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Mediterranean School of Oncology Highlights in
the management of ovarian cancer
Chemotherapy in advanced ovarian cancer Angiolo
Gadducci Department of Gynecology and Obstetrics,
Unit of Gynecologic Oncology, University of Pisa
Rome October 5-6 2007
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Integrated therapies in ovarian cancer (OC)

• Early stage Surgery
• Adjuvant therapy
• Advanced stage Surgery Primary cytoreduction
• Interval surgery
• Second-look
• Chemotherapy
• Consolidation/manteinance therapy Recurrent
  disease Chemotherapy
• Surgery

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Advanced Ovarian Cancer Trialist Group

• Subjects 8139 patients (6408 deaths) included in
  45 trials.
• Conclusions in term of survival
• Platinum based treatment was better than
  non-platinum
• regimens (RR 0.93 95 CI, 0.83-1.05)
• Platinum in combination was better single agent
  platinum
• when used as the same doses (RR 0.85 95
  CI, 0.72-1.00)
• CDDP and CBDCA were equally effective RR 1.05
  95 CI,
• 0.94-1.18)
• (B.M.J., 1991)
  
  
• 
  
• 
  
  

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Chemotherapy for advanced OC
49 trials involving 8763 women
HR for survival (95
CI) Platinum combination chemotherapy versus
single non-platinum 0.93 (0.83-1.05) CDDP
non-platinum regimen versus non-platinum
regimen 0.88 (0.79-0.98) Platinum
combination versus single platinum 0.91
(0.79-1.05) CDDP versus CBDCA 1.02
(0.93-1.12)
Advanced Ovarian Cancer Trialists Group 2000
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Ovarian Cancer Meta-Analysis Project PAC vs PC
pathologic response 6-y survival rate
PAC 27
31 PC 21 25

p value 0.01
lt0.02

(1991)







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Impact of DOX on survival in advanced OC

• The addition of DOX improves survival (RR 0.85
  95 CI
• 0.76-0.95, p0.003) and the size of this benefit
  is of a similar
• magnitudo to that of platinum

• Overview of the data from
• Advanced Ovarian Cancer Trialist Group
• Ovarian Cancer Metanalysis Project

AHern and Gore, 1995
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ICON 2 randomised trial of CBDCA versus
CAP (CTX, DOX, and CDDP)
Patient population 1526 patients from 132
centres in nine countries.
CBDCA CAP
360/ 760
368/766 Deaths Median survival 33
months 33 months 2-year survival
60 60 HR 1.00 (95
CI 0.86-1.16) p0.98
International Collaborative Ovarian Neoplasm
Group Lancet 1998
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Using the expected survival to explain
differences between the results of randomized
trials a case in advanced OC
Buyse et al, 2003

• A prognostic model for survival obtained in the
  meta-analysis included residual disease, age,
  grade and FIGO stage.
• A proportional hazard model, fitted the
  meta-analysis data, was used to construct the
  expected survival curve for each treatment arm of
  the ICON 2 trial.
• Expected survival curves were compared with
  observed survival curves in the ICON 2 trials.

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The addition of DOX to platinum-based regimen
in OC

• When this model was applied to the ICON 2 data,
  there was no difference between the observed and
  expected curves in the CAP arm.
• In contrast, the observed survival curve for
  CBDCA was superior to the expected survival
  curve.

Buyse et al, 2003
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The addition of DOX to platinum-based regimen
in OC

• The difference between the survivals in ICON 2
  and in the meta-analysis may be related to the
  better results achieved with CBDCA alone at an
  optimally tolerated dose compared with PC at a
  CDDP dose of 50-60 mg/m2.

