Ovarian Cancer Dr Helen Mackay. Ovarian Cancer: A huge subject! The basics First line treatment GOG...
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Transcript of Ovarian Cancer Dr Helen Mackay. Ovarian Cancer: A huge subject! The basics First line treatment GOG...
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!