Corso su Tumori dei tessuti molli Roma, 24-25 ottobre 2005 Lunedi 24 Ottobre 9.00-13.00 Quanto...

Corso su “ Tumori dei tessuti molli” 

Roma, 24-25 ottobre 2005 

Lunedi 24 Ottobre

9.00-13.00 

Quanto l'istologia influenza la chemioterapia precauzionale

( S. Frustaci, Aviano )

 Quanto l'istologia influenza la chemioterapia precauzionale

Argomenti in discussione- Istologia e prognosi- Storia e Ruolo della chemioterapia adiuvante- Sintesi

Istologia e prognosi

- Storia naturale

- Esperienze mono-istituzionali

- Dati dalla meta-analisi

Adult soft tissue sarcomas (STSs) of the extremities and trunk wall comprise less than 1% of all malignant tumors and consist of more than 50 histopathologic subtypes.

-- Fletcher CDM, Unni KK, Mertens FE. Pathology and genetics oftumours of soft tissue and bone. In: Fletcher CDM, Unni KK, MertensF, editors. World Health Organisation classification of tumours. Lyon7IARC Press; 2002.-- Weiss SW, Goldblum JR. In: Strauss M, editor. Enzinger and Weiss’ssoft tissue tumors. 4th ed. St Louis (Mo)7 CV Mosby Co; 2001.

Local recurrences (LRs) are seldom lethal in STS of the extremities or trunk wall, but often cause considerable morbidity and occur in up to 20% of the patients with longterm follow-up.

-- Weitz J, Antonescu CR, Brennan MF. Localized extremity soft tissuesarcoma: improved knowledge with unchanged survival over time.J Clin Oncol 2003;21:2719- 25.-- Zagars GK, Ballo MT, Pisters PW, et al. Prognostic factors for patientswith localized soft-tissue sarcoma treated with conservation surgeryand radiation therapy: an analysis of 1225 patients. Cancer 2003;97:2530- 43.-- Gustafson P. Soft tissue sarcoma. Epidemiology and prognosis in 508patients. Acta Orthop Scand Suppl 1994;259:1 - 31.-- Trovik CS. Local recurrence of soft tissue sarcoma. A ScandinavianSarcoma Group Project. Acta Orthop Scand Suppl 2001;72:1 - 31.

Despite local control, disseminated disease, most commonly as lung metastasis, develops in about one third of the patients.

A multitude of prognostic factors for metastasis in STS have been proposed, and the most consistent strong factors are tumor size, tumor depth, histological malignancy grade, presence of vascular invasion, and tumor necrosis-- Gustafson P. Soft tissue sarcoma. Epidemiology and prognosis in

508 patients. Acta Orthop Scand Suppl 1994;259:1 - 31.-- Coindre JM, Terrier P, Bui NB, et al. Prognostic factors in adult patients with locally controlled soft tissue sarcoma A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869- 77.-- Gustafson P, Akerman M, Alvegard TA, et al. Prognostic information in soft tissue sarcoma using tumour size, vascular invasion and microscopic tumour necrosis—the SIN-system. Eur J Cancer 2003;39: 1568- 76.-- Pisters PW, Leung DH, Woodruff J, et al. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996;14:1679- 89.

Gronchi et al.J Clin Oncol 23:96-104. © 2005

Gronchi et al.J Clin Oncol 23:96-104. © 2005

…….Significant prognostic factors for survival were: - tumor depth, - size, - presentation, - FNCLCC grade, - histotype, - radiotherapy……….

Gronchi et al.J Clin Oncol 23:96-104. © 2005

Eilber FC et al. Ann Surg Oncol 12:3;228, 2005

Eilber FC et al. Ann Surg Oncol 12:3;228, 2005

…………The adverse prognostic factors for primary extremity STS have been well established by numerous studies. - High histological grade, - large size, - deep location have consistently proven to be predictive of decreased disease-specific survival………

1. Brennan MF. The enigma of local recurrence. Ann Surg Oncol 1997;4:1–12.2. Pisters PWT. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996;14:1679–1689.3. Coindre J, et al. Prognostic factors in adult patients with locally controlled soft tissue sarcoma: a study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869–77.4. Lewis JJ, et al. Multifactorial analysis of long-term follow-up (more than 5 years) of primary extremity sarcoma. Arch Surg 1999;134: 190–4.5. Eilber FC, et al. Treatment induced pathologic necrosis: a predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high grade extremity soft tissue sarcomas. J Clin Oncol 2001;19:3203–9.6. Eilber FC, et al. High grade extremity soft tissue sarcomas. Factors predictive of local recurrence and its effect on morbidity and mortality. Ann Surg 2003;237:218–26.

