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State of the Art in Ovarian cancer
Jan B. Vermorken, MD, PhD
Department of Medical Oncology
Antwerp University Hospital
Edegem, Belgium
3rd EASO Masterclass in Clinical OncologyAmman, 2011
Epithelial Ovarian CancerEpidemiology
• The crude incidence of ovarian cancer in the European Union is 18/100.000 women per year, the mortality is 12/100.000 women per year
• The median age at diagnosis is 63 years. The incidence increases with age and peaks in the 8th decade. Between the age of 70-74 years the age-specific incidence is 57/100.000 women per year
* ESMO minimum Clinical Recommendations
Ann Oncol 19 (suppl 2): ii14-ii16, 2008
Five-year Survival in Ovarian Cancer30 years of experience
Vol. Year Cases Ia IV Overall
(n) %
16 1963-68 4588 66.7 5.0 27.3
19 1976-78 6724 72.3 4.5 29.8
21 1982-86 10912 82.3 8.0 35.0
23 1990-92 7059 83.5 11.1 41.6
25 1996-98 4116 89.3 13.4 46.4
26* 1999-01 4911 89.3 18.6 49.7
Int. J Gynecol Obstet 2006 (Suppl 1)
Epithelial Ovarian CancerMilestones
• Surgery according to FIGO guidelines– At least LNS and peritoneal staging in early
ovarian cancer– Upfront maximal surgical debulking in advanced
ovarian cancer• Chemotherapy evolution
– Introduction of platinum compounds– Introduction of taxanes
• The set-up of the GCIG in 1997
Epithelial Ovarian CancerMilestones
http://ctep.cancer.gov/resources/gcig/index.html
Are There Any New Developments in Early Ovarian Cancer?
FIGO I-IIa
• Grade and completeness of staging are the most strongest prognostic factors
• Low risk patients do not need chemotherapy as an adjuvant treatment (5-yr survival ≥ 95%)
• High-risk patients do need adjuvant platinum-based chemotherapy: combined analysis of ICON-1 and ACTION trial* showed 5-yr OS 82%vs 74%, p=.008
• Three vs six cycles: no significant difference in outcome, but recurrence rate with 6 cycles was 24% lower than with 3 cycles, and significantly more toxicity
*Trimbos et al, JNCI 2003Bell et al, Gynecol Oncol 2006
Prognostic Factors in Advanced-Stage Ovarian CancerStages IIb-IV
Postsurgery During RelapsePre-chemotherapy Chemo • Residual disease Type of chemo Time since last CT• Performance status CA 125 fall Disease bulk• Stage Interval debulking Histology• Grade No. disease sites• Age Perf. Status• Ascites Time since DX• Histology• Proliferation markers• Quantitative pathol. features• Ploidy• Molecular markers (unclear)
Eisenhauer et al, 1999 (modified)
Management of Advanced-Stage Ovarian Cancer
Stages IIb-III (IV)
• Upfront radical cytoreductive surgery
• In case this is not possible, a second attempt should be made
• Platinum-based chemotherapy
• Six cycles
• No second-look
Consensus meeting, 1998 Bergen (the Netherlands)
Optimal First-line Chemotherapy in ADOVCA: Historical Perspective
1970 1975 1980 1985 1990 1995/1997
L-Pam AC CHAP CHAC (C)P TP/TC
VAC HAD EP (C)C TEC
HexaCAF CAP CEP CEP DEC
HexaCAP CAC CAP
HexaMM
Alkylating Cisplatin Carboplatin PaclitaxelAgents
Doxorubicintopotecan?, LPD?gemcitabine?
Epirubicin
Advanced Ovarian Cancer1998-2011 Treatment
• Paclitaxel + Carboplatin (TC)– Generally agreed standard– “Control Arm” of all recent randomized trials– No other regimen shown to outperform it
• However, results far from perfect:– Median TTP: 15-18 mo– Median OS: <3 yrs
Standard of Care
Optimal Surgery
( = « No residual Disease » )
+ TC Chemotherapy
Lessons from Studies of Histotype
• Histotype matters
• Mucinous, endometrioid and clear cell cancers are distinct entities with different genetic changes, gene expression profiles and sensitivities to chemotherapy
• Separate trials will be required
• Recent discoveries in clear cell cancer suggest changes in chromatine remodeling may provide a target
Bast, presented at Valencia meeting 2011
How to Improve Outcome in Advanced OCBeyond PAC-CARBO
• Increase rate of optimal cytoreduction (definition ODS)– concept of NACT– role for interval debulking?
