26
Focus su algoritmi terapeutici condivisi
Angiolo Gadducci (Pisa)
Algoritmo di trattamento nel carcinoma ovarico avanzato alla diagnosi
6-12 months
Sensitive
Valutazione clinica, radiologica ed anestesiologica:
-Condizioni generali compatibili con chirurgia citoriduttiva aggressiva-Diffusione di malattia potenzialmente compatibile condebulking ottimale
SI NO
Esplorazione chirurgica (LPT, LPS) CBDCA+ PTX + BEV x 3 cicli^
Fattibilità di debulking ottimale chirurgia citoriduttiva di intervallo*
SI NO CBDCA+PTX+^BEV x 3 cicli (BEV mantenimento)
Chirurgia citoriduttiva primaria
CBDCA+ PTX +BEV x 6 cicli^ (BEV mantenimento)
*se RC o RP o SD
^BEV raccomandato in assenza di controindicazioni specifiche
CP (Arm I)
Arm I
CP
(n=625)
Patients with event, n (%)423
(67.7)
Median PFS, months 10.3
Stratified analysis HR
(95% CI)
One-sided p-value (log rank)
GOG-0218: Investigator-Assessed PFS
+ BEV (Arm II)
ap-value boundary = 0.0116
+ BEV → BEV maintenance (Arm III)Prop
ortion
sur
viving
pro
gress
ion
free
Months since randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 12 24 36
Arm III
CP + BEV BEV(n=623)
360
(57.8)
14.1
0.717
(0.625–0.824)
<0.0001a
4
Arm II
CP + BEV
(n=625)
418
(66.9)
11.2
0.908
(0.759–1.040)
0.080a
Number at riskControl 764 723 693 556 464 307 216 143 91 50 25Research 764 748 715 647 585 399 263 144 73 36 19
Progression-free survival1.00
0.75
0.50
0.25
Prop
orti
on a
live
wit
hou
t pr
ogre
ssio
n
Time (months)
0 3 6 9 12 15 18 21 24 27 30
Control Research
Events, n (%) 392 (51) 367 (48)
Median, months 17.3 19.0
Log-rank test p=0.0041
HR (95% CI) 0.81 (0.70–0.94)
17.3 19.0
ControlResearch
Academic analysis
Percentage of relapse
• About 75% gain clinical response with 1st line treatment
• About 80% relapse
Hennessy BT et al. Lancet 2009;374:1371-82
Platinum-free interval (time from last platinum dose to progression)
On treatment or within 1 month 1-6 months 6-12 months >12 months
Refractory Resistant Partially resistant Sensitive
Algoritmo di trattamento nel carcinoma ovarico recidivante
6-12 months
Sensitive
Malattia platino-refrattaria
(progressione durante terapia di I linea)
PTX settimanale
PLD
GEM
Topotecan
Monochemioterapia
Inclusione in trial clinici
Best supportive care
Algoritmo di trattamento nel carcinoma ovarico recidivante
6-12 months
Sensitive
Malattia platino-resistente (intervallo libero < 6 mesi)
PTX settimanale
PLD
GEM
Topotecan
Monochemioterapia
Inclusione in trial clinici
BEV combined with CT for platinum-resistant recurrent EOC : The AURELIA open-label randomized phase III trial.
Pujade-Lauraine JCO 2014
6-12 months
Sensitive
BAROCCO Study
An Italian multicenter randomized phase II study of weekly Paclitaxel
vs. Cediranib-Olaparib continuous schedule vs. Cediranib-Olaparib
intermittent schedule in platinum-resistant high-grade epithelial
ovarian, fallopian tube, or primary peritoneal cancer.
Sponsor: Istituto di Ricerche Farmacologiche Mario Negri – MaNGO
Study Lead Investigator: Prof. Nicoletta Colombo
Supporter: AstraZeneca
6-12 months
Sensitive
BAROCCO Study
A. Comparator
Paclitaxel 80 mg/m2 weekly
(max 6 cycles = 24 weeks)
B. Continuous schedule
Cediranib 20 mg/day 7 days per weekOlaparib 600 mg/day 7 days per week
C. Intermittent schedule
Cediranib 20 mg/day 5 days per week Olaparib 600 mg/day 7 days per week
Progression,
unacceptable
toxicity,patient/physician
decision, death
Platinum-
resistant
Ovarian Cancer
n=100
Randomization ratio 1:1:1
Stratification factors
Number of previous chemotherapy lines
Germline mutational BRCA status
Prior antiangiogenetic drugs
Randomised phase III trials in recurrent platinum-sensitive EOC
Parmar MK et al. 2003; Pfisterer et al. J 2006; Pujade-Lauraine E et al. 2010;
Agents Median PFS (months)
CBDCA + PTX 13
CBDCA + GEM 8,6
CBDCA + PLD 11,3
Aghajanian 2012
CT +
BEV
CT +
placebo
HR 95% CI P value
Median
PFS (mos)
12.4 8.4 0.484 0.388-0.605 <0.0001
Median OS
(mos)
35.5 29.6 0.751 0.537-1.052 0.094
RR 78.5% 57.4% - - <0.0001
•EOC•Platinum-sensitive•Previous BEV•ECOG 0-2•Availability of samples for translational res.•No BEV contraindications
R
CBDCA AUC5 + PAC 175 mg/m2 q3w orCBDCA AUC4, d1 + GEM 1000mg /m2, d1&8 q3worCBDCA AUC5+PLD 30mg/m2 q4w
