ICT role in 21st century education and it's challenges.
01-Ca Intro_2016.pdf pharmacy student ca
1. Fekede B. (M.Pharm, RPh)
Mobile: +251911758845
Email: fekedeb@gmail.com
Institutional Email: fekede.bekele@ju.edu.et
Cancer Treatment
and
Chemotherapy
2. Introduction
Cancer is a group of many different diseases characterized
by uncontrolled cellular growth, local tissue invasion, and
distant metastases
It may spread to other parts of the body through the
lymphatic system or the blood stream.
It arises from the transformation of normal cells into tumor
cells in a multistage process.
Progresses from a pre-cancerous lesion to a malignant
tumor.
2
3. Introduction ….
3
The changes are the result of the interaction b/n a person's
genetic factors and external agents;
physical carcinogens [eg, UV and ionizing radiation]
chemical carcinogens [asbestos, components of tobacco smoke,
food contaminants)
biological carcinogens, such as infections from certain viruses,
bacteria, or parasites
Ageing ….. also a factor for the development of cancer.
4. Introduction ….
4
It is characterized by…..
uncontrolled cellular growth
local tissue invasion
distant metastases
5. Introduction ….
5
Cancer is a leading cause of death worldwide,
nearly 10 m deaths in 2020, or nearly one in six deaths.
The most common cancers ….
breast, lung, colon and rectum and prostate
1/3rd of deaths from ca …. due to the following behavioral
and dietary risks:
high BMI, low fruit and vegetable intake, lack of physical activity,
tobacco use, alcohol use.
tobacco use ….. ~22% of cancer deaths
https://www.who.int/news-room/fact-sheets/detail/cancer
6. Introduction ….
Cancer-causing infections, such as human papillomavirus
(HPV) and hepatitis …
responsible for ~30% of cancer cases in low- and lower-
middle-income countries
Many cancers can be cured if detected early and treated
effectively.
6
https://www.who.int/news-room/fact-sheets/detail/cancer
8. Cancer Types
8
Categorized based on the functions/locations of the cells
from which they originate;
Tumors are named based on the tissue of origin.
Carcinoma:
a tumor derived from epithelial cells, those cells that line the
surface of our skin and organs
accounts for….80-90% of all cancer cases
Sarcoma:
malignant growths of muscle or connective tissue
9. Cancer Types….
9
Leukemia:
a cancer derived from white blood cells or their precursors.
Lymphoma:
a cancer of bone marrow derived cells that affects the lymphatic
system.
Myelomas:
a type of blood cancer that develops from cells in the bone
marrow called plasma cells.
a cancer of plasma cells, a type of white blood cell normally
responsible for producing antibodies.
10. Characteristics of Cancer Cells
10
Tumors …. may be either benign or malignant.
Benign tumors are noncancerous growths
The cells of benign tumors resemble the cells from which they
developed.
seldom metastasize
rarely recur after removal
Malignant tumors invade and destroy the surrounding tissue.
tend to metastasize
recurrences are common after removal or destruction of the
primary tumor.
11. Characteristics of Cancer Cells….
11
Excessive autonomous cell growth
Tumor cells produce growth factors that stimulate their own
proliferation
angiogenesis …a critical element in primary tumor growth and
metastasis
Invasiveness
ability to grow into adjacent tissue
marked by a tendency to spread into healthy tissue
12. Characteristics of Cancer Cells….
12
Ability to metastasize
metastasis is the spread of cancer cells from the primary tumor
site to distant sites.
when distant metastases are clinically evident, cancers are
seldom curable.
hematogenous & lymphatic…the primary pathways of metastasis
Defective differentiation and immortality
uncontrolled growth of less differentiated cells
failure of cancer cells to undergo programmed cell death.
13. Cancer response criteria
13
The response definitions are applicable to solid tumors b/c
leukemias & multiple myeloma are not characterized by
discrete, measurable masses.
Cure is considered when….
a patient is entirely free of disease and has the same life
expectancy as someone without cancer.
the patient is alive 5 years from the time of diagnosis without
disease recurrence.
breast cancer and melanoma patients are still at significant risk
of relapse after 5 years.
14. Cancer response criteria ….
14
Complete response (CR)
When a patient experiences complete disappearance of all
cancer without evidence of new disease for at least 1 month
after treatment.
