Chemioterapia raka jajnika Radosław Mądry Klinika Onkologii Uniwersytety Medycznego im. K. Marcinkowskiego w Poznaniu

Chemioterapia raka jajnika

Radosław MądryKlinika Onkologii Uniwersytety

Medycznego im. K. Marcinkowskiego w Poznaniu

TIME LINE OF ADVANCES IN OVARIAN CANCER THERAPY

1960

1970

1980

1990

2000

CISPLATIN/ALKYLATORCOMBINATIONS

COMBINATION WITH SIGNAL REGULATORS

PACLITAXEL/CARBOPLATIN

ALKYLATORS

CISPLATIN

5 YR SURVIVAL ADVANCED (III/IV) DISEASE

40%35%15%15%0%

1960 1970 1980 1990 2000

I linia

GOG111

McGuire et al, N Engl J Med 334: 1-6, 1996

+5 Mon.

+14 Mon.

N = 386, FIGO III/IV, >1cmCisplatin/Cycloph. vs. Cisplatin/PaclitaxelCrossover to Paclitaxel 8% ‘early’ 34% overall

HR 0,7

HR 0,6

OV10

Piccart et al, J Natl Cancer Inst 92: 699-708, 2000

+4 Mon.

+10 Mon.

N = 680, FIGO IIB/IIC/III/IV6-9x Cisplatin/Cycloph. vs. 6-9x Cisplatin/PaclitaxelCrossover to Paclitaxel Higher (49%)

HR 0,74

HR 0,73

GOG132

Muggia et al, J Clin Oncol 18: 106-115, 2000

HR 1,06

HR 0,99

+2,3 Mon.

+3,9 Mon.

N = 614, FIGO IIB/IIC/III/IVCisplatin. vs. Cisplatin/Paclitaxel vs.Paclitaxel

High Cross-over

„the high rate of early crossover to paclitaxel that had occurred in this single-agent platinum armprior to progression (24%)”Piccard 2003

ICON3

ICON Group, Lancet 360: 505-515, 2002

N = 2027, FIGO I-IVCarboplatin/Paclitaxel vs. Carboplatinvs CAP 1/3 cross-over to Paclitaxelu po progresji

HR 0,93

HR 0,98

GOG 158

Ozols et al, J Clin Oncol 21: 3194-3200, 2003

N = 792, FIGO III, <1cmCispl./Paclit. vs. Carbopl./Paclit.

HR 0,88 ns

HR 0,84 ns

+1,3 Mon.

+8,7 Mon.

OVAR-3 AGO

Du Bois et al, J Natl Cancer Inst 95: 1320-2330, 2003

N = 798, FIGO IIB-IV, <1cmCispl./Paclit. vs. Carbopl./Paclit.

HR 1,05

HR 1,05

SCOTR0C

Vasey et al, J Natl Cancer Inst 96: 1682-1691, 2004

HR 0,97

HR 1,13

N = 1077, FIGO IC-IVCarboplatin/ Paclitaxel vs. Carboplatin/Docetaxel

Badania negatywne I rzutu

• paclitaxel / carboplatin with or without epirubicin - Kristensen

2004

• GOG 182 / ICON 5 Bookman 2005

• paclitaxel / carboplatin with or without topotecan Scarfone 2006

• paclitaxel / carboplatin with or without epirubicin Du Bois 2006

• paclitaxel / carboplatin / 4x topotecan vs. follow up Pfisterer 2006

• cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel Hoskins 2008

• paclitaxel / carboplatin with or without gemcitabine Du Bois 2008

NSGO-EORTC-NCIC-GEICO

The addition of epirubicin to the standard carboplatin and paclitaxel treatment did not improve progression-free survival

Kristensen 2004 ASCO Annual Meeting First line treatment of ovarian/tubal/peritoneal cancer FIGO stage IIb-IV with paclitaxel/carboplatin with or without epirubicin (TEC vs TC). A Gynecologic Cancer Intergroup study of the NSGO, EORTC GCG, and NCIC CTG. Results on progression free survival.

MITO

Scarfone G, Scambia G, Raspagliesi F, et al. A multicenter, randomized, phase III study comparing paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with stage III (residual tumor > 1 cm after primary surgery) and IV ovarian cancer. Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology; June 2–6, 2006; Atlanta, Ga. abstract 5003

Conclusions: The addition of topotecan to standard PC primary chemotherapy does not increase RR and TTP in stage III (residual tumor > 1 cm) or IV OC compared to PC alone. The TPC regimen was well tolerated with a minority of patients experiencing G3/4 hematological toxicity

AGO GINECO

Du Bois et al, J Clin Oncol 24: 1127-1135, 2006

N = 1282, FIGO IIB-IVCarboplatin/ Paclitaxel vs. Carboplatin/Paclitaxel/Epirubicin

