Cancer Treatment and

Prevention
 Modalities of treatment
• Local therapy:
– -surgery
– -radiation therapy

• Systemic treatment:
– chemotherapy
– Hormonal therapy
– Monoclonal antibodies
– Radioactive material

• Supportive care
• Non-conventional therapy

2
 Surgery
• Surgery was the first modality used successfully in the
treatment of cancer.

• It is the only curative therapy for many common solid tumors.

• The most important determinant of a successful surgical

therapy are the absence of distant metastases and no local
infiltration.

• Surgery may be used for palliation in patients for whom cure is

not possible.

• Has significant role in cancer prevention.

3
 Surgery for prevention
• Patients with conditions that predispose them
to certain cancers or with genetic traits
associated with cancer can have normal life
span with prophylactic surgery.
-colectomy .
-oophorectomy.
-thyroidectomy.
-removal of premalignant skin lesion .
4
 Radiation therapy
Teletherapy

• Radiation therapy is a local modality used in

the treatment of cancer .

• Success depends in the difference in the

radiosensitivity between the tumor and
normal tissue.

• It involves the administration of high energy

ionizing radiation in the form of x-ray or
gamma rays to the tumor site.

• Method of delivery: Gordon Isaacs, the first

– External beam(teletherapy).
– Internal beam therapy(Brachytherapy).
patient treated with the
linear accelerator
(radiation therapy) for
retinoblastoma in 1957.
5
 • Radiation therapy is planned
and performed by a team of
physicians, and radiation
oncologist.

• A course of radiation therapy

Brachytherapy for prostate cancer
is administered using "seeds," small
radioactive rods implanted directly
into the tumour.
is preceded by a simulation
session in which low-energy
beam are used to produce
radiograghic images that
indicate the exact beam
location.

6
• Telepathy often delivered in the form of photon beams
(either x-rays or gamma rays).

• Brachytherapy is radiation delivered from radiation sources

(radioactive materials) placed inside or on the body

• Radiation therapy with curative intent is the main treatment

in limited stage Hodgkin’s disease, some NHL, limited stage
cancer (prostate, gynecologic tumors & CNS tumor).

• Also can be used in palliative & emergency setting.

7
 Complications of radiation
• There are two types of toxicity:
– acute and long-term toxicity.

• Systemic symptoms such as fatigue, local skin reaction, GI

toxicity, or pharyngeal mucositis & xerostomia (dry mouth due to a
lack of saliva), myelosuppression.

• Long-term sequel: may occur many months or years after

radiation therapy.

• Radiation therapy is known to be mutagenic, carcinogenic,

and teratogenic, and having increased risk of developing both
secondary leukemia and solid tumor.
8
 Nuclear medicine

Radionuclides
• For decades have been used systemically to treat
malignant disorders.

• They are administered by specialists in nuclear

medicine or radiation oncologist.

• Radioactive iodine: in the from of 131I is effective

therapy for well differentiated thyroid cancer .

• Strontium-89 is used for the treatment of body

metastasis.

• Co-60 is also under used for cancer treatment . 9

 Classification of cytotoxic drugs
• Cytotoxic agent can be roughly categorized based on their
activity in relation to the cell cycle.

• Phase non-specific:
– The drugs generally have a linear dose-response curve ( the drug
administration,  in the fraction of cells killed).
• Phase specific:
– Above a certain dosage level, further increase in drug doesn’t result in
more cell killing, but one can alter duration of infusion.

10
 Chemotherapeutic agents:
• Alkylating agents
• Antimetabolites
• Antitumor antibiotics
• Plant alkaloids
• Other agents
• Hormonal agent
• Immunotherapy

11
 Alkylating Agents

Nitrogen
Ethylenimines Alkyl Sulfonates Nitrosoureas
Mustards

Cyclophosphamide Thiotepa Busulfan Carmustine

Legend
Drug Class
Sub-class
Prototype Drug
12
 Alkylating Agents
Mechanism of Action

• Alkylate within DNA at the N7 position of

guanine
• Resulting in miscoding through abnormal
base-pairing with thymine or in depurination
by excision of guanine residues, leading to
strand breakage
• Cross-linking of DNA and ring cleavage may
also occur
13
 Antimetabolites

