La chemioterapia neoadiuvante e adiuvante nei sarcomi delle parti molli Padova, 30 Maggio, 2008 A.Buonadonna, CRO-Aviano

La chemioterapia neoadiuvante e adiuvante nei sarcomi delle parti molli

Padova, 30 Maggio, 2008

A.Buonadonna, CRO-Aviano

Topics

- Review-1st Italian randomized study - National Survey- 2nd Italian, neo-adjuvant, randomized trial- EORTC Trial - Conclusions

Adjuvant chemotherapy in STS

For adult soft tissue sarcomas , stage III encompasses tumors larger than 5 cm, high grade (3-4), located deep to the superficial fascia, that have no evidence of distant metastasis.

Adjuvant chemotherapy in STS

After definitive loco-regional treatment only, approximately 50% of these patients will develop a recurrence, and 45% will die of sarcoma within 5 years.

Greene FL, Page DL, Fleming ID, et al. (2002) AJCC cancerstaging handbook, 6th edn. Berlin, Heidelberg, New York: Springer.

Chemioterapia adiuvante: Studi di Ia

generazione(1)Institution

Years of accrual

Stages No. of

pts

Scheme Med. F.U.

(months)

DFS %

F.U. CT P

OS %

F.U. CT P

Last analysis

DFC/MGH, 1978/83

ECOG, ISSG, 1985/87

IIB –

IVA

168 ADM 52 53 66 NS 65 68 NS ANTMAN

1990

RIZZOLI 1981 – 1986 III –

IVA

77 ADM 106 29 56 0.1 49 63 .06 GHERLINZONI

1993

UCLA 1981 - 1984 III 119 ADM 28 54 58 NS 80 85 NS EILBER

1987

SSG 1981 - 1986 III –

IVA

240 ADM 40 56 62 NS 70 75

NS

ALVEGARD

1989

GOG 1973 - 1982 FIGO

I/II

136 ADM 24 47 59 NS 42 45

NS

OMURA

1985

Chemioterapia adiuvante: Studi di Ia generazione(2)

Institution

Years of accrual

Stage Pts Scheme Med F.U. DFS %

F.U. CT

p OS %

F.U. CT

p Author

MDAH 1973 - 1976

Extremities

IIB –

IIIB

43

47

ACVAd 120

120

83 76

35 54

NS

0.05

n.d. n.d

36 65 0.06

BENJAMIN

1987

MAYO

1975 – 1981

I –

IVB

61 AVDAd 64 68 65 n.a 70 70 NS EDMONSON

1984

NCI Extremities II-III 67 ACD 85 75 51 0.04 60 58 NS CHANG

1988

EORTC

1977 – 1988

IA –

IIIB

468 ACVD

q 4w

80 43 56 NS 55 63 NS BRAMWELL

1994

F. BERGONIE

1980 – 1988

IIB –

IVA

59 ACVD

q 3w

52 16 57 0.0003 53 87 .002 RAVAUD

1990

Trials included in the meta-analysis: 14

• Single patient data records analyzed: 1568

• Reliability: evaluated 98% of included patients

• ADM total dose: 200-500 mg/m2

• ADM per cycle: 50-90 mg/m2 either as single agent or in combination

Sarcoma Meta-analysis Collaboration (Lancet, 350:1647-54, 1997)

Survival P value 10 years results Treated Controls

% abs. benefit

Local RFS 0.016 75 81 6



% abs. benefit

Distant RFS

0.70 60 70 10



% abs. benefit

Overall RFS

0.0001 45 55 10



% abs. benefit

Overall Survival

0.12 50 54 4

Chemioterapia adiuvante: Meta-analisiSarcoma Metanalysis Collaboration III

(Lancet, 350:1647-54, 1997)

Subgroups OS Absolute benefit at 10 years

Extremity (886pts) 0.029 7 %Age(<30;30-60; >60 0.31 /

Sex (m vsF) 0.49 /Status (prim. vs rel.) 0.24 /Histology(4 vs others) 0.75 /

Grade (low vs high) 0.97 /Dimension(<5; 5-10; >10) 0.40 /Marginality 0.88 /Radiotherapy 0.40 /

