1. Ovarian Cancer
Dr Helen Mackay

2. Ovarian Cancer: A huge subject!
The basics
First line treatment
GOG 172 (IP chemotherapy) and its aftermath!!!
Second line and beyond!!!!
Where do we go from here???

4. Cancer Incidence Cancer Deaths*
Women 668,470
Women 272,810
32% Breast
12% Lung & bronchus
11% Colon & rectum
6% Uterine corpus
4% Ovary
4% Non-Hodgkin lymphoma
4% Melanoma of skin
3% Thyroid
2% Pancreas
2% Urinary bladder
20% All Other Sites
25% Lung & bronchus
15% Breast
10% Colon & rectum
6% Ovary
6% Pancreas
4% Leukemia
3% Non-Hodgkin lymphoma
3% Uterine corpus
2% Multiple myeloma
2% Brain/ONS
24% All other sites
ONS=Other nervous system.
Source: American Cancer Society, 2004.

5. Ovarian TNM FIGO Description Tx T0 T1 T1a T1b T1c T2 T2a T2b T2c T3IB IC II
IIA
IIB
IIC
III
IIIA
IIIB
IIIC IV
Not assessed
No tumor
Ovaries alone
One ovary
Both
Rupture/+washings
Pelvic ext
Uterus+/-tubes
Other tissues ascites-ve
Above +ascites positive
Peritoneal mets outside pelvis
Microscopic
2 cm or less
2 cm +/- regional node
Metastasis excluding peritoneum

6. Ovarian Cancer Is often asymptomatic in its early stages
Most patients have widespread disease at the time of diagnosis
Yearly mortality in ovarian cancer is approximately 65% of the incidence rate
Suboptimally debulked stage III-IV patients reveals a 5-yr survival rate of <10%
Early stages of the disease are curable in a high percentage of patients

7. Ovarian Cancer

8. Ovarian Cancer - Prognosis
Stage 1 a + b >90%
Stage 1 c 80%
Stage %
Stage %
Stage %
But really depends on response to chemotherapy and PS!

9. Treatment
Surgery
Upfront,delayed or interval?
Chemotherapy
Radiation

10. Surgery Accurate staging Debulking disease
Midline incision; full exploratory laparotomy
TAH & BSO
Omentectomy
Lymph node assessment/sampling
Washings

11. Interval debulking surgery
Improve PFS
Response may decrease the extent of surgery
Increase rate of optimal cytoreduction
Information on chemosensitivity

12. IDS EORTC improved survival GOG same
Cochrane review 2009 no conclusive evidence for or against
BUT benefit in pts undergoing inadequate initial surgery. All patients should be optimally debulked if possible!

13. Neoadjuvant chemotherapy
Who?
Traditionally poor PS, Extensive disease, significant co morbitidities.
Resource availability?
But
EORTC Survival is the same neoadjuvant chemo vs upfront debulking surgery
NEJM paper eagerly awaited!!!!

15. Who do you treat? Stage II,III,IV Stage Ib/c, stage 1a?
ICON 2/ACTION trials
Stage 1A ovarian cancer
Adjuvant Carbo vs no treatment post surgery
Overall improvement in survival by 7% with Carbo
Impact most apparent in patients who did not have optimal staging surgery
Meta analysis Trope and Kaern JCO 25 (2007)

16. Advanced Ovarian Cancer
Advanced disease, sub-optimally debulked disease
GOG 111: Cisplatin and paclitaxel significantly better than cisplatin/cyclophosphamide
N=386
RR 73% vs 60%
PFS: 18 vs 13 months (p<0.001)
OS: 38 vs 24 months (p<0.001)

17. Confirmatory Studies EORTC/NCIC Trial. N= 680 (OV10) Additional trials
Cisplatin/Taxol (3hr) better than cisplat/cyclo
RR 59% vs 45%
PFS 15.5 vs 11.5 months
OS 35.6 vs 25.8 months
Additional trials
Carboplatin+ taxol instead of cisplatin+ taxol (reduced neurotoxicity) GOG 158
Carboplatin + taxotere similar activity to carbo + taxol
GOG 132: High dose cisplatin = cisplatin/taxol

18. But
ICON 3. N= 2074 patients
Carboplatin or CAP vs Carbo/Taxol
Median OS 35.4 vs 36.1 months
Med. PFS16.1 vs 17.3 months
No difference in any of the subgroups
Would suggest standard dose carboplatin is sufficient.

