Transcript Slide 1

Neoadjuvant
Chemotherapy in Ovarian
Cancer
Key issues in trial design
Key Issue #1

What are the most current consensus
recommendations on developing large phase III
trials in ovarian cancer?
3rd International Ovarian Cancer Consensus Conference
3rd - 5th September 2004, Black Forest, Germany
1-A 1:
Is there a need to strictly define the extent and type of surgery for
patients in first-line trials?
•
Tissue should be obtained for histopathologic diagnosis to
confirm the presence of primary ovarian or peritoneal carcinoma.
• Staging should be performed according to FIGO guidelines. For
example, this includes at least lymph node sampling and
peritoneal staging in early stage invasive disease (FIGO I – IIA).
• Up-front maximal surgical effort at cytoreduction with the goal of
no residual disease should be undertaken.
Level of Acceptance: 13 / 13
3rd International Ovarian Cancer Consensus Conference
3rd - 5th September 2004, Black Forest, Germany
4-A4:
•
Which regimen / kind of regimens can be regarded as standard
comparator for future first-line trials?
Within a given trial the chemotherapy regimen should be
standardized and consistent with respect to drugs, dose, and
schedule.
• The recommended standard comparator for trials on medical
treatment in advanced ovarian cancer (FIGO IIB-IV) is carboplatinpaclitaxel
• The recommended regimen is carboplatin with a dose of AUC 5 - 7.5
and paclitaxel 175 mg/m²/ 3h given every three weeks for 6 courses
Randomised EORTC-GCG/NCIC-CTG trial
on NACT + IDS versus PDS
Per protocol population (PP1)
ITT
Disabling disease
Histology
Disease stage
CA125/CEA ratio
No pelvic mass-FNA
Did not start allocated R/
Other
Remaining (PP1)
PDS
N = 361
1
4
3
1
1
13
9
NACT -> IDS
N = 357
1
1
2
3
0
5
6
329
339
GOG 182: OS based on Residual Disease
AIOM 2000
Multivariate analysis for OS(PP1)
P values
Optimal debulking
0.0001
Histological type (9 categories)
Largest tumor size at randomisation
0.0003
0.0008
Figo Stage (IIIc vs IV)
Country (14 categories)
0.0008
0.0014
Age
WHO PS
Differentiation Grade
0.0020
NS
NS
Treatment arm
NS
Key Issue # 2

What is the primary hypothesis?

Neoadjuvant chemotherapy will improve OS or PFS
NACT + IDS versus PDS: ITT
Overall survival
100
90
80
Median survial
70
PDS: 29 months
60
IDS: 30 months
50
HR for IDS:0.98 (0.85, 1.14)
40
30
20
10
0
(years)
0
O N
259 361
251 357
2
4
Number of patients at risk :
183
68
191
56
6
8
16
11
2
1
AIOM 2000
10
Treatment
Upfront debulking surgery
Neoadjuvant chemotherapy
GOG0182-ICON5: Overall
Survival
Median OS and HR (95% CI)
40.0
40.4
42.8
39.1
40.2
1.000
0.978
0.972
1.068
1.035
(0.838-1.141)
(0.832-1.136)
(0.918-1.244)
(0.888-1.206)
Bookman, ASCO 2006, #5002
GOG 172 – IV vs. IP
Overall survival
1.0
0.9
Proportion Surviving
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Treatment
IV
IP
0.1
0.0
0
12
Censored Failed Total
63 147 210
81 124 205
24
36
48
Months from Randomization
60
72
Key Issue # 2

What is the primary hypothesis?

