Chemoherapy Of Bone Cancers


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Chemoherapy Of Bone Cancers

  1. 1. CHEMOTHERAPY IN BONE CANCERS Prof. V. Vedhamoorthy. MD DM Professor and Head Department of Medical Oncology MMC, Chennai-3.
  2. 2. INTRODUCTION <ul><li>CHEMOTHERAPY IN </li></ul><ul><ul><li>Osteogenic sarcoma </li></ul></ul><ul><ul><li>Ewing’s sarcoma </li></ul></ul><ul><ul><li>Multiple myeloma </li></ul></ul><ul><ul><li>Bone lymphoma </li></ul></ul><ul><ul><li>Other bone primaries </li></ul></ul>
  4. 4. <ul><li>Impact of chemo in osteogenic sarcoma </li></ul><ul><ul><li>5 years survival with surgery alone was less than 20% </li></ul></ul><ul><ul><li>Addition of chemotherapy as adjuvant increased the 5 year survival more than 80% </li></ul></ul>
  5. 5. <ul><li>2. Chemo as neo-adjuvant increased the percentage of limb conservative surgery </li></ul>
  6. 6. <ul><li>3. Addition of chemo </li></ul><ul><ul><li>Delayed the development of lung metastasis </li></ul></ul><ul><ul><li>Number of metastasis are fewer </li></ul></ul><ul><ul><li>Metastesectomy chances are improved </li></ul></ul><ul><ul><li>Increased the survival </li></ul></ul>
  7. 7. <ul><li>Drugs effective in osteogenic sarcoma </li></ul><ul><ul><li>Adriamycin </li></ul></ul><ul><ul><li>Methotrexate </li></ul></ul><ul><ul><li>Cisplatinum </li></ul></ul><ul><ul><li>Ifosfamide </li></ul></ul>
  8. 8. <ul><li>Combination of drugs is the best </li></ul><ul><ul><li>To increase the cell kill </li></ul></ul><ul><ul><li>To overcome drug resistance clones </li></ul></ul>
  9. 9. <ul><li>Drug combination may be 3 or 4 drugs </li></ul><ul><li>Example </li></ul><ul><ul><li>Adriamycin, Cisplatinum, Ifosfamide </li></ul></ul><ul><ul><li>Adriamycin, Methotrexate, Ifosfamide </li></ul></ul>
  10. 10. <ul><li>SITUATION - 1 </li></ul><ul><ul><li>Osteogenic sarcoma </li></ul></ul><ul><ul><li>Limited to the bone of its origin </li></ul></ul><ul><ul><li>Smaller in size </li></ul></ul><ul><ul><li>Fit for immediate limb conservative surgery </li></ul></ul>
  11. 11. <ul><li>26 year male </li></ul><ul><li>Osteosarcoma of upper end of left tibia </li></ul>
  12. 12. <ul><li>X- ray chest </li></ul><ul><li>Normal </li></ul>
  13. 13. <ul><li>CT chest </li></ul><ul><li>Normal </li></ul>
  14. 14. PROTOCOL <ul><li>Limb conservative surgery </li></ul><ul><li>Combination chemo administered as adjuvant </li></ul><ul><li>6 courses </li></ul>
  15. 15. <ul><li>PRINCIPLE OF ADJUVANT CHEMO </li></ul><ul><ul><li>To sterilize distant micro metastasis </li></ul></ul><ul><ul><li>To reduce distant relapse </li></ul></ul><ul><ul><li>To increase disease free interval </li></ul></ul><ul><ul><li>To improve overall survival </li></ul></ul>
  16. 16. <ul><li>ADVANTAGES OF ADJUVANT CHEMO </li></ul><ul><ul><li>Primary surgical treatment is executed immediately </li></ul></ul><ul><ul><li>Patient is mentally happy </li></ul></ul><ul><ul><li>Risk of progression and dissemination are avoided </li></ul></ul><ul><ul><li>Risk of development of drug resistance is avoided </li></ul></ul>
