Pathophysiology of oncologenesis

1. Oncology
Yonas Ademe
Sep, 2017
1

2. Epidemiology
• The 5 most common cancers worldwide
– Men: lung, prostate, colorectal cancer, stomach, and
liver
– Women: breast, colorectal, cervix, lung, and stomach
• 4 most common worldwide (overall): lung, breast,
colorectal cancer, stomach cancer
• For several cancer types there is wide geographical
variability in cancer incidence and mortality
– Genetic differences, including racial and ethnic
differences
– Differences in environmental and dietary exposures
2

3. Cancer biology
3

4. Cell-Cycle dysregulation
• The cell cycle is divided into four phases
– During the synthetic or S phase, the cell generates a
single copy of its genetic material
– In the mitotic or M phase, the cellular components are
partitioned between two daughter cells
– The G1 and G2 phases represent gap phases during
which the cells prepare themselves for completion of
the S and M phases, respectively
– When cells cease proliferation, they exit the cell cycle
and enter the quiescent state referred to as G0
• Mitogenic growth factors can drive a quiescent cell from into
the cell cycle
4

5. Cont.
5

6. Malignant transformation
• Cancer Initiation
– Tumorigenesis is proposed to have 3 steps:
initiation, promotion, and progression
– Initiating events such as gain of function of genes
known as oncogenes or loss of function of genes
known as tumor-suppressor genes may lead a
single cell to acquire a distinct growth advantage
• Subsequent events can lead to accumulations of
additional deleterious mutations in the clone
6

7. Cont.
• Cont.
– Although tumors usually arise from a single cell or
clone (monoclonal theory), it is thought that
sometimes not a single cell but rather a large
number of cells in a target organ may have
undergone the initiating genetic event (polyclonal
theory)
• Thus, many normal-appearing cells may have an
increased malignant potential
– This is referred to as a field effect
7

8. Cont.
• Cont.
– Cancer is thought to be a disease of clonal
progression as tumors arise from a single or a
number of cells and accumulate mutations that
confer on the tumor an increasingly aggressive
behavior
• Most tumors go through a progression from benign
lesions to in situ tumors to invasive cancers
8

9. Cont.
• Cell proliferation and transformation
– In normal cells, cell growth and proliferation are
under strict control
– In cancer cells, cells become unresponsive to
normal growth controls, which leads to
uncontrolled growth and proliferation
9

10. Characteristics of Malignancy
• Although there are >100 types of cancer, it has been proposed that
there are 6 essential alterations in cell physiology that dictate
malignant growth:
– Establish an autonomous lineage
• Self-sufficiency of growth signals
• Insensitivity to growth-inhibitory signals
– Obtain immortality
• Potential for limitless replication
– Evasion of apoptosis
– Angiogenesis
– Invasion
– Metastasis
– Recently added hallmarks
• Evading immune destruction
• Reprogramming of energy metabolism
• Genomic instability
• Jettison excess baggage
• Subvert communication to and from the environment
10

11. Autonomy
• The proliferative advantage of tumor cells is a
result of their ability to bypass quiescence
• Cancer cells often show alterations in signal
transduction pathways that lead to proliferation in
response to external signals
– Mutations or alterations in the expression of cell-cycle
proteins can lead to disturbance of the basic regulatory
mechanisms that control the cell cycle, allowing
unregulated cell growth and proliferation
11

12. Immortality
• Normal cells are permitted to undergo only a finite
number of divisions
– For humans, this number is between 40 and 60
– The limitation is imposed by the progressive shortening of
the end of the chromosome (the telomere) that occurs each
time a cell divides
– Telomeric shortening is like a molecular clock and, when
time is up, the lineage will die out
• Cancer cells can use the enzyme telomerase to rebuild
the telomere at each cell division, so there is no
telomeric shortening and the lineage will never die out
12

13. Evading Apoptosis
• Apoptosis (programmed cell death) is a physiologic
process mainly controlled by P53
• The growth of a tumor mass is dependent not only
on an increase in proliferation of tumor cells but
also on a decrease in their apoptotic rate
• Evasion of apoptosis helps the wrong cells with the
wrong information to be in the wrong places at
the wrong times
13

