Modalities of

Cancer Treatment
 Cancer Treatment
Modalities
With present methods of treatment, about 1/3 of
patients are cured with local treatment strategies,
such as surgery or radiotherapy, when the tumor
remains localized at the time of diagnosis.

Earlier diagnosis might lead to increased cure

rates w/ such local treatment.
 However!, in the remaining cases, early
micrometastasis is a characteristic feature of these
neoplasms,

➢indicating that a systemic approach w/

chemotherapy is required for effective cancer
management.
• Surgery
remains the treatment of
choice for most solid tumors
diagnosed in the early stages

• Chemotherapy (including
hormonal therapy) accesses the
systemic circulation and can
theoretically treat the primary
tumor and any metastatic
disease.
 In patients with locally advanced disease,
chemotherapy is often combined w/ radiotherapy to
allow for surgical resection to take place, & such a
combined modality approach has led to improved
clinical outcomes.
 At present, about 50% of patients who are
initially diagnosed with cancer can be cured.
In contrast, chemotherapy alone is able to
cure only 10-15% of all cancer patients.
Cancer Treatment Modality
A. Surgery
B. Radiotherapy
C. Chemotherapy
D. Biologic Response Modifiers
E. Combined-Modality Therapy
A. Surgery
• Oldest,most established and most effective
way to cure most cancers

• The choice only if the cancer is limited to one

area and if it is anticipated that all cancer cells
can be removed without compromising vital
structures.
 A. Surgery
Not recommended:
• If the risk of surgery is greater than the risk of the
cancer
• If metastasis always occurs despite complete removal
of the primary tumor
• If the patient will be left so debilitated,
disfigured/impaired that although cured of cancer,
he/she might feel that life is not worthwhile
B. Radiotherapy
• Frequentlyused as the primary or curative
mode of therapy

• Tx of local or regional disease when surgery

cannot completely remove the cancer
OR
• When it would unduly disrupt normal structures
or functions
B. Radiotherapy
• Insome cases, radiotherapy is as effective as
surgery for eradicating the tumor.

• Inherent sensitivity of the cancer to ionizing

radiation one determinant of the
appropriateness of radiotherapy
lymphomas → highly sensitive
melanoma & sarcoma → less sensitive
C. Chemotherapy
• Has
its primary role in the tx of disease that is
no longer confined to one site/region and has
spread systemically
D. Biologic Response Modifiers
• Also called Immunotherapy
• substancesthat are able to trigger the immune
system to indirectly affect tumors

• Ex. Monoclonal antibodies, Interferons

E. Combined-Modality Therapy
• Frequently,
patients present with cancer in
which there is a bulky primary lesion,
macroscopically evident regional disease and
presumed microscopic or submicroscopic
disease.
E. Combined-modality Therapy
• Thepractice of multidisciplinary approaches
provides best opportunity to exploit the
advantages of each mode of treatment.
 Principles of
Cancer Chemotherapy

16
 CHEMOTHERAPY
As a group, the anticancer drugs are more toxic than any other
pharmaceutic agents

The ultimate goal in cancer chemotherapy:

To use advances in cell biology to develop drugs that
selectively target specific cancer cells.
An ideal chemotherapeutic agent must be:

a. Selectively toxic, that is, more toxic to the

diseased cells or disease causing microorganisms
than to the healthy host cells being treated.
b. Relatively soluble in bodily fluids, so that it can
be transported to reach its destination.
c. Maintain a standard toxicity and not be made
more or less potent by interactions with food or
other drugs, or by conditions like other diseases or by
pregnancy.
d. Not be allergenic.
e. Sufficiently stable to maintain a constant
therapeutic concentration in the blood and tissues.
f. Must not generate or lead to resistance to its
effects.
g. Must have a long shelf life with a minimum of
special procedures, such as refrigeration or shielding
from the light.
h. Must be affordable to patients of reasonable
means.

Obviously, there is no existing chemotherapeutic agent

which possesses all these attributes. We are very lucky
when an agent has over 50% of the points listed above.
 Most anticancer drugs act by inhibiting cell
proliferation. Generally, this is achieved by
damaging DNA or preventing DNA repair.
Essentially, there are 4 ways in which most
anticancer drugs inhibit proliferation:
1. Cross linking DNA – prevent DNA strand
separation
2. Linking alkyl groups to DNA bases – inhibit
DNA repair
3. Mimicking DNA bases, resulting in:
i. incorporation of drug into DNA or RNA
4. Intercalating between base pairs of DNA –
disrupt triplicate codons or produce oxygen
free radicals w/c damage DNA
Chemotherapy encompasses a wide variety of therapy
treatments. Terms such as "adjuvant," "neoadjuvant,"
"consolidation," and "palliative" often add to the confusion
surrounding chemotherapy if not properly defined and
explained.