SECOND GENERATION TRIALS IISECOND GENERATION TRIALS II

Institution Date Site Selection

NCI92-CO21

6 / 92 Extremities High-grade> 3 cm

EORTC62931

4 / 92 All sites High gradeAny dimension

RTOG95-14

6 / 95 All sites High-grade> 5 cm

CNR ITALY

6 /92 Extremities High-grade> 5 cm; subfascial

SECOND GENERATION TRIALS IVSECOND GENERATION TRIALS IV

Institution Schedule mg/m2

Time D.I. mg/m2/w)

NCI 92-CO21

ADM 70; d 1 IFO 4; d 1-5 vs control

Every 4 w x 5

+ G-CSF

ADM 17.5 IFO 1000

EORTC 62931

ADM 75; d 1 IFO 5; 24 h inf. vs control

Every 3 w x 5

+ GM-CSF

ADM 25 IFO 1667

RTOG 95-14

ADM 20; d1-3 c.i. IFO 2500; d1-3c.i. DTIC 225; d1-3c.i. vs control

Every 3 w x 2 + 4

+G-CSF

ADM 20 IFO 2500 DTIC 225

CNR ITALY

EPI 60; d 1-2 IFO 1800; d1-5 vs control

Every 3 w x 5

+ G-CSF

EPI 40 IFO 3000

SECOND GENERATION TRIALS SECOND GENERATION TRIALS

Similarities • More homogeneous selection criteria• Use of Ifosphamide• 2 drugs combinations• Use of Growth factorsDifferences• Dose intensity• Sequence of approaches( S/RT/CT)

Topics

- Review-1st Italian randomized study - National Survey- 2nd Italian, neo-adjuvant, randomized trial-EORTC Trial - Conclusions

Controversy: Adjuvant chemotherapy in STS

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STS1st 1st ItalianItalian Sarcoma Group Trial: Sarcoma Group Trial: StudyStudy design design

BBIIOOPPSSYY

SSTTAAGG I INNGG

L T - RADL T - RADO R SURG.O R SURG.O EO EC A - SURG.+C A - SURG.+A T POSTOP-RTA T POSTOP-RTL ML M E - PREOP-RT E - PREOP-RT N + SURG. N + SURG. T T

SSTTRRAATTIIFFYY

--PRIMARYPRIMARY < 10 CM < 10 CM-PRIMARY-PRIMARY >> 10 CM 10 CM-RELAPSE-RELAPSE < 10 CM < 10 CM-RELAPSE-RELAPSE >> 10 CM 10 CM

RRAANNDDOOMMIIZZAATTIIOONN

CCTT

FFUU

S. Frustaci et al. JCO; 19: 1238-1247, 2001

•Age >16 <65 years•PS <2 ECOG•High grade (G3-G4 Broder), subfascial spindle cell and polymorphous locally controlled sarcomas•Extremities and/or girdles•No previous radio/chemotherapeutic treatment•Primary >5 cm; relapse of any dimension•Written informed consent

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STS

INCLUSION CRITERIAINCLUSION CRITERIA

4/97

Chemotherapy(one cycle every 21 days)

• Epirubicine 60mg/m2/die, days 1 and 2

• Ifosfamide 3g/m2/die, days 1, 2, 3

• Mesna 1000mg/m2 x 3/die, days 1, 2, 3

• Hydration with 2000 cc/die during days 1, 2, 3

• Anti-HT3 and corticosteroids

• G-CSF from day +7 to complete haematological recovery• Adequate dose modifications according to the nadirs

1ST ITALIAN ADJUVANT STUDY1ST ITALIAN ADJUVANT STUDY

MEDIAN RELATIVE DOSE-INTENSITY (%)

I Cycle II Cycle III Cycle IV Cycle Average

EPI 88 83.1 75.7 73.2 80.0

120/m2 (47.2-106) (37.5-107.0) (36.6-103.4) (25-104.3)

IFO 89.1 89.5 86.2 82.1 86.7

9g/m2 (49.8-101.6) (55.5-107.0) (60-104.5) (30.6-103.4) Average 90.9 85.2 80.9 77.7 83.7

R.D.I. Range (49.9-104.6) (55.5-107.1) (52.2-103.4) (37.4-103.8)

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STS1st Italian Sarcoma Group Trial: Dose intensity1st Italian Sarcoma Group Trial: Dose intensity

P=0.04

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STS1st Italian Trial: Disease free survival1st Italian Trial: Disease free survival

JCO, 2001, Vol. 19, N° 5,

Median F.U.=59 mMinimum F.U.=36 m

P = 0.03

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STS

1st Italian Trial: Overall survival1st Italian Trial: Overall survival

JCO, 2001, Vol 19, N° 5,JCO, 2001, Vol 19, N° 5,

JCO, 2001, Vol. 19, N° 5,

Median F.U.=59 mMinimum F.U.=36 m

Date of analysis

OS DFS l-DFS d-DFS FU Comments

11/96 0.007 0.001 0.009 0.002 Stop of pts accrual due to the foreseen stopping rules

11/97 0.002 0.009 0.02 0.03 24 ASCO 1997; oral pres.

