1.
Ovarian Cancers:
Evolving Paradigms in Research and Care
Report Release
Wednesday, March 2, 2016

2.
• Congressionally mandated report
• Sponsored by the Centers for
Disease Control and Prevention
• IOM charged with completing the
work
• Multidisciplinary committee
assembled
• Four in-person meetings
Background

3.
Statement of Task
An ad hoc committee under the auspices of the
Institute of Medicine will review the state of the
science in ovarian cancer and formulate
recommendations for action to advance the field.
The committee will:
• Summarize and examine the state of the
science in ovarian cancer research,
• Identify key gaps in the evidence base and the
challenges to addressing those gaps,
continued

4.
Statement of Task (continued)
• Consider opportunities for advancing ovarian
cancer research, and
• Examine avenues for translation and
dissemination of new findings and
communication of new information to patients
and others.
The committee will make recommendations for
public- and private-sector efforts that could
facilitate progress in reducing the incidence of
and morbidity and mortality from ovarian cancer.

5.
Biology
Innovative Research Designs
Supportive Care Research &
Practice
Prevention &
Early
Detection
Diagnosis &
Treatment
Secondary
Prevention &
Monitoring
for
Recurrence Management
of Recurrent
Disease
End-of-Life
Care
Long-Term
Survivorship
Methods to Reduce Practice-
Related Disparities
Intervention Development
Previvorship Survivorship
Conceptual Model

6.
1. Prioritize study of high-grade serous carcinoma
2. More subtype-specific research is needed to
define various subtype characteristics
3. Collaboration is essential
a. Pooling and sharing of data and biospecimens
b. Use of consortia
4. Dissemination and implementation are final steps
for knowledge translation
Overarching Concepts

7.
Ovarian Cancers:
Evolving Paradigms in
Research and Care
#Ovarian Cancers
www.nas.edu/OvarianCancers

8.
High-grade serous
carcinoma
Carcinosarcoma
Endometrioid
carcinoma
70% - 74%
7% - 24%
10% - 26%
2% - 6% 0.6% - 7.1%
3% - 5%
1% - 7%
Ovarian Carcinomas – Not one disease

9.
Ovarian Carcinomas – Origins

10.
The fallopian tube is a likely site of most HGSC and
genetic models are expanding

11.
Recommendation
• Strategies to increase genetic counseling and
testing for all women with ovarian cancer
• Wider offering of cascade testing
• Determine analytic performance and clinical
utility of testing for germline mutations
beyond BRCA1 and BRCA2 and mismatch
repair genes associated with Lynch Syndrome.

12.
Supportive Care Along the
Survivorship Trajectory

13.
• Most research focuses on treatment rather than on
how to improve the management of the acute and
long-term physical and psychosocial effects of
diagnosis and treatment across the trajectory of
survivorship.
• Most research on survivorship aggregates patients
of all cancer types
• Survivorship research on ovarian cancer rarely
distinguishes different subgroups – age, racial and
ethnic groups, stage, histology, etc.
Key Findings in IOM Report

14.
Dissemination &
Implementation of Knowledge
“an active approach of spreading evidence-based
interventions to the target audience via determined
channels using planned strategies”

15.
Biology
Innovative Research Designs
Supportive Care Research
& Practice
Prevention &
Early
Detection
Diagnosis &
Treatment
Secondary
Prevention &
Monitoring
for
Recurrence Management
of Recurrent
Disease
End-of-Life
Care
Long-Term
Survivorship
Intervention Development
Previvorship Survivorship
Prevention
& Early
Detection
Diagnosi
s &
Treatmen
t
Secondary
Prevention
&
Monitoring
for
Recurrence
Previvorshi
p
Survivorship
Managemen
t of
Recurrent
Disease
End-of-Life
Care
Long-Term
Survivorship
Methods to Reduce
Practice-Related
Disparities
Methods to Reduce
Practice-Related
DisparitiesSupportive Care Research
& Practice
Final steps for knowledge translation into practice
for all stakeholders

