Clique para editar o título mestre. Non-Epithelial Uterine Cancer (NEUC) Robert L. Coleman, M.D....
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Transcript of Clique para editar o título mestre. Non-Epithelial Uterine Cancer (NEUC) Robert L. Coleman, M.D....
Clique para editar o título mestre
Non-Epithelial Uterine Cancer (NEUC)
Robert L. Coleman, M.D.Professor, Vice Chair Clinical Research
University of Texas, M.D. Anderson Cancer Center
Mortality by Histology
2-3% of cases are sarcomas or carcinosarcomas with 50% mortality rate
Proportion of Cases
G1,G2 EC G3 EC USC Clear Cell
Proportion of Cancer Deaths
Parameter Type 1 Type 2Age 50s-60s 60s-70sObesity Common UncommonEstrogen Related Common UncommonEndometrium Hyperplastic AtrophicPrecursor EIN EGD, EICTransition Slow RapidType Endometrioid Serous, CCA or MixedMolecular deletions MSI, PTEN p53, 17p+1p,(her2-neu)Familial HNPCC BRCA?Depth of invasion Superficial DeepSpread LN, distal LN, peritonealConcurrent Ovarian Some UncommonPrognosis Good Poor
Pathogenesis of Uterine Cancer
Bokhman JV, Gynecol Oncol 15(1):10, 1983
Endometrial Cancer: TCGA
Dedes Nat Clin Oncol Rev 2011GainLoss
EndometrioidGrade 1 or 2
EndometrioidGrade 3 Serous
Andrew Cherniack, Broad
Challenges in Studying NEUC
• Few studies addressing the histology specifically– Included in phase III studies and stratified– Excluded from clinical trials (particularly early stage trials)
• Even when included…– Majority are clinically staged– Many combine outcomes for both Stage I and II– Multiple treatment regimens administered– Pre-operative vaginal radiation therapy– Limited follow-up– Unclear pathology criteria
OS in GOG Trials: Histology
McMeekin, Gynecol Oncol. 2007 Jul;106(1):16-22
Challenges in Studying NEUC
• Few studies addressing the histology specifically– Included in phase III studies and stratified– Excluded from clinical trials (particularly early stage trials)
• Even when included…– Majority are clinically staged– Many combine outcomes for both Stage I and II– Multiple treatment regimens administered– Pre-operative vaginal radiation therapy– Limited follow-up– Unclear pathology criteria
“Radical Surgery”(TAH-BSO)
CT RTor
RT CTChemo: Platinum-
based
RT(Ext ± Brachy)
NSGO EC-9501/EORTC-55991MaNGO (ILIADE-III)
• Primary Endpoint: PFS (ITT), TTP• NSGO
– N = 378– Stage I, II, IIIA (cytology), IIIC (pelvic)– All histology (including USC & CCA)
• MaNGO– N = 156– Stage IIA-IIIC– Only endometrioid
• Staging optional in both
Hogberg, Eur J Cancer (2010) 46:2422
NSGO EC-9501/EORTC-55991MaNGO (ILIADE-III)
Hogberg, Eur J Cancer (2010) 46:2422
OSPFS
NCCN Guidelines
Lymphadenectomy: USC
Early stage, Intermediate risk, Node negative
Node positive
Chan, Cancer (2006) 107:1823
Omentectomy in NEUC
• Frequently recommended given the intraperitoneal spread of even stage I disease limited to a polyp (>25%)
• Gehrig, et al., (2003)– 52 patients with omentectomy
