Osteosarcoma ppt
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This deals with the current paradigm of treatment of osteosarcoma. It is an honest effort to clear the prevailing confusion in the treatment of osteosarcoma. I would be happy to get anyone
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Osteosarcoma ppt
- 1. Dr Sameer Rastogi MD, DM Medical Oncology Assistant Professor AIIMS, New Delhi
- 2. Adjuvant Chemotherapy - Evidence Life-Table analysis of Relapse-Free Survival after Surgery in Patients Accepting Randomization Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986; 314:1600
- 3. Points that will be covered ο Double drug regimen vs triple drug therapy (MAP) vs four drugs therapies (MAP plus ifosfamide) ο Changing therapy based upon response ο Dose dense therapy ο Three drug non high dose methotrexate containing regimen ο Mifamurtide/ IFN alpha/zoledronic acid/ Metronomic chemotherapy
- 4. Methotrexate (Mtx) vs non Mtx regimen (double vs triple) ο Single randomized trial comparing CDDP / doxo vs CDDP/ doxo/ HDMtx1 ο No difference in Overall survival (OS) ο DFS was superior in doublet arm ο Trial design and conduct ? 1. Bramwell et al. A comparison of two adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the EOI. JCO 1992
- 5. Trial design and conduct
- 6. ο CDDP /doxorubicin vs Multidrug regimen ??
- 7. Meyers et al . J Clin Oncol 23:2004-2011
- 8. MAP MAP+ MTP PE MAP+ ifos MAP+ ifos+MTP PE 2x2 Factorial Design 1.Patients received ifos or not 2 Patients who received MTP- PE or not
- 11. Anninga et al. Eur J Cancer. 2011 Nov;47(16):2431-45
- 13. Guidelines ESMO and NCCN Esmo guidelines 2012
- 14. Isakoff et al. J Clin Oncol 33:3029-3035.
- 15. Points that will be covered ο Double drug regimen vs triple drug therapy (MAP) vs four drugs therapies (MAP plus ifosfamide) ο Changing therapy based upon response ο Dose dense therapy? ο Three drug non high dose methotrexate containing regimen ο Mifamurtide/ IFN alpha/zoledronic acid
- 16. ο Changing therapy based upon histopathological response
- 17. EURAMOS Trial ο Phase 3 open label ο newly diagnosed, ο resectable, high-grade osteosarcoma ο Age <40 years or younger ο Primary outcome was event free survival Lancet Oncol 2016; 17: 1396β408
- 20. Lancet Oncol 2016; 17: 1396β408
- 21. Toxicity β’ Grade 4 non hematological toxicity was 24% in MAP IE vs 12% in MAP chemotherapy arm β’ Numerically higher second malignancy in patients with MAP IE chemotherapy EURAMOS-1 demonstrates achievability.
- 22. Points that will be covered β’ Double drug regimen vs triple drug therapy (MAP) vs four drugs therapies (MAP plus ifosfamide) β’ Changing therapy based upon response β’ Dose dense therapy? β’ Three drug non high dose methotrexate containing regimen β’ Mifamurtide/ IFN alpha/zoledronic acid
- 23. ο Histopathological response improved ο Good pathological response was 50% in DI arm vs 36% in non DI arm J Natl Cancer Inst 2007;99: 112 β 28
- 24. J Natl Cancer Inst 2007;99: 112 β 28
- 26. Points that will be covered ο Double drug regimen vs triple drug therapy (MAP) vs four drugs therapies (MAP plus ifosfamide) ο Changing therapy based upon response ο Dose dense therapy ο Three drug non high dose methotrexate containing regimen ο Mifamurtide/ IFN alpha/zoledronic acid
- 27. Requirements of high dose methotrexate ο Hydration and alkalanization β admission and cost ο Leucovorin administration ο Routine monitoring of serum methotrexate concentration.
- 28. Renal failure risk ο 1.8-2% in clinical trials with optimal supportive care ο Hemodialysis β High flux dialyzer ο carboxypeptidase-G2 (CPDG2)- a recombinant bacterial enzyme
- 29. Indian Perspective ο Admission cost ο Methotrexate levels not widely available ο Carboxypeptidase G2 not available ο Hemodialysis facilities might be available in our institute but what about others?
- 30. Rastogi, S. et al.
