
Trump et al. Cancer. 2006;106:2136.
           Novel Agents for the
           Treatment of HRPC:
           Phase II/III Studies (cont’d)
                                                  PSA
                                                 Decline
    Agents + Regimen (n)                        ≥50% (%)       OS (mo)
    Prednisone 10 mg bid (23)
                                                   9            11.9
    Prednisone 10 mg bid +
    Satraplatin 100 mg/m2 days 1-5
    Hydrocortisone 40 mg/d (208)                   33*            14.9
    q35d (27)                                       19            15.2
    Vinorelbine 30 mg/m2 days 1+8
    q3w + Hydrocortisone 40 mg/d
                                                   30†            14.7
    (206)
*        Odds ratio of response vs prednisone alone = 5.26 (95% CI,
 1.00-2.78).
†       P=0.01 vs hydrocortisone alone.
Abratt et al. Ann Oncol. 2004;15:1613.
Sternberg et al. Oncology. 2005;68:2.
            Novel Agents for the
            Treatment of HRPC:
            Bevacizumab Phase II Trial
            Design


                                      N=15     Bevacizumab
           Patients (aged 62-834)
                                                (10 mg/kg)
           with metastatic HRPC                    q2w




• Primary end points: Tumor and PSA response rate
• Secondary end points: Response duration, TTP

Reese et al. Prostate J. 2001;3:65.
            Novel Agents for the
            Treatment of HRPC:
            Bevacizumab Efficacy
                                      (N=15)




Reese et al. Prostate J. 2001;3:65.
            Novel Agents for the
            Treatment of HRPC:
            Bevacizumab Adverse Events

                                      Grade 3/4 Toxicities, %
                                             (n=15)

        Hyperkalemia                             20


        Hyperglycemia                            13


        Anemia                                   13

Reese et al. Prostate J. 2001;3:65.
          Docetaxel + Gefitinib in HRPC:
          Phase II Trial Design



                                                            Gefitinib
   Patients (median age = 67 y)                    (250 mg/m2 on days 5-18) +
                                          N=37             Docetaxel
   with metastatic HRPC and no
                                                 (35 mg/m2 weekly for 3 wk with
        prior chemotherapy
                                                      4th week of cycle off)
                                                          Up to 6 cycles




• End points: PSA response rate, time to PSA progression, toxicity

Borner et al. ASCO, 2006. Abstract 258.
               Docetaxel + Gefitinib in HRPC:
               Efficacy
                                          (n=37)
    Rate (%)
    Days




Borner et al. ASCO, 2006. Abstract 258.

				
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