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

2. Topics - Review -1 st Italian randomized study - National Survey - 2 nd Italian, neo-adjuvant, randomized trial - EORTC Trial - Conclusions Adjuvant chemotherapy in STS

3. 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 cancer staging handbook, 6th edn. Berlin, Heidelberg, New York: Springer.

4. Chemioterapia adiuvante: Studi di I a generazione(1)

5. Chemioterapia adiuvante: Studi di I a generazione(2)

6. 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

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

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

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

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

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

12. SECOND GENERATION TRIALS II

13. SECOND GENERATION TRIALS IV

14. SECOND GENERATION TRIALS Similarities More homogeneous selection criteria Use of Ifosphamide 2 drugs combinations Use of Growth factors Differences Dose intensity Sequence of approaches( S/RT/CT)

15. Topics - Review -1 st Italian randomized study - National Survey - 2 nd Italian, neo-adjuvant, randomized trial -EORTC Trial - Conclusions Controversy: Adjuvant chemotherapy in STS

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

18. 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

19. 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 haematological recovery Adequate dose modifications according to the nadirs 1ST ITALIAN ADJUVANT STUDY

20. 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

21. P=0.04 ADJUVANT CHEMOTHERAPY IN STS 1st Italian Trial: Disease free survival JCO, 2001, Vol. 19, N° 5, Median F.U.=59 m Minimum F.U.=36 m

22. P = 0.03 ADJUVANT CHEMOTHERAPY IN STS 1st Italian Trial: Overall survival JCO, 2001, Vol. 19, N° 5, Median F.U.=59 m Minimum F.U.=36 m

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

24. 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

25. 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)

26. 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

27. 1st ISG Study: 06/’92-11/’96 Analysis of 09/02 Subgroup analysis: Dose intensity of chemotherapy Median follow-up: 89.4m Overall Survival

28. 1st ISG Study: 06/’92-11/’96 Analysis of 09/02 Subgroup analysis: Dose intensity of chemotherapy Median follow-up: 89.4m 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

29. 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

30. Topics - Review -1 st Italian randomized study - National Survey - 2 nd Italian, neo-adjuvant, randomized trial -EORTC Trial - Conclusions Controversy: Adjuvant chemotherapy in STS

31. 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 ‘99 2) Prospective data collection, spontaneous referral of unregistered patients, homogeneous selection criteria and treatment modality.

32. 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

33. 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

34. UPDATED RESULTS OF THE ITALIAN SURVEY 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)

35. UPDATED RESULTS OF THE ITALIAN SURVEY Survival: comparison with CNR study(11/98) 01224364860728496 0 10 20 30 40 50 60 70 80 90 100 TREATMENT CONTROL SURVEY MONTHS % OS

36. Topics - Review -1 st Italian randomized study - National Survey - 2 nd Italian, neo-adjuvant, randomized trial -EORTC Trial - Conclusions Controversy: Adjuvant chemotherapy in STS

37. 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 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 Controversy: Adjuvant chemotherapy in STS

38. Italian Sarcoma Group Localized 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 Surgery  INTEGRATED APPROACH Synchronous chemo & pre-op RT

39. Controversy: Adjuvant chemotherapy in STS Localized adult soft tissue sarcoma of the extremities and trunk: Inclusion Criteria Adult STS, primary or relapsed or considered inadequately locally treated. Spindle or polimorphous (Fibrosarcoma, MFH, Lipos., Leiomios., Synovial s., m. Schwannoma, Angiosarcoma, 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

40. 1st Trial Random Survey Neo-adj. Random Controversy: Adjuvant chemotherapy in STS Italian Trials

41. 1st Trial Random Survey Neo-adj. Random Controversy: Adjuvant chemotherapy in STS

42. 1st Trial Random Survey Neo-adj. Random 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 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 Controversy: Adjuvant chemotherapy in STS

43. 1st Trial Random Survey Neo-adj. Random 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 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 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 Controversy: Adjuvant chemotherapy in STS

