Malignant disorders

1. Dr. Sana’ AL Aqqad
Clinical Pharmacy, PhD
10/2/2018
1

2. Outline
1- Solid tumours
**Breast cancer
**Lung cancer
**Colorectal cancer
*Prostate cancer
*Ovarian cancer
*Melanoma
*Renal Cell carcinoma
2-Haematological Malignancies
**Lymphoma
**Leukaemia
*Multiple Myeloma
3-Chemotherapy Complications
2

3. LearningObjectives
By the end of the session, you should be able
to:
1. Cancer vs. tumour
2. Epidemiology in Palestine
3. Aetiology
4. Cancer Mechanism
5. How cancer grow & spread?
6. Screening
7. Staging
8. Sign and symptoms
9. Diagnosis
10. Treatment
11. Side effects
3

4.  2nd leading cause of death in Palestine
 In 2016, the total number of new reported cancer cases in
West Bank was 2,536 (as compared to 2,400 new reported
cases in 2015).
 Increase by 5.7%
 Incidence rate = 86.4 new cases per 100,000 populations.
4
Mortality rate
Heart Diseases 30.6%
Cancer 14%
CVA 12%
DM 8%

5.  Female > male
5

6. 6

7.  The reported cancer cases shows that Bethlehem
governorate had the highest incidence rate of
cancer cases (160.1 per 100,000 populations).
 Jericho and Al Aghwar governorate become 2nd
highest incidence rate (123.2 per 100,000
population).
 Followed by Tulkarm with an incidence rate of
108.5 per 100,000 populations.
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8. 8

9. 9

10. 10

11. 11

12.  Mortality:
 The most common cause of cancer-related deaths in WB :
 Lung CA is the most common cause of mortality among
males
 While breast CA in females was most common death case.
 Colon Cancer is the 2nd most common of mortality
among both sex.
Cancer Mortality Rate
2015
Mortality Rate
2016
Lung cancer 17.5% 18.6 %
Colon Cancer 12.4% 15.1%
Breast Cancer 11.2% 9.8%
Brain Cancer 8.9% 10.4%
Leukaemia 8.6% 6.6%
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13. 13

14.  Cancer: Uncontrolled cellular growth (grow out of body
control).
 Local tissue invasion (the surrounding tissue).
 Has ability to spread to adjacent or distant organs
(Metastasis)
 Tumour: Reserved for new growth or neoplasm (abnormal
growth tissue).
 Not all tumours / neoplasms are cancer
 Tumour classifications:
 Benign (size can affect health ??? Eg: meningioma)
 Malignant (cancer)
 Cancer  any malignant tumour or neoplasm.
14

15. Benign Malignant
Grow slowly Grow rapidly
Low mitotic index High mitotic index
Well differentiated  Poorly differentiate
(anaplasia)
 No anatomic boundaries
Usually encapsulated with
fibrous tissue
(not invasive)
Not encapsulated
(to invade)
 Do not invade local tissue
 No metastasis
 Local invasion
 Metastasis (spread
distantly through bld or
lymph)
15

16.  The mitotic index is simply a measurement to
determine % of cells undergoing mitosis.
 High mitotic index  ongoing proliferation.
 Cell differentiation: a less specialized cell becomes
a more specialized cell type (mature).
 Anaplasia: Lack of differentiation (without form).
 Anaplastic cell  usually variable shape & size.
 Low-grade dysplasia or with high-grade dysplasia
 Anaplasia is irreversible.
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17. 17
Dysplasia
 Loss in uniformity of individual cells
 abnormal growth and differentiation (not normal but that are
not obviously malignant)
 Has not spread into surrounding tissue (basement membrane)
 Can lead to malignancy

18.  2 types of cancer :
 Solid malignancy (breast, colon, lung, ,,,,,,,,)
 Haematological malignancy (leukaemia, lymphoma,
multiple myeloma).
 Cancer cells can:
1. Stimulate their own growth (sustained proliferation)
2. Resist inhibitory signals (antigrowth signals)
3. Avoid programmed cell death (Evading apoptosis)
4. Grow new blood vessels (angiogenesis)**
5. Limitless replicative (replicative immortality)
6. Invade local tissues & Spread to distant sites
(metastases).
18

