Chemotherapy Final 30 08.ppt ppt

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1. Basics of Cancer Basics of Cancer
Chemotherapy Chemotherapy
Dr. Amit JoshiDr. Amit Joshi
Associate ProfessorAssociate Professor
Dept. Of Medical OncologyDept. Of Medical Oncology
Tata Memorial CentreTata Memorial Centre

2. 50.2 Rang
EtiolopathologyEtiolopathology

3. Characteristics of Cancer CellsCharacteristics of Cancer Cells

The problem:The problem:
–Cancer cells divide rapidly (cell cycle is Cancer cells divide rapidly (cell cycle is
accelerated) accelerated)
–They are “immortal”They are “immortal”
–Cell-cell communication is alteredCell-cell communication is altered
– uncontrolled proliferationuncontrolled proliferation
– invasiveness invasiveness
–Ability to metastasise Ability to metastasise

4. Six Established Rx ModalitiesSix Established Rx Modalities
1.1.SurgerySurgery
2.2.RadiotherapyRadiotherapy
3.3.ChemotherapyChemotherapy
4.4.Endocrine therapyEndocrine therapy
5.5.ImmunotherapyImmunotherapy
6.6.Biological therapyBiological therapy

5. Major approaches to therapy of Major approaches to therapy of
cancers cancers

6. Interphase
Prophase
Daughter cells
Telophase
Anaphase
Metaphase
ONCOLOGYONCOLOGY
Principles of chemotherapyPrinciples of chemotherapy
The mitosis stagesThe mitosis stages

7. Cell Cycle = Cell Cycle =
Growth, DivisionGrowth, Division

9. Cancer ChemotherapyCancer Chemotherapy

After completion of mitosis, the resulting After completion of mitosis, the resulting
daughter cells have two options: daughter cells have two options:

(1) they can either enter G1 & repeat the cycle or (1) they can either enter G1 & repeat the cycle or

(2) they can go into G0 and not participate in the (2) they can go into G0 and not participate in the
cell cycle.cell cycle.

Growth fraction - at any particular time some Growth fraction - at any particular time some
cells are going through the cell cycle whereas cells are going through the cell cycle whereas
other cells are resting. other cells are resting.

The ratio of proliferating cells to cells in G0, is The ratio of proliferating cells to cells in G0, is
called the growth fraction. called the growth fraction.

A tissue with a A tissue with a large percentage of large percentage of
proliferating cellsproliferating cells & few cells in & few cells in G0G0 has a has a high high
growth fraction. growth fraction.

Conversely, a tissue composed of Conversely, a tissue composed of mostly of cells mostly of cells
in G0in G0 has a has a low growth fraction.low growth fraction.

10. Historical PerspectiveHistorical Perspective
- Paul Ehrlich- Paul Ehrlich – coined term Chemotherapy – coined term Chemotherapy

- Clowes and colleagues - Clowes and colleagues at Roswell Park at Roswell Park
Memorial Institute in early 1900 – developed Memorial Institute in early 1900 – developed
inbred rodent lines bearing transplanted inbred rodent lines bearing transplanted
tumors to screen potential anticancer drugs.tumors to screen potential anticancer drugs.
- This in vivo system : foundation for mass - This in vivo system : foundation for mass
screening of novel compound.screening of novel compound.

11. Historical PerspectiveHistorical Perspective

Alkylating agents : first class of Alkylating agents : first class of
chemotherapeutic agent used in clinical chemotherapeutic agent used in clinical
practice.practice.

Nitrogen mustard: first compound Nitrogen mustard: first compound
developed by US scientists during world war developed by US scientists during world war
as a war weapon which causes bone as a war weapon which causes bone
marrow suppression and lymphoid marrow suppression and lymphoid
hypoplasia and later used to treat NHL hypoplasia and later used to treat NHL
patients.patients.

12. Historical PerspectiveHistorical Perspective

Sideny farber : Folic acid had proliferative Sideny farber : Folic acid had proliferative
effect on leukemia cell growth. effect on leukemia cell growth.