  17. 17. <ul><li>DISADVANTAGES OF ADJUVANT CHEMO </li></ul><ul><ul><li>Delay in care of distant micro metastasis </li></ul></ul><ul><ul><li>Risk of dissemination during surgical procedure is high </li></ul></ul><ul><ul><li>Clinical response of drug is not assessed </li></ul></ul>
  18. 18. <ul><li>SITUATION - 2 </li></ul><ul><ul><li>Osteogenic sarcoma </li></ul></ul><ul><ul><li>Limited to the bone of its origin </li></ul></ul><ul><ul><li>Larger in size </li></ul></ul><ul><ul><li>Not fit for immediate limb conservative surgery </li></ul></ul>
  19. 19. <ul><li>25 year old male </li></ul><ul><li>Osteosarcoma of lower end of left femur </li></ul>
  20. 20. <ul><li>X-ray chest </li></ul><ul><li>Normal </li></ul>
  21. 21. <ul><li>CT chest </li></ul><ul><li>Normal </li></ul>
  22. 22. PROTOCOL <ul><li>3 courses of combination chemo as neo-adjuvant </li></ul><ul><li>Limb conservative surgery </li></ul><ul><li>3 courses of adjuvant chemo </li></ul>
  23. 23. <ul><li>Pain and swelling reduced after 3courses of neo-adjuvant chemo </li></ul>
  24. 24. Underwent limb conservative surgery
  25. 25. X-ray after limb conservative surgery
  26. 26. Patient ambulant after limb conservative surgery
  27. 27. <ul><li>PRINCIPLES OF NEO-ADJUVANT CHEMO </li></ul><ul><ul><li>To reduce the size of the primary tumor </li></ul></ul><ul><ul><li>Making the tumor amenable for limb conservative surgery </li></ul></ul>
  28. 28. <ul><li>ADVANTAGES OF NEO-ADJUVANT CHEMO </li></ul><ul><ul><li>Distant micrometastasis is taken care immediately </li></ul></ul><ul><ul><li>Size and vascularity of the tumor is reduced, hence dissemination risk is minimized during surgery </li></ul></ul><ul><ul><li>Clinical response is assessed </li></ul></ul>
  29. 29. <ul><li>DISADVANTAGES OF NEO-ADJUVANT CHEMO </li></ul><ul><ul><li>Delay in the primary surgical treatment </li></ul></ul><ul><ul><li>Patient is psychologically upset </li></ul></ul><ul><ul><li>Risk of progression and dissemination of the disease is high </li></ul></ul><ul><ul><li>Development of drug resistance is increased </li></ul></ul>
  30. 30. <ul><li>ASSESSMENT OF RESPONSE OF NEO-ADJUVANT CHEMO </li></ul><ul><ul><li>Symptoms </li></ul></ul><ul><ul><ul><li>The size of the tumor is reduced </li></ul></ul></ul><ul><ul><ul><li>Pain is lessened </li></ul></ul></ul>
  31. 31. <ul><li>X-ray, CT, MRI </li></ul><ul><ul><li>Size of the tumor is reduced </li></ul></ul><ul><ul><li>Margins become more clear and defined </li></ul></ul><ul><ul><li>Soft tissue infiltration recedes </li></ul></ul><ul><ul><li>Thickness of cortical involvement is not altered </li></ul></ul>
  32. 32. <ul><li>Technetium 99 Bone scan </li></ul><ul><ul><li>Size is reduced </li></ul></ul><ul><ul><li>Intensity of the hot spot decreased </li></ul></ul>
  33. 33. <ul><li>Angiogram </li></ul><ul><ul><li>In very good response </li></ul></ul><ul><ul><ul><li>Arterial phase and capillary mess are reduced </li></ul></ul></ul><ul><ul><li>In intermediate response </li></ul></ul><ul><ul><ul><li>Arterial phase alone is reduced </li></ul></ul></ul><ul><ul><li>In poor response </li></ul></ul><ul><ul><ul><li>No change in arterial phase and capillary mess </li></ul></ul></ul>