14. Angiogenesis
• A mass of tumour cells cannot, in the absence of a blood
supply, grow beyond a diameter of about 1 mm
• Angiogenesis is the establishment of new blood vessels from
a pre-existing vascular bed
– This neovascularization is essential for tumor growth and
metastasis
• Tumors develop an angiogenic phenotype as a result of
accumulated genetic alterations and in response to local
selection pressures such as hypoxia
• It is mediated by factors produced by various cells, including
tumor cells, endothelial cells, stromal cells, and inflammatory
cells 14

15. Cont.
• The process of angiogenesis
– In response to the angiogenic switch, the endothelium
secretes several growth factors
• Fibroblast growth factor, platelet-derived growth factor, and
insulin-like growth factor
– The basement membrane and stroma around the
capillary are proteolytically degraded
– The endothelium then migrates through the degraded
matrix, initially as a solid cord and later forming lumina
– Finally, sprouting tips anastomose to form a vascular
network surrounded by a basement membrane
15

16. Cancer Invasion
• A feature of malignant cells is their ability to
invade the surrounding normal tissue
• The ability to invade involves:
– Changes in adhesion (intercellular)
• Increase in the interstitial pressure within a tissue
– Proteolysis of the extracellular matrix
– Initiation of motility
16

17. Metastasis
• Metastases arise from the spread of cancer cells
from the primary site and the formation of new
tumors in distant sites
• The metastatic process consists of a series of steps
that need to be completed successfully
• For dissemination the cells use the Testudo
approach (moving in clamps) and for implantation
the subversion approach (subverting the normal
mechanism of inflammation)
17

18. Cont.
• The steps
– The primary cancer must develop access to the circulation
through either the blood circulatory system or the lymphatic
system
– After the cancer cells are shed into the circulation, they must
survive
– Next, the circulating cells lodge in a new organ and
extravasate into the new tissue
– Next, the cells need to initiate growth in the new tissue and
eventually establish vascularization to sustain the new tumor
• Only a small subset of cancer cells is then able to initiate
micrometastases, and an even smaller portion goes on to grow into
macrometastases
• Occult micrometastases remain dormant for years
18

19. Cont.
19

20. Cont.
• Metastases can sometimes arise several years after the
treatment of primary tumors - this phenomenon is
referred to as dormancy
– Explanation
• Survival of cells viable in a quiescent state and then become
reactivated by a physiologically perturbing event
• Persistence of solitary cancer cells in a secondary site such as the
liver or bone marrow
• Tendency of cells to establish preangiogenic metastases in which
they continue to proliferate but that the proliferative rate is balanced
by the apoptotic rate
– Metastases become detected when they become vascularized
– E.g
• Although most breast cancer recurrences occur within the first 10
years after the initial treatment and recurrences are rare after 20
years, breast cancer recurrences have been reported decades after
the original tumor 20

21. Cont.
• Several types of tumors metastasize in an organ-
specific pattern
– Explanation
• Mechanical reasons
– Based on the different circulatory drainage patterns of the tumors
• “Seed and soil” theory
– The dependence of the seed (the cancer cell) on the soil (the
secondary organ)
– Once cells have reached a secondary organ, their growth efficiency
in that organ is based on the compatibility of the cancer cell’s
biology with its new microenvironment
– E.g: breast cancer cells may grow more efficiently in bone than in
some other organs
21

22. Cont.
• The ability of a primary tumor to metastasize
may be predictable by analysis of its gene
expression profile
– The metastatic potential of a tumor is already
predetermined by the genetic alterations that the
cancer cells acquire early in tumorigenesis
– Many of the oncogenes, such as HER2 and ras, are
thought to potentiate not only malignant
transformation but also one or more of the steps
required in the metastatic process
22

23. Evade Detection/Elimination
• Cancer cells, or at least those that give rise to
clinical disease, appear to gain the ability to escape
detection by the immune system
• This may be by suppressing the expression of
tumor-associated antigens (the stealth approach),
or it may be through actively coopting one part of
the immune system to help the tumour to escape
detection by other parts of the immune
surveillance system (be friend with the guard
approach)
23

24. Ability to Change Energy Metabolism
• Compared to the corresponding normal cells, some
cancer cells may be better able to survive in
hypoxic conditions
– This ability may enable tumors to grow and develop
despite an impoverished blood supply
• Cancer cells break down glucose by a phenomenon
of aerobic glycolysis, which leads to the production
of lactate
– In an act of symbiosis, lactate-producing cancer cells
may provide lactate for adjacent cancer cells which are
then able to use it, via the citric acid cycle, for energy
production
24

