15th Annual CTOS Meeting November 5–7, 2009 PRELIMINARY RESULTS OF A RANDOMIZED TRIAL OF...

15th Annual CTOS MeetingNovember 5–7, 2009

PRELIMINARY RESULTS OF A RANDOMIZED TRIAL OF NEOADJUVANT CHEMOTHERAPY WITH METHOTREXATE (MTX), CISPLATIN (CDP), DOXORUBICIN (ADM), WITH OR WITHOUT IFOSFAMIDE (IFO) FOR NON-METASTATIC OSTEOSARCOMA OF THE EXTREMITY: ANALYSIS OF HISTOLOGIC RESPONSE AND TOXICITY (ISRCTN1335128)

S. Ferrari, G. Cefalo, A. Tamburini, A. Comandone, A Brach Del Prever, P.G. Casali, M Alberghini , E. Palmerini , A. Longhi,M. Mercuri, R. Capanna, S. Mappelli, P. Picci, G. Bacci.

0

20

40

60

80

100

Chemotherapy Surgery S+CDP/ADM s+MTX CDP ADM IFO

%DFS

NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITYNON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITY

IOR/OS-2 IOR/OS-2

1986-891986-89

HDMTX-CDP-ADM±IFOHDMTX-CDP-ADM±IFO 10 year DFS 63%10 year DFS 63%

SSG II SSG II

1982-891982-89

HDMTX-BCD±CDP-ADMHDMTX-BCD±CDP-ADM 5 year DFS 54%5 year DFS 54%

COSS-86 COSS-86

1986-19901986-1990

HDMTX-CDP-ADM-IFOHDMTX-CDP-ADM-IFO 10 year EFS 66%10 year EFS 66%

EOI EOI

1983-861983-86

CDP-ADMCDP-ADM 5 year PFS 44%5 year PFS 44%

CCG-782 CCG-782

1983-19861983-1986

HDMTX-V-BCD-ADM±CDPHDMTX-V-BCD-ADM±CDP 8 year EFS 53%8 year EFS 53%

FSPO FSPO

1989-19931989-1993

HDMTX-CDP-ADM-IFO-VDSHDMTX-CDP-ADM-IFO-VDS 5 year DFS 64%5 year DFS 64%

CCG/POGCCG/POG

1993-19971993-1997

HDMTX-CDP-ADM-IFO+MTPHDMTX-CDP-ADM-IFO+MTP 5 year EFS 71%5 year EFS 71%

ISG/SSG IISG/SSG I

1997-20001997-2000

HDMTX-CDP-ADM-HDIFOHDMTX-CDP-ADM-HDIFO 5 year EFS 64%5 year EFS 64%

MTX-CDP-ADM-IFOMTX-CDP-ADM-IFO

MTX-CDP-ADM and IFO only in PR?

IFO since primary chemo added to MTX-CDP-ADM?

IFO alone or coupled to CDP and ADM?

IFO added to MTX-CDP-ADM in all patients?

Best combination?

NON METASTATIC HIGH-GRADE OSTEOSARCOMA NON METASTATIC HIGH-GRADE OSTEOSARCOMA OF THE EXTREMITYOF THE EXTREMITY

ISG/OS-1ISG/OS-1

AIMSAIMS

• Evaluation of toxicity of two chemotherapy protocols with MTX, Evaluation of toxicity of two chemotherapy protocols with MTX, CDP, ADM and IFO, given according to different schemes, but CDP, ADM and IFO, given according to different schemes, but same cumulative dosesame cumulative dose

• Evaluation of efficacy (EFS, MFS, DFS) of two chemotherapy Evaluation of efficacy (EFS, MFS, DFS) of two chemotherapy protocols with MTX, CDP, ADM and IFO, given according to protocols with MTX, CDP, ADM and IFO, given according to different schemes, but same cumulative dosedifferent schemes, but same cumulative dose

• Evaluation of the efficacy of high-dose IFO (15g/m2) as second-Evaluation of the efficacy of high-dose IFO (15g/m2) as second-line treatment for patients relapsed after ISG/OS-1line treatment for patients relapsed after ISG/OS-1