HR 0,95

HR 0,93

AGO OVAR GINECO

N = 1308, FIGO IIB-IV 6x Carboplatin/Paclitaxel 4x Topotecan vs. Follow up

HR 0,97

HR 1,01

Pfisterer et al, J Natl Cancer Inst 98: 1036-1045, 2006

GOG 182 / ICON 5

ASCO 2006

GOG 182 / ICON 5

ASCO 2006

GOG 182 / ICON 5

ASCO 2006

GOG 182 / ICON 5

ASCO 2006

GOG 182 / ICON 5

ASCO 2006

NCIC-EORTC-GEICO OV16

Hoskins PJ. A phase III trial of cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel as first-line chemotherapy in women with newly diagnosed advanced epithelial ovarian cancer. A Gynecologic Cancer Intergroup Study of the NCIC CTG, EORTC, GCG, and GEICO. ASCO 2008

AGO OVAR9

A phase III study of paclitaxel, carboplatin, and gemcitabine in previously untreated patients with epithelial ovarian cancer FIGO stage IC–IV (AGO-OVAR protocol OVAR-9) A. du Bois 2008

AGO-OVAR-9; du Bois A i wsp

Randomized phase-III GCIG study (AGO-OVAR-9,GINECO TCG, NSGO-OC-0102): gemcitabine-paclitaxel-carboplatin (TCG) vs. paclitaxel-carboplatin (TC) as firstline treatment of ovarian cancr (OC)

• VII’02 – IV’04• FIGO IC-IV• 1 724 pts

Więcej powikłań hematologicznych w ramieniu TCGBrak zysku z chth 3-lekowej

W trakcie badań

I linia - nowość

• Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T consolidation in advanced ovarian cancer (OC): Interim analysis of induction chemotherapy Gordon 2008 ASCO

• Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology

Isonishi ASCO 2008

Vergote I i wsp - Neoadjuvant chemotherapy

EORTC-GCG/NCIC-CTG randomised trial comparing primarydebulking surgery with neoadjuvant chemotherapy instage IIIC-IV ovarian, fallopian tube and peritoneal cancer

• IX’98 – XII’06• Potwierdzenie hist-pat raka jajnika LUB• Sugestia cytologiczna +

– guz w miednicy– zmiany przerzutowe ≥ 2 cm poza miednicą– CA125/CEA ≥ 25

• Follow up = 4,8 lat

Late-Breaker Presentation Vergote I i wsp - Neoadjuvant chemotherapy

FIGO IIIC-IV718 pts

Operacja pierwotna▼

6 x chth z platyną

3x chth▼

Operacja odroczona▼

3 x chth



Operacja pierwotna

Operacja odroczona

Śmiertelność ≤ 28 dni

2,7% 0,6%

Posocznica 8% 2%

Krwawienie 3/4° 7% 4%


Operacja pierwotna

Chth neoadj.

OS 29 msc 30 msc HR: 0,98;

CI: 0,85-1,14

PFS 11 msc 11 msc HR: 0,99;

CI: 0,87-1,13

Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T

consolidation in advanced ovarian cancer (OC): Interim analysis of induction chemotherapy.

Gordon A, et al. ASCO 2008. Abstract 5536.

Anything other than CR(PR, SD, PD)

Anything other than CR(PR, SD, PD)

Clinical CR

Single-agent crossoverPaclitaxel 175 mg/m2 Day 1

Single-agent crossoverGemcitabine 1000 mg/m2 Days 1,

8

ElectiveT Consolidation Therapy

Paclitaxel 135 mg/m2 every 28 days for 12 cycles

Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal,

or fallopian tube carcinoma

Induction GCGemcitabine 1000 mg/m2 Days 1,

8 + Carboplatin AUC 5 Day 1

x 6 cycles every 21 days

Induction TCPaclitaxel 175 mg/m2 Day 1+ Carboplatin AUC 6 Day 1

x 6 cycles q 21 days

Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective

T consolidation in advanced ovarian cancer (OC):

Interim analysis of induction chemotherapy Response Rates


Best response, n (%)Induction GC

(n = 66)Induction TC

(n = 58)P Value

CR* 30 (45.5) 26 (44.8)

PR 13 (19.7) 12 (20.7)

SD 5 (7.6) 8 (13.8)

PD 6 (9.1) 4 (6.9)

Data not available 12 (18.2) 8 (13.8)

ORR (CR + PR) 43 (65.2) 38 (65.5) .999

DCR (CR + PR + SD) 48 (72.7) 46 (79.3) .410

*CR required a normalized CA-125.