Adjuvant chemotherapy - Chemotherapy given to destroy

left-over (microscopic) cells that may be present after the
known tumor is removed by surgery. Adjuvant chemotherapy
is given to prevent a possible cancer reoccurrence.
Neoadjuvant chemotherapy - Chemotherapy given prior to
the surgical procedure. Neoadjuvant chemotherapy may be
given to attempt to shrink the cancer so that the surgical
procedure may not need to be as extensive.

Induction chemotherapy - Chemotherapy given to induce a

remission. This term is commonly used in the treatment of
acute leukemias.
Consolidation chemotherapy - Chemotherapy given once a
remission is achieved. The goal of this therapy is to sustain a
remission. Consolidation chemotherapy may also be called
intensification therapy. This term is commonly used in the
treatment of acute leukemias.

First line chemotherapy - Chemotherapy that has, through

research studies and clinical trials, been determined to have
the best probability of treating a given cancer. This may also
be called standard therapy.
Second line chemotherapy - Chemotherapy that is given if
a disease has not responded or reoccurred after first line
chemotherapy. Second line chemotherapy has, through
research studies and clinical trials, been determined to be
effective in treating a given cancer that has not responded
or reoccurred after standard chemotherapy. In some cases,
this may also be referred to as salvage therapy.

Palliative chemotherapy - Palliative is a type of

chemotherapy that is given specifically to address symptom
management without expecting to significantly reduce the
cancer.
 Table 1. The Role of chemotherapy in the Treatment of Cancer
Chemotherapy used alone with curative intent
Acute lymphocytic leukemia Acute myelogenous leukemia
Burkitt’s lymphoma Diffuse large cell lymphoma
Hodgkin’s lymphoma Testicular cancer
Choriocarcinoma (gestational
trophoblastic neoplasm)
Chemotherapy used as adjuvant therapy with curative intent
Breast cancer Colorectal cancer
Ewing’s sarcoma Osteosarcoma
Wilms tumor Ovarian cancer
Chemotherapy used as neoadjuvant therapy
Anal carcinoma Bladder cancer
Breast cancer (locally advanced) Cervical cancer
Esophageal cancer Head and neck cancers
Osteosarcoma Rectal cancer
Soft tissue sarcoma
Chemotherapy used to palliate symptoms in advanced disease
Bladder cancer Brain tumors
Breast cancer Carcinoid tumors
Cervical cancer Chronic lymphocytic leukemia
Chronic myelogenous leukemia Colorectal cancer
Endometrial cancer Esophageal cancer
Gastric cancer Head and neck cancers
Hairy cell leukemia Kaposi’s sarcoma
Indolent lymphomas Metastatic melanoma
Multiple myeloma Mycosis fungoides
Neuroblastoma Non-small cell lung cancer
Osteosarcoma Ovarian cancer
Pancreatic cancer Prostate cancer
Small cell lung cancer Soft-tissue sarcoma
Chemotherapy has little or no effect on palliation
Hepatocellular cancer Renal cell carcinoma
Thyroid cancer
 Modern Cancer Chemotherapy
World War II
→it was discovered that people exposed to nitrogen
mustard developed significantly reduced white blood
cell counts

1941
→ first use of successful administration of alkylating
agent nitrogen mustard by Goodman and Gilman to
patients with lymphoma
→ First, they established lymphomas in mice and
showed that the tumors could be treated with mustard
agents.

→ Then, together with a thoracic surgeon called

Gustav Linskog, they injected a less volatile form of
mustard gas called mustine (nitrogen mustard) into a
patient who had nonHodgkin's lymphoma.
After World War II
→A pathologist from Harvard Medical
School called Sidney Farber studied the
anticancer effects of folic acid - an essential
vitamin in DNA metabolism.

→Faber and colleagues developed folate

analogues (such as methotrexate) which they found were
antagonistic to folic acid and prevented the action of enzymes
that required folate.

