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principles of chemotherapy
1.
2. • German chemist Paul Ehrlich- Coined
the term ‘‘chemotherapy’’
• Originally chemotherapy referred to
treatment of disease with drugs or chemical
• but by mid 1950’s the term was only being
used primarily in reference to drugs which
were used to treat cancer.
3. • Diseases of cells that shows uncontrolled
proliferation , anaplsia, invasivness and
ability to metastasis .
• Due to Chromosomal abnormality and
expression of oncogens .
• Second most common cause of death after
cardiovascular disorders in world.
4. • Surgery
• Radiotherapy
• Chemotherapy, Immunotherapy, Gene therapy
Choice of therapy depends upon the
• Location of tumour
• Stage of tumour
• General state of the patient.
• For solid cancers
• 1/3 of patients can be cured,
• Effective when tumor has not
metastasized
5. • 1943 - During World War II , soldiers
were exposed to nitrogen mustard
gas and shows marked depletion in
marrow and lymphoid cells.
• Based on this finding, Alfred Gilman
and Louis Goodman from Yale
university used Nitrogen Mustard to
induced remission of Lymphoma in
mice.
6. 1948 - Sidney Farber showed that
aminopterin, a folic acid analogue,
developed by Y. Subbarao can induced
remission in acute lymphoblastic
leukemia.
Latter more safer amethopterin
( Methotrexate ) was developed.
7. 1950- Actinomycin D was developed as antibiotics, but found
to be very toxic but have significant antitumour activity
1951 - Hitchings and Elion isolated 6-thioquanine and 6-
mercaptopurine that inhibited purine metabolism, which are
widely used for various cancer and as immunosuppressant.
8. • 1970’s - “Golden Age” of medical oncology.
Development of effective combination chemotherapy
regimens.
• New classes of drug developed - anthracyclines, platinum
compounds .
• Cures achieved in some forms of cancer (lymphomas,
leukemias, testis cancer).
• Significant responses in some common types of cancer (breast,
stomach, small cell lung cancer)
•
Effective use of chemotherapy to prevent recurrence in high risk
breast cancer patients.
9. • Scientist continue to look for “the magic bullet” to
eliminate cancer.
• Nowdays research is being focused on specific agents
that interfere with cell division, as well as monoclonal
antibodies, biologic modifiers, gene therapies, etc.
10. • Wilm’s tumor, ALL, Testicular
cancer, Burkitt’s lymphoma,
NHL
To Cure
• Prolong remission
• Decreases rate of relapseTo Control
• Relive symptoms and
improved quality of lifePalliation
11. 1. Primary
Chemotherapy
• Chemotherapy is main
modality of treatment
• Can be single drug or
combination chemotherapy
• e.g. Hematological
malignancy-
• ABVD regimen for hodgkins
lymphoma.
2. Adjuvant
Chemotherapy
• Combined with radiation or
surgery.
• For advanced cancer
• e.g. Ca breast After surgery
to remove microscopic foci.
12. 3. Neoadjuvant
chemotherapy
• Chemotherapy is given
before surgery.
• Shrink a large cancerous
tumour to make surgery
easy.
• e.g. laryngeal carcinoma
before surgery.
4. Concurrent
chemotherapy
• Simultaneously with
• Radiation.
• mainly act as
radiation sensitizer, encoura
ges the cancer cells to take
radiotherapy.
• e.g.Head and neck CA,
rectal CA, lung CA
13. High Intermediate Low
Lymphoma Breast Head and neck
Leukemia Colon Prostate
Small Cell Lung cancer Non-small cell lung
cancer
Gastric
Testicular cancer Pancreatic
14. • Cell life cycle and drug
• Log kill hypothesis
• Growth fraction
• Tumour burden
15. cell cycle and drugs
G1 – L- Asparginase
S – Methotrexate
6-Mercaptopurine
5-Fluorouracil
Mitomycin C
Hydroxyurea
Doxorubicin
G2 – Bleomycin
Etoposide,
Topotecan
Daunorubicin
M – Vincristine
Vinblastine
Paclitaxel,
Docetaxel
16.
17. • Cell kill by first order kinetics.
• A constant fraction of cells are killed by a given drug
dose, not constant number.
• A constant percentage of the total number of cancer
cells present in tumor will be killed with each course of
chemotherapy.
• Hence repeated doses of chemotherapy must be used
for total cells kill.
18. 1 log regrowth
3 log cell kill
Tumor regrowth after
premature Cessation of
Therapy.
19. Growth fraction is the percentage of actively dividing cells at
any given point in time.
1. High growth fraction tumour : more sensitive to cycle-
specific drugs.
e.g. 1. leukemia and lymphoma
2. Normal with tissues high growth fraction like bone
marrow, hair follicles, and intestinal
2. Low growth fraction tumour : Solid tumour e.g.
carcinomas of the colon, lung cancer) are less
responsive to cycle-specific drugs.
