Relapsed Ovarian CancerRelapsed Ovarian CancerH é CURÉ MD PhDHervé CURÉ, MD, PhD

Institut Jean-Godinot, ReimsChampagne-Ardenne University, Reimsp g y,

11th Meeting of the ISGO, Paris-FranceNovember 4-5, 2011

OVCA in elderly patientsOVCA in elderly patients

• Pts 65 years = 48 % in USPts 65 years = 48 % in US• Peak incidence between 75 and 80 years

M d d t (FIGO III C d IV)• More advanced stages (FIGO III C and IV)• Less radical surgery• Bulky residual disease more frequently• Chemotherapy feasibleChemotherapy feasible• Underrepresentation in clinical trials

Hall et al

Cancer. 2003 May 15;97(10

C

Suppl):2701-6.

Click to add text

Hutchins et al.N Engl J Med. 1999 Dec 30;341(27):2061-7.Underrepresentation of patients 65 years of age or older in cancer- treatment trials.

1st L Chemotherapy : is CbP the standard ?1st L Chemotherapy : is CbP the standard ?

•• AGO AGO –– OVAR phase III study OVAR phase III study –– Retrospective subgroup analysisRetrospective subgroup analysis

103 pts (13 %) > 70 years old (Med. 73.5 years)103 pts (13 %) > 70 years old (Med. 73.5 years)

Chemo received / planned dose, tolerance and QoL : NO DIFFERENCE exceptChemo received / planned dose, tolerance and QoL : NO DIFFERENCE except

f b il t i 5 % 1 % ( < 0 001)f b il t i 5 % 1 % ( < 0 001)febrile neutropenia : 5 % vs 1 % (p < 0.001)febrile neutropenia : 5 % vs 1 % (p < 0.001)

early treatment discontinuationearly treatment discontinuation

Hilpert F. et al. Ann Oncol. 2007 Feb;18(2):282Hilpert F. et al. Ann Oncol. 2007 Feb;18(2):282--77p ; ( )p ; ( )

•• COHORT STUDY at the MSKCC COHORT STUDY at the MSKCC

108 pts (37 %) > 65 years old. 108 pts (37 %) > 65 years old. No effect of age on treatment tolerance, PFS and OS No effect of age on treatment tolerance, PFS and OS

Gynecol Oncol 2007 Aug;106(2):381Gynecol Oncol 2007 Aug;106(2):381--77Gynecol Oncol. 2007 Aug;106(2):381Gynecol Oncol. 2007 Aug;106(2):381--77

1st L Chemotherapy : is CbP the standard ?1st L Chemotherapy : is CbP the standard ?

Cb C trial Cb P trial

Pooled analysis of 2 consecutive phase II GINECO studies Pooled analysis of 2 consecutive phase II GINECO studies –– nb= 155 pts nb= 155 pts

Multicentric, specific, few exclusion criteriaMulticentric, specific, few exclusion criteria

Cb C trial Cb P trialMedian age 76 [70 – 90] 75 [70 – 89]PS 0-1 / 2-3 (%) 56 / 44 74 / 26 [p = 0.08]

Optimal surgery (%) 21 41 [p = 0.03]Serous histology (%) 73 71

Stage III / IV (%) 76 / 24 78 / 22Stage III / IV (%) 76 / 24 78 / 22Ascites (%) 59 690 – 3 drugs daily 45 65 [p = 0.03]

FEASIBILITY 72 % vs 68.5 % (NS)

Tredan Freyer et al Annals of

BETTER, BUT…

Tredan, Freyer et al, Annals of Oncology 2007, 18: 256-262

1st L Chemotherapy1st L Chemotherapy : is CbP the standard ?: is CbP the standard ?O ll i l f 2 ti h II GINECO t diO ll i l f 2 ti h II GINECO t diOverall survival of 2 consecutive phase II GINECO studies Overall survival of 2 consecutive phase II GINECO studies

Multivariate analysis :Multivariate analysis :Multivariate analysis :Multivariate analysis :

Paclitaxel use = poor Paclitaxel use = poor prognostic factorprognostic factor

HR = 2.42, p = 0.01HR = 2.42, p = 0.01

Multivariate analysis : poorer Multivariate analysis : poorer survivalsurvival

Stage IV : HR=3,05 Stage IV : HR=3,05 -- p=0.001p=0.0011st L Chemotherapy1st L Chemotherapy : : prognostic factorsprognostic factors g ,g , pp