• 34 – negative• 18 – positive
– 16 grossly positive– 2 microscopically positive (11%)
Stage is Prognostic in NEUC
Growdon, Int J Gynecol Oncol (2012)22:417
Stage I NEUC: Recurrence by Modality
Author N Observation N Pelvic RT
Huh 40 17% 12 16%
Elit 27 19% 4 25%
Grice 5 0% 6 33%
Kelley 21 29% 6 100%
Nguyen 5 0% 5 0%
Bristow 11 9% - -
Gallion 9 0% - -
Gehrig 6 33% - -
Stage I NEUC*: Recurrence by Modality
Study N Observation or RT Chemotherapy
Huh§ 70 31% (19/62) 0% (0/8)
Kelley 74 63% (20/32) 3% (1/29)
Havrilesky§ 81 30% (19/64) 24% (4/17)
TOTAL 215 37% (58/158) 9% (5/54)
* Completely Staged§ Omentectomy unspecified or no obtained in all patients
Early Stage NEUC: Chemotherapy
• Ten institutions• All patients were
comprehensively staged• Radiation was not used
– 1 recurrence in paclitaxel/carboplatin was vaginal and salvaged with XRT
• Recurrence (mean f/u: 41 mos)– 2 of 8 with non-taxane
regimen– 1 of 21 in taxane doublet
• Recurrence risk overall: 17%
Dietrich III, Gynecol Oncol (2005) 99:557
Stage IA Disease
Tumor at Hysterectomy
Chemotherapy ± XRT
XRT Observation
No residual 0/2 0/1 0/10
Polyp-Confined 0/7 0/3 1/9 (11%)
Other IA findings 2/28 (7%) 4/12 (33%) 2/27 (7%)
Del Carmen Gynecol Oncol (2012) ePub
NCCN Guidelines: Advanced Disease
Advanced Stage Disease
Author N FIGO Stage
Optimal Def % Optimal OS (mos) P
Rauh-Hain 79 IIIC/IV ≤ 1 cm 62% 36 vs 12 0.0001
Thomas 70 IIIC/IV ≤ 1 cm 60% 20 vs 12 0.02
Bristow 65 IVB ≤ 1 cm 55% 34 vs 11 0.0001
Lambrou 58 IIIC/IV ≤ 2 cm 72% 7 vs 2 0.0001
Chi 55 IV ≤ 2 cm 44% 31 vs 3 <0.01
Moller 52 IV ≤ 1 cm 53% 15 vs 8 <0.05
Bristow 31 IV ≤ 1 cm 52% 26 vs 10 <0.001
Advanced Stage Disease
• Data primarily from prospective adjuvant trials not exclusive for USC or CCA
Phase III Trials- Advanced Recurrent Disease
AC AP AT TAP TC
A GOG 48
GOG 107
AC GOG 139
AP GOG 163
GOG 177
TAP GOG 209
A=doxorubicin, AC= doxorubicin + cisplatin, TAP= paclitaxel + doxorubicin + cisplatin, TC= paclitaxel + carboplatin
Cont
rol A
rm
Experimental Arm
Endometrial Cancer: Chemotherapy
• Single agents vs Combos:– GOG 48: A vs. AC
• RR: 22% vs 33%• HROS: 0.83 (p = 0.048)• More toxicity
– GOG 107: A vs. AP (cisplatin)
• RR: 25% vs. 42% (P = 0.004)• PFS: 0.74 (P = 0.014)• OS: 9.0 vs 9.2 (NS)• More toxicity
• Combination comparisons: – GOG 163: AP vs. AT
• RR: 40% vs. 44% (NS)
– GOG 177: AP vs. TAP• RR: 34 vs. 57%• HRPFS: 0.60 P<0.001
• HROS: 0.75, P=0.038• More cardiac & neuro in TAP
GOG-209: Schema
Advanced, Recurrent Endometrial Cancer
Adriamycin 45 mg/m2 day 1Cisplatin 50 mg/m2 day 1Paclitaxel 160 mg/m2 24 hour day 2
G-CSF 5 mcg/kg days 3-12Q 21 days x 7
Carboplatin AUC 6 Paclitaxel 175 mg/m2 3 hr
Q 21 days x 7
Planned accrual: 900 patients/795 failures - 60 months (now 1312 includes non-measurable disease)Sample not inflated for LVEF-related crossover (0 pts)HR: 1.20 for Carboplatin/paclitaxel armOpened: 8/25/2003; Closed 4/20/2009