19. 19

20. Benign Malignant
 Named according
to tissue rise from
(with suffix – oma)
eg: Lipoma,
adenoma, Fibroma ,
Haemangiomas,
Osteoma,
Rhabdomyoma
 Named according to cell type of
origin:
 CA in enod/epithelial tissue 
carcinoma eg: hepatocellular carcinoma
 CA in ductal/ glandular tissue 
adenocarcinoma
 CA in connective tissue/ soft tissue 
(suffix – sarcoma). Eg: CA in skeletal
muscle = rhabdomyosarcoma, CA in the
bone =Osteosarcoma
 CA in lymphoid tissue Lymphoma
 CA in bld forming cell Leukaemia
 Some named for historical reasons
20

21.  Cancer  Multi-factorial
 For normal cells to become cancer cells  physical,
chemical or biological agent must damage the cell and
cause a genetic alteration that is subsequently
propagated during cell division
Carcinogens / initiators include:
 Chemical agents: Benzene cause leukemia, drugs &
HR.
 Physical agents: Ionizing radiation and UV light
 Biologic agents: Viruses
21

22.  Environmental factors/ cofactors:
 Tobacco use nicotine (1/3 of all cancer death are linked to
tobacco): Lung, colon, bladder, pharynx, ,,,,,,,,,)
 Diet high in fat, Red or processed meat/low fibers
 Physical inactivity & obesity
 Alcohol (excessive)
 Job related factor (Asbestosis)
 Intensive sunburn. (UV radiation)gene mutation, ↑
release to TNF-ᾳ in the epidermis.
 Ionizing radiation (x-ray, gama-ray)
 Electromagnetic field ???? (thermal effect of cellular phone)
 Air pollution: Radon gas
22

23.  Hormones
 Bacteria & Viruses ** (oncogenic)
 Genetic factors (inherited)
 Age
 Gender
 Chronic inflammation** (Crohn’s disease)
 Pre- cancer conditions (Colon Villeous adenoma)
 Role of immune system is complex
 immunodeficiency inc. risk of viral associated cancer
23

24.  Viruses
 Epstein virus (EBV)  Burkitt lymphoma
 Kaposi sarcoma herpesvirus  Kaposi sarcoma
 Hep. B or C Liver cancer (hepatocellular)
 Human papillomavirus (HPV) Cervical cancer
 Retrovirus  T-cell leukaemia/ lymphoma
 Bacteria
 Helicobacter pylori (H. pylori) B cell lymphoma with the
stomach
 Tumour arise in the mucosa- associated lymphoid tissue
(MALT)
 Chronic inflammation:
 Crohn’s disease, ulcerative colitis (over 10 ys  incr. colon
CA by 30 folds)
 Hep. B & C (chronic inflame.) liver CA
24

25.  Lifestyle factors  Primary prevention
 Screening  Secondary prevention
Designed to detect signs of cancer/pre-clinical cancer in
people who have not yet developed symptoms from
cancer.
25

26.  Cancer screening programs
 Signs & symptoms (vary widely/depend on the cancer,
some non- specific)
 **Tumour Markers (CA 125, CEA, CA 19-9)
 7 Warning Signs of Cancer (ADULT)
 C: Change in bowel or bladder habits
 A: A sore that does not heal
 U: Unusual bleeding or discharge
 T:Thickening or lump in breast or elsewhere
 I: Indigestion or difficulty in swallowing
 O: Obvious change in wart or mole
 N: Nagging cough or hoarseness
26

27.  Tumour markers (Biological markers)
substances produced by cancer (or other) cells of the body in
response to cancer or certain benign (noncancerous)
conditions.
 Produced at much higher levels in cancerous conditions.
 Found in:
blood, urine, stool, tumour tissue, or other tissues or bodily
fluids of some patients with cancer
 Could be:
 Hormones, Enzyme, Genes, Antigens, Antibodies
 Used for: Screening, help in diagnosis, follow with the
clinical course of cancer.
27

28.  Examples:
 CA 125 Ovarian cancer
 CEA (carcinoembryonic Ag) Colon, others
 CA 19-9  Panceatic, gallbladder, bile duct, gastric.
 AFP (alpha fetoprotein) Hepatic, (germ cells)
 PSA (prostate spesific Ag) Prostate
 BRAC 1, BRACA 2 gene mutation  Breast, ovaries
 HER2/neu (proto-oncogene)  breast cancer
28