STUDY DESIGNSTUDY DESIGN

Arm AArm A : : MTX CDP ADM ± IFOMTX CDP ADM ± IFORANDOMRANDOM

Arm BArm B : : MTX CDP ADM IFOMTX CDP ADM IFO

STATISTICSSTATISTICS

Study power : 80%Study power : 80%

Significance : 0.05Significance : 0.05

Expected difference < 15%Expected difference < 15%

Sample : 246 pazientiSample : 246 pazienti

Recruitment : 5 anniRecruitment : 5 anni

ISG/OS-1ISG/OS-1

ELIGIBILITY CRITERIAHistologic diagnosis of osteosarcoma G 3-4

Extremity location

Age ≤ 40 years

No metastases

Normal epatic, renal, marrow functions. FE >50%

No previous chemotherapy/surgery for osteosarcoma

Informed consent

Centralization of radiologic and histologic documentation

ISG/OS-1ISG/OS-1

Preoperative chemotherapyPreoperative chemotherapy

M P/A M P/AM P/A M P/A-------------------------------------------------------------------------------- Surgery Surgery

M = methotrexate 12g/m2; P = cisplatin 120 mg/m2; A = Adriamycin 75 mg/m2 A* = 90 mg/m2; I = ifosfamide 10 g/m2

Arm AArm A

Postoperative chemotherapyPostoperative chemotherapy

A M M P A M M P A M M P M MA M M P A M M P A M M P M M----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

A I M M P A I M M P A I M M P M M----------------------------------------------------------------------------------------------------------------9 12 15 16 17 20 23 26 27 28 31 34 37 38 39 42 43 weeks

≥≥90%90%

< 90%< 90%

0 1 4 5 8 weeks0 1 4 5 8 weeks

9 12 13 14 17 20 21 22 25 28 29 30 33 34 weeks9 12 13 14 17 20 21 22 25 28 29 30 33 34 weeks

ISG/OS-1ISG/OS-1

M P/A M I/P I/A---------------------------------------------- Surgery0 1 4 5 8 11 weeks

M = methotrexate 12g/m2; P = cisplatin 120 mg/m2; A = Adriamycin 70 mg/m2; I = ifosfamide 6 g/m2

Arm BArm BPreoperative chemotherapyPreoperative chemotherapy

Postoperative chemotherapyPostoperative chemotherapy

P/A M M I/P I/A M M P/A M M I/A M MP/A M M I/P I/A M M P/A M M I/A M M----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------12 15 16 17 20 23 24 25 28 29 30 33 34 weeks12 15 16 17 20 23 24 25 28 29 30 33 34 weeks

ISG/OS-1ISG/OS-1

AR M A AR M B

MT X 120 g 120 g

CDP 600 mg 600 mg

ADM 420 mg 420 mg

IF O 30 g* 30 g

Cumulative doseCumulative dose

* 0 in GR

Arm BArm B34 weeks34 weeks

Arm AArm A43 weeks43 weeks

ISG/OS-1ISG/OS-1

All A B p

246 123 (50%) 123 (50%)

Age Median

14

(4-39)

14

(6-39)

14

(4-34)

Sex M

F

146 (59%)

100 (41%)

74 (60%)

49 (40%)

72 (59%)

51 (41%)

0.8

Site Femur

Tibia

Humerus

Other

131 (53%)

60 (25%)

34 (14%)

21 (8%)

62 (50%)

34 (28%)

14 (11%)

13 (11%)

69 (56%)

26 (21%)

20 (16%)

8 (7%)

0.3

April 2001April 2001December 2006December 2006

Clinical CharacteristicsClinical Characteristics

ISG/OS-1ISG/OS-1

All A B p

SAP209 pz

Normal

High

125 (60%)

84 (40%)

65 (62,5%)

39 (37,5%)

60 (57%)

45 (43%)

0.3

LDH198 pz

Normal

High

136 (69%)

62 (31%)

72 (72%)

28 (28%)

64 (65%)