11/98 0.01 0.02 0.05 0.05 36 n.r.

11/99 0.03 0.04 0.09 0.48 59 JCO, 2001, Vol 19, N° 5,

11/00 0.04 0.06 n.v. n.v. 74 n.r.

09/02 0.07 0.08 n.v. n.v. 89 5 years OS: 66 vs 46% (p=0.04)

Classic Paper & Current Comments 2002, Vol 7N°4 Oncology 2003,Suppl.2:80-84

The First Adjuvant I.S.G. Trial; 06/92- 11/96

Summary of performed analyses

Adjuvant therapy in soft tissue sarcomasISG Study:06/’92-11/’96

Analysis of 09/02Disease free survival

0 12 24 36 48 60 72 84 96 108 1200.00

0.25

0.50

0.75

1.00

Treatment

Control

Treat F.U.

N°pts 53 51Cens 24 19Events 29 32m.DFS 48.8 16.2

p=0.08

Median follow-up: 89.4m

Adjuvant therapy in soft tissue sarcomasISG Study:06/’92-11/’96

Analysis of 09/02 Overall survival

0 12 24 36 48 60 72 84 96 108 1200

25

50

75

100

Treatment

Control

Treat F.U.

N°pts 53 51Cens 31 23Events 22 28m. OS n.r. 50.4

p=0.07


5 years OS: 66 vs 46% (p=0.04)

1st ISG Study: 06/’92-11/’96; Analysis of 09/02 Subgroup analysis: Efficacy of chemotherapy

7 pts never started CT because of early relapse or refusal

0 12 24 36 48 60 72 84 96 108 1200

25

50

75

100

Treatment

Control

p = 0.038

time (months)

Per

cent

sur

vivi

ng

Treat F.U.

N°pts 46 51Cens 28 23 Events 18 28m.Surv n.r. 54.3

p=0.038


Overall Survival

1st ISG Study: 06/’92-11/’96 Analysis of 09/02 Subgroup analysis: Dose intensity of chemotherapy

0 12 24 36 48 60 72 84 96 108 1200

25

50

75

100

TreatmentControl>/=85%

<85%

months

perc

ent

surv

ivin

g


Overall Survival

1st ISG Study: 06/’92-11/’96 Analysis of 09/02 Subgroup analysis: Dose intensity of chemotherapy

0 12 24 36 48 60 72 84 96 108 1200

25

50

75

100

TreatmentControl>/=85%

<85%

months

perc

ent

surv

ivin

g


Overall Survival

MEDIAN RELATIVE D.I. %

Cycle 1st 2nd 3rd 4th Average

EPI 88 83.1 75.7 73.2 80.0

IFO 89.1 89.5 86.2 82.1 86.7% 90.9 85.2 80.9 77.7 83.7

Adjuvant therapy in soft tissue sarcomas1st ISG Study: 06/’92-11/’96 Analysis of 09/02

Post relapse survival

0 25 50 75 1000

25

50

75

100

Treatment

Control

Treat F.U.

N°pts 29 32Cens 7 4Events 29 32m.Surv 21.8 17.8

p=0.37

Topics



Survey dell’Italian Sarcoma Group.- Aims: to verify the reproducibility, efficacy, reliability of the prospective trial when applied spontaneously outside the protocol.

- Period: 11/’96 to 06/’99

- Methods:1) Call for data launched in June ‘992) Prospective data collection, spontaneous

referral of unregistered patients, homogeneous selection criteria and treatment modality.