29.  TNM System (tumor, nodes, metastasis)
 T – primary tumor size
 T1-T4
 Usually based on the size of the primary tumor
 N – extend of lymph nodes involvement
 N0 – N3
 N0 – no lymph nodes involved
 Extent and quality of nodal involvement – not
necessarily # of nodes involved
 N3 – more extensive nodal involvement than N1
 M – metastasis (spread of cancer cells from the primary
tumor site to distant sites)
 M0 – no distant metastases found
 M1 – distant organs have cancer cells present
29

30.  For staging:
 Biopsy
 Radiographs
 Computed tomography scans (CT)
 Magnetic resonance imaging (MRI)
 Positron emission tomography (PET) scans (can
show the location of the cancer, the size of the
tumor, and whether the cancer has spread)
 Ultrasound
 Bone marrow biopsies
 Bone scans
 Lumbar puncture
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31.  To simplify the staging process:
 stage I-IV
 Stage I: localized tumor
 Stages II and III : local & regional spread of disease
 Stage IV: distant metastases
Example:
T3 N1M0:
moderate-large, with regional lymph node
involvement and no distant metastases and for most
cancers is stage III
*** Staging of cancer help to determine prognosis and
treatment. (should be staged before treatment )
31

32.  Exact mechanisms incompletely understood.
 Carcinogenesis:
 Change from normal tissue to tumour
 Genetically regulated.
 Multiple genetic mutations are required to convert
normal cells to cancerous cells.
 Carcinogens: Substances and exposures that can lead to
cancer. (not in all case cause cancer)
 Substances labeled as carcinogens may have different
levels of cancer-causing potential.
i.e; Some cause cancer only after prolonged, high levels
of exposure, particular person.
 Carcinogenesis is multistep process (4 steps).
32

33. 33
Takes months-
years
Muted cell 
cancerous cell

34. 34

35.  Oncogenes & tumor suppressor genes major classes of
genes involved in carcinogenesis
1. Tumor suppressor genes (Retinoblastoma(Rb)
and p53genes) regulate & inhibit inappropriate cellular
growth & proliferation.
 If agents damage DNA cell P53 accumulate  Switch off
replication of abnormal cells  arresting in the cell cycle
(time to repair) if not repair  trigger apoptosis.
 If normal cell lose/impaired p53 function, uncontrolled
growth will result, produce malignant clones.
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36. 36
Guardians
Caretakers

37.  If normal cell lose/impaired p53 function,
uncontrolled growth will result, produce malignant
clones.
37

38. 2. Alternatively, cells in which oncogenes are activated may
also give arise to malignant clones.
 Oncogenes: genes responsible for malignant transformation.
 Oncogenes: develop from normal genes (proto-oncogenes),
have important roles in all phases of carcinogenesis.
 Mutation of p53 is one of the most common genetic changes
associated with cancer, (estimated to occur in half of all
cancers)
 Proto-oncogenes : in all normal cell, control how
often cell divides/ regulate normal cellular function.
 Proto-oncogenes genetic alteration  oncogenes
 no regulation on how quickly the cells divides.
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39.  Oncogene examples:
Human epidermal growth factor receptor EGFR.
I. Human epidermal growth factor receptor type 1
(HER 1) technically called epidermal growth factor
receptor EGFR
II. Human epidermal growth factor receptor type 2
(HER 2)
{This family of receptor tyrosine kinases contains 4 members:
epidermal growth factor receptor (EGFR), HER2, HER3, and
HER4}.
 Cancer cell differ from normal cell (function, display
different proteins/enzymes, appearance, susceptibility
to chemotherapy/ radiotherapy).
39

40.  A mutation: a change that occurs in our DNA sequence,
either due to mistakes when the DNA is copied or as the
result of environmental factors (UV light and cigarette
smoke).
 Could be hereditary or acquired.
 Most CA happened by chance and not inherited
(Acquired sometime during life).
 Most of those genetic events occur in somatic cell, so not
inherited.
 If occur in germline cells  vertical transmission of CA
from generation to other.
Eg: Rb gene Retinoblastoma (child eye CA,), BRACA1 (breast CA),
APC (familial polyposis coli)
40