Buyse et al, 2003
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Retrospective analysis of 33 published Trials
using CDDP in advanced OC
.
Conclusions Relationship between
dose-intensity (mg/m2/w) of CDDP, response
rate,and survival
Bias analysis performed on
trials not designed to assess value of the
dose-intensity concept






Levin et al, 1989
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Studies designed to explore the dose-response
curve of CDDP
.
High dose arm CDDP
dose CDDP Survival
intensity total dose
advantage Kaye et al.1992 double
double yes McGuire et al.1992 double
identical no Colombo et al. 1992
double identical no Conte et al.
1996 double double no





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First Line Chemotherapy Randomized trials
comparing TAX CBDCA vs CDDP TAX
Author pts median PFS median S n
(months) (months) Neijt 2000
208 TAX 175 mg/m2 (3-h) CBDCA AUC 5 16
32 TAX 175 mg/m2
(3-h) CDDP 75 mg/m2 16 30

p ns pns
Bookman 2003 840 TAX 175 mg/m2 (3-h)
CBDCA AUC 7.5 20.7 56.7
TAX 135 mg/m2 (24-h) CDDP 75 mg/m2 19.4
48.8
p ns pns
Du Bois 2003 798 TAX 185 mg/m2 (3-h)
CBDCA AUC 6 17.2 43.3 TAX
185 mg/m2 (3-h) CDDP 75 mg/m2 19.1
44.1
p ns pns
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Vasey P. Proc ASCO 2001(abstract and oral
presentation 804)
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SCOTROC ASCO 2002Progression Free Survival
Vasey P. Proc ASCO 2002(abstract and oral
presentation 804)
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SCOTROC Overall Survival
Vasey P. Proc ASCO 2002(abstract and oral
presentation 804)
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PC vs DCToxicity

• DC PC
• Myelosuppression
• Neurotoxicity
• Allergy
• Stomatitis
• Diarrhea
• Myalgia/Arthralgia

Ozols, ASCO 2001
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1st CT Phase III randomized study of TAX CDDP
vs CDDP vs TAX in stage III-IV with RD gt 1 cm
GOG 132
TAX 135 mg/m2 (24-h) CDDP 75 mg/m2 14.0
26.6 CDDP 100 mg/m2
16.4 30.2 TAX 200 mg/m2 (24-h)
11.2 26.0 Braccio 12
versus 3 plt 0.001 p ns

Braccio 1 versus 2
p ns p ns
614 evaluable patients median PFS median
S (months) (months)
Muggia, 2000
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First Line Chemotherapy ICON 3 randomized study
2074 randomized patients Median
PFS Median S months
months TAX 175 mg/m2 (3-h) CBDCA AUC 5-6
17.3 36.1 CBDCA AUC 5-6 or
16.1 35.4 CDDP 50 mg/m2
DOX 50 mg/m2 CTX 500 mg/m2 pns
pns
International Collaborative Ovarian Neoplasm
Group 2002
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Explanations for different results between GOG
111 and OV 10 versus GOG 132 and ICON 3

• Statistical bias
• Different extent of crossover to the
  taxane-based
• treatment in the control arm
• The use of CBDCA instead of CDDP in the
  experimental arm
• Type of treatment used in the control arm

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Explanations for different results between GOG
111 and OV 10 versus GOG 132 and ICON 3

• The large effect seen in GOG 111 which maintained
  at 5-years of follow up excludes the possibility
  of a type I error.
• ICON 3 enrolled 2074 patients and the chance of
  missing the effect of TAX as large as seen in GOG
  111 is only 1.

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Explanations for different results between GOG
111 and OV 10 versus GOG 132 and ICON 3
Crossover to taxanes OV
10 48 GOG 132
24 ICON 3 30
(on progression)

6 (before progression)
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Explanations for different results between GOG
111 and OV 10 versus GOG 132 and ICON 3

• The experimental arm in ICON 3 differ from that
  of the other trials, because CBDCA was used
  instead of CDDP and because TAX was given at
  the dose of 175 mg/m2 3-h infusion. However,
  recent randomized studies showed that CBDCA
  TAX 3-h infusion can substitute CDDP TAX 24-h
  infusion without abrogation of activity

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Explanations for different results between GOG
111 and OV 10 versus GOG 132 and ICON 3
Control arm GOG 111 CTX 750 mg/m2
CDDP 75 mg/m2 OV 10 CTX 750 mg/m2 CDDP 75
mg/m2 GOG 132 CDDP 100 mg/m2 ICON 3 CDDP
50 mg/m2 DOX 50 mg/m2 CTX 500 mg/m2 or
CBDCA AUC 5-6
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Explanations for different results between GOG
111 and OV 10 versus GOG 132 and ICON 3