20. • The tumor burden is the size of the tumor as determined
by the number of cells present.
• Small tumor burden → more responsive
• Higher the tumor burden → probability of drug resistance.
• Cancer cells usually follows Gompertzian growth pattern.
21.
22. It is model of cancer cell growth.
“Cell rapidly divide early in life, then plateaus.”
Significance :
1. Most anticancer drugs are ineffective in advanced
cancers which have very low growth fraction.
2. Debulking procedures makes tumour again
responsive to drugs by inducing remaining cells to
divide.
23. Alkylating Agents e.g. Nitrogen mustards , Nitrourea
Antimetabolites
e.g. Folic acid analogue, Pyrimidine and
Purine analogue
Natural Agents e.g. Vinca alkaloid, Taxens, Tecans.
Antibiotics and
enzymes
e.g. Dactinomycin, Daunorubicin , L-
Asparaginase
Hormones and
antagonists
e.g. Progestins , Estrogen, GnRH, Anti-
estrogens
Miscellaneous
agents
e.g. Hydroxyurea , Immunomodulators ,
Tyrosine kinase inhibitor, Biological
Response Modifiers ,monoclonal antibody
24. Purine Synthesis Pyrimidine Synthesis
Ribonucleotides
Deoxyribonucleotides
DNA
RNA
Proteins
Enzymes Microtubules
6-Mercaptopurine
6-Thioguanine
Methotrexate → DHFR
5-Fluorouracil
Cytarabine
Gemcitabine
Hydroxyurea
Etoposide
Topoisomerase II
Inhibitor- DNA break
Antibiotics
L-Asparaginase
Vinca Alkaloids →
prevent polymerization
Taxens →enhance
polymerization
Antimetabolites
Alkylating agents
Alkylation→ Alter
structure & function of
DNA by cross linking
and/or fragmenting DNA
26. CLASS DRUGS MAJOR USES
Folic acid
analogue
Methotrexate
ALL; choriocarcinoma breast,
head, Lung cancer; osteogenic
sarcoma; bladder ca
Pemetrexed Mesothelioma, lung cancer
Pyrimidine
analogue
Fluorouracil
Capecitabine
Breast, colon, esophageal,
stomach cancer.
Cytarabine AML, ALL, NHL
Gemcitabine Pancreatic, ovarian, lung ca.
Purine analogue
and related
inhibitors
Mercaptopurine AML, ALL
Pentostatin
Hairy cell leukaemia; CLL,
small cell NHL.
Fludarabine CLL
27. CLASS DRUGS MAJOR USES
Vinca
alkaloids
Vinblastine HL, NHL, Testis cancer
Vinorelbine Non small cell lung cancer
Vincristine
ALL, Neuroblastoma;
Wilms’ tumor;
Taxanes
Paclitaxel,
Docetaxel
Metastatic ovarian, breast
ca.
Epipodo-
phyllotoxins
Etoposide
Testicular tumour, lung
cancer ,HL, NHL
Camptothecins Topotecan, Irinotecan
Ovarian cancer; small-cell
lung cancer; colon ca.
28. CLASS DRUGS MAJOR USES
Antibiotics
Dactinomycin
(actinomycin D)
Choriocarcinoma; Wilms’ tumor;
Rhabdomyosarcoma
Daunorubicin AML, ALL.
Doxorubicin
Soft-tissue, osteogenic, and other
sarcoma; HL, NHL , AML, ALL.