41.  Mutation create oncogenes:
 Point mutation
 Chromosome translocation
 Chromosome amplification
 Tumour suppressor gene mutation:
 Loss of heterozygosity
 Gene silencing
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42.  Angiogenesis:
 It is formation of new blood vessels.
 Plays critical role in growth/spread of cancer
(metastasis).
 Controlled by chemical signal in the body:
1. Angiogenesis activators (formation of new bld
vessels & repair damages vessels) eg: Vascular
endothelial growth factor (VEGF)
2. Angiogenesis inhibitors (interfere with bld vessels
formations).
 Tumour can give chemical signals to stimulate
angiogenesis.
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43. Tumour Growth Tumour Spread
 Local invasion: destruction
of the surrounding tissue
 Metastasis: Tumour cells
leave original tumour and
implanted in other place.
 Metastasis pathways:
Malignant cells can
infiltrate bld & lymphatic
vessels, proliferate at
other sites.
 Seeding.
 Pattern of spread tend to
be predictable.
 New bld vessels ‘‘feed’’
growing tumours with O2
& nutrients, allowing
cancer cell to invade
nearby tissue, form new
colonies.
 Cancer cells without bld
circulation grow 1-2 mm3
diameter then stop, but
grow beyond 2 mm3 in
area where angiogenesis
possible.
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44. Tumour Growth Tumour Growth
 Doubling time (time it
takes for tumour mass to
double in size) for most
solid tumours is 2-3
months.
 Most solid tumours,
growth rate is very rapid
initially then slow as the
tumour increase in size &
age.
 Growth fraction: the % of
actively dividing cells in
the tumour.
 Growth fraction:
Decreases with tumour
size.
 Early stage: high growth
fraction, more sensitive
(successful) to
chemotherapy.
 Late stage: low growth
fraction, less sensitive to
chemotherapy (Less
responsive to cell cycle-
specific drugs, more
responsive to DNA damage
drugs)
 Chemotherapy most
successful when the
number of the tumour cells
is low and the growth
fraction is high (early stage).
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45. 45

46. 1. Local
a) Surgery:
 Treatment of choice for most solid tumors.
 Can be curative in early stage/localized disease.
 Play role in diagnosis/staging.
 De-bulk (reduce tumour size).
b) Radiotherapy:
 Therapy use ionizing radiation
 Destroys the cancer cells in the treated area by
damaging the DNA within these cells.
 Curative, adjuvant ‫,مساعد‬ synergistic, palliative
therapy).
46

47. 2. Chemotherapy
 Target rapidly dividing cells.
 Cancer cell divided more rapidly than normal cell.
 Non- selective cytotoxic drugs
A. Cell Cycle phase Specific: Generally given more
frequently or as continuous infusions.
B. Nonspecific chemotherapies: usually given as a
single dose.
 More usual to combine 2 or more drugs for additive/
synergistic effects, avoid single drug resistance.
 Chemotherapy dose base on Body surface area (BSA):
mg/m2
m2 = √[( Height (cm) x Weight (kg) / 3600]
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48. 48

49. 3. Targeted therapy: targeted specific cell receptors.
eg: Tyrosin kinase inhibitor
4. Biologic therapy:
eg: MoABs, growth factors inhibitors, cytokines.
5. Hormonal/endocrine therapy
 Depends on cancer type (Breast, prostate, endometrial,
adrenal, lymphoma, leukemia).
 Receptor activation or blocking
 Eg: Aromatase inhibitors, estrogens, androgens, LH-RH
analogos, corticosteroids.
6. Usually Combinations (Local + Systemic).
49

50.  Systemic therapy (solid tumours) can be used as:
Adjuvant therapy  Eradicate micrometastatic disease.
 After local therapy.
 Reduce recurrence rate & prolong
survival
Neo-adjuvant therapy  Before surgery to shrink a large
tumour and make it amendable to
surgical resection.
 Chemo. prior local therapy
 Reduce tumour burden & eliminate
any micrometastatic disease.
Palliative therapy  Symptoms management, disease
control.
50

51.  Treatment goals:
 Cure is the primary goal of treatment.
 If cure not feasible, the goal is to prolong survival while
maintaining patient QoL.
 If not, then the 3rd goal is palliative care with relief of
symptoms (pain).
51