25. Genomic instability
• If a tumor is a genetic ferment, then there is
abundant opportunity for mutations to occur in
the DNA of tumor cells, some of these
mutations may themselves be capable of
facilitating the persistence of further mutations
25

26. Jettison excess baggage
• Cancer cells do not need to develop or retain those
specialised functions that make them good cellular
citizens
• They can therefore afford to repress or
permanently lose those genes that control such
functions (cells get leaner and meaner)
• This may bring some short-term advantages
• The longer-term disadvantage is that what is today
superfluous may, tomorrow, be essential
– This can leave cancer cells vulnerable to external stress
and may, in part, explain why some cancer treatments
work
26

27. Subvert communication to and from
the environment/milieu
• Providing false information and degrading the
command and control systems of their host
• Yet to be proven
27

28. The growth of a tumor
28

29. Introduction
• The division of a cell produces two daughter
cells
• The relationship 2n will describe the number of
cells produced after n generations of division
• There are between 1013 and 1014 cells in a
typical human being
• A tumor 10 mm in diameter will contain about
109 cells
29

30. Cont.
• As 230 = 109, this implies that it would take 30
generations to reach the threshold of clinical
detectability and, as 245 = 3 × 1013, fewer than 15
subsequent generations to produce a tumor that,
through sheer bulk alone, would be fatal
• This is an oversimplification because cell loss is a feature
of many tumors
– Exfoliation and competition for nutrition/oxygen
• It will, in the presence of cell loss, take many cellular
divisions to produce a clinically evident tumor
– Abundant opportunity for further mutations to occur during
the preclinical phase of tumour growth 30

31. Cont.
• The growth of a typical human tumor can be described
by an exponential relationship, the doubling time of
which increases exponentially (Gompertzian growth)
– In its early stages, growth is exponential but, as the tumor
grows, the growth rate slows
– This decrease in growth rate probably arises because of
difficulties with nutrition and oxygenation
• The tumor cells are in competition; not only with the tissues of the host, but
also with each other
31

32. Cont.
• Gompertzian curve
32

33. Clinical implications
• The majority of the growth of a tumor occurs before it is
clinically detectable
• There has been plenty of time, before diagnosis, for
individual cells to detach, invade, implant and form
distant metastases
– In many patients cancer may, at presentation, be a systemic
disase
• ‘Early tumors’ are genetically old
– Plenty of time for mutations to have occurred, mutations
that might confer spontaneous drug resistance
33

34. Cont.
• By the time they are detected, tumors have
passed the period of most rapid growth, that
period when they might be most sensitive to
anti-proliferative drugs
• The rate of regression of a tumor will depend
upon its growth rate at the time of treatment
(Norton–Simon hypothesis)
34

35. Related concepts
35

36. Oncogenes
• Normal cellular genes that contribute to cancer
when abnormal are called oncogenes
– The normal counterpart of such a gene is referred to as
a proto-oncogene
• Oncogenes are usually designated by 3-letter
abbreviations, such as myc or ras
– Oncogenes are further designated by the prefix “v-” for
virus or “c-” for cell or chromosome, corresponding to
the origin of the oncogene when it was first detected
• More than 100 oncogenes have been identified
36

37. Cont.
• Oncogenes may be:
– Growth factors (e.g., platelet-derived growth factor)
– Growth factor receptors (e.g., HER2)
– Intracellular signal transduction molecules (e.g., ras)
– Nuclear transcription factors (e.g., c-myc)
– Other molecules involved in the regulation of cell
growth and proliferation
37

38. Cont.
• Proto-oncogenes can be activated (show
increased activity) or overexpressed (expressed
at increased protein levels) by:
– Translocation (e.g., abl)
– Promoter insertion (e.g., c-myc)
– Mutation (e.g., ras)
– Amplification (e.g., HER2/neu)
38

39. Epithelial-Mesenchymal transition
• It is a regulatory program that is a fundamental
event in morphogenesis by which epithelial
cells are converted to migratory and invasive
cells
• It has been implicated as the mechanism
through which epithelial cells acquire the ability
to migrate, invade, resist apoptosis and
metastasize
39

