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Chemotherapy For Common Bone Tumors

Chemotherapy For Common Bone Tumors. G Naheed Usmani, MD Division of Pediatric Oncology/Hematology University of Massachusetts Medical Center. Osteogenic Sarcoma. Prognostic Factors For OS. Extent of disease at diagnosis: metastatic vs nonmetastatic

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Chemotherapy For Common Bone Tumors

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  1. Chemotherapy For Common Bone Tumors G Naheed Usmani, MD Division of Pediatric Oncology/Hematology University of Massachusetts Medical Center

  2. Osteogenic Sarcoma

  3. Prognostic Factors For OS • Extent of disease at diagnosis: metastatic vs nonmetastatic • Histology with Parosteal & intraosseous well-differentiated with best prognosis, Telengiectatic with worse prognosis • Paget’s disease • DNA content with hyperdiploid worse • Axial skeletal primaries have worse outcome • Tumor size >1/3 the bone or >9 cm • Skip lesions or intramedullary extensions of tumor worse prognosis • Longer duration of symptoms superior outcome • Age < 10 years worse, >20 years better outlook

  4. Kaplan-Meier Survival In Osteogenic Sarcoma Stratified By Tumor Size (n=123) Wunder J et al. JCO 2000:18(14);pp 2685-94

  5. Pre-surgical Chemotherapy Representative Trials

  6. Chemotherapy Induced Tumor Necrosis: An Important Prognostic Marker Huvos Grading System for Tumor Response 5 Year EFS • Grade I, II & III <95% necrosis 49% • Grade IV >95% necrosis 87% • Results from CCG 782 study • Intra-arterial preoperative chemo showed improved tumor necrosis but did not translate into any major improvements in EFS; • MD Anderson hospital, Rizzoli Institute and COSS-86 German study

  7. Kaplan-meier Survival In Osteogenic Sarcoma: Stratified By Tumor Necrosis (n=123) Wunder J et al. JCO 2000:18(14);pp 2685-94

  8. Adjuvant Therapy Of Osteosarcoma: Phase II TrialSouthwest Oncology Group Study 9139 Zalupski et al. Cancer 2004;100:818–25. Overall Survival In Eligible Patients With Follow-up Chemotherapy: Doxorubicin 75 mg/m2 with Cisplatin 120 mg/m2, alternating with Doxorubicin 50 mg/m2 and ifosfamide 8 g/m2. Four cycles were given prior to surgical resection, and four cycles were given after surgery. The proposed treatment plan resulted in a total doxorubicin dose of 500 mg/m2, a total cisplatin dose of 480 mg/ m2, and a total ifosfamide dose of 32 g/m2.

  9. Patient Treatment Variables Related To Survival From Date Of Surgery Adjuvant Therapy of OS: Cancer 2004;100:818–25 SWOG 9139/Zalupski et al.

  10. Received Dose And Dose-intensity Of Chemotherapy And Outcome In Nonmetastatic Extremity Osteosarcoma Alan W. Craft et al, for the European Osteosarcoma Intergroup Journal of Clinical Oncology, Vol 18, No 24 (December 15), 2000: pp 4028-4037

  11. Received Dose And Dose-intensity Of Chemotherapy And Outcome In Nonmetastatic Extremity Osteosarcoma PFS from day 122 by number of cycles received. Craft A et al; J Clin Onco 2000, Vol 18, No 24 : pp 4028-4037

  12. Osteosarcoma: A Randomized, Prospective Trial Of TheAddition Of Ifosfamide And/Or Muramyl Tripeptide ToCisplatin, Doxorubicin, And High-dose MethotrexatePaul A. Meyers, Cindy L. Schwartz, Mark Krailo, Eugenie S. Kleinerman, Donna Betcher,Mark L. Bernstein, Ernest Conrad, William Ferguson, Mark Gebhardt, Allen M. Goorin,Michael B. Harris, John Healey, Andrew Huvos, Michael Link, Joseph Montebello, Helen Nadel,Michael Nieder, Judith Sato, Gene Siegal, Michael Weiner, Robert Wells, Lester Wold, Richard Womer,and Holcombe Grier PROTOCOL ROAD MAPDOXORUBICIN; CISPLATIN; HIGH-DOSE METHOTREXATE; LIPOSOMAL MURAMYL TRIPEPTIDE PHOSPHATIDYLETHANOLAMINE; IFOSFAMIDE J Clin Oncol 2005; 23:2004-2011