Toxicity, n (%)Induction GC

(n = 219)Induction TC

(n = 220)P Value

Hematologic

G3/4 thrombocytopenia88 (40.2)55 (25.1)

30 (13.6)10 (4.5)

.0001

G3/4 anemia 52 (23.7) 20 (9.1) .0001

Nonhematologic G2 neuropathy 24 (11.0) 43 (19.5) .0165

G2 alopecia 79 (36.1) 110 (50.0) .0038

Platelet transfusion 7 (3.2) 0 (0) .0073

Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective

T consolidation in advanced ovarian cancer (OC): Interim analysis of induction chemotherapy

Toxicity

NOVEL (New Ovarian ELaborate); Isonishi S i wsp

Randomized phase III trial of conventional paclitaxel andcarboplatin (c-TC) versus dose dense weekly paclitaxeland carboplatin (dd-TC) in women with advancedepithelial ovarian, fallopian tube, or primary peritonealcancer: Japanese Gynecologic OncologyASCO 2008: J Clin Oncol 2008; 26 (20 May suppl): A5506

• 637 pts

• Follow up - 29 msc

Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and

carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer:

Japanese Gynecologic Oncology.Ovarian epithelial, primary peritoneal, or

fallopian tube cancer withFIGO stage II-IV

Conventional TC (c-TC)Paclitaxel 180 mg/m2 Day 1 +Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles

Dose-dense weekly TC (dd-TC)Paclitaxel 80 mg/m2 Days 1, 8, 15 +

Carboplatin AUC 6.0 Day 1every 21 days for 6-9 cycles

Dose-dense weekly TC (dd-TC)Paclitaxel 80 mg/m2 Days 1, 8, 15 +

Carboplatin AUC 6.0 Day 1every 21 days for 6-9 cycles

Stratified by residual disease ≤ 1 cm vs > 1 cm;

FIGO stage II vs III vs IV;histology: clear cell/mucinous vs serous/others

Isonishi S, et al. ASCO 2008. Abstract 5506.

P = .72 Evaluated by WHO criteria

Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and

carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer:

Clinical Responses

MeasurablePatients, %

c-TC(n = 135)

dd-TC(n = 147)

Objective response 53 56

• CR 16 20

• PR 38 36

NC 31 29

PD 7 3

NE 9 12


Treatment n Event Median PFS, mos P Value HR 95 %CI

c-TC 319 200 17.2

dd-TC 312 160 28.0 .0015 0.714 0.581-0.879


NOVEL (New Ovarian ELaborate); Isonishi S i wsp

Analiza podgrup – nie uzyskano poprawy PFS przy

raku jasnokom. i śluzowym.

Większa toksyczność hematologiczna w dd-CT.

Neurotoksyczność podobna w obu grupach.

c-TC dd-CT

2-letnie OS (p=0,05)

77,7% 83,6%

GOG 218: Bev in Primary Adjuvant Treatment and Consolidation Therapy

GOG Statistical Report, July 2008.

GOG 218

Patients with FIGO stage III epithelial ovarian or primary peritoneal cancer with any

gross (macroscopic or palpable) residual disease

or FIGO stage IV

Paclitaxel 175 mg/m2 over 3 hours x 6 cycles + Carboplatin AUC 6

x 6 cycles + Placebo every 3 weeks x 5 (cycles 2-6)


x 6 cycles + Bevacizumab 15 mg/kg every 3 weeks

x 5 (cycles 2-6)


x 6 cycles + Bevacizumab 15 mg/kg every 3 weeks

x 5 (cycles 2-6)

Placebo every 3 weeks x 16

Placebo every 3 weeks x 16

Bevacizumab 15 mg/kg every 3 weeks x 16

GOG 170D: Bevacizumab as Maintenance (Ongoing Phase III Trial)

Patients with stage III/IV ovarian

epithelial or primary peritoneal cancer

(N = 2000)

Arm 1: Paclitaxel over 3 hrs and Carboplatin over 30 mins on Day 1; Placebo* over 30-90 mins on Day 1 every 21 days for 6 courses; Placebo† over 30-90 mins

on Day 1 every 21 days for up to 22 courses

Arm 2: Paclitaxel and Carboplatin as in Arm 1 Day 1; Bevacizumab* over 30-90 mins on Day 1 every 21 days for 6 courses; Placebo† over 30-90 mins on

Day 1 every 21 days for up to 22 courses

Arm 2: Paclitaxel and Carboplatin as in Arm 1 Day 1; Bevacizumab* over 30-90 mins on Day 1 every

21 days for 6 courses; bevacizumab† over 30-90 mins on Day 1 every 21 days for up to 22 courses

*Beginning with course 2.†Beginning with course 7.

ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/results?term=NCT00262847.

• Primary endpoint: OS

• Secondary endpoints: PFS, severe toxicity and severe AEs, QoL, translational objectives by angiogenic markers and gene arrays

ICON-7

EOC, PP cancer

PaclitaxelCarboplatin

placebo

PaclitaxelCarboplatin

Bevacizumab

Bevacizumabx 12 cykli

IP

HISTORY OF IP CHEMO

• Weisberger 1955– Nitrogen mustard intraperitoneally for malignant

ascites

• Jones 1978– signicantly greater concentrations of certain

chemotherapeutic drugs in the peritoneal cavity than in the blood.

