Principles of cancer chemotherapy: a deep insight by RxVichuZ!

PRESENTED TO : DR. SHARMILA CHATTERJEE, DR. SASWATI SINHA
PRESENTED BY:
(DR.)VISHNU.R.NAIR,
PHARM.D INTERN(AMRI HOSPITAL ACADEMIC TRAINEE),
NATIONAL COLLEGE OF PHARMACY, KERALA.

HEADINGS INVOLVED:
1. CANCER DEFINITION
2. FEATURES OF CANCER CELLS(SUMMARIZED)
3. TYPES OF CANCER
4. ETIOLOGY
5. DIAGNOSTIC PARAMETERS ENUMERATION
6. CANCER STAGING.
PRINCIPLES OF ONCOLOGY

“CANCER refers to a HETEROGENOUS group of diseases, that are
caused by an IMPAIRMENT of NORMAL FUNCTIONING of GENES,
leading to GENETIC DAMAGE”
DEFINITION OF CANCER
Bernhardt B. Comprehensive pharmacy review for NAPLEX. 8th ed. Shargel L, editor. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013. Pg:1001

 Cancer cells are also known as “TUMORS”/ “NEOPLASMS”
 Single abnormal cell continues to divide INDEFINITELY  causes TUMORS
 The unique features of cancer cells can be explained under the heading
“CARCINOGENESIS”
CARCINOGENESIS:
- Process of cancer formation
- Occurs in three stages, namely initiation, promotion & progression.
FEATURES OF CANCER CELLS

A. INITIATION:
- Normal cells  exposed to carcinogen  causes genetic damage to cell
B. PROMOTION:
- Alteration in environment  allows growth of mutated cells (preferentially
over normal cells)  results in mutated cells becoming “CANCEROUS”.
C. PROGRESSION:
- Increased proliferation of cancer cells  allows invasion into local tissue 
results in METASTASIS!
FEATURES OF CANCER CELLS

 Tumors can either be BENIGN or MALIGNANT
 BENIGN TUMORS:
- Slow-growing
- Resemble normal cells
- Localized
- Less harmful!
 MALIGNANT TUMORS:
- Proliferate rapidly
- Have a typical appearance
- Invade & destroy surrounding tissues
- Harmful!!
TYPES OF CANCERS

 Malignant tumors are further classified according to the origin of tumor cell development:
A. SOLID TUMORS:
- Include:
i. CARCINOMAS:
• Tumors of epithelial cells
• Eg: Breast, colon, lung cancers
ii. SARCOMAS:
• Tumors of connective tissue
• Eg: Osteosarcoma, leiomyosarcoma
TYPES OF CANCERS

B. HEMATOLOGICAL MALIGNANCIES:
- Include:
i. LYMPHOMAS:
- Tumors of lymphatic system
- Eg: HL, NHL, etc
ii. LEUKEMIAS:
- Tumors of blood-forming elements
- Classified as ACUTE/CHRONIC & MYELOID/LYMPHOID
TYPES OF CANCERS

Causes include:
A. VIRUSES:
i. EBV(Ebstein-Barr Virus)
ii. HBV(Hepatitis B Virus)
iii. HPV(Human Papilloma Virus)
B. ENVIRONMENTAL & OCCUPATIONAL EXPOSURES:
i. Ionizing radiations
ii. UV-radiations
iii. Exposure to chemicals like vinyl chloride, benzene, asbestos, etc.
WHAT CAUSES CANCERS?

C. LIFESTYLE FACTORS:
i. High-fat diet
ii. Low-fiber diet
iii. Tobacco usage
iv. Ethanol usage.
D. MEDICATIONS:
i. Alkylating agents
ii. Immunosuppressants, etc.

