Bone Cancer


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Introduction- Etiology- Pathophysiology -Clinical manifestations- Diagnosis- Treatment.

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Bone Cancer

  1. 1. BONE CANCER Youan Bi Beniet Marius, PharmD, Master of clinical pharmacy. University of Nairobi
  3. 3. Understanding Bone The skeletal system is vital during our lifetime. An adult human body has 212 bones Each bone constantly undergoes during life : Modeling Remodeling to help it adapt to changing biomechanical forces to remove old, micro damaged bone and replace it with new, mechanically stronger bone to help preserve bone strength
  4. 4. Function of bones 1. Support - form the framework that supports the body and cradles soft organs 2. Movement – provide levers for muscles 3. Protection - provide a protective case for the brain, spinal cord, and vital organs
  5. 5. Function of bones cont’d 4. Mineral storage- reservoir for minerals, especially calcium and phosphorus 5. Growth factors and cytokines storage. 6. Blood cell formation – hematopoiesis occurs within the marrow cavities of bones
  6. 6. Classification of bones
  7. 7. Macroscopic structure of bone
  8. 8. Microscopic Structure of Bone: Compact Bone Haversian system, or osteon – the structural unit of compact bone Lamella – weight- bearing Haversian, or central canal – central channel containing blood vessels and nerves Volkmann’s canals – channels lying at right angles to the central canal
  9. 9. Microscopic Structure of Bone: Trabecula of Spongy bone
  10. 10. Cellular structure
  11. 11. BONE FORMATION (OSSIFICATION) • It is a process of formation of bone and it includes proliferation of collagen and ground substance with subsequent deposition of calcium salts.  Two types Intramembranous ossification Endochondral ossification
  12. 12. INTRAMEMBRANOUS OSSIFICATION  It is the direct laying down of bone into the primitive connective tissue(Mesenchym).  It results in bones of the skull then in formation of cranial  All bones formed this way are flat bones  It is also an important process during natural healing of bone fractures
  13. 13. Endochondral Ossification Results in the formation of all the others bones Begins in the second month of development Uses hyaline cartilage “bones” as models for bone construction Requires breakdown of hyaline cartilage prior to ossification
  14. 14. Endochondral Ossification
  15. 15. BONE REGULATORS Growth factors Paracrine regulators Autocrine regulators Neurotransmitters & hormones • -factor Bone morphogenetic protein(BMP) - Insulin-like growth factors -Transforming –growth factors -Platelet derived growth • -Fibroblast growth factor • RANKL (produced locally) • OPG Produced intracellulary Growth hormones and sex hormones
  16. 16. Dynamic bones Bone is dynamic or active . Bones are remodeled continuously in response to two factor 1. Calcium level in the blood 2.The pull of gravity and muscles in the skeleton Ca PTH activates osteoclast which lead to bone resorption Ca Calcium is deposited into bone matrix by osteoblast: bone Deposition Osteoblast lay down new Matrix
  17. 17. Modeling versus Remodeling Coupled sequence of catabolic and anabolic events to support calcium homeostasis and repair / renew aged or damaged mineralized tissue. Changes the shape, size, or position of bones in response to mechanical loading or wounding. Modeling Remodeling
  18. 18. Bone remodeling steps
  19. 19. Regulation of Osteoclastogenesis by RANK & OPG
  20. 20. Regulation of Osteoclastogenesis cont’d
  21. 21. Balance RANKL/OPG in Bone resorption
  22. 22. Regulation of osteoblastogenesis
  23. 23. Definition Cancer is a class of diseases in which abnormal cells divide uncontrollably and are able to invade other tissues. There are over 100 different type of cancer and each is classified by the name of organ or type of cell that is initially affected
  24. 24. Different Kinds of Cancer Lung Breast (women) Colon Bladder Prostate (men) Some common sarcomas: Fat Bone Muscle Lymphomas: Lymph nodes Leukemias: Bloodstream Some common carcinomas:
  25. 25. Naming Cancers Prefix Meaning adeno- gland chondro- cartilage erythro- red blood cell hemangio- blood vessels hepato- liver lipo- fat lympho- lymphocyte melano- pigment cell myelo- bone marrow myo- muscle osteo- bone Cancer Prefixes Point to Location