→ In 1948, these agents became the first to lead to remission in

children with acute lymphoblastic leukemia, showing that
antifolates had the potential to restore normal bone marrow.
1950s
→Eli Lilly and company announced that plant
alkaloids such as those extracted from Vinca
rosea were beneficial to leukemia patients. This
led to the introduction of vinca alkaloids as
anticancer agents in the 1960s.
→Examples:
- vinblastine used to treat Hodgkin's disease
- vincristine used to treat pediatric leukemia
1950-1960’s
→major alkylating agents and anti-metabolites
currently in use were synthesized

→ effective against wide range of cancer types,

particularly rapidly growing leukemias and
lymphomas
 The Log-Kill Hypothesis
Cytotoxic effects of anticancer drugs follow log cell-
kill kinetics!

The log-kill hypothesis proposes that the magnitude

of tumor cell kill by anticancer drugs is a logarithmic
function.
 Evolution of Chemotherapy
1970’s - “Golden Age” of medical oncology.

- Development of effective combination

chemotherapy regimens.

New classes of drug developed

- anthracyclines, platinum compounds
 Evolution of Chemotherapy
• Cures achieved in some forms of cancer
(lymphomas, leukemias, testis cancer).
Significant responses in some common types of
cancer (breast, stomach, small cell lung cancer)

• Effectiveuse of chemotherapy to prevent

recurrence in high risk breast cancer patients.
 Evolution of Chemotherapy
1980’s – disillusion sets in

- Development of increasingly complex, toxic (and

expensive) treatment protocols

- Some improvement in response rates, but hope

fades for curing common forms of cancer
Evolution of Chemotherapy
- Intensive search for analogues of existing
drugs, hoping for greater anticancer effect or
less toxicity

- Introduction of remaining major types of

chemotherapy (taxanes, topoisomerase I
inhibitors)
 Evolution of Chemotherapy
1990’s –still hard going in the clinic, but …..

Post-operative adjuvant chemotherapy established

to reduce mortality in some major causes of cancer
death (breast, colon cancer)

Biochemical basis of drug resistance established the

idea that development of cancers involves
suppression of cell death pathways, and that drug
resistance results from failure of damaged cells to
undergo apoptosis
- e.g. bcl2, p53 stories
 Evolution of Chemotherapy
2000’s – rapid development of molecular
targeted agents as alternatives to classical
chemotherapy

Evolution of molecular oncology and rational

cancer therapeutics
- integrating basic science, pharmacology,
pathology, and clinical oncology
Role of Cancer Chemotherapy
• Indicated in 75% of tumors (100) (25% surgery & radiation)

• Examples of responsive tumors (cure):

leukemia, lymphoma, Choriocarcinoma, Ewing’s
sarcoma, Burkitt's lymphoma, Testicular carcinoma

• Examples of intermediate response:

Bladder, head and neck, SCLC, sex-related cancers
(breast, ovary, endometrium, , prostate) osteogenic
sarcoma (after surgery and irradiation.)
Role of Cancer Chemotherapy

Characteristics of cancer cells:

1.Uncontrolled proliferation
2.Less differentiation & Loss of function (Abnormal
forms)
3.Invasiveness (like microbes)
4.Metastasize (e.g. breast cancer►lung, brain, bone)
attracted by chemokines in these organs to
receptors in cancer cells.
5.Tendency to retain some characteristics of tissue of
origin
Role of Cancer Chemotherapy
Why do cancer cells have the ability of
uncontrolled proliferation?
Due to changes in;
1. Growth factors and/or their receptors,
signalling pathways
2. The cell cycle transducers (cyclins, cdks, cdk
inhibitors)
3. Apoptotic machinery
4. Tumor-related angiogenesis.
 Indications of chemotherapy
A. Cancers:
1. Main treatment of some cancers like Leukemia,
Hodgkin’s lymphoma. Cure (60-80%) in 10% of cancers
2. Supplement surgery & radiation. Breast-lung-bowel
3. Disseminated tumors.