E. GENETIC FACTORS:
i. Inherited mutations
ii. Oncogenes
iii. Defective tumor-suppressing genes.

DRUG OR HORMONE TYPE OF CANCER ASSOCIATED
Alkylating agents(chlorambucil, mechlorethamine,
melphalan, nitrosoureas)
Leukemia
Anabolic steroids Liver
Anthracyclines(doxorubicin) Leukemia
Analgesics containing phenacetin Renal, urinary bladder
Antiestrogens(tamoxifen) Endometrium
DRUGS OR HORMONES THAT CAUSE CANCERS
Compagni A, Christofori G. Recent advances in research on multistage tumorigenesis. Br J Cancer 2000;83:1 -5
Stricker TP, Kumar V. Neoplasia. In: Kumar V, Abbas AK, Aster JC, Fausto N. Robbins and Cotran Pathologic Basis of Disease, 8th ed. Philadelphia, PA: Saunders, 2010:259-330.

DRUG OR HORMONE TYPE OF CANCER ASSOCIATED
Coal tars(topical) Skin
Non-steroidal estrogens(diethylstilbestrol) Vagina or cervix, endometrium, breast, testes
Steroidal estrogens(Estrogen replacement therapy, oral
contraceptives)
Endometrium, breast, liver
Epipodophyllotoxins(etoposide, teniposide) Leukemia
Immunosuppressants(cyclosporine, azathioprine) Lymphoma, skin
Oxazaphosphorines(cyclophosphamide, ifosfamide) Urinary bladder.
DRUGS OR HORMONES THAT CAUSE CANCERS
Compagni A, Christofori G. Recent advances in research on multistage tumorigenesis. Br J Cancer 2000;83:1 -5
Stricker TP, Kumar V. Neoplasia. In: Kumar V, Abbas AK, Aster JC, Fausto N. Robbins and Cotran Pathologic Basis of Disease, 8th ed. Philadelphia, PA: Saunders, 2010:259-330.

Include:
A. WARNING SIGNS & SYMPTOMS:
1. Unexplained weight loss
2. Fatigue
3. Fever
4. Pain
5. Skin changes
6. Sore, that does not heal
7. White patches/ spots in mouth/on tongue
8. Unusual bleeding/discharge
9. Recent change in wart/mole
10. Thickening or lump in breast/ other body part, etc.
DIAGNOSTIC MEASURES FOR CANCER
Bernhardt B. Comprehensive pharmacy review for NAPLEX. 8th ed. Shargel L, editor. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013. Pg:1001-2.

B. TUMOR MARKERS:
- Biochemical indicators of presence of neoplastic proliferation
- Detected in serum, plasma/ other body fluids
- Examples include:
i. CARCINOEMBRYONIC ANTIGEN(CEA) : For COLORECTAL CANCER
ii. ALPHA-FETOPROTEIN(AFP): For HCC/ HEPATOBLASTOMA
iii. PROSTATE-SPECIFIC ANTIGEN(PSA): For PROSTATE CANCER.
C. TUMOR BIOPSY
D. IMAGING STUDIES:
i. Radiograph
ii. MRI-Scan
iii. PET
iv. CT-Scan.

E. OTHER LABORATORY TESTS:
1. CBCs
2. Blood chemistries, etc.
Bernhardt B. Comprehensive pharmacy review for NAPLEX. 8th ed. Shargel L, editor. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013. Pg:1002.

 Refers to “CATEGORIZING of patients, with respect to extent of their disease”
 Helps to determine PROGNOSIS & TREATMENT
 There are 2 different staging systems currently employed:
A. TNM CLASSIFICATION:
i. “T’:
- Indicates TUMOR SIZE - “0” value : Indicates “absence of tumor”
ii. “N”:
- Indicates PRESENCE & EXTENT of REGIONAL LYMPH NODE SPREAD
- Classified from 0(no lymph node involvement) to 3(extensive involvement).
STAGING OF CANCER

iii. “M”:
- Indicates presence/absence of METASTASES
- Classified as 0(absence) OR 1(presence of metastases).
B. AJCC STAGING:
- Developed by American Joint Committee on Cancer
- Classifies cancers as stages 0 to IV
- Higher number indicates:
i. Larger tumors
ii. Extensive nodal involvement
iii. With/without metastases
iv. Worsening prognosis.
STAGING OF CANCER