  26. 26. Normal cell versus cancer cell  Well differentiated  Develop anaplasia undifferentiated Normal cell Cancer cell  Grow and replicate only when stimulated by growth factor signaling  Rate of growth=rate of death  Respond to apoptosis signals  Grow even without stimulating factor  Undergo unlimited replication  don’t respond to apoptosis signals
  27. 27. Loss of Normal Growth Control Cell Suicide or Apoptosis Cell damage no repair Normal cell division Cancer cell division First mutation Second mutation Third mutation Fourth or later mutation Uncontrolled growth
  28. 28. Example of Normal Growth Cell migration Dead cells shed from outer surface Epidermis Dividing cells in basal layer
  29. 29. The Beginning of Cancerous Growth Underlying tissue
  30. 30. Tumors (Neoplasms) Underlying tissue
  31. 31. Invasion and Metastasis 1 Cancer cells invade surrounding tissues and blood vessels 2 Cancer cells are transported by the circulatory system to distant sites 3 Cancer cells reinvade and grow at new location
  32. 32. Malignant versus Benign Tumors Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis
  33. 33. What Causes Cancer? Some viruses or bacteria Heredity Diet Hormones RadiationSome chemicals
  34. 34. Viruses Virus inserts and changes genes for cell growth Cancer-linked virus
  35. 35. Examples of Human Cancer Viruses Some Viruses Associated with Human Cancers
  36. 36. Bacteria and Stomach Cancer H. pyloriPatient’s tissue sample
  37. 37. Heredity and Cancer Inherited factor(s) All Breast Cancer Patients Other factor(s)
  38. 38. Heredity Can Affect Many Types of Cancer Inherited Conditions That Increase Risk for Cancer
  39. 39. Genes and Cancer Chromosomes are DNA molecules Heredity RadiationChemicals Viruses
  40. 40. DNA Structure DNA molecule Chemical bases G C T A
  41. 41. DNA Mutation Additions Deletions Normal gene Single base change DNA C T A G C G A A C TAC A G G C G C T AAC A C T A G C T A A C TAC A G A A C TAC
  42. 42. Oncogenes Mutated/damaged oncogene Oncogenes accelerate cell growth and division Cancer cell Normal cell Normal genes regulate cell growth
  43. 43. Proto-Oncogenes and Normal Cell Growth Receptor Normal Growth-Control Pathway DNA Cell proliferation Cell nucleus Transcription factors Signaling enzymes Growth factor
  44. 44. Oncogenes are Mutant Forms of Proto-Oncogenes Cell proliferation driven by internal oncogene signaling Transcription Activated gene regulatory protein Inactive intracellular signaling protein Signaling protein from active oncogene Inactive growth factor receptor
  45. 45. Tumor Suppressor Genes Normal genes prevent cancer Remove or inactivate tumor suppressor genes Mutated/inactivated tumor suppressor genes Damage to both genes leads to cancer Cancer cell Normal cell
  46. 46. Tumor Suppressor Genes Act Like a Brake Pedal Tumor Suppressor Gene Proteins DNACell nucleus Signaling enzymes Growth factor Receptor Transcription factors Cell proliferation
  47. 47. p53 Tumor Suppressor Protein Triggers Cell Suicide Normal cell Cell suicide (Apoptosis) p53 protein Excessive DNA damage
  48. 48. DNA Repair Genes Cancer No cancer No DNA repair Normal DNA repair Base pair mismatch T CATC A GTCG T CAGC A GTCG A GTG A GTAG T CATCT CATC
  49. 49. Cancer Tends to Involve Multiple Mutations Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites More mutations, more genetic instability, metastatic disease Proto-oncogenes mutate to oncogenes Mutations inactivate DNA repair genes Cells proliferate Mutation inactivates suppressor gene Benign tumor cells grow only locally and cannot spread by invasion or metastasis Time
  50. 50. Mutations and Cancer Genes Implicated in Cancer
  51. 51. Cancer Tends to Corrupt Surrounding Environment Growth factors = proliferation Blood vessel Proteases Cytokines Matrix Fibroblasts, adipocytes Invasive Cytokines, proteases = migration & invasion
  52. 52. Now, what is bone cancer
  53. 53. Bone cancer can be divided into primary bone cancer and secondary bone cancer. Primary bone cancer : a cancer started from cells in the hard bone tissue. Secondary (metastatic) bone cancer : means a cancer which started in another part of the body has spread to a bone. Definition
  54. 54. Primary Bone Cancer  uncommon cancer : It accounts for only two in every 1,000 cancers diagnosed.  Males > females  most commonly affect the long bones that up the arms and legs
  55. 55. Types of Primary bone cancer They are classified by the type of cell which occurs in the Cancer From bone forming cell (osteoblast)Osteosarcoma From mesenchymal stem cellEwing’s sarcoma From cartilage-forming cells ( chondrocyte) Chondrosarcoma Other rare types fibrosarcoma,, chondroma, multiple myeloma.