  34. 34. <ul><li>Thallium bone scan and PET scan </li></ul><ul><ul><li>Both give biological response directly </li></ul></ul><ul><ul><li>In good response – because of heavy necrosis, uptake is reduced </li></ul></ul><ul><ul><li>In poor response – because of no much change in viable cancer cell volume, uptake is not altered </li></ul></ul>
  35. 35. <ul><li>Pathological response </li></ul><ul><ul><li>Grade I </li></ul></ul><ul><ul><ul><li>Volume of viable cancer cells is not altered </li></ul></ul></ul><ul><ul><li>Grade II </li></ul></ul><ul><ul><ul><li>Minimal reduction of viable cancer cells </li></ul></ul></ul><ul><ul><li>Grade III </li></ul></ul><ul><ul><ul><li>Good reduction of viable cancer cells </li></ul></ul></ul><ul><ul><li>Grade IV </li></ul></ul><ul><ul><ul><li>Complete disappearance of viable cancer cells, replaced by necrosis </li></ul></ul></ul>
  36. 36. <ul><li>SITUATION – 3 </li></ul><ul><ul><li>Osteogenic sarcoma </li></ul></ul><ul><ul><li>Limited to the bone of its origin </li></ul></ul><ul><ul><li>Presence of pathological fracture </li></ul></ul><ul><ul><li>(seen in less than 1%) </li></ul></ul>
  37. 37. <ul><li>X-ray left femur </li></ul><ul><li>OS of lower end </li></ul><ul><li>Pathological fracture </li></ul>
  38. 38. PROTOCOL <ul><li>Fractured segments are kept in alliance </li></ul><ul><li>Limb is immobilized by POP </li></ul><ul><li>2 courses of combination chemo </li></ul>
  39. 39. <ul><li>If good callus formation occurs – suggests chemo clears tumor tissue in between fractured fragments </li></ul><ul><li>Proceed with limb conservative surgery </li></ul><ul><li>Followed by 4 more courses of adjuvant chemo </li></ul>
  40. 40. <ul><li>If no callus formation occurs </li></ul><ul><li>Suggests tumor tissue is not sterilized by chemo </li></ul><ul><li>Proceed with amputation </li></ul><ul><li>6 courses of tailored adjuvant chemo </li></ul>
  41. 41. <ul><li>SITUATION – 4 </li></ul><ul><ul><li>Osteogenic sarcoma </li></ul></ul><ul><ul><li>Presence of resectable pulmonary secondary </li></ul></ul>
  42. 42. <ul><li>X-ray chest shows solitary coin shadow at right lower zone </li></ul>
  43. 43. <ul><li>CT chest </li></ul><ul><li>Solitary lung secondary </li></ul>
  44. 44. PROTOCOL <ul><li>Manage the primary tumor by LCS / amputation </li></ul><ul><li>2 courses of combination chemo </li></ul><ul><li>CT chest confirms no progression of pulmonary secondary </li></ul><ul><li>Metastesectomy </li></ul><ul><li>4 courses of combination chemo </li></ul>
  45. 45. <ul><li>SITUATION – 5 </li></ul><ul><ul><li>Osteogenic sarcoma </li></ul></ul><ul><ul><li>Unresectable, multiple, bilateral pulmonary secondaries </li></ul></ul>
  46. 46. <ul><li>X-ray chest </li></ul><ul><li>Multiple, bilateral, subpleural and basal lung secondaries </li></ul>
  47. 47. <ul><li>CT chest </li></ul><ul><li>Multiple bilateral lung secondaries </li></ul><ul><li>Cavitating secondary left lower lobe </li></ul>
  48. 48. PROTOCOL <ul><li>Palliative combination chemo </li></ul><ul><li>If chemo has not given good response to primary tumor </li></ul><ul><li>Proceed with palliative surgical resection </li></ul>