40. Cancer Stem Cells
• Stem cells are cells that have the ability to
perpetuate themselves through self-renewal and
to generate mature cells of a particular tissue
through differentiation
• Currently available drugs can shrink metastatic
tumors but often cannot eradicate them
– The failure of these treatments usually is attributed to
the acquisition of drug resistance by the cancer cells
– The cancer stem cell hypothesis raises the possibility
that existing therapies may simply fail to kill cancer
stem cells effectively
40

41. Hereditary Cancer
• To date, over 70 genes have been associated with hereditary
cancers
– A few of these hereditary cancer genes are oncogenes, but most
are tumor-suppressor genes
– rb1Gene and retinoblastoma
– p53 and Li-Fraumeni Syndrome
– BRCA1/ BRCA2 and Hereditary Breast-Ovarian Cancer
– APC Gene and FAP
– Mismatch Repair Genes and HNPCC
– PTEN and Cowden Disease
– E-cadherin and Hereditary Diffuse Gastric Cancer
– RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2
– p16 and Hereditary Malignant Melanoma
41

42. Cont.
• The following factors may suggest the presence of
a hereditary cancer
– Clustering of the same cancer type in relatives
– Tumor development at a much younger age than usual
– Presentation of a cancer in the less affected sex (e.g.,
male breast cancer)
– Presence of bilateral disease
– Presence of multiple primary malignancies
– Occurrence of cancer in association with other
conditions such as mental retardation or
pathognomonic skin lesions
42

43. Cancer etiology
43

44. Etiologies
• Genetics (20%)
• Environmental (80%)
– Chemical carcinogens
– Physical carcinogens
– Viral carcinogens
44

45. Genetics
• Cancer is a genetic disease that arises from an
accumulation of genomic alterations that leads
to the selection of cells with increasingly
aggressive behavior
• These alterations may lead either to a gain of function by
oncogenes or to a loss of function by tumor-suppressor
genes
• Somatic mutations Vs. Germline mutations
45

46. Chemical Carcinogens
• Chemicals are classified into 3 groups based on how they
contribute to tumor formation
– Genotoxins
• They an initiate carcinogenesis by causing a mutation
– Co-carcinogens
• By themselves cannot cause cancer but potentiate carcinogenesis by
enhancing the potency of genotoxins
– Tumor promoters
• Enhance tumor formation when given after exposure to genotoxins
• Cigarette, aflatoxins, benzene, 2-Napthylamine, Soot
46

47. Physical Carcinogens
• Carcinogenesis can occur through induction of
inflammation and cell proliferation over a period of time
or through exposure to physical agents that induce DNA
damage
– Foreign bodies
– Organisms
• H. pylori, liver fluke, bladder shistosomia
– Radiation
• Ionizing radiation (X-rays, gamma rays, and alpha and beta particles)
• Non-ionizing radiation (UV)
– Chronic irritation and inflammation
• Chronic non-healing wounds, burns, and IBD
– Asbestosis
47

48. Viral Carcinogens
• 15% of all human tumors worldwide are caused by viruses
• Viruses may cause or increase the risk of malignancy through
several mechanisms:
– Direct transformation
– Expression of oncogenes that interfere with cell-cycle checkpoints
or DNA repair
– Expression of cytokines or other growth factors
– Alteration of the immune system
• Oncogenic viruses may be RNA (retroviruses that contain a
reverse transcriptase) or DNA viruses
• HBV/HCV, HIV, HPV (16 and 18), EBV, HTCV
48

49. Approach to cancer
49

50. Cancer screening
• Screening involves the detection of disease in an asymptomatic
population in order to improve outcomes by early diagnosis
• Early detection is the key to success in cancer therapy
• Screening for common cancers using relatively non-invasive tests is
expected to lead to early diagnosis, allow more conservative surgical
therapies with decreased morbidity, and potentially improve surgical
cure rates and overall survival rates
• Screening guidelines are developed for the general baseline risk
population
– These guidelines need to be modified for patients who are at high risk
50

51. Cont.
• Key factors that influence screening guidelines are:
– The disease
• Sufficiently common to warrant screening
• Recognisable early stage
• Treatment at an early stage more effective than at a later stage
– The test
• Sensitive and specific
• Safe
• Inexpensive
• Acceptable to the screened population
– The programme
• Adequate diagnostic facilities for those with a positive test
• High-quality treatment for screen-detected disease
• Screening repeated at intervals if the disease is of insidious onset51

