Ovarian cancer

1
Ovarian cancer

• Dr Geoff Hall - Senior LecturerSt Jamess
  Institute of Oncology

2
Types of Ovarian Cancer
3
Ovarian Cancer

• Epithelial cancers (gt 90)
• Arise from mesothelial cells lining ovary (or
  peritoneum)
• Cells undergo Müllerian differentiation
• Fallopian tube mucosa - Serous
• Endocervical mucosa - Mucinous
• Endometrium - Endometrioid or Clear cell
• Primary peritoneal cancer
• Ovarian cancer with no ovarian mass
• Why dont men get PPC ????

4
(No Transcript)
5
Prognosis related to stage

• Overall - 30 5-year survival
• Stage 1 - 90
• Stage 2 - 65
• Stage 3 - 35
• Stage 4 - 10

6

• Overall - 30 5-year survival
• Stage 1 - 90
• Stage 2 - 65
• Stage 3 - 35
• Stage 4 - 10

7
Ovarian Cancer Surgery

• Surgery should comprise
• Total abdominal hysterectomy, bilateral
  salpingo-oophrectomy
• Biopsy of peritoneal surfaces
• Visualisation and biopsy of under-surface of
  diaphragm
• Pelvic para-aortic lymph nodes biopsies
• Peritoneal washings
• Debulking of other lesions omentectomy
• Target - no residual disease

8
The Reality
9
Ovarian cancer PFS and debulking (ICON5)
10
Ovarian cancer PFS and debulking (ICON5)
11
What first ?CHORUS EORTC 55971
Suspected ovarian cancerPelvic mass abdominal
metastasesCA125CEA gt 25
Randomise
Primary surgery
Chemotherapy x 3
Interval surgery
Chemotherapy x 6
Chemotherapy x 3
12
EORTC 55971

• 718 patients randomised.
• Median follow-up was 4.8 years.
• Postoperative mortality (lt 28 days) 2.7 v 0.6
• Sepsis 8 v 2
• Haemorrhage G3/4 7 v 4.
• Median OS 29 v 30 months (HR 0.98)
• Median PFS 11 v 11 months
• Neoadjuvant chemotherapy produces similar OS and
  PFS outcomes compared to standard primary
  debulking.
• Due to the lower morbidity of IDS compared with
  PDS, NACT can be considered as the preferred
  treatment.

13
Surgery or chemo ?

• Definitely operable - Surgery
• Uncertain - CHORUS
• Definitely inoperable - Chemotherapy

14
Surgery or chemo ?

• Definitely operable - CHORUS
• Uncertain - Chemotherapy
• Definitely inoperable - Chemotherapy

15
Chemotherapy

• Highly effective
• 70 to 80 response rates
• Median progression-free survival - 1 to 2 years
• Rarely curative
• Median overall survival - 2 to 3 years
• 5-year survival 30 to 40

16
ICON 3

• Carboplatin -v- Carboplatin/Taxol 2074 patients
• CAP -v- Carboplatin/Taxol 653 patients

Overall survival
Progression-free survival
17
Early Ovarian Cancer

• Does chemotherapy help in early ovarian cancer?
• ICON1
• Uncertain indication for chemotherapy
• ACTION
• Stage 1a-1c, G2 to G3
• Stage 2a, all grades
• Clear cell

JNCI, 2003, 95, 105
18
ICON 1 and Action Combined
JNCI, 2003, 95, 105
19
ACTION Effect of good surgery
20
Early Ovarian Cancer

• Clear indication for chemotherapy
• Stage 1c
• Clear cell histology
• Chemotherapy advised
• Surgical rupture of cyst (surgical 1c)
• Grade 3 differentiation
• Inadequate staging
• ? Is second laparotomy less toxic ?