  49. 49. <ul><li>SITUATION – 6 </li></ul><ul><ul><li>Osteogenic sarcoma </li></ul></ul><ul><ul><li>Limited to the bone of its origin </li></ul></ul><ul><ul><li>Underwent surgery and chemo </li></ul></ul><ul><ul><li>While on follow up develops resectable pulmonary secondary </li></ul></ul>
  50. 50. PROTOCOL <ul><li>Resect the pulmonary secondary </li></ul><ul><li>Observation </li></ul><ul><li>or </li></ul><ul><li>Second line chemo </li></ul>
  51. 51. <ul><li>SITUATION – 7 </li></ul><ul><ul><li>Osteogenic sarcoma </li></ul></ul><ul><ul><li>Limited to the bone of its origin </li></ul></ul><ul><ul><li>Underwent surgery and chemo </li></ul></ul><ul><ul><li>While on follow up develops unresectable pulmonary secondary </li></ul></ul>
  52. 52. <ul><li>Option 1 </li></ul><ul><ul><li>Symptomatic treatment </li></ul></ul><ul><li>Option 2 </li></ul><ul><ul><li>Second line combination chemo </li></ul></ul><ul><li>Option 3 </li></ul><ul><ul><li>High dose chemo with autologous peripheral stem cell transplant </li></ul></ul>
  53. 53. <ul><li>Newer experimental drugs </li></ul><ul><ul><li>Muramyl Triphosphate (Macrophage stimulant) </li></ul></ul><ul><ul><li>Aerosol GM-colony stimulating factor </li></ul></ul><ul><ul><li>Herceptin – If Her 2 over expression present </li></ul></ul>
  55. 55. INTRODUCTION <ul><li>Second common bone primary in the paediatric age group </li></ul><ul><li>Highly radio and chemo sensitive </li></ul>
  56. 56. <ul><li>SITUATION - 1 </li></ul><ul><ul><li>Ewing’s sarcoma </li></ul></ul><ul><ul><li>Limited to the bone of its origin </li></ul></ul><ul><ul><li>Size is less than 8cm </li></ul></ul><ul><ul><li>Cured by surgery or radiotherapy </li></ul></ul>
  57. 57. PROTOCOL <ul><li>ADJUVANT CHEMOTHERAPY </li></ul>
  58. 58. <ul><li>EVOLUTION </li></ul><ul><ul><li>1960s </li></ul></ul><ul><ul><ul><li>Vincristine, Actinomycin-D, Cyclophosphamide </li></ul></ul></ul><ul><ul><li>1970s </li></ul></ul><ul><ul><ul><li>Intergroup Ewing’s sarcoma study -1 </li></ul></ul></ul><ul><ul><ul><ul><li>Vincristine, Actinomycin-D, Cyclophosphamide, Adriamycin and pulmonary irradiation </li></ul></ul></ul></ul><ul><ul><ul><li>Intergroup Ewing’s sarcoma study -2 </li></ul></ul></ul><ul><ul><ul><ul><li>Vincristine, Actinomycin-D, Cyclophosphamide, Adriamycin in escalated dose </li></ul></ul></ul></ul>
  59. 59. <ul><li>1980s onwards </li></ul><ul><ul><li>Pediatric Oncology Group </li></ul></ul><ul><ul><li>Vincristine, Adriamycin, Cyclophosphamide, alternated with Etoposide, Ifosfamide </li></ul></ul><ul><ul><li>Every 3 weeks </li></ul></ul><ul><ul><li>8 courses each </li></ul></ul><ul><ul><li>Covering 48 weeks </li></ul></ul><ul><ul><li>Gives longest disease free interval and overall survival </li></ul></ul>
  60. 60. <ul><li>SITUATION - 2 </li></ul><ul><ul><li>Ewing’s sarcoma </li></ul></ul><ul><ul><li>Limited to the bone of its origin </li></ul></ul><ul><ul><li>Size is more than 8cm </li></ul></ul><ul><ul><li>Planed for limb conservative surgery </li></ul></ul><ul><ul><li>(No role for curative radiotherapy) </li></ul></ul>
  61. 61. <ul><li>26 year old male </li></ul><ul><li>Ewing’s sarcoma of right forearm </li></ul>
  62. 62. PROTOCOL <ul><li>Neo-adjuvant 3 courses of VAC / IE </li></ul><ul><li>Tumor size is reduced </li></ul><ul><li>Limb conservative surgery is done </li></ul><ul><li>5 more courses of adjuvant VAC / IE </li></ul>
