The document discusses soft tissue sarcomas (STS) in adolescents and young adults, highlighting the relative frequencies, histologic subtypes, treatment approaches, and survival outcomes for specific types, particularly rhabdomyosarcoma (RMS). It emphasizes the challenges in clinical trial enrollment and the need for collaboration between adult and pediatric oncology to improve treatment efficacy and outcomes. The piece addresses the importance of targeted therapies and ongoing research efforts to enhance understanding and treatment of these cancers.

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

2. Childhood Soft Tissue Sarcomas7%RMSNRSTS

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 NRSTSNRSTSAge > 10ExtremitiesResected (70%)Many histologic typesChemorresistantUnproven benefit of adjuvant therapy Metastases: lung; other sites are rareRX:If/Dox; Targeted therapiesRMSAge < 10HNUnresected (50%)Two histologic typesChemosensitiveAdjuvant therapy is effectiveMetastases: lung, bone, bone marrowRx: Risk based-VAC

9. Classification of sarcomasSpecificVariable

10. Classification of sarcomas

11. RhabdomyosarcomaMost common pediatric STS Heterogeneous, poor survivalCollaboration in 1972 CCSGCALGBSWOG Over 4800 patients treated in 4 consecutive trialsIRS (STS-COG)

12. Survival in RhabdomyosarcomaThree Decades of ProgressIRS-IVIRS-IIIIRS-IIIRS-IPreCooperativeGroup

13. Histologic Subtypes of RMSEmbryonalAlveolar

14. Fusion positive vs Fusion negative ARMS

15. Risk-Assignment in RMSLow: ~ 35% of RMSFavorable histology, site and lower Group/stageIntermediate: ~ 50%Non met ARMSEmbryonalunresected and met < 10 yr High: ~ 15% of RMSRemaining metastatic disease1.0Low0.8Intermediate0.6Proportion FFS0.4High0.20.08100246Years

16. Intermediate Risk RMSFFS for patients with intermediate risk RMS has not improved1.00.9IRS-III (1984-1991)0.80.7IRS-IV (1991-1997)0.6Failure-Free Survival0.50.40.30.20.10.0012345Years

17. Survival of Patients with Metastatic RMS in IRS-III, IRS-IVP, and IRS IV(1984-1997)1.00.90.80.70.6 Survival0.50.4IRS-IIIIRS-IVP0.3IRS-IV0.2p=0.610.10.0012345 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 1997-2002Cancer 103:1891, 2005

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

24. Intermediate Risk RMSFFS for patients with intermediate risk RMS has not improved1.00.9IRS-III (1984-1991)0.80.7IRS-IV (1991-1997)0.6Failure-Free Survival0.50.4D 9803 7% > 18 yrs0.30.20.10.0012345Years

25. NRSTS

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

27. NRSTS Histologic SubtypesJ Pediatr Surg 35:948, 2000

28. IFS with KMS

29. Infantile HPC

30. Pediatric GIST

31. Mutational status7/65 (11%) KIT or PDGFR mutation-6/7 males Kit exons 11 and 9 3/7 PDGFR

32. KIT mutant GISTPediatric WT GISTIGF1RActin

34. Synovial sarcoma survival

35. ARST 0332

36. NRSTS: “not chemo-sensitive”

37. ARST0332865 pts

38. 5 yr

39. 306 pts

40. Accrual on target

41. 7% > 20 yrSarcomas comprise many diseases and molecular genotypesRhabdomyosarcomaEmbryonal Alveolar FGFR4 mutated

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) trial12/2007-8/09111 eligible patientsAge: 9-78 (median 26) 20% ≤ 18 yr73 M; 81 WBone (n=60)Primary (n=67); Secondary (n=44)