52. Cont.
• Screening biases
– Lead time bias
• Early detection will improve outcome???
– Artefactual increase in survival (if years of survival is counted from
the time of diagnosis)
» If therapeutic measures don’t affect the course of the disease
– Selection bias
• Individuals agreeing or coming for screening have better
health and live longer
– Length bias
• Slowly growing tumors may be picked up by screening more
commonly than aggressive tumors
52
Solution: whole population based randomized screening

53. Cont.
• Breast
– Breast self-examination
• Age ≥ 20 years
– Clinical breast examination
• Women in their 20s and 30s
– At least every 3 years
• Women aged ≥40 y
– Annually
– Imaging
• Mammography
– Should be started at age 40 years
• Ultrasonography
– It can be used for breast cancer screening in women with dense breasts
• MRI
– Family history, BRCA mutation carriers, those individuals who have a family
member with a BRCA mutation, and individuals who received radiation to
the chest between the ages of 10 to 30 years 53

54. Cont.
• Colorectal (men and women aged ≥50 y)
– Fecal occult blood test
• Annually, starting at age 50 years
– Stool DNA test
• Interval uncertain, starting at age 50 years
– Flexible sigmoidoscopy
• Every 5 years, starting at age 50 years
– Double-contrast barium enema
• Every 5 years, starting at age 50 years
– Colonoscopy
• Every 10 years, starting at age 50 years
– CT colonography
• Every 5 years, starting at age 50 years
54

55. Cont.
• Lung (Current or former smokers aged 50–74
in good health with at least a 30 pack-year
history)
– Low-dose helical CT
• Prostate (Men, aged ≥50 years)
– DRE and PSA
55

56. Cancer diagnosis
• The definitive diagnosis of solid tumors is
obtained by performing a biopsy specimen of the
lesion
– FNAC
– Core needle biopsy
– Open biopsy
• Excisional
– Should be of curative intent
• Incisional
– Reserved for very large lesions in which a definitive diagnosis
cannot be made by needle biopsy specimen
56

57. Cont.
• Principles of open biopsy
– The biopsy specimen incision should be oriented to
allow for excision of the biopsy specimen scar if repeat
operation is necessary
– The biopsy specimen incision should directly overlie the
area to be removed rather than tunneling from another
site, which runs the risk of contaminating a larger field
– Meticulous hemostasis during a biopsy specimen is
essential
• A hematoma can lead to contamination of the tissue planes
and can make subsequent follow-up with physical
examinations much more challenging
57

58. Cancer staging
• Staging assists in:
– Selection of therapy
– Estimation of prognosis
– Exchange of information among treatment centers
• Stage migration
58

59. Cont.
• Both the AJCC (American Joint Committee on
Cancer) and the UICC (Union Internationale Contre
le Cancer (International Union Against Cancer))
have adopted a TNM staging system
– Applies only to tumors that have been microscopically
confirmed to be malignant
– Clinical staging (cTNM or TNM) is based on information
gained up until the initial definitive treatment
– Pathologic staging (pTNM) includes clinical information
and information obtained from pathologic examination
of the resected primary tumor and regional lymph
nodes
59

60. Tumor markers
• Tumor markers are substances that can be detected
in higher than normal amounts in the serum, urine,
or tissues of patients with certain types of cancer
• They are produced either by the cancer cells
themselves or by the body in a response to the
cancer
• Uses
– Early diagnosis of a new cancer
– Follow cancer response to therapy
– Monitor for recurrence
60

61. Cont.
• Many of the tumor markers proposed so far
have had low sensitivities and specificities
– They may not be elevated in all patients with cancer,
especially in the early stages
– Their levels can be elevated in benign conditions
61

62. Cont.
• PSA
– Prostate cancer
• CEA
– Colorectal cancer
– Breast, lung, ovarian, prostate, liver, and pancreatic cancer
• AFP
– Primary liver cancer, germ cell tumor of the ovary or testicle
• CA 19-9
– Colonic and pancreatic cancer
• Beta hCG
• LDH
62

63. Treatment of cancers
63

64. Introduction
• Goals of management
– Prevention
• Primary, secondary, tertiary
– Cure
• Definitive cure
• Prolong survival
– Palliation
– Rehabilitation
• Modes of management
– Surgery
– Radiotherapy
– Chemotherapy
– Biological therapy
• Hormonal therapy, immunotherapy, gene therapy
64

