1. nordic society of gynecologic oncology ( nsgo ) denmark, finland, norway, sweden

A randomized, phase III study gemcitabine-paclitaxel-carboplatin (TCG) versus

paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer: survival of FIGO stage I-IIA

patients

1. Nordic Society of Gynecologic Oncology Nordic Society of Gynecologic Oncology ((NSGO))

Denmark, Finland, Norway, SwedenDenmark, Finland, Norway, Sweden

2. Arbeitsgemeinschaft Gynäkologische Arbeitsgemeinschaft Gynäkologische OnkologieOnkologie

((AGO) Studiengruppe Ovarialkarzinom) Studiengruppe Ovarialkarzinom

3. Groupe d’Investigateurs Nationaux pour Groupe d’Investigateurs Nationaux pour

l’Etudel’Etude des Cancers Ovariens (des Cancers Ovariens (GINECO), France), France

a GCIG Intergroup Studya GCIG Intergroup Study

Jørn Herrstedt1, Jens Huober2, Franck Priou3, Hans-Helge Müller2,

Mark Baekelandt1, Christian Kurzeder2, Jacobus Pfisterer2,

Anne Stähle2, Isabelle Ray-Coquard3, Andreas du Bois2 (PI).

ADDING A THIRD CYTOSTATIC DRUG TO TC RESULT

Triplet combination Gemcitabine AGO-GINECO-NSGO GOG-ANZGOG-MRC

Epirubicin1,2 AGO-GINECO NSGO-EORTC-NCIC-GEICO

Peg.-lip. Dox3 GOG-ANZGOG-MRC

Sequential doublet Gemcitabine3 GOG-ANZGOG-MRC

Topotecan3,4 NCIC-EORTC-GEICO

GOG-ANZGOG-MRC

Sequential single Topotecan5 AGO-GINECO

negative

negative

negative

negative

negative

?negative

1. du Bois A et al. J Clin Oncol 2006;24:1127-35.

2. Kristensen GB et al. J Clin Oncol 2004;22 (suppl):A5003

3. Bookman MA et al. J Clin Oncol 2009;27:1419-1425.

4. Hoskins PJ et al. J Clin Oncol 2008;26(suppl):LBA5505

5. Pfisterer J et al. JNCI 2006;98;1036-45.

RANDOMISATION

q 21 x 6

Paclitaxel 175 mg/m² d1

Carboplatin AUC 5 d1

q 21 x 6

Gemcitabine 800 mg/m² d1+8

Paclitaxel 175 mg/m² d1

Carboplatin AUC 5 d1

STUDY DESIGN

• Center

• Interval debulking surgery planned (yes/no)

• FIGO Stage and Tumor Residuals

•Stratum 1: FIGO IA/B G3 or IC – IIA

•Stratum 2:Stratum 2: FIGO IIB - IIIC + Tumor residual FIGO IIB - IIIC + Tumor residual << 1 cm 1 cm

•Stratum 3: Stratum 3: FIGO IV or FIGO IV or Tumor residual > 1 cm Tumor residual > 1 cm

STRATIFICATION

1st ENDPOINT Overall Survival in stratum 2+3

2nd ENDPOINTS PFS in stratum 2+3

PFS and OS in stratum 1

PFS and OS in all strata

Response Rate

Toxicity (NCI/CTC grade 3/4)

EORTC QLQ-C 30 , QLQ-OV 28

ENDPOINTS

PATIENT CHARACTERISTICS

RECRUITMENT AND COHORTS

Number of patients

Recruitment 1742

Analysed for primary endpoint in stratum 2 + 3

1567

Analysed for secondary end-point in stratum 1

175

PATIENT CHARACTERISTICS (%)

ALL PATIENTS TC

N = 882

TCG

N = 860

AGE

(mean years) 58.0 58.2

PS

(ECOG 0/1) 91.5 92.3

STAGE I-IIA

(FIGO) IIB-III

IV

10.8

73.0

16.2

10.5

73.1

16.4

PATIENT CHARACTERISTICS (%)

STRATUM 1 TC

N = 89

TCG

N = 86

AGE

(mean years) 56.1 55.9

PS

(ECOG 0/1) 95.5 98.8

STAGE IA

(FIGO) IB

IC

IIA

12.4

2.3

56.2

20.2

13.9

1.2

60.5

19.8

PATIENT CHARACTERISTICS (%)

ALL PATIENTS TC

N = 882

TCG

N = 860

HISTOLOGY

SEROUS

ENDOMETROID

MUCINOUS

73.7

9.1

4.2

75.1

7.7

3.8

TUMOR POST OP.

UNKNOWN

MICRO OR 0 CM

0.1-1 CM

> 1 CM

9.0

39.2

25.3

26.5

9.0

39.0

24.1

28.0

STRATUM 1 TC

N = 89

TCG

N = 86

HISTOLOGY

SEROUS

ENDOMETROID

MUCINOUS

55.1

16.9

9.0

54.7

20.9

9.3

TUMOR POST OP.