• SWOG/GOG– The first phase III trial– since 1980s, presented in 1996– In favor of IP arm

CLINICAL ASPECTS OF IP CHEMO

• Front-line chemotherapy

• Consolidation

• 2nd-line chemotherapy

PHASE III TRIALS OF IP vs IV CISPLATIN BASED CHEMOTHEPAY

(Hamilton, 2006)

PHASE III TRIALS OF IP vs IV CISPLATIN BASED CHEMOTHEPAY

Study Identifier /

Year published

Control Regimen Experimental Regimen Target population

No. of patients

SWOG/GOG-104

(Alberts et al. 1996)

Cisplatin 100 mg/m2 IV

Ctx 600 mg/m2 IVq 3 weeks x 6

Cisplatin 100 mg/m2 IP

Ctx 600 mg/m2 IVq 3 weeks x 6

Stage III

< 2 cm residual

546

Greece

(Polyzos et al. 1999)

Crbpt 350 mg/m2 IVCtx 600 mg/m2 IVq 3 weeks x 6

Crbpt 350 mg/m2 IVCtx 600 mg/m2 IVq 3 weeks x 6

Stage III

< or > 2 cm residual

90

GONO

(Gadducci et al. 2000)

Cisplatin 50 mg/m2 IVCtx 600 mg/m2 IVEpidox 60 mg/m2 IVq 4 weeks x 6

Cisplatin 50 mg/m2 IPCtx 600 mg/m2 IVEpidox 60 mg/m2 IVq 4 weeks x 6

Stage II-IV

< 2 cm residual

113+

GOG-114/SWOG

(Markman et al. 2001)

Cisplatin 75 mg/m2 IVTax 135 mg/m2 (24 hr) IV q 3 weeks x 6

Crbpt AUC 9 IV q 28 days x 2Cisplatin 100 mg/m2 IPTax 135 mg/m2 (24 hr) IV q 3 weeks x 6

Stage III

< 1 cm residual

462

Taiwan

(Yen et al. 2001)

Cisplatin 50 mg/m2 IVCtx 500 mg/m2 IVEpi/Adr 50 mg/m2 IVq 3 weeks x 6

Cisplatin 100 mg/m2 IVCtx 500 mg/m2 IVEpi/Adr 50 mg/m2 IVq 3 weeks x 6

Stage III

< 1 cm residual

118+

GOG-172

(Armstrong et al. 2006)

Cisplatin 75 mg/m2 IVTax 135 mg/m2 (24 hr) IVq 3 weeks x 6

Tax 135 mg/m2 (24 hr) IVCisplatin 100 mg/m2 IPTax 60 mg/m2 IV on day 8q 3 weeks x 6

Stage III

< 1 cm residual

415

MAIN RESULTS

• Eight randomized trials studied 1819 women receiving primary treatment for ovarian cancer.

• Women were less likely to die if they received an intraperitoneal (IP) component to the chemotherapy (hazard ratio (HR) =0.79; 95% confidence interval (CI): 0.70 to 0.90)and the disease free interval (HR =0.79; 95%CI: 0.69 to 0.90) was also significantly prolonged.

• There may be greater serious toxicity with regard to gastrointestinal effects, pain and fever but less ototoxicity with the intraperitoneal than the intravenous route.

HAZARD RATIO FOR TIME TO RECURRENCE (IP vs IV CH)

HAZARD RATIO FOR TIME TO DEATH (IP vs IV CH)

Alberts et al, N Engl J Med: 1950-1955, 1996

+8 Mon.

HR 0,76

n = 546 FIGO III, <2cm

Cisplatin 100 mg/m2i.v. vs. i.p.+Cyclophosphamid i.v.

GOG 104 (Alberts et al, 1996) CISPLATIN IV vs. IP

OS


• As compared with IV cisplatin, IP cisplatin significantly improves survival and has significantly lower toxic effects in patients with stage III ovarian cancer and residual tumor mass of 2cm or less.

• The only same “dose-intensity” in both arms phase 3 RCT


• GOG 111– Median survival from 24 months (P+C)

to 38 months ( P+T)


GOG 114 (Markman et al, 2001) CISPLATIN/PACLITAXEL vs.

CARBO – PACLITAXEL / CISPLATIN IP

Markman et al, J Clin Oncol 19: 1001-1007, 2001

n = 462 FIGO III, <1cm

6x CP i.v. vs. 2x Carboplatin AUC9 –6x Paclitaxel i.v. /Cisplatin i.p.

HR 0,78

+6 Mon.

HR 0,81

+11 Mon.



PFS

OS



• The 2nd phase 3 RCT to show IP cisplatin is superior to IV cisplatin in small volume residual advanced ovarian cancer

• The 1st phase 3 trial in ovarian cancer to a median survival of >5 years

• Trial demonstrated that IP cisplatin favorably impacts survival, even through IV paclitaxel is a component of regimen



• More complications in IP arm– Neutropenia, thrombocytopenia– G-I & metabolic toxicities

• Carbopltin x 2 cycles ( AUC 9)

GOG 172(Armstrong et al, 2006) CISPLATIN/PACLITAXEL IV vs. IP

Armstrong et al, N Engl J Med 354: 34-43

n = 415 FIGO III, < 1 cm

6x CP vs. 6x Paclitaxel i.v. d1+Cisplatin i.p. d2 + Paclitaxel i.p. d8

42% all 6 IP cycles

HR 0,77

HR 0,73

+5,5 Mon.