34 (35%)

0.2

Histology Osteoblastic

Chondroblastic

Fibroblastic

Teleangiectatic

NAS

157 (64%)

24 (10%)

23 (9%)

23 (9%)

19 (8%)

76 (62%)

12 (10%)

11 (9%)

10 (8%)

16 (13%)

81 (66%)

12 (10%)

12 (10%)

9 (7%)

9 (7%)

0.5

Clinical CharacteristicsClinical CharacteristicsISG/OS-1ISG/OS-1

Delayed 48,5%

Median delay 5 days

(1-40)

A B

Courses 3,134 1,569 (50%) 1,565 (50%)

ComplianceComplianceISG/OS-1ISG/OS-1

All A B Planned Dose

MTX

Median Median (Min-Max)(Min-Max)

115,5

(44-132)

115,4

(44-132)

115

(60-122)

120 g/m2

CDP


589

(237-616)

590

(237-613)

588

(467-616)

600 mg/m2

ADM


413

(327-440)

410

(327-422)

415

(344-440)

420 mg/m2

IFO


29

(20-36)

30

(20-31)

29

(21-36)

30 g/m2

Cumulative dose (m2)Cumulative dose (m2) ComplianceCompliance

ISG/OS-1ISG/OS-1

A1,1±0,3

B1,24±0,3P=0.005

Received dose intensityReceived dose intensity

ISG/OS-1ISG/OS-10.820.82

A0.92±0,03

B0.74±0,05P=0.02P=0.02

RealReal /planned durationplanned durationComplianceCompliance

ISG/OS-1ISG/OS-1

Disseminated intravascular coagulation 1 B

Fatal cardiopathy 2 A-B

Stevens-Johnson syndrome 1 B

ToxicityToxicityISG/OS-1ISG/OS-1

22,5

15,5

67,5

20

13

15,5

26

0 20 40 60 80

%

WBC G4PLT G4HospitalFebrile NeuCSFsTransf PLTTransf RBC

CDP-ADM-IFO1236 cycles ToxicityToxicity

ISG/OS-1ISG/OS-1

CDP-ADM-IFO1236 cycles ToxicityToxicity

0

10

20

30

40

50

60

70

80

A B

Transf RBCTransf PLTCSFsFebrile NeuHospitalPLT G4WBC G4

AA BB pp

WBC G4WBC G4 160 (24%)160 (24%) 336 (58%)336 (58%) <0.0001<0.0001

PLT G4PLT G4 93 (14%)93 (14%) 231 (40%)231 (40%) <0.0001<0.0001

RBC TransfRBC Transf 84 (13%)84 (13%) 206 (33%)206 (33%) <0.0001<0.0001

PLT TransfPLT Transf 39 (6%)39 (6%) 159 (26%)159 (26%) <0.0001<0.0001

CSFsCSFs 412 (63%)412 (63%) 422 (73%)422 (73%) <0.002<0.002

Febrile NeutropeniaFebrile Neutropenia 109 (16%)109 (16%) 145 (24%)145 (24%) <0.002<0.002

HospitalizationHospitalization 48 (7%)48 (7%) 118 (19%)118 (19%) <0.0001<0.0001

AA

PR onlyPR only

BB pp

WBC G4WBC G4 110 (28%)110 (28%) 336 (58%)336 (58%) <0.0001<0.0001

PLT G4PLT G4 43 (11%)43 (11%) 231 (40%)231 (40%) <0.0001<0.0001

RBC TransfRBC Transf 54 (10.5%)54 (10.5%) 206 (33%)206 (33%) <0.0001<0.0001

PLT TransfPLT Transf 27 (5%)27 (5%) 159 (26%)159 (26%) <0.0001<0.0001

CSFsCSFs 339 (66%)339 (66%) 422 (73%)422 (73%) <0.002<0.002

Febrile NeutropeniaFebrile Neutropenia 86 (16.5%)86 (16.5%) 145 (24%)145 (24%) <0.002<0.002

HospitalizationHospitalization 39 (7.7%)39 (7.7%) 118 (19%)118 (19%) <0.0001<0.0001