52.  Response to chemotherapy:
1. Complete response (remission):
 Disappear of all cancer for at least 1 month (no sign &
symptoms).
 No evidence of new disease
 Disappear of all target lesions
2. Partial response:
 No new lesions for at least 1 month
 ≥ 50% decrease in tumour size.
52

53. 3. Progression
 Occurrence of any new lesion or increase in diameters of the
disease.
 Increase of cancer signs & symptoms.
 ≥20% increase in tumour size
4. Stable disease:
 No change
 Change is smaller than those describe in partial response or
less than progressive disease for at least a month.
5. Relapse:
After partial or complete remission
53

54.  Alkylating agents:
 Damage DNA directly (not phase specific)
 2ndry malignancy, dose dependent (5-10 years)
eg: Cyclophosphamide, Ifosfamide, Chlorambucil. Melphalan
 Common toxicity:
 Cyclophosphamide (Oral, IV)
 Haemorrhagic cystitis ( W/ ↑ dose)
 2ry malignancy
 Infertility
 Ifosfamide (Ifex)® (IV)
 CNS toxicity. (somnolence, hallucination, confusion, agitation)
 Haemorrhagic cystitis (give with Mesna)
54

55.  Use Mesna (Uroprotection)
 Acrolein is urologic metabolite (excreted into urine)
 Mensa bind to Acrolein acrolein inactivation
 Mesns Dosing: (prophylaxis) :
60% of ifo/ dose (divided into 3 doses 0,4,8 hrs).
i.e: If receiving 1.2 g/m² ifosfamide dose:
60% X 1200 mg/m² = 720 (720 divide to 3 doses)  240
mg/m² 15 minutes before & 4 & 8 hours after ifosfamide
administration.
 The incidence of haemorrhagic cystitis is considerably
lower with cyclophosphamide as compared with ifosfamide
 Mesna use is unnecessary with standard doses of
cyclophosphamide i.e.<1g/m²
55

56.  20% of cyclophosphamide dose when injected, 4 and 8
hours after each dose
 Neurotoxic chloroacetaldehyde (Metabolite) from
ifosfamide
 Antimetabolites:
 Interfere with DNA & RNA growth (damage the cell
during S phase).
 Purine Antimetabolites , Pyrimidine antimetabolites.
56
 5-fluorouracil (5-FU)
 6-mercaptopurine (6-
MP)
 Capecitabine (Xeloda®)
 Cytarabine
 Fludarabine
 Gemcitabine (Gemzar®)
 Hydroxyurea
 Methotrexate
 Pemetrexed
Antifolates

57.  Microtubule-targeting drug (mitotic inhibitors)
 Most commonly natural product/plant alkaloids
 M-phase specific (stop mitosis)
 These drugs may cause nerve damage (peripheral
neuropathy)which can limit the amount that can be given.
I. Vinca alkaloids: Vincristine (Oncovin®), Vinblastine,
Vinorelbine.
(S.E; periephtal neuropathy, alopecia, constipation)
II. Taxins: (Pacific Yew tree)
 Pacliaxel (Taxol®) S.E: hypersensitivity*,
myelospression (DLT), peripheral neuropathy (Cum
CDT), alopecia
 Docetaxel (Taxotere®)S.E: Fluid retention syndrome*,
myelospression (DLT) & febrile neutropinea, alopecia,
peripheral neuropathy
57

58. *** Premedication to prevent hypersensitivity rxn. with
Paclitaxel:
Dexamrthasone 20mg IV (or PO at 12hr & 6 hrs before the
dose), 50mg IV diphenhydramine, 50 mg Ranatidine 30
minutes before the treatment.
*** Premedication to prevent fluid retention syndrome in
Docetaxel:
Dexamrthasone 8mg PO BID X 3 days starting day before the
dose of docetaxel)
58

59.  Topisomerase Inhibitors (I, II):
 Interfere with enzymes topoisomerases (help separate
the strands of DNA so they can be copied)
 Interfere DNA synth.
 Topoisomerase inhibitors are grouped according to
which type of enzyme they affect (Topo. I, Topo. II)
 Inhabit Topoisomerase inhabit break single/double
DNA strand  no copies.
 Risk 2dry Leukemia (AML 2-3 Y), especially Topo.II
 Eg: Topo.I initiators: Irinotecan (G2 Phase), Topotecan
 Eg. Topo.II initiators: Etoposide (G2/S phase),
anthracyclines, Mitoxantrone (Mitoxantronealso acts as an
anti-tumor antibiotic)
59