Neoadjuvant chemotherapy will improve OS or PFS
Question # 1: Can we develop a rational
superiority trial incorporating neoadjuvant
chemotherapy?
Key Issue # 2

What is the primary hypothesis?
Neoadjuvant chemotherapy will improve OS or PFS
 Neoadjuvant chemotherapy will achieve the same
survival with a lower operative morbidity

Randomised EORTC-GCG/NCIC-CTG trial
on NACT + IDS versus PDS
Surgical characteristics (PP1)
PDS
(n = 329)
NACT -> IDS
(n = 339)*
2,7%
0,6%
8%
2%
1,2% / 0,3%
0,3% / 0,6%
Operative time (minutes)
180
180
Red blood cell transfusion
51%
53%
Hemorhage Grade 3/4
7%
1%
2,4%
0,3%
Postoperative mortality
(< 28 days)
Postoperative sepsis
Fistula (bowel/GU)
Venous Gr 3/4
Key Issue # 2

What is the primary hypothesis?
Neoadjuvant chemotherapy will improve OS or PFS
 Neoadjuvant chemotherapy will achieve the same
survival with a lower operative morbidity

Question # 2: What is the best trial design
based on a primary endpoint of QOL?
Key Issue # 2

What is the primary hypothesis?
Neoadjuvant chemotherapy will improve OS or PFS
 Neoadjuvant chemotherapy will achieve the same
survival with a lower operative morbidity
 Neoadjuvant chemotherapy will allow more patients
to receive optimal surgery and optimal
chemotherapy

Randomised EORTC-GCG/NCIC-CTG trial
on NACT+ IDS versus PDS
Protocol Compliance (PP1)
PDS
(n = 329)
NACT -> IDS
(n = 339)
Primary debulking
100 %
0%
Interval debulking
19%
90%
Second look surgery
5%
4%
At least 6 courses CT
83%
86%
GOG 182: Residual Disease after
Primary Surgery
AIOM 2000
Randomised EORTC-GCG/NCIC-CTG trial on
NACT + IDS versus PDS
Surgical findings and results (PP1)
Metastases before > 2 cm
PDS
(n = 329)
95%
NACT -> IDS
(n = 339)*
68%
Metastases before > 10 cm
62%
27%
No residual after surgery
21%
53%
≤ 1 cm after surgery
46%
82%
* % calculated on the 306 patients who underwent IDS.
Key Issue # 2

What is the primary hypothesis?



Neoadjuvant chemotherapy will improve OS or PFS
Neoadjuvant chemotherapy will achieve the same survival
with a lower operative morbidity
Neoadjuvant chemotherapy will allow more patients to
receive optimal surgery and optimal chemotherapy
Question # 3: Is there a patient population where this
would have an impact on outcome?
Key Issue # 3


Neoadjuvant chemotherapy should be applied to
all advanced ovarian cancer patients
OR
Neoadjuvant chemotherapy should be only for
select populations:
Elderly
 Poor performance status
 Extensive disease
 Medical co-morbidities

GOG 182





Median age on trial 58 (62 in neoadjuvant trial)
Only 14% of patients ≥ 70
Less than 5% ≥ 75
Performance status 0, 1, 2
15% were stage IV
Clearly a large patient population is not being enrolled
onto current trials due to advanced age and poor
performance status
Key Issue # 3: Special Populations

Question # 4: How to best determine extensive
disease?


Radiographic, CA-125
Question # 5: What is the best way to
incorporate neoadjuvant chemotherapy into
advanced age and poor performance
populations?
Endpoints
 Inclusive study design

Key Issue # 4: Surgical Timing

Question # 6: What is the best timing for
surgery in patients undergoing neoadjuvant
chemotherapy (3 vs. 6 months)?

Which patients should not undergo surgical
intervention?
Key Issue # 5: Endpoints

Question # 7: What are the appropriate
endpoints and how should they be measured?
OS/PFS
 QOL
 Surgical morbidity
 Response

Clinical
 Radiologic
 Serum Markers
 Surgical complete response

Key Issue # 6: Proof-of-Concept designs

Using neoadjuvant chemotherapy for proof-ofconcept type studies
Novel strategies
 Novel cytotoxic or biologic agents
 Molecular mechanisms and biomarkers

Question # 8: Can we develop a standard queue
for proof-of-concept studies in advanced
ovarian cancer patients?