Eilber FC et al. Ann Surg Oncol 12:3;228, 2005

Chemioterapia adiuvante: Meta-analisiSarcoma Meta-analysis Collaboration I

Lancet, 350:1647-54, 1997)

Trials evaluated: 23 - 4 not adjuvant - 1 i.a. ADM in all patients - 1 unresectable disease - 2 still open - 1 closed at 11/96 (CNR ‘92)• 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

Different characteristics of all patient included in the meta-analysis(1568)

Different characteristics of all patient included in the meta-analysis(1568)

Different characteristics of all patient included in the meta-analysis(1568)

Different characteristics of all patient included in the meta-analysis(1568)

Chemioterapia adiuvante: Meta-analisiSarcoma Meta-analysis Collaboration II

(Lancet, 350:1647-54, 1997)

Survival P value % relapse 10 years resultsTreated Controls

%abs. benefit

Local RFS 0.016 27 75 81 6

Distant RFS 0.70 30 60 70 10

Overall RFS 0.0001 25 45 55 10

OverallSurvival

0.12 / 50 54 4

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

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

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

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

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 /

Sarcoma Metanalysis Collaboration IV (Lancet, 350:1647-54, 1997)

• The metanalyis revealed that ADM based adjuvant

chemotherapy induced a clear advantage in DFS.

• Overall, there was a trend also for the OS.

• A significant (p=0.029) advantage also for the OS was observed in the subgroup (886 pts) of extremities

Chemioterapia adiuvante: Meta-analisi

Pathological and molecular gebnetic evaluation

-A significant subset of STS (in children and young adults) and the adipocytic tumours are characterised by specific chromosomal aberrations

- reciprocal translocationsdiagnosticallyprognsotically relevant

The kariotype should be evaluated in every fatty sarcoma in pts < 40 years.

-“The commoner sarcoma type in oldere ages lack specificaberrations”

Pathological and molecular genetic evaluation

For conventional histopathological examination, the most

important information to provide by the pathologist are:

- Histological subtype

- tumor size

- grade(when appropriate)

- status of resection margins.

Pathological and molecular genetic evaluation

• Liposarcoma- well differentiated- dedifferentiated - myxoid- pleiomorphicTotally different biologies, patterns of behaviour.

• Myogenic differentiation in pleiomorphic sarcomas- increased risk of metastases.

• MFH “wastebasket” category which has obscured different subtypes which different prognostic factors.

Istologia e prognosi

Fattori prognostici istologici

Fattori prognostici immunoistochimici

 Quanto l'istologia influenza la chemioterapia precauzionale

Argomenti in discussione- Istologia e prognosi- Storia e Ruolo della chemioterapia adiuvante- Sintesi

Argomenti in discussione- Istologia e prognosi- Storia e Ruolo della chemioterapia adiuvante- Sintesi

Argomenti in discussioneArgomenti in discussione

• Stato dell’arte della chemioterapia adiuvanteStato dell’arte della chemioterapia adiuvante- Studi di 1- Studi di 1aa generazione generazione- Metanalisi- Metanalisi- Studi di 2- Studi di 2aa generazione generazione

• Esperienze degli anni 2000Esperienze degli anni 2000

SECOND GENERATION TRIALS ISECOND GENERATION TRIALS I

General remarksSimilarities• More homogeneous selection criteria• Introduction of ifosfamide• Use of the 2-3 active agents only • Introduction of growth factorsDifferences• Timing of radio-chemo treatment• Dose-intensity

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 Schedulemg/m2

Time D.i mg/m2/w)