21
Towards better chemotherapy

• ICON 5
• ICON 7
• JGOG 3016
• IP chemotherapy GOG 172

22
ICON 5Are three drugs better than two
23
ICON5 No benefit for three drugs

• 4312 patients recruited - Jan 01 to Sept 04

24
JGOG 3016 ASCO 2008Weekly dose dense
chemotherapy

• Standard 3-weekly chemotherapy
• Carboplatin (AUC 6) / Paclitaxel (80 mg/m2)
• Dose Dense Weekly Chemotherapy
• Carboplatin (AUC6 q21)
• Paclitaxel (80 mg/m2) D1, D8, D15
• 631 patients

25
JGOG 3016 Weekly dose dense chemotherapy
PFS
OS
26
Biological therapy for ovarian cancer

• VEGF in ovarian cancer
• VEGF expression high
• 31 primary tumours
• 80 peritoneal metastases
• Circulating VEGF elevated
• Advanced stage, presence of ascites
• Association with poor prognosis
• Animal models
• IP VEGF infected ovarian cancer cells ? ???
  haemorrhagic ascites
• IP Ad-VEGF ? ??? haemorrhagic ascites
• Anti-VEGF Abs dry up ascites, cytostatic to
  tumour,
• Recurrent ascites dominates end-stage ovarian
  cancer

27
New agents targeting the VEGF Pathway
? Permeability
VEGF
VEGFR1 FLT1
Cation channel
VEGFR2 KDR
P
P
P
P
P
P
P
P
P
P
P
P
Migration, permeability, DNA synthesis, survival
Angiogenesis
Lymphangiogenesis
28
ICON7 The clinical trialCarboplatin /
Paclitaxel /- Bevacizumab
Epithelial ovarian cancer Stage Ic to IV
2200 patientsInternational collaboration
Cytoreductive surgery
Carboplatin AUC6Paclitaxel 175 mg/m2 (3
hours) q21 x 6 or until disease progression
Carboplatin AUC6Paclitaxel 175 mg/m2 (3
hours) Bevacizumab 7.5 mg/kg q21 x 6 or until
disease progression
Bevacizumab 7.5 mg/kg q21 x 12 or until disease
progression
No maintenance
29
ICON7 The clinical trialCarboplatin /
Paclitaxel /- Bevacizumab

• Closed to recruitment Jan 2009
• PFS planned for ASCO 2010
• OS expected ASCO 2011

30
Current / Planned trials

• Serous Endometrioid ICON 8
• Carboplatin/Paclitaxel
• Weekly Carboplatin/Paclitaxel
• Weekly Dose dense Carboplatin/Paclitaxel
• /- Bevacizumab
• Clear cell Japanese
• Carboplatin/Paclitaxel v Cisplatin/Irinotecan
• Mucinous MRC
• Carboplatin/Paclitaxel
• Oxaliplatin / Capecitabine
• /- Bevacizumab

31
Intraperitoneal chemotherapyThe new challenge

• Ovarian cancer remains confined to peritoneal
  cavity
• Why deliver chemotherapy intravenously
• Intraperitoneal delivery increases chemotherapy
  to tumour
• Platinum 4-fold
• Paclitaxel 1000-fold
• Series of clinical trials show benefit
• Meta-analysis
• Recent GOG study

32
IP ChemotherapyGOG 172 Armstrong et al, NEJM,
2006
Stage 3 ovarian cancerResection to less than 1cm
Randomise
IV Chemotherapy Paclitaxel 135/m2 Cisplatin 75/m2
IV plus IP chemotherapy Paclitaxel
135/m2 Cisplatin 100/m2 IP, day 2 Paclitaxel
60/m2 IP, day 8
33
IP Chemotherapy GOG 172 Armstrong et al, NEJM,
2006
Overall survival
Progression-free survival

• Is IP chemotherapy the new standard of care ?
• NCI clinical alert
• No International consensus
• No clarity on which IP chemotherapy to use

34
PETROC

• Primary chemotherapyIDS to lt 1 cm
• Arm 1 Paclitaxel 175 mg/m2 D1 IV
  Carboplatin AUC 5/6 D1 IV
• Arm 2 Paclitaxel 135 mg/m2 D1 IV and 60 mg/m2
  D8 IP Cisplatin 100mg/m2 D1 IP
• Arm 3 Paclitaxel 135 mg/m2 D1 IV and 60 mg/m2
  D8 IV Carboplatin AUC 5/6 D1 IP