B. Other conditions:
1. Organ transplantation
2. Auto-immune disorders
 Total Tumor Burden (Size)

-Clinicaldetectable tumor: 109 cells (1 cm); lethal

tumors: 1012 cells (20 cm)

The larger the tumor the harder it is to kill

1. more difficult for drugs to penetrate
(poor vascularization)
2. many cells not proliferating
3. increased incidence of metastasis
ONCOLOGY
Principles of chemotherapy
Electron
micrograph
of mitotic
cell
 Classification of cytotoxic agents
Alkylating Anti- Mitotic Antibiotics Others
Agents metabolites Inhibitors
Busulfan Cytosine Etoposide Bleomycin L-
asparaginase
Carmustine Arabinoside Teniposide Dactinomycin Hydroxyurea

Chlorambucil Floxuridine Vinblastine Daunorubicin Procarbazine

Cisplatin Fluorouracil Vincristine Doxorubicin

Cyclophospha- Mercaptopurine Vindesine Mitomycin-C

mide
Ifosfamide Methotrexate Taxoids Mitoxantrone

Melphalan Plicamycin
Action sites of cytotoxic agents
Antibiotics

Antimetabolites

S
(2-6h)
G2
(2-32h) Vinca alkaloids

M Mitotic inhibitors
(0.5-2h)

Taxoids

Alkylating agents

G1
Cell cycle level (2-h)

G0
The Cell Cycle
- a conceptual depiction of
the cell cycle phases that all
cells – normal & neoplastic –
must traverse before & during
cell division.

Cells pass through 4 stages of growth during each mitotic

cycle:
› Cells that contain a double complement of DNA (G2
cells) divide during Mitosis (M phase).
› Following a “gap” (G1 phase) cells may either
› Differentiate and remain out of the cycle for long
period of time (G0 period) or
› Begin the process of DNA synthesis (S phase).
› Another gap (G2) follows.
 Since the mechanism of
chemotherapy is primarily demonstrated on a
cellular level, it is relevant to understand the
concept of cell cycle. All living tissues are
made of cells.
Cells grow and reproduce to replace
worn out ones. By definition, cell cycle is
composed of all steps in the process of
reproduction, and that period extending from
one mitosis to the next..
 In normal cell population, inhibitory
control slows or stop reproduction (as in
wound healing, contact inhibition causes
fibrous tissue growth to cease at the point
where the edges of the wound come
together) whereas stimulating factors cause
the process to move rapidly ( cellular
responses to injury – inflammation and cellular
repair). However, cancer cells go through the
same cycle, uncontrollably.
 The cell cycle has five phases. After a cell
reproduces, the two new cells are identical. Each of
the two cells made from the first cell can go through
the same cycle again when needed.

G0 phase : resting phase; The cell has not yet started

to divide. Cells spend much of their lives in this phase.
When cells get the signal to reproduce, it moves to
the G1 Phase.

G1 phase: During this phase, RNA and protein

synthesis occurs. The cell starts making more proteins
and growing larger, so the new cells will be of normal
size. Some key process occurs to signal its entrance
into the S phase of DNA synthesis.
 S phase: DNA synthesis occurs.
Replication of DNA begins resulting in
two exact sets, which will occupy the
nuclei of the two daughter cells.

G2 phase: DNA synthesis ceases. RNA

and protein synthesis continue in
preparation for mitosis

M phase: In this phase, the cell

actually splits into 2 new cells.
The mitosis stages

Daughter cells Prophase

Interphase

Telophase Metaphase

Anaphase
 Most chemotherapy drugs act
on cells that are actively
replicating that’s why having the
knowledge about the cell cycle
is important.
Some of these drugs attack cells
specifically on the cell cycle
phase and some on all phases.
Understanding how these drugs work
helps oncologists predict which drugs
are likely to work well together.
When chemotherapy drugs attack
reproducing cells, they cannot
differentiate normal cells from cancer
cells. Thus, the damage on normal
cells results to a number of side
effects.
• Agents with major activity in a particular
phase of the cell cycle are known as cell-
cycle phase specific agents.

• Cell-cycle phase-nonspecific agents are

those with significant activity in multiple
phases
Cell Cycle Phase Specific Drugs
S phase–dependent

– Capecitabine - Cytarabine
– Doxorubicin - Fludarabine
– Floxuridine - Fluorouracil
– Gemcitabine - Hydroxyurea
– Mercaptopurine - Methotrexate
– Prednisone - Procarbazine
– Thioguanine
Cell Cycle Phase Specific Drugs
M phase–dependent
– Vinca alkaloids - Podophyllotoxins
• Vinblastine - Etoposide
• Vincristine - Teniposide
• Vinorelbine

– Taxanes
• Docetaxel
• Paclitaxel
Cell Cycle Phase Specific Drugs
G2 phase–dependent
• Bleomycin
• Irinotecan
• Mitoxantrone
• Topotecan

G1 phase–dependent
• Asparaginase
• Corticosteroids