NCI92-CO21

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

Every 4 wx 5

+ G-CSF

ADM 17.5IFO 1000

EORTC62931

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

Every 3 wx 5

+ GM-CSF

ADM 25IFO 1667

RTOG95-14

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

vs control

Every 3 wx 2 + 4

+G-CSF

ADM 20IFO 2500DTIC 225

CNR ITALY

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

vs control

Every 3 wx 5

+ G-CSF

EPI 40IFO 3000

SECOND GENERATION TRIALS VSECOND GENERATION TRIALS V

Institution Status

NCI92-CO21

Closed for difficultaccrual

EORTC62931

Closed 2003

RTOG95-14

Phase II instead ofphase III

CNR ITALY

Closed at the interimanalysis of 11/96

• 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

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STSEXCLUSION CRITERIAEXCLUSION CRITERIA

•Metastatic disease•Positive lymph-nodes•Pregnancy•Previous malignancies (except ca in situ of the cervix and basal cell carcinoma of the skin)•Medical or psychiatric problem precluding to obtain a correct informed consent•Cardiovascular disease (NYHA functional status >2)•Uncontrolled bacterial or micotic disease•Patient likely to be lost to follow-up

4/97

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

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STSCHEMOTHERAPYCHEMOTHERAPY

- EPIRUBICIN 60 mg/m2; day 1 and 2

- IFOSFAMIDE 1.8 g/m2; day 1-5

- MESNA 20% of IFO dose x 3/days, days 1-5

- HYDRATION 2000 ml/day of fluids

- ANTIEMETICS (5HT3 antagonist) x 2-3 days

- G-CSF 300 g from day 8 to + 15

- Treatment repeated every 3 w., for 5 cycles

4/97

Characteristic Groups Chemot. Control TotalEntered 53 51 104M/F 33/20 28/23 61/43Age 18-39y 16 16 32

40-54y 19 19 3855-65y 18 16 34

Center of surgery Bologna 25 35 60Aviano 3 8 1Other 8 2 0Milan 8 1 9Florence 5 3 8Turin 4 2 6

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STSPatient characteristicsPatient characteristics

Characteristic Groups Chemot. Control Total Histology MHF 14 14 28 Liposa 12 9 21 Synov. 15 12 27 Other 12 16 28 Grading G3 24 22 46 G4 29 29 58 Site upper arm 14 10 24 lower arm 39 41 80 Presentation Primary

Relapse 45 8

41 10

86 18

median diameter range

10 5-18

10 2-32

10 2-32

<10 cm 25 22 47

Diameters

>10 cm 28 29 57

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STSPatient characteristicsPatient characteristics

Characteristic Groups Chemot. Control TotalStage IIIB 45 41 86

rIIIA 2 2 4rIIIB 6 8 14

Local treatment Radical surgery 19 16 35Surgery + post-op RT 25 20 45Pre-op RT + surgery 9 15 24

Stratification Primary <10 cm 20 17 37Primary >10 cm 25 24 49Relapse < 10 cm 5 5 10Relapse > 10 cm 3 5 8

ADJUVANT CHEMOTHERAPY IN STSADJUVANT CHEMOTHERAPY IN STSPatient characteristicsPatient characteristics

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 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 m

Date ofanalysis

OS DFS l-DFS d-DFS FU Comments

11/96 0.007 0.001 0.009 0.002 Stop of pts accrual due to theforeseen 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. 895 years OS: 66 vs 46% (p=0.04)

Classic Paper & CurrentComments 2002, Vol 7N°4Oncology 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

Median follow-up: 89.4m

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

Median follow-up: 89.4m

Overall Survival

0 12 24 36 48 60 72 84 96 108 1200

25

50

75

100

Control

>/=85%

p= 0.034

time (months)

per

cen

t su

rviv

ing

D.I.> 85% F.U.

N°pts 18 51Cens 13 23 Events 5 28m.Surv n.r. 54.3

p=0.034

Median follow-up: 89.4m

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

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

Median follow-up: 89.4m

Overall Survival

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

Esperienze degli anni 2000Esperienze degli anni 2000 • Report di fasi II o studi retrospettivi. • Survey dell’Italian Sarcoma Group.

• Studi randomizzati

Survey dell’Italian Sarcoma Group.

- Aims: to verify the reproducibility, efficacy, reliability of the prospective trial when applied spontaneously outside the protocol.

