Soft Tissue Sarcomas

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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.

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Soft Tissue Sarcomas

  1. 1. Soft Tissue Sarcomas in Adolescents and Young Adults <br />Alberto S. Pappo, M.D.<br />St Jude Children’s Research Hospital<br />Memphis, TN<br />
  2. 2. Childhood Soft Tissue Sarcomas<br />7%<br />RMS<br />NRSTS<br />
  3. 3. Relative frequency of common cancer types in 15-39 yr olds 1992-2002 (Bleyer Nat Cancer Rev april 2008)<br />
  4. 4.
  5. 5.
  6. 6. Histologic subtypes of STS by age group<br />
  7. 7.
  8. 8. RMS vs NRSTS<br />NRSTS<br />Age > 10<br />Extremities<br />Resected (70%)<br />Many histologic types<br />Chemorresistant<br />Unproven benefit of adjuvant therapy <br />Metastases: lung; other sites are rare<br />RX:If/Dox; Targeted therapies<br />RMS<br />Age < 10<br />HN<br />Unresected (50%)<br />Two histologic types<br />Chemosensitive<br />Adjuvant therapy is effective<br />Metastases: lung, bone, bone marrow<br />Rx: Risk based-VAC<br />
  9. 9. Classification of sarcomas<br />SpecificVariable<br />
  10. 10. Classification of sarcomas<br />
  11. 11. Rhabdomyosarcoma<br />Most common pediatric STS <br />Heterogeneous, poor survival<br />Collaboration in 1972 <br />CCSG<br />CALGB<br />SWOG <br />Over 4800 patients treated in 4 consecutive trials<br />IRS (STS-COG)<br />
  12. 12. Survival in RhabdomyosarcomaThree Decades of Progress<br />IRS-IV<br />IRS-III<br />IRS-II<br />IRS-I<br />Pre<br />Cooperative<br />Group<br />
  13. 13. Histologic Subtypes of RMS<br />Embryonal<br />Alveolar<br />
  14. 14. Fusion positive vs Fusion negative ARMS<br />
  15. 15. Risk-Assignment in RMS<br />Low: ~ 35% of RMS<br />Favorable histology, site and lower Group/stage<br />Intermediate: ~ 50%<br />Non met ARMS<br />Embryonalunresected and met < 10 yr <br />High: ~ 15% of RMS<br />Remaining metastatic disease<br />1.0<br />Low<br />0.8<br />Intermediate<br />0.6<br />Proportion FFS<br />0.4<br />High<br />0.2<br />0.0<br />8<br />10<br />0<br />2<br />4<br />6<br />Years<br />
  16. 16. Intermediate Risk RMS<br />FFS for patients with intermediate risk RMS has not improved<br />1.0<br />0.9<br />IRS-III (1984-1991)<br />0.8<br />0.7<br />IRS-IV (1991-1997)<br />0.6<br />Failure-Free Survival<br />0.5<br />0.4<br />0.3<br />0.2<br />0.1<br />0.0<br />0<br />1<br />2<br />3<br />4<br />5<br />Years<br />
  17. 17. Survival of Patients with Metastatic RMS <br />in IRS-III, IRS-IVP, and IRS IV<br />(1984-1997)<br />1.0<br />0.9<br />0.8<br />0.7<br />0.6<br /> Survival<br />0.5<br />0.4<br />IRS-III<br />IRS-IVP<br />0.3<br />IRS-IV<br />0.2<br />p=0.61<br />0.1<br />0.0<br />0<br />1<br />2<br />3<br />4<br />5<br /> Time<br />
  18. 18.
  19. 19. Incidence and survival of RMS 1975-2005<br />
  20. 20. Outcome of adult RMS<br />
  21. 21. Estimated % of pts with STS and bone sarcomas enrolled on clinical trials by age 1997-2002<br />Cancer 103:1891, 2005<br />
  22. 22. Average annual change in 5 yr survival compared to accrual on national trails <br />1997-2002<br />
  23. 23.
  24. 24. Intermediate Risk RMS<br />FFS for patients with intermediate risk RMS has not improved<br />1.0<br />0.9<br />IRS-III (1984-1991)<br />0.8<br />0.7<br />IRS-IV (1991-1997)<br />0.6<br />Failure-Free Survival<br />0.5<br />0.4<br />D 9803 7% > 18 yrs<br />0.3<br />0.2<br />0.1<br />0.0<br />0<br />1<br />2<br />3<br />4<br />5<br />Years<br />
  25. 25. NRSTS<br />
  26. 26. Incidence of RMS and NRSTS Differs by Age Group<br />SEER Program 1975-1995, NCI<br />
  27. 27. NRSTS Histologic Subtypes<br />J Pediatr Surg 35:948, 2000<br />
  28. 28. IFS with KMS<br />
  29. 29. Infantile HPC<br />
  30. 30. Pediatric GIST<br />
  31. 31. Mutational status<br />7/65 (11%) KIT or PDGFR mutation-<br />6/7 males <br />Kit exons 11 and 9 <br />3/7 PDGFR<br />
  32. 32. KIT mutant GIST<br />Pediatric WT GIST<br />IGF1R<br />Actin<br />
  33. 33.
  34. 34. Synovial sarcoma survival<br />
  35. 35. ARST 0332<br />
  36. 36. NRSTS: “not chemo-sensitive”<br />
  37. 37. ARST0332<br /><ul><li>865 pts
  38. 38. 5 yr
  39. 39. 306 pts
  40. 40. Accrual on target
  41. 41. 7% > 20 yr</li></li></ul><li>Sarcomas comprise many diseases and molecular genotypes<br />Rhabdomyosarcoma<br />Embryonal<br /> Alveolar<br /> FGFR4 mutated<br />
  42. 42. Increasing cure rates and “shrinking populations” <br />
  43. 43. How will we design new studies? <br />
  44. 44. The biospecimen “gap”Tumor bank specimens vs. incidence of cancer as a function of patient age<br />
  45. 45. Combination therapy-why and which agents?<br />One year, Dr. Flaherty thought, when he heard the news. Certainly no triumph. But it was something. Something to be built on.<br />''We just need,'' Dr. Flaherty said, ''to find the right combination.'' <br />
  46. 46. “The list”<br />
  47. 47. The Combinations Problem in Cancer: Rhabdo as an example<br />
  48. 48. Incorporation of targeted therapies will improve the outcome of rhabdomyosarcoma: ARST08P1 - PI Suman Malempati<br />*<br />*<br />*<br />*<br />*<br />* Dexrazoxane with all Doxorubicin cycles<br /># IMC-A12 held during XRT (Pilots 1 and 3)<br />
  49. 49.
  50. 50. SARC 011 (R1507) trial<br />12/2007-8/09<br />111 eligible patients<br />Age: 9-78 (median 26)<br /> 20% ≤ 18 yr<br />73 M; 81 W<br />Bone (n=60)<br />Primary (n=67); Secondary (n=44)<br />
  51. 51. Best Recorded Variation in Tumor Size: Ewing’s Cohorts <br />
  52. 52.
  53. 53. Conclusions<br />STS account for 7-8% of cancers in AYA<br />Clinical trial enrollment suboptimal<br />Sample acquisition suboptimal<br />Progress stalled<br />Cooperation between adult and pediatric groups essential<br />Consortia to study specific diseases<br />

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