1. Treatment of Relapsed Osteosarcoma After Contemporary Therapy: The Memorial Sloan-Kettering Experience Chou AJ, Merola PR, Vyas Y, Wexler L, Gorlick R, LaQuaglia M, Healey J, Huvos A, Meyers PA

2. Scope of the Problem > 400 new pediatric cases of OS / year > 400 new pediatric cases of OS / year survival for localized disease > 70% survival for localized disease > 70% < 20% for recurrent disease < 20% for recurrent disease optimal strategy for recurrent disease is undefined optimal strategy for recurrent disease is undefined

3. Treatment for Recurrent OS

4. Study Objective To determine the outcome for patients with recurrent OS who were treated at MSKCC after 1 st relapse (R1) To determine the outcome for patients with recurrent OS who were treated at MSKCC after 1 st relapse (R1)

5. Study Description Retrospective chart review Retrospective chart review Eligibility criteria: Eligibility criteria: biopsy proven high grade osteosarcoma biopsy proven high grade osteosarcoma documented CR after receiving “contemporary” therapy = surgery + chemotherapy [HD MTX, CDDP, DOX, + IFOS] documented CR after receiving “contemporary” therapy = surgery + chemotherapy [HD MTX, CDDP, DOX, + IFOS] tx for R1 at MSKCC after 1990 tx for R1 at MSKCC after 1990 Definitions: Definitions: RFS = time from CR2 to either R2 or death from any cause RFS = time from CR2 to either R2 or death from any cause RFS=0 if never achieved CR2 RFS=0 if never achieved CR2 Overall-survival = time from 1 st relapse to death from any cause Overall-survival = time from 1 st relapse to death from any cause RFI = time from initial diagnosis to 1 st relapse RFI = time from initial diagnosis to 1 st relapse

6. Patient Characteristics N=43 N=43 Males = 27 (63%) Males = 27 (63%) Females = 16 (37%) Females = 16 (37%) median age at primary Dx = 15 y (4.5 – 31.4) median age at primary Dx = 15 y (4.5 – 31.4) primary extremity tumors = 38 (88%) primary extremity tumors = 38 (88%) primary axial tumors = 5 (12%) primary axial tumors = 5 (12%) metastases at primary diagnosis = 10 (23%) metastases at primary diagnosis = 10 (23%)

7. Median time to 1 st relapse < 24 months after diagnosis median time to 1 st relapse = 21.7 months (4.6 – 135.7) from primary dx median time to 1 st relapse = 21.7 months (4.6 – 135.7) from primary dx # achieved CR2 = 26 / 43 (60%) # achieved CR2 = 26 / 43 (60%)

8. Lungs are the most common sites of relapse Sites of relapse Sites of relapse lungs alone = 22 lungs alone = 22 unilateral = 13 unilateral = 13 bilateral = 9 bilateral = 9 multiple nodules = 13 multiple nodules = 13 solitary nodules = 9 solitary nodules = 9 local = 6 local = 6 bone = 14 bone = 14 lung + other = 11 lung + other = 11 soft tissue (incl. liver) = 3 soft tissue (incl. liver) = 3

9. 35% Crude Overall Survival Total alive = 15 / 43 (35%)* Total alive = 15 / 43 (35%)* Alive with disease = 4 Alive with disease = 4 Alive without disease = 11 Alive without disease = 11 Median Follow-Up after R1 = 15.2 months (0.7- 158.3) Median Follow-Up after R1 = 15.2 months (0.7- 158.3) Survival at Median Follow-Up after R1 = 26 / 43 (60.5%) Survival at Median Follow-Up after R1 = 26 / 43 (60.5%) *as of July 2004

10. Overall Survival from 1 st Relapse Time (months) Proportion Surviving

11. Progressive disease is the most common cause of death after 1 st relapse Causes of death: Causes of death: progressive OS = 23 progressive OS = 23 sepsis = 2 (1 in CR) sepsis = 2 (1 in CR) ARDS = 2 (1 in CR) ARDS = 2 (1 in CR) 2 o AML/MDS = 1 (in CR) 2 o AML/MDS = 1 (in CR)