This lead to development of folic acid This lead to development of folic acid
analogue for treatment of leukemia.analogue for treatment of leukemia.

13. Anti-cancer drugsAnti-cancer drugs

15. Cell Cycle Specific (CCS) & Cell Cycle Non-Cell Cycle Specific (CCS) & Cell Cycle Non-
Specific Agents (CCNS)Specific Agents (CCNS)

16. Principles of Cancer Cell KineticsPrinciples of Cancer Cell Kinetics
- - The key principles of chemotherapy were The key principles of chemotherapy were
initially defined by Skipper et al using the initially defined by Skipper et al using the
murine leukemia L1210 cells as their murine leukemia L1210 cells as their
experimental model system.experimental model system.

According to the According to the log-kill hypothesislog-kill hypothesis, ,
chemotherapeutic agents chemotherapeutic agents kill a constant kill a constant
fraction of cells fraction of cells (first order kinetics),(first order kinetics), rather rather
than a than a specific number of cellsspecific number of cells, after , after each each
dosedose

17. LOG kill hypothesisLOG kill hypothesis
The example shows the effects The example shows the effects
of tumor burden, scheduling, of tumor burden, scheduling,
initiation/duration of initiation/duration of
treatment on patient survival. treatment on patient survival.
The tumor burden in an The tumor burden in an
untreated patient would untreated patient would
progress along the path progress along the path
described by the RED LINE – described by the RED LINE –
The tumor is detected (using The tumor is detected (using
conventional techniques) conventional techniques)
when the tumor burden when the tumor burden
reaches 10reaches 10
99
cells cells
The patient is symptomatic at The patient is symptomatic at
1010
1010
-10-10
1111
cells cells
Dies at 10Dies at 10
1212
cells. cells.

18. Log kill hypothesis:Log kill hypothesis:

19. MUTATIONS AT SPECIFIC LOCUS MUTATIONS AT SPECIFIC LOCUS
OCCUR AT A FREQUENCY OF OCCUR AT A FREQUENCY OF
1/1,000,000 CELL DIVISIONS1/1,000,000 CELL DIVISIONS

20. Cancer ChemotherapyCancer Chemotherapy

Combinations of agents with differing toxicities & Combinations of agents with differing toxicities &
mechanisms of action are often employed to mechanisms of action are often employed to
overcome the limited cell kill of individual anti overcome the limited cell kill of individual anti
cancer agents. Each drug selected should be cancer agents. Each drug selected should be
effective aloneeffective alone
3 advantages of combination therapy:3 advantages of combination therapy:

1. Suppression of drug resistance - less chance of a 1. Suppression of drug resistance - less chance of a
cell developing resistance to 2 drugs than to 1 drug.cell developing resistance to 2 drugs than to 1 drug.

2. Increased cancer cell kill - administration of drugs 2. Increased cancer cell kill - administration of drugs
with different mechanisms of action.with different mechanisms of action.

3. Reduced injury to normal cells - by using a 3. Reduced injury to normal cells - by using a
combination of drugs that do not have overlapping combination of drugs that do not have overlapping
toxicities, we can achieve a greater anticancer effect toxicities, we can achieve a greater anticancer effect
than we could by using any one agent alone.than we could by using any one agent alone.

21. CHEMOTHERAPY STRATEGYCHEMOTHERAPY STRATEGY
Given a series of drugs (or drug combinations),Given a series of drugs (or drug combinations),
what is the optimal strategy:what is the optimal strategy:

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
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
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22. GOLDIE-COLDMAN HYPOTHESISGOLDIE-COLDMAN HYPOTHESIS
Optimal tumor treatment would use a large series of Optimal tumor treatment would use a large series of
non-repeating drugs or drug combinationsnon-repeating drugs or drug combinations
ABCDEFGHIJKL…ABCDEFGHIJKL…
This hypothesis is based on several assumptions:This hypothesis is based on several assumptions:
Log growth of tumor cells Log growth of tumor cells
Equal effectiveness of drugs Equal effectiveness of drugs
Different mechanisms of action of drugs Different mechanisms of action of drugs
Different toxicities of drugs Different toxicities of drugs

