1. Clinicopathologic Features of Diaphyseal Osteosarcoma Anne N. Normand, MD Patrick P. Lin, MD Norman Jaffe, MD Robert S. Benjamin, MD Shreyaskumar R. Patel, MD Christopher P. Cannon, MD Valerae O. Lewis, MD A. Kevin Raymond, MD Alan W. Yasko, MD, MBA CTOS Meeting November 2005

2. High-grade intramedullary osteosarcoma Most common in metaphyseal region of long bones Rare in the diaphyseal region –Previously reported to occur <10% of cases –Site of osteosarcoma variants (eg, periosteal, high-grade surface OS)

3. Bone: Structural Differences Metaphysis –Many trabeculae –Thin cortices –Rich vascular supply –Vascular sinusoids –Large surface area exposed to circulation –Extensive remodeling, growth Diaphysis –Fewer trabeculae –Thick lamellar cortical bone –Nutrient artery & periosteum –Diffusion –Slower bone turnover –Slower healing

4. Literature Sim et al, 1995 –Mayo Clinic –51 cases –1912-1979 –~7% of all long bone OS treated during that period –No chemotherapy protocols –73% (38/51) no chemo –5-year survival 29% Haworth et al, 1981 –Bristol Royal Infirmary –Radiographic review –Heterogeneous presentation, broad DDx –5-year survival 23%

5. Hypothesis Diaphyseal and metaphyseal bone differ anatomically and metabolically. –Clinicopathologic features of tumors may differ –Response to treatment may differ

6. Purpose Describe clinicopathologic features of diaphyseal osteosarcoma Determine differences in outcome between diaphyseal and metaphyseal osteosarcoma with contemporary treatment

7. Materials & Methods

8. Study Design Retrospective review High-grade intramedullary OS of long bones 1980 to 1999 5-year potential follow-up 51 diaphyseal, 240 metaphyseal

9. Exclusion criteria Surface OS Low- and intermediate-grade OS Secondary OS

10. Definition: Diaphyseal OS Epicenter within the area between parallel cortices –Radiographic –Pathologic

11. Treatment algorithm Pre-operative chemotherapy - 4 cycles Surgical treatment Post-operative chemotherapy - tailored –Good responders (≥90%) –Poor responders (<90%)

12. Pre-op chemotherapy Intra-arterial cis-platin (120 mg/m2) Intravenous doxorubicin (90 mg/m2) 4 cycles

13. Surgical treatment DiaphysealMetaphyseal Amputation1242 Limb- salvage 39198 p = 0.321

14. Post-operative chemotherapy Good responders - short course –IV cis-platin –IV doxorubicin Poor responders - extended course –High-dose methotrexate (12.5 g/m 2 ) –High-dose ifosfamide (14 g/m 2 )

15. Statistics Kaplan-Meier analysis –Disease-specific survival –Log rank test Chi-square test Independent student’s t test

16. Results

17. Demographics DiaphysealMetaphysealp Number51240 Age (yrs) Mean Range 22 4-72 19 4-75 0.286 Gender Male Female 31 (61%) 20 (39%) 141 (59%) 99 (41%) 0.869 F/u (mo.) Mean Range 106 3-288 99 1-283 0.177 Stage Non-metas Metastatic 48 (94%) 3 (6%) 225 (94%) 15 (6%) 0.916

18. Affected sites p=0.339

19. Presentation Symptoms –Pain most common –Local swelling, mass Pathologic fracture –Diaphyseal 9/51 (18%) –Metaphyseal 39/240 (16%) –p = 0.657

20. Radiographic presentation Lytic Mixed Blastic

21. Histology

22. Tumor necrosis DiaphysisMetaphysis Good16134 Poor3296 p = 0.0016

23. Disease-specific survival

24. DiaphysealMetaphyseal 5 years62%69% 10 years59%60% 20 years56%60%

25. DSS & Tumor Necrosis

26. Impact of metastatic disease

27. Discussion

28. Similarities Diaphyseal & metaphyseal OS share many features –Age –Gender –Sites –Presentation –Histological subtypes

29. Key Difference Response to pre-op chemotherapy Diaphyseal OS less sensitive than metaphyseal OS to doxorubicin & IA- cisplatin –?Anatomical/vascular/structural differences

30. Similar outcomes Disease-specific survival same Supports tailoring of post-op chemotherapy –Switch to HD-MTX & HD-IFX –Historical data survival w/ poor response to pre-op chemo significantly worse

31. Conclusion Clinicopathological characteristics of diaphyseal OS are similar to metaphyseal OS Diaphyseal OS responds less well to pre-op chemo Tailoring of post-op chemo for poor responders to include HD-MTX & HD-IFX may be important to achieve good survival

32. Thank you