UNKNOWN

MICRO OR 0 CM

0.1-1 CM

> 1 CM

3.3

89.9

4.5

2.3

1.1

95.4

1.2

2.3

PATIENT CHARACTERISTICS (%)

FEASIBILITY

ALL PATIENTS TC

N = 882

TCG

N = 860

At least 1 course 874 850

> 6 courses 88.0% 87.2%

< 6 courses 12.0% 12.8%

FEASIBILITY

STRATUM 1 TC

N = 89

TCG

N = 86

At least 1 course 89 84

> 6 courses 93.3% 86.9%

< 6 courses 6.7% 13.1%

DOSE DEVIATIONS (%)

ALL PATIENTS TC

N = 882

TCG

N = 860

Interval 28+ days 7.5 11.6

P < 0.0001

> 1 dose reduction on day 1

1.9 3.4P < 0.0001

Dose omission gemcitabine day 8

--- 46.8

DOSE DEVIATIONS (%)

STRATUM 1 TC

N = 89

TCG

N = 86

Interval 28+ days 5.7 8.0

P = 0.1834

> 1 dose reduction on day 1

1.0 1.9P < 0.0001

Dose omission gemcitabine day 8

--- 40.6

RESULTS

STRATUM 1

0

0,25

0,5

0,75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

PROGRESSION-FREE SURVIVAL (RECIST & CA125) BY THERAPY: STRATUM 1 (FIGO I-IIA)

Patients at risk

TCTC 89 pts. / 21 evts.89 pts. / 21 evts. median - mos.median - mos.

TCGTCG 86 pts. / 17 evts.86 pts. / 17 evts. median - mos.median - mos.P

r o

b a

b i

l i

t y

[[monthsmonths]]

HR = 0.85 [95% CI: 0.45-1.61]

p = 0.6199

89 87 82 79 75 67 62 57 46 29 17 5 1 0 0

86 79 76 75 72 67 58 51 46 33 15 4 2 0 0

0

0,25

0,5

0,75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

OVERALL SURVIVAL BY THERAPY STRATUM 1 (FIGO I-IIA)

89 88 85 81 79 75 73 69 56 41 23 6 1 0 0

86 80 79 78 75 72 67 58 52 38 19 4 2 0 0Patients at risk

TCTC 89 pts. / 5 evts.89 pts. / 5 evts.median - mos.median - mos.

TCGTCG 86 pts. / 10 evts.86 pts. / 10 evts.median - mos.median - mos.

P r

o b

a b

i l

i t

y

[[monthsmonths]]

HR = 2.19 [95% CI: 0.75-6.41]

p = 0.1419

RESULTS

STRATUM 2 +3

0

0,25

0,5

0,75

1

0 6 12 18 24 30 36 42 48 54 60 66 72

PROGRESSION-FREE SURVIVAL (RECIST & CA125) BY THERAPY: STRATUM 2+3 (FIGO IIB-IV)

[[monthsmonths]]793 699 511 351 270 225 191 152 95 43 14 2

774 685 483 307 228 185 155 116 72 36 12 2

Patients

at risk

HR = 1.17 [95% CI: 1.05-1.31]

Logrank test: p = 0.0065

TCTC 793 pts. / 588 evts.793 pts. / 588 evts. median 16.0 [14.9-17.4] mos.median 16.0 [14.9-17.4] mos.

TCGTCG 774 pts. / 629 evts.774 pts. / 629 evts. median 14.7 [14.0-15.9] mos.median 14.7 [14.0-15.9] mos.

OVERALL SURVIVAL BY THERAPY STRATUM 2+3 (FIGO IIB-IV)

0

0,5

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78

P r

o b

a b

i l

i t

y

[[monthsmonths]]

TCTC 793 pts. / 401 evts.793 pts. / 401 evts. median 48.9 [43.1-51.2] mos.median 48.9 [43.1-51.2] mos.

TCGTCG 774 pts. / 404 evts.774 pts. / 404 evts. median 45.8 [40.0-49.5] mos.median 45.8 [40.0-49.5] mos.

