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?