CELL LIFE-CYCLE: A BRIEF INSIGHT

Includes:
A. PHASES OF CELL-CYCLE
B. CELL-GROWTH KINETICS(THEORIES INVOLVED)
C. TUMOR CELL BURDEN(HYPOTHESIS INVOLVED)
D. PHASE-SPECIFIC ANTITUMOR AGENTS
E. PHASE-NONSPECIFIC ANTITUMOR AGENTS
F. CELL-CYCLE NONSPECIFIC AGENTS
CELL LIFE-CYCLE

 Useful to get an insight into activity of chemotherapeutic agents
 Phases include:
A. M-PHASE(MITOSIS):
- In this phase  cell divides into 2 daughter cells
B. G1-PHASE:
- Also known as “POSTMITOTIC GAP”
- In this phase  RNA & proteins required for specialized cell functions  synthesized for DNA
synthesis.
C. S-PHASE:
- Here  DNA synthesis and replication occurs
CELL-CYCLE PHASES

D. G2-PHASE:
- Also known as “PRE-MITOTIC/ POST-SYNTHETIC GAP”
- In this phase  RNA & enzymes “TOPOISOMERASE I & II” produced  helps in cell duplication
E. G0-PHASE:
- Also known as “RESTING PHASE”
- In this phase  CELL DOESN’T DIVIDE!
- Cells in this phase  INSENSITIVE TO CHEMOTHERAPY!
- Some of the cells in this phase  re-enter the actively –dividing cell-cycle
- By a process called RECUITMENT(initiated by some anticancer agents)  a large number of
actively-dividing cells are killed  thus facilitates G0 cells re-entry!
CELL-CYCLE PHASES

 There are some terminologies that describe cell-growth kinetics, which include:
A. CELL-GROWTH FRACTION:
- “Proportion of cells(inside the tumor), that are dividing/preparing to divide”
- As tumor enlarges  large number of cells may not be able to obtain sufficient
nutrients & blood supply for replication  GROWTH FRACTION REDUCES!!
B. CELL-CYCLE TIME:
- “Average time for a cell(that has just completed MITOSIS), to grow & again divide &
again pass through mitosis”
- Time varies, according to each individual tumor
CELL-GROWTH KINETICS

C. TUMOR DOUBLING TIME:
- “Time required for tumor to DOUBLE IN SIZE!”
- As tumor gets larger  fewer cells gets nutrients & blood supply for growth
 few cells only actively divide  DOUBLING TIME GETS LONGER!!
CELL-GROWTH KINETICS

 Refers to “NUMBER OF TUMOR CELLS IN THE BODY”
 A large number of cells are required to produce symptoms & be clinically detectable(Approx.
109 cells!)
 According to CELL-KILL HYPOTHESIS :
a. Certain PERCENTAGE of TUMOR CELLS will be killed with each course of cancer chemotherapy
b. Since tumor cells are killed  cells in G0-phase may be recruited into G1-Phase  results in
TUMOR REGROWTH
c. Thus  REPEATED CYCLES of CHEMOTHERAPY required to achieve a complete
response/remission!
d. Percentage of cells killed  depends on CHEMOTHERAPY DOSE!
e. In theory  tumor burden WOULD NEVER REACH ABSOLUTE ZERO(since only a percentage of
cells are killed with each cycle)
f. Less than 104 cells may depend on elimination by host’s immune system!
TUMOR CELL BURDEN

Most active against cells, that ARE IN A SPECIFIC PHASE OF CELL-CYCLE
Most effective against tumors with a HIGH GROWTH FRACTION
Giving such drugs as CONTINUOUS I.V INFUSION / by MULTIPLE REPEATED
DOSES  increase likelihood of targeting majority of cells in the specific phase
at any one time!
Also known as “SCHEDULE-DEPENDANT AGENTS”
Include:
1. M-PHASE: Mitotic inhibitors(vinca alkaloids, taxanes)
2. G1-PHASE: Asparaginase, prednisone
3. S-PHASE: Antimetabolites
4. G2-PHASE: Bleomycin, etoposide.
PHASE-SPECIFIC CHEMOTHERAPEUTIC AGENTS