Paclitaxel : HR=2,42 Paclitaxel : HR=2,42 -- p=0.01p=0.01Depression : HR=5,11 Depression : HR=5,11 -- p

1st L Chemotherapy :1st L Chemotherapy : the GINECO «the GINECO « Elderly Elderly ––CarboplatinCarboplatin » trial (completed end 2009)» trial (completed end 2009)

Med Age 78 years (70 Med Age 78 years (70 –– 93)93)≥ 80 years≥ 80 years 45/11145/111 (40 5%)(40 5%) Etude épigénétique : détermination é è≥ 80 years≥ 80 years 45/111 45/111 (40,5%)(40,5%)PS≥2 PS≥2 48/111 48/111 (43,2%)(43,2%)Depression Depression 20/111 20/111 (18,0%)(18,0%)≥4 drugs / day≥4 drugs / day 76/11176/111 (68,5%)(68,5%)

de la taille des télomères

≥4 drugs / day≥4 drugs / day 76/111 76/111 (68,5%)(68,5%)ADL dependence ADL dependence 61/111 61/111 (55%)(55%)IADL dependence IADL dependence 83/111 83/111 (74,8%)(74,8%)

Measure of telomere length (frailty)

Psychometric / psychological evaluation

Carbo-cyclo trial Carbo-paclitaxel trial

2001 2004 72 pts

Carbo trial

2007 – 2009 – 111 pts1997 – 2000 – 83 pts 2001 – 2004 – 72 pts

p

1st L. Chemotherapy : EWOC i l (i i )EWOC trial (in preparation)

• EWOC = Elderly Women Ovarian CancerEWOC = Elderly Women Ovarian Cancer• International prospective clinical trial

(GINECO + GCIG)(GINECO + GCIG)• Randomized phase II

– Arm A = Carbo AUC 5 + Pacli 135 mg/sqm– Arm B = Carbo AUC 5– Arm C = weekly Carbo AUC 2 + Pacli 60 mg/sqm

(MITO protocol)

RELAPSE in OVCA : id i lepidemiology

• 75 % of recurrence after 1st L. CT (10 % per % ( % pyear in pCR)

• Median TTP after 1st L. CT = 16 to 22 months• Median time of survival after recurrence of 2

yearsP ti f t f l• Prognostic factors of relapse :– pCR after 1st L.CT– Histological typeHistological type

• Prognostic factor after relapse = length of free interval without CT

RELAPSE in OVCA

• Retrospective study of GINECO h II/III

1,0> 18

TFI in months

GINECO phase II/III studies (nb =583 pts)

viva

l

,8

,6

12-18

3-12

p= . 0001

• Objective : – Impact of free interval o

vera

ll su

rv,4

0-3

0-3non-progressive

on overall survival

10008006004002000

,2

0,0

progressive

E.Pujade-Lauraine - Proc. ASCO 2002

days

RELAPSE in OVCA :Guidelines of the NICE

( f C )

RELAPSE in OVCA :Guidelines of the NICE

( f C )(National Institute for Clinical Excellence)(National Institute for Clinical Excellence)

1st L Paclitaxel-Carboplatin1st L Paclitaxel-Carboplatin

55% 25%20%

SensibleSensible Partially sensiblePartially sensible

Resistant/RefractoryResistant/Refractory

55% 25%20%

(> 12 months)(> 12 months)sensible

(6-12 months)sensible

(6-12 months)Refractory

(< 6 monthsRefractory

(< 6 months

Paclitaxel-CarboplatinCaelyx-Carboplatin

Paclitaxel-CarboplatinCaelyx-Carboplatin

Paclitaxel-CarboplatinCAELYX® mono

Yondelis Caelyx

Paclitaxel-CarboplatinCAELYX® mono

Yondelis Caelyx

Paclitaxel mono(weekly +++)CAELYX® mono

Topotecan

Paclitaxel mono(weekly +++)CAELYX® mono

Topotecan

NHS. Paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer. Guidance 28, 45 and 55. Mai 2005

y py p Yondelis-CaelyxYondelis-Caelyx TopotecanTopotecan

P l t d li l d bi i dPegylated liposomal doxorubicin and carboplatin versus paclitaxel and carboplatin

in platinum sensitive ovarian cancerin platinum-sensitive ovarian cancer patients:

Treatment at recurrence and overall survival final analysis from CALYPSO phase IIIfinal analysis from CALYPSO phase III

GCIG trial

Marth et al. J Clin Oncol 2011;29 (suppl; abstr 5052)

Background

CALYPSO is a large international randomized phase III trial comparing C-PLD and C-P in pts with OC in late relapse.

