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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 (

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Presentation on theme: "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 ("— Presentation transcript:

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2 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 )

3 Quanto l'istologia influenza la chemioterapia precauzionale Argomenti in discussione - Istologia e prognosi - Storia e Ruolo della chemioterapia adiuvante - Sintesi

4 Istologia e prognosi - Storia naturale - Esperienze mono-istituzionali - Dati dalla meta-analisi

5 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 of tumours of soft tissue and bone. In: Fletcher CDM, Unni KK, Mertens F, editors. World Health Organisation classification of tumours. Lyon7 IARC Press; 2002. -- Weiss SW, Goldblum JR. In: Strauss M, editor. Enzinger and Weisss soft tissue tumors. 4th ed. St Louis (Mo)7 CV Mosby Co; 2001.

6 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 tissue sarcoma: 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 patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer 2003;97: 2530- 43. -- Gustafson P. Soft tissue sarcoma. Epidemiology and prognosis in 508 patients. Acta Orthop Scand Suppl 1994;259:1 - 31. -- Trovik CS. Local recurrence of soft tissue sarcoma. A Scandinavian Sarcoma Group Project. Acta Orthop Scand Suppl 2001;72:1 - 31.

7 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 necrosisthe 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.

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

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10 …….Significant prognostic factors for survival were: - tumor depth, - size, - presentation, - FNCLCC grade, - histotype, - radiotherapy………. Gronchi et al.J Clin Oncol 23:96-104. © 2005

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

12 …………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.

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

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15 Chemioterapia adiuvante: Meta-analisi Sarcoma 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/m 2 ADM per cycle: 50-90 mg/m 2 either as single agent or in combination

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

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

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

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

20 Chemioterapia adiuvante: Meta-analisi Sarcoma Meta-analysis Collaboration II (Lancet, 350:1647-54, 1997)

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

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

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

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

25 Chemioterapia adiuvante: Meta-analisi Sarcoma Metanalysis Collaboration III (Lancet, 350:1647-54, 1997)

26 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

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30 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 translocations diagnostically prognsotically relevant The kariotype should be evaluated in every fatty sarcoma in pts < 40 years. -The commoner sarcoma type in oldere ages lack specific aberrations

31 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.

32 Pathological and molecular genetic evaluation Liposarcoma - well differentiated - dedifferentiated - myxoid - pleiomorphic Totally 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.

33 Istologia e prognosi

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37 Fattori prognostici istologici

38 Fattori prognostici immunoistochimici

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42 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

43 Argomenti in discussione Stato dellarte della chemioterapia adiuvante Stato dellarte della chemioterapia adiuvante - Studi di 1 a generazione - Metanalisi - Studi di 2 a generazione Esperienze degli anni 2000 Esperienze degli anni 2000

44 SECOND GENERATION TRIALS I General remarks Similarities More homogeneous selection criteria Introduction of ifosfamide Use of the 2-3 active agents only Introduction of growth factors Differences Timing of radio-chemo treatment Dose-intensity

45 SECOND GENERATION TRIALS II

46 SECOND GENERATION TRIALS IV

47 SECOND GENERATION TRIALS V

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49 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 STS INCLUSION CRITERIA 4/97

50 ADJUVANT CHEMOTHERAPY IN STS EXCLUSION 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

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52 ADJUVANT CHEMOTHERAPY IN STS CHEMOTHERAPY - EPIRUBICIN 60 mg/m 2 ; day 1 and 2 - IFOSFAMIDE1.8 g/m 2 ; day 1-5 - MESNA 20% of IFO dose x 3/days, days 1-5 - HYDRATION 2000 ml/day of fluids - ANTIEMETICS (5HT 3 antagonist) x 2-3 days - G-CSF 300 g from day 8 to + 15 - Treatment repeated every 3 w., for 5 cycles 4/97

53 ADJUVANT CHEMOTHERAPY IN STS Patient characteristics

54 ADJUVANT CHEMOTHERAPY IN STS Patient characteristics

55 ADJUVANT CHEMOTHERAPY IN STS Patient characteristics

56 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 STS 1st Italian Sarcoma Group Trial: Dose intensity

57 P=0.04 ADJUVANT CHEMOTHERAPY IN STS 1st Italian Trial: Disease free survival JCO, 2001, Vol. 19, N° 5, Median F.U.=59 m

58 P = 0.03 ADJUVANT CHEMOTHERAPY IN STS 1st Italian Trial: Overall survival JCO, 2001, Vol. 19, N° 5, Median F.U.=59 m

59 The First Adjuvant I.S.G. Trial; 06/92- 11/96 Summary of performed analyses

60 Adjuvant therapy in soft tissue sarcomas ISG Study:06/92-11/96 Analysis of 09/02 Disease free survival Treat F.U. N°pts 53 51 Cens 24 19 Events 29 32 m.DFS 48.816.2 p=0.08 Median follow-up: 89.4m

61 Adjuvant therapy in soft tissue sarcomas ISG Study:06/92-11/96 Analysis of 09/02 Overall survival Treat F.U. N°pts 53 51 Cens 31 23 Events 22 28 m. OS n.r. 50.4 p=0.07 Median follow-up: 89.4m 5 years OS: 66 vs 46% (p=0.04)