Chemotherapy(one cycle every 21 days)

• Epirubicine 60mg/m2/die, days 1 and 2

• Ifosfamide 3g/m2/die, days 1, 2, 3

• Mesna 1000mg/m2 x 3/die, days 1, 2, 3

• Hydration with 2000 cc/die during days 1, 2, 3

• Anti-HT3 and corticosteroids

• G-CSF from day +7 to complete hematologic recovery• Adequate dose modifications according to the nadirs

UPDATED RESULTS OF THE ITALIAN SURVEYUPDATED RESULTS OF THE ITALIAN SURVEY


Evaluation of the “post-trial” treatmentEvaluation of the “post-trial” treatment

TREATMENT TREATMENT

- Completed CT (5 cycles) 43/55 (78.2%)

- Interrupted - for toxicity G3 - G4 8/55- for other reasons 4/55


Dose Intensity Dose Intensity

Cycles I II III IV Average

EPI 96.4 94.2 86.6 77.7 88.7Range (38.1-116) (48.3-111) (43.5-106) (24-109)

IFO 99.3 95.8 91.1 74.4 90.1Range (38.1-117) (41.6-111) (26.6-105) (23-105)

Median 97.9 94.8 88.2 75.0 89.4Range (38.1-116.5) (52-111) (35.5-105.5) (23.5-105) (52 - 116)


Survival: comparison with CNR study(11/98)

0 12 24 36 48 60 72 84 960

10

20

30

40

50

60

70

80

90

100TREATMENTCONTROLSURVEY

MONTHS

% O

S

Topics



Italian Sarcoma Group

Localized adult soft tissue sarcoma of the extremities and trunk:

Integrated approach of 3 neodjuvant cycles or 3 neoadjuvant and 2 adjuvant cycles.

Controlled prospective randomized studyClinical coordinators Coordinating and Data Center

S.Frustaci, Aviano P.Valagussa, Milano

A.Gronchi, Milano

M.Mercuri, Bologna Statistical analysis

P.Verderio, Milano

Activation September 2001



Italian Sarcoma GroupLocalized adult soft tissue sarcoma of the

extremities and trunk:Local Treatments (multiple options)

RADICAL SURGERY SEQUENTIAL APPROACH Surgery and Radiation therapy: - Post-op radiation therapy - Peri-op brachyther.& post-op RT - Pre-op radiation therapy Chemo-ipertermic perfusion and SurgeryINTEGRATED APPROACH Synchronous chemo & pre-op RT



Inclusion Criteria•Adult STS, primary or relapsed or considered inadequately locally treated.

•Spindle or polimorphous (Fibrosarcoma, MFH, Lipos., Leiomios., Synovial s., m. Schwannoma, A ngiosarcoma, Rabdomios.)

• Diagnosys in accordance with Enzinger e Weiss criteria(10).

• High grade (2-3/3, according to Coindre et al.) (11).

• Deep seated

• SITE: limbs, girdles, sup. Trunk.

• SIZE: primary >5 cm (Clinical evalutaion:CT, RM)

relapse of any size.

• Age: > 18, < 65 years.

• Performance status <1 secondo ECOG (12).

STAGE III only

1st Trial

Random

Survey

Neo-adj.

Random


Italian Trials

1st Trial

Random

Survey

Neo-adj.

Random


1st Trial

Random

Survey

Neo-adj.

Random



Integrated approach of 3 neodjuvant cyclesor 3 neoadjuvant and 2 adjuvant cycles.

Controlled prospective randomized studyClinical coordinators Coordinating and Data CenterS.Frustaci, Aviano P.Valagussa, MilanoA.Gronchi, MilanoM.Mercuri, Bologna Statistical analysis

P.Verderio, MilanoActivation September 2001


1st Trial

Random

Survey

Neo-adj.

Random



Integrated approach of 3 neodjuvant cyclesor 3 neoadjuvant and 2 adjuvant cycles.

Controlled prospective randomized studyClinical coordinators Coordinating and Data CenterS.Frustaci, Aviano P.Valagussa, MilanoA.Gronchi, MilanoM.Mercuri, Bologna Statistical analysis

P.Verderio, MilanoActivation September 2001

Local Treatments (multiple options)

RADICAL SURGERY

SEQUENTIAL APPROACH

Surgery and Radiation therapy: - Post-op radiation therapy - Peri-op brachyther.& post-op RT - Pre-op radiation therapy Chemo-ipertermic perfusion and Surgery

INTEGRATED APPROACH Synchronous chemo & pre-op RT


Study period

1st Trial

Random

06/’92

11/’96

Survey11/’96

06/’99

Neo-adj.

