It will be useful to understand basic principles of cancer chemotherapy

1. Principles of cancer
chemotherapy
Dr Deenadayalan T
Asst Professor
Department of Medical Oncology
Madurai Medical College
23-10-2021

2. Timeline of Turning points in Modern
Oncology

3. Definition of Chemotherapy
Chemotherapy -
coined by Paul
Ehrlich during the
identification of
agents that inhibited
bacterial cell growth
Term now applied to
use of cytotoxic
drugs used to treat
cancer

4. INTRODUCTION
• Cancer chemotherapy is a modality of cancer therapy
that involves the administration of chemical agents to
destroy cancer cells.
• The aim of cancer chemotherapy is to cure where
possible and palliative where cure is impossible
• The effective use of chemotherapy needs a deep
understanding of the principles of tumor biology,
cellular kinetics, pharmacology and drugs resistance

5. CANCER AND NORMAL CELLS
CANCER CELLS NORMAL CELLS
Loss of contact inhibition
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
Oncogene expression is rare
Intermittent or co-ordinated
growth factor secretion
Presence of tumor suppressor
genes
Frequent
mitoses
Nucleus
Blood vessel
Abnormal
heterogeneous cells
Normal
cell
Few
mitoses

6. Phases of Cell Cycle
M: Mitosis, cell division, 60 minutes
G0: resting phase, non-dividing cells
G1: post-mitotic phase, enzyme synthesis
prior to DNA synthesis, 11 hrs
S: DNA synthesis, 8 hrs
G2: pre-mitotic phase, protein and RNA
synthesis, 4 hrs
Most non-malignant cells are in G0

7. Tumour kinetic
Growth rate depends on:
growth fraction
-percent of proliferating cells within a given system
-human malignacy ranges from 20-70%
-bone marrow 30 %
cell cycle time
-time required for tumour to double in size
rate of cell loss

8. Doubling times of some human
tumours
Burkitt’s lymphoma 1.0
Choriocarcinoma 1.5
Hodgkin’s disease 3-4
Testicular embryonal carcinoma 5-6
Colon 80
Lung 90
Tumour Doubling times
(days)

9. Clinically detectable cancer
It requires about 30 DT for a tumor to grow from 1 cell to 1 billion
(109) cells( roughly 1 cm mass or 1gm mass)
A tumor mass cannot be detected by physical examination or
radiological studies until it is at least 1 cm in diameter.
Tumors of deep internal organs e.g. colon, escape detection until
they are much larger
Takes approximately 5-7 years for solid tumors
It takes only an additional 10 DT for this 1 gram mass to be 1 kg
(1012) cells
A tumor of a mass of 1-2 kg is considered lethal

10. TUMOR GROWTH

12. Doubling time of proliferating cancer cells is constant
(L1220 cells leukemia cell line), i.e., it follows first order
kinetics.
Does not depend on the burden of tumor cells.
Death results when malignant cells reach a critical
number or fraction of the mouse body weight
Cell kill by chemotherapy follows first-order kinetics-
log cell kill (% of cells killed at a given dose is constant,
regardless of tumor size)
Cell kill would increase with repeated treatment

13. Skipper’s Law-Controversies
Applicable for leukaemia and lymphoma
( where constant exponential growth exists)
Not applicable for slow growing solid tumours
(where growth fraction decreases exponentially
over the time –explained by Gompertazian
model)
Homogenous Sensitivity-proved incorrect by the
Delbruck Luria Concept.
‘Emergence of drug resistant clones as the
tumor had increased cell divisions and mitosis’
- basis for GOLDIE COLDMAN MODEL

14. TUMOR GROWTH
number of
cancer cells
diagnostic
threshold
(1cm)
time
undetectable
cancer
detectable
cancer
limit of
clinical
detection
host
death
10 12
10 9

15. GOLDIE COLDMAN MODEL
Mathematical model of genetic Resistance
Tumor cells acquire mutation even before exposure to
chemotherapy drugs (103- 106 )
Genetic resistance - spontaneous mutation due intrinsic
genetic instability
Probability of resistance to one drug 105 then probability of
resistance to 2different drugs 1010 - Rationale of giving
combination chemotherapy
Thus, tumors >1 cc are almost incurable with single agents.
Large tumor populations are likely to have > 1 resistant cell
population
Best strategy is to start the therapy as soon as possible,
before dev resistance, and with as many drugs as possible.