+15,9 Mon.


PFS

OS




• Significantly survival benefit in IP arm

• The 65.6 months median survival is the longest survival reported to date from a randomized trial in advanced ovarian cancer


• The IP regimen uses higher and more frequent dosing than the IV regimen

• Toxicities were greater on the IP arm

• Fewer patients on the IP arm were able to complete 6 cycles of therapy


• Although fewer than half the patients assigned to the IP group received six cycles of IP treatment, the group as a whole had a significant improvement in survival as compared with the intravenous group. It is possible that most of the benefit of IP therapy occurs early, during the initial cycles, or that the benefit of IP therapy may be greater if more patients can successfully complete six cycles of treatment.

IP vs IV IN ADVANCED OVARIAN CANCER

Progression-free survival

Investigators No. of Progression-free survival (mo)

year published pts Control arm Exp. Arm

Alberts et al, 1996 546 ND ND

Polyzos et al, 1999 90 19 18

Gadducci et al, 2000 113 25 42

Markman et al, 2001 462 22 281

Yen et al, 2001 118 ND ND

Armstrong et al, 2006 415 18 242

1 p = 0.01; 2 p = 0.05

IP vs IV IN ADVANCED OVARIAN CANCER

Overall survival

Investigators No. of Overall survival (mo)

year published pts Control arm Exp. Arm

Alberts et al, 1996 546 41 491

Polyzos et al, 1999 90 25 26

Gadducci et al, 2000 113 51 67

Markman et al, 2001 462 52 632

Yen et al, 2001 118 48 43

Armstrong et al, 2006 415 50 663

1 p = 0.02; 2 p = 0.05; 3 p = 0.03

IP CHEMOTHERPAY IN OPTIMAL STAGE III OVARIAN CANCER

WHY DID IT TAKE SO LONG?

• It was not a sexy drug

• The treatment was cumbersome

• There was always a reason why the results were interpreted differently– GOG 104: not better than using paclitaxel– GOG 114: because 8 cycles were used– GOG 172: it is toxic, but …

Conclusions on IPCT

• Combined use of IV and IP chemotherapy leads to a significant survival benefit in women with optimally debulked EOC (median + 12 mo).

• Based on the most recent trials, strong consideration should be given to a regimen with IP cisplatin (100 mg/m²) and a taxane (whether IV or IP).

• Toxicities, inconvenience and costs of IP therapy are justified by the improved survival.

Vermorken 2007

FIRST LINE

www.cancer.gov 2008

• the standard treatment approaches are subdivided into:– Treatment options for patients with optimally cytoreduced stage

III disease.– Treatment options for patients with suboptimally cytoreduced

stage III and stage IV disease.

• it is preferable to treat patients with several cycles of chemotherapy before interval debulking surgery.

http://www.cancer.gov/

Konsolidacja / leczenie podtrzymujące

“Still investigational”

Study Patients Randomization Results

Scarfone ’02

n=162

III-IV, SSL, pCR

Pt-Tax based

Epirubicin x 4

vs observation

OS NS

Pfisterer (2003)

n=1308

IIb-IV

Tax-Carbo

Topotecan x 4

vs observation

PFS NS

OS NS

De Placido (2004)

n=273

III-IV, SSL, pCR

< 2 cm, Pt-based

Topotecan x 4

vs observation

PFS NS

OS NS

Markman ’03

N=277

III-IV

Tax-Carbo, cCR

Paclitaxel

3 or 12 cycles

PFS 21 mo

vs 28 mo

P < 0.005

Consolidation/Maintenance TherapiesCytotoxic therapy

Markman et al, JCO 2003; 21: 2460-2465

Final Results of After-6 Protocol

• Methods: 200 pts in cCR (48%) or pCR (52%) after 6 cycles of platinum/paclitaxel were randomized to observation or 175 mg/m² paclitaxel x 6 q 3 weeks

• Results: – No difference in PFS or OS.– Irrespective of treatment arm median PFS was 34.4 mo with PCR

and 24.5 mo with cCR– 3-yr survival 87% (pCR) and 79% (cCR): p=0.04

Conte et al, ASCO abstract #5505 (2007)

II linia

Chore platyno - wrażliwe

Wznowa > 6 mieśięcy

Re -platynizacja

Chore platyno - oporne

Wznowa < 6 miesięcy

Leki nie oparte na platynie

Tradycyjny podział wznowy raka jajnika po leczeniu I rzutu

Chore platyno - oporne

*Approved by the US Food and Drug Administration.