Folic Acid Pyrimidine

Purine Analogs
Analogs Analogs

Methotrexate Mercaptoguanine Fluorouracil

Legend
Drug Class
Sub-class
Prototype Drug
14
 Folate

• An essential dietary factor, from which THF

cofactors are formed which provide single
carbon groups for the synthesis of
precursors of DNA and RNA
• To function as a cofactor folate must be
reduced by DHFR to THF

15
 Methotrexate
Mechanism of Action

• The enzyme DHFR is the 1º site of action

• MTX prevents the formation of THF, causing an
intracellular deficiency of folate coenzymes and
accumulation of the toxic inhibitory substrate,
DHF polyglutamate
• The one carbon transfer reactions for purine and
thymidylate synthesis cease, interrupting DNA
and RNA synthesis
16
 Methotrexate
Therapeutic Uses

• Methotrexate- psoriasis, rheumatoid

arthritis, acute lymphoblastic leukemia,
meningeal leukemia, choriocarcinoma,
osteosarcoma, mycosis fungoides, Burkitt’s
and non-Hodgkin’s lymphomas, cancers of
the breast, head and neck, ovary, and
bladder

17
 Pyrimidine Antagonists
• Fluorouracil - S-phase
• Cytarabine
• Gemcitabine
• Capecitabine

18
 MTX X

5-FU
X

Figure 2. This figure illustrates the effects of MTX and 5-FU on the
biochemical pathway for reduced folates.
19
 Mechanism of Action 5-FU
• 5-FU inhibits thymidylate synthase
therefore causing depletion of Thymidylate

• 5-FU is incorporated into DNA

• 5-FU inhibits RNA processing

20
 Therapeutic Uses of 5-FU

• Metastatic carcinomas of the breast and the

GI tract
• carcinomas of the ovary, cervix, urinary
bladder, prostate, pancreas, and
oropharyngeal areas
• Combined with levamisole for colon cancer

21
 Plant Alkaloids

Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes

Vinblastine
Vincristine Etoposide Topotecan Paclitaxel
Vinorelbine

22
 Vinca Alkaloids
Mechanism of Action

• Binds to the microtubular protein tubulin in a dimeric

form
• The drug-tubulin complex adds to the forming end
of the microtubules to terminate assembly
• Depolymerization of the microtubules during
metaphase of M-phase occurs
• Resulting in mitotic arrest at metaphase, dissolution
of the mitotic spindle, and interference with
chromosome segregation
• Cell Cycle Suppressor agents- M phase 23
 Therapeutic Uses

• Vinblastine
– Systemic Hodgkin’s disease
– Lymphomas
• Vincristine
– With prednisone for remission of Acute Leukemia
• Vinorelbine
– non-small cell lung cancer

24
 Taxanes
Mechanism of Action
• Mitotic “spindle poison” through the enhancement
of tubulin polymerization

• Taxanes have a unique way of preventing the growth

of cancer cells: they affect cell structures called
microtubules, which play an important role in cell
functions.
– In normal cell growth, microtubules are formed when a
cell starts dividing. Once the cell stops dividing, the
microtubules are broken down or destroyed.
– Taxanes stop the microtubules from breaking down;
cancer cells become so clogged with microtubules that
they cannot grow and divide

25
 Taxanes
Therapeutic Uses

• Paclitaxel- ovarian and advanced breast

cancer
• Docetaxel- advanced breast cancer

26
 Antibiotics

• Anthracyclines- Doxorubicin & Daunorubicin

• Dactinomycin
• Plicamycin
• Mitomycin
• Bleomycin

27
 Anthracyclines
Mechanism of Action

• High-affinity binding to DNA through

intercalation, resulting in blockade of DNA
and RNA synthesis
• Binding to membranes altering fluidity
• Generation of the semiquinone free radical
and oxygen radicals

28
 Anthracyclines
Therapeutic Uses

• Doxorubicin- carcinomas of the breast,

endometrium, ovary, testicle, thyroid, and
lung, Ewing’s sarcoma, and osteosarcoma

