Ovarian Cancer

Dr Helen Mackay

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???

Cancer Incidence Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2004.

Women272,810

•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

•32% Breast

•12% Lung & bronchus

•11% Colon & rectum

•6% Uterine corpus

• 4% Ovary

• 4% Non-Hodgkin lymphoma

•4% Melanomaof skin

•3% Thyroid

•2% Pancreas

•2% Urinary bladder

•20% All Other Sites

Women668,470

TNM FIGO Description

Tx

T0

T1

T1a

T1b

T1c

T2

T2a

T2b

T2c

T3

T3a

T3b

T3c

I

IA

IB

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

Ovarian

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

Ovarian Cancer

Ovarian Cancer - Prognosis

• Stage 1 a + b >90%

• Stage 1 c 80%

• Stage 2 50%

• Stage 3 30%

• Stage 4 10%• But really depends on response to chemotherapy and

PS!

Treatment

• Surgery– Upfront,delayed or interval?

• Chemotherapy

• Radiation

Surgery

• Accurate staging

• Debulking disease– Midline incision; full exploratory laparotomy– TAH & BSO– Omentectomy– Lymph node assessment/sampling– Washings

Interval debulking surgery

• Improve PFS

• Response may decrease the extent of surgery

• Increase rate of optimal cytoreduction

• Information on chemosensitivity

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!

Neoadjuvant chemotherapy

• Who?

Traditionally poor PS, Extensive disease, significant co morbitidities.

Resource availability?• But

EORTC 55971 Survival is the same neoadjuvant chemo vs upfront debulking surgery

NEJM paper eagerly awaited!!!!

Ovarian Cancer Survival

0

10

20

30

40

50

60

70

80

90

100

1960s

1980s

1990s

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)

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)

Confirmatory Studies• EORTC/NCIC Trial. N= 680 (OV10)

– 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

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.

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!

• 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)

Chemotherapy

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

More is better?

• 11 randomised trials increasing platinum dosage

• 2 positive

• Phase II high dose chemotherapy: no benefit

• BUT…………..

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

What next??

ICON-7

1520stage IIB-

IV patients Carboplatin/

paclitaxel + bevacizumab

bevacizumab

observation

Carboplatin/paclitaxel

Stratification factors: stage, residual disease status, country

6 cycles(4.5 months)

12 cycles(7.5 months)Treatment:

Carboplatin AUC = 6Paclitaxel 175 mg/m2

Bevacizumab 7.5 mg/kg(All treatments q 3 weeks)

Bevacizumab yes or no? coming to a journal near you

Fall 2010!!!!

