ovarian cancer dr helen mackay. ovarian cancer: a huge subject! the basics first line treatment gog...
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Ovarian Cancer
Dr Helen Mackay
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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???
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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
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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
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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
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Ovarian Cancer
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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!
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Treatment
• Surgery– Upfront,delayed or interval?
• Chemotherapy
• Radiation
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Surgery
• Accurate staging
• Debulking disease– Midline incision; full exploratory laparotomy– TAH & BSO– Omentectomy– Lymph node assessment/sampling– Washings
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Interval debulking surgery
• Improve PFS
• Response may decrease the extent of surgery
• Increase rate of optimal cytoreduction
• Information on chemosensitivity
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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!
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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!!!!
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Ovarian Cancer Survival
0
10
20
30
40
50
60
70
80
90
100
1960s
1980s
1990s
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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)
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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)
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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
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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.
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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!
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• 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
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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
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More is better?
• 11 randomised trials increasing platinum dosage
• 2 positive
• Phase II high dose chemotherapy: no benefit
• BUT…………..
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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
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What next??
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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)
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Bevacizumab yes or no? coming to a journal near you
Fall 2010!!!!
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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
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Limitations
• Poor penetration of bulky disease
• Less exposure of drug to extraperitoneal disease
• Complications
– Catheter problems
– Infection
– Abdominal pain
• Inadequate drug distribution
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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
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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*
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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
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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”
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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%
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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
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Ozols et al. NEJM 2006
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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
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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.
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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
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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
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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%
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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
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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.
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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.
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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
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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)
%%
%
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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
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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
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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
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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
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# 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%)
--
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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!