• Clinical trial– GOG 126 (cytotoxic)

series– GOG 170 (biologic)

series– Trabectedin– Patupilone– Phenoxodiol– TLK286

Pegylated liposomal doxorubicin*

Topotecan*

Paclitaxel*

Docetaxel

Gemcitabine

Oral etoposide

Bevacizumab

Therapeutic Approaches for Relapsed Platinum-Resistant Disease

Topotecan vs PLD: Survival in Platinum Refractory/Resistant Subset

Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

Treatment n CR, % PR, % SD, % CB, % Median PFS, wks

Median OS, wks

Topotecan 124 0.8 5.6 42.7 49.1 13.6 41.3

PLD 130 0.8 11.5 27.7 40.0 9.1 35.6

P value .733 .455

Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.

Intent-to-treat analysis

Primary endpoint: PFS


years

survival rates n 1 2 3

Topotecan 124 43.2% 17.2% 9.5%

PLD 130 41.5% 21.1% 13.8%

Gordon AN, et al. Gynecologic Oncology 2004


GOG-126: Phase II Trial Series in Platinum Resistant/Refractory OC

Study N Regimen Principal Grade 3/4 Toxicity

ORR, %

GOG 126-N[1] 48Paclitaxel 80 mg/m2 weekly

Neuropathy (grade 3): 4%

Fatigue (grade 3): 8%20.9

GOG 126-J[2] 60 (58 eval)

Docetaxel 100 mg/m2

every 3 weeks

Neutropenia (grade 4): 75%

22.4

GOG 126-H[3] 41Oral etoposide

50 mg/m2* 21 of 28 days

Neutropenia (grade 3: 20%; grade 4: 25%)

26.8

Markman M, et al. Gynecol Oncol. 2006;101:436-440.Rose PG, et al. Gynecol Oncol. 2003;88:130-135.Rose PG et al. J Clin Oncol. 1998;16:405-410.

*30 mg/m2 for prior radiotherapy.

Gemcitabine 1000 mg/m2 IV on Days 1, 8

every 21 days

PLD 50 mg/m2 IV Day 1 every 28 days

Crossover*

Each treatment given for up to 2 cycles after CR attained

*Optional; allowed in case of progressive disease, undue toxicity, or cumulative PLD dose of 500 mg/m2.

Gemcitabine 1000 mg/m2 IV on Days 1, 8

every 21 days

PLD 50 mg/m2 IV Day 1 every 28 days

Patients with platinum-

resistant taxane-pretreated

ovarian cancer

(N = 195)

Mutch D, et al. SGO 2006. Abstract 28.

Gemcitabine vs PLD: Phase III Recurrent (Platinum Resistant)

Gemcitabine (median:15.6 weeks)

PLD (median: 13.3 weeks)

Log-rank P = .87

Mutch D, et al. SGO 2006. Abstract 28.

Gemcitabine vs PLD Phase III Recurrent (Platinum Resistant): PFS

Chore platyno - wrażliwe

Blackledge G, et al. Br J Cancer. 1989;59:650-653.Thigpen JT, personal communication.

Interval, % Platinum,Response

Other Agents, Response

0-6 mos 10 15

7-12 mos 29 20

13-18 mos 63 30

19-24 mos 94 30

Chemosensitive Disease: TFI

Retreatment With Cisplatin-Based Regimen

Markman, et al Gore, et al

Markman M, et al. J Clin Oncol. 1991;9:389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211.

Effect of Platinum-Free Interval on Response Rate

Res

po

nse

Rat

e (%

)

< 12 13-24 > 24

27%

33%

59%

17%

27%

57%

n = 39

n = 20

n = 14

n = 29

n = 11

n = 39

0

10

20

30

40

50

60

Months

Res

po

nse

Rat

e (%

)

< 12 13-24 > 240

10

20

30

40

50

60

Months

Chemosensitive Disease: Major Trials

Trial Regimen

ICON 4/AGO-OVAR 2.2 Carboplatin ± paclitaxel

GCIG OVAR 2.5 Carboplatin ± gemcitabine

PLD/Topotecan PLD vs topotecan

ICON 4/AGO-OVAR 2.2

Paclitaxel + Platinum-based chemotherapy

(n = 392)

Platinum-based chemotherapy(n = 410)

Patients with platinum-sensitive

recurrent ovarian cancer

TFI ≥ 6 months

(N = 802)

Parmar MK, et al. Lancet. 2003;361:2099-2106.

• 2 parallel randomized, multicenter trials


Time Since Completion of Last Chemotherapy, %

Platinum(n = 410)

Paclitaxel/ Platinum (n = 392)

Total(N = 802)

≤12 mos 27 23 25

> 12 mos 73 77 75

ICON 4/AGO-OVAR 2.2: Patient Characteristics

Difference: 12% (-0.1 to 24.0); P = .06


Response, % Platinum(n = 128)

Paclitaxel/

Platinum (n = 119)

ORR (CR + PR) 54 66

ICON 4/AGO-OVAR 2.2: Response

• Hazard ratio: 0.76 (95% CI: 0.66-0.89; P = .0004)

• Absolute difference at 1 year: 10% (95% CI: 4-15)