• From 04/05 to 09/07, 976 eligible pts were randomized to either C-P(carboplatin AUC 5 iv d1 + paclitaxel [P] 175 mg/m2 3h iv d1, q3w) orC-PLD (Carboplatin + PLD 30 mg/m2 iv d1 q4w) for at least 6 cycles.

• Results of the progression-free survival (PFS), the primary endpoint,show a benefit in pts treated with C-PLD with a hazard ratio (HR) of 0.82 (P =.005)1.

• Overall severe non-hematologic toxicity (36 8% v 28 4%; P < 01)Overall severe non-hematologic toxicity (36.8% v 28.4%; P < .01) including alopecia, neurotoxicity and carboplatin hypersensitivity leading to early discontinuation (15% v 6%; P < .001) –occurred more frequently in the C-P arm

• It was explored whether the treatment effect on PFS recently observed in CALYPSO was maintained after further treatment. OS of pts was analysed.

Patients were followed for 49 months (range 0-68 mo)Patients were followed for 49 months (range 0 68 mo)

1 : E. Pujade-Lauraine et al., J Clin Oncol. 2010 Jul 10;28(20):3323-9. Epub 2010 May 24.

CALYPSO: Study designCALYPSO: Study designInternational, Intergroup, Open-label, Randomized Phase III Study

Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line

RA

Experimental arm: CDPLD 30 mg/m2 IV d 1after 1 or 2 line

platinum-based therapy (previous taxane

required)

NDOM

PLD 30 mg/m IV d 1Carboplatin AUC 5 d 1

Q 28 days x 6 courses*q )

Stratification:•Therapy-free interval (6-12 mo vs > 12 mo)

MIZE

Control arm: CPPaclitaxel 175 mg/m2 IV d 1Carboplatin AUC 5 d 1( )

•Measurable disease (yes vs no)•Center

E Carboplatin AUC 5 d 1Q 21 days x 6 courses*

*or progression in patients with SD or PRor progression in patients with SD or PR

Pujade-Lauraine E et al. J Clin Oncol 2010; 28(30): 3323-3329

Overall Survival

1.0

0.8

Median OS30.7 (C-PLD) vs 33.0 (C-P) monthsHR 0.994, (95% CI 0.85-1.16); p=0.937

0.6

0.4

C-P

C-PLD

opor

tion

Aliv

e

0.2

0.00 6 12 18 24 30 36 42 48 54

logRank = 0.937

Pro

0 6 12 18 24 30 36 42 48 54Months from randomisationNumber at risk

466509

408446

285327

194213

9177

C-PLDC-P

C-PLD C-P

663 Deceased ( 312 censored) 317 (149) 346 (163)

Median Overall Survival (months) (HR 0.994 (95% CI: 0.85-1-16); p=0.937 30.7 33.0

Therapy fee interval (6-12 m vs > 12m) (p1 (p

Number of treatment lines post CalypsoNumber of treatment lines given after Calypso

0 li5 11 li

Number of treatment lines post Calypso

10%

21%

13%10%

0 line

1 line4 lines

5-11 lines

21%

21% 2 lines

3 lines

25%

Most patients (70%) received 2 or more lines of chemotherapy after Calypso treatment

Cross Over Post Calypso

20%

16%

18%

20%

10%

12%

14%

ss-o

ver

Arm CaC

4%

6%

8%Cro

s Arm CaCArm TC

0%

2%

1 2 3 4 5 6 7 8

N b f li ft C lThe number of patients who received PLD in C-P arm (68%) was significantly higher (p

Elderly patients in CALYPSO studyElderly patients in CALYPSO study

• 157 pts (= 16 %) > 70 years old157 pts ( 16 %) 70 years old• Median age = 73 years old (70-82 y)• PS

CONCLUSIONSCONCLUSIONS• OVCA is a chemosensitive but not a

chemocurative disease• Effectiveness of relapse treatments but not

lastinglasting• Dramatic underrepresentation of elderly patients

in clinical trials

Urgence to enrolle 5 % and more of patients 75 years old in specific clinical trials conformed to INCay precommandation (National Institute of Cancer, France) with the support of SoFOG (French Society of Geriatric Oncology)gy)