65. Cont.
• Although surgery is an effective therapy for most solid tumors,
patients who die from cancer usually die of metastatic disease
– Therefore, to improve patient survival rates, a multimodality approach,
including systemic therapy and radiation therapy is key for most tumors
65

66. Surgical management
• Although radiation therapy and systemic therapy
can assist in decreasing local recurrence rates in the
setting of positive margins, adjuvant therapy
cannot substitute for adequate surgery
• The goal of surgical therapy for cancer is to achieve
oncologic cure
– The uniform goal for all successful oncologic operations
seems to be achieving widely negative margins with no
evidence of macroscopic or microscopic tumor at the
surgical margins
66

67. Cont.
• In the past it was presumed that the more
radical the surgery, the better the oncologic
outcome would be
– Over the past three decades, this has been
recognized as not necessarily being true, which has
led to more conservative operations, with wide local
excisions replacing compartmental resections
67

68. Cont.
• Role of surgery in cancer treatment
– Diagnosis and staging
– Resection of primary tumor
– Lymphadenectomy
– Metastasectomy
– Palliation
– Treatment of complications
– Reconstruction
– Mode of hormonal therapy
68

69. Cont.
• Resection of primary tumor
– Patients in whom the primary tumor is not resectable
with negative surgical margins are considered to have
inoperable disease
• Same is true with a disease involving multiple distant
metastases
• The operability of primary tumors is best determined before
surgery with appropriate imaging studies
– On occasion, primary tumors are resected in these
patients for palliative reasons, such as improving the
quality of life by alleviating pain, infection, or bleeding
69

70. Cont.
• Lymphadenectomy
– Most oncologic operations have been designed to
remove the primary tumor and draining lymphatics
en bloc
• This type of operative approach usually is undertaken
when the lymph nodes draining the primary tumor site lie
adjacent to the tumor bed, as is the case for colorectal
cancers and gastric cancers
– Unlike most carcinomas, soft tissue sarcomas rarely
metastasize to the lymph nodes (<5%)
• Therefore lymph node surgery usually is not necessary
70

71. Cont.
• Metastasectomy
– Although once a tumor has metastasized it usually is not
curable with surgical therapy, such therapy has resulted in
cure in selected cases with isolated metastases to the liver,
lung, or brain
• Very effective results: liver mets from the colon, lung mets from
kidneys, brain mets from lung
– Factors
• Cancer type
– A liver metastasis from a colon cancer is more likely to be an isolated and
thus resectable lesion than a liver metastasis from a pancreatic carcinoma
• Sites of metastases
• Number of metastases
• Rate of tumor growth
• Patient’s age and general condition
71

72. Radiotherapy
• Ionizing radiation is energy strong enough to
remove an orbital electron from an atom
• The dose of radiation absorbed correlates with
the energy of the beam
– The basic unit is the amount of energy absorbed per
unit of mass (joules per kg) and is known as a
gray(Gy)
• One gray is equivalent to 100 rads, the unit of radiation
measurement used in the past
72

73. Cont.
• Radiation deposition results in DNA damage
manifested by single- and double-strand breaks in
the sugar phosphate backbone of the DNA
molecule
• The most radiation-sensitive phases are G2 and M,
whereas G1 and late S phases are less sensitive
• Types
– External beam radiotherpy
– Brachytherpay
– Interstitial brachytherpy
73

74. Cont.
• Side effects
– The side effects of radiation therapy can be acute,
occurring during or 2 to 3 weeks after therapy, or
chronic, occurring weeks to years after therapy
– The side effects depend on the tissue included in
the target volume
• In addition to tissue specific effects, a small increase in
the risk for secondary malignancies is attributable to
radiation therapy
74

75. Cont.
• Side effects
75

76. Chemotherapy
• In patients with documented distant metastatic
disease, chemotherapy is usually the primary
modality of therapy
• The goal of therapy in this setting is to decrease
the tumor burden, thus prolonging survival
– It is rare to achieve cure with chemotherapy for
metastatic disease for most solid tumors
76

77. Cont.
• Chemotherapy destroys cells by first-order kinetics,
which means that with the administration of a drug
a constant percentage of cells is killed, not a
constant number of cells
– If a patient with 1012 tumor cells is treated with a dose
that results in 99.9% cell kill (3-log cell kill), the tumor
burden will be reduced from 1012 to 109 cells (or 1 kg to
1 g)
– If the patient is re-treated with the same drug, which
theoretically could result in another 3-log cell kill, the
cells would decrease in number from 109 to 106 (1 g to 1
mg) rather than being eliminated totally
77