23. 2323
Classification of Chemotherapeutic AgentsClassification of Chemotherapeutic Agents

24. 2424
AntimetabolitesAntimetabolites
MOA: Inhibition of DNA or RNA synthesisMOA: Inhibition of DNA or RNA synthesis
MethotrexateMethotrexate: Folic acid analog (antagonist): Folic acid analog (antagonist)
–Acute Lymphoblastic LeukemiaAcute Lymphoblastic Leukemia
–GI tract, myelosuppression and hepatic dysfunctionGI tract, myelosuppression and hepatic dysfunction
5-Fluorouracil5-Fluorouracil: Pyrimidine analog (prodrug): Pyrimidine analog (prodrug)
–Breast and GI carcinomas, and skin cancer Breast and GI carcinomas, and skin cancer
–Ulcerations of GI tract, myelosuppressionUlcerations of GI tract, myelosuppression
MecaptopurineMecaptopurine: Purine analog (prodrug): Purine analog (prodrug)
–Acute leukemia in childrenAcute leukemia in children
–GI tract, gradual myelosuppression and jaundiceGI tract, gradual myelosuppression and jaundice

25. 2525
Antitumor AntibioticAntitumor Antibiotic
Cell-cycle SpecificCell-cycle Specific

BleomycinBleomycin: : Causes fragmentation of DNACauses fragmentation of DNA
–Clinical uses: Hodgkin’s and non-Hodgkin’s lymphomas, testicular Clinical uses: Hodgkin’s and non-Hodgkin’s lymphomas, testicular
cancer, and squamous cell carcinomacancer, and squamous cell carcinoma
–mucocutaneous reactions, exacerbation of rheumatoid arthritis and mucocutaneous reactions, exacerbation of rheumatoid arthritis and
pulmonary toxicitypulmonary toxicity

Pulmonary Toxicity (PT)Pulmonary Toxicity (PT)
–5-10% develop PT5-10% develop PT
–1-2% of all patients die from PT1-2% of all patients die from PT
–Higher risk for ARDS due to free radicals from hyperoxygenation, Higher risk for ARDS due to free radicals from hyperoxygenation,
which destroy alveolar liningwhich destroy alveolar lining
–Signs/Symptoms: Cough, dyspnea, basilar rales, developing into Signs/Symptoms: Cough, dyspnea, basilar rales, developing into
interstitial pneumonitis and fibrosis. Increased A-a gradient and interstitial pneumonitis and fibrosis. Increased A-a gradient and
decreased diffusion capacitydecreased diffusion capacity

26. 2626
EpipodophyllotoxinsEpipodophyllotoxins
Derived from mayapple root Derived from mayapple root
extractextract (podophyllotoxin)(podophyllotoxin)
–Blocks cell division by Blocks cell division by
damaging DNA strands, causing damaging DNA strands, causing
breakagebreakage
EtoposideEtoposide:: germ cell cancer, germ cell cancer,
small cell and non-small cell small cell and non-small cell
lung cancer, Hodgkin’s/non-lung cancer, Hodgkin’s/non-
Hodgkin’s and gastric cancerHodgkin’s and gastric cancer
–alopecia and myelosuppressionalopecia and myelosuppression
TenoposideTenoposide: : acute lymphoblastic acute lymphoblastic
leukemialeukemia
–similar to abovesimilar to above

27. 2727
TaxanesTaxanes

Alkaloid esters derived from the Alkaloid esters derived from the
Pacific and European yewPacific and European yew
–Mitotic spindle poisonMitotic spindle poison

PaclitaxelPaclitaxel: broad range of solid : broad range of solid
tumors and Kaposi’s sarcomatumors and Kaposi’s sarcoma
–GI, Sensory neuropathy, GI, Sensory neuropathy,
myelosuppressionmyelosuppression