16.
• Current methods for early detection in the general or
high-risk population do not have substantial impact
on mortality.
• Proven preventive strategies exist.
• All women with invasive ovarian cancer should
receive germline genetic testing.
• Genetic counseling and testing for the first-degree
relatives of women with a hereditary cancer
syndrome or germline mutation.
• Uniform implementation of the standard of care and
the inclusion of supportive care across the
survivorship trajectory.
Some key messages

17.
Survivors’ acceptance of treatment side
effects evolves as goals of care change over
the cancer continuum
Melissa K. Frey
New York University Langone Medical Center

18.
Verbal Disclosure
• Nothing to disclose.

19.
• Ovarian cancer disease course
– Long overall survival
– Multiple treatment regimens
• What are meaningful clinical trial endpoints?
– Overall survival
– Progression-free survival
– Patient reported outcomes
– Health-related quality of life
• FDA workshop on alternative clinical trial endpoints (September 3, 2015)
– Co-sponsored by:
• Society of Gynecologic Oncology (SGO)
• American Society of Clinical Oncology (ASCO)
• American Association for Cancer Research (AACR)
Herzog TJ et al. Gynecol Oncol. 2014.
Background

20.
• Exploring patient preferences
– OCNA Clinical Trial Endpoints: What do our patients consider important (2013)
– NYU/SHARE: A qualitative study of ovarian cancer survivors' perceptions of
endpoints and goals of care (2014)
• Shared decision-making
– Physician awareness of patient goals
– Incorporating goals when selecting treatment
– Maximizing treatment efficacy AND quality of life
Minion LE et al. Gynecol Oncol. 2016.
Frey MK et al. Gynecol Oncol. 2014.
Background

21.
To determine whether survivors’ acceptance of
treatment side effects changes over the disease
continuum.
Objective

22.
• Ovarian Cancer Survivorship Questionnaire
– Developed by Annie Ellis
– Combination of OCNA Clinical Trial Endpoints and NYU/SHARE
– 30 questions, Likert-type scale and multiple choice
• Questionnaire available online (8/1/2015-8/12/2015)
– Survivor networks
– Social media
• Completed online by self-identified ovarian cancer
survivors
• Consent for participation provided electronically
• Exempt status from NYU Langone Medical Center
Institutional Review Board
Annie Ellis
Patient Advocate
Methods

23.
Age (years) (N = 328)
18-35 7 (2%)
36-50 63 (19%)
51-60 142 (43%)
61-70 91 (28%)
>70 25 (8%)
Race / Ethnicity
Non-Hispanic white 303 (92%)
Hispanic 10 (3%)
Non-Hispanic black 5 (2%)
Asian/Pacific Islander 3 (1%)
Other or Unknown 7 (2%)
Disease site
Ovary 267 (81%)
Fallopian tube 21 (6%)
Primary peritoneal 37 (11%)
Unknown 3 (1%)
Disease stage
I 55 (17%)
II 33 (10%)
III 194 (59%)
IV 37 (11%)
Unknown 9 (3%)
Results - Demographics

24.
Time since cancer diagnosis (N = 328)
<12 months 44 (13%)
1-4 years 184 (56%)
5-9 years 59 (18%)
10-14 years 23 (7%)
15-19 years 10 (3%)
> 20 years 7 (2%)
Recurrent disease
Yes 142 (43%)
No 180 (55%)
No answer 6 (2%)
Undergoing treatment at time of questionnaire completion
Yes 119 (36%)
No 205 (63%)
No answer 4 (1%)
Results – Demographics
0
20
40
60
80
100
0 1 2 3 4 > 5
#Participants
# Prior treatment regimens received
Prior treatment regimens

25.
What is your treatment goal?
Overall survival
45%
Progression-free
survival
12%
Quality of life
41%
No answer
2%

26.
What is most meaningful to you?
Overall survival
39%
Minimizing treatment
side effects
11%
Minimizing disease
symptoms
6%
Ability to engage in
daily activities
35%
Attend a life event
0%
Time off treatment
6%
Other
3%

27.
When selecting a treatment, what is your expectation?
Cure
35%
Remission
49%
Stable
disease
16%
All participants

28.
When selecting a treatment, what is your expectation?
P < 0.001
Cure
50%
Remission
45%
Stable
disease
5%
Participants without recurrence
(N = 180)
Cure
16%
Remission
53%
Stable
disease
31%
Participants with at least one
recurrence (N = 142)