19. But GOG 111 high risk stage ¾ suboptimally debulked
ICON 3 stage ¾ >2cm trend to benefit for carbo tax
2:1 randomisation 331 patients high risk.
Carbo taxol remains the standard of care!

20. Chemotherapy Current Standard of Care:
Carboplatin AUC 5 or 6 and taxol 175mg/m2 over 3 hours
Well tolerated, low neurotoxicity
Single agent carboplatin AUC 5 (measured) or AUC 6 (Calculated)

21. Improve outcome How? Treat earlier higher dose
more drugs: doublets /triplets
Better drugs: targeted agents
longer time: more is better?
administer it differently -
intra-peritoneally
intra-operatively
All of the above!
mechanisms of failure
drug resistance

22. More is better? 11 randomised trials increasing platinum dosage
2 positive
Phase II high dose chemotherapy: no benefit
BUT…………..

23. Doublets triplets and different designs: or lets make things complicated!!!
NCIC OV16
Randomized clinical trial:
Taxol and Carboplatin (8 cycles) vs
Sequential couplets of Cisplatin/topotecan (4) and carboplatin/taxol (4)
Endpoints:
Progression Free survival
Overall survival, response rate, toxicity
ICON5
4 arms
Carbo/Taxol vs doublets triplets including gemcitabine/topotecan/liposomal doxorubicin

25. What next??

26. Carboplatin/paclitaxel Carboplatin/paclitaxel + bevacizumab
ICON-7
Stratification factors: stage, residual disease status, country
Carboplatin/paclitaxel
observation
1520
stage IIB-IV patients
Carboplatin/paclitaxel + bevacizumab
bevacizumab
6 cycles
(4.5 months)
12 cycles
(7.5 months)
Treatment:
Carboplatin AUC = 6
Paclitaxel 175 mg/m2
Bevacizumab 7.5 mg/kg
(All treatments q 3 weeks)

27. Bevacizumab yes or no? coming to a journal near you Fall 2010!!!!

28. IP chemotherapy: Rationale
Peritoneal cavity is the major route of spread of ovarian cancer
Debulking surgery can reduce cancer volume
Lengthy exposure to high concentration of drugs
Diffusion of drug across 2-3 layers of cells

29. Limitations Poor penetration of bulky disease
Less exposure of drug to extraperitoneal disease
Complications
Catheter problems
Infection
Abdominal pain
Inadequate drug distribution

31. Results GOG 172 N =415 IV IP Neg second look N=202 41% 57% PFS
18.3 mos
23.8 mos
Overall Survival
49.7 mos
65.6 mos
Rel. Risk PFS
.77

32. Median survival time for randomized trials comparing IV versus IV/IP
Study Identifer/ Authors/ Year Published
Number of patients
Median duration of survival for control regimen (months)
Median duration of survival for experimental regimen (months)
SWOG 8502/ GOG 104, Alberts et al, 1996
546 41
49*
Polyzos et al, 1999 90 52 63
Gadduci et al, 2000
113 25 26
GOG 114/ SWOG 9227, Markman et al, 2001
462 51
67*
Yen et al, 2001
118 48 43
Armstrong et al, 2006
415
49.7
65.6*

