Update on GU Cancers: The Good, The Bad, and the Ugly (and the Really Ugly)

1
Update on GU CancersThe Good, The Bad, and the
Ugly (and the Really Ugly)

• Dr. Kim N. Chi
• Medical Oncologist
• Assistant Professor of Medicine
• Chair - GU Systemic Therapy Group

2
Agenda

• The Good - Testicular cancer
• What to do with the high risk clinical stage I
  non-seminoma
• Adjuvant Carboplatin in clinical stage I seminoma
• The Bad - Prostate Cancer
• Docetaxel for hormone refractory disease
• Zoledronate for hormone refractory disease
• The Ugly - Bladder Cancer
• Gemcitabine and cisplatin for metastatic disease
• Neoadjuvant and adjuvant chemotherapy for locally
  advanced disease
• The Really Ugly - Kidney Cancer
• Interferon
• Nephrectomy in metastatic disease

3
Agenda

• The Good - Testicular cancer
• What to do with the high risk clinical stage I
  non-seminoma
• Adjuvant Carboplatin in clinical stage I seminoma
• The Bad - Prostate Cancer
• Docetaxel for hormone refractory disease
• Zoledronate for hormone refractory disease
• The Ugly - Bladder Cancer
• Gemcitabine and cisplatin for metastatic disease
• Neoadjuvant and adjuvant chemotherapy for locally
  advanced disease
• The Really Ugly - Kidney Cancer
• Interferon
• Nephrectomy in metastatic disease

4
High risk clinical stage I NSGCT

• Definition of high risk (Risk of relapse 40-50)
• Embryonal predominant
• Vascular invasion
• lack of yolk sac elements
• Current treatment possibilities
• RPLND
• Surveillance
• Adjuvant chemotherapy

5
Primary RPLND for high risk CSI NSGCT Indiana
experience
125 Patients with CS1
RPLND
85 (68) PS I
40 (32) PS II
25 - adjuvant chemo 5 - for distant relapse
18 relapsed - chemo
Bottom Line 48/125 (38) Received Chemo 125/125
had RPLND
Sweeney, JCO, 2000
6
Surveillance or primary RPLND for high risk CS I
NSGCT BCCA Experience
103 Patients with CS1
32 (32) RPLND
71 (68) Surveillance
14 (44) PS II
18 (56) PS I
24 (33) Relapsed All treated with chemo 6 RPLND
11 Received adjuvant chemo 3 received chemo for
distant relapse
Bottom Line 24/71 (33) Received Chemo 6/71 (8)
had RPLND
Bottom Line 14/32 (44) Received Chemo 32/32
(100) had RPLND
Al-Tourah, Proc ASCO, 2003
7
Conclusions

• NSGCT Clinical Stage I patients - High Risk
• Strategy of primary RPLND does not seem to spare
  patients chemotherapy
• Surveillance offers the best management to
  minimize treatment toxicity
• Patient must be willing and able to undergo
  surveillance (3 deaths in patients refusing
  recommended therapy)
• Adjuvant chemotherapy tested only in case
  series/phase II setting
• Over-treating many
• Potentially under-treating some?

8
Seminoma - Clinical Stage I

• Risk factors for recurrence
• Rete testis invasion
• T gt 4 cm
• Current treatment strategies
• Adjuvant XRT
• Increased risk of secondary malignancy
• Surveillance
• No tumour marker to follow
• Late relapses

9
Seminoma CS I adjuvant carboplatin

• 107 Patients
• Carboplatin 400 mg/m2 x 2
• Median follow-up 54 months
• Randomized controlled trial pending
• Results soon
• Only using 1 cycle
• A treatment option for patients with
  contraindications for radiotherapy or surveillance

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Agenda

• The Good - Testicular cancer
• What to do with the high risk clinical stage I
  non-seminoma
• Adjuvant Carboplatin in clinical stage I seminoma
• The Bad - Prostate Cancer
• Docetaxel for hormone refractory disease
• Zoledronate for hormone refractory disease
• The Ugly - Bladder Cancer
• Gemcitabine and cisplatin for metastatic disease
• Neoadjuvant and adjuvant chemotherapy for locally
  advanced disease
• The Really Ugly - Kidney Cancer
• Interferon
• Nephrectomy in metastatic disease

11
Docetaxel in Prostate Cancer
N Regimen PSA RR ORR 35 75 mg/m2
q3w 46 28 21 75 mg/m2
q3w 38 60 60 36 mg/m2/wk q6/8w
34 33 25 36 mg/m2/wk q6/8w 43
NR

Picus, Semin Oncol 1999 Friedland, Semin Oncol
1999 Beer, Proc ASCO 2000 Berry, Proc ASCO 1999
12
Docetaxel and Estramustine

• N Regimen PSA RR ORR
• 46 D 70 mg/m2 d2 68
  50
• E 10 mg/kg/d d1-5
• q3w
• 37 D 70 mg/m2 d2 68 55
  