Although an individual must have a CR to be cured, many
individuals who achieve a CR will eventually relapse.
Partial response
a 30% or greater decrease in the tumor size or other disease
markers and has no evidence of any new disease for at least 1
month.
15. Cancer response criteria ….
15
Progressive disease
When a patient experiences a 20% increase in tumor size or
they develop new lesions while receiving treatment.
Stable disease
When a patient's tumor neither grows nor shrinks
Clinical benefit
When a patient experiences subjective improvement in their
disease (decrease in pain or analgesic consumption or
improved quality of life or functional status) without an
objective response.
16. Cancer response criteria ….
16
Survival endpoints
Disease-free survival how long a patient survives without the
cancer
Progression-free survival how long a patient survives without
disease progression
17. Principles of Chemotherapy
17
Primary induction chemotherapy
when surgery is not an option and chemotherapy will be
administered on its own.
Adjuvant chemotherapy
when the most appropriate course of action is surgery but when
it is followed by chemotherapy that is aimed to kill microscopic
cells not removed during surgery or those that traveled to other
parts of the body as a result of surgery.
18. Principles of Chemotherapy….
18
Neoadjuvant chemotherapy
giving chemotherapy before surgery to de-bulk the tumor,
making its removal easier.
combination of chemotherapy and radiation therapy can be
used.
Consolidation or intensification chemotherapy
giving chemotherapy to sustain a remission once a remission is
achieved.
19. Principles of Chemotherapy….
19
Maintenance chemotherapy
giving low doses of chemo to assist in prolonging remission and
to prevent the cancer from recurring,
may include combination chemotherapy,
only used for certain types of cancer ….
acute lymphocytic leukemia and acute promyelocytic
leukemia.
20. Principles of Chemotherapy….
20
The main goals of treatment with chemotherapy are
determined by….
the cancer type and stage
Goals
to cure the cancer
to control the cancer (prolongation of life)
to relieve symptoms caused by the cancer
21. Principles of Chemotherapy….
21
Single drugs at tolerable doses rarely able to cure cancers.
Combinations of chemotherapeutic agents are often used to
take advantage of…..
different mechanisms of action to avoid resistance
different toxicity profiles
possible synergistic actions
22. Principles of Chemotherapy ….
22
Drugs with non-overlapping mechanisms of action and
toxicities are preferable for combination use.
Drugs are chosen based on non-overlapping toxicities;
to minimizes the risk for permanent organ damage or lethal
toxicity caused by overloading individual organs.
Drugs should have different mechanisms of action;
Attacking multiple targets is better than risking the selection of
resistant clones.
23. Principles of Chemotherapy ….
23
Drugs should be given at optimal doses and schedules.
The goal is to maximize cell kill and avoid unnecessary toxicity,
drug resistance
Doses should be individually titrated.
Standard toxicity criteria for each organ system allows for
adequate recovery between cycles, while helping to keep
cycles on schedule at the maximum tolerated dose.
24. Chemotherapy Cycles
24
There are a wide variety of chemotherapy regimens, and
their use varies depending on the type of cancer and patient
factors.
Generally, chemotherapy doses are administered in cycles;
it gives the patient time to recover from the toxicities.
cycles are courses of chemotherapy and are usually defined
by number of days.
cycles may be the same each time or vary based on toxicity
concerns or the protocol being used.
25. Chemotherapy Cycles…
25
Dose-dense chemotherapy (DDC) …….
shortens the time between cycles, (e.g., every 2 weeks instead
of every 3 weeks)
shorten the overall time of therapy,
decrease the amount of time that the tumor can grow between
cycles
Dose-intense chemotherapy (DIC) …..
ing the total dose of chemo given during a fixed cycle
period
26. Calculating Chemo Doses
26
In the early days most chemotherapy was given at fixed
doses or doses based on body weight.
Currently, most chemotherapeutic agents are dosed by
body surface area as an estimate of blood volume,
cardiac output, and resulting drug distribution to the
kidneys and liver.
27. Calculating Chemo Doses….
27
Limitation of dosing based on BSA and the accuracy of BSA
calculations.
