Ovarian Cancer: Consolidation

1
New Treatments for Newly Diagnosed Gynecologic
Cancers
Neil S. Horowitz MD Director Clinical
Research Brigham and Womens/Dana Farber Cancer
Institute
2
Ovarian Cancer
3
Ovarian Carcinoma Natural History
Symptoms
Slide Modified from original slide of Robert
Coleman, M.D.
4
The Balance of Angiogenesis
Jain RK, Science 200530758-62.
5
The VEGF Pathway
VEGF
VEGF Receptor
Signaling
Proliferation Survival Migration
Of Tumor Cells and Endothelial Cells
6
VEGF Levels in Ascites
VEGF Protein Levels (pg/ml)
12150
Cirrhotic Ascites
1500 695
Colon CA Ascites
2776960
Gastric CA Ascites
5192990
Ovarian CA Ascites
Zebrowski, BK et al. Ann Surg Onc. 1999.
7
Anti-VEGF Strategies
Ligand (VEGF) Binder Bevacizumab
(Genentech) VEGF Trap
(Sanofi-Aventis) VEGF Receptor Blocker
Su11248 (Pfizer) BAY43-9006 (Bayer) PTK787
(Novartis) ZD6474 (AstraZeneca)
VEGF
VEGF-R
Signaling
8
Bevacizumab (AvastinTM)

• Recombinant humanized monoclonal IgG1 antibody
• Recognizes all isoforms of VEGF and blocks VEGF
  function
• Half-life is approximately 20 days (range, 11 to
  50 days)
• Presta et al. Cancer Res. 1997574593.

9
Bevacizumab Blocks Angiogenesis

10
DFCI Trial Treatment Schema
IV
C
Carboplatin AUC 6
Bevacizumab 15 mg/kg IV
IP
T
Taxol 60mg/m2
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Debulk Port
PORT
PK
PK
PK
11
DFCI Protocol 07-039
Stage III /IV Ovarian, Fallopian Tube, Peritoneal
Ca Or Stage IV PS or Clear Cell Endometrial
CA Optimal or Suboptimal
Bevacizumab 15 mg/kg q 21 days x 1 year
Carboplatinum AUC 5 Paclitaxel 175 mg/m2 Avastin
15 mg/kg Every 21 days x 6 cycles
RANDOMIZE
Bevacizumab 15 mg q 3 weeks Erlotinib 150 mg PO
Daily X 1 year
Target accrual N 60 Primary endpoint PFS of
AE vs A alone and assess toxicities of
regimens Secondary endpoint Response rate CTA
12
GOGFrontline Trials
GOG-218
Suboptimal (gt 1 cm) EOC, PPC, FT cancer
Paclitaxel Carboplatin Placebo
Paclitaxel Carboplatin Bevacizumab
Paclitaxel Carboplatin Bevacizumab
Bevacizumab 15 months
Placebo 15 months
Placebo 15 months
N 1,200 - 1,400 patients Survival, PFS primary
endpoints Biologic QOL endpoints
EOC Epithelial ovarian cancer PPC Primary
peritoneal cancer FT Fallopian tube PFS
Progression-free survival QOL Quality of life.
13
Surrogate Markers for Angiogenesis

• Tissue biopsy
• Interstitial fluid pressure measurements
• Circulating endothelial cells
• Circulating progenitor cells

• VEGF, bFGF, PlGF,
• PET imaging
• MRI imaging

14
(No Transcript)
15
EGFR in Vulvar Malignancies
16
Vulvar Cancer

• I. Incidence
• 4th most common GYN malignancy
• 90 squamous cell carcinoma (SCC)
• In 2007, 3480 new cases in USA with 880 deaths
• Incidence increasing, though largely due VIN
  and early stages

• II. Epidemiology
• FIGO reported mean age affected is 65 years old
• Recent trend towards younger age at presentation
  
• No racial distribution
• Possible socioeconomic correlation with increased
  incidence in lower socioeconomic populations
• HPV dependent and independent pathways

17
Vulvar Cancer Treatment
Massive Generalization

• Early stage disease treated with radical
  surgical excision
• Late stage disease a clinical challenge
• - Surgery
• Radiation Therapy
• Chemotherapy

18
EGF Binds to Receptor Resulting in Dimerization
and Autophosphorylation
EGF
EGF
EGF
TK
TK
TK
Activation of intracellular signaling molecules
Increased cell proliferation, inhibition of
apoptosis, neoplastic angiogenesis
19
EGFR Vulvar Cancer
Increased EGFR expression has been associated
with squamous cell cancer of the vulva

• Early models utilized to characterize EGFR
  activity were in vulvar carcinoma cell lines
• EGFR over-expression has been shown to have
  a positive correlation with advanced stage, lymph
  node involvement and decreased survival