- 31. Rastogi, S. et al. JGO. 2017
- 32. Points that will be covered ο Double drug regimen vs triple drug therapy (MAP) vs four drugs therapies (MAP plus ifosfamide) ο Changing therapy based upon response ο Dose dense therapy? ο Three drug non high dose methotrexate containing regimen ο Mifamurtide/ IFN alpha/zoledronic acid
- 33. IFN ο Anti tumor, anti angiogenensis, immune regulators ο Interferon alpha inhibits the growth of osteosarcoma cells in vitro. ο Data from Scandinavian studies β ο N=89 ο After surgery only IFN alpha was given ο 10 year disease free survival 38% Pediatr Blood Cancer 2010;54:350β354
- 36. Mifamurtide ο Muramyl tripeptide (MTP) phosphatidylethanolamine synthetic lipophilic analog of muramyl dipeptide. ο Liposomes for the delivery of the drug to monocytes and macrophages ο Active in rodent model and canine osteosarcoma
- 37. Contradictory trial results Mifamurtide 1. J Clin Oncol 23:2004-2011 2005 2. J Clin Oncol 26:633-638. 2008
- 40. ο Background Anti tumor effect on cell lines and reduce primary and lung metastasis in mouse. ο N= 318 patients ο 17% were metastatic
- 43. Points that will be covered ο Double drug regimen vs triple drug therapy (MAP) vs four drugs therapies (MAP plus ifosfamide) ο Changing therapy based upon response ο Dose dense therapy? ο Three drug non high dose methotrexate containing regimen ο Mifamurtide/ IFN alpha/zoledronic acid
- 44. Summary ο Triple drug protocol IAP might be the most apt protocol for us ο Carefully designed trials with collaborative efforts ο Biologicals/ zoledronic acid/ metrnomics have failed ο While developed countries are doing good research, we should first focus on early detection, decreased abandonment, multidisciplinary meet/ proper diagnosis and optimising treatment gaps and delays.
- 46. When we blindly adopt a religion, political dogma, we become automations and thus we cease to grow Anais Nin French born American author
Editor's Notes
- Debate against the sine qua non need for methotrexate in osteosarcoma
- projected six-year event-free survival for the control group is 11% compared to 61% for the chemotherapy group Multi-Institutional Osteosarcoma Study (MIOS). The biologic behavior is consistent with the premise that silent pulmonary micrometastases are present in at least 80% of patients at diagnosis. These metastases are not visible on imaging studies, but in the absence of effective systemic therapy, they generally surface 6 to 9 months after surgical ablation of the primary tumor
- Contrary to expectations! Disease free survival was better in doublet arm
- Extremity osteosarcoma, high dose methotrexate dose, 4 cycles vs 6 cycles. Low DFS for the 5 years. Weak comparison arm. Rather than showing benefit in 3 drugs arm, the trial favoured 2 drugs regimen.
- What was the components of multidrug regimens-- (preoperatively vincristine, high-dose methotrexate, and doxorubicin; postoperatively bleomycin, cyclophosphamide, dactinomycin, vincristine, methotrexate, doxorubicin, and cisplatin; this protocol took 44 weeks
- The appeal of such designs is obvious: two different treatment questions may be asked of the same pool of patientstrade-off between potential gains from testing more questions with fewer patients versus how often a factorial trial might arrive at an incorrect conclusion
- Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity
- Osteosarcoma: Current Treatment and a Collaborative Pathway to Success
- EURAMOS-1 was an open-label, international, randomised, phase 3, controlled trial. The structure and design of this trial have been previously published.After a diagnostic biopsy, patients with newly diagnosed osteosarcoma could be registered to this trial. Patients were registered from 325 sites in 17 countries.
- 3 years survival was 60% in MAP and 57% in MAP IE.
- Our fi ndings do not support the intensifi cation of postoperative chemotherapy by adding ifosfamide and etoposide for patients.. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. with a poor response to preoperative chemotherapy
- 500 odd patients were randomized to 3 weekly chemotherapy regimen vs 2 weekly regimen.
- High dose methotrexate defined by 1gm/m2 (reference - Br J Clin Pharmacol. 2012 Jan; 73(1): 106β114. ) Admission for hydration as well as alkalinization. Concurrent cisplatin adminstration
- A major limitation on the use of dialysis-based methods is the marked rebound in plasma MTX concentrations that can occur when the dialysis is stopped. Rebound increases in the postdialysis plasma MTX concentration were in the range of 10%β221% of the postprocedure MTX level [44, 49, 50] and 90%β100% of the preprocedure MTX level [51β54]. Further limitations of these methods are the accompanying risks for complications from these invasive procedures. Reported complications include cardiac arrest in one patient after plasma exchange [51], bleeding from the catheter exit site [52], anemia [52, 55], thrombocytopenia [52, 56], and hypokalemia and severe hypophosphatemia [48].
- Last p
- Pegylation of therapeutic proteins is a well established method for delaying clearance and reducing protein immunogenicity. Interferon has a short half-life and requires dosing at least three times a week. A pegylated form of interferon a-2b is available which has an elimination half-life of 40 hr compared with 4 hr for standard interferon.
- which is a component of the cell wall of Bacille Calmette-Guerin. Factorial design and interaction is the root of controversy in factorial design study. MTP-PE has been encapsulated in liposomes to deliver the agent selectively to monocytes and macrophages to activate them to become tumoricidal
- 4 preoperative and 6 post operative zoledronic acid infusion should be given (ten monthly infusions of zoledronic acid Primary end point was event free survival. Assuming a 3 year evvent fee survival of 55% and 80% power to detect 13% difference in 3 year event free survival
- insightful, bold, irreverent, and raw