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

Limitations

• Poor penetration of bulky disease

• Less exposure of drug to extraperitoneal disease

• Complications

– Catheter problems

– Infection

– Abdominal pain

• Inadequate drug distribution

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

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*

Study / Year

Control Regimen Experimental Regimen Eligible patients No of patients

1994 Cisplat 100 mg.m2 IV; cyclo 600 mg/m2Q 3 weeks x 6

Cisplat 200 mg/m2 IP; etoposide 350 mg/m2 IP Q 4 weeks x 6

Stage IIC-IV 62

GOG 1041996

Cisplat 100 mg/m2 IVCyclo 600 mg/m2 IVQ 3 weeks x 6

Cisplat100 mg/m2 IPCyclo 600 mg/m2 IVQ 3 weeks x 6

Stage III, < 2 cm residual

546

Greek1999

Carbo 350 mg/m2 IV; Cyclo 600 mg/m2 IVQ 3 weeks x 6

Carbo 350 mg/m2 IP; Cyclo 600 mg/ m2 IVQ 3 weeks x 6

Stage III 90

GONO 2000

Cisplat 50 mg/m2 IV; Cyclo 600 mg/m2 IV; Epi 60 mg/m2 IVQ 4 weeks x 6

Cisplat 50 mg/m2 IP; Cyclo 600 mg/ m2 IV; Epi 60 mg/m2 IVQ 4 weeks x 6

Stage II-IV, < 2 cm residual

113

GOG 114 2001

Cisplat 75 mg/m2 IVtaxol 135 mg/m2 (24 hr) IVQ 3 weeks x 6

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 2001

Cisplat 50 mg/m2 IV; Cyclo 50 mg/m2 IV; Epi/ Dox 50 mg/m2 IVQ 3 weeks x 6

Cisplat 100 mg/m2 IPCyclo 500 mg/m2 IV; Epi/ Dox 50 mg/m2 IVQ 3 weeks x 6

Stage III, < 1 cm residual

118

GOG 172 2005

Cisplat 75 mg/m2 IV; Taxol 135 mg/m2 (24 hr) IVQ 3 weeks x 6

Taxol 135 mg/m2 (24 hr) IV; Cisplat 100 mg/m2 IP; Taxol 60 mg/m2 IP on day 8Q 3 weeks x 6

Stage III, < 1 cm residual

415

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”

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 104GI toxicity 18% vs 2%leucopenia 40% vs 50%

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 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

Ozols et al. NEJM 2006

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

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.

Radiation

• Radiation - Alon Dembo et al.– early stage disease– optimally debulked disease– Whole abdomen and pelvis field

• BUT– no RCT comparing with

• chemotherapy

• no treatment

Treatment of Advanced Ovarian Cancer

100 patients

70 respondPartially or completely

30 do not respondIntrinsic drug resistance

20 remain disease free50 will recur

25 < 1 year - platinum resistant

25 > 1 year – platinum sensitive

Treatment of Advanced Ovarian Cancer

100 patients

70 respondPartially or completely

30 do not respondIntrinsic drug resistance

20 remain disease free50 will recur

25 < 1 year - platinum resistant

25 > 1 year – platinum sensitive

< 6 months

6-12 months

10-15%

15%

40%

50-70%

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

100

90

80

70

60

50

40

30

20

10

0

Pat

ien

t A

live

(%

)

Time (Weeks)

0 26 52 78 104 130 156 182 208 234

Pegylated Liposomal DoxorubicinePegylated Liposomal DoxorubicineTopotecanTopotecan

Hazard Ratio = 0.63 [0.47 – 0.85]Stratified Log-rank p = 0.002

Median 112 weeksMedian 112 weeks

Median 77 weeksMedian 77 weeks

Caelyx™ vs Topotecan(Survival Platinum Sensitive)

Caelyx™ vs Topotecan(Survival Platinum Sensitive)

Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322; European Cancer Conference 2003.

100

90

80

70

60

50

40

30

20

10

0

Pat

ien

t A

live

(%

)

Time (Weeks)

0 26 52 78 104 130 156 182 208 234

Pegylated Liposomal DoxorubicinePegylated Liposomal DoxorubicineTopotecanTopotecan

Hazard Ratio = 0.63 [0.47 – 0.85]Stratified Log-rank p = 0.002

Median 112 weeksMedian 112 weeks

Median 77 weeksMedian 77 weeks

Caelyx™ vs Topotecan(Survival Platinum Sensitive)

Caelyx™ vs Topotecan(Survival Platinum Sensitive)

Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322; European Cancer Conference 2003.

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 4.6% vs 29%

• Quality of life the same

Carboplatin Combinations In Ovarian Cancer(Efficacy Results)

Carboplatin Combinations In Ovarian Cancer(Efficacy Results)

63

32

66

29

47

18

9.412.0

8.6

0

10

20

30

40

50

60

70

Response (%)

Progression-free(months)

Overal Survival(months)

Caelyx/Carbo (GINECO)Taxol/Carbo (ICON 4)Gem/Carbo (OV-15)

(n = 105)

(n = 392)(n = 178)

%%

%

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

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 AUC5Paclitaxel 175 mg/m2 q3/52

Cyclophosphamide 50 mg/d

Erlotinib 150 mg/d

Prev. regimens 0 ≤3 ≤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

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

PARP inhibitors

PAR chains are degraded via PARG

RepairedDNA

PARPDNA 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

  # evaluable Responders by RECIST (%)

Responders by RECIST or GCIG (%)

Phase I (23)

Phase II (24)

Phase I (23)

Phase II (24)

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%)

 -- 

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!