Random

09/’01

03/’07


Study period Pts

1st Trial

Random

06/’92

11/’96

CT: 53

FU: 51

Survey11/’96

06/’99CT: 55

Neo-adj.

Random

09/’01

03/’07

CT: 150

CT: 150


Study period Pts Selection

1st Trial

Random

06/’92

11/’96

CT: 53

FU: 51

High grade

Deep

>5cm

Limbs/girdle

Survey11/’96

06/’99CT: 55

High grade

Deep

>5cm

Limbs/girdle

Trunk

Neo-adj.

Random

09/’01

03/’07

CT: 150

CT: 150

High grade

Deep

>5cm

Limbs/girdle

Trunk


Study period

Pts Selection Treatment/m2

1st Trial

Random

06/’92

11/’96

CT: 53

FU: 51

High grade

Deep

>5cm

Limbs/girdle

EPI 60mg x2dIFO3g x3dX 5 cycles

//

Survey11/’96

06/’99CT: 55

High grade

Deep

>5cm

Limbs/girdle

Trunk

id

Neo-adj.

Random

09/’01

03/’07

CT: 150

CT: 150

emended

High grade

Deep

>5cm

Limbs/girdle

Trunk

id

3pre-op

+2 post

3pre-op


Study period

Pts Selection Treatment/m2

5-y-OS

1st Trial

Random

06/’92

11/’96

CT: 53

FU: 51

High grade

Deep

>5cm

Limbs/girdle

EPI 60mg x2dIFO3g x3dX 5 cycles

//

64%

P=0.004

46%

Survey11/’96

06/’99CT: 55

High grade

Deep

>5cm

Limbs/girdle

Trunk

id 66%

Neo-adj.

Random

10/’01

Ongoing

CT: 150

CT: 150

emended

High grade

Deep

>5cm

Limbs/girdle

Trunk

id

3pre-op

+2 post End point:

No diff.3pre-op


Topics

- Review-1st Italian randomized study - National Survey- 2nd Italian, neo-adjuvant, randomized trial- EORTC Trial - Conclusions


A systematic meta-analysis of randomized controlled trials for adjuvant

chemotherapy for localized resectable soft-tissue sarcoma

Nabeel PervaizNigel Colterjohn

Forough FarrokhyarRichard Tozer

Alvaro FigueredoMichelle Ghert

Ten years later…

• Further published RCTs

• Intensification of doxorubicin dosage and addition of ifosfamide to regimens

Objective

• To update the 1997 meta-analysis with data from subsequent published randomized controlled trials

• Increase statistical power and narrow confidence intervals

Methods: Study Identification

• Databases: Medline, EMBASE, Cochrane

• Search criteria: sarcoma, chemotherapy, randomized controlled trial

• Over 700 results

• Inclusion criteria: soft-tissue, localized, resectable, control arm: no chemotherapy, adult

• Exclusion criteria: bone sarcoma, advanced disease, no control arm, pediatric (rhabdomyoscaromca), non-randomized

Study Evaluation

• Studies evaluated by 2 independent reviewers

• Modified Detsky Quality Scale for Randomized trials

• Interobserver reliability

Outcome measures

• Local recurrence

• Distant recurrence

• Overall recurrence

• Overall survival

Background

• Sarcoma Meta-analysis Collaboration (SMAC)---originated at Hamilton Regional Cancer Centre

• Landmark publication, Lancet 1997• 14 RCTs• Results:

– Hazard ratio 0.75 (95% CI .64-0.87) for overall recurrence– Hazard radio 0.89 (95% CI 0.76-1.03)* for survival (absolute

benefit of 4%)– *not statistically significant

Statistical Methods

• Funnel plot for publication bias

• Test for heterogeneity between studies

• Pooled odds ratio

• 95% confidence intervals

• Fixed effect method (statistical control for non-analzyed variables)

Results

• 4 studies met inclusion and exclusion criteria, 385 patients

• Total 18 studies and 1953 patients

• One study: neo-adjuvant vs control (analysis performed with and without data)

• Mean follow-up 4.9 years (3.4-7.8 years)