12. Survival correlated with RFI > 24 months and achievement of CR2 RFI > 24 months = 9/17 (53%) RFI > 24 months = 9/17 (53%) Achieving CR2 = 15/26 (58%) Achieving CR2 = 15/26 (58%) Lungs – unilateral = 7/13 (54%) Lungs – unilateral = 7/13 (54%) Lungs – solitary = 5/9 (56%) Lungs – solitary = 5/9 (56%) RFI < 24 months = 6/26 (23%)* Not achieving CR2 = 0/17 (0%)* Lungs – bilateral = 2/9 (22%) Lungs – multiple = 4/13 (31%) * p<0.05

13. Treatment Strategies for R1 Surgery alone = 4 Surgery alone = 4 2/4 relapsed after CR2 2/4 relapsed after CR2 overall survival = 3/4 overall survival = 3/4 Chemotherapy alone = 7 Chemotherapy alone = 7 overall survival = 0/7 overall survival = 0/7 Chemotherapy + Surgery = 32 Chemotherapy + Surgery = 32 For those +CR2, 11/22 relapsed For those +CR2, 11/22 relapsed overall survival = 12/32 overall survival = 12/32

14. Multiple chemotherapeutic strategies were utilized in 1 st relapse Ifosfamide / Etoposide Ifosfamide / Etoposide Cisplatin / Doxorubicin Cisplatin / Doxorubicin HD Methotrexate HD Methotrexate HD Cyclophosphamide HD Cyclophosphamide Irinotecan Irinotecan Gemcitabine + Docetaxel Gemcitabine + Docetaxel Mitoxantrone Mitoxantrone Cyclophosphamide / Topotecan Carboplatin 5-Flourouracil Thioguanine Other agents (trimetrexate, ET-743, STI571, trastuzumab, Dx- 8951f, interferon/VP16, Gm-CSF)

15. Chemo + Surg (n=32): Overall Survival since R1

16. Chemo + Surg (n=32): Relapse Free Survival since R1

17. For Chemo + Surg: regimens +IFOS confer advantage in preventing 2 nd relapse 23 patients received IFOS as part of R1 treatment 23 patients received IFOS as part of R1 treatment CR2 = 18 CR2 = 18 R2 = 8 R2 = 8 9 patients did not receive IFOS as part of R1 treatment 9 patients did not receive IFOS as part of R1 treatment CR2 = 4 CR2 = 4 R2=3 R2=3

18. +IFOS (n=23) vs. -IFOS (n=9) regimens: Relapse Free Survival after R1 =+Ifos =-Ifos

19. HD IFOS (n=22) vs. all other chemo regimens (n=10): Overall Survival after R1 =HD Ifos =other

20. Conclusions Chemotherapy with curative-intent surgery can successfully salvage 22/32 of patients at 1 st relapse  9/32 remain NED. Chemotherapy with curative-intent surgery can successfully salvage 22/32 of patients at 1 st relapse  9/32 remain NED. Chemotherapy regimens containing ifosfamide appear to confer an advantage in preventing a 2 nd relapse. Chemotherapy regimens containing ifosfamide appear to confer an advantage in preventing a 2 nd relapse.

21. Paul A. Meyers, MD Paul A. Meyers, MD Pediatric Sarcoma Team Pediatric Sarcoma Team Leonard H. Wexler, MD Leonard H. Wexler, MD Richard Gorlick, MD Richard Gorlick, MD Pamela R. Merola, MD Pamela R. Merola, MD Yatin Vyas, MD Yatin Vyas, MD Karen Allison, CPNP Karen Allison, CPNP Jamie Viccola, CPNP Jamie Viccola, CPNP Stephanie Vitolano, CPNP Stephanie Vitolano, CPNP Surgical Team Michael P. LaQuaglia, MD John H. Healey, MD Andrew G. Huvos, MD

24. DFS For HD IFOS group: IFOS naïve (n=19) vs. IFOS exposed (n=3) =IFOS naive =IFOS exposed

25. From Hawkins et al, Cancer 2003 Comparison of DFS =chemo + surg =surg Time (months) Proportion Surviving

26. From Hawkins et al, Cancer 2003 Comparison of Overall Survival Time (months) Proportion Surviving