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

1. BONE CANCER
Youan Bi Beniet Marius, PharmD, Master of
clinical pharmacy. University of Nairobi

2. OUTLINES
 UNDERSTANDING BONE
 UNDERSTANDING CANCER
 BONE CANCER
 TREATMENT OF BONE CANCER

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. 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. 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. Classification of bones

7. Macroscopic structure of bone

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. Microscopic Structure of Bone:
Trabecula of Spongy bone

10. Cellular structure

12. 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

14. 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

15. 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

16. Endochondral Ossification

17. 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

18. 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

19. 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

20. Bone remodeling steps

22. Regulation of Osteoclastogenesis
by RANK & OPG

23. Regulation of Osteoclastogenesis cont’d

24. Balance RANKL/OPG in Bone resorption

26. Regulation of osteoblastogenesis

28. 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

29. 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:

30. 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

31. 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

32. 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

33. Example of Normal Growth
Cell migration
Dead cells
shed from
outer surface
Epidermis
Dividing cells
in basal layer

34. The Beginning of Cancerous Growth
Underlying tissue

35. Tumors (Neoplasms)
Underlying tissue

36. 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

37. 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

38. What Causes Cancer?
Some viruses or bacteria
Heredity
Diet
Hormones
RadiationSome chemicals

39. Viruses
Virus inserts
and changes
genes for
cell growth
Cancer-linked virus

40. Examples of Human Cancer Viruses
Some Viruses Associated with Human Cancers

41. Bacteria and Stomach Cancer
H. pyloriPatient’s
tissue sample

42. Heredity and Cancer
Inherited factor(s)
All Breast Cancer Patients
Other factor(s)

43. Heredity Can Affect Many Types of Cancer
Inherited Conditions That Increase Risk for Cancer

44. Genes and Cancer
Chromosomes
are DNA
molecules
Heredity
RadiationChemicals
Viruses

45. DNA Structure
DNA molecule
Chemical
bases
G
C
T
A

46. 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

47. Oncogenes
Mutated/damaged oncogene
Oncogenes
accelerate
cell growth
and division
Cancer cell
Normal cell Normal
genes
regulate
cell growth

48. Proto-Oncogenes and Normal Cell Growth
Receptor
Normal Growth-Control Pathway
DNA
Cell proliferation
Cell nucleus
Transcription
factors
Signaling enzymes
Growth factor

49. 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

50. 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

51. Tumor Suppressor Genes
Act Like a Brake Pedal
Tumor Suppressor
Gene Proteins
DNACell nucleus
Signaling
enzymes
Growth factor
Receptor
Transcription
factors
Cell proliferation

52. p53 Tumor Suppressor Protein
Triggers Cell Suicide
Normal cell Cell suicide
(Apoptosis)
p53 protein
Excessive DNA damage

53. 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

54. 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

55. Mutations and Cancer
Genes Implicated in Cancer

56. Cancer Tends to
Corrupt Surrounding Environment
Growth factors = proliferation
Blood vessel
Proteases
Cytokines
Matrix
Fibroblasts,
adipocytes
Invasive
Cytokines, proteases = migration & invasion

57. Now, what is
bone cancer

58. 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

59. 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

60. 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.

61. Primary Bone Cancer Risk Factor
Radiotherapy and chemotherapy
Paget’s disease
Family heredity : hereditary
retinoblastoma

62. 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

63. 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

65. 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

66. X- ray
radiographic
appearance
is aggressive
lesion
producing
osteoid
matrix.

67. Osteosarcoma

68. Prognosis
Without metastasis the 5
years survival is 70 %
If metastasis the 5 years
survival is 25 %

69. 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

70. Ewings sarcoma distribution

71. Diagnosis
Radiology studies
 X- ray
 CT scan
 Bone scan
 MRI
X-ray finding
 Lytic medullary lesion
 onion skin appearance

72. Ewings sarcoma X-ray
Destructive
lesion in the
diaphyses of long
bone with and
“onion skin”
periosteal
reaction.

73. Ewings sarcoma

74. Prognosis
the 5 years survival with the
first approach is 80 %
the 5 years survival with the
second approach (amputation)
is 75 %

75. 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

77. Diagnosis
Radiology studies
 X- ray
 CT scan
 Bone scan
 MRI

78. Chondrosarcoma x - ray
lesion arising in
medullary cavity with
irregular matrix
calcification. Pattern is
described as
“punctate,” “popcorn,”
or “comma-shaped”.

79. Chondrosarcoma

80. Prognosis
Level Five years survival
Grade I 90%
Grade II 81%
Grade III 29%
Grade IV < 10%

81. 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.

82. 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.

83. Resorption / Formation

84. Vicious cycle of rank : osteolytic
metastasis

85. Vicious cycle of rank : excessive
bone resorption

86. Wnt secreted by tumor cells :
osteoblastic phase

87. Regulation of osteoblastogenesis

88. Sclerotic Metastasis

89. Denosumab : a solution on the way

90. 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

91. 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

92. Bone Cancer Treatment
Treatment Options for bone cancer are
three in number
1. Surgery
2. Chemotherapy
3. Radiotherapy

93. 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.

94. 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.

95. Surgery : Reconstruction

96. 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

97. 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:

98. 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)

99. Mechanism of cytotoxic agent:
cell cycle

100. mechanism cytotoxic agent :Cell
cycle cont’d

101. Normal Cell cycle

102. Sites of Action of cytotoxic agents
AM: Methotrexate
AA: Doxorubicin
PC: Cisplatin
AA: Ifosfamide,
Cyclophosphamide
ET: Etoposide
VA:Vincristine

103. Percentage of time in each portion
for a neoplastic cell

104. CCS drugs/CCNS drugs
AA: Methotrexate
AA: Doxorubicin
PC: Cisplatin
AA: Ifosfamide,
Cyclophosphamide
ET: Etoposide
VA: Vincristine

105. 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)

106. 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

107. 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:

108. 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).

109. 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:

110. 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

111. 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

112. 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:

113. 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

114. 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

115. 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

116. Regimen IV
Ifosfamide 9 g/m2 over 5d
plus etoposide 100 mg/m2 given daily for 5d
Ifosfamide and etoposide protocol :

117. 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

118. 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

119. 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

120. 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

121. 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.

122. 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.

123. 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

124.  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

125.  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

126. 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

127. 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

128. 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.

129. 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.

130. 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

131. 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