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Unanswered Questions in Primary Treatment of Ovarian Cancer: Controversial Areas. Deborah K. Armstrong, M.D. May 29, 2009. Initial Therapy of Ovarian Cancer: Controversial Areas. How can we best use targeted biologics with initial chemotherapy improve outcome? - PowerPoint PPT Presentation
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Unanswered Questions Unanswered Questions in Primary Treatment in Primary Treatment of Ovarian Cancer: of Ovarian Cancer: Controversial AreasControversial Areas
Deborah K. Armstrong, M.D.Deborah K. Armstrong, M.D.May 29, 2009May 29, 2009
Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas
• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?
• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response
to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated
differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing
clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the
“real world”“real world”
Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas
• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?
• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response
to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated
differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing
clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the
“real world”“real world”
Models for addition of targeted biologic Models for addition of targeted biologic therapy to initial chemotherapytherapy to initial chemotherapy
Concurrent Chemo & Biologic
Concurrent Chemo & Biologic with Maintenance/Consolidation
Sequential Chemo followed by Biologic (as Maintenance/Consolidation)
Biologic AgentChemotherapy
GOG 218GOG 218
OvCa OvCa III/IVIII/IVSuboptSubopt
Paclitaxel Paclitaxel 175 mg/m175 mg/m22/3h/3hCarboplatinCarboplatin AUC = 6 AUC = 6
q 21 d x 6q 21 d x 6BevBev d1 X 5 d1 X 5
begin cycle 2begin cycle 2
Paclitaxel Paclitaxel 175 mg/m175 mg/m22/3h/3hCarboplatinCarboplatin AUC = 6 AUC = 6
q 21 d x 6q 21 d x 6PlaceboPlacebo d1 X 5 d1 X 5begin cycle 2begin cycle 2
Paclitaxel Paclitaxel 175 mg/m175 mg/m22/3h/3hCarboplatinCarboplatin AUC = 6 AUC = 6
q 21 d x 6q 21 d x 6BevBev d1 X 5 d1 X 5
begin cycle 2begin cycle 2
RRAANNDDOOMMIIZZEE
Burger, R. GOG 218 Burger, R. GOG 218
Placebo
q 21d X 15 mos
Placebo
q 21d X 15 mosBev
q 21d X 15 mos
Bevacizumab 15 mg/kg IV
ICON 7 (Front-line European Trial)ICON 7 (Front-line European Trial)
Stages I-IV ovarian and Stages I-IV ovarian and peritoneal cancerperitoneal cancer
– Stratified according to Stratified according to stage, optimal status stage, optimal status region or countryregion or country
Carboplatin AUC 6 pluspaclitaxel 175 mg/m2 (3 hr) q 21d x 6
RANDOMIZE
Carboplatin AUC 6 pluspaclitaxel 175 mg/m2 (3 hr) q 21d x 6plus bevacizumab at 7.5 mg/kgfollowed by bevacizumab at 7.5 mg/kgq 21 d x 12 months
Accrual goal: 1,444 patientsPrimary endpoint: PFSOther endpoints: OS (10 mo), RR, Toxicity
Translational Research• Tissue and serum markers of angiogenesis• Genomics• DCE-MRI• Quality of life• Health economics
DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging ICON = International Collaborative Ovarian Neoplasm GroupOS = overall responseRR = response rate
DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging ICON = International Collaborative Ovarian Neoplasm GroupOS = overall responseRR = response rate
RANDOM I S E
Observation
Tarceva 150 mg daily for up to 2 years or until PD
Stage Ic to IV epith. ovarian cancer, having achieved CR/PR/SD on platinum-based chemo (6-9 courses)
N = 830
Endpoints: PFS and overall survival
Recruitment completed, study ongoing
FIRST LINE MAINTENANCE (EORTC) – WITH TRANSLATIONAL SUB-STUDY
Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas
• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?
• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response
to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated
differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing
clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the
“real world”“real world”
GOG #178GOG #178SWOG #9701SWOG #9701
Ovarian cancerOvarian cancerStage III or IVStage III or IV5-6 cycles 5-6 cycles platinum and platinum and Paclitaxel, inPaclitaxel, inClinical CRClinical CR
RRAANNDDOOMMIIZZEE
Paclitaxel Paclitaxel 135 mg/m2/3h135 mg/m2/3hQ 28 days x Q 28 days x 33
Paclitaxel Paclitaxel 135 mg/m2/3h135 mg/m2/3hQ 28 days x Q 28 days x 1212
GOG #178GOG #178SWOG #9701SWOG #9701
12 months12 months 3 months3 months
# pts at risk# pts at risk 110110 112112
# relapsed# relapsed 2020 3434
Median PFSMedian PFS 28 months28 months 21 months21 months
P=.0023
Overall Survival
0%
20%
40%
60%
80%
100%
0 24 48 72 96Months After Registration
Paclitaxel 12 coursesPaclitaxel 3 courses
At Risk150146
Deaths6680
Medianin Months
5346
SWOG 9701/GOG 178:Overall Survival
Markman M, et al. J Clin Oncol. 2006;24(18S):Abstract 5005.
Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas
• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?
• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response
to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated
differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing
clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the
“real world”“real world”
Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas
• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?
• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response
to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated
differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing
clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the
“real world”“real world”
In response to DNA damage the Fanconi Anemia (FA) complex is activated, translocated and binds with chromatin containing the BRCA1 protein and BRCA2 proteins. This complex promotes DNA repair.
In the presence of mutated, nonfunctional or absent BRCA1 or BRCA2 proteins, DNA repair is compromised increasing sensitivity to chemotherapeutic agents, particularly the platinum salts.
Olopade and Wei, Cell 2003
Ovarian Cancer Relapse:Effect of BRCA Mutations
Boyd et.el. JAMA 2000
Ovarian Cancer Survival:Effect of BRCA Mutations
Cass et.al. Cancer May 2003
BRCA1 and BRCA2 Mutated Ovarian Carcinomas
• BRCA1 and BRCA2 are critical proteins in DNA repair via homologous recombination
• BRCA-associated cancers develop after a deletion or mutation of the wildtype allele
• Normal non-malignant cells retain the wildtype allele and intact BRCA function
• Cells defective in BRCA1 or BRCA2 are more sensitive to ionizing radiation and platinum compounds
• BRCA-deficient cells are dependent on an alternate, PARP-dependent DNA repair pathway
Questions about the use of Questions about the use of PARP inhibitors in ovarian cancerPARP inhibitors in ovarian cancer
• Is there a role for PARP inhibitors in ovarian cancer Is there a role for PARP inhibitors in ovarian cancer patients without a BRCA mutation?patients without a BRCA mutation?– Other defects in the homologous recombination Other defects in the homologous recombination
pathwaypathway– BRCA promoter methylation to silence BRCA genes BRCA promoter methylation to silence BRCA genes
• Will resistance develop to PARP inhibitors?Will resistance develop to PARP inhibitors?– Documentation of second BRCA mutations that Documentation of second BRCA mutations that
revert to wild type functionrevert to wild type function• Are platinum resistant patients likely to be PARP Are platinum resistant patients likely to be PARP
inhibition resistant?inhibition resistant?
Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas
• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?
• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response
to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated
differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing
clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the
“real world”“real world”
Comparative EffectivenessComparative Effectiveness• $1.1 Billion of ARRA funds slated for comparative $1.1 Billion of ARRA funds slated for comparative
effectiveness research (CER)effectiveness research (CER)• No agreement on definition of CERNo agreement on definition of CER
– Efficacy is determined within specific populations Efficacy is determined within specific populations under controlled conditionsunder controlled conditions
– Effectiveness is closer to what actually happens Effectiveness is closer to what actually happens in the real worldin the real world
• ““Cooperative groups, being publicly funded, may be Cooperative groups, being publicly funded, may be best positioned to conduct such studies”best positioned to conduct such studies”
• The CER agenda may conflict with the mission to The CER agenda may conflict with the mission to advance scienceadvance science
The Cancer Letter, May 22, 2009
From Edmonson, Gynecologic Oncology , 2000