• E 280 mg tid d1-5
• q3w
• 17 Arm A D 20-30 mg/m2/wk
  82 71 E 420 mg tid d1-4
  q6/8w
• Arm B D 30-40 mg/m2 d2,9
• E tid (420 mg ? 4280 mg ? 5)
• d1-3, d8-10 q3w
• 21 D 43 mg/m2 d2 71 11 E 140
  mg/d d1-5
• q3/4w

Savarese, JCO 2001 Petrylak, Proc ASCO, 2000
Natale, Proc ASCO 1999 Kosty, Proc ASCO 2001
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Tax 327
Docetaxel 75 mg/m2 q3w
1003 Patients HRPC with Metastases
RANDOMIZATION
Docetaxel 30 mg/m2 q1w
Mitoxantrone 12 mg/m2 q3w
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SWOG 9916
Docetaxel 60 mg/m2 Estramustine 280 mg TID
d1-5 q3w
620 Patients HRPC with Metastases
RANDOMIZATION
Mitoxantrone 12 mg/m2 q3w
15
Docetaxel EMCYT vs Mitoxantrone Randomized
Phase II Trial
RAND OMIZATION
H R P CStratified by Baseline PSA level(?
150 ng/ml vs ? 150 ng/ml) - and - PS (ECOG)
(0 vs, 1-2)
Docetaxel 70 mg/m2 IV d2 Estramustine 280 mg po
TID d1-5 d-7-11 Prednisone 10 mg po daily 6
CYCLES
DEP q21d
A
Docetaxel 35 mg/m2 IV d2 d8 Estramustine 280
mg po TIP d1-5 d7-11 Prednisone 10 mg po
daily 6 CYCLES
DEP d1,8 q21d
B
Mitoxantrone 12 mg/m2 IV d1 Prednisone 10 mg po
daily 6 CYCLES
MP q21d
C
DEP treated patients coumadin 2 mg p.o. daily
S. Oudard, Abstract 325 ESMO 2002
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Best Clinical Benefit Response
A
B
C
p
MP (n 42)
DEP D2 8/21 (n 42)
DEP D2/21 (n 43)
1. Pain control 10 (30)
9 (26) 7 (21) NS 2.
Analgesic 15 (45) 10 (29) 6
(18) 0.04 consumption 3. Improved pain
26 (79) 19 (56) 14 (41)
0.007 index (12) 4. Improved PS
26 (79) 20 (59) 12 (35)
0.001 Improved clinical 23 (70)
17 (50) 11 (32) 0.009
benefit (34)
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Best PSA Response Rate (? 6 weeks)
A
B
C
DEP D2 8/21 (n 42)
MP (n 42)
DEP D2/21 (n 43)
p

• gt 50 29 (67) 26 (62) 7 (17)
  0.00001
• gt 75 12 (28) 9 (21) 2 ( 5)
  0.01
•  Normalisation  10 (23) 7
  (17) 1 ( 2) 0.01
• (lt 4 ng/mL)

PSA response definition according to PSA
Working Group, JCO 1999
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Conclusions

• Docetaxel has a significant PSA and objective
  response rate in HRPC
• Currently class II
• Survival data will be presented at ASCO 2004

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Zoledronic Acid (4 or 8) mg vs Placebo in
Prostate Cancer Patients with Hormone-refractory
Metastatic Bone Lesions

• No bisphosphonate has previously been shown to be
  useful in prostate cancer
• Primary endpoint skeletal related events
• Pathological fractures
• Spinal cord compression
• Radiation for bone pain or to treat or prevent
  pathologic fractures or spinal cord compression
• Surgery to bone
• Change of antineoplastic therapy for bone pain
• Hypercalcemia of malignancy (HCM)

Saad, JNCI, 941458, 2002
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Skeletal Related Events
P0.021
P0.221



of patients
221
208
214
N
23
SRE Over Time
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Pain Scores

• Scale out of 10 - clinically significant
  differences?
• Analgesics and therapy not accounted for

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Zoledronate Conclusions

• A postive trial, but...
• Why were there so few events?
• SRE statistically significantly decreased - but
  what is the patient benefit?
• Costly
• Potentially toxic - renal failure
• PEC proposal submitted
• Degree of benefit similar to that seen for
  bisphosphonates in breast cancer

26
Agenda

• The Good - Testicular cancer
• What to do with the high risk clinical stage I
  non-seminoma
• Adjuvant Carboplatin in clinical stage I seminoma
• The Bad - Prostate Cancer
• Docetaxel for hormone refractory disease
• Zoledronate for hormone refractory disease
• The Ugly - Bladder Cancer
• Gemcitabine and cisplatin for metastatic disease
• Neoadjuvant and adjuvant chemotherapy for locally
  advanced disease
• The Really Ugly - Kidney Cancer
• Interferon
• Nephrectomy in metastatic disease