ISG/OS-1ISG/OS-1

HDMTX1553 courses

Delayed clearanceDelayed clearance118 (8%)118 (8%)

Arm AArm A54 (7.6%)54 (7.6%)

Arm BArm B64 (8.2%)64 (8.2%)

NephrotoxicityNephrotoxicity4 patients4 patients

(1 requiring dialysis)(1 requiring dialysis)

Transaminases G4Transaminases G4353/1525353/1525

23%23%

Mucositis >G1Mucositis >G135/151235/1512

3%3%


Renal failure 8/246 patients (3,2%)1 patient required dialysis

Cardiotoxicity 17/246 patients (7%)

2 Acute fatal cardiopathy11 EF change >10% baseline. 4 clinical evidence of cardiopathy


92 96

0

10

20

30

40

50

60

70

80

90

100

% Resection

Arm A Arm B

2 PD in primary chemotherapy. No surgery

Resection 230 (94%)

Amputation 12 (5%)

Rotation plasty 2 (1%)

P = 0.5

SurgerySurgery

Margins Tot A B

Adequate 204 (95%) 93% 96%

Inadequate 11 (5%) 7% 4%

ISG/OS-1ISG/OS-1

A+B

≥ 90% 45%

< 90% 55%

A vs B: p = 0.3

4842

0

10

20

30

40

50

60

70

80

90

100

% GR

Arm A Arm B

Tumor Tumor necrosisnecrosis

ISG/OS-1ISG/OS-1

SurvivalSurvival

0

,2

,4

,6

,8

1

Cum

. Sur

viva

l

0 12 24 36 48 60 72 84 96 108 120Months

0

,2

,4

,6

,8

1C

um. S

urvi

val

0 12 24 36 48 60 72 84 96 108 120Months

Overall SurvivalOverall Survival

Event-free SurvivalEvent-free Survival

62%A 65%B 58%

OS: Median time 58 months (23-101)

ISG/OS-1ISG/OS-1

0

,2

,4

,6

,8

1

Cum

. Sur

viva

l

0 12 24 36 48 60 72 84 96 108 120Months

75%

0

,2

,4

,6

,8

1

Cum

. Sur

viva

l

0 12 24 36 48 60 72 84 96 108 120Months

A 75%B 75%


ISG/OS-1ISG/OS-1

As expected, aroud 60% of 5-year EFS and 75% 5-year OS with the four drug combination

A similar probability of survival can be expected when ifosfamide is given in a selected population (poor responders to MTX CDP ADM) or in all patients added to MTX CDP ADM

The use of ifosfamide since the primary phase added to MTX-CDP-ADM does not increase the rate of good histological responders compared to MTX-CDP-ADM

Ifosfamide + MTX-CDP-ADM given to all patients and since the primary phase resulted in a significantly higher toxicity

Istituto Ortopedico Rizzoli, BolognaIstituto Ortopedico Rizzoli, BolognaIstituto Nazionale Tumori, MilanoIstituto Nazionale Tumori, MilanoOspedale Meyer, FirenzeOspedale Meyer, FirenzeOIRM, TorinoOIRM, TorinoOspedale Bambin Gesù, RomaOspedale Bambin Gesù, RomaIst. Gaslini, GenovaIst. Gaslini, GenovaClinica Pediatrica, PadovaClinica Pediatrica, PadovaOncoematologia Pediatrica, PisaOncoematologia Pediatrica, PisaCRO, AvianoCRO, AvianoOrtopedia Oncologica Careggi, FirenzeOrtopedia Oncologica Careggi, FirenzeOrtopedia Oncologica G. Pini, MilanoOrtopedia Oncologica G. Pini, Milano

Standard chemotherapyStandard chemotherapyMTX CDP ADM Surgery MTX CDP ADMMTX CDP ADM Surgery MTX CDP ADM ± IFO± IFO


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15th Annual CTOS Meeting November 5–7, 2009 PRELIMINARY RESULTS OF A RANDOMIZED TRIAL OF...

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