HR = 1.03 [95% CI: 0.90-1.18]

p = 0.6955

Patients at risk

793 750 705 638 557 489 420 338 226 89 31 5774 740 693 628 554 484 411 322 208 87 28 5

TOXICITY

ALL PATIENTS

Anemia (5168/5067) 1.0 4.9 < .0001

Thrombocytopenia (5168/5068) 1.1 11.4 < .0001

Leukopenia (5168/5067) 9.3 28.3 < .0001

Neutropenia (4905/4882) 32.3 45.2 < .0001

Febrile Neutropenia (5115/5003) 0.4 1.2 < .0001

Inf. without Neutropenia (5122/5009) 0.7 0.9 0.2705

G-CSF 5.2 12.5 < .0001

EPO 5.6 12.3 < .0001

Antibiotics 3.2 5.3 < .0001

Blood Products 2.3 9.3 < .0001

HEMATOLOGICAL TOXICITIES Grade 3/4 WORST OF ALL COURSES

Toxicity (NTC/NTCG) TC TCG p-value

Fatigue Fatigue (865/840)(865/840) 7.17.1 10.510.5 .0125.0125

Nausea (865/841) 3.2 4.3 .2579

Constipation (865/841) 4.5 6.5 .0672

Neuropathy-motor (865/840) 2.2 3.0 .3139

Neuropathy-sensory (865/840) 6.5 7.4 .4655

Athralgia (865/840) 4.7 4.1 .4871

Myalgia (865/840) 4.7 3.6 .2281

Pain (865/842) 6.1 6.1 .9475

Alopecia grade 2 (859/827) 93.8 92.9 .4330

NON-HEMATOLOGICAL TOXICITIES Grade 3/4 WORST OF ALL COURSES

Toxicity (NTC/NTCG) TC TCG p-value

ADDING A THIRD CYTOSTATIC DRUG TO TC RESULT

Triplet combination Gemcitabine3 AGO-GINECO-NSGO GOG-ANZGOG-MRC

Epirubicin1,2 AGO-GINECO NSGO-EORTC-NCIC-GEICO

Peg.-lip. Dox3 GOG-ANZGOG-MRC

Sequential doublet Gemcitabine3 GOG-ANZGOG-MRC

Topotecan3,4 NCIC-EORTC-GEICO

GOG-ANZGOG-MRC

Sequential single Topotecan5 AGO-GINECO

negative

negative

negative

negative

negative

negativenegative

1. du Bois A et al. J Clin Oncol 2006;24:1127-35.

2. Kristensen GB et al. J Clin Oncol 2004;22(suppl)A5003.

3. Bookman MA et al. J Clin Oncol 2009;27:1419-1425.

4. Hoskins PJ et al. J Clin Oncol 2008;26(suppl)LBA5505.

5. Pfisterer J et al. JNCI 2006;98;1036-45.

AGO-OVAR Coordinating GroupA. Belau (Greifswald)A. Burges (München)U. Canzler (Dresden)A. du Bois - PI

(Wiesbaden)M. Gropp (Düsseldorf)P. Harter (Wiesbaden)V. Heilmann (Ulm)F. Hilpert (Kiel)J. Huober (Tübingen)Ch. Jackisch (Marburg)R. Kimmig (Essen)S. Loibl (Frankfurt)H.-J. Lück (Hannover)W. Meier (Düsseldorf)J. Pfisterer (Kiel)B. Richter (Radebeul)B. Schmalfeldt (München)W. Schröder (Bremen) J. Sehouli (Berlin)A. Stähle (Karlsruhe) U. Wagner (Marburg)K. Wollschlaeger (Magdeburg)

GINECOA.-C. Hardy-Besard (Saint-Brieuc)F. Joly (Caen)B. Weber (Nancy)E. Lévy (Paris)F. Priou (La-Roch-Sur-Yon)J.-P. Guastalla (Lyon) J. Plaza (Montbéliard)D. Berton-Rigaud (Nantes)S. Abadie-Lacourtoisie (Angers)C. Platini (Metz)F. Mefti (Saint-Cloud)K. Yakendji (Créteil)H. Bourgeois (Poitiers)L. Bastit (Rouen)P. Chinet-Charrot (Rouen)

E. Pujade-Lauraine –PI (Paris)

Statistics and Data management Study Office Monitoring

AGO-OVAR H.-H. Müller G. Elser, C. Ackermann P. Schantl, S. Oxe, S. BigusM. Hahmann, B. Aminossadati A. Igler, U. Weitzel F. Gottwald, S. Lang, H. Lüers

K. Friccius, B. Saile, C. Renné,

GINECO D. Paraiso, N. Le Fur C. Dumont-Puléo M. Bekhiti, S. Lahmar

NSGO R. DePont Christensen G. Andersen C. Ramstad, L. Rosquist,H. Holst

Supported by Eli Lilly and Company

NSGOJ. Herrstedt - PI (Herlev)G. Kristensen (Oslo)J. Kaern (Oslo)T. Skeie-Jensen (Oslo)E. Lorenz (Trondheim)K. Bertelsen (Odense)M. Mirza (Odense)J. Lindegaard (Aarhus)H. Havsteen (Aarhus)E. Aavall-Lundqvist (Stockholm)B. Tholander (Stockholm)M. Kalling (Lund)T. Høgberg (Linkøping)K. Boman (Umeaa)J. Mâenpââ (Tampere)S. Jelic (Beograd)Ljiljana Stamatovic (Beograd)I. Takac (Maribor)

Acknowledgement: Patients, all centres, IDMSC, and…