29.
Which of these treatment side effects would you tolerate?
Goal of treatment:
Cure
Remission
Stable disease
Cure
Remission
Stable
disease
Bowel obstruction
Shortness of breath
Infection
Mucositis
Ototoxicity
Hand-foot syndrome
Pain
Memory loss
Nausea/vomiting
Headache
Sexual side effects
Flu-like symptoms
Arthralgia
Skin changes
Neuropathy
Constipation
Diarrhea
Fatigue
Alopecia

30.
Treatment side effects (Goal = Cure)
% Participants willing to accept the side effect
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Bowel obstruction
Shortness of breath
Infection
Mucositis
Ototoxicity
Hand-foot syndrome
Pain
Memory loss
Nausea/vomiting
Headache
Sexual side effects
Flu-like symptoms
Arthralgia
Skin changes
Neuropathy
Constipation
Diarrhea
Fatigue
Alopecia

31.
Percentage of survivors who would accept treatment side effects based on the goal
of treatment (Goal = Cure)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%

32.
Percentage of survivors who would accept treatment side effects based on the goal
of treatment (Cure vs. Remission)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%

33.
Percentage of survivors who would accept treatment side effects based on the goal
of treatment (Cure vs. Remission vs. Stable disease)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%

34.
Expectation of cure among survivors with recurrent disease
Cure
16%
Remission
53%
Stable
disease
31%
Participants with recurrent disease
(N=142, 43%)

35.
Expectation of cure among survivors with recurrent disease
Participants with recurrent disease
(N=142, 43%)
Stable
disease
Cure
(22 participants)
Remission
0% 20% 40% 60% 80% 100%
Bowel obstruction
Shortness of breath
Infection
Mucositis
Ototoxicity
Hand-foot syndrome
Pain
Memory loss
Nausea/vomiting
Headache
Sexual side effects
Flu-like symptoms
Arthralgia
Skin changes
Neuropathy
Constipation
Diarrhea
Alopecia
Fatigue

36.
Cure Remission Stable disease
I would accept any side effects for
a CURE!!
I’d take anything that has less than
20% chance
of killing me immediately.
I would tolerate these side
effects if they were temporary.
I'd rather not tolerate any side
effects.
None!
Depends on severity and quality of
life tradeoffs.
This is a much bigger issue if
‘stable disease’is the best you can
get.
Facing this now, I have learned that
my tolerance for
side effects is pretty low under
these conditions.
Survivor comments by goal of treatment

37.
• Acceptance of treatment side effects declines with changing goals
– Cure  remission  stable disease
• Goal of cure drives willing acceptance of treatment toxicity
• When selecting treatment balance treatment toxicities and quality
of life measures
• Survivors’ decision tool for selecting treatment therapies for
recurrent disease in development
Conclusions

38.
Co-authors
• Annie E. Ellis, Patient Advocate
• Laura Koontz, PhD
• Savannah Shyne, MPH
• Jing-Yi Chern, MD
• Jessica Lee, MD
• Stephanie V. Blank, MD
Acknowledgements

39.
Higher rates of clinically actionable multigene
panel results in Ashkenazi Jewish patients
Melissa Frey
New York University Langone Medical Center

40.
Verbal disclosure
• Nothing to disclose.

41.
• Next-generation sequencing
– Rapid
– Cost-effective
– Virtually unlimited number of genes
– Ovarian cancer genes – BRCA1, BRCA2, BARD1, BRIP1, MLH1, MSH2, MSH6, PALB2,
PMS2, RAD51C, RAD51D
• Clinical actionability
– Actionable mutations
• Mutations with known clinical manifestations and well-outlined cancer screening guidelines
– Non-actionable mutations
• Mutations in low- to moderate-risk genes for which consensus management guidelines have
not been established
Norquist BM et al. JAMA Oncol. 2015
Multigene panel testing for cancer syndromes

42.
To determine if there are specific patient
populations in which multigene panels would
be more likely to affect clinical management.
Objective