• Daunorubicin- acute leukemia

29
 Hormonal Agents

Estrogen & Gonadotropin-

Aromatase
Androgen Releasing
Inhibitors
Inhibitors Hormone Agonists

Tamoxifen Leuprolide Aminogluthethimide

Legend
Drug Class
Sub-class30
Prototype Drug
 Anti-Estrogens
• Tamoxifen (SERMs)
• Raloxifene (SERMs)
• Faslodex

31
 Tamoxifen
• Selective estrogen receptor modulator (SERM), have both estrogenic
and antiestrogenic effects on various tissues
• Binds to estrogen receptors (ER) and induces conformational changes
in the receptor
• Most of tamoxifen’s affects occur in the G1 phase of the cell cycle

32
 Tamoxifen
Therapeutic Uses

• Tamoxifen can be used as primary therapy for

metastatic breast cancer in both men and
postmenopausal women

• Patients with estrogen-receptor (ER) positive tumors

are more likely to respond to tamoxifen therapy,
while the use of tamoxifen in women with ER
negative tumors is still investigational

• When used prophylatically, tamoxifen has been

shown to decrease the incidence of breast cancer in
women who are at high risk for developing the
disease 33
 Anti-Androgen
• Flutamide
– Antagonizes androgenic effects
– approved for the treatment of prostate cancer
• 5a-Reductase Inhibitors
– Block the enzyme that converts testosterone to DHT.
OH
OH CH3
CH3
CH3
CH3

O H
O H
Testosterone Dihydrotestosterone
(DHT)

Converting Enzyme: Finasteride

5-alpha-Reductase 34
 Gonadotropoin-Releasing Hormone Agonists

• Leuprolide
• Goserelin
LHRH (Secreted LHRH-Agonist
by hypothalamus) Added

LHRH-Receptor
(On Pituitary Cell)

LH
(Secreted) Initially: Chronically:
Secreted Levels LHRH-Receptors
of LH Increase disappear, LH
(Flare) secretion decreases
35
(Castrate)
 Gonadotropoin-Releasing Hormone Agonist
Mechanism of Action

• Agents act as GnRH agonist, with paradoxic

effects on the pituitary
• Initially stimulating the release of FSH and LH,
followed by inhibition of the release of these
hormones
• Resulting in reduced testicular androgen
synthesis
36
 Aromatase Inhibitors
• Aminogluthethimide
• Anastrozole

37
 Aminogluthethimide
Mechanism of Action

• Inhibitor of adrenal steroid synthesis at the

first step, conversion of cholesterol of
pregnenolone
• Inhibits the extra-adrenal synthesis of
estrone and estradiol
• Inhibits the enzyme aromatase that converts
androstenedione to estrone

38
 Miscellaneous Anti-cancer Agents

• Asparaginase
• Hydroxurea
• Mitoxantrone
• Mitotane
• Retinoic Acid Derivatives
• Amifostine

39
 Asparaginase
• An enzyme isolated from bacteria
• Causes catabolic depletion of serum
asparagine to aspartic acid and ammonia
• Resulting in reduced blood glutamine levels and
inhibition of protein synthesis
• Neoplastic cells require external source of
asparagine
• Treats childhood acute leukemia
• Can cause anaphylactic shock
40
 Hydroxyurea

• An analog of urea
• Inhibits the enzyme ribonucleotide reductase
• Resulting in the depletion of deoxynucleoside
triphosphate pools
• Thereby inhibiting DNA synthesis
• S-phase specific agent
• Treats melanoma and chronic myelogenous
leukemia
41
 Mitoxantrone
• Structure resembles the anthracyclines
• Binds to DNA to produce strand breakage
• Inhibits DNA and RNA synthesis
• Treats pediatric and adult acute myelogenous
leukemia, non-Hodgkin’s lymphomas, and
breast cancer
• Causes cardiac toxicity

42
 Complication of Chemotherapy:
• Every chemotherapeutic will have some
deleterious side effect on normal tissue .

– E.g., Myelosuppression, nausea & vomiting,

stomatitis, and alopecia are the most frequently
observed side effects.