• 50% (paclitaxel/platinum) vs 40%


ICON 4/AGO-OVAR 2.2: Progression-Free Survival

Patients at riskPaclitaxel + platinumConventional treatment

392410

179157

5245

2517

177

Patients at riskPaclitaxel + platinumConventional treatment


ICON 4/AGO-OVAR 2.2: Overall Survival

392410

306295

167150

9668

4333

1811

• Hazard ratio: 0.82 (95% CI: 0.69-0.97; P = .023)

• Absolute difference at 2 years: 7% (95% CI: 1-12)

• 57% (paclitaxel/platinum) vs 50%

ICON 4/AGO-OVAR 2.2: Previous Taxanes

OS

PFS

Paclitaxel/Platinum Platinum

No

Yes

0 0.5 1.0 1.5 2.0

No

Yes

P = .49

P = .62


• Randomized, phase III trial

Gemcitabine (1000 mg/m2) Days 1 and 8Carboplatin (AUC = 4) Day 1

every 21 days x 6 cycles(n = 178)

Carboplatin (AUC = 5) Day 1every 21 days x 6 cycles

(n = 178)

Patients with platinum-sensitive

recurrent ovarian cancer

≥ 6 months out from initial

platinum therapy

(N = 356)

Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.

AGO-OVAR 2.5 (GCIG): Gemcitabine/ Carboplatin vs Carboplatin

Gemcitabine/Carboplatin (n = 178)

Carboplatin(n = 178)

Platinum-free interval, %

• 6-12 mos 39.9 39.9

• > 12 mos 59.6 60.1

First‑line therapy, %

• Platinum taxane 70.2 71.3

• Platinum nontaxane 28.7 27.5

• Platinum monotherapy 1.1 1.1


AGO-OVAR 2.5 (GCIG): Platinum-free Interval and Previous Treatment

Parameter, % Gemcitabine/

Carboplatin (n = 178)

Carboplatin (n = 178)

Overall response (CR + PR)*

47.2 30.9

• CR 14.6 6.2

• PR 32.6 24.7

Stable disease 38.2 38.8

Progressive disease 7.9 16.3


AGO-OVAR 2.5 (GCIG): Response Data

*P = .0016


AGO-OVAR 2.5 (GCIG): Progression-free Survival

HR: 0.72 (95% CI: 0.58-0.90); P = .0031

Median: 8.6 mos (range: 7.9-9.7)



HR: 0.96 (95% CI: 0.75-1.23); P = .7349



AGO-OVAR 2.5 nie zaplanowane do oceny całkowitego przeżycia.

AGO-OVAR 2.5 (GCIG): Overall Survival*

Carboplatin

Therapy, % Gemcitabine/Carboplatin(n = 178)

Carboplatin(n = 178)

Any therapy postrecurrence or progression

83.7 78.7

Chemotherapy 75.8 72.5

• 1 regimen 16.3 13.5

• 2 regimens 12.4 15.7

• ≥ 3 regimens 9.6 10.7

• Unspecified no. regimens 37.6 32.6

Hormonal/immunologic/biologic therapy

19.7 18.0

Radiation 5.1 9.6

Other therapy—not specified 15.7 15.2

AGO-OVAR 2.5 (GCIG): Therapy After Recurrence/Progression

Patients with advanced ovarian cancer

(90% stage II/IV)

Recurrent or failed platinum-based therapy

Measurable disease

Median age: 60 years (range: 25-87)

(N = 474)

Topotecan 1.5 mg/m2/d IV for 5 consecutive days every 3 weeks

PLD 50 mg/m2 IV every 4 weeks

Stratification by platinum sensitivity and presence/absence of bulky disease


Pegylated Liposomal Doxorubicin vs Topotecan: Phase III Study Design

Patient Group, % PLD Topotecan P Value

Platinum sensitive(n = 220; PLD: 109; T: 111)

28 29 .964

Platinum refractory(n = 254; PLD: 130; T: 124)

12 7 .118


PLD vs Topotecan: Response Rates


PLD vs Topotecan: Median Survival

Median Survival

Pegylated liposomal doxorubicin: 62.7 weeks

Topotecan: 59.7 weeks

HR: 1.23

(95% CI: 1.01-1.50;

P = .038)


PLD vs Topotecan: Median Survival (Platinum-Sensitive Disease)

Median Survival

Pegylated liposomal doxorubicin: 107.9 weeks

Topotecan: 70.1 weeks

HR: 1.432 (95% CI: 1.066-1.923; P = .017)

Ferrero JM, et al. Ann Oncol. 2007;18:263-268.

• Patients with advanced ovarian cancer

– N = 105 (104 received treatment)

– TFI ≥ 6 months

• PLD 30 mg/m2 + carboplatin AUC 5 every 4 weeks

• Selected patient characteristics

– ECOG PS 1-2: 47%

– 2 prior regimens: 39%

– Measurable disease: 57%

GINECO Phase II Trial: Schema

*Median 6 cycles of therapy.

Ferrero JM, et al. Ann Oncol. 2007;18:263-268.