DoxetaxelDoxetaxel: second line therapy : second line therapy
in advance or refractory cancer in advance or refractory cancer
of solid tumorsof solid tumors
–Neurotoxicity, fluid retention, Neurotoxicity, fluid retention,
neutropenianeutropenia

28. 2828
Alkylating AgentsAlkylating Agents
Classified by the different Classified by the different
moiety attachmentsmoiety attachments
–Bis (chloroethyl) aminesBis (chloroethyl) amines
(nitrogen mustards)(nitrogen mustards)
–NitrosoureasNitrosoureas
–AziridinesAziridines
–Alkyl sulfonatesAlkyl sulfonates
MOA: transfers an alkyl MOA: transfers an alkyl
group (carbon with group (carbon with
hydrogens) to the DNA hydrogens) to the DNA
causing cell deathcausing cell death

29. 2929
Alkylating AgentsAlkylating Agents
Nitrogen MustardNitrogen Mustard

MechlorethamineMechlorethamine: Hodgkin’s disease in combination with other chemo drugs: Hodgkin’s disease in combination with other chemo drugs
–GI, myelosuppression, herpes zosterGI, myelosuppression, herpes zoster
NitroureaNitrourea

StreptozosinStreptozosin: pancreatic cancer: pancreatic cancer
–70% produce renal or hepatic injury70% produce renal or hepatic injury
AziridinesAziridines

ThiotepaThiotepa: ovarian/bladder/breast cancer: ovarian/bladder/breast cancer
–MyelosuppressionMyelosuppression
AlkylsulfonateAlkylsulfonate

BusulfanBusulfan: chronic granulocytic leukemia: chronic granulocytic leukemia
–Myelosuppression with an increase in thrombocytopeniaMyelosuppression with an increase in thrombocytopenia

30. 3030
AnthracyclinesAnthracyclines

Antibiotics isolated from Antibiotics isolated from Streptomyces Streptomyces
–Not only prevent DNA/RNA replication, but also promote free radicals Not only prevent DNA/RNA replication, but also promote free radicals
and cell destructionand cell destruction

DaunorubicinDaunorubicin: acute lymphocytic and granulocytic leukemia, : acute lymphocytic and granulocytic leukemia,
and wide range of solid tumorsand wide range of solid tumors

DoxorubicinDoxorubicin: metastatic adenocarcinoma and thyroid : metastatic adenocarcinoma and thyroid
carcinoma, bladder and lung cancer.carcinoma, bladder and lung cancer.

Side effects: Side effects: acutely:acutely: conduction problems, myocarditis, and conduction problems, myocarditis, and
pericarditis; pericarditis; chronically:chronically: dilated cardiomyopathy and CHF. dilated cardiomyopathy and CHF.
–Myelosuppression with an increase in neutropeniaMyelosuppression with an increase in neutropenia

31. 3131
Antitumor AntibioticsAntitumor Antibiotics
Cell-cycle non-specificCell-cycle non-specific

Derived from StreptomycesDerived from Streptomyces
–Inhibits DNA/RNA synthesisInhibits DNA/RNA synthesis

DactinomycinDactinomycin: pediatric tumors; Wilms’ tumor : pediatric tumors; Wilms’ tumor
(nephroblastoma),(nephroblastoma), rhabdomyosarcoma, Ewing’s sarcoma rhabdomyosarcoma, Ewing’s sarcoma (rare (rare
bone/soft tissue tumor)bone/soft tissue tumor)
–GI, alopecia and myelosuppressionGI, alopecia and myelosuppression

MitomycinMitomycin: squamous cell cancers: squamous cell cancers
–MyelosuppressionMyelosuppression