35
After Chemotherapy

• Complete chemotherapy
• Final CT scan
• Clinical review
• Clinical assessment
• CA-125
• No routine CT scans
• 3 months in years 1 and 2
• 4 months in year 3
• 6 months in years 4 and 5
• Annual thereafter
• ? Role for maintenance chemotherapy

36
Maintenance Chemotherapy

• Role of extended paclitaxel in patients with CR
• 3 -v- 12 cycles of paclitaxel administered every
  28 days
• 277 patients
• 54 PFS events in 222 patients
• no major differences in toxicity between the
  regimens (except peripheral neuropathy
• Median PFS
• 3 cycles 21 months (p0.0035)
• 12 cycles 28 months (p0.0023)
• TRIAL STOPPED EARLY UNDER PRE-DEFINED RULE

Markman et al, 2002 J Clin Oncol, 212460-2465
37
Maintenance Chemotherapy
Markman et al, 2002 J Clin Oncol, 212460-2465
38
Platinum sensitive relapse

• Platinum-free interval
• Platinum refractory
• Disease progresses through platinum
• Platinum resistance
• Disease recurrence within 6 months of platinum
• Partially platinum sensitive
• Disease recurrence 6 to 12 months after platinum
• Platinum sensitive relapse
• Disease recurrence gt 12 months after platinum

39
Platinum sensitive relapse

• Platinum-free interval
• Platinum refractory
• Disease progresses through platinum
• Platinum resistance
• Disease recurrence within 6 months of platinum
• Partially platinum sensitive
• Disease recurrence 6 to 12 months after platinum
• Platinum sensitive relapse
• Disease recurrence gt 12 months after platinum

40
Platinum sensitive - ICON 4

• Relapsed disease
• Taxol / Platinum -v- Platinum-only chemotherapy
• Recurrence gt 6 months after primary treatment
• Platinum only
• Cisplatin 75 mg/m2 single agent
• Cisplatin 50 mg/m2 other drugs
• Carboplatin AUC5 single agent
• Taxol /Platinum combination
• Taxol 175 mg/m2 Carboplatin AUC5
• Taxol 175 mg/m2 Cisplatin 50 mg/m2

Parmar et al, 2003, Lancet, 3612099-106
41
ICON 4 Overall Survival
Parmar et al, 2003, Lancet, 3612099-106
42
ICON 4 Progression Free
Parmar et al, 2003, Lancet, 3612099-106
43
ICON6Carboplatin (/Paclitaxel) /- Cediranib
44
New agents targeting the VEGF Pathway
? Permeability
VEGF
VEGFR1 FLT1
Cation channel
VEGFR2 KDR
P
P
P
P
P
P
P
P
P
P
P
P
Migration, permeability, DNA synthesis, survival
Angiogenesis
Lymphangiogenesis
45
ICON6Carboplatin (/Paclitaxel) /- Cediranib
46
Platinum resistant relapse

• Dose Intensive Weekly Carbo/Taxol
• Carboplatin (AUC4) D1, D8, D15
• Paclitaxel (90 mg/m2) D1, D8, D15
• Q28
• 2 cycles followed by standard regimen

47
Results (90/4 regimen)
Resistance defined as lt6months since last
exposure
48
Results (90/4 regimen)
10/25 not radiologically evaluable 5 received
lt2 cycles because of allergic reaction (4)
clinical PD/death (1) 5 did not have CT
scans 5/25 not CA125 evaluable 5 received lt2
cycles because of allergic reaction/ clinical
PD/death
49
Dose Intensive Weekly Carbo/Taxol
Median PFS 12.6 (95CI, 5.0-20.1) months
50
Dose Intensive Weekly Carbo/Taxol
Median OS 6.0 (95CI, 5.6-6.4) months
51
Caelyx v Topotecan

• Both NICE approved in ovarian cancer
• Response rate in platinum sensitive 15 to 20
• Response rate in platinum-resistant disease lt 10

Gordon et al, 2004, Gynecol Oncol, 951-8
52
PARP inhibitionBRCA mutation or Defective HR
phenotype
53
Ovarian cancer New treatments

• New chemotherapy drugs
• Active in platinum-resistant patients
• Improve platinum-based therapy
• New biological agents
• Oral agents role as maintenance therapy

Will ovarian cancer become a chronic condition ?