Changes in EGFR activity may have a role in
tumorgenesis making it an attractive candidate
for targeted therapy
20
EGFR Targeted Therapy

• Receptor binding monoclonal antibodies
  (Cetuximab/ Erbitux)
• Bind extracellular domain
• Competes with ligand
• Small-molecule reversible TKI (Gefitinib/ Iressa
  and Erlotinib/Tarceva)
• Competes with ATP binding in the TK domain
• Abrogates catalytic activity
• Oral dosing

21
Tyrosine Kinase Inhibitor Toxicity

• Diarrhea (dose limiting)
• Acne-like rash (face, neck, scalp, chest, back)
• Loss of appetite
• Nausea/Vomiting
• Fatigue
• Headache

22
The Fingerprint
EGFR gene amplification (18) 3 IHC (30)
10x
4x
23
Clinical Correlation

• FISH-positive correlates with
• Intense IHC staining
• Non-smokers
• Patients aged gt70
• Absence of high-risk HPV

24
Conclusions
EGFR amplification appears to be present in a
subset of invasive SCC vulvar tumors

• Associated with advanced age
• Non-smoking
• Independent of HPV
• Aggressive phenotype leading to decreased
  survival

Retrospective data suggests that a subset of
women with vulvar cancer may be candidates for
biologic therapies targeting the EGFR cascade
25
Phase II trial of Erlotinib in Women with Vulvar
SCCA
Cohort 1
Definitive surgery or chemoradiation
4- 6 wks
Erlotinib 150 mg/day
Cohort 2
Until progression or adverse effects prohibit
further therapy
Q 28 days
26
Patient G.R.
Pre Tarceva
Post Tarceva
27
Patient S.F.
Pre Tarceva
Post Tarceva
28
Endometrial Cancer
29
Minimal Impact SurgeryDefinition

• Reduce the frequency, magnitude, duration and
  cost of surgical procedures.
• Reduce or eliminate inpatient hospital stay
• Reduce short and long term disability
• Reduce the interval to adjuvant therapy
• Minimize changes in body image
• Reduce psychological impact

30
Minimal Impact SurgeryThe Golden Rules

• The effectiveness of cancer treatment must be
  equivalent to or better than in traditional
  surgical approaches.
• New minimally invasive surgical techniques do not
  change tumor biology.
• Refining indications for surgery critical to
  reducing surgical morbidity.

31
Conventional Laparoscopy

• Surgeons view is devoid of depth perception
• Instrument movement is counterintuitive and
  limited
• Ergonomics are often poor

32
Robotic Assisted LaparoscopyAdvantages

• Surgeons view is stable and three dimensional
• Normal depth perception with magnification
• Instruments perfectly simulate hand and wrist
  movement
• Superior ergonomics
• Less dependent upon pneumoperitoneum

33
Robotic SurgeryDisadvantages

• Devoid of tactile feedback
• Limited quadrant surgery
• Total surgical time prolonged during the
  learning curve
• Port placement critical
• Significant initial investment
• Knowledgeable surgical team

34
GOG 209
Reasons Off Study Q
P Progression 51 vs 76 Toxicity 85
vs 60 Death 15 vs 8
35
Rationale for Using mTOR Inhibitors in the
Treatment of Solid Tumors
36
mTOR Inhibition in Gynecologic Malignancies
1. Treeck O, et al. Gynecol Oncol.
2006102292-299. 2. Mabuchi S, et al. Cancer
Res. 2007672408-2413. 3. Mabuchi S, et al.
Clin Cancer Res. 2007134261-4270. 4. Hudes C,
et al. N Engl J Med. 20073562271-2281. 5. Oza
AM, et al. ASCO 2008. Abstract 5515.
37
mTOR Inhibitor Current Clinical Trials in
Endometrial Cancer
38

• Cervical Cancer

39
Estimates of the worldwide incidence of cervical
cancer
450,000 cases
11, 150 cases
3,670 deaths
250,000 deaths
/100.000 women
Source GLOBOCAN 2000 IARC
40
Staging of Cervical Cancer
Husband Reznek, Imaging in Oncology, 1998
41
Staging of Cervical Cancer
Husband Reznek, Imaging in Oncology, 1998
42
FIGO Stage and Treatment
FIGO Stage Distribution
Treatment I 38 II
33 III 25 IV 4
Surgery Chemoradiation
Chemoradiation
43
(No Transcript)
44
Radical Trachelectomy Patient selection

• Desire to preserve fertility/ Age lt 40
• Stage IA2 or IB1 (?IA1 with LVI)
• Lesion lt 2 cm
• No LVI
• No evidence of lymph node metastases
• No upper endocervical involvement

45
Abu Rustum, Gyn Onc, 2006
46
(No Transcript)
47
(No Transcript)
48
Recurrences and Deaths
Plante, Gyn Onc, 2004
49
Obstetrical Outcomes