Alberto Pappo, MD, St. Jude Children’s Hospital, Memphis TN Presented at the 2010 Texas Adolescent and Young Adult Oncology Conference hosted by Methodist Healthcare-San Antonio. October 2010.

1. Soft Tissue Sarcomas in Adolescents and Young Adults Alberto S. Pappo, M.D. St Jude Children’s Research Hospital Memphis, TN

2. Childhood Soft Tissue Sarcomas 7% RMS NRSTS

3. Relative frequency of common cancer types in 15-39 yr olds 1992-2002 (Bleyer Nat Cancer Rev april 2008)

6. Histologic subtypes of STS by age group

8. RMS vs NRSTS NRSTS Age > 10 Extremities Resected (70%) Many histologic types Chemorresistant Unproven benefit of adjuvant therapy Metastases: lung; other sites are rare RX:If/Dox; Targeted therapies RMS Age < 10 HN Unresected (50%) Two histologic types Chemosensitive Adjuvant therapy is effective Metastases: lung, bone, bone marrow Rx: Risk based-VAC

9. Classification of sarcomas SpecificVariable

10. Classification of sarcomas

11. Rhabdomyosarcoma Most common pediatric STS Heterogeneous, poor survival Collaboration in 1972 CCSG CALGB SWOG Over 4800 patients treated in 4 consecutive trials IRS (STS-COG)

12. Survival in RhabdomyosarcomaThree Decades of Progress IRS-IV IRS-III IRS-II IRS-I Pre Cooperative Group

13. Histologic Subtypes of RMS Embryonal Alveolar

14. Fusion positive vs Fusion negative ARMS

15. Risk-Assignment in RMS Low: ~ 35% of RMS Favorable histology, site and lower Group/stage Intermediate: ~ 50% Non met ARMS Embryonalunresected and met < 10 yr High: ~ 15% of RMS Remaining metastatic disease 1.0 Low 0.8 Intermediate 0.6 Proportion FFS 0.4 High 0.2 0.0 8 10 0 2 4 6 Years

16. Intermediate Risk RMS FFS for patients with intermediate risk RMS has not improved 1.0 0.9 IRS-III (1984-1991) 0.8 0.7 IRS-IV (1991-1997) 0.6 Failure-Free Survival 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 Years

17. Survival of Patients with Metastatic RMS in IRS-III, IRS-IVP, and IRS IV (1984-1997) 1.0 0.9 0.8 0.7 0.6 Survival 0.5 0.4 IRS-III IRS-IVP 0.3 IRS-IV 0.2 p=0.61 0.1 0.0 0 1 2 3 4 5 Time

19. Incidence and survival of RMS 1975-2005

20. Outcome of adult RMS

21. Estimated % of pts with STS and bone sarcomas enrolled on clinical trials by age 1997-2002 Cancer 103:1891, 2005

22. Average annual change in 5 yr survival compared to accrual on national trails 1997-2002

24. Intermediate Risk RMS FFS for patients with intermediate risk RMS has not improved 1.0 0.9 IRS-III (1984-1991) 0.8 0.7 IRS-IV (1991-1997) 0.6 Failure-Free Survival 0.5 0.4 D 9803 7% > 18 yrs 0.3 0.2 0.1 0.0 0 1 2 3 4 5 Years

25. NRSTS

26. Incidence of RMS and NRSTS Differs by Age Group SEER Program 1975-1995, NCI

27. NRSTS Histologic Subtypes J Pediatr Surg 35:948, 2000

28. IFS with KMS

29. Infantile HPC

30. Pediatric GIST

31. Mutational status 7/65 (11%) KIT or PDGFR mutation- 6/7 males Kit exons 11 and 9 3/7 PDGFR

32. KIT mutant GIST Pediatric WT GIST IGF1R Actin

34. Synovial sarcoma survival

35. ARST 0332

36. NRSTS: “not chemo-sensitive”

38. 5 yr

39. 306 pts

40. Accrual on target

42. Increasing cure rates and “shrinking populations”

43. How will we design new studies?

44. The biospecimen “gap”Tumor bank specimens vs. incidence of cancer as a function of patient age

45. Combination therapy-why and which agents? One year, Dr. Flaherty thought, when he heard the news. Certainly no triumph. But it was something. Something to be built on. ''We just need,'' Dr. Flaherty said, ''to find the right combination.''

46. “The list”

47. The Combinations Problem in Cancer: Rhabdo as an example

48. Incorporation of targeted therapies will improve the outcome of rhabdomyosarcoma: ARST08P1 - PI Suman Malempati * * * * * * Dexrazoxane with all Doxorubicin cycles # IMC-A12 held during XRT (Pilots 1 and 3)

50. SARC 011 (R1507) trial 12/2007-8/09 111 eligible patients Age: 9-78 (median 26) 20% ≤ 18 yr 73 M; 81 W Bone (n=60) Primary (n=67); Secondary (n=44)

51. Best Recorded Variation in Tumor Size: Ewing’s Cohorts

53. Conclusions STS account for 7-8% of cancers in AYA Clinical trial enrollment suboptimal Sample acquisition suboptimal Progress stalled Cooperation between adult and pediatric groups essential Consortia to study specific diseases