27
Gemcitabine-Cisplatin vs MVAC
405 patients
von der Masse, JCO 2000
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Overall Survival
GC 13.8 m (12.3-15.8 m) MVAC 14.8 m (13.2-16.8
m) HR 1.04 (0.82-1.32) LR p0.746 W p0.908
GC 13.8 months (12.3-15.8 ) MVAC 14.8
months (13.2-16.8 ) HR 1.04
(0.82-1.32)
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Hematologic toxicity
30
Non-hematologic toxicity
31
Neoadjuvant chemotherapy in invasive bladder
cancer a systematic review and meta-analysis of
individual patient data from 10 randomised trials
THE LANCET Vol 361 June 7, 2003
32
Survival - combination chemotherapy trials
Events
Total
1.0
588
1062
NeoCT
0.9
636
1054
Control
0.8
0.7
0.6
Survival
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10
Patients at risk
Years
NeoCT
1062
838
655
558
489
420
321
214
139
89
53
Control
1054
797
614
527
452
381
277
188
122
78
46
33
Absolute benefit
34
Sensitivity analyses

• Omitting data from the largest trial (MRC/EORTC)
• Reduced power of the analysis
• Did not significantly alter the overall result
• Overall survival HR0.89, 95 CI 0.77-1.04,
  p0.157
• Including summary survival data from the
  unavailable SWOG trial
• Increased the power of the analysis
• Did not significantly alter the overall result
• Overall survival HR0.86, 95 CI 0.77-0.95,
  p0.004
• No significant heterogeneity (p0.51)

35
SWOG neoadjuvant trial

• Median survival 77 vs 46 months (p0.05)
• 5 Year survival 57 vs 43 (p0.06)

Grossman, N Engl J Med 2003349859-66
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Conclusions

• Neoadjuvant chemotherapy appears to confer an
  overall survival improvement - absolute 5 at 5
  years
• Being discussed at the GU tumour group level for
  approval
• What about adjuvant?
• Potentially more benefit
• pathologically staged patients
• pN disease
• not delaying definitive local therapy
• Randomized trial (NCIC.BL8/EORTC) accruing very
  slowly

37
Agenda

• The Good - Testicular cancer
• What to do with the high risk clinical stage I
  non-seminoma
• Adjuvant Carboplatin in clinical stage I seminoma
• The Bad - Prostate Cancer
• Docetaxel for hormone refractory disease
• Zoledronate for hormone refractory disease
• The Ugly - Bladder Cancer
• Gemcitabine and cisplatin for metastatic disease
• Neoadjuvant and adjuvant chemotherapy for locally
  advanced disease
• The Really Ugly - Kidney Cancer
• Interferon
• Nephrectomy in metastatic disease

38
Interferon-? MRC Trial

• IFN vs MPA
• 350 patients
• Response rate 14 (CR 2) vs. 2
• 29 reduction in risk of death at 1 year
• Median Survival 8.5 vs. 6 months

MRC Renal Cancer Collaborators, Lancet, 35314,
1999
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Interferon-? Helsinki Study

• Vinblastine /- Interferon- ?
• 160 patients
• Response rate 16.5 (8.9CR) vs. 2.5
• 31 reduction in risk of death at 1 year
• Median Survival 16.9 vs. 9.5 months

Pyrhonen, JCO, 172859, 1999
40
Interferon-? Toxicity
Moderate or severe side effects at 4 weeks
41
IFN /- Nephrectomy in Metastatic Disease - SWOG

• 241 randomized patients
• Interferon Response rate 3.3 vs 3.6

Flanigan, NEJM, 345 1655, 2001
42
IFN /- Nephrectomy in Metastatic Disease - SWOG
Flanigan, NEJM, 345 1655, 2001
43
Nephrectomy in Metastatic Disease - EORTC

• 85 randomized patients
• Interferon response rate 19 vs 12

Mickisch, Lancet, 358 966, 2001
44
Conclusions

• A true result
• Highly selected group of patients
• Performance status 0 were the ones who benefitted
• Large bulk primary with small bulk metastases
• Debulking surgery - a better response rate than
  interferon alone

45
Current and upcoming GU trials - 2004

• Prostate
• Phase III Docetaxel /- Calcitriol
• Phase III Docetaxel /- Antisense Bcl-2
• Phase II Docetaxel 2nd Generation Antisense to
  Clusterin
• Phase II ABT-751 (2nd line)
• Phase II BAY 439006 (biochemical HRPC)
• Phase II NHT and Docetaxel prior to XRT
• Phase II/III NHT and Docetaxel prior to Radical
  Prostatectomy
• Bladder
• Phase III Gem-Cis vs Gem-Cis-Paclitaxel
• Phase III Adjuvant vs Deferred Gem Cis for
  pT3/T4/N
• Kidney
• Phase II ABT-751
• Phase III Interferon /- Bevacuzimab
• Phase III Interferon /- CCI-779 (poor prognosis
  only)