43.
• Review of multigene panel testing results at a single institution
• Study period: June 2013 - January 2015
• All genetic testing performed after consultation by a certified genetic
counselor
• Mutations were characterized as actionable or non-actionable
– National Comprehensive Cancer Network (NCCN) guidelines
– Genes not addressed by NCCN guidelines
– Consensus statements
– Expert opinion
• Statistical methods: T-test, Chi-square, Fisher’s exact test
Methods

44.
Results - Patient Demographics
Gender (N = 454)
Female 435 (96%)
Male 19 (4%)
Race/ethnicity
Non-Hispanic white 362 (80%)
Non-Hispanic black 31 (7%)
Hispanic 29 (6%)
Asian/Pacific
Islander
32 (7%)
Ashkenazi Jewish ancestry
Ashkenazi Jewish 138 (30%)
Non-Ashkenazi Jewish 316 (70%)
Personal history of cancer 354 (78%)
Breast 251 (55%)
Ovarian 49 (11%)
Uterine 26 (6%)
Colorectal 20 (4%)
Family history of cancer 417 (92%)

45.
Results - Multigene panels
454 patients
Pathogenic mutations
62 mutations identified
56 patients (12%)
19 genes
VUS
291 VUS identified
196 patients (43%)
38 genes
Actionable mutations
APC, ATM, BARD1, BRCA1, BRCA2,
BRIP1, CHEK2, MEN1, MLH1, MSH6,
PALB2, PMS2, PTEN, RAD51D
Non-actionable mutations
CDKN2A, FAM175A, FANCC,
FLCN, MUTYH

46.
Actionable
79%
Non-
actionable
21%
• Actionable mutations
– 10% of all patients (47/454)
– 79% of all mutations (49/62)
• Non-actionable mutations
– 2% of all patients (9/454)
– 21% of all mutations (13/62)
• Age, gender, race, ethnicity, personal history of cancer and
family history of cancer were NOT associated with finding an
actionable mutation
Results – Clinical Actionability
Mutations (N = 62)

47.
• No differences when comparing Ashkenazi to non-Ashkenazi
patients:
– Gender, personal history of cancer, family history of cancer, # mutations, #
VUS
• Mutations in Ashkenazi patients were significantly more
likely to be clinically actionable
Results - Ashkenazi Jewish ancestry
Ashkenazi
Jewish
(N=20)
Non-Ashkenazi
Jewish
(N=42)
P
value
Actionable
mutations
(N = 49)
19 (95%) 30 (71%)
Non-actionable
mutations
(N = 13)
1 (5%) 12 (29%) 0.04

48.
Ashkenazi Jewish (N=138)
Actionable mutation
Non-actionable mutation
Pathogenic mutations in Ashkenazi and non-Ashkenazi Patients
Non-Ashkenazi Jewish (N=316)
FANCC, 1
APC, 6
BARD1, 1
BRCA2, 1
BRCA1, 1
BRIP1, 1
CHEK2, 7
MLH1, 1
MSH6, 1
CDKN2A, 1 FAM175A, 1
FANCC, 2
FLCN, 1
MUTYH, 7
ATM, 3
BRCA2, 4
BRCA1, 2
BRIP1, 5
CHEK2, 6
MEN1, 1
MLH1, 2
PALB2, 2
PMS2, 1
PTEN,
3
RAD51D, 1

49.
Ashkenazi Jewish (N=138)
Actionable mutation
Non-actionable mutation
Pathogenic mutations in Ashkenazi and non-Ashkenazi Patients
Non-Ashkenazi Jewish (N=316)
FANCC, 1
APC, 6
BARD1, 1
BRCA2, 1
BRCA1, 1
BRIP1, 1
CHEK2, 7
MLH1, 1
MSH6, 1
CDKN2A, 1 FAM175A, 1
FANCC, 2
FLCN, 1
MUTYH, 7
ATM, 3
BRCA2, 4
BRCA1, 2
BRIP1, 5
CHEK2, 6
MEN1, 1
MLH1, 2
PALB2, 2
PMS2, 1
PTEN,
3
RAD51D, 1
2 BRCA1/2 mutations
BRCA1 (1)
BRCA2 (1)
6 BRCA1/2 mutations
BRCA1 (2)
BRCA2 (4)