BSA has been called one of the most difficult human
measurements to determine since there is no accepted way to
measure it.
the weight to use in BSA calculations
Actual body weight is most often used, but some clinicians prefer
to use an adjusted body weight in obese patients (>30% over
ideal body weight)
28. Calculating Chemo Doses….
28
Prescribers are encouraged to write out their calculations
and equations on the order form of standardized chemo
order forms.
Errors in dosing equations account for >15% of prescribing
errors and BSA-based dosing is very calculation intense.
It is recommended to recalculate doses when body weight
changes by more than 5% to 10%.
29. Calculation of body surface area
29
DuBois method:
Mosteller equation for BSA:
BSA(m2) = 0.007184 x Wt (kg)0.425 x Ht (cm)0.725
30. Calculation of body weight
30
Ideal body weight in kg (IBW):
Males IBW = 50kg + 2.3kg for each inch over 5 feet
Females IBW = 45.5kg + 2.3kg for each inch over 5 feet
Adjusted body weight in kg (ABW):
ABW = IBW + 0.4 x (actual weight - IBW), or
ABW = (IBW + actual weight) / 2
31. Measurements necessary to administer
chemotherapy
31
Monitor several clinical and lab values
before administration of myelosuppressive agents
WBC >3,000 cells/mm3 or ANC >1,500 cells/mm3
Platelet count >100,000 cells/mm3
These parameters may not apply when the cancer is of the
bone marrow such as with leukemia.
Renal function
Hepatic function
32. Cancer treatment
32
Classical types of cancer treatment…often in combination,
either simultaneously or sequentially;
Surgery: first line for many solid tumors. If the cancer is detected
at an early stage, surgery may be curative.
Radiation: The goal of radiation is to kill the cancer cells directly
by damaging them with high energy beams.
Chemotherapy: a term used for a wide array of drugs used to
kill cancer cells.
Hormonal treatments: drugs designed to prevent cancer cell
growth by preventing the cells from receiving signals necessary
for their continued growth and division.
33. General rules of chemotherapy
33
Some supportive therapies:
Antiemetics (5-HT3 -antagonists)
Amifostine: reduces hematotoxicity, ototoxicity and neurotoxicity
of alkylating agents
Antifolate (methotrexate) ………. folate (leucovorin)
Antibiotic prophylaxis and therapy (febrile neutropenia)
Prophylaxis of urate nephropathy (allopurinol)
Enteral and parenteral nutrition
Analgesic drugs for pain
Psychological support
34. General rules of chemotherapy….
34
Cell cycle phase-specific
Agents with major activity in a particular phase of cell cycle
schedule dependent
Cell cycle phase-nonspecific
Agents with significant activity in multiple phases
dose dependent
35. Phases in the cell cycle
35
G0: Resting phase
G1: Growth,
prereplicative
phase
S: DNA-synthesis
and replication
M: The chromosomes
are separated
(mitosis) & the cell
divides into two
daughter cells
G2: The cell checks that
DNA-replication is
completed & prepares
for cell division
37. Antimetabolites
37
Antimetabolites induce cell death during ……
the S phase when incorporated into RNA and DNA, or
inhibit enzymes needed for nucleic acid production.
When the cancer cell uses an antimetabolite instead of the
natural substances, it cannot produce normal DNA or RNA
and the cell dies.
These agents are used for ……….
a variety of cancer therapies including …..
leukemia, breast, ovarian and gastro-intestinal cancers.
39. 5-FU
39
Incorporates into RNA and interferes with RNA function;
Inhibits the activity of thymidylate synthase and inhibits
DNA synthesis.
thymidylate synthase …an enzyme required for synthesis of
thymidine.
5-FU is a prodrug
Widely used in the treatment of cancer including …
colorectal, breast cancer
cancers of the digestive tract
40. 5-FU…
40
5-FU may be administered by ….
bolus IV or continuous IV infusion
Method of administration influences its mechanism of action;
continuous-infusion regimens ….role in thymidylate synthesis
inhibition
intermittent bolus schedules ….. more important for incorporation
into RNA
41. 5-FU…
41
Cardiotoxicity
Continuous infusion regimen …..
hand-foot syndrome (dermal pain in hands and feet)
less hematologic and GI toxicity
Bolus ….
myelosuppression, oral mucositis, and GI disturbances (diarrhea,
nausea, vomiting, abdominal pain)
42. 5-FU…
42
Ocular toxicity
Blepharitis, conjunctivitis, excessive lacrimation, ocular pruritus
and burning
This is due to tear duct stenosis
Hyperbilirubinemia
43. Capecitabine
43
Orally active pyrimidine analog of uracil
a prodrug of 5-FU
Enzymatically converted to 5-FU,
it shares the same mechanisms of action with 5-FU.