43
 Criteria used to describe response are

• Complete response (complete remission) is the

disappearance of all detectable malignant disease.
• Partial response is decrease by more than 50% in the
sum of the products of the perpendicular diameters
of all measurable lesions.
• Stable disease: no increase in size of any lesion nor
the appearance of any new lesions.
• Progressive disease means an increase by at least
25% in the sum of the products of the perpendicular
diameters of measurable lesion or the appearance of
new lesions.
44
 Biological therapy
• Immunotherapy:
– Cytokines
– Cellular therapy
– Tumor vaccine

• Hematopoietic growth factors.

45
 Tumour Immunotherapy: questions

• Can immune stimulators combat cancer?

• Which forms of immunotherapy can be used?
• Is vaccination effective against established tumours?
• Can anti-tumour responses be generated in vitro?
• Can in vitro responses translate into in vivo effects?
• What barriers are there to development of effective IT?

46
 How can we harness the immune response?

Tumour cell present

Ab / ADCC /
cytokine attack

B Th
Th cells educate
other T/B cells

CTL CTL
APC recruits T cells
Broken up to able to recognise CTL recognise
release antigens tumour antigens and destroy other
T tumour cells

APC T

47
 ‘Passive’ immunotherapy

• Adminstration of monoclonal antibodies which

target either tumour-specific or over-expressed
antigens.
• Kill tumour cells in a variety of ways:

MØ NK

Apoptosis Complement- ADCC Conjugated to

induction mediated toxin / isotope
cytotoxicity
48
 Antibody-based immunotherapy

Name Malignancy Target

Rituxan B cell lymphoma CD20
Herceptin Breast, lymphoma Her-2/neu
Campath B-CLL CD52
Erbitux Colo-rectal EGFR
Avastin Colo-rectal VEGF

Name Malignancy Target

Mylotarg AML CD33
(calicheamicin)
Bexxar B cell lymphoma CD20
(131In / 90Y)

49
 ‘Active’ immunotherapies

• Cytokines- IL-2 / IFNs / TNFα

• Vaccination strategies- single peptide

multiple peptides HSP
complexes whole tumour cells

• Cell-based therapies - tumour-specific CTL

tumour-derived APC DC
priming

50
 Effective
therapies

Complete regression of a
large liver metastasis from
kidney cancer in a patient
treated with IL-2.

Regression is ongoing
seven years later

Rosenberg (2001) Nature, 411;381-4

51
 Other Immunostimulants

• BCG (bacterial preparation) injected intra-tumour-

Can be effective for early-stage bladder cancer.

• IFNα was ‘gold standard’ for CML until recent

introduction of Gleevec (imatinib) – affects
MHC Class I expression and cell division.

• TNFα effective in vitro, but too toxic to use in

patients (pyrexia / -algias).

52
 Heat Shock Proteins for Therapy

ST
RE HSPs protect the delicate
SS functions of the cell.
ES

53
 Heat Shock Proteins
(HSP70)

NH4 COOH

ATPase peptide-binding domain

tumour peptide sequence

54
 How is the anti-tumour effect produced?

Hsp70 or gp96 / CTL

peptide complex

NK

tumour
peptides
TAP system presented to
Transporter Associated with CTL / NK
Peptide processing cells via HLA
CD91 Class I
endocytosis
receptor

APC
55
 Using whole cells for immunization

• Killed tumour cells effective vaccinating agents in mouse

models- not effective in humans.
• Novel methods can enhance immunogenicity of tumour cells.

CTL

CTL
CTL
CTL
CTL CTL

tumour
tumour tumour tumour
tumourtumour

56
 Allogeneic Transplant-
The Original Immunotherapy.

• Allogeneic bone marrow or stem cells –

repopulate patient with entirely new immune
system (matched to donor closely)
• Relatively crude- associated with significant
morbidity / mortality
• Modification using T cell depletion or reduced-
intensity allogeneic stem cell transplantation
(RISCT)

57
 Dendritic cell sources for therapy
Common
Myeloid
Haemopoietic
Progenitor
Stem Cell
Circulating
Myeloid DC

Monocyte
CD34+
Stem Cell Ex vivo
GM-CSF + IL-
4

Ex vivo Immature
GM-CSF + mdDC
Flt-3 + TNF

Maturation
factors Mature
mdDC

CD34+ DC

Copland et al (2005) Cancer Immunol. Immunother. 54:297

58
mdDC; Monocyte-derived DC
 DC-based therapy

DC developed from
patient monocytes

Pulsed with target Currently in Phase II

antigens and Phase III trials
for melanoma,
prostatic carcinoma
Stimulated to maturation and lymphoma.
and inoculated back into
patient

Tumour-specific
immune responses
measured
59
 Radioimmunotherapy (RIT)

RIT is an exciting and relatively new personalized cancer treatment that

combines the cancer killing of radiation therapy with the precise targeting
capacity of immunotherapy.