50.
FANCC, 1
APC, 6
BARD1, 1
BRCA2, 4
BRCA1, 4BRIP1, 1
CHEK2, 7
MLH1, 1
MSH6, 1
Ashkenazi Jewish (N=183)
Actionable mutation
Non-actionable mutation
Non-Ashkenazi Jewish (N=374)
CDKN2A, 1 FAM175A, 1
FANCC, 2
FLCN, 1
MUTYH, 7
ATM, 3
BRCA2, 4
BRCA1, 2BRIP1, 5
CHEK2, 6
MEN1, 1
MLH1, 2
PALB2, 2
PMS2, 1
PTEN,
3
RAD51D, 1
8 BRCA1/2 mutations
BRCA1 (4)
BRCA2 (4)
6 BRCA1/2 mutations
BRCA1 (2)
BRCA2 (4)
BRCA1/2 mutations from multigene panels and targeted single gene
BRCA1/2 screening (N=557)

51.
Ashkenazi Jewish (N=138)
Actionable mutation
Non-actionable mutation
Pathogenic mutations in Ashkenazi and non-Ashkenazi Patients
Non-Ashkenazi Jewish (N=316)
FANCC, 1
APC, 6
BARD1, 1
BRCA2, 1
BRCA1, 1
BRIP1, 1
CHEK2, 7
MLH1, 1
MSH6, 1
CDKN2A, 1 FAM175A, 1
FANCC, 2
FLCN, 1
MUTYH, 7
ATM, 3
BRCA2, 4
BRCA1, 2
BRIP1, 5
CHEK2, 6
MEN1, 1
MLH1, 2
PALB2, 2
PMS2, 1
PTEN,
3
RAD51D, 1
Evolving understanding of
actionable vs. non-actionable

52.
• Multigene panel testing discovered:
• Mutations in 56 patients (12%)
• VUS in 196 patients (43%)
• Multigene panel testing should be considered in
Ashkenazi Jewish patients
• Majority of mutations are actionable (95%)
• Mutations occur in multiple genes and are not limited to
BRCA1/2
Conclusions

53.
Co-authors
• Gabriella Sandler, BS
• Rachel Sobolev, BS
• Sarah Kim, MD
• Rachelle Chambers, MS, CGC
• Jessica Martineau, MS, CGC
• Rebecca Y. Bassett, MS, CGC
• Stephanie V. Blank, MD
Acknowledgments

54.
Gene Recommendations Source
APC Actionable Colorectal cancer - Colonoscopy every 5 years starting at age 40 Expert opinion
ATM Actionable Breast cancer - Recommend breast MRI NCCN Guidelines
BARD1
Emerging evidence
suggesting actionability
Ovarian cancer - Consider risk-reducing salpingo-oophorectomy
Norquist et al. JAMA
Oncol . 2015.
Ovarian cancer - Recommend/consider risk-reducing salpingo-oophorectomy
Breast cancer - Recommend breast MRI, discuss option of risk-reducing mastectomy
Ovarian cancer - Recommend/consider risk-reducing salpingo-oophorectomy
Breast cancer - Recommend breast MRI, discuss option of risk-reducing mastectomy
BRIP1 Actionable Ovarian cancer - Risk-reducing salpingo-oophorectomy NCCN Guidelines
CHEK2 Actionable Breast cancer - Recommend breast MRI NCCN Guidelines
Parathyroid glands, anterior pituitary, enteropancreatic endocrine cell tumors
Biochemical tests – calcium, PTH, gastrin, gastric acid output, secretin-stimulated
gastrin, fasting glucose, insulin, PRL, IGF-1
Imaging tests – MRI/CT scan
Colorectal cancer - Colonoscopy
Endometrial and ovarian cancer - Consider option of risk-reducing hysterectomy and
bilateral salpingo-oophorectomy, annual office endometrial sampling is an option
Gastric and small bowel cancer - Selected individuals or families or those of Asian
descent may consider EGD with extended duodenoscopy
Urothelial cancer - Consider annual urinalysis
Colorectal cancer - Colonoscopy
Endometrial and ovarian cancer - Consider option of risk-reducing hysterectomy and
bilateral salpingo-oophorectomy, annual office endometrial sampling is an option
PALB2 Actionable Breast cancer - Recommend breast MRI, discuss option of risk-reducing mastectomy NCCN Guidelines
Colorectal cancer - Colonoscopy
Endometrial and ovarian cancer - Consider option of risk-reducing hysterectomy and
bilateral salpingo-oophorectomy, annual office endometrial sampling is an option
Endometrial cancer - Discuss option of risk-reducing hysterectomy, consider annual
random endometrial biopsies and/or ultrasound
Breast cancer - Recommend breast MRI, discuss option of risk-reducing mastectomy
Thyroid cancer - Annual thyroid ultrasound
Colorectal cancer - Colonoscopy
Renal cancer - Consider renal ultrasound
RAD51D Actionable Ovarian cancer - Recommend/consider risk-reducing salpingo-oophorectomy NCCN Guidelines
Actionable Mutations
PMS2 Actionable NCCN Guidelines
PTEN Actionable NCCN Guidelines
MSH6 Actionable NCCN Guidelines
MLH1 Actionable NCCN Guidelines
MEN1 Actionable
Expert opinion /
consensus statements
BRCA1 Actionable NCCN Guidelines
BRCA2 Actionable NCCN Guidelines
CDKN2A Non-actionable
FAM175A Non-actionable
FANCC Non-actionable
FLCN Non-actionable
MUTYH Non-actionable
Non-Actionable Mutations