33. Study / Year
Control Regimen
Experimental Regimen
Eligible patients
No of patients
1994
Cisplat 100 mg.m2 IV; cyclo 600 mg/m2
Q 3 weeks x 6
Cisplat 200 mg/m2 IP; etoposide 350 mg/m2 IP Q 4 weeks x 6
Stage IIC-IV 62
GOG 104
1996
Cisplat 100 mg/m2 IV
Cyclo 600 mg/m2 IV
Cisplat100 mg/m2 IP
Stage III, < 2 cm residual
546
Greek
1999
Carbo 350 mg/m2 IV; Cyclo 600 mg/m2 IV
Carbo 350 mg/m2 IP; Cyclo 600 mg/ m2 IV
Stage III 90
GONO
2000
Cisplat 50 mg/m2 IV; Cyclo 600 mg/m2 IV; Epi 60 mg/m2 IV
Q 4 weeks x 6
Cisplat 50 mg/m2 IP; Cyclo 600 mg/ m2 IV; Epi 60 mg/m2 IV
Stage II-IV, < 2 cm residual
113
GOG 114
2001
Cisplat 75 mg/m2 IV
taxol 135 mg/m2 (24 hr) IV
Carbo(AUC9) IV q 28 days x 2; Cisplatin 100 mg/ m2 IP; Paclitaxel 135 mg/m2 (24 hr) IV q 3 weeks x 6
Stage III, < 1 cm residual
462
Taiwan
Cisplat 50 mg/m2 IV; Cyclo 50 mg/m2 IV; Epi/ Dox 50 mg/m2 IV
Cisplat 100 mg/m2 IP
Cyclo 500 mg/m2 IV; Epi/ Dox 50 mg/m2 IV
118
GOG 172
2005
Cisplat 75 mg/m2 IV; Taxol 135 mg/m2 (24 hr) IV
Taxol 135 mg/m2 (24 hr) IV; Cisplat 100 mg/m2 IP; Taxol 60 mg/m2 IP on day 8
415

35. NCI clinical statement 2006
“ Based on the evidence of these 3 randomised phase III trials a combination of IV and IP chemotherapy conveys a significant survival benefit to women with optimally debulked epithelial ovarian carcinoma”

36. BUT……toxicity GOG 172: GI toxicity 46% vs 24% Infection 16% vs 1%
leuopenia 76% vs 64%
GOG 114
GI toxicity 20% vs 8%
leucopenia 96% vs 62%
GOG 104
GI toxicity 18% vs 2%
leucopenia 40% vs 50%

37. Completion rate for prescribed courses of chemotherapy (%)
Study identifier/ Author/ Year of publication
IV regimen (%)
IP/IV regimen for IP administration (%)
SWOG 8501/ GOG 104, Alberts et al, 1996 58
GOG 114/ SWOG 9227, Markman et al, 2001 86 71
Gadducci et al, 2000 96 65
EORTC 55875, Piccart et al, 2003 NA 56
GOG 172, Armstrong et al, 2005 90 42

38. Ozols et al. NEJM 2006

39. Summary 21.6% decrease in risk of death!
Unproven benefit ,toxic,quality of life issues (North American detractors/ Europe)
Limited population stage III optimally debulked UPFRONT!
Cost/resources

40. Consolidation of Remission
More chemotherapy - doesn’t work
6 vs 12 cycles – no difference
Monthly taxol – 3 months vs 12 months paclitaxel
improvement in TTP – improvement in DFS by 3 months for 12 months additional therapy
DSM closed trial on basis of difference in TTP so no information on survival or QL
Not been adopted as recommendation until survival difference and QL evaluated.

41. Radiation Radiation - Alon Dembo et al. BUT early stage disease
optimally debulked disease
Whole abdomen and pelvis field
BUT
no RCT comparing with
chemotherapy
no treatment

42. Treatment of Advanced Ovarian Cancer

43. Treatment of Advanced Ovarian Cancer
10-15%
15%
40%
50-70%

44. Standard of Care – Second Line
Platinum Sensitive
Platinum free interval > 6m
Platinum combination
ICON 4 – TC > C
OS 29 vs 24m
OV15 – GemC > C
47% vs 31%
PFS 8.6 vs 4.8 m
Calypso Carbo caelyx> CT
PFS 11.3 vs 9.4 (p=0.0005)
High completion rates
Platinum Resistant
What agent?
Any differentiation?
QL and Toxicity
Caelyx
Topotecan
Gemcitabine
Etoposide
Capecitabine

45. Caelyx™ vs Topotecan (Survival Platinum Sensitive)
100 90 80 70 60 50 40 30 20 10
Pegylated Liposomal Doxorubicine
Topotecan
Hazard Ratio = 0.63 [0.47 – 0.85]
Stratified Log-rank p = 0.002
Patient Alive (%)
Median 112 weeks
Median 77 weeks 26 52 78
104
130
156
182
208
234
Time (Weeks)
Gordon AN, et al. J Clin Oncol. 2001;19: ; European Cancer Conference 2003.