32. 3232
Platinum AnalogsPlatinum Analogs
Inorganic metal complexInorganic metal complex
–Thought to have cytotoxic effects similar to Thought to have cytotoxic effects similar to
alkylating agentsalkylating agents
CisplatinCisplatin: broad range of solid tumors: broad range of solid tumors
–Nephrotoxicity, ototoxicity, peripheral sensory neuropthyNephrotoxicity, ototoxicity, peripheral sensory neuropthy
CarboplatinCarboplatin (second generation): Same spectrum as (second generation): Same spectrum as
cisplatincisplatin
–Less nephrotoxic, myelosuppressionLess nephrotoxic, myelosuppression

33. General problems with General problems with
anticancer drugsanticancer drugs

Most of them are antiproliferative, i.e. they Most of them are antiproliferative, i.e. they
damage DNA and so initiate apoptosis.damage DNA and so initiate apoptosis.
They also affect rapidly dividing They also affect rapidly dividing normal normal
cells.cells.
This leads to toxicity which are usually This leads to toxicity which are usually
severe.severe.
To greater or lesser extent the following To greater or lesser extent the following
toxicities are exhibits by all anticancer toxicities are exhibits by all anticancer
drugs.drugs.

34. MucositisMucositis
Nausea/vomitingNausea/vomiting
DiarrheaDiarrhea
CystitisCystitis
SterilitySterility
MyalgiaMyalgia
NeuropathyNeuropathy
Alopecia
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Renal failure
Myelosuppression
Phlebitis
ONCOLOGYONCOLOGY
Principles of chemotherapyPrinciples of chemotherapy
Side effects of chemotherapySide effects of chemotherapy

35. ADR of Antineoplastic Drugs in ADR of Antineoplastic Drugs in
Humans Humans

36. Distinctive Toxicities of Some Anticancer Distinctive Toxicities of Some Anticancer
DrugsDrugs
ToxicityToxicity Drug(s)Drug(s)
RenalRenal Cisplatin,* methotrexateCisplatin,* methotrexate
HepaticHepatic 6-MP, busulfan, cyclophosphamide6-MP, busulfan, cyclophosphamide
PulmonaryPulmonary Bleomycin,* busulfan, procarbazineBleomycin,* busulfan, procarbazine
CardiacCardiac Doxorubicin, daunorubicinDoxorubicin, daunorubicin
NeurologicNeurologic Vincristine,* cisplatin, paclitaxelVincristine,* cisplatin, paclitaxel
ImmunosuppressiveImmunosuppressive Cyclophosphamide, cytarabine, Cyclophosphamide, cytarabine,
dactinomycin, methotrexatedactinomycin, methotrexate
OtherOther Cyclophosphamide (hemorrhagic cystitis);Cyclophosphamide (hemorrhagic cystitis);
procarbazine (leukemia); procarbazine (leukemia); asparaginase* asparaginase*
(pancreatitis)(pancreatitis)
*Less Bone marrow suppression – “marrow sparing”*Less Bone marrow suppression – “marrow sparing”

37. 
Proliferating cellsProliferating cells are are
especially sensitive to especially sensitive to
chemotherapy chemotherapy
because because cytotoxic cytotoxic
drugsdrugs usually act by usually act by
disrupting DNA disrupting DNA
synthesis or mitosissynthesis or mitosis, ,
cellular activities that cellular activities that
only proliferating only proliferating
cells carry out. cells carry out.

toxicity to the toxicity to the
anticancer agents is anticancer agents is
to any rapidly to any rapidly
dividing cells. (e.g. dividing cells. (e.g.
bone marrow, hair bone marrow, hair
follicles, sperm follicles, sperm
forming cells).forming cells).
Chemotherapeutic agents are much more toxic to
tissues that have a high growth fraction than to tissues
that have a low growth fraction.