- Methods:1) Call for data launched in June ‘992) Prospective data collection, spontaneous referral of unregistered patients, homogeneous selection criteria and treatment modality.

Survey dell’Italian Sarcoma Group.RESULTS

• Centers: Aviano, Bologna, Firenze, Napoli, Brescia, Torino,

• Period: 11/96- 6/99

•Accrual: 55 patients,• Sex: Male: 40 Female: 15

• Median age: 46 (range 17 - 70)

• Site: Extremity: 51 Trunk: 4

• Size: median size 6 (range 2 - 33)

• Presentation: primary: 49 relapse: 6

• Localization: superficial: 5 deep: 50

Survey dell’Italian Sarcoma Group.

RESULTS II

- Histology: MFH 13 liposarcoma 9LMS 8schwannoma 7synovial 5others 13

- Grading: Grade 3: 33 Grade 4: 22

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

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

UPDATED RESULTS OF THE ITALIAN SURVEYUPDATED RESULTS OF THE ITALIAN SURVEY

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

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)

UPDATED RESULTS OF THE ITALIAN SURVEYUPDATED RESULTS OF THE ITALIAN SURVEY

Overall Disease free Survival: comparison with CNR study(11/98)

0 12 24 36 48 60 72 84 960

25

50

75

100TreatmentFollow-upSurvey

months

%D

FS

UPDATED RESULTS OF THE ITALIAN SURVEYUPDATED RESULTS OF THE ITALIAN SURVEY

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

100TREATMENTCONTTROLSURVEY

MONTHS

% O

S

UPDATED RESULTS OF THE ITALIAN SURVEYUPDATED RESULTS OF THE ITALIAN SURVEY

Figure 3: Post relapse survival

0 12 24 36 48 600

10

20

30

40

50

60

70

80

90

100

Post relapse survival of all 23 relapsed patientsMedian survival = 17.1 months

Censored

months

per

cen

t su

rviv

ing N°pts 23

Cens 4

Events 19

m-Surv. 17.1

Esperienze degli anni 2000Esperienze degli anni 2000 • Report di fasi II o studi retrospettivi. • Survey dell’Italian Sarcoma Group.

• Studi randomizzati- Studio EORTC- 2° Studio dell’Italian Sarcoma Group

Italian Sarcoma Group

Localized adult soft tissue sarcoma of the extremities and trunk:

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

Controlled prospective randomized study

Clinical coordinators Coordinating and Data CenterS.Frustaci, Aviano P.Valagussa, MilanoA.Gronchi, MilanoM.Mercuri, Bologna Statistical analysis

P.Verderio, Milano

Activation November 2001

2nd 2nd ItalianItalian Trial: STUDY DESIGN Trial: STUDY DESIGN

BBIIOOPPSSYY

SSTTAAGG I INNGG

RRAANNDDOOMMIIZZAATTIIOONN

ARM A:ARM A:3 CYCLES3 CYCLES

FFOOLLLLOOWW

UUPP

ARM B:ARM B:3 CYCLES3 CYCLES

ARM B:ARM B:2 CYCLES2 CYCLES

LLOOC.C.

TTRREEAATTMMEENNTT

Option:Concurrent CT + RT

Objectives

Primary objectives:• Overall survival• Disease Free Survival

Secondary objectives:• Response rate after the neo-adjuvant phase • Toxicity & compliance to an intensified and short program • Feasibility of the integrated approach

- chemotherapy & pre-op radiation therapy- pre-op loco-regional treatments

2nd Italian Trial: STUDY DESIGN2nd Italian Trial: STUDY DESIGN

Selection criteria• Presentation: Primary, locally relapsed, previously excised • Histology: -Fibrosa. -IFM -Liposa. -LMS -Synovial sarcoma -Schwannoma

-Angiosarcoma -RMS poli.• Site: Deep seated sarcoma of the girdles, trunk

and extremities• Dimensions: 5 cm (T2)• Grade: Grade 3 (Coindre)• Age: 18-65 years• PS: 1 ECOG• Functions: normal organ functions• Consent: written informed consent

2nd Italian Trial: STUDY DESIGN2nd Italian Trial: STUDY DESIGN

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

2nd Italian Trial: STUDY DESIGN2nd Italian Trial: STUDY DESIGN

Local Treatments (multiple options)