62 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 Treat F.U. N°pts 46 51 Cens 28 23 Events18 28 m.Surv n.r. 54.3 p=0.038 Median follow-up: 89.4m Overall Survival

63 D.I.> 85% F.U. N°pts 18 51 Cens 13 23 Events 5 28 m.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

64 1st ISG Study: 06/92-11/96 Analysis of 09/02 Subgroup analysis: Dose intensity of chemotherapy Median follow-up: 89.4m Overall Survival

65 Adjuvant therapy in soft tissue sarcomas 1st ISG Study: 06/92-11/96 Analysis of 09/02 Post relapse survival Treat F.U. N°pts 29 32 Cens 7 4 Events29 32 m.Surv 21.8 17.8 p=0.37

66 Esperienze degli anni 2000 Report di fasi II o studi retrospettivi. Survey dellItalian Sarcoma Group. Studi randomizzati

67 Survey dellItalian 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 99 2) Prospective data collection, spontaneous referral of unregistered patients, homogeneous selection criteria and treatment modality.

68 Survey dellItalian 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: 51Trunk: 4 Size:median size 6 (range 2 - 33) Presentation: primary: 49 relapse: 6 Localization:superficial: 5 deep: 50

69 Survey dellItalian Sarcoma Group. RESULTS II - Histology:MFH 13 liposarcoma 9 LMS 8 schwannoma 7 synovial 5 others13 - Grading:Grade 3: 33Grade 4: 22

70 Chemotherapy (one cycle every 21 days) Epirubicine 60mg/m 2 /die, days 1 and 2 Ifosfamide 3g/m 2 /die, days 1, 2, 3 Mesna 1000mg/m 2 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 SURVEY

71 Evaluation of the post-trial treatment TREATMENT - Completed CT (5 cycles) 43/55 (78.2%) - Interrupted - for toxicity G3 - G4 8/55 - for other reasons 4/55

72 UPDATED RESULTS OF THE ITALIAN SURVEY Evaluation of the post-trial treatment Dose Intensity CyclesIIIIIIIV Average EPI 96.4 94.2 86.6 77.7 88.7 Range (38.1-116) (48.3-111) (43.5-106) (24-109) IFO 99.3 95.8 91.1 74.4 90.1 Range (38.1-117) (41.6-111) (26.6-105) (23-105) Median 97.9 94.8 88.2 75.0 89.4 Range (38.1-116.5) (52-111) (35.5-105.5) (23.5-105) (52 - 116)

73 UPDATED RESULTS OF THE ITALIAN SURVEY Overall Disease free Survival: comparison with CNR study(11/98)

74 UPDATED RESULTS OF THE ITALIAN SURVEY Survival: comparison with CNR study(11/98)

75 UPDATED RESULTS OF THE ITALIAN SURVEY N°pts 23 Cens 4 Events 19 m-Surv. 17.1

76 Esperienze degli anni 2000 Report di fasi II o studi retrospettivi. Survey dellItalian Sarcoma Group. Studi randomizzati - Studio EORTC - 2° Studio dellItalian Sarcoma Group

77 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 study Clinical coordinatorsCoordinating and Data Center S.Frustaci, AvianoP.Valagussa, Milano A.Gronchi, Milano M.Mercuri, BolognaStatistical analysis P.Verderio, Milano Activation November 2001

78 Option: Concurrent CT + RT

79 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 DESIGN

80 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 F unctions: normal organ functions Consent: written informed consent 2nd Italian Trial: STUDY DESIGN

81 Chemotherapy (one cycle every 21 days) Epirubicine 60mg/m 2 /die, days 1 and 2 Ifosfamide 3g/m 2 /die, days 1, 2, 3 Mesna 1000mg/m 2 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 DESIGN

82 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 DESIGN

83 Prospettive future Studio su fattori prognostici innovativi Metodologia - Revisione centralizzata dei casi trattati dallISG nei 2 studi consecutivi(159 paz.). Scopi - Definizione dellimpatto dellistologia sulla prognosi(DFS, OS) - Analisi di nuovi fattori prognostici - Correlazione con la chemioterapia(108 paz) e con la storia naturale(51pazienti)

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85 Disease free survival: 159 pts Treat F.U. N°pts 108 51 Cens 63 19 Events 45 32 m. OS n.r. 18.2 P= 0.003

86 Overall survival: 159 pts Treat F.U. N°pts 108 51 Cens 78 23 Events 30 28 m. OS 91.3 57.3 P=0.004

87 Post-relapse survival: 77 pts Treat F.U. N°pts 45 32 Cens 16 4 Events 29 28 m. OS 20.4. 17.8 P= 0.4.

88 Istologia e Chemioterapia adiuvante Ruolo ancora controverso Ruolo ancora controverso Differenti criteri di selezione portano a differenti risultati. Differenti criteri di selezione portano a differenti 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 selezione Miglioramento delle conoscenze, maggior selezione ….ruolo non ancora condiviso da tutti…… ….ruolo non ancora condiviso da tutti…… LISG non ha accettato altri studi vs. controllo LISG non ha accettato altri studi vs. controllo

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