16. Norton Simon Hypothesis
Smallest Tumors have largest growth fraction
 Optimal Cytoreduction
 Adjuvant chemotherapy
 Tumor Repopulation after neoadjuvant chemotherapy

17. The Norton–Simon hypothesis states that the rate of tumor volume regression is proportional
to the rate of growth.
Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493
© Oxford University Press

18. Dose Intensity

19. NORTON SIMON MODEL…
An all out attack will destroy the highly
sensitive and less sensitive tumor cells and
not allow resistant cells to grow back
Alternating regimen impairs dose density-
hence sequential approach is the opt one
Eg: Bonadona et al-CMF –ADR ;sequential is
better than alternative cycle
Base for current dose dense approach

20. DOSE INTENSITY
mg/ sq.met/week
 Can be increased by increasing the dose (dose
escalation) or decreasing the intervals (dose density)
 Dose escalation –not a practical one always
 Levels higher than certain concentration may not increase the
killing of cancer cells
 Often intolerable toxicity
So Dose dense is the best approach

21. Classification of Antitumor Agents
Cell Cycle Specific Agents
Have activity in specific phases of cell
cycle
Examples: vinca alkaloids work in M-
phase, antimetabolites work in S-phase
Cell Cycle Nonspecific Agents
Examples: alkylating agents,
anthracyclines

23. Tumor factors influencing cell
kill
Tumor type – poorly differentiated tumors, Germ
cell tumors etc..
Site –Reach of chemotherapy (i.e. brain, Testis)
Size – poor vascularization, low growth fraction
Drug resistance (inherent)
 decreased accumulation
 altered metabolism
 increased tolerance
 increased efflux
 altered mechanisms of cell cycle

24. Host factors
Body surface area- commonest
tool to calculate the dose
BSA- function of cardiac output
↓
Hepatic flow (metabolism)
Distribution (to tumor effect,
to other parts side effects)
Renal (excretion)
AUC (area under curve)- indicates
drug concentration over a given
period of time (correlates with
efficacy in all drugs- but with
toxicity also in few drugs like
carboplatin)

25. Host factors
Renal function (tumor lysis)
Hepatic function (metastasis)
Nutrition (cancer cachexia)
Performance status
Co morbid conditions (DM, HT, CHD)
Prior treatments (bone marrow)
The need of an internist !!

26. Types of chemotherapy
Primary/ curative
Adjuvant
Neo-adjuvant
Concurrent
Palliative

28. Chemotherapeutic
Terminology
Induction chemotherapy – Dose intensive
therapy aimed at achieving a CR
Consolidation – Moderate dose intensity with
goal of providing additional log-kill
Maintenance - Low dose therapy aimed at
preventing regrowth from minimal disease
state
Sanctuary therapy – More localized therapy
to target sanctuary sites (i.e. brain, testes)

29. Combined Modality
Approaches
Combines chemotherapy with surgery,
radiation or other modalities in order to
achieve best response.
Examples include mastectomy followed by
radiation and adjuvant chemotherapy to
prevent systemic metastasis

30. Gompertzian Cell Growth –
Combined modality

31. Types of Administration
Oral (Mtx, 6 MP, ATRA, Capicitabine etc..)
Bolus/ Infusional therapy - IV
Subcutaneous/ trans dermal
Intra muscular (MTx)
Intra thecal
Intra arterial
Intra cavitary (vesical, pleural, peritoneal)
Inhalation

32. AIM OF COMBINATION
THERAPY
INCREASED EFFICACY
Different mechanisms of action Compatible side effects
Different mechanisms of resistance
ACTIVITY SAFETY

33. Precautions
Physical examination
Blood counts and biochemistry
Good I V line
Premedications
Monitoring toxicity
Trained medical oncologist

34. SIDE EFFECTS OF
CHEMOTHERAPY
Mucositis
Nausea/vomiting
Diarrhea
Cystitis
Sterility
Myalgia
Neuropathy
Alopecia
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Renal failure
Myelosuppression
Phlebitis

35. Measuring response
Reduction in tumor size
 Clinical, Radiological measurements
Reduction in tumor cell counts (ex:leukemia)
Reduction in tumor cell markers
 Immunoglobulins in myeloma
 Beta-HCG in germ cell tumors
 PSA in prostate cancer
Reduction of ascites or effusions
Improvement in organ function

36. Definition of Response RECIST
Complete response (CR) – complete elimination
of all evidence of disease for at least one month
Partial response (PR) - > 30% reduction in tumor
burden
Overall response (OR) = CR + PR
Stable disease (SD) – no change in tumor size
Progressive disease (PD) – increase in tumor
burden >20% or new lesions during therapy

37. Curable malignancies with chemo
Acute leukemia
Chorio carcinoma
Testicular cancer
Hodgkin’s disease
High-grade NHL
Wilms
Rhabdomyosarcoma

38. Era of Precision Oncology has just begun....

39. Thank you…