RADICAL SURGERY

SEQUENTIAL APPROACH• Surgery and Radiation therapy:

- Post-op radiation therapy - Perioperative brachytherapy and post-op RT- Pre-op radiation therapy

• Chemo-ipertermic perfusion and Surgery

INTEGRATED APPROACH• Synchronous chemo & pre-op radiation therapy

2nd Italian Trial: STUDY DESIGN2nd Italian Trial: STUDY DESIGN

Prospettive futureProspettive future

• Studio su fattori prognostici innovativiMetodologia- Revisione centralizzata dei casi trattati

dall’ISG nei 2 studi consecutivi(159 paz.).Scopi- Definizione dell’impatto dell’istologia sulla prognosi(DFS, OS)- Analisi di nuovi fattori prognostici- Correlazione con la chemioterapia(108

paz) e con la storia naturale(51pazienti)

Variabile X2 df p X2 df p X2 df p X2 df p- X2 df p

sesso 0,5105 1 0,4749 1,4999 1 0,2207 0,3107 1 0,577 0,157 1 0,692 0,3148 1 0,5747Centro 3,3985 3 0,3342 4,9396 3 0,1763 4,6925 3 0,196 2,01 3 0,57 3,8885 3 0,2738Istologia 9,3108 3 0,0254 4,5532 3 0,2076 6,2611 3 0,1 9,348 3 0,025 3,1796 3 0,3648Grading 2,2628 1 0,1325 7,4198 1 0,0065 0,2884 1 0,591 0,142 1 0,706 4,676 1 0,0306Site 0,0004 1 0,9845 0,2656 1 0,6063 0,0896 1 0,765 0,014 1 0,906 0,4705 1 0,4927Present 0,0004 1 0,9839 0,0578 1 0,8101 0,3059 1 0,58 0,613 1 0,434 0,4943 1 0,482Max Diam 1,3524 1 0,2449 0,7168 1 0,3972 2,7852 1 0,095 2,894 1 0,089 1,5496 1 0,2132Sede 0,4004 1 0,5269 2,9723 1 0,0847 1,1802 1 0,277 0,385 1 0,535 0,1568 1 0,6921Loct 3,4126 2 0,1815 2,476 2 0,29 10,1465 2 0,006 5,064 2 0,08 1,5482 2 0,4611RT 1,6005 1 0,2058 0,0002 1 0,9897 4,2937 1 0,038 2,786 1 0,095 0,0087 1 0,9258Dos Int 5,5771 2 0,0615 3,8354 2 0,1469 1,846 2 0,397 8,394 2 0,015 2,4712 2 0,2907

postdfs loc dfs dis dfs surv

0 12 24 36 48 60 72 84 96 1081200

25

50

75

100

Chemo

Control

Time

Disease free survival: 159 pts

Treat F.U.

N°pts 108 51Cens 63 19Events 45 32 m. OS n.r. 18.2

P= 0.003

Overall survival: 159 pts

Treat F.U.

N°pts 108 51 Cens 78 23 Events 30 28m. OS 91.3 57.3

P=0.004 0 12 24 36 48 60 72 84 96 108

0

25

50

75

100

Control

Chemo

Time

Post-relapse survival: 77 pts

0 12 24 36 48 600

25

50

75

100

chemo

control

time

Treat F.U.

N°pts 45 32Cens 16 4Events 29 28m. OS 20.4. 17.8

P= 0.4.

Istologia e Chemioterapia adiuvanteIstologia e Chemioterapia adiuvante• Ruolo ancora controverso Ruolo ancora controverso • Differenti criteri di selezione portano a differenti Differenti criteri di selezione portano a differenti

risultati.risultati.

• Possibili fattori confondenti non ancora noti.Possibili fattori confondenti non ancora noti.

• Differenti approcci alla malattia locale, Differenti approcci alla malattia locale,

• Miglioramento delle conoscenze, maggior selezioneMiglioramento delle conoscenze, maggior selezione

• … ….ruolo non ancora condiviso da tutti…….ruolo non ancora condiviso da tutti……

• L’ISG non ha accettato altri studi vs. controlloL’ISG non ha accettato altri studi vs. controllo