  63. 63. <ul><li>SITUATION – 3 </li></ul><ul><ul><li>Ewing’s sarcoma as disseminated disease with </li></ul></ul><ul><ul><li>Pulmonary / bone / marrow metastasis </li></ul></ul>
  64. 64. <ul><li>16 year old boy </li></ul><ul><li>Ewing’s sarcoma of left tibia </li></ul>
  65. 67. <ul><li>Principle </li></ul><ul><ul><li>Palliative </li></ul></ul><ul><li>Plan </li></ul><ul><ul><li>Combination chemo </li></ul></ul><ul><li>Schedule </li></ul><ul><ul><li>3 drugs regimen – V Act C </li></ul></ul><ul><ul><li>4 drugs regimen – V Act C + Adriamycin </li></ul></ul><ul><ul><li>5 drugs regimen – VAC / IE </li></ul></ul><ul><li>Results </li></ul><ul><ul><li>All the regimens give equal results of survival </li></ul></ul>
  66. 68. <ul><li>Newer approaches </li></ul><ul><ul><li>High dose chemo with autologous peripheral stem cell transplant </li></ul></ul><ul><ul><li>Indicated in </li></ul></ul><ul><ul><ul><li>High risk limited stage Ewing’s sarcoma </li></ul></ul></ul><ul><ul><ul><li>Post chemo relapse </li></ul></ul></ul><ul><ul><ul><li>Disseminated stage </li></ul></ul></ul>
  67. 69. <ul><li>Newer drugs </li></ul><ul><ul><li>Topoisomerase – I inhibitor </li></ul></ul><ul><ul><ul><li>Topotecan </li></ul></ul></ul><ul><ul><ul><li>Irinotecan </li></ul></ul></ul><ul><ul><li>Taxanes </li></ul></ul><ul><ul><ul><li>Paclitaxel </li></ul></ul></ul><ul><ul><ul><li>Docitaxel </li></ul></ul></ul>
  68. 70. <ul><li>Chondrosarcoma </li></ul><ul><li>Malignant giant cell tumor </li></ul><ul><li>Protocol as osteogenic sarcoma </li></ul>
  69. 71. <ul><li>Fibrosarcoma of bone </li></ul><ul><li>Malignat fobrous histiocytoma of bone </li></ul><ul><li>Angiosarcoma of bone </li></ul><ul><li>Chemo protocol is MAID schedule </li></ul><ul><ul><li>Messna </li></ul></ul><ul><ul><li>Adriamycin </li></ul></ul><ul><ul><li>Ifosfamide </li></ul></ul><ul><ul><li>D-actinomycin </li></ul></ul>
  70. 72. <ul><li>Bone lymphoma </li></ul><ul><ul><li>CHOP schedule </li></ul></ul><ul><ul><ul><li>Cyclophosphamide </li></ul></ul></ul><ul><ul><ul><li>Hydroxyl doxorubicin </li></ul></ul></ul><ul><ul><ul><li>Oncovin </li></ul></ul></ul><ul><ul><ul><li>Predinisolone </li></ul></ul></ul><ul><ul><li>R-CHOP </li></ul></ul><ul><ul><ul><li>Rituximab with CHOP </li></ul></ul></ul>
  71. 73. <ul><li>Multiple myeloma </li></ul><ul><ul><li>VAD (Vincristine, Adriamycin, Dexamethasone) </li></ul></ul><ul><ul><li>Thalidomide with dexamethasone </li></ul></ul><ul><ul><li>High dose melphalan with ABMT / APSCT </li></ul></ul>
  72. 74. CONCLUSION <ul><li>Bone lymphoma and multiple myeloma </li></ul><ul><ul><li>Primary modality of treatment is chemo </li></ul></ul><ul><li>Ewing’s sarcoma </li></ul><ul><ul><li>Radiotherapy and surgery are equal options </li></ul></ul><ul><li>Osteogenic sarcoma, chondrosarcoma </li></ul><ul><ul><li>Surgery is the primary modality </li></ul></ul>
  73. 75. <ul><li>Role of chemo in osteogenic sarcoma as </li></ul><ul><ul><li>Neo-adjuvant </li></ul></ul><ul><ul><li>Adjuvant </li></ul></ul><ul><ul><li>Palliative role </li></ul></ul><ul><ul><li>has been clearly established </li></ul></ul>
  74. 76. Thank you