Neoadjuvant Chemotherapy in Ovarian Cancer Key issues in trial design.
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Transcript of Neoadjuvant Chemotherapy in Ovarian Cancer Key issues in trial design.
Neoadjuvant Neoadjuvant Chemotherapy in Chemotherapy in Ovarian CancerOvarian Cancer
Key issues in trial Key issues in trial designdesign
Key Issue #1Key Issue #1
What are the most current What are the most current consensus recommendations on consensus recommendations on developing large phase III trials in developing large phase III trials in ovarian cancer?ovarian cancer?
3rd International Ovarian Cancer Consensus Conference3rd - 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 Conference3rd - 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 carboplatin-
paclitaxel
•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
Level of Acceptance: 13 / 13
Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Per protocol population (PP1)
ITT PDS N = 361
NACT -> IDS
N = 357
Disabling disease 1 1
Histology 4 1
Disease stage 3 2
CA125/CEA ratio 1 3
No pelvic mass-FNA 1 0
Did not start allocated R/
13 5
Other 9 6
Remaining (PP1) 329 339
AIOM 2000
GOG 182: OS based on Residual Disease
Multivariate analysis for OS(PP1)
P values
Optimal debulking 0.0001
Histological type (9 categories)
0.0003
Largest tumor size at randomisation
0.0008
Figo Stage (IIIc vs IV) 0.0008
Country (14 categories) 0.0014
Age 0.0020
WHO PS NS
Differentiation Grade NS
Treatment arm NS
Key Issue # 2Key Issue # 2
What is the primary hypothesis?What is the primary hypothesis?
Neoadjuvant chemotherapy will Neoadjuvant chemotherapy will improve OS or PFSimprove OS or PFS
AIOM 2000
NACT + IDS versus PDS: ITT
(years)
0 2 4 6 8 10
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment259 361 183 68 16 2
251 357 191 56 11 1
Upfront debulking surgery
Neoadjuvant chemotherapy
Overall survival
Median survial
PDS: 29 months
IDS: 30 months
HR for IDS:0.98 (0.85, 1.14)
GOG0182-ICON5: Overall GOG0182-ICON5: Overall SurvivalSurvival
Median OS and HR (95% CI)Median OS and HR (95% CI)
40.0 1.00040.0 1.00040.4 0.978 (0.838-1.141)40.4 0.978 (0.838-1.141)42.8 0.972 (0.832-1.136)42.8 0.972 (0.832-1.136)39.1 1.068 (0.918-1.244)39.1 1.068 (0.918-1.244)40.2 1.035 (0.888-1.206)40.2 1.035 (0.888-1.206)
Bookman, ASCO 2006, #5002Bookman, ASCO 2006, #5002
GOG 172 – IV vs. IPOverall survival
Prop
ortio
n Su
rviv
ing
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from Randomization0 12 24 36 48 60 72
Treatment Censored Failed Total IV 63 147 210
Censored Failed Total
IP 81 124 205
Key Issue # 2Key Issue # 2
What is the primary hypothesis?What is the primary hypothesis?
Neoadjuvant chemotherapy will improve OS Neoadjuvant chemotherapy will improve OS or PFSor PFS
Question # 1: Can we develop a Question # 1: Can we develop a rational superiority trial incorporating rational superiority trial incorporating neoadjuvant chemotherapy?neoadjuvant chemotherapy?
Key Issue # 2Key Issue # 2
What is the primary hypothesis?What is the primary hypothesis? Neoadjuvant chemotherapy will Neoadjuvant chemotherapy will
improve OS or PFSimprove OS or PFS Neoadjuvant chemotherapy will achieve Neoadjuvant chemotherapy will achieve
the same survival with a lower the same survival with a lower operative morbidityoperative morbidity
Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDSSurgical characteristics (PP1) PDS
(n = 329)NACT -> IDS(n = 339)*
Postoperative mortality (< 28 days)
2,7% 0,6%
Postoperative sepsis 8% 2%
Fistula (bowel/GU) 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%
Venous Gr 3/4 2,4% 0,3%
Key Issue # 2Key Issue # 2
What is the primary hypothesis?What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or Neoadjuvant chemotherapy will improve OS or
PFSPFS Neoadjuvant chemotherapy will achieve the Neoadjuvant chemotherapy will achieve the
same survival with a lower operative morbiditysame survival with a lower operative morbidity
Question # 2: What is the best trial design Question # 2: What is the best trial design based on a primary endpoint of QOL?based on a primary endpoint of QOL?
