Highlights in Gynecological Cancer

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Highlights in Gynecological Cancer

• Jan B. Vermorken, MD, PhD
• University Hospital Antwerp
• Edegem, Belgium
• ECLU, Lugano, July 6, 2007

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Ovarian CancerIncidence and Mortality
Worldwide USA Eurocare Europe No. of
cases 202.520 22.801 33.691 61.757 No. of
deaths 124.381 14.471 24.869 43.801 In
Eurocare 21 European countries IACR estimates
for year 2000
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Five-year Survival in Ovarian Cancer30 years of
experience

• Vol. Year Cases Ia IV Overall
• (n)
• 16 1963-68 4588 66.7 5.0 27.3
• 19 1976-78 6724 72.3 4.5 29.8
• 21 1982-86 10912 82.3 8.0 35.0
• 23 1990-92 7059 83.5 11.1 41.6
• 25 1996-98 4116 89.3 13.4 46.4
• Int. J Gynecol Oncol 2003 (Suppl 1)

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Epithelial Ovarian CancerMilestones

• Surgery according to FIGO guidelines
• At least LNS and peritoneal staging in EOVCA
• Upfront maximal surgical debulking in ADOVCA
• Chemotherapy evolution
• Introduction of platinum compounds
• Introduction of taxanes

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Milestones
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Epithelial Ovarian CancerHighlights

• Chemotherapy beneficial for high-risk EOVCA
• NACT in ADOVCA promising?
• Consolidation/maintenance disappointing?
• Intraperitoneal chemotherapy recognition!
• Combination CT superior in Pt-S relapsed disease
• New targets in ovarian cancer interesting?

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Early Ovarian Cancer(EOVCA)
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Risk Groups in Early Ovarian Cancer

• Low risk
• Grade I
• Intact capsule
• No tumor ext. surface
• Negative washings
• No ascites
• Growth confined to
• ovaries

• High risk
• Grade 2-3
• Ruptured capsule
• Tumor on ext. surface
• Positive washings
• Ascites
• Growth outside ovaries

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ICON1 ACTION

• Two Parallel Randomised Phase III Trials of
• Adjuvant Chemotherapy in Patients with Early
  Stage Epithelial Ovarian Cancer

ICON1 (International Collaborative Ovarian
Neoplasm studies) launched in 1991 ACTION (EORTC
Adjuvant Clinical Trial In Ovarian Neoplasm)
launched in 1990
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Principal Difference in Eligibility Criteria

• ICON1 any patients in which the clinician was
  uncertain whether patient should receive
  chemotherapy
• ACTION FIGO Stages Ia, Ib (grades II, III) /
  Stages Ic, IIa (all grades) / all clear cell
  carcinomas

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Adjuvant Chemotherapy
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Results in High-Risk Early Ovarian
CancerAdjuvant platinum-based Chemotherapy
ICON1 ACTION
Recurrence-free survival Overall
survival
1.0
0.9
0.8
0.7
0.6
S
u
r
v
0.5
i
v
HR0.68 P0.01
a
HR0.64 P0.001
l
0.4
0.3
0.2
Events
Total
0.1
75
465
Adjuvant chemotherapy
105
460
No adjuvant chemotherapy
0.0
0
12
24
36
48
60
72
84
96
108
120
Months from randomisation
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Conclusion of Continued Analysis

• Adjuvant chemotherapy in these series improved
• recurrence-free survival by 11 (65 to 76) at
• 5 years
• overall survival by 7 (75 to 82) at 5 years
• No evidence that the effect of adjuvant
  chemotherapy is smaller or larger in within the
  subgroups age, stage, histological type and
  differentiation
• Trimbos et al, JNCI 2003 95 105-112