  13. Patients treated with regimen A- had a 64% probability of EFS at 5 years. • The addition of MTP (regimen A+) resulted in a 63% probability of EFS at 5 years. • Patients who received cisplatin, doxorubicin, HDMTX, and ifosfamide (regimen B-) had a 53% probability of EFS at 5 years. • Patients who received cisplatin, doxorubicin, HDMTX, ifosfamide, and MTP (regimen B+) had a 72% probability of EFS at 5 years. J Clin Oncol 2005;23:2004-2011

  14. Prognostic Factors • Age, sex, and race did not correlate with EFS • Patients with alkaline phosphatase levels above their institution’s upper limit of normal had worse prognoses. • Patients with lactate dehydrogenase levels above institutional upper limit of normal also had worse prognoses. • Patients with primary tumors of the distal appendicular skeleton had the best prognosis, followed by those with tumors of the proximal appendicular skeleton. Patients with axial primary tumors had the worst prognosis. • There was no difference in outcome between patients who had primary ablation of their tumor and patients who had definitive surgery after induction. J Clin Oncol 2005;23:2004-2011

  15. J Clin Oncol 2005;23:2004-2011 Rates Of Favorable Necrosis For The Two Induction Arms Were Identical. Ifosfamide And Cisplatin Are Equivalent In Their Ability To Contribute To Favorable Necrosis.

  16. Chemotherapy Treatment For OS • 80% of patients treated with surgery alone develop metastasis • With current regimens, 60-70% of patients with nonmetastatic OS survive. • Majority of patients surviving 3 years without evidence of recurrence are cured. • Drugs with activity include Doxorubicin, Cisplatinum, HD Methotrexate and Ifosfamide. • Marginal benefits for patients given prophylactic lung irradiation

  17. Primary Metastatic Osteosarcoma: Presentation And Outcome Of Patients Treated On Neoadjuvant Cooperative Osteosarcoma Study Group Protocols Metastatic sites in 202 patients Journal of Clin Onco, Vol 21, No 10, May 15, 2003:P 2011-2018

  18. Primary Metastatic Osteosarcoma: Presentation And Outcome Of Patients Treated On Neoadjuvant Cooperative Osteosarcoma Study Group Protocols: Kager L, et al, for the Cooperative German-Austrian-Swiss Osteosarcoma Study Group Journal of Clinical Oncology, Vol 21, No 10 (May 15), 2003: pp 2011-2018

  19. Kaplan-Meier Curves Of Overall Survival For Variables With Prognostic Significance In Univariate Analysis. A: Site Of Metastases; B: Number Of Lung Metastases; C: Distribution Of Lung Metastases Journal of Clin Onco, Vol 21, No 10: May 15, 2003: pp 2011-2018

  20. Primary Metastatic Osteosarcoma: Presentation And Outcome Of Patients Treated On Neoadjuvant Cooperative Osteosarcoma Study Group Protocols Cooperative German-Austrian-Swiss Osteosarcoma Study Group Leo Kager et al: J Clin Onco, Vol 21, No 10, May 15, 2003: pp 2011-2018

  21. Primary Metastatic Osteosarcoma: Presentation And Outcome Of Patients Treated On Neoadjuvant Cooperative Osteosarcoma Study Group Protocols Cooperative German-Austrian-Swiss Osteosarcoma Study Group Overall Survival Curves As A Function Of Surgical Remission: Method According To Simon And Makuch Leo Kager et al: J Clin Onco, Vol 21, No 10, May 15, 2003: pp 2011-2018

  22. Treatment of Metastatic OS Disease • Complete surgical resection of all overt metastasis • Bilateral lesions are operated in stages 1-2 weeks apart • Disruption of pleura by tumor has an adverse prognosis • Patients with late appearing metastasis > 1 year and solitary nodules are most likely to be cured • Nodules disappearing with chemotherapy have not translated into improved outcome • Role of Adjuvant chemotherapy for recurrent metastatic disease is unclear, XRT may be possible