Effective, while cells are in the active cycle, regardless of particular phase
Usually show activity against SLOW-GROWING TUMORS
Given as SINGLE BOLUS DOSES (since their activity is independent of cell-cycle)
Also known as “DOSE-DEPENDENT AGENTS”
Examples include:
1. ALKYLATING AGENTS
2. ANTITUMOR ANTIBIOTICS.
PHASE-NONSPECIFIC CHEMOTHERAPEUTIC AGENTS

Effective in ALL PHASES, including G0!!!
Examples include:
1. Carmustine
2. Lomustine
3. Radiation therapy.
CELL-CYCLE NONSPECIFIC CHEMOTHERAPEUTIC AGENTS

CANCER CHEMOTHERAPY:
PRINCIPLES INVOLVED

Includes the following headings:
A. OBJECTIVES OF CHEMOTHERAPY
B. CHEMOTHERAPY DOSING
C. DOSING ADJUSTMENTS
D. COMBINATION CHEMOTHERAPY
E. ADMINISTRATION PRINCIPLES
F. RESPONSE TO CHEMOTHERAPY
G. FACTORS AFFECTING CHEMOTHERAPY RESPONSE
CANCER CHEMOTHERAPY: PRINCIPLES INVOLVED

Objectives depend on nature of cancer/tumor
A. FOR HEMATOLOGICAL MALIGNANCIES:
- Several chemotherapy phases will be required
- With aggressive therapy for a prolonged period  CURE may be obtained!
- For LEUKEMIAS  objectives of therapy include:
i. REMISSION INDUCTION: Therapy, with the intention of MAXIMUM KILL
ii. CONSOLIDATION THERAPY:
- Also known as post-remission therapy
- Intends to lower tumor cell burden below 103!
- Aims to eradicate any clinically undetectable disease.
OBJECTIVES OF CANCER CHEMOTHERAPY

iii. MAINTENANCE THERAPY:
- Therapy given in LOW DOSES
- Major objective is to maintain/prolong REMISSION!
B. FOR SOLID TUMORS:
- One/ more strategies may be used, depending on whether surgery/radiation is
required along with chemotherapy OR not
- Consists of 2 types:
i. ADJUVANT CHEMOTHERAPY:
- In this  chemotherapy is given AFTER SURGERY to eliminate any remaining disease or so
ii. NEOADJUVANT CHEMOTHERAPY:
- In this  chemotherapy is given BEFORE SURGERY/RADIATION, to reduce tumor burden!

C. PALLIATIVE THERAPY:
- Given in the following conditions:
i. Complete tumor eradication is unlikely
ii. Patient refuses aggressive therapy
- Can be given, to:
i. Reduce tumor size
ii. Control growth
iii. Reduce symptoms.
D. SALVAGE CHEMOTHERAPY:
- Given to assist in remission, on NON-EFFECTIVENESS OF PREVIOUS CHEMOTHERAPIES!

- Dosing can be done, based on:
i. Body weight
ii. BSA(Body Surface Area)
iii. AUC(Area under the curve)
- BSA is most frequently used!
- BSA  correlates with C.O(cardiac output)  C.O determines hepatic & renal
blood flow  thus affects drug elimination  thus frequently used!
- In children (especially infants/ children of weight < 10-12 kg)  usage of BSA 
can OVERESTIMATE PATIENT’S SIZE  leads to OVERDOSING OF THERAPY 
can lead to TOXICITIES!
- In such(children) cases  dosing is based on BODY WEIGHT(in kilograms).
CHEMOTHERAPY DOSING

Dosing adjustments may be required for KIDNEY/LIVER
DYSFUNCTION
Doses can also be adjusted, based on HEMATOLOGIC/ NON-
HEMATOLOGIC TOXICITIES
DOSING ADJUSTMENTS