• Increase efficacy of cytotoxic chemotherapy– adding a third drug– maintenance/consolidation therapy– dose-dense therapy
• Modulate resistance– modulating agents– increase dose / exposure (systemic / regional)
• The use of targeted therapies
New Data for Advanced Ovarian Cancer
• NACT an alternative for not optimal resectable FIGO IIIc (Vergote et al, NEJM 2010)
• No benefit from adding a third drug to TC
• No role for consolidation/maintenance cytotoxic CT?1 study positive for PFS (12 vs 3 cycles paclitaxel PFS 28 vs 21 months, p<.005): Markman et al, JCO 2003)
• Dose dense TC superior (JGOG study)Confirmatory studies ongoing
• IP therapy finally recognized
Targeted Therapies in Ovarian Cancer
Target Drug(s)
ErbB kinases Gefitinib, erlotinib, lapatinib, canertinib, cetuximab,
pertuzumab, matuzumab, trastuzumab
MUC1 / PEM Pemtumomab
MUC16 (CA 125) Oregovomab
mTOR / AKT Temsirolimus, everolimus, deforolimus
Apoptosis pathway AEG35156, OGX-011
Angiogenesis Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib
Endothelial cells Combretastatin, Oxi4503
Matrix metalloproteinases BAY 12-9566, marimastat
First-Line Trial of Bevacizumab in Ovarian Cancer (GOG#218)
Stage III°
Optimal and
Suboptimal or
Stage IV
RANDOMIZE
Paclitaxel/Carbo (PC) + placebo x6
placebo x16
PC+bev* x6 placebo x16
PC+bev x6 bev x16
*Dose of bevacizumab 15 mg/kg q 3 weeks
°Total number of patients 2000
Key Results There is clear clinical effect of bevacizumab on PFS
• Per protocol analysis:
– Significant improvement of PFS in Arm III only
– Per protocol analysis: 3.8 mo increase PFS (med)HR 0.717, p <0.0001
– ~ half of all progression events occurred on therapy
Pro
po
rtio
n s
urv
ivin
g p
rog
ress
ion
fre
e
Months from randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
+ BEV (Arm II)
Chemo (Arm I)
+ BEV → BEV maintenance (Arm III)
• CA 125 censored PFS (sensitivity analysis):CA 125 censored PFS (sensitivity analysis):– Similar outcomes (HR 0.645), but 25% fewer events Similar outcomes (HR 0.645), but 25% fewer events
• Overall survival and QoL: to be discussedOverall survival and QoL: to be discussed
First-Line Trial of Bevacizumab in Ovarian Cancer (ICON - 7)
Stage Ic - IV°
Excluding those scheduled for further surgery
RANDOMIZE
Paclitaxel/Carbo (PC)
PC+bev* x6 bev x12
*Dose of bevacizumab 7.5 mg/kg q 3 weeks
°Total number of patients 1500
ICON-7: PFS
http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf Accessed 15 October 2010
Academic analysis
Number at riskControl 234 205 98 36 14 2Research 231 213 159 56 10 1
Number at riskControl 234 205 98 36 14 2Research 231 213 159 56 10 1
PFS: FIGO stage III suboptimal and FIGO stage IV with debulking
1.00
0.75
0.50
0.25
0
1.00
0.75
0.50
0.25
0
Pro
port
ion
alive w
ith
ou
t p
rog
ressio
nP
rop
ort
ion
alive w
ith
ou
t p
rog
ressio
n
Time (months)Time (months)0 3 6 9 12 15 18 21 24 27 300 3 6 9 12 15 18 21 24 27 30
Control(n=234)
Research (n=231)
Events, n (%) 173 (74) 158 (68)Median, months 10.5 15.9Log-rank test p<0.001Hazard ratio (95% CI) 0.68 (0.55–0.85)Restricted mean 13.3 16.5
10.5 15.9
ControlResearch
http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf Accessed 15 October 2010