  56. 56. Primary Bone Cancer Risk Factor Radiotherapy and chemotherapy Paget’s disease Family heredity : hereditary retinoblastoma
  57. 57. Signs and symptoms  Bones pain that often is nocturnal  Swelling and tenderness near the affected area  Pathological fracture  Fatigue  Unintended weight loss  Fever  Night sweet
  58. 58. Osteosarcoma characterised by production of osteoid by malignant cells most common primary bone Incidence : 2.8 per 1 million population Age: 10-25 M>F (except parosteal osteosarcoma) Strong genetic predisposition (chromosome 13) Metastatic spread usually is pulmonary
  59. 59. Diagnosis 1.Radiology studies  X- ray  CT scan  Bone scan  MRI 2. Bone biopsy a small sample of tissue is removed from a part of the body. To be examined on microscope
  60. 60. X- ray radiographic appearance is aggressive lesion producing osteoid matrix.
  61. 61. Osteosarcoma
  62. 62. Prognosis Without metastasis the 5 years survival is 70 % If metastasis the 5 years survival is 25 %
  63. 63. Ewings sarcoma Identified en 1921 by James Ewings The second most common bone malignancies in pediatric Incidence : 0.6 per 1 million of the population M> F Age :10-20 years Metastasis 30 % most commonly in the lung and other bone , less commonly in bone marrow
  64. 64. Ewings sarcoma distribution
  65. 65. Diagnosis Radiology studies  X- ray  CT scan  Bone scan  MRI X-ray finding  Lytic medullary lesion  onion skin appearance
  66. 66. Ewings sarcoma X-ray Destructive lesion in the diaphyses of long bone with and “onion skin” periosteal reaction.
  67. 67. Ewings sarcoma
  68. 68. Prognosis the 5 years survival with the first approach is 80 % the 5 years survival with the second approach (amputation) is 75 %
  69. 69. chondrosarcoma  Males are affected about twice as frequent as females.  May also develop within a bone, or on the surface of a bone. Occur in older patients, usually in their 40s or older  Arises from cartilage-forming cells. Most common malignancy in hand
  70. 70. Diagnosis Radiology studies  X- ray  CT scan  Bone scan  MRI
  71. 71. Chondrosarcoma x - ray lesion arising in medullary cavity with irregular matrix calcification. Pattern is described as “punctate,” “popcorn,” or “comma-shaped”.
  72. 72. Chondrosarcoma
  73. 73. Prognosis Level Five years survival Grade I 90% Grade II 81% Grade III 29% Grade IV < 10%
  74. 74. Secondary bone cancer: Metastasis Many types of cancer can spread to the bone. Most commonly, cancers of the breast, prostate, lung, kidney and thyroid. Secondary bone cancer is common.
  75. 75. Pathophysiology Of bone metastases Metastases are usually osteolytic with extensive destruction of bone. Osteosclerotic (extensive formation of bone)are seen particularly in cancers of the prostate and breast.
