Basic Principles of Oncology

ศาสตราจารย ดร. นพ. พรชัย โอเจริญรัตน

สาขาวิชาศัลยศาสตรศรี ษะ-คอ และเตานม

ภาควิชาศัลยศาสตร
คณะแพทยศาสตรศิริราชพยาบาล
 Basic Principles of Oncology
• Cancer Epidemiology
• Cancer Biology
• Surgical Therapy
• Radiotherapy
• Chemotherapy
• Biologic Therapy
 Basic Principles of Oncology
• Cancer Epidemiology
• Cancer Biology
• Surgical Therapy
• Radiotherapy
• Chemotherapy
• Biologic Therapy
 Ten Leading Cancers Worldwide
Lung cancer - most common cancer both incidence and mortality
- most common cancer among men

Stomach cancer - second most common cancer

- relatively less common in women
- incidence is highest in Japan and China

Breast cancer - most common malignancy of women

- incidence are high in “developed” areas (except Japan)
- highest in USA, lowest in China

Colorectal cancers - higher in western countries

Liver cancer - 80% occur in developing countries

- fourth in terms of mortality
- hepatitis viruses and aflatoxin
 Ten Leading Cancers Worldwide
Prostate cancer - predominantly cancer of the elderly, with 81%
occurring after age 65

Cervical cancer - seventh most common cancer overall

- third most common in women
- more common in developing countries

Esophageal cancer - the fourth site characterized by very poor survival,

the other three being the liver, pancreas, and lung

Bladder cancer - only one-fifth of the cases occur in women

- long-term exposure to tobacco smoking

Pancreas cancer - top 10 causes of cancer deaths in the world because of

very poor prognosis
 Basic Principles of Oncology
• Cancer Epidemiology
• Cancer Biology
• Surgical Therapy
• Radiotherapy
• Chemotherapy
• Biologic Therapy
The six hallmark traits of cancer

• Self-sufficiency in proliferative growth signals

• Insensitivity to growth inhibitory signals
• Evasion of apoptosis
• Acquisition of limitless replicative potential
• Sustained angiogenesis
• Induction of invasion and metastasis

Hanahan D. and Weinberg A. Cell, 2000

 Carcinogenesis
Tumor initiation = exposure of cells to agents that induce
an inheritable change.

Tumor promotion = exposure of initiated cells to agents

that induce their proliferation.
This proliferation may allow other spontaneous mutations
to occur (malignant transformation).

Tumor progression = successive development of

increased local growth, invasion, and metastasis by
transformed cells.
 Carcinogens

• Physical carcinogens

• Chemical carcinogens

• Viral carcinogens
 Physical Carcinogens
Two major mechanisms:
• Induce damage or changes in cellular DNA
• Long-term induction of inflammation and cell
proliferation, which increases the opportunity for events
leading to transformation

The best known physical carcinogen is radiation

• Ionizing radiation includes x-rays and gamma rays, and
alpha and beta particles
• Non-ionizing radiation is ultraviolet (UV) radiation
 Physical Carcinogens
Ionizing Radiation
• dose and time related
• induction of breaks in DNA strands
• cells with high mitotic activity

Non-ionizing Radiation
• UV radiation is absorbed by DNA and induces DNA
damage
• human skin tumors: basal cell carcinoma, squamous
carcinoma, and melanoma

Other physical factors

• foreign-body reactions induced by asbestos, silica
• chronic inflammation and irritation ie burns, H. Pylori
 Chemical Carcinogens
Group 1: Genotoxin
Group 2: Co-carcinogen
Group 3: Tumor promoter

• Tobacco products, alcohol, chemical reagents

• DNA damage by carcinogen metabolism depends on the

balance between the rate of oxidation to carcinogenic
intermediates and the rate of detoxification of these oxidative
products
 Imbalance of alcohol metabolism

PHASE II ENZYMES
ALDH2

PHASE I ENZYMES
ADH3
CYP
 Viral Carcinogen

• 15% of all human tumors worldwide are caused

by viruses.

• Viruses are packages of genetic information; in

the form of either DNA or RNA.

• Viruses may insert their genetic material into

host cells and induce neoplastic transformation.
 Viral Carcinogen
Retroviruses
• RNA genome
• gag (core proteins), pol (reverse transcriptase), env (virion)
• viral oncogenes

Human Papillomaviruses
• DNA viruses that infect epithelial cells
• HPV serotypes 16 and 18
• E7 protein interacts with the retinoblastoma gene product
• E6 causes degradation of p53 gene product

Hepatitis B and C Viruses

• HBV causes chronic tissue damage
• activation of oncogenes and inactivation of tumor suppressor
genes
• Cancers develop as the result of changes
(mutations) in specific genes that, when
working normally, control the growth of
cells in the body.

• All cancers are “genetic” because they

involve changes in the genetic material.