Kristensen G. et al, ASCO 2011, abstract #LBA5006
Kristensen G. et al, ASCO 2011, abstract #LBA5006
GOG #218: Patient Inconvenience and Toxicity
• 23% risk of developing grade 2 hypertension
• 10% risk for grade 3 to 4 hypertension
• 2.3% risk for ≥ grade 3 GI perforationhemorrhagefistula formation
GOG #218: Cost-Effectiveness
• Based on PFS and bowel perforation rates• Incremental cost-effectiveness ratios (ICERs) per PF live-year saved (PF-LYS)
were estimated
• For the 600 patients entered onto each arm of GOG #218:
Cohn DE et al, J Clin Oncol 2011; 29: 1247-1251
Treatment Total Cost ICER ($) ICER per PF-LYS ($)
TC 2.5 M 247.616 Referent
TCB 21.4 M 1.9 M 479.712
TCB + B 78.3 M 5.6 M 401.088
Recurrent Ovarian Cancer: Important Issues
• Presentation (asymptomatic 55-70%; TFI*)
• Realistic goals
• When to treat
• How to treat
• New combinations and compounds
*<6 months; 6-12 months; <12 months
Realistic Goals of Second-line Therapy in Ovarian Cancer
• Improve cancer-related symptoms
• Optimize overall quality of life
• Delay time to symptomatic disease progression
• Prolong overall survival
• Achieve an “objective response”
Markman M, 2002
Harries and Gore, 2002
When to Treat?
Trial Design
Ovarian cancer in complete remission after first-line platinum based chemotherapy
and a normal CA125
CA125>2 x upper limit of normalRANDOMIZED
Early treatmentClinician and patient informed
Delayed treatmentClinician not informed, treatment delayed until clinically indicated
REGISTERBlinded CA125 measured
every 3 months
Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
Overall Survival
HR=1.00 (95%CI 0.82-1.22) p=0.98
EarlyDelayed
Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%)
Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
Time from Randomisation to FirstDeterioration in Global Health Score
(or death)P
rop
ort
ion
ali
ve w
ith
ou
t d
eter
iora
tio
n i
n G
HS
Number at risk
Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
Chemotherapy Options in Platinum-Sensitive Recurrent Ovarian Cancer (ROC)
• Traditionally, ROC patients with TFI > 6 mo have been retreated with platinum-based chemotherapyICON-4 trial: Platinum/paclitaxel > Pt-alone (PFS, OS )
• Cumulative toxicity from primary therapy (neuro) can preclude retreatment with paclitaxel/carboplatin– AGO OVAR 2.5: carbo/gemcitabine vs carbo (PFS )– OCEANS: carbo/gemcitabine ± bevacizumab (study)– CALYPSO: PLD/carbo vs paclitaxel/carbo (PFS )
OCEANS Trial : a Randomized, Double-Blind Placebo-Contr. Ph III Trial of CT +/- Bev
In Platinum (Pt) –Sensitive Recurrent EOC
Stratification variables:
• Platinum-free interval (6–12 vs >12 months)
• Cytoreductive surgery for recurrent disease (yes vs no)
Gemcitabine 1,000mg/m2, days 1, 8 q3w
Carboplatin AUC4 q3w
Gemcitabine 1,000mg/m2, days 1, 8 q3w
Carboplatin AUC4 q3w
Platinum-sensitive recurrent ovarian
cancer• Measurable disease• ECOG PS 0/1• No prior
chemotherapy for recurrent disease
• No prior Avastin(n=484)
Placebo q3w
Avastin 15mg/kg q3w
Carboplatin/gemcitabine for 6 (up to 10) cycles
PD
PD
Aghajanin C et al –MSKCC (LBA # 5007)
PFS PFS ??