In RIT, a tumor-killing dose of a radioactive substance is linked to a

monoclonal antibody that targets and binds selectively to a malignant tumor
(cancer) when injected into the body.

The ability of the antibody to bind to a tumor-associated antigen (a molecule

that can stimulate an immune response) ensures that the tumor gets a high
dose of radiation, which can kill the targeted cancer cells and nearby cancer
cells, while normal tissue gets only a minimal dose. This minimizes toxicity to
normal tissues.

RIT Product Examples

The two FDA approved RIT regimens are Zevalin (approved by FDA in 2002) and
Bexxar (approved by FDA in 2003).
Targeted Diseases: Zevalin and Bexxar were the first FIT agents
approved for the treatment of patients whose non-Hodgkins
lymphoma (NHL) proved unresponsive or resistant (refractory) to
conventional chemotherapy.
RIT also has therapeutic potential for other types of cancers,
including prostate cancer, metastatic melanoma, ovarian cancer,
leukemia, high-grade brain tumors, metastatic colorectal cancer and
neoplastic meningitis.

Benefits of RIT
1. Targeted therapy
2. less severe side effects than chemotherapy
3. Ability to directly target and kill the cancer cells
Conformal radiotherapy, 3D conformal radiotherapy (3DCRT)

Three-dimensional conformal radiation therapy (3D-CRT) is an advanced type

of electron beam radiation therapy which is used as a prostate cancer treatment.

3D-CRT works by aiming an external beam of radiation at the prostate gland

while trying to minimize the exposure of healthy tissue in the surrounding
organs.

3D-CRT immobilizes the patient in a bed of styrofoam that is customized for his
body. A computer generates a precise image of his internal organs.

The radiation oncologist then aims waves of photons generated by a linear

accelerator at the image to irradiate the malignant area. The waves are formed
exactly to the shape of the treated to be treated so the surrounding healthy
tissue is spared being damaged by radiation.
 Intensity modulated radiotherapy (IMRT)

One type of conformal radiotherapy is called intensity modulated

radiotherapy (IMRT).

Like conformal radiotherapy, IMRT shapes the radiation beams to

closely fit the area where the cancer is. But it also changes the
radiotherapy dose depending on the shape of the tumour. This means
that the central part of the cancer receives the highest dose of
radiotherapy and a surrounding area of tissue gets lower doses.

A machine called a linear accelerator (LINAC) gives the radiotherapy.

The LINAC has a special device called a multileaf collimator that moves
around the patient and shapes the beams of radiotherapy to fit the
tumour.
Cancer Prevention and Early Detection

64
 Risk Factors
 Age(>40)

 Life style (personal behaviors or habits): 50-75% of cancer

deaths are related to this

 Cigarette smoking: 30% or more of all cancer deaths related to

this.

 Poor nutrition & inactivity leading to obesity: 30% of all cancer

deaths in the U.S. are related to this.

 Immunological factors:
Immunosuppressive drugs after transplantation
Immune disorder

65
Biological factors
Viruses (e.g., Human Papilloma Virus-HPV, hepatitis B and C ) and
Bacteria (Helicobacter pylori)

Age at first pregnancy

Environmental Factors: Benzene

Benzopyrene
Chloropyrifos
Industrial dye waste
Heavy metals(Pb, As, Asbestos)

Occupational exposures (e.g., radiation, second-hand smoke, radon,

asbestos, organic vapors, and pesticides)
 Strategies for Cancer Prevention

• Stop using tobacco

• Maintain a reasonable weight
• Increase physical activity
• Eat 5-9 fruits and vegetables daily
• Increase fiber and reduce fat
• Limit alcohol consumption
• Limit exposure to the sun
67
 Barriers to Screening
• Lack of knowledge/awareness of symptoms of cancer
• Cost/lack of insurance
• Lack of physician recommendation
• Language barrier
• Cultural beliefs
• Psychological factors: Socioeconomic Status (poverty,
education, unemployment)
• Racism/Casteism
• Fear