  76. 76. Resorption / Formation
  77. 77. Vicious cycle of rank : osteolytic metastasis
  78. 78. Vicious cycle of rank : excessive bone resorption
  79. 79. Wnt secreted by tumor cells : osteoblastic phase
  80. 80. Regulation of osteoblastogenesis
  81. 81. Sclerotic Metastasis
  82. 82. Denosumab : a solution on the way
  83. 83. Bone Cancer Treatment  The treatment of bone cancer is administered by cancer specialists or oncologists  Treatment plans are designed to meet the unique needs of each person with cancer
  84. 84. Bone Cancer Treatment • Size and location of the tumor • Stage of cancer • Type of bone cancer • Ability to completely remove the tumor by surgery • Age of the person with • Overall health of the person affected Decisions relating to the treatment of bone cancer are based on the following elements
  85. 85. Bone Cancer Treatment Treatment Options for bone cancer are three in number 1. Surgery 2. Chemotherapy 3. Radiotherapy
  86. 86. Treatment option : Surgery  Resection - bone tumor and some of the neighboring normal tissue are removed.  Conserving surgery of a member - the cancer but not the arm or leg is removed.  Amputation - cancer and the member is partially or wholly removed.
  87. 87. Surgery cont’d  Curettage - tumor of bone is scraped without removing a section of bone.  Removal of metastases - We sometimes removed metastases to the lungs. Reconstruction - It helps to restore the structure and function of bone.
  88. 88. Surgery : Reconstruction
  89. 89. Treatment option : Chemotherapy  It most often used to treat Ewing's sarcoma and osteosarcoma.  It is administered prior to surgery or radiation therapy to reduce the tumor size. neoadjuvant It is given after surgery to destroy any remaining cancer cells and reduce the risk of recurrence of cancer. adjuvant
  90. 90. Treatment option : Chemotherapy  treat a recurrence of bone cancer  relieve pain or control the symptoms of bone cancer advanced stage.  It uses as the primary treatment, with or without radiation therapy to destroy cancer cells (impossible to remove by surgery)  It may be given in some cases to:
  91. 91. Treatment option : Chemotherapy  High-dose methotrexate( HDMTX)  Doxorubicin (Adriamycin)(DOXO)  Cisplatin (CDDP)  Ifosfamide (IFX or IFO) The chemotherapeutic agents most often used to treat bone cancer are:  Etoposide (ETO)  Cyclophosphamide(CTX)  Vincristine (VCR)
  92. 92. Mechanism of cytotoxic agent: cell cycle
  93. 93. mechanism cytotoxic agent :Cell cycle cont’d
  94. 94. Normal Cell cycle
  95. 95. Sites of Action of cytotoxic agents AM: Methotrexate AA: Doxorubicin PC: Cisplatin AA: Ifosfamide, Cyclophosphamide ET: Etoposide VA:Vincristine
  96. 96. Percentage of time in each portion for a neoplastic cell
  97. 97. CCS drugs/CCNS drugs AA: Methotrexate AA: Doxorubicin PC: Cisplatin AA: Ifosfamide, Cyclophosphamide ET: Etoposide VA: Vincristine
  98. 98. CCS versus CCNS CELL CYCLE SPECIFIC DRUGS (CCS) CELL CYCLE NON-SPECIFIC DRUGS (CCNS)  primary action only during specific phase of the cell cycle o plant alkaloids: G2-M o DNA synthesis inhibitors: S  any phase, including G0, although final toxicity may be manifested during a specific phase o crosslinking agents o anthracycline antibiotics • proliferating cells killed (high growth factor preferentially eliminated)  both proliferating and non- proliferating cells killed (attack both high and low growth factor tumours) • schedule dependent (duration and timing rather than dose)  dose dependent (total dose rather than schedule)
  99. 99. Mechanism of cytotoxic agents used in bone cancer Folic acid Tetrahydrofolic acid Purines Guanine Adenine Pyrimidine Cytosine Thymine Uracil nucleotide DNA mRNA Cell mitosis Proteines 1. Methotrexate 2. Ifosfamide Cyclophosphamide cisplatin 3. doxorubicin 4. Etoposide vincristine
  100. 100. Treatment option : Radiotherapy  Use is made of radiation or high energy particles to kill cancer cells.  prior to surgery or chemotherapy to reduce the size of the tumor  after surgery or chemotherapy to destroy cancer cells that remain and reduce the risk of recurrence of cancer  Radiation therapy can be administered in the presence of a bone cancer:
  101. 101. Radiotherapy cont’d  as a primary treatment, with or without chemotherapy to kill cancer cells; tumor that can not be completely removed by surgery treatment  to treat a recurrence or to relieve pain or control the symptoms of bone cancer advanced stage (palliative radiotherapy).