55.
A PHASE III CLINICAL TRIAL OF BEVACIZUMAB WITH IV VERSUS IP
CHEMOTHERAPY IN OVARIAN, FALLOPIAN TUBEAND PRIMARY PERITONEAL
CARCINOMA NCI-SUPPLIED AGENT(S): BEVACIZUMAB (NSC #704865, IND #7921)
NCT01167712 a GOG/NRG Trial (GOG 252)
Joan L. Walker; Mark F Brady; Paul A DiSilvestro; Keiichi Fujiwara; David Alberts; Wenxin Zheng; Krishnansu
Tewari; David E Cohn; Matthew Powell; Linda van Le; Stephen Rubin; Susan A Davidson; Heidi J Gray;
Steven Waggoner; Tashanna Myers; Carol Aghajanian; Angeles Alvarez Secord; Robert S Mannel

56.
GOG 252: IP chemo and dose dense Paclitaxel showed
improved OS, both have toxicities; which is best?
Should we use dose
dense Paclitaxel?
Should we use IP
chemotherapy?
Should we use
Bevacizumab?
• JGOG 3016 showed improved OS, but not
replicated in the US
• GOG 172 showed survival advantage, but was
toxic, with only 42% receiving 6 cycles;
additional studies were done to address the
toxicity:
-GOG9916/17 Substituted IP carbo for cisplatin
-GOG9921 Reduced IP cisplatin dose
• GOG 218 showed improved PFS with Bev, and
feasibly safe with IP Chemo
Arm 1: Dose dense Paclitaxel
Arm 2: IP Chemo substitute
Arm 3:
Include Bevacizumab
Key questions
for GOG 252 Indications and contemporary results
Implications for
GOG 252 schema
All:
IP chemo, reduced
cisplatin dose

57.
Arm 1
Arm 2
Arm 3
GOG 252: Schema
• Stage II-III Epithelial
Carcinoma: Ovary,
Fallopian Tube,
Peritoneal
• Resected to optimal:
less than or equal to
1 cm visible tumor
by surgeon report
• Exploratory:
suboptimal (7%)
and Stage IV (5%)
Eligibility

58.
Differences in Dosing in GOG 252 Arm 3 IP
Cisplatin compared to GOG 172
• Dose reduction cisplatin(100 down to 75 mg/m2)
• Infusion time reduction 135 mg/m2 paclitaxel(3 hr instead of 24h)
• All outpatient therapy
• Bevacizumab 15 mg/m2 for all arms on cycles 2-22
• Comparison arm dose dense paclitaxel with carbo IV AUC 6- GOG
262 (JGOG)
• Second experimentalArm IP carbo and dose dense paclitaxel