Breast, Genitourinary, Thyroid, lung,
stomach cancer; Neuroblastoma
Mitoxantrone AML, breast and prostate cancer
Bleomycin Testis, cervical cancer; HL, NHL
Mitomycin Stomach, anal, and lung cancer
Enzymes L-Asparaginase ALL
29. CLASS DRUGS MAJOR USES
Glucocorticoides Prednisone ALL, CLL, HL, breast cancer,
multiple myeloma
Progestins Hydroxyprogesterone caproate,
Medoxyprogesterone
acetate, Megestrol acetate
Endometrial,
breast cancer
Estrogens Diethylstilbestrol, Ethinyl
estradiol
Breast, prostate cancer
Anti-estrogens Tamoxifen, Toremifene, Breast cancer
Aromatase
inhibitors
Anastrozole, Letrozole, Breast cancer
Androgens Testosterone propionate Breast cancer
Antiandrogen Flutamide , casodex Prostate cancer
GnRH analogue Leuprolide Prostate cancer
30. CLASS DRUGS MAJOR USES
Substituted urea Hydroxyurea CML ; Polycythemia vera;
Essential thrombocytosis
Differentiating agents Tretinoin,
Arsenic trioxide
Acute Promyelocytic Leukemia
Protein tyrosine
kinase inhibitor
Imatinib CML, GIST
Gefitinib Non-small-cell lung cancer
Sorafenib Hepatocellular cancer,
Renal cancer
Proteasome inhibitor Bortezomib Multiple myeloma
Immunomodulators Thalidomide Multiple myeloma
Lenalidomide Myelodysplasia , multiple myeloma
mTOR Inhibitors Temsirolimus,
Everolimus
Renal cancer
31. CLASS DRUGS MAJOR USES
Biological
Response
Modifiers
Interferon-α,
Interleukin 2
Hairy cell leukemia; Kaposi’s
sarcoma; Melanoma; carcinoid;
Renal cell; Ovary; Bladder;
Mycosis fungoides;
Multiple myeloma; NHL, CML
CD20 Rituximab B-cell lymphoma and CLL
CD52 Alemtuzumab B-cell CLL and T-cell lymphoma
CD33 Gemtuzumab Acute Myelocytic Leukemia
HER2/neu Trastuzumab Breast cancer
EGFR Cetuximab colorectal, pancreatic, breast ca.
VEGF Bevacizumab colorectal cancer
32. Dosage of chemotherapy are difficult: If the dose is too
low, it will be ineffective , whereas excessive causes
toxicity .
In most cases, the dose is adjusted for the patient's body
surface area (BSA), a measure that correlates with blood
volume.
The BSA is usually calculated with a mathematical formula
using a patient's weight and height, rather than by direct
measurement.
W is weight in kg, and
H is height in cm.
33. • Standard doses –doses in which anticipate side effect are
mild and no supportive therapy required
• High dose therapy – Increases in dosing amount, severe side
effects are present. Supportive therapy is essential.
Large amounts of free drug in the serum not only increase
efficacy of the drug but also facilitate penetration into the
tumour cells.
Example :
In AML , High-dose cytarabine (2000 to 3000 mg /m2 of BSA)
have higher rates of relapse-free survival than standard dose of
100 to 400 mg /m2.
34. Dose intensification (DI) – higher than standard dose given
in short interval
Achieved by
1. Increasing the dose of the chemotherapy per cycle (dose
escalation)
2. Decreasing the time between the treatments (dose density)
Steep dose-response curve, meaning that relatively small
increases in the chemotherapy dose will have a substantial effect
on the number of tumor cells killed.
35. Combination therapy involves the use of two or more drugs
proven effective against a tumor type.
Major advances in cancer treatment in the past 20 years.
RATIONALE OF COMBINATION CHEMOTHERAPY
• Prevention of resistant clones.
• Cytotoxicity to resting and dividing cells.
• Biochemical enhancement or effect –
Synergistic effect
36. Combination therapy is superior to single-drug therapy in
terms of
• Higher tumor response rates
• Increased duration of remissions.
• Minimal chances of resistance.
37. Active as single agents
Different mechanism of action
Different dose limiting toxicity
Used at optimal dose and schedule
Given at consistent interval
Different resistance mechanism
Drugs with known synergistic biochemical interaction
Cell kinetics scheduling: on basis of cell cycle specificity /
non specificity of drugs and phase of cycle at which drug
exert toxicity.
39. REGIMEN CANCER DRUGS
ABVD Hodgkin's Doxorubicin, Bleomycin, Vinblastine,
Dacarbazine
CHOP-R NHL Cyclophosphamide,
Hydroxydaunorubicine, Vincristine,
Prednisolone, Rituximab
VAMP AML Vincristine, Amethopterine, 6 MP,
Prednisolone
FOLIFIRI COLON
CANCER
5 FU, Leucovorin, Irinotecan,
40. 1. Complete response – disappearance of disease on
imaging test.
2. Partial response – size decrease of 50% or more
from original tumor. No new lesions.
3. Stable disease – less than 50% response without
actual progression of disease.
4. Disease progression – 25% increase in the size of the
original tumor. Or new lesions developed.
41. Infection
Previous chemotherapy given < 2 weeks
Leukopenia and thrombocytopenia
Severely debilitated patients
Pregnancy (1st trimester)
Major surgery < 2 weeks
Poor patient follow-up
Psychological problems
42. Not all patients can tolerate drugs, and not all drug regimens are
appropriate for a given patient.
Choice of drug depends on following factor
• Tumour type
• General performance status of patient
• Renal and hepatic function
• Bone marrow reserve
• Concurrent medical problems
• Patient's willingness
• Patient's physical and emotional tolerance for side effects
44. Resistance constitutes a lack of response to drug-induced tumour
growth inhibition
1. Primary resistance: No response from
very first exposure.
e.g. malignant melanoma, renal tumours.