Key Issue # 2Key Issue # 2
What is the primary hypothesis?What is the primary hypothesis? Neoadjuvant chemotherapy will Neoadjuvant chemotherapy will
improve OS or PFSimprove OS or PFS Neoadjuvant chemotherapy will achieve Neoadjuvant chemotherapy will achieve
the same survival with a lower the same survival with a lower operative morbidityoperative morbidity
Neoadjuvant chemotherapy will allow Neoadjuvant chemotherapy will allow more patients to receive optimal more patients to receive optimal surgery and optimal chemotherapysurgery and optimal chemotherapy
Randomised EORTC-GCG/NCIC-CTG trial on NACT+ IDS versus PDSProtocol 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%
AIOM 2000
GOG 182: Residual Disease after Primary Surgery
Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDSSurgical findings and results (PP1)
PDS(n = 329)
NACT -> IDS(n = 339)*
Metastases before > 2 cm
95% 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 # 2Key Issue # 2
What is the primary hypothesis?What is the primary hypothesis? Neoadjuvant chemotherapy will improve OS or PFSNeoadjuvant chemotherapy will improve OS or PFS Neoadjuvant chemotherapy will achieve the same Neoadjuvant chemotherapy will achieve the same
survival with a lower operative morbiditysurvival with a lower operative morbidity Neoadjuvant chemotherapy will allow more Neoadjuvant chemotherapy will allow more
patients to receive optimal surgery and optimal patients to receive optimal surgery and optimal chemotherapychemotherapy
Question # 3: Is there a patient population Question # 3: Is there a patient population where this would have an impact on where this would have an impact on outcome?outcome?
Key Issue # 3Key Issue # 3 Neoadjuvant chemotherapy should Neoadjuvant chemotherapy should
be applied to all advanced ovarian be applied to all advanced ovarian cancer patientscancer patients
OROR Neoadjuvant chemotherapy should Neoadjuvant chemotherapy should
be only for select populations:be only for select populations: ElderlyElderly Poor performance statusPoor performance status Extensive diseaseExtensive disease Medical co-morbiditiesMedical co-morbidities
GOG 182GOG 182
Median age on trial 58 (62 in neoadjuvant Median age on trial 58 (62 in neoadjuvant trial)trial)
Only 14% of patients ≥ 70 Only 14% of patients ≥ 70 Less than 5% ≥ 75Less than 5% ≥ 75 Performance status 0, 1, 2Performance status 0, 1, 2 15% were stage IV15% were stage IV
Clearly a large patient population is not being Clearly a large patient population is not being enrolled onto current trials due to advanced enrolled onto current trials due to advanced age and poor performance statusage and poor performance status
Key Issue # 3: Special Key Issue # 3: Special PopulationsPopulations
Question # 4: How to best Question # 4: How to best determine extensive disease?determine extensive disease? Radiographic, CA-125Radiographic, CA-125
Question # 5: What is the best way Question # 5: What is the best way to incorporate neoadjuvant to incorporate neoadjuvant chemotherapy into advanced age chemotherapy into advanced age and poor performance populations?and poor performance populations? EndpointsEndpoints Inclusive study designInclusive study design
Key Issue # 4: Surgical Key Issue # 4: Surgical TimingTiming
Question # 6: What is the best Question # 6: What is the best timing for surgery in patients timing for surgery in patients undergoing neoadjuvant undergoing neoadjuvant chemotherapy (3 vs. 6 months)?chemotherapy (3 vs. 6 months)? Which patients should not undergo Which patients should not undergo
surgical intervention?surgical intervention?
Key Issue # 5: EndpointsKey Issue # 5: Endpoints
Question # 7: What are the appropriate Question # 7: What are the appropriate endpoints and how should they be endpoints and how should they be measured?measured? OS/PFSOS/PFS QOLQOL Surgical morbiditySurgical morbidity ResponseResponse
ClinicalClinical RadiologicRadiologic Serum MarkersSerum Markers Surgical complete responseSurgical complete response
Key Issue # 6: Proof-of-Key Issue # 6: Proof-of-Concept designsConcept designs
Using neoadjuvant chemotherapy for Using neoadjuvant chemotherapy for proof-of-concept type studiesproof-of-concept type studies Novel strategiesNovel strategies Novel cytotoxic or biologic agentsNovel cytotoxic or biologic agents Molecular mechanisms and biomarkersMolecular mechanisms and biomarkers
Question # 8: Can we develop a Question # 8: Can we develop a standard queue for proof-of-concept standard queue for proof-of-concept studies in advanced ovarian cancer studies in advanced ovarian cancer patients?patients?