78. Cont.
• Response to chemotherapy is monitored
clinically with imaging studies as well as physical
examinations
– Response usually is defined as:
• Complete response
• Partial response
• Stable disease
• Progression
78

79. Cont.
• Role of chemotherapy
– Primary/curative intent
– Palliative
– Adjuvant
– Neo-adjuvant
79

80. Cont.
• Chemotherapy administered to a patient who is at
high risk for distant recurrence but has no evidence
of distant disease is referred to as adjuvant
chemotherapy
– The goal is eradication of micrometastatic disease, with
the intent of decreasing relapse rates and improving
survival rates
– It can be administered after surgery (postoperative
chemotherapy) or before surgery (preoperative
chemotherapy, neo-adjuvant chemotherapy, or
induction therapy)
80

81. Cont.
• Preoperative chemotherapy has 3 potential
advantages
– Preoperative regression of tumor can facilitate
resection of tumors that were initially inoperable or
allow more conservative surgery for patients whose
cancer was operable to begin with
– Treatment of micrometastases without the delay of
postoperative recovery
– Ability to assess a cancer’s response to treatment
clinically
81

82. Cont.
• Potential disadvantages to preoperative
chemotherapy
– Although disease progression while the patient is
receiving preoperative chemotherapy is rare in
chemotherapy-sensitive tumors such as breast cancer, it
is more frequent in relatively chemotherapy-resistant
tumors such as sarcomas
– It can introduce special challenges to tumor localization,
margin analysis, lymphatic mapping, and pathologic
staging
– Patient might get too sick to withstand the surgery
– Chemo might delay the surgery
82

83. Cont.
• Implicit within the concept of adjuvant therapy
is the realisation that much of what is done is
unnecessary or futile, or both
– The need for adjuvant therapy, to treat the risk that
residual disease might be present after apparently
curative surgery, is an acknowledgement of the
current inability to detect or predict, with sufficient
precision, the presence of residual disease
83

84. Hormonal therapy
• Some tumors, most notably breast and
prostate cancers, originate from tissues whose
growth is under hormonal control
• Types
– Surgical
– Medical
• Androgens, antiandrogens, estrogens, antiestrogens,
progestins, gonadotropin inhibitors, aromatase
inhibitors, glucocorticoids, and somatostatin analogues
– E.g. the estrogen antagonist tamoxifen
84

85. Immunotherapy
• The aim of immunotherapy is to induce or potentiate
inherent antitumor immunity that can destroy cancer cells
• Central to the process of antitumor immunity is the ability of
the immune system to recognize tumor-associated antigens
present on human cancers and to direct cytotoxic responses
through humoral or T-cell–mediated immunity
• Examples
– BCG
– Cytokines such as interleukin-2, interferon-α, and interferon-γ
85

86. Gene therapy
• It is being pursued as a possible approach to
modifying the genetic program of cancer cells as
well as treating metabolic diseases
• The field of cancer gene therapy uses a variety
of strategies, ranging from replacement of
mutated or deleted tumor-suppressor genes to
enhancement of immune responses to cancer
cells
86

87. Cancer prevention
87

88. Introduction
• Cancer prevention can be divided into three
categories:
– Primary prevention
• Prevention of initial cancers in healthy individuals
– Secondary prevention
• Prevention of cancer in individuals with premalignant
conditions
– Tertiary prevention
• Prevention of second primary cancers in patients cured of
their initial disease
88

89. Chemoprevention
• The systemic or local administration of
therapeutic agents to prevent the development
of cancer
– Tamoxifen administration to reduce the risk of
breast cancer
89

90. Surgical prevention
• In selected circumstances, the risk of cancer is
high enough to justify surgical prevention
– Hereditary cancer syndromes
• Hereditary breast-ovarian cancer syndrome, hereditary
diffuse gastric cancer, FAP, HNPCC, MEN type 2, as well as
some nonhereditary conditions such as chronic ulcerative
colitis
• Most prophylactic surgeries are large ablative
surgeries
– Bilateral risk reducing mastectomy or total
proctocolectomy
90

91. End!
91