60.  Antitumor antibiotics.
 Anthracyclines:
 Multiple mechanisms of action: topoisomerase II inhibitors,
antitumor antibiotics
 Cell-cycle non specific
 Doxorubicin (Adriamycin®)
 Daunorubicin
 Epirubicin
 Idarubicin
 Work in all cell phases (inhabit DNA replication)
 Cardiac toxicity (free-radical formation)
 Give Dexrazoxane  cardio-protective
 Anti-tumor antibiotics that are not anthracyclines
 Mitoxantrone (less cardiac toxicity)
 Bleomycin
60

61.  Miscellaneous agents:
I. Anti-tumour antibiotic:
Mitomycin C
Bleomycine
 (Inhibits DNA synthesis).
 Bleomycine effect on cells in the G2 and M phases
of the cell cycle
 baseline pulmonary function tests and monitoring
for pulmonary toxicity are necessary for
Bleomycine Tx.
61

62. II. Platinum analogues:non-cell cycle specific
Cisplatin (Plantinol),
Carboplatin
Oxaliplatin
 S.E Cisplatin: Nephrotoxicity (renal tubular necrosis),
Ototoxicity
 Carboplatin: Low incidence nephrotoxicity
 Prevention of nephrotoxicity: Aggressive hydration
maintain high urine flow (1L pre/post NS over 2hrs)
 Aggressive use of anti-emitting agents
62

63.  Targeted therapy (inhibit intracellular signaling)
 Tyrosin kinase inhibitor :
 Oral agents (small molecules)
 Competitive ATP inhibition
 Tyrosine kinases are proteins that cells use to signal to each
other to grow. They act as chemical messengers.
 It transfer a phosphate group from ATP to a tyrosine
residue in a protein.
 Tyrosine kinase enzyme, is stuck on the "on" position, and
keeps adding phosphate groups
 Examples:
1. Imatinib (Gleevec®) (treatment option for newly
diagnosed Philadelphia chromosome +ve (Ph+) CML)
(BCR-Abl)
2. Nilotinib (Tasigna®): Treat leukaemia. QT prolongation
63

64.  Monoclonal Antibodies (MoABs):
 Designed to target particular antigen.
 Bind to extracellular receptor & prevent the activation
of intracellular signaling
 Consists of IMG sequences, which recognize specific
cell surface antigen (protein)
 Induce apoptosis, block growth factor receptors
 Infusion related rxn.
 Bevacizumab(Avastin®),
 Rituximab (Rituxan®),
 Trastuzumab (Herceptin®)
64

65. 65

66.  Short term S.E:(General)
 GI symptoms: N/V/Diarrhoea/constipation
stomatitis, mucositis (Tx: antiemeting, good oral care)
 Loss of appetite
 BM suppression/myelosuppression (WBC, RBC, Plt)
 Fatigue ( anaemia)
 Loss of hair (alopecia) temporary
 Bleeding ( plt)
 Dermatitis (skin) (↓renewal of epidermal layers)
66

67.  Long term S.E
1. Infertility:
 eg: Alkylating agent: (cyclophosphamide ), Procarbazine.
 For men, even a single dose of nitrogen mustard
or chlorambucil can cause sterility
2. 2ndary malignancy:
 Etoposide (topoisomerase II inhibitor) AML (2-3 Y),
 cyclophosphamide dose dependent (5-10 y)
3. Heart failure
Anthracyclines
67

68.  Extravasation
 It is severe tissue damage
 (Complication)
 The incidence is decreasing probably due to improvements
in the infusion procedure, early recognition of drug leakage
and training in management techniques
68

69. Specific side effects
(Some irreversible)
Doxorubicin Cardiotoxicity
Bleomycin Lung fibrosis
Vinblastine Myelosuppression
Vincristine Neurotoxicity (Peripheral neuropathy)
Procarbazine Impairment of fertility
Cyclophosphamide Haemorrhagic cystitis
Methotrexate Stomatitis
Cisplatin Nephrotoxicity (renal tubular necrosis)
69

70. THANKS
70