Because chronic twice-daily oral dosing of capecitabine
produces sustained 5-FU levels similar to continuous IV infusions
of 5-FU,
similar toxicity pattern to that of 5-FU infusions
44. Capecitabine ….
Hand-foot syndrome
Supportive care in hand-foot syndrome
Pyridoxine (vitamin B6)….. for prevention
moisturizer to hands and feet, avoid hot water because this can
dry hands
Avoid tight clothing
Protect skin from sun (5-FU is photosensitizer and can cause 3rd
degree burns if excessive sun exposure)
44
45. Capecitabine ….
Gastrointestinal
Diarrhea, nausea/vomiting, abdominal pain, vertigo
low emetic potential……
Concomitant administration with warfarin
Bleeding events have occurred within several days to several
months after initiation of capecitabine therapy
45
46. Cytarabine
46
Effective in …… acute myelogenous leukemia (AML)
Incorporated into all standard induction regimens in
combination with an anthracycline.
The toxicity of cytarabine is dose dependent.
At high-dose (>1 g/m2 per dose)
cerebellar syndrome of dysarthria, nystagmus, and ataxia.
Risk of CNS toxicity is strongly correlated with advanced age
and renal dysfunction.
48. Toxicities of fluoropryrmidines
48
Most common toxicities of fluoropryrmidines ….
neutropenia, thrombocytopenia, and anemia when
administered as an IV bolus,
hand–foot syndrome and diarrhea when administered as a
continuous IV infusion.
49. 6-Mercaptopurine (6-MP)
49
6-MP ….
purine agent ….used against acute lymphocytic leukemia (ALL).
It is active in the S phase of cell proliferation.
Metabolized to produce multiple metabolites responsible for the
efficacy, hepatic toxicity, and myelosuppression.
its initial metabolism step depends on xanthine oxidase.
Its metabolism is decreased by concomitant administration of the
xanthine oxidase inhibitor allopurinol, and serious toxicity may result.
Reduce the oral 6-MP doses when allopurinol is administered
together.
50. Methotrexate (MTX)
50
Folate antagonists, produce folate deficiency
Folate acid is essential for DNA synthesis.
Dietary folates must be chemically reduced to their
tetrahydrofolate forms to be active.
enzyme responsible for this reduction is dihydrofolate reductase
Methotrexate (MTX) inhibits dihydrofolate reductase,
results in the depletion of intracellular pools of reduced folates
(tetrahydrofolates) essential for thymidylate & purine synthesis.
Methotrexate …the most commonly used folate antagonist
active in the S phase of cell growth
51. MTX …
51
Effective in many malignancies;
Breast, head and neck, colorectal, lymphomas,
osteosarcoma, bladder and choriocarcinoma
acute lymphocytic leukemia,
some types of meningeal carcinomas.
Patients must have adequate marrow, liver, and renal
function before therapy.
Antifolates are associated with toxicities.
52. MTX …
52
Neutropenia and thrombocytopenia
Mucositis
3 to 5 days after treatment, can be life threatening, requiring
dose interruption
Nausea and vomiting (dose dependent)
53. MTX …
53
Renal tubular necrosis with high-doses of MTX (1-30 g/m2)
renal damage from crystallization
decrease risk of renal failure by;
vigorous hydration ….(maintain UOP >100 mL/hr)
alkalinization of the urine ….(pH >7)
add sodium bicarbonate or acetate to IVF,
give oral sodium bicarbonate
54. MTX …
54
Hepatic cirrhosis …common with chronic low dose oral
therapy;
Pulse dosing decreases risk
High dose MTX, transient increases in transaminases within 24 hrs,
Requires dosing adjustment in hepatic insufficiency
Pulmonary…….less common, but potentially fatal
Fever, dry cough, dyspnea, chest pain
Responsive to corticosteroids
55. MTX …
55
Neurotoxicity
motor paralysis, nerve palsy, seizures, coma during 2nd or 3rd
week of treatment, typically in pts with meningeal leukemia
headache, nuchal rigidity, fever, vomiting - common, acute in
onset
coma – can occur months to years after treatment (irreversible)
Rash
Teratogenicity
Alopecia
56. MTX …
56
Therapeutic drug monitoring;
The threshold serum levels for cytotoxic effects of MTX is about
0.02 mg/L.