GOG-209: Demographics
Miller, LBA1, SGO 2012
GOG 209: Toxicity
Toxicity TAP TC PNeutropenia 52% 79% <0.01
Complicated Neutropenia 7% 6% NS
Thrombocytopenia (Gr 3/4) 23% 12% <0.01
Other Hematologic 30% 22% <0.01
Neurologic (G2+) 26% 19% <0.01
Vomiting 7% 4% <0.01
Diarrhea 6% 2% <0.01
Metabolic 14% 8% <0.01
Discontinued because of Toxicity 18% 12% 0.01
Completed 7 Planned 62% 69% 0.01
Miller, LBA1, SGO 2012
GOG: Outcomes
Outcome Measure TAP TC HRMedian PFS 14
mos14
mos1.03
Median OS 38 mos
32 mos
1.01
OS (90% CI, Non-inferiority) 1.16 P>0.1
Miller, LBA1, SGO 2012
Opened Jun 29, 2009Accrual Goal = 804
Study Chair D Matei
Surgical stage III or IVA endometrial carcinoma All Cell types Must have TAH and
BSO Pelvic node sampling and aortic node sampling optional
REGIMEN ICisplatin 50 mg/m2 IVDays 1 and 28plus Volume-directed RTfollowed by Carboplatin AUC 5*plus Paclitaxel 175 mg/m2q 21 days for 4 cycles
REGIMEN IICarboplatin AUC 6 plus Paclitaxel 175 mg/m2q 21 days for 6 cycles
Secondary endpoints TR and QOL
GOG-258: Replacement
RANDOMIZE
Novel Biologics in Endometrial Cancer
• PI3K pathway– PI3Ki’s– Rapalogs– MK2206 (Akt)– OSI-906 (IGF1-R)– Multiple combo’s
• Ras/raf Pathway– ZD6244 (MEK/Erk)
• EGFR– Cetuximab– ZD6474
• Other targets– Folate receptor (EC145)– PARP (BSI-201)
• Angiogenesis:– VEGF/R:
• Bevacizumab• Aflibercept• Sorafenib• Sunitinib• BIBF-1120• Pazopanib• On and on and on
– FGF/R:• Brivanib
– Endothelial• ACE-041 (Alk1)• TRC-105• AMG-386 (Ang/Tie)
Endometrial Cancer: GOG 229-series
STUDY AGENT N RR (%) PFS at 6 months (%)
229-C Gefitinib 26 3.8 15
229-D Lapatinib 30 3.3 10
229-E Bevacizumab 53 13.5 40
229-F Aflibercept 44 7% 41
229-G Bevacizumab-Temsirolimus 49 24.5% 47
229-H AZD6244 (MEKi) 50 6% 22
229-I Brivanib 53 19% 30
229-J Cediranib Second stage in progress
229-K BIBF-1120 First stage accrual
229-L AMG-386 First stage accrual
229-M OSI-906 (IGF1R) On hold for drug supply
MK-2206 (AKT) SU2C - Closed
GOG Randomized Ph II
GOG-86P
PI: Aghajanian
Bevacizumab
Bevacizumab
Temsirolimus
Maintenance Tx To Progression
Paclitaxel/CarboplatinBevacizumab
Paclitaxel/CarboplatinTemsirolimus
Ixabepilone/CarboplatinBevacizumab
No Prior ChemotherapyStage IVB (may be measurable)Recurrent (measurable mostly)N = 349 (closed)
New Targets: Dasatinib
• Phase 0/I pilot trial• Patients:
– Advanced/recurrent endometrial cancer
– No prior therapy for recurrent disease
– Biopsy amenable
• Endpoints:– EphA2 expression alteration in
post-treatment tissue bx– Toxicity, efficacy– Translational
• miR520d-3p expression• Downstream signaling (FAK,
paxillin, p130 cas)• EphB2, EphB4• CTC’s
Paclitaxel
Carboplatin
Tumor Biopsy
Dasatinib
weeks
-2 -1 0 1 2 3 4 5 6 7 8 9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Imaging X X
If not progressiveContinue treatment21 day cyclesImaging every 3 cyclesMaximum # of cycles: 6
PI: Coleman, RL
Thank You!