38. Prevention or Management of Prevention or Management of
Drug Induced toxicitiesDrug Induced toxicities

The toxicities of some anticancer drugs The toxicities of some anticancer drugs
can be well anticipated and hence be can be well anticipated and hence be
prevented by giving proper medicationsprevented by giving proper medications

E.g. mesna is given to prevent E.g. mesna is given to prevent
hemorrhagic cystitis by hemorrhagic cystitis by
cyclophosphamidecyclophosphamide

Dexrazoxane, is used to reduce the risk Dexrazoxane, is used to reduce the risk
of anthracycline-induced cardiomyopathy of anthracycline-induced cardiomyopathy

39. INCREASED EFFICACYINCREASED EFFICACY
Different mechanisms of action Compatible side
effects Different mechanisms of resistance
ACTIVITYACTIVITY SAFETYSAFETY
ONCOLOGYONCOLOGY
Principles of chemotherapyPrinciples of chemotherapy
Aim of combination therapyAim of combination therapy

40. The Goal of Cancer The Goal of Cancer
TreatmentsTreatments

Curative:Curative:
–Total irradication of cancer cells Total irradication of cancer cells
–Curable cancers include testicular tumors, Wills tumorCurable cancers include testicular tumors, Wills tumor

PalliativePalliative
–Alleviation of symptomsAlleviation of symptoms
–Avoidance of life-threatening toxicityAvoidance of life-threatening toxicity
–Increased survival and improved quality of lifeIncreased survival and improved quality of life

Adjuvant therapyAdjuvant therapy
–Attempt to eradicate microscopic cancer after surgeryAttempt to eradicate microscopic cancer after surgery
–e.g. breast cancer & colorectal cancere.g. breast cancer & colorectal cancer

41. Types of chemotherapyTypes of chemotherapy

Palliative chemotherapy : This is for Palliative chemotherapy : This is for
advanced disease or for cancers for which advanced disease or for cancers for which
there are no other effective treatment there are no other effective treatment
approaches.approaches.

Neoadjuvant chemotherapy : patients with Neoadjuvant chemotherapy : patients with
localized disease for whom local forms of localized disease for whom local forms of
therapy, such as surgery, radiation, or both, therapy, such as surgery, radiation, or both,
are ineffective by themselves are ineffective by themselves

42. Types of chemotherapyTypes of chemotherapy

Adjuvant treatment, either concurrent or Adjuvant treatment, either concurrent or
following local methods of treatment, following local methods of treatment,
including surgery, radiation therapy, or including surgery, radiation therapy, or
both.both.

Definitive chemotherapy : as in Leukemia Definitive chemotherapy : as in Leukemia
and lymphoma , where the primary mode and lymphoma , where the primary mode
of treatment is by chemotherapy. of treatment is by chemotherapy.

43. Primary Chemotherapy: Neoplasms for Primary Chemotherapy: Neoplasms for
Which Chemotherapy is a Primary Which Chemotherapy is a Primary
Treatment Modality Treatment Modality
Acute Leukemias
Primary central nervous
system lymphoma
Non-Hodgkin's
lymphoma
Small-cell lung cancer
Myeloma
Wilms' tumor
Hodgkin's lymphoma
Embryonal
rhabdomyosarcoma
Germ cell cancer

44. Neoadjuvant Chemotherapy: Neoplasms for Neoadjuvant Chemotherapy: Neoplasms for
Which Neoadjuvant Chemotherapy is Which Neoadjuvant Chemotherapy is
Indicated for Locally Advanced Disease Indicated for Locally Advanced Disease
Anal cancer Head and neck cancer
Bladder cancer Ovarian cancer
Breast cancer Osteogenic sarcoma
Cervical cancer Rectal cancer
Gastroesophageal cancer Soft tissue sarcoma
Lung cancer

45. Adjuvant Chemotherapy: Neoplasms for Which Adjuvant Chemotherapy: Neoplasms for Which
Adjuvant Therapy is Indicated after Surgery Adjuvant Therapy is Indicated after Surgery
Anaplastic
astrocytoma
Non–small-cell lung
cancer
Breast cancer Osteogenic sarcoma
Colorectal cancer Pancreatic cancer
Gastric cancer
Melanoma

46. Thank YouThank You