For MTX doses requiring leucovorin rescue (doses >1g/m2)
leucovorin (folinic acid) must be administered until serum levels
fall below 0.02 mg/L.
to neutralize effects of antifolates on normal and tumor cells
Started 24 hours after MTX
After 48 hours, MTX toxicity may not be reversible with leucovorin
May compromise antitumor efficacy if given early.
57. MTX …
57
MTX drug Interactions
Avoid concomitant nephrotoxins such as cisplatin, probenecid
Salicylates and sulfonamides …may displace MTX from
binding sites
58. Antimitotics
58
Damage cancer cells by blocking a process called mitosis
(cell division), preventing the cancer cells from dividing &
multiplying.
Vinca alkaloids (vinblastine, vincristine, vinorelbine)
Although the alkaloids are very similar structurally, they
have different activities and patterns of toxicity.
Vinblastine inhibits angiogenesis
Angiogenesis is an essential step in a tumor’s transition to
malignancy.
59. Antimitotics ….
59
Side effects of vinblastine …
Myelosuppression, nausea, vomiting, constipation, dyspnea, chest
or tumor pain, wheezing, and fever.
Vinorelbine side effects ….
Myelosuppression, bruising or bleeding, constipation, diarrhea,
nausea, peripheral neuropathy, inflammation at the injection site.
Vincristine …most common side effects ….
peripheral neuropathy, suppression of bone marrow activity,
constipation, nervous system toxicity, nausea, and vomiting.
60. Antimitotics …
60
Taxanes (paclitaxel, docetaxel)
Taxanes …..are plant alkaloids with antimitotic activity.
also have some nonmitotic actions that can promote cancer cell
death, such as inhibition of angiogenesis.
61. Antimitotics …
61
Myelosuppression is common with both taxanes,
Docetaxel …..increased fluid retention
Paclitaxel …..increased neurotoxicity and hypersensitivity
reactions
Both taxanes require premedications with corticosteroids
Paclitaxel ….also requires antihistamines to decrease the
likelihood of hypersensitivity reactions.
62. Anthracyclines
62
Doxorubicin (Adriamycin) …. the most widely used
Daunorubicin (daunomycin), idarubicin, epirubicin.
Anthracyclines are classified as antitumor antibiotics, but
they have multiple mechanisms of action.
primarily inhibit topoisomerase II, producing double-strand
DNA breaks
cause structural changes that interfere with DNA and RNA
synthesis
63. Alkylating agents
63
Nitrogen mustards, platinum analogs
Nitrogen Mustards (cyclophosphamide, ifosfamide)
Platinum derivatives (cisplatin, carboplatin, oxaliplatin)
Cyclophosphamide, ifosfamide
widely used in the treatment of solid tumors and hematologic
malignancies.
Broadest spectrum in ….combination therapy for many types of
cancers
64. Alkylating agents….
64
Cyclophosphamide, ifosfamide
activated by cytochrome P450 (CYP) enzymes to metabolites…
phosphoramide mustard (anticancer),
acrolein (has little antitumor activity).
Acrolein ….causes hemorrhagic cystitis
prevented by 2-mercaptoethanesulfonate (mesna)
mesna binds ……acrolein
65. Alkylating agents….
65
Hemorrhagic cystitis
Symptoms …dysuria and urinary frequency
Excretion of acrolein into the urinary bladder
Greater with bolus regimen
Higher incidence after ifosfamide than after equivalent doses of
cyclophosphamide
Treatment ……requires evacuation of clots and continuous
bladder irrigation
Mesna is routinely recommended to protect against toxicity.
66. Alkylating agents….
66
Encephalopathy (ifosfamide) …. is reversibile
CNS toxicity occurring in patients receiving high doses of the
drug…within 48 to 72 hours following the infusion,
manifested as ….cerebellar ataxia, mental confusion, complex
visual hallucinations,
Methylene blue ….as an effective treatment for ifosfamide-
induced encephalopathy …………….. controversial.