46. Caelyx™ vs Topotecan (Survival Platinum Sensitive)
100 90 80 70 60 50 40 30 20 10
Pegylated Liposomal Doxorubicine
Topotecan
Hazard Ratio = 0.63 [0.47 – 0.85]
Stratified Log-rank p = 0.002
Patient Alive (%)
Median 112 weeks
Median 77 weeks 26 52 78
104
130
156
182
208
234
Time (Weeks)
Gordon AN, et al. J Clin Oncol. 2001;19: ; European Cancer Conference 2003.

47. Caelyx™ vs Topotecan Grade 4 toxicity 17.2% vs 71%
Caelyx grade 3 PPE 22%
Neuropenia grade 3/4 12%vs 77%
PCC transfusion 57.8% vs 14.9%
G CSF % vs 29%
Quality of life the same

48. Carboplatin Combinations In Ovarian Cancer (Efficacy Results)% %
(n = 392)
(n = 178) %

49. Ovarian Cancer and Bevacizumab (phase II)
GOG
CCC
Bevacizumab 15mg/kg q 3/52
Bevacizumab 10mg/kg q 2/52
Cyclophosphamide 50mg od
N=62
N=29
1 or 2 previous chemotherapy courses
At least 1 previous course of chemotherapy
RR 17.7% (CR 4.8%)
RR 21%
SD 54.8%
SD 59%
6month PFS 38.7%
6month PFS 57%
Median PFS 4.7months
Median PFS 5.8months
Median OS 17months
Median OS not reached

50. Combination Bevacizumab Regimens in Ovarian Cancer
Carboplatin Paclitaxel
(n=43, Penson, ASCO 2006)
Cyclophosphamide
(N=70) (Schultheis ASCO 2006)
Erlotinib
(n= 13) Friberg ASCO 2006
Bevacizumab
15 mg/kg q3w (+maintenance)
10 mg/kg q2w
15 mg/kg q3w
Other drugs
Carboplatin AUC5
Paclitaxel 175 mg/m2 q3/52
50 mg/d
Erlotinib 150 mg/d
Prev. regimens ≤3
Pt sensitivity
Pt Refractory
4 refractory, 2 resistant, 7 sensitive
Toxicity
Neuro, HT, PE, Wound healing (No GI perf, ATE)
III/IV (>5%): HT, fatigue, Na↓, pain
Diarrhoea, GI perforation (2/13), HT
Response
CT: CR 56%, PR 22%
Ca-125: CR 89%, PR 7%
CR 0%, PR 25%, SD 15%
CR 1 (8%), PR 1 (8%) SD 7 (54%)
Median PFS (m)
6.6
4.1

51. GI Perforation Historically, incidence of GIP in ovarian cancer is low
Clinical trials to date (3-15%)
Associations with:
GI involvement of tumor
Bowel obstruction / thickening
Heavily-pretreated patients
? response

52. PARP inhibitors PAR chains are degraded via PARG DNA damage
Repaired DNA
PARP
DNA damage
Binds directly to SSBs
Repair enzymes
PAR
Nicotinamide +pADPr
NAD+
Once bound to damaged DNA, PARP modifies itself producing large branched chains of PAR

53. Responders by RECIST (%) Responders by RECIST or GCIG (%)
# evaluable
Responders by RECIST (%)
Responders by RECIST or GCIG (%)
Phase I (23)
Phase II (24)
Total 46 33
13 (28%)
11 (33%)
21 (46%)
20 (61%)
Platinum Sensitive (>6 months) 10 7
5 (50%)
1 (14%)
8 (80%) --
Platinum Resistant (≤6 months) 25 26
8 (32%)
10 (38%)
11 (44%)
Platinum Refractory 11
0 (0%)
2 (18%)

54. The Future Personalised oncology? rare tumors: clear cell etc
BRCA 1 and 2
Molecular signatures
MTOR
Hedgehog
Trials trials and more trials of which more from Dr Oza!