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overall survival by staging performanceEORTC
Action trialchemotherapy arm / observation arm
Test for treatment-staging interaction p gt 0.1
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Overall Survival All Women
HR0.71, 95 CI0.52-0.98, p0.04 Absolute
difference at 10 years 9 (64 ?73)
no adj chemo
adj chemo
PATIENTS AT RISK no adj chemo adj chemo
236 241
184 202
158 179
134 151
101 111
63 69
27 39
6 8
Swart et al, ASCO abstract 5509 (2007)
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Overall Survival Low/Intermediate Risk Stage I
Group
HR0.86, 95 CI0.49-1.53, p0.61 Absolute
difference at 10 years 3 (75 ?78) 95 CI for
difference -11 to 12
Low/intermediate, no adj chemo
Low/intermediate, adj chemo
PATIENTS AT RISK IA/IB G1/2, IC G1, no adj IA/IB
G1/2, IC G1, adj
99 107
88 96
80 86
71 70
55 55
33 31
14 14
5 1
Swart et al, ASCO abstract 5509 (2007)
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Overall Survival High Risk Stage I Risk Group
HR0.52, 95 CI0.33-0.83, p0.01 Absolute
difference at 10 years 17 (58 ?75)
High risk, no adj chemo
High risk, adj chemo
PATIENTS AT RISK IA/IB G3, IC G2/3, clear cell,
no adj IA/IB G3, IC G2/3, clear cell, adj
89 96
73 82
63 75
50 67
34 45
19 31
7 19
0 4
Swart et al, ASCO abstract 5509 (2007)
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Advanced Ovarian Cancer(ADOVC)
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Potential Role of Interval Debulking in
OCSuboptimally debulked
Study Stage of Chemotherapy No.
of Outcome Group disease pts EORTC IIb-IV 3 x
CP II 3 x CP 319 49 ? 1995/2001 RD gt 1 cm vs 6
x CP risk of death GOG III-IV 3 x TP II 3 x
TP 550 no risk 2002 RD gt 1 cm vs 6 x
TP reduction van der Burg et al (NEJM 1995
2001) Rose et al (NEJM, 2004)
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Survival By Treatment
100 90 80 70 60 50 40 30 20 10 0
p0.0032
0 2 4 6 8 10
Years
O N Number of patients at risk
Treatment
122 159 84 40 16 5 Surgery 138 160 64 21 10 4 No
Surgery
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Biologic Characteristics of Tumor vs
Aggressiveness of Surgery in ADOVCAA basis for
NACT?
Chemosensitive Successful Debulk
ing Survival
22
Neoadjuvant Chemotherapy followed by IDS versus
Surgery followed by chemotherapyA prospective
randomized study

• Phase III trial India (New Delhi)
• 128 stage III/IV (pleural effusion only)
• Arm A primary surgery ? 6 x TC
• Arm B 3 x TC ? IDS ? 3 x TC
• Results
• Higher optimal debulking rate in B (plt.0001)
• Decrease blood loss in B (plt.003)
• Reduced postoperative infections (plt.04)
• Quality of life score better in B (plt.001)
• Disease-free and overall survival not different
  to date
• Kumar et al, ASCO abstract 5531 (2007)

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EORTC 55971 / Intergroup Trial
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Consolidation/MaintenanceStill investigational
25
Consolidation/Maintenance TherapiesCytotoxic
therapy
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Markman et al, JCO 2003 21 2460-2465
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Final Results of After-6 Protocol

• Methods 200 pts in cCR (48) or pCR (52) after
  6 cycles of platinum/paclitaxel were randomized
  to observation or 175 mg/m² paclitaxel x 6 q 3
  weeks
• Results
• No difference in PFS or OS.
• Irrespective of treatment arm median PFS was 34.4
  mo with PCR and 24.5 mo with cCR
• 3-yr survival 87 (pCR) and 79 (cCR) p0.04
• Conte et al, ASCO abstract 5505 (2007)

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IP Chemotherapy in ADOVCARecognition at last
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History of Intraperitoneal ChemotherapyOvarian
Cancer

• 1970s IPCT used for its cytotoxic properties
• High concentrations, large volumes
• 1978 Landmark paper by Dedrick et al.
• A sound pharmacokinetic rationale for IPCT
• 1991 IP therapy times up (Ozols)
• Times not up (Muggia, Alberts)
• 1996 Survival benefit for IPCT (Alberts et al.)
• 2004 IPCT not widely adopted (GCIG OCCC)
• 2006 NCI Clinical Announcement / Survival
  benefit with IP therapy

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IPCT vs IVCT in Advanced Ovarian CancerOverall
survival
Investigators No. of Overall survival
(mo) year published pts Control arm Exp.
Arm Alberts et al, 1996 546 41 491 Polyzos et
al, 1999 90 25 26 Gadducci et al,
2000 113 51 67 Markman et al,
2001 462 52 632 Yen et al, 2001 118 48 43 Arms
trong et al, 2006 415 50 663 1 p 0.02 2 p
0.05 3 p 0.03
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Pooled Data (all cisplatin studies)
HR 0.79 (95 CI 0.70, 0.89)
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Conclusions on IPCT

• Combined use of IV and IP chemotherapy leads to a
  significant survival benefit in women with
  optimally debulked EOC (median 12 mo).
• Based on the most recent trials, strong
  consideration should be given to a regimen with
  IP cisplatin (100 mg/m²) and a taxane (whether IV
  or IP).
• Toxicities, inconvenience and costs of IP therapy
  are justified by the improved survival.

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Recurrent Ovarian CancerA changing history
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When to Treat?
Harries and Gore, 2002
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What Have we Learned from Randomized Trials?