67. Alkylating agents….
67
Platinum analogs
Cisplatin, carboplatin, and oxaliplatin
Broad spectrum anticancer drugs for solid tumors (high cure rate)
Cisplatin
the cornerstone of treatment of many cancers.
initial platinum responsiveness is high but ……
the majority of cancer patients will eventually relapse with
cisplatin-resistant disease
Paclitaxel may be …..useful in the treatment of cisplatin-
resistant cancer.
68. Alkylating agents….
68
Cisplatin is a highly toxic anticancer agent
cause serious nephrotoxicity, ototoxicity, peripheral neuropathy,
emesis, and hemolytic anemia, electrolyte disturbance
(hypomagnesaemia, hypokalaemia, hypocalcaemia)
most of which can be prevented or managed with aggressive
supportive care measures.
69. Alkylating agents….
Nephrotoxicity …a major concern
Nephrotoxicity is a dose-limiting side effect.
reduce the dose when the creatinine clearance is reduced.
Preventive measures
aggressive saline hydration (enhance urinary excretion)
pretreatment with amifostine
avoid other nephrotoxic agents
magnesium supplementation
69
70. Alkylating agents….
70
Nausea and vomiting
cisplatin is one of the most emetogenic chemotherapy agents
this symptom is managed with prophylactic antiemetics
(ondansetron, granisetron, etc.) in combination with
corticosteroids.
Ototoxicity (hearing loss)
at present no effective treatment to prevent this side effect,
which may be severe.
Avoid other drugs (such as aminoglycosides) in patients
receiving cisplatin.
71. Alkylating agents….
71
Carboplatin
a cisplatin derivative with broad antitumour activity
shares a similar spectrum of clinical activity with cisplatin,
cross-resistance is common
cause nephrotoxicity, peripheral neuropathy, ototoxicity, and
moderately emetogenic
much less than cisplatin
72. Alkylating agents….
72
Carboplatin ….
Its administration is limited by hematologic toxicity
(myelosuppression)….. especially thrombocytopenia.
Hypersensitivity reaction
incidence correlated with increased number of cycles of carboplatin
administered
Calvert formula…. most widely used to estimate the
carboplatin dose.
uses a target area under curve and renal function parameters
….
74. Bisphosphonates
74
Are used to treat high levels of calcium in the blood caused
by certain cancers, including myeloma.
Bisphosphonates will not slow or stop the spread of cancer,
but can slow bone breakdown, increase bone thickness and
reduce bone pain and the risk of fracture.
Pamidronate (Aredia®)
Zoledronic acid (Zometa®)
75. DNA-repair enzyme inhibitors
75
Attack the cancer cell proteins (enzymes) that normally
repair any damage to the DNA.
Repair of DNA damage is a normal and vital process within
the cell.
Without this repair process, the cancer cell is much more
susceptible to damage and is prevented from growing.
Etoposide, Teniposide, Topotecan
76. Tyrosine Kinase Inhibitors
76
Block the action of a specific, abnormal protein that signals
cancer cells to grow.
Dasatinib, Nilotinib, Imatinib mesylate
Imatinib mesylate (Gleevec®)
is a standard treatment option for newly diagnosed CML (chronic
myeloid leukemia)
Adverse events of imatinib …
Severe fluid retention (pleural effusion, pericardial effusion, and
ascites)
mild or moderate superficial edema, elevation of liver enzymes,
nausea, muscle cramps, headache, and rash.
77. Hormones (Corticosteroids) that can kill
Lymphocytes
77
Are thought to work by blocking cell metabolism through
their effect on specific genes.
However, the way these drugs work is under study.
In high doses, these synthetic hormones, relatives of the
natural hormone cortisol, can kill malignant lymphocytes.
Dexamethasone, methylprednisolone, prednisone
78. Miscellaneous agents
78
Bleomycin ….. an antitumor antibiotic
has greatest effect on cells in the G2 and M phases of the cell
cycle.
inactivated within cells by the enzyme aminohydrolase.
Baseline pulmonary function tests and monitoring for pulmonary
toxicity are necessary during bleomycin therapy.
Hydroxyurea ….inhibits ribonucleotide reductase.
inhibit DNA synthesis
used to cause rapid reduction in WBCs before more potent
chemotherapy is initiated.