44. Study period 1st Trial Random 06/’92 11/’96 Survey 11/’96 06/’99 Neo-adj. Random 09/’01 03/’07 Controversy: Adjuvant chemotherapy in STS

45. Study periodPts 1st Trial Random 06/’92 11/’96 CT: 53 FU: 51 Survey 11/’96 06/’99 CT: 55 Neo-adj. Random 09/’01 03/’07 CT: 150 Controversy: Adjuvant chemotherapy in STS

46. Study periodPtsSelection 1st Trial Random 06/’92 11/’96 CT: 53 FU: 51 High grade Deep >5cm Limbs/girdle Survey 11/’96 06/’99 CT: 55 High grade Deep >5cm Limbs/girdle Trunk Neo-adj. Random 09/’01 03/’07 CT: 150 High grade Deep >5cm Limbs/girdle Trunk Controversy: Adjuvant chemotherapy in STS

47. Study period PtsSelectionTreatment /m2 1st Trial Random 06/’92 11/’96 CT: 53 FU: 51 High grade Deep >5cm Limbs/girdle EPI 60mg x2d IFO3g x3d X 5 cycles // Survey 11/’96 06/’99 CT: 55 High grade Deep >5cm Limbs/girdle Trunk id Neo-adj. Random 09/’01 03/’07 CT: 150 emended High grade Deep >5cm Limbs/girdle Trunk id 3pre-op +2 post 3pre-op Controversy: Adjuvant chemotherapy in STS

48. Study period PtsSelectionTreatment /m2 5-y-OS 1st Trial Random 06/’92 11/’96 CT: 53 FU: 51 High grade Deep >5cm Limbs/girdle EPI 60mg x2d IFO3g x3d X 5 cycles // 64% P=0.004 46% Survey 11/’96 06/’99 CT: 55 High grade Deep >5cm Limbs/girdle Trunk id66% Neo-adj. Random 10/’01 Ongoing CT: 150 emended High grade Deep >5cm Limbs/girdle Trunk id 3pre-op +2 post End point: No diff. 3pre-op Controversy: Adjuvant chemotherapy in STS

49. Topics - Review -1 st Italian randomized study - National Survey - 2 nd Italian, neo-adjuvant, randomized trial - EORTC Trial - Conclusions Controversy: Adjuvant chemotherapy in STS

63. A systematic meta-analysis of randomized controlled trials for adjuvant chemotherapy for localized resectable soft-tissue sarcoma Nabeel Pervaiz Nigel Colterjohn Forough Farrokhyar Richard Tozer Alvaro Figueredo Michelle Ghert

64. Ten years later… Further published RCTs Intensification of doxorubicin dosage and addition of ifosfamide to regimens

65. Objective To update the 1997 meta-analysis with data from subsequent published randomized controlled trials Increase statistical power and narrow confidence intervals

66. 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

67. Study Evaluation Studies evaluated by 2 independent reviewers Modified Detsky Quality Scale for Randomized trials Interobserver reliability

68. Outcome measures Local recurrence Distant recurrence Overall recurrence Overall survival

69. 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

70. 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)

71. 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)

72. 1.Brodowicz et al, Sarcoma 2000 2.Frustaci et al, JCO 2001 3.Gortzak et al, EJC 2001 4.Petrioli et al, AJCO 2002

73. 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%)

74. Odds ratio for local recurrence Test for heterogeneity Q=15.81, df=16, p=0.4664

75. 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%)

76. Odds ratio for distant recurrence Test for heterogeneity Q=7.8451, df=16, p=0.9533

77. 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%)

78. Odds ratio for overall recurrence Test for heterogeneity Q=10.2308, df=17, p=0.8937

79. 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%)

80. Odds ratio for overall survival Test for heterogeneity Q=15.9325, df=17, p=0.5286

81. 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%)

82. 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”

83. EORTC 62931 Data not available for inclusion in this analysis (authors felt that release of information would be premature)

84. 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