• The control PC regimen (GOG 111 and OV 10) may
  be inferior to the control arm used in ICON 3
  (PAC or CBDCA) and GOG 132 (high-dose CDDP)
• The addition of CTX to CDDP may increase the
  hematologic toxicity of the regimen, causing
  excessive treatment delay and dose reduction.
• Although there is no evidence of an improvement
  in survival with higher platinum dose-intensity,
  the addition of CTX to CDDP may have induced a
  dose reduction below the minimum standard.

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Explanations for different results between GOG
111 and OV 10 versus GOG 132 and ICON 3

• The lack of benefit associated to platinum/taxane
  combination in ICON 3 may be due to the
  superiority of the control arm in this trial
  compared to the control arms of the previous
  trials.
• A meta-analysis with individual patient data from
  the 4 trials revealed a significant benefit for
  TAX/platinum-based regimen, which was smaller
  than that originally expected on the basis of GOG
  111.

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Advanced Ovarian Cancer Current accepted
Treatment

• Paclitaxel Carboplatin (TC)
• Accepted standard
• Control Arm of all recent randomized trials
• No other regimen shown to outperform it
• Median TTP 15-18 months
• Median OS lt36-40 months

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Management of Advanced EOCSearch for progress

• More active 1st line regimens
• Tailored treatments
• IP CT
• Maintenance/Consolidation therapy
• New treatment strategies (IDS, NACT)
• Novel (targeted) agents

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GOG-182 (ICON 5)
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GOG 182- ICON 5 Trial
Bookman MA, ASCO 2006
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Phase II trial of the Northeastern German Society
of Gynecological Oncology
Study population 105 pts with stage II-IV EOC.
CT regimen CBDCA AUC 5 every 3 weeks x 4 cycles
followed by TAX 80 mg/m2/week x 12 cycles No
grade 3 or 4 neurotoxicity and/or
nausea/vomiting Grade 3-4thrombocytopenia, 16
anemia, 3 leucopenia, 22 After a median
follow-up of 10 months (range 1-27), 20 pts
died Median OS not yet reached Median PFS 19
months (range 10-23)
Oskay-Oezcelik, ASCO Meeting 2007
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CBDCA TAX vs CBDCA DOXIL in advanced EOC
Preliminary results of phase III MITO-2 trial

• RANDOMIZATION
• CBDCA AUC 5 TAX 175 mg/m2 CBDCA AUC 5
  DOXIL 30 mg/m2 every 3 weeks x 6 cycles
  every 3 weeks x 6 cycles
• Preliminary data
• Among 137 pts assigned to CBDCA DOXIL, 87 were
  not eligible for response assessment by RECIST
• Among 50 pts eligible for response assessment, 14
  CR and 20 PR were recorded, for a RR of 68
• Among 35 pts with not-target lesions, 9 (26) CR
  and 18 (51) PR were observed

Pignata, ASCO Meeting 2007
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ASCO 2007Educational SessionRare Subtypes of
Ovarian Cancer

• Clear Cell Tumors of the Ovary
• Toru Sugiyama, Iwate University, Japan
• Mucinous Ovarian Cancer
• Martin Gore, Royal Marsden, UK

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Progress in the management of EOC

• Evidence-based optimal care of EOC should
  include
• - an accurate surgical staging
• - a debulking surgery (no macroscopic
  peritoneal RD, systematic LY )
• - IP CT
• In daily practice, a minority of the pts receive
  an optimal surgery and NONE is treated with IP CT
• Tailored treatments should be developed on the
  basis of clinico-pathological parameters
  (histology, tumor grade, stage of disease, RD
  after surgery)
• Education and training of health professionals
  might have a major impact on survival

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Conclusions

• Molecular targeted agents able to interfere with
  fundamental steps in tumor cell re-growth (i. e.
  neoangiogenesis and growth factor signaling
  pathways) should be investigated.
• CT based on extreme drug resistance (EDR) assay
• CT-based on gene-profiling