1. Brodowicz et al, Sarcoma 2000

2. Frustaci et al, JCO 2001

3. Gortzak et al, EJC 2001

4. Petrioli et al, AJCO 2002

Local Recurrence

• 17 trials

• 1700 patients

• 296 events

• Overall hazard ratio of 0.73 (95% CI: 0.56- 0.94) in favor of chemotherapy

• Absolute risk reduction of 4% (15% vs. 19%)

Citation NTotal Treated Control PValue Effect Lower Upper

Bergonie et al 54 6 / 28 8 / 26 .43 .61 .18 2.10Brodowicz et al 59 2 / 31 6 / 28 .09 .25 .05 1.38DFCI/MGH 46 3 / 21 3 / 25 .82 1.22 .22 6.81EORTC 381 30 / 193 51 / 188 .01 .49 .30 .82Frustaci et al 104 9 / 53 11 / 51 .55 .74 .28 1.98GOG 221 20 / 112 16 / 109 .52 1.26 .62 2.59Gortzak et al 134 11 / 67 13 / 67 .65 .82 .34 1.98IGSC 86 6 / 40 8 / 46 .76 .84 .26 2.66Mayo 45 4 / 22 5 / 23 .77 .80 .18 3.47MDA 35 2 / 18 5 / 17 .18 .30 .05 1.82NCI4 25 2 / 17 4 / 8 .04 .13 .02 1.01NCI5 79 8 / 38 9 / 41 .92 .95 .32 2.78NCI6 41 0 / 21 0 / 20 .98 .95 .02 50.34Petrioli et al 88 6 / 45 9 / 43 .34 .58 .19 1.80Rizzoli et al 38 1 / 16 6 / 22 .10 .18 .02 1.66SAKK 24 0 / 12 0 / 12 1.00 1.00 .02 54.46SSG 240 19 / 121 13 / 119 .28 1.52 .71 3.23

Fixed Combined (17) 1700 129 / 855 167 / 845 .02 .73 .56 .94

0.01 0.1 1 10 100

Chemotherapy Control

Odds ratio for local recurrence

Test for heterogeneity Q=15.81, df=16, p=0.4664

Distant Recurrence

• 17 trials

• 1700 patients

• 553 events

• overall hazard ratio of 0.65 (95% CI: 0.53-0.80) in favor of chemotherapy

• Absolute risk reduction 9% (28% vs 37%)

Odds ratio for distant recurrence


Bergonie et al 54 8 / 28 14 / 26 .06 .34 .11 1.06Brodowicz et al 59 6 / 31 10 / 28 .16 .43 .13 1.41DFCI/MGH 46 6 / 21 7 / 25 .97 1.03 .28 3.73EORTC 381 51 / 193 56 / 188 .47 .85 .54 1.32Frustaci et al 104 23 / 53 26 / 51 .44 .74 .34 1.60GOG 221 21 / 112 36 / 109 .02 .47 .25 .87Gortzak et al 134 26 / 67 31 / 67 .38 .74 .37 1.46IGSC 86 4 / 40 13 / 46 .03 .28 .08 .95Mayo 45 6 / 22 6 / 23 .93 1.06 .28 3.98MDA 35 8 / 18 8 / 17 .88 .90 .24 3.41NCI4 25 4 / 17 3 / 8 .47 .51 .08 3.16NCI5 79 12 / 38 16 / 41 .49 .72 .29 1.82NCI6 41 7 / 21 10 / 20 .28 .50 .14 1.77Petrioli et al 88 7 / 45 11 / 43 .24 .54 .19 1.54Rizzoli et al 38 6 / 16 10 / 22 .62 .72 .19 2.68SAKK 24 3 / 12 4 / 12 .65 .67 .11 3.93SSG 240 41 / 121 53 / 119 .09 .64 .38 1.08

Fixed Combined (17) 1700 239 / 855 314 / 845 .00 .65 .53 .80

0.01 0.1 1 10 100



Overall Recurrence

• 18 trials

• 1747 patients

• 884 events

• Overall hazard ratio of 0.67 (95% CI: 0.56-0.82) in favor of chemotherapy

• Absolute risk reduction 10% (46% vs 56%)