  102. 102. Osteogenic Sarcoma Treatment Protocols General treatment recommendations Stages IA-IB (low grade): Primary treatment includes wide excision only. Chemotherapy, either prior to excision or postoperatively, is not typically recommended Stages IIA-IVB (high grade): Chemotherapy is warranted for all stages of high-grade osteogenic sarcomas 2-3 cycles preoperatively ; 3-4 cycles postoperatively Primary, neoadjuvant, or adjuvant therapy for metastatic disease:
  103. 103. Regimen I Doxorubicin and cisplatin therapy •Doxorubicin 25 mg/m2 IV on days 1 to 3 plus cisplatin 100 mg/m2 IV on day 1; repeat cycle every 21days
  104. 104. Regimen II MAP (high-dose methotrexate, cisplatin, and doxorubicin) High-dose methotrexate 12 g/m2 IV given over 4h on weeks 0, 1, 5, 6, 13, 14, 18, 19, 23, 24, 37, and 38, alternating with cisplatin 60 mg/m2 IV plus doxorubicin 37.5 mg/m2/day IV for 2d each on weeks 2, 7, 25, and 28.  Neoadjuvant setting
  105. 105. Regimen II cont’d High-dose methotrexate 12 g/m2 IV given over 4h on weeks 3, 4, 8, 9, 13, 14, 18, 19, 23, 24, 37, and 38, alternating with cisplatin 60 mg/m2 IV plus doxorubicin 37.5 mg/m2/day IV for 2d each on weeks 5, 10, 25, and 28 ;  Adjuvant setting:
  106. 106. Regimen II cont’d •Requires administration of 15 mg leucovorin every 6h for 10 doses, starting 24h after initiation of high- dose methotrexate •If methotrexate elimination is delayed, then immediately administer 50 mg IV leucovorin every 3h until serum methotrexate levels are undetectable  precaution for MAP protocol
  107. 107. Regimen III patients receive 2 cycles of doxorubicin 90 mg/m2 and 3 cycles each of high-dose ifosfamide, methotrexate, and cisplatin 120-150 mg/m2  Doxorubicin, cisplatin, ifosfamide, and HD methotrexate Ifosfamide 15 g/m2plus methotrexate 12 g/m2plus cisplatin 120 mg/m2plus doxorubicin 75 mg/m2  Preoperatively  Postoperatively
  108. 108. Regimen III cont’d Granulocyte colony-stimulating factor (G-CSF) support is mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination •lenograstim (Granocyte®) •filgrastim (Neupogen®, Nivestim®, Ratiograstim®, ) •pegylated filgrastim (Neulasta®).  Precaution for high-dose ifosfamide/cisplatin/doxorubicin combination protocol
  109. 109. Regimen IV Ifosfamide 9 g/m2 over 5d plus etoposide 100 mg/m2 given daily for 5d Ifosfamide and etoposide protocol :
  110. 110. Treatment of Ewings sarcoma lasts 6-9 months and consists of alternating courses of 2 chemotherapeutic regimens: 1. Vincristine, Doxorubicin, and Cyclophosphamide 2. Ifosfamide and Etoposide Ewings Sarcoma Treatment: chemotherapeutics Protocols
  111. 111. Ewings Sarcoma chemotherapeutics Protocols 2 mg of vincristine /m2 , doxorubicin given as a bolus infusion at a dose of 75 mg /m2 , and 1200 mg of cyclophosphamide /m2 , followed by mesna. 1800 mg of ifosfamide /m2 per day for five days, given with mesna, and 100 mg of etoposide /m2 per day over the same five days
  112. 112. Ewings Sarcoma chemotherapeutics Protocols cont’d European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) The courses of chemotherapy is administered every three weeks for a total of 17 courses
  113. 113. Ewings Sarcoma chemotherapeutics Protocols cont’d Dose intensity is critical in the treatment of these tumors. To facilitate maximum dosing of chemotherapeutic agents, anticipatory supportive care is necessary  Neutrophil support  Red blood cell and platelet support  Surgery and/or radiotherapy
  114. 114. Ewings Sarcoma : Radiotherapy  it can be administered after surgery if the margins contain cancerous cells can not widely be removed.  We can provide a radiation therapy to treat Ewing's sarcoma located.  It uses radiation rather than surgery if the tumor is inoperable.