Outcome PLD/Carboplatin (n = 104)*

ORR (CR+ PR), % 63

• CR, % 38

PFS, mos 9.4

OS, mos 32

GINECO Phase II Trial: Results

Dostępna analiza pośrednia

• Pegylated liposomal doxorubicin (PLD)-carboplatin (C) (C-D) vs paclitaxel-carboplatin (C-P) in relapsing sensitive ovarian cancer (OC): A 500-patient interim safety analysis of the CALYPSO GCIG Intergroup phase III study.

Åvall-Lundqvist 2008 J Clin Oncol / ASCO

Conclusions: This planned interim safety analysis on the first 500 patients confirmed different toxicity profiles in the two arms, with less drug-related SAE and less early therapy termination in the C-D arm.

Chemosensitive Disease: Conclusions

• Platinum regimens superior to nonplatinum regimens tested to date

• Paclitaxel/carboplatin yields superior PFS and OS compared with carboplatin

• Gemcitabine/carboplatin produces superior response and PFS compared with carboplatin

• PLD/carboplatin produces excellent response, PFS, and OS

Chemosensitive Disease: Doublets

• Paclitaxel/carboplatin

• Gemcitabine/carboplatin

• PLD/carboplatin

• An Open-label Multicenter Randomized Phase 3 Study Comparing CAELYX® and YONDELIS™ with CAELYX alone in Relapsed Ovarian Cancer

ESMO 2008

II linia - nowość

Cluster of Ecteinascidia turbinata, a “sea squirt” or tunicate

from the Caribbean Sea

Yondelis: Tetrahydroisoquinoline

alkaloid, MW=762.

Yondelis™, trabectedin, ET-743

1996: PharmaMar starts clinical development of ET-7432001: Joint development of ET-743 by Johnson & Johnson Pharm R&D andPharmaMar

Yondelis™, trabectedin, ET-743

• Wiązanie do rowka mniejszego łańcucha DNA

• Najaktywniejsza w fazie G1• Działanie w czasie

transkrypcji• Interakcja z

mechanizmami naprawczymi DNA

An Open-label Multicenter Randomized Phase 3 Study Comparing CAELYX® and YONDELIS™ with CAELYX alone in Relapsed Ovarian Cancer

• Advanced Recurrent Epithelial Ovarian Cancer

– One prior regimen– Evaluable and measurable

disease– Platinum sensitive and resistant

Primary endpoint: OSOther endpoints: PFS, RR, Safety

Translational Research•Pharmacokinetics•Pharmacogenomics•Pharmacoeconomics•Quality of Life•Circulating tumor cells

RANDOMIZE

Caelyx® 50 mg/m2 q 4 wks

Caelyx® 30 mg/m2 plusYondelis® 1.1mg/m2Every 3 weeks

Accrual 7/11/2006: 374/650

33rd ESMO Congress Stockholm, 12-16 September 2008

OVA-301 Study Shows Significant Prolongation In

Progression Free Survival

• Positive final results of the Phase III randomized pivotal study of Yondelis® in ovarian cancer were presented during the Presidential Symposium at the ESMO congress in Stockholm.

• ESMO selects clinical studies that may result in a change in the current standard of care for presentation at the 2008 Presidential Symposium.

Progression-free survival (PFS)

• Median PFS was 7.3 months (trabectedin + PLD) vs 5.8 months in control arms (PLD)

• The hazard ratio (HR) was 0.79 (p=0.019) • 21% reduction in the risk of progression or

death during the observation period.

• Response rate 28% ( trabectedin and PLD) vs 19% in control arms (PLD)

Overall survival

• The interim survival data presented at ESMO are immature (55% censored) and the final analysis will be conducted after the occurrence of 520 events.

• Nonetheless, a positive trend with a 15% reduction in the risk of death favored patients treated with the Yondelis® and PLD combination.

Toxicity• Neutropenia was the most common toxicity (77%) in the

combination arm compared with 38% of patients in the Doxil®-only arm

• Similarly, reversible liver enzyme (transaminase) elevations were more common with the combination although without permanent liver damage or other clinical consequences.

• The addition of trabectedin enabled a lower dose of Doxil®, which may have contributed to the lower incidence of Doxil®-related toxicity observed with the combination.

• Specifically, hand and foot syndrome was seen in 54% of patients receiving alone compared with 24% of patients treated with trabectedin + Doxil.

• Similarily, stomatitis occurred in fewer patients receiving the trabectedin + Doxil® combination (20%) compared with those receiving Doxil® monotherapy (33%).

Podsumowanie

• I rzut:– Karboplatyna / Paclitaxel– Cisplatyna / Paclitexel IP

• II rzut:– Chore platyno – oporne: PLD, topotekan,

gemcitabine– Chore platyno – wrażliwe: Karboplatyna/ paclitaxel vel gemcitabine, PLD

Pytanie bez odpowiedzi

• - III rzut

• - sekwencyjność chemioterapii

• - miejsce VP-16

• - Leczenie celowane

Documents

Chemioterapia raka jajnika Radosław Mądry Klinika Onkologii Uniwersytety Medycznego im. K. Marcinkowskiego w Poznaniu