• Some dose schedules or routes of administration
  are better than others for a specific drug
• Some drugs are better than others in terms of
  efficacy
• In specific circumstances some drugs are to be
  preferred with respect to toxicity
• In specific circumstances combination
  chemotherapy is superior to single agent
  chemotherapy

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Randomized Trials Combo versus MonoMeta-analysis

• Methods
• Systematic review (8 RCT 6 phase III)
• Data pooled (Mantel Hanzsel Peto model)
• Total number of patients 2312
• Results
• Improved response rate (HR 1.32), PFS (HR 0.67)
  and OS (HR 0.77) with combo but, only in
  pt-sensitive population.
• Orlando et al, ASCO abstract 5524 (2007)

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Overall Survival at 2 years
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Targets for Next-generation Therapy
Tumor cell
Nucleus
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New Non-Cytotoxics in Ovarian Cancer
Target Drug(s) ErbB kinases Gefitinib,
erlotinib, C225, EMD-7200, 2C4 MUC1 /
PEM Pemtumomab MUC16 (CA 125) Oregovomab mTOR /
AKT CCI-779, RAD001C Apoptosis pathway AEG35156,
OGX-011 Angiogenesis Bevacizumab, SU 11248,
Bay-43-9006, AZD2171 Endothelial
cells Combretastatin Matrix metalloproteinases BAY
12-9566, marimastat
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Inhibition of Tumor Angiogenesis (1)

• Agents that specifically inhibit newly sprouting
  vessels
• Ligand antibodies
• Receptor antibodies
• Soluble decoy receptors
• Ribozymes
• Tyrosine kinase inhibitors
• Radioligands
• Rasila et al, 2005

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Inhibition of Tumor Angiogenesis (2)

• Agents that specifically target the vascular
  endothelium.
• Vasculotoxins
• Adhesion inhibitors
• Agents that are both cytotoxic to tumor cells and
  EC
• Cytotoxic agents
• Coagulation products
• Others
• Interferons
• Thalidomide
• Cyclooxygenase-2 inhibitors
• Rasila et al, 2005

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Toxicity of Anti-angiogenic Molecules

• Relatively favorable
• Side effects fatigue, fever, chills,
  neurotoxicity, vertigo, ataxia, loss of
  concentration, headache, nose bleeds, rash,
  nausea, vomiting, hypercoagulability,
  asymptomatic QT prolongation, hypertension,
  proteinuria, transaminases ??, change in bowel
  habits
• Lethal hemorrhage and bowel perforation have been
  observed
• Rasila et al, 2005

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Phase II Trial with Bevacizumab

• Treatment
• Bevacizumab 15 mg/kg IV q 21 d, no dose
  modification (except weight ? gt 10)
• Results in 62 patients
• CR 3 (4.8) RR 17.7 (90 CI 10.3-27.7)
• PR 8 (12.9) MDR 10.25 months
• NC 34 (54.8)
• PD 16 (25.8) PFS gt 6 months (n24)
• ID 1 (1.6) 38.7 (90 CI 28.3-49.9)
• ID inditerminate
• Burger et al, ASCO 2005 (abstract 5009)

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Phase II Trial with Bevacizumab

• Treatment Bevacizumab 15 mg/kg IV q 3 wks
• Results in 44 pts (of the originally planned 53)
• ORR 7/44 (16), MDR 12 weeks
• SAEs overall 18/44 (41)
• 5/44 (11) gastrointestinal perforation
• 5/44 (11) bowel obstruction
• 4/44 (9) arterial thromboembolic events
• 2/44 (5) delayed wound healing
• 1/44 pulmonary hypertension
• 1/44 hypertensive encephalopathy
• Study stopped
• Cannistra et al, ASCO 2006 (abstract 5006)

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Cervical CancerIncidence and mortality

• Second most common form of cancer among women
  worldwide and the leading cause of death from
  cancer among women in developing countries
• At least 493.000 new cases of cervical cancer per
  year (83 in developing countries) and 274.000
  deaths
• In USA 10.370 cases of invasive CC in 2005
• 3.700 deaths
• Parkin et al, 2005
• Jemal et al, 2005

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Cervical cancerMilestones

• Surgery vs radiotherapy in early CC
• NCI consensus statement in 1999 on the role of
  concurrent chemotherapy and radiation
• The importance of Hb-level during radiation
  therapy for CC
• The potential of hyperthermia

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Chemotherapy or Hyperthermia added to RTCervical
Cancer
Outcome RT CT1 RT HT2 Odds ratio Pelvic
control 0.61 0.48 Hazard ratio for
death 0.71 0.53 1Green et al, 2001 2van der
Zee et al, 2002 (absolute benefit of 12)
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Cervical CancerHighlights