  23. Ewing’s Sarcoma/ PPNET

  24. Prognostic Markers For ESFT Negative Factors Metastasis at Diagnosis Over 8 cm in diameter or large volume Pelvic primaries Neuro-ectodermal differentiation HNK-1 ( neural marker) associated with more aggressive behavior High LDH > 2 X Institutional norms Positive Factors Histo-pathologic response to chemotherapy Radiological response to chemotherapy S-100 linked to more favorable outcome

  25. Prognostic Factors in Ewing’s Sarcoma of Bone Results from EICESS Cotterill S et al. JCO2000 18: 3108-14

  26. Prognostic Factors in Ewing’s Sarcoma of Bone Results from EICESS Cotterill S et al. JCO2000 18: 3108-14

  27. Prognostic Factors in Ewing’s Sarcoma of Bone: Results from EICESS Cotterill S et al. JCO2000 18: 3108-14

  28. THERAPY FOR ESFT: LOCAL CONTROL • Surgery • 30% local recurrence rate for pelvic & humeral lesions with Chemo/XRT only • Improved survival in many groups with surgical treatment of primary lesions • Radiotherapy • Whole bone irradiation with dose ranges 45 to 50 Gy to the medullary cavity (microscopic involvement of the bone marrow of the involved bone) • Boost of 10-15 Gy to the primary tumor

  29. RESULTS OF INTERGROUP STUDY POG 9354/CCG 7942 NON-METASTATIC EWING’S SARCOMA FAMILY OF TUMORS

  30. Chemotherapy Induced Tumor Necrosis As A Predictor Of Survival In ESFT

  31. Addition Of Ifosfamide And Etoposide To Standard Chemotherapy For Ewing's Sarcoma And Primitive Neuroectodermal Tumor Of Bone Volume 348:694-701 February 20, 2003 Holcombe E. Grier, M.D., Mark D. Krailo, Ph.D., Nancy J. Tarbell, M.D., Michael P. Link, M.D., Christopher J.H. Fryer, M.D., Douglas J. Pritchard, M.D., Mark C. Gebhardt, M.D., Paul S. Dickman, M.D., Elizabeth J. Perlman, M.D., Paul A. Meyers, M.D., Sarah S. Donaldson, M.D., Sheila Moore, M.D., Aaron R. Rausen, M.D., Teresa J. Vietti, M.D., and James S. Miser, M.D. Methods: The patients were randomly assigned toreceive 49 weeks of standard chemotherapy with doxorubicin,vincristine, cyclophosphamide, and dactinomycin or experimentaltherapy with these four drugs alternating with courses of ifosfamideand etoposide. Results: Of 120 patients with metastatic disease, there was no significant difference in five-year event-freesurvival between the treatment groups (P=0.81). Among the 398patients with nonmetastatic disease, the mean (±SE) five-yearevent-free survival among the 198 patients in the experimental-therapygroup was 69±3 percent, as compared with 54±4percent among the 200 patients in the standard-therapy group(P=0.005). Conclusions: The addition of ifosfamide and etoposide to a standardregimen does not affect the outcome for patients with metastaticdisease, but it significantly improves the outcome for patientswith nonmetastatic Ewing's sarcoma, primitive neuroectodermaltumor of bone, or primitive sarcoma of bone.

  32. Survival According to Study Group and the Presence or Absence of Metastatic Disease Grier et al. 348 (8): NEJM 694,  February 20, 2003

  33. Event-free Survival According to Study Group and Tumor Site among Patients without Metastases Grier et al. NEJM 348 (8): 694, February 20, 2003

  34. JCO 2003: Meyers P et al; 21: 3423-3440

  35. THERAPY FOR ESFT: CHEMOTHERAPY • Micrometastasis at the time of diagnosis • Rapid acquisition of multi-drug resistance • Tumor necrosis after chemotherapy induction important prognostic factor • Active drugs: Dactinomycin, Doxorubicin, Cyclophosphamide, Vincristine, Ifosfamide, Etoposide, Topotecan, Melphalan • Supportive care with GCSF & other cytokines

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