59.
Progression Free Survival Optimal Stage II-III
(10% stage II)
• Estimated hazard ratios, and logrank tests are adjusted for stage of disease and size of
residual disease micro vs < 1cm
• CT required every 6 months for surveillance (not required in GOG 114/172)
Arm N Events Median PFS HR [95% CI] Logrank Logrank
IV Carbo 461 303 26.8 months Reference arm P-value Chi square
IP Carbo 464 300 28.7 months 0.947 [0.808-
1.11]
0.416 0.661
IP Cisp 456 307 27.8 months 1.01 [0.858-1.18] 0.727 0.122

60.
P r o g r e s s i o n - F r e e S u r v iv a l b y T r e a t m e n t G r o u p
S ta g e II o r III O p ti m a l l y D e b u l k e d
T r e a tm e n t G r o u p E ve n ts T o ta l M e d i a n ( m o s )
1 : C r b ( IV ) + T + B e v 3 0 3 4 6 1 2 6 .8
2 : C r b ( IP ) + T + B e v 3 0 0 4 6 4 2 8 .7
3 : C i s ( IP ) + T + B e v 3 0 7 4 5 6 2 7 .8
0 .2
0 .4
0 .6
0 .8
1 .0
ProportionSurviving
Progression-Free
3 : C i s ( IP ) + T + B e v
2 : C r b ( IP ) + T + B e v
1 : C r b ( IV ) + T + B e v
T r e a tm e n t G r o u p
2 6 .8
2 8 .7
2 7 .8
E ve n ts T o ta l M e d i a n ( m o s )
3 0 3 4 6 1
3 0 0 4 6 4
3 0 7 4 5 6
Progression Free Survival Optimal Stage II-III
0.0 0 12 24 36 48 60 72
Months on Study
1 461 387 244 169 111 37 0
2 464 391 262 177 125 39 0
3 456 372 255 168 120 34 0

61.
P r o g r e s s i o n -F r e e S u r v iv a l b y T r e a tm e n t G r o u p
S ta g e III w i th N o G ro s s R e s i d u a l D i s e a s e
• T re a tm e n t G ro u p E ve n ts To ta l M e d i a n ( m o s ) 1 : C rb (IV )+ T + B e v
1 4 4 2 3 9 3 1 .3
• 2 : C rb (IP )+ T + B e v 1 4 5 2 3 8 3 1 .8
• 3 : C i s (IP )+ T + B e v 1 3 8 2 3 9 3 3 .8
0 .2
0 .4
0 .6
0 .8
1 .0
ProportionSurviving
Progression-Free
3 : C i s (IP )+ T + B e v
2 : C rb (IP )+ T + B e v
1 : C rb (IV )+ T + B e v
T re a tm e n t G ro u p
3 1 .3
3 1 .8
3 3 .8
1 4 4 2 3 9
1 4 5 2 3 8
1 3 8 2 3 9
E ve n ts T o ta l M e d i a n ( m o s )
Progression Free Survival Optimal Stage III NGR
0.0 0 12 24 36 48 60 72
Months on Study
1 239 203 141 97 66 21 0
2 238 209 152 103 72 21 0
3 239 204 150 104 76 24 0

62.
Across Study Comparisons for PFS
Arm Study PFS Median in mos
No visible dx Stage 3
PFS median mos
1 cm or less visible dx
GOG 114 & 172 IV cisplatin 33.4
GOG 172 IV cisplatin 43.2 18.3
GOG 252 IV carbo 31.3 26.8 (10% stage II)
GOG 114 & 172 IP cisplatin 43.2
GOG 172 IP cisplatin 60.4 23.8
GOG 252 IP carboplatin 31.8 28.7 (10% Stage II)
GOG 252 IP cisplatin 33.8 27.8 (10% Stage II)

63.
Discussion
• Survival for optimal and no residual disease participants will not be
available for a few years.
• Dose reductions of paclitaxel and cisplatin as well as cross- over may
have compromised efficacy.
• Dose dense paclitaxel may have improved efficacy to allow us to
abandon IP chemo- must we wait- combine both?
• Bevacizumab interactions could have clouded analysis

64.
Conclusions
• All arms have excessive toxicity
• Neurotoxicity is similarly high in all arms
• Reserve changes in treatment recommendations until survival data
available for no residual disease high grade serous Stage III
participants.
• IP Cisplatin increases bevacizumab associated HTN