Usually more effective than SINGLE-AGENT THERAPY
Factors to be considered while combining chemotherapeutic agents:
A. Antitumor activity
B. Different MOAs(mechanism of action)
C. Minimally overlapping toxicities!
WHY COMBINATION CHEMOTHERAPY???
A. To overcome/prevent resistance
B. To confer cytotoxicity to resting & dividing cells
C. Biochemical enhancement of effect
D. Rescue of normal cells!
COMBINATION CHEMOTHERAPY

DOSING & SCHEDULING of combination regimens are significant,
since they ALLOW RECOVERY OF NORMAL CELLS
Combination regimens  usually given as SHORT-COURSES OF
THERAPY IN CYCLES!
Acronyms are often used to designate chemotherapy regimens
Eg: CMF refers to Cyclophosphamide, Methotrexate, & 5-FU (used in
treatment of breast cancer)
COMBINATION CHEMOTHERAPY

 Routes of administration  vary, depending on AGENT & DISEASE STATE
 Although i.v route is most commonly employed  oral route is also emerging!
 Other administration techniques include:
1. Oral
2. S.C
3. Intrathecal
4. Intra-arterial
5. Intraperitoneal
6. Intravesical
7. Continuous i.v infusion
8. Bolus i.v infusion
9. Hepatic artery infusion.
CHEMOTHERAPEUTIC DRUG ADMINISTRATION PRINCIPLES

Drugs given INTRATHECALLY include:
1. MTX(Methotrexate)
2. Cytarabine
3. Hydrocortisone
• Accidental administration of VINCA ALKALOIDS via intrathecal route
 results in PARALYSIS & DEATH!
• Products with different formulations(liposomal/ pegylated agents) 
used to reduce frequency of administration & toxicities(Eg:
Liposomal doxorubicin, pegfilgrastim, etc)
CHEMOTHERAPEUTIC DRUG ADMINISTRATION PRINCIPLES

Response to chemotherapy is defined in several ways
Does not always correlate with patient survival
Terms used include:
A. CR(Complete Response):
- Includes disappearance of all clinical, gross & microscopic disease
B. PR(Partial response):
- Indicates greater than 50% reduction in tumor size, lasting for a reasonable period
- Some evidence of disease remains even after therapy
C. RR(Response Rate):
- RR= (CR +PR)
RESPONSE TO CHEMOTHERAPY

d. SD(Stable Disease):
- Indicates that tumor neither grows nor shrinks significantly(> 25% change in
size)
e. PD(Progressive Disease; no response):
- Indicates by tumor size increasing by >25% / appearance of NEW LESIONS!
RESPONSE TO CHEMOTHERAPY

A. TUMOR CELL HETEROGENEITY:
- Large tumors  go through MULTIPLE CELL-DIVISIONS  results in SEVERAL MUTATIONS
 produces GENETICALLY DIVERSE CELLS
B. DRUG-RESISTANCE:
- According to GOLDIE-COLDMAN HYPOTHESIS :
i. Genetic changes are associated with drug resistance
ii. Probability of resistance  directly proportional to TUMOR SIZE!
- Mechanism of resistance includes MDR(multidrug resistant) gene  codes for
MEMBRANE-BOUND P-GLYCOPROTEIN
- P-glycoprotein  serves as a channel, through which CELLULAR TOXINS(chemotherapeutic
agents) are EXCRETED FROM THE CELL!
FACTORS AFFECTING RESPONSE TO CHEMOTHERAPY

C. DOSE INTENSITY:
- Defined as SPECIFIC DOSE, DELIVERED over a SPECIFIC PERIOD
- In most situations  full dose cannot be given(or a cycle is delayed) , owing to
complications/toxicities
- With SUBOPTIMAL DOSING  reduced response rates & survival
- Dose intensity involves SHORTENING the usual interval between doses, to MAXIMIZE DRUG
EFFECTS on the tumor growth kinetics
D. PATIENT-SPECIFIC FACTORS:
- Include the following factors, that determine how therapy should be given & how patient responds
to treatment:
i. Poor functional status
ii. Impaired organ function
iii. Presence of concomitant disease!
FACTORS AFFECTING RESPONSE TO CHEMOTHERAPY

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