Odds ratio for overall recurrence


Bergonie et al 54 11 / 28 19 / 26 .01 .24 .08 .75Brodowicz et al 59 7 / 31 12 / 28 .10 .39 .13 1.20DFCI/MGH 46 7 / 21 8 / 25 .92 1.06 .31 3.66ECOG 47 9 / 24 11 / 23 .47 .65 .20 2.09EORTC 381 92 / 193 105 / 188 .11 .72 .48 1.08Frustaci et al 104 28 / 53 32 / 51 .31 .66 .30 1.46GOG 221 52 / 112 62 / 109 .12 .66 .39 1.12Gortzak et al 134 30 / 67 35 / 67 .39 .74 .38 1.46IGSC 86 14 / 40 25 / 46 .07 .45 .19 1.08Mayo 45 12 / 22 11 / 23 .65 1.31 .41 4.23MDA 35 12 / 18 15 / 17 .13 .27 .05 1.57NCI4 25 9 / 17 5 / 8 .65 .67 .12 3.77NCI5 79 22 / 38 24 / 41 .95 .97 .40 2.38NCI6 41 9 / 21 11 / 20 .44 .61 .18 2.11Petrioli et al 88 13 / 45 20 / 43 .09 .47 .19 1.13Rizzoli et al 38 7 / 16 13 / 22 .35 .54 .15 1.98SAKK 24 4 / 12 4 / 12 1.00 1.00 .18 5.46SSG 240 65 / 121 69 / 119 .51 .84 .51 1.40

Fixed Combined (18) 1747 403 / 879 481 / 868 .00 .67 .56 .82

0.01 0.1 1 10 100



Overall Survival

• 18 trials

• 1953 patients

• 829 deaths

• overall hazard ratio of 0.77 (95% CI: 0.64-0.93) in favor of chemotherapy

• Absolute risk reduction of 6% (40% vs 46%)


Bergonie et al 65 10 / 33 18 / 32 .03 .34 .12 .94Brodowicz et al 59 1 / 31 3 / 28 .25 .28 .03 2.84DFCI/MGH 46 6 / 21 7 / 25 .97 1.03 .28 3.73ECOG 47 9 / 24 10 / 23 .68 .78 .24 2.51EORTC 467 94 / 234 96 / 233 .82 .96 .66 1.39Frustaci et al 104 20 / 53 28 / 51 .08 .50 .23 1.09GOG 225 51 / 113 55 / 112 .55 .85 .50 1.44Gortzak et al 134 22 / 67 28 / 67 .28 .68 .34 1.38IGSC 92 16 / 43 23 / 49 .35 .67 .29 1.54Mayo 57 14 / 28 12 / 29 .51 1.42 .50 4.03MDA 54 15 / 26 20 / 28 .29 .55 .18 1.69NCI4 25 9 / 17 5 / 8 .65 .67 .12 3.77NCI5 79 22 / 38 23 / 41 .87 1.08 .44 2.62NCI6 41 8 / 21 9 / 20 .65 .75 .22 2.61Petrioli et al 88 13 / 45 23 / 43 .02 .35 .15 .85Rizzoli et al 77 12 / 34 25 / 43 .05 .39 .16 .99SAKK 29 5 / 14 3 / 15 .34 2.22 .42 11.83SSG 240 57 / 121 57 / 119 .90 .97 .58 1.61

Fixed Combined (18) 1929 384 / 963 445 / 966 .01 .77 .64 .93

0.01 0.1 1 10 100


Odds ratio for overall survival


Discussion

• Additional 385 patients narrowed confidence intervals

• Overall survival became statistically significant

• Definite but minimal benefit of chemotherapy in reducing LR, DR, OR and overall survival (6% risk reduction, 40% vs 46%)

EORTC 62931

• Presented at ASCO meeting June 2007 RCT adjuvant chemo (Dox and Ifos) vs. control in resectable STS

• 351 patients recruited 1995-2003

• 5 yr RFS 52% in both groups, OS 64% (control) and 69% (chemo)

• Conclusion: “The hypotheses that adjuvant CT improves RFS and OS…can both be rejected”

EORTC 62931

• Data not available for inclusion in this analysis (authors felt that release of information would be premature)

Conclusions

• Absolute risk reductions:– Local recurrence 4%– Distant recurrence 9%– Overall recurrence 10%– Overall survival 6% (40% vs. 46%)

• Individual patient care: These real but small benefits must be weighed against the toxicities associated with intensive chemotherapy

Documents

La chemioterapia neoadiuvante e adiuvante nei sarcomi delle parti molli Padova, 30 Maggio, 2008 A.Buonadonna, CRO-Aviano