68
 Screening/Early Detection
Techniques
• Breast Self Exam
• Breast Cancer • Mammograms
– Ages 40-49 every one to two
years
– 2nd leading cause of – Age 50 and over - yearly
cancer death in • Clinical Breast Exam
women • High risk women may
need to begin screening at
earlier ages

69
 Screening/Early Detection
Techniques
Colon/Rectum Cancer
Third most common cancer in both
men and women
• Beginning at Age 50:
• Stool blood test annually
• Digital rectal exam annually
• Sigmoidoscopy
• Colonoscopy (virtual)

70
Lung Cancer

• Leading cause of cancer death

• Routine chest x-rays no proven benefit.

• Screening Clinical Trials (e.g., National Lung

Screening Trial)

71
 Screening/Early Detection
Techniques

Prostate Cancer
• 2nd Leading cause of cancer death in men
• Beginning at Age 50
• DRE
• PSA

72
 Screening/Early Detection
Techniques
Ovarian Cancer
• Annual pelvic exam should be performed to
try and detect an ovarian mass.
• Pelvic ultrasound with vaginal probe may
become routine

73
Screening/Early Detection Techniques
Cervical Cancer • Pelvic Exam
• Screening should begin • PAP Test
approx. 3 years after a
women begins to have
sexual intercourse, but
no later than 21 years
old.

74
 Other Screening Possibilities
• Tumor Markers
• EX: PSA – Prostate Cancer, CA-125 Ovarian Cancer

– Can be useful when used along with other tests.

– CAN NOT be used alone as a screening tool.

75
 Diagnostic Tests
• Physical Exam
– Examination of the entire body
– Lymph node bearing areas
– Abdomen is checked to detect enlargement of
any organs
– Exam of the pelvic area in women, including
PAP smear.
– Digital rectal exam for men and women

76
 Diagnostic Tests
• Lab Tests
– If cancer is present
blood tests can show
any effects of the
disease on the body.
– FOBT - fecal occult
blood test
– Urinalysis –
examination of the
urine
– CBC - complete blood
count
77
 Radio imaging and Cancer
Cancer imaging can be categorized into :
a. Anatomic: Anatomic images, primarily obtained using x-ray
computerized tomography (CT), magnetic resonance imaging (MRI),
or ultrasound (US), can be used for tumor detection and
determination of tumor size.

b. Physiologic: These Images provide physiologic information such as

1. Tumor blood perfusion can be obtained using contrast enhanced
x-ray CT and MRI
2. Radionuclide imaging modalities, such as positron emission
tomography (PET)
3. Single- photon emission computerized tomography (SPECT).

c. Molecular imaging: which involves using molecular imaging probes

to detect biologic molecules in living subjects, can be performed with
PET, SPECT, MRI, US, and optical imaging modalities. 78
79
 Optical Imaging
• Bioluminescence and fluorescence optical imaging are molecular
imaging modalities (Figure 23-5), with applications limited to
preclinical cancer research in small animals.

• Bioluminescence results from emission of photons during catalytic

conversion of a probe and fluorescence is the emission of light in a
certain wavelength spectrum from molecules exposed to light of
different wavelengths.

• These photons with wavelengths between 400 and 1,000nm are of

low energies and subject to significant tissue attenuation (especially
due to light absorption by hemoglobin) in visible light range and lipid
and water in the infrared region. Therefore, detection of these
photons, especially emanating from bioluminescent molecules,
from living subjects requires ultrasensitive cooled charge-coupled
device (CCD) cameras.
80
• Bioluminescence imaging in small animals involves luciferase reporter genes, such
as Firefly (Fluc), Renilla (Rluc), or Gaussia (Gluc) luciferases.

• The Fluc enzyme catalyzes adenosine triphosphate (ATP)–, Mg2+-, and O2-
dependent conversion of d-Luciferin to Oxyluciferin, emitting
bioluminescence. The Rluc and Gluc enzymes catalyze ATP-independent
oxidation of Coelenterazine, emitting light.

81