  115. 115. Ewing sarcoma :Surgery .  It is possible to perform the following types of surgery:  We can offer surgery to treat a localized Ewing sarcoma following chemotherapy  conserving surgery of a member;  amputation;  reconstruction.
  116. 116. Chondrosarcoma treatment Surgery is the main treatment for chondrosarcoma . Types of surgeries performed are as follows:  resection  conserving surgery a Member: The surgeon tries to use this technique whenever possible for chondrosarcoma in the arm or leg
  117. 117.  curettage curettage can be perform for low-grade tumors that are found in bone that are not a member .  amputation amputation is performed only if it is not possible to perform surgery conservation of a member or if it is impossible to reconstruct a useful member .  reconstruction Chondrosarcoma treatment
  118. 118.  a high-grade tumor, as a dedifferentiated or mesenchymal tumor.  It can be administered before or after surgery for:  a tumor that can not be completely removed by surgery because of its location  Radiotherapy can be suggest as treatment of chondrosarcoma. Chondrosarcoma treatment
  119. 119. Possible side effects of chemotherapy for bone cancer Kidney failure constipation diarrhea Skin Changes pain bone marrow aplasia Nausea and vomiting Loss of appetite Pain in the mouth Hair loss
  120. 120. Classifications of Chemotherapy Side Effects The side effects commonly associated with chemotherapy treatment are classified as: 1. Acute, which develop within 24 hours after chemotherapy administration. 3. Short term, combination of both acute and delayed effect. 2. Delayed, which develop after 24 hours and up to 6 to 8 weeks after chemotherapy treatment
  121. 121. Classifications of Chemotherapy Side Effects cont’d 4. Late/ long term, which develop after months or years of chemotherapy treatment. 5. Expected, which developed among 75% of the patients. 6. Common, occurred in 25%-75% of the patients.
  122. 122. Classifications of Chemotherapy Side Effects cont’d WHO also provides a classification of the severity of these side effects in 4 grades from lowest to highest. GO, G1 ,G2, G3,G4 9. Very rare, occur with less than 1% of the patients 8. Rare, occur in only 5% of the patients. 7. Uncommon, happened is less than 15% of the patients.
  123. 123. Methotrexate Toxicity Prevention leukopenia Folic acid (leucoverin) Digestive: diarrhea, nausea, vomiting and stomatitis hydration, antiemetics, oral hygiene Alopecia Hepatic toxicity: icterus , cirrhosis , cytolytic hepatitis monitoring of transaminases Renal toxicity: kidney failure, cystitis Alkaline hydration , Hydration by bicarbonate for 6 hours before infusion of methotrexate
  124. 124. Conclusion Primary bone cancer is rare compare to secondary bone cancer Prevention of bone metastasis remains one of the major challenges in the management of cancers. great responsibility for the clinical pharmacist in the prevention of their toxicity The discovery of denosumab is a step forward. the Association chemotherapy and surgery remains the main treatment of bone cancer. The side effects of the chemotherapy are numerous and are partly responsible for the death of patients