This presentation deals with PRINCIPLES OF CANCER CHEMOTHERAPY. The following headings are included: A. PRINCIPLES OF ONCOLOGY B. CELL-CYCLE C. PRINCIPLES OF CANCER CHEMOTHERAPY Precise details have been provided. Do go through!!

1. PRESENTER DETAILS:
VISHNU.R.NAIR,
5TH YEAR PHARM.D,
NATIONAL COLLEGE OF PHARMACY(NCP).

2. PRINCIPLES OF ONCOLOGY

3. Under “PRINCIPLES OF ONCOLOGY”  the following will be discussed:
A. CANCER DEFINITION
B. FEATURES OF CANCER CELLS(SUMMARIZED)
C. TYPES OF CANCER
D. ETIOLOGY
E. DIAGNOSTIC PARAMETERS ENUMERATION
F. CANCER STAGING.

4. CANCER DEFINITION

5. “CANCER refers to a HETEROGENOUS group of diseases,
that are caused by an IMPAIRMENT of NORMAL
FUNCTIONING of GENES, leading to GENETIC DAMAGE”

6. FEATURES OF CANCER
CELLS(SUMMARIZED)

7.  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 the following stages:
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”.

8. C. PROGRESSION:
- Increased proliferation of cancer cells  allows invasion into local tissue 
results in METASTASIS!

9. TYPES OF CANCERS

10.  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!!

11.  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

12. 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

13. WHAT CAUSES CANCERS??

14. Causes include:
A. VIRUSES:
- Include:
i. EBV
ii. HBV
iii. HPV
B. ENVIRONMENTAL & OCCUPATIONAL EXPOSURES:
- Include:
i. Ionizing radiations
ii. UV-radiations
iii. Exposure to chemicals like vinyl chloride, benzene, asbestos, etc.

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

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

17. CANCER DIAGNOSTIC
MEASURES

18. Include:
A. WARNING SIGNS & SYMPTOMS:
Include:
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.

19. 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:
Include:
i. Radiograph
ii. MRI-Scan
iii. PET
iv. CT-Scan.

20. E. OTHER LABORATORY TESTS:
Include:
1. CBCs
2. Blood chemistries, etc.

21. CANCER STAGING

22.  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
- Classified from 0 to 4
- 0 : 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).

23. 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.

24. CELL LIFE-CYCLE: A BRIEF
INSIGHT

25.  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

26. CELL-CYCLE PHASES

27.  Useful to get an insight into activity of chemotherapeutic agents
 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:
- In this phase DNA synthesis & replication occurs.

28. 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  GENERALLY INSENSITIVE TO CHEMOTHERAPY!
- Some of the cells in this phase  re-enter the actively –dividing cell-cycle, by
strategic chemotherapeutic regimen(known as RECRUITMENT!)
- In the process of RECRUITMENT  a large number of actively-dividing cells are
killed  thus facilitates G0 cells re-entry!!!!!!!

29. CELL-GROWTH
KINETICS(THEORIES
INVOLVED)

30.  There are some terminologies that describe cell-growth kinetics
 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

31. 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!!
- The GOMPERTZIAN GROWTH CURVE illustrates these cell-growth concepts!!

32. TUMOR CELL
BURDEN(HYPOTHESIS
INVOLVED)

33.  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!

34. PHASE-SPECIFIC
CHEMOTHERAPEUTIC
AGENTS

35.  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 CONTIINUOUS 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.

36. PHASE-NONSPECIFIC
CHEMOTHERAPEUTIC
AGENTS

37.  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.

38. CELL-CYCLE NONSPECIFIC
CHEMOTHERAPEUTIC
AGENTS

39.  Effective in ALL PHASES, including G0!!!
 Examples include:
1. Carmustine
2. Lomustine
3. Radiation therapy.

40. CHEMOTHERAPY:
PRINCIPLES INVOLVED

41.  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

42. OBJECTIVES OF
CHEMOTHERAPY

43. 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

44. 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!

45. 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!

46. CHEMOTHERAPY DOSING

47. - Dosing can be done, based on:
i. Body weight
ii. BSA
iii. AUC
- BSA is most frequently used!
- BSA  correlates with C.O  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 cases  dosing is based on BODY WEIGHT(in kilograms).

48. DOSING ADJUSTMENTS

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

50. COMBINATION
CHEMOTHERAPY

51.  Usually more effective than SINGLE-AGENT THERAPY
 Factors to be considered while combining chemotherapy agents:
A. Antitumor activity
B. Different MOAs
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!

52.  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)

53. ADMINISTRATION
PRINCIPLES

54.  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.

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

56. RESPONSE TO
CHEMOTHERAPY

57.  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:
- 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)

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

59. FACTORS AFFECTING
RESPONSE TO
CHEMOTHERAPY

60.  Includes:
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!

61. 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!

62. THANK YOU!!!