2. Acquired resistance : During continuation
of therapy .
Due to adaption of tumour cells or due to mutation in one or
more gene.
45. 1. ↑ drug efflux via P-glycoprotein transporters e.g. doxorubicin, paclitaxel,
vincristine, etoposide
2. Overexpression of the multidrug resistance protein 1(MRCP1) →
↑resistance to natural drugs e.g. vinca alkaloid, anthracyclins .
3. ↓ inward transport e.g. methotrexate
4. Insufficient activation of the drug (e.g. mercaptopurine , fluorouracil and
cytarabine.
5. Increase in inactivation (e.g. cytarabine and mercaptopurine )
6. Increased concentration of target enzyme (methotrexate)
7. Rapid repair of drug-induced lesions (alkylating agents).
8. Altered activity of target proteins, for example modified topoisomerase II
(doxorubicin).
46. • Use of combination drug therapy using different
classes of drugs with different mechanism of action.
• With narrowest cycle intervals, necessary for bone
marrow recovery.
• Drugs that reverse multidrug resistance include
verapamil, quinidine, and cyclosporine .
48. Cause by almost all anticancer drugs except Bleomycin,
Vincristin and Asparginase.
Most serious toxicity and often limit dose of chemotherapy
• Granulocytopenia
• Agranulocytosis
• Thrombocytopenia
• Aplastic anemia
• Lymphocytopenia
• immunosppression
Drug causing severe
myelosuppression
Carmustin
Cytarabine
Daunorubicine
Paclitaxel
Alkylating agents
Antimetabolites
Complications :
• Opportunistic infections
• Bleeding
53. The practice of cancer medicine has changed dramatically
over the years from palliative → curative.
e.g.
Wilms tumour, Ewing sarcoma, Choriocarcinoma, Hodgkins
disease, testicular cancer can be cured with chemotherapy.
Adjuvant chemotherapy and hormonal therapy can extend
life and prevent disease recurrence following surgical
resection of localized breast, colorectal, and lung cancers.
54. Increasingly used in autoimmune diseases like rheumatoid
arthritis (methotrexate and cyclophosphamide), Crohn's
disease (6-mercaptopurine), organ transplantation
(methotrexate and azathioprine) etc.
As part of multimodal treatment of locally advanced head
and neck, breast, lung, and esophageal cancers, thereby
allowing for more limited surgery and even cure in these
formerly incurable cases
Toxicities of Cytotoxic drugs have become more
manageable with the development of better supportive
therapy like G-CSF, IL-11 to restore bone marrow
function
55. Newer target molecules or monoclonal antibody are not
likely to replace cytotoxics in the future. Rather, both will be
used in combination.
e.g. For instance, monoclonal antibodies or small targeted
molecules, used as single agents against solid tumors,
produce low response rates and modest benefits; however,
in combination with cytotoxics they are dramatically
effective .
56. Bevacizumab plus irinotecan, fluorouracil, and leucovorin
(IFL) for metastatic colorectal cancer.
The median duration of survival was 20.3 months in the group given IFL plus
bevacizumab, as compared with 15.6 months in the group given IFL plus
placebo,
57. Molecular tests are increasingly employed to identify patients likely
to benefit from treatment and those at highest risk of toxicity
Pre-treatment testing has become standard practice for following
tumours
1. Estrogen receptor –breast cancer- transtuzumab
2. B cell non Hogdkins lymphoma- Rituximab (CD20)-
3. EGFR- for colorectal cancer- to use Cetuximab
58. • The future may see the development of agents which could
induce differentiation in tumour cells, rendering them non-
neoplastic.
• By inhibiting an abnormal oncogene product but not the
normal equivalent.
• By using antisense oligonucleotides to
inhibit translation of an abnormal
oncogene messenger RNA.
• By introducing MDR-1 gene into bone
marrow cells and rendering them
less susceptible to myelosuppressant
drugs.
Notas del editor
Cancer is a disease in which there is uncontrolled multiplication and spread within the body of abnormal forms of bodys own cells. It is one of the major causes of death in developed nations atleast 1 in 5 of the population of europe and north america can expect to die of cancer. Cancers are more common in aged people as life expectancy is increasing the incidence of cancers is also increasing, with the present methods of treatment one third of the patients are cured with local modalities of treatment (surgery or irradiation therapy) which are quite effective when the tumor has not metastatized. In metastasis systemic chemotherpy is required along with surgery or irradiation at present 50 % of the patients of cancer can be treated with chemotherapy contributing to cure in 10 -15% of the patients. The terms cancer,malignant neoplasm and malignant tumor are synonymous
Chemotherapy is essentially required with surgery or irradiation when metastasis has occurred
Majority of cytotoxic drugs have more profound effects on rapidly multiplying cells