CBDCA AUC5 + PAC 175 mg/m2 q3w + BEV** 15mg/kg q3worCBDCA AUC4, d1 + GEM 1000mg /m2, d1&8 q3w+ BEV 15mg/kg q3worCBDCA AUC5+PLD 30mg/m2 q4w + BEV 10mg/kg q2w
*Pts without PD after 6 cycles of combined treatment will receive BEV maintenance until PD
n=400 pts International(MITO, MANGO, ENGOT)
MITO 16/MANGO OV2 project: the Phase III trial
Algoritmo di trattamento nel carcinoma ovarico recidivante
6-12 months
Sensitive
Malattia platino-sensibile (intervallo libero >12 mesi)
BEV eseguito in linea
Se AGO-score+Valutare chirurgia citoriduttiva secondariaA)
CT di II lineaCBDCA doublet CBDCA doubletPTX + CBDCA PTX + CBDCAGEM + CBDCA GEM + CBDCAPLD + CBDCA PLD + CBDCA
RC, RP o SD RC, RP o SD
SI NO SI NO
OLAPARIB CT III linea NIRAPARIB CT III linea
BRCA+ BRCA-
Algoritmo di trattamento nel carcinoma ovarico recidivante
6-12 months
Sensitive
Malattia platino-sensibile (intervallo libero >12 mesi)
BEV non eseguito in linea
Se AGO-score+Valutare chirurgia citoriduttiva secondariaA)
CT di II lineaCBDCA doublet CBDCA doublet
PTX + CBDCA PTX + CBDCAGEM + CBDCA GEM + CBDCAPLD + CBDCA PLD + CBDCA
RC, RP o SD RC, RP o SD
SI NO SI NO
OLAPARIB CT III linea NIRAPARIB CT III linea
BRCA+ BRCA-
B) GEM+CBDCA+BEV (soprattutto in pazienti con ascite e/o high tumor load)
DESKTOP trial: an exploratory study based on data from a retrospective analysis of hospital records from 25 institutions (267 pts)
RESULTS: Complete resection: longer OS than any postoperative RD (median 45.2
vs. 19.7 mos ; HR 3.71; 95% CI 2.27-6.05)
Variables associated with complete resection: ECOG PS (0 vs > 0, p< 0.001)FIGO stage (I/II vs III/IV, p= 0.036), RD after primary surgery (none vs. present, P< 0.001),Ascites > 500 ml (no vs yes, P< 0.001)
Combination of PS, early stage or no RD after first surgery, and absence of ascites predict complete resection in 79% of pts
SCS in recurrent EOC: the AGO DESKTOP trial
Harper 2006
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
A randomized trial evaluating cytoreductive surgery in pts with platinum-sensitive recurrent EOC
Complete resection
seems feasible and a
positive AGO-score
Strata:
PFI 6-12 vs >12 mos
- 1st line platinum
based CT: yes vs no
RANDOM
Cytoreductivesurgery
platinum-basedCT*recommended
* Recommended platinum-based CT regimens: - carboplatin/paclitaxel- carboplatin/gemcitabine- carboplatin/pegliposomal doxorubicin (if calypso-trial shows equivalence to carboplatin-paclitaxel)
-or other platinum combinations in prospective trials
no surgery
Trabectedin: OVA-301Platinum Sensitive Stratum (PFI > 6 mo)
PFS OS
Monk B, et al. J Clin Oncol. 2010;28:3107-14.Monk B, et al. Eur J Cancer. 2012;48:2361-8.
Poveda A, et al. Cancer Treat Rev. 2014;40:366-75.
Trabectedin: OVA-301 OS by PFI and Treatment
PFI (month)Median (month)
HR (95% CI)PLD T+PLD
0-6 12.3 14.2 0.94 (0.71-1.25)
6-12 16.4 22.4 0.64 (0.47-0.86)
>12 31.7 36.5 0.83 (0.59-1.16)
Poveda et al. Cancer Treat Rev 2014; 40:366-75
Relapsed partially platinum sensitive Ovarian Cancer after end of 1st
or 2nd-line platinum therapy
Group A:PLD 30 mg/m² + Carboplatin AUC 5 q4 wks
At PD, subsequent platinum rechallenge is mandatory
At PD, subsequent therapy at investigator discretion
Group B:PLD 30 mg/m2 +Trabectedin1.1 mg/m2
q3wks
RECIST tumor evaluation at 12 and 24 weeks
R(1:1) Up to 6 cycles or PD
Primary Endpoint: Overall Survival
Primary analysis: Intention to treat ,442 events/588 patients
INOVATYON
NER-deficient cell – sensitive to platinum, reduced sensitivity to trabectedin
Solid tumorNER-proficient cell – sensitive to trabectedin, reduced sensitivity to platinum
Trabectedin
Tumor at relapse
Increased sensitivity to platinum
Sequence Effect Hypothesis: May Trabectedin Resensitize Ovarian Cells to Next Platinum?
Algoritmo di trattamento nel carcinoma ovarico recidivante
6-12 months
Sensitive
Malattia platino-sensibile (intervallo libero 6-12 mesi)
A) CT di II linea
CBDCA doublet CBDCA doubletPTX + CBDCA PTX + CBDCAGEM + CBDCA GEM + CBDCAPLD + CBDCA PLD + CBDCA
RC, RP o SD RC, RP o SD
SI NO SI NO
OLAPARIB CT III linea NIRAPARIB CT III linea
BRCA+BRCA-
B) PLD + trabectedinaC) GEM+CBDCA + BEV (soprattutto in pazienti con ascite e/o high tumor load)