• Neoadjuvant chemotherapy in locally advanced
  cervical cancer a role?
• Role of chemotherapy in R/M disease A new
  standard?
• Targeted therapy
• HPV-vaccines

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NACT followed by Radiotherapy (RT) vs RT in
locally Advanced Cervical CancerMeta-analysis
Endpoint Events/pts HR (95 CI) P
value Survival 1084/2074 1.05
(0.94-1.19) 0.393 DFS 938/1724 1.00
(0.88-1.14) 1.000 LR-DFS 911/1724 1.03
(0.90-1.17) 0.654 Distant DFS 899/1724 1.00
(0.88-1.14) 1.000 Meta-analysis Group, 2003 (18
trials/2074 pts median FUP 5.7 yrs)
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NACT followed by Radiotherapy (RT) vs RT in
Locally Advanced Cervical CancerMeta-analysis
Subgroup Trials HR (95 CI) P value Risk of
death Interval gt 14 d 11 1.25 (1.07-1.06) 0.005
25 ? (8) lt 14 d 7 0.83 (0.69-1.00) 0.046 17
? (7) Dose Intensity lt 25 mg/m² 7 1.35
(1.11-1.64) 0.002 35 ? (11) gt 25
mg/m² 11 0.91 (0.78-1.05) 0.200 9
? (3) Meta-analysis Group, 2003
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NACT followed by Surgery ( RT) vs Radical RT in
Locally Advanced Cervical CancerMeta-analysis
Endpoint HR (95 CI) P value Absolute
benefit Survival 0.65 (0.53-0.80) 0.00004 14
(50 ? 64) DFS 0.68 (0.56-0.82) 0.0001 13 (45
? 58) LR-DFS 0.68 (0.56-0.82) 0.0001 13 (45 ?
58) Distant DFS 0.63 (0.52-0.78) 0.00001 15
(45 ? 60) Meta-analysis Group, 2003 (5
trials / 872 pts median FUP 5 yrs)
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NACT followed by Surgery vs ChemoradiationEORTC
Protocol 55994
Pt-based CT followed by type III-V FIGO stage
IB2, Piver Rutledge RH IIA gt 4 cm or IIB WHO-PS
0-2 Age 18-75 yrs P 40 mg/m²/wk x 6 EBRT 45-50
Gy ? EB or BT total dose point A 85 Gy
R A N D O M I Z A T I O N
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Single-Agent Chemotherapy in Cervical CancerNew
cytotoxic agents (1)
Agents No. of No. of Prior Response
Rate studies pts CT Paclitaxel
(24h) 1 55 (52) -/ 17 Paclitaxel
(3h) 1 32 - 25 Docetaxel 1 18 (16) -/ 13 Irino
tecan (wk) 4 181 (172) -/ 0-24 Irinotecan (3
wks) 1 37 (34) - 23.5 Topotecan 1 22 18
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Single-Agent Chemotherapy in Cervical CancerNew
cytotoxic agents (2)
Agents No. of No. of Prior Response
Rate studies pts CT Pirarubicin 1 31
(28) -/ 19 Vinorelbine (wk) 2 81 (74)
- 17-18 Vinorelbine (NACT) 1 43 (42)
- 45 Gemcitabine (1250) 1 45 - 11 Gemcitabine
(800) 2 47 (44) -/ 8-9
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GOG 179 Relapsed Cervix
Median PFS 2.9 vs 4.6 months HR 0.76 (95 CI,
0.597 - 0.969) p.014
Median S 6.5 vs 9.4 months HR 0.76 (95 CI, 0.593
0.979) p.017
Progression-free (PF) survival by treatment
group. Rx, drug treatment.
Survival by treatment group. Rx, drug treatment.
Long H et al, JCO 23 4626-4633, 2005
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New Non-cytotoxics in Cervical Cancer

• Anti-EGF Receptor Therapies
• EGFR expression observed in 75-100 of CC
• Phase II study ZD1839 (500mg/d), no responses
• Inhibition of angiogenesis a/o matrix
  metalloproteinases. Phase I TNP 470
  (vasculotoxin) 1/18 CR gt 7 years.Bevacizumab
  5-FU 1CR, 1 PR, 2SD, 2 PD
• Inhibition of COX-2 ? enhanced cytotoxicity in
  vitro of chemotherapy agents potentiates tumor
  cell radiosensitivity in vivo

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Conclusions

• Both for ovarian cancer and cervical cancer the
  highlights suggest an improvement in outcome.
• The new targeted therapies, in particular the
  anti-angiogenesis molecules seem to have some
  promise for the treatment of ovarian cancer.
  Results of intergration of TATs in the primary
  therapy of advanced ovarian cancer are eagerly
  awaited.
• In case Gardasil does what it suggests to do this
  indicates the beginning of the end of cervical
  cancer.