Main reason for discontinuation of Bev = PD
CALYPSO (n=973 patients)
PLD 30 mg/m², d1Carbo AUC 5
PACL 175 mg/m², d1Carbo AUC 5, d1
Efficacy*PFS 11.3 mo PFS 9.4 mo*
ToxicityPLT, HFS, nausea**mucositis
ANC, alopecia, HSR**sensory neuropathy
*HR 0.82 (95% CI 0.72-0.94), p=0.005**p<0.01Pujade-Laurain et al, J Clin Oncol 2010; 28: 3323-3329
q 4 wks q 3 wks
Chemotherapy Options in Platinum-Resistant Recurrent OC or for those with Partially
Platinum-Sensitive Disease (TFI 6-12 mo)
• Numerous agents are available that can be used as a single agent: – gemcitabine, PLD, topotecan, paclitaxel, docetaxel,
oral etoposide, altretamine, trabectedin, and hormonal agents
• Take into consideration the patient’s anticipated tolerability and cumulative toxicity from front-line therapy
Trabectedin – Structure and Origin
Scotto. Anticancer Drugs 2002; 13 (Sup 1): s3-s6
A
B
C
Trabectedin Structure: 3 tetrahydroisoquinolone rings
• Trabectedin (ET-743; Yondelis®) is a novel, marine-derived anticancer agent originally isolated from marine Caribbean tunicate Ecteinascidia turbinata and is now produced synthetically.
• Chemically comprised of three fused rings (A, B and C), each of them with one or more different functions.
An Open-label Multicenter Randomized Phase 3 Study Comparing DOXIL/CAELYX and
Trabectedin with DOXIL/CAELYX Alone in Advanced ROC
Advanced Recurrent Epithelial Ovarian Cancer
– One prior regimen– Evaluable and measurable
disease– Platinum-sensitive and -
resistant
Accrual Goal: 650 patientsPrimary endpoint: PFS/OSOther endpoints: RR, Safety
Translational Research:• Pharmacokinetics• Pharmacogenomics• Pharmacoeconomics• Quality of Life• Circulating tumor cells
RANDOMIzE
doxil 50 mg/m2 every 4 wks
doxil 30 mg/m2 plustrabectedin 1.1mg/m2
every 3 wks
Monk BJ et al, J Clin Oncol 2010; 28(19):3107-14.
Monk BJ et al, J Clin Oncol 2010; 28(19):3107-14.
An Open-label Multicenter Randomized Phase 3 Study Comparing
DOXIL/CAELYX and Trabectedin with DOXIL/CAELYX Alone in Advanced ROC
Monk BJ et al, submitted
PARP Inhibitors
• Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a key enzyme in the repair of DNA. Inhibition of PARP leads to accumulation of breaks in DS-DNA and cell death.
• PARP inhibitors are in particular exciting in cancers with germline mutations in the BRCA gene, but benefit might be wider (> 50% of patients with high-grade sporadic EOC possibly have loss of BRCA function
– Continuous oral olaparib (AZD 2281) 57.6% clinical benefit
– Phase II ongoing in platinum-sensitive serous OC after 2 or more platinum-containing regimen
Phase 2 Randomized Placebo-controlled Study of Olaparib in Pts with Platinum-
Sensitive relapsed Serous OCLedermann J et al (# 5003)
n = 265n = 265
Phase 2 Random. Placebo-controlled Study of Olaparib in Pts with Platinum-Sensitive
Relapsed Serous OCLedermann J et al (# 5003)
• Overall survival data : immature• QoL : no ≠ in improvement / time to worsening
Take-Home Messages for ADOVCA
• Upfront surgery followed by 6 cycles of Pt-Tax-based CT is still standard
• Paclitaxel + carboplatin (TC) generally agreed standard arm for trials
• NACT followed by surgery in stages IIIc-IV OC showed the same OS and PFS as PDS with less morbidity in one large randomized GCIG trial.
• A dose-dense therapy approach may be of benefit• Intraperitoneal chemotherapy suitable for selected patients• Targeted therapy is promising (in particular anti-angiogenic
approaches), but not yet standard
Recommended