• Genetic changes that cause cancer can be

categorized into:
Sporadic, Familial and Inherited
Sporadic Cancers
• Most cancer (80% - 85%)

Familial Cancers
• Cluster in a family, but not by a mutation in one
gene.
• The risk to family members is modestly increased.
• Many are the result of multi-factorial influences.
• Risks to develop cancer are based on population
data.
Hereditary Cancers
• 5% - 10% of cancers
• Single gene mutation when conceived and is in
every cell.
• Other changes in growth-control genes must
occur.
• Cancer diagnosed at earlier ages.
• Multiple family members have similar diagnoses.
• Presence of multiple primary malignancies.
• Rare diagnoses, such as male breast cancer, are
present.
• Cancer associated with other conditions ie mental
retardation.
Genes responsible for cancer development

• Oncogenes
- growth factors
- growth factor receptors: c-erbB receptors
• Tumor suppressor and apoptosis-related genes
• Cell cycle control genes
• Genes involved in motility and adhesion
• Extracellular matrix degrading enzymes
• Angiogenic factors
 Oncogenes
• Protooncogenes

• Genes which normally serve to modulate growth and

differentiation, but through genetic alteration have lost the
regulatory mechanisms

Cell proliferation
• binding of growth factors to membrane-bound receptors
• receptor activation
• signal transduction between plasma membrane and
nucleus
• activation of DNA replication
 Tumor Suppressor Genes

• The role of tumor suppressor genes is to keep cellular

growth in check

• Loss or inactivation shifts the balance toward the

unregulated cell replication.

• Retinoblastoma gene (RB1) on chromosome 13q1.1

• Affected individuals inherit one germline mutation.

Expression of the RB1 mutation phenotype requires loss of
the second allele by somatic mutation

“Two-hit” hypothesis
 Basic Principles of Oncology
• Cancer Epidemiology
• Cancer Biology
• Surgical Therapy
• Radiotherapy
• Chemotherapy
• Biologic Therapy
 Changing Role of Surgery in
Cancer Treatment
Before 1800 Cancer was a systemic disorder
“cancer was caused by an excess of ‘black
bile’ and treated by bleeding, purging, and
dietary restrictions” Galen of Pargamum

1800-1850 Heroic attempts to resect cancer

1850–1950 Development of standard surgical

techniques for resection, better anesthesia,
safe blood transfusion, antiseptics
 Changing Role of Surgery in
Cancer Treatment

1950–1960 Extended radical surgical procedures

1960–1980 Exploration of combined-modality
treatment
1980–2000 Improved organ preservation and
survival with combination therapy with
surgical resection
Organ-preservation Therapy
• Breast conservation surgery

• Anal sphincter preservation

• Limb-sparing bone/soft tissue sarcoma

surgery

• Laryngeal preservation surgery

 Basis for Surgical Therapy

• 90 percent of patients undergo surgical therapy for

diagnosis, primary treatment, or management of
complications.

• Resection is the initial curative treatment for 75

percent of patients.

• The surgeon’s principles should be the accurate

diagnosis and staging with adequate operative
removal of localized disease and palliation of
symptoms when possible.
Surgeon’s Role in Cancer Treatment

1. Diagnosis --- Clinical

--- Laboratory Complete Staging
--- Pathologic

2. Primary therapy – en bloc resection of tumor with adequate

margins of normal tissue + regional nodes

3. Adjunctive therapy – radiotherapy, chemotherapy and

immunotherapy

4. Therapy of complications due to disease treatment

Surgeon’s Role in Cancer Diagnosis

Goal: to obtain sufficient tissue and

information to diagnose and stage a cancer

Biopsy can be accomplished by

• fine-needle aspiration
• large-core needle biopsy
• open surgical biopsy
• resection of the tumor
Surgeon’s Role in Cancer Diagnosis

• Establish an accurate histologic diagnosis

and stage prior to beginning treatment

• Sufficient biopsy material prior to treatment

to allow for assessment of tumor biological
markers, special immunohistochemical
staining, and genetic studies
Surgeon’s Role in Cancer Diagnosis

Lymph node biopsy

Lymphoma
• The goal is to make the general diagnosis
and to establish the lymphoma type and
subtype
• Complete excision of node that has been
minimally manipulated
Surgeon’s Role in Cancer Diagnosis

Lymph node biopsy

Metastatic carcinoma
• Often requires less tissue than is needed for
lymphoma
• FNA, core biopsy, or subtotal removal of a
single node
Surgeon’s Role in Cancer Diagnosis

Biopsy of a tissue-based mass

Mass in the aerodigestive tract
• Include a representative amount of tissue
taken preferably from the periphery of the
lesion
• Adequate depth to determine penetration of
the tumors
Surgeon’s Role in Cancer Diagnosis

Biopsy of a tissue-based mass

Breast mass
• Core biopsy, performed either under image
guidance (U/S or mammography) or
directly for palpable lesions, is the method
of choice
• Radio-opaque clip can be placed in the
tumor to guide the surgical extirpation
Surgeon’s Role in Cancer Diagnosis

Biopsy of a tissue-based mass

Mass in the trunk or extremities
• The biopsy technique should be selected on
the basis of the planned subsequent tumor
resection
• The incision should be made along the long
axis of the extremity
• Core biopsy is preferable
Surgeon’s Role in Cancer Diagnosis

Resection of the tumor

• Preoperative or intra-operative diagnosis
cannot be confirmed
• Preoperative discussion with the patient
about the possibility that the final diagnosis
may be a benign lesion
“The jaundiced patient with a firm mass in
the pancreatic head”
Surgeon’s Role in Cancer Staging
1. Size and extent of the primary tumor (T)
2. Extent of regional spread in lymph nodes (N)
3. Evidence of distant metastatic spread (M)

Clinical stage: clinical evaluation of the tumor

supplemented by information from
appropriate diagnostic studies

Pathologic stage: study of the removed tumor, other

removed tissue, or biopsies
Surgeon’s Role in Primary Therapy
Principles of resection are based on
• the surgical goal (complete resection vs
debulking)
• degree of functional significance of the
involved organ or structure
• ability to reconstruct the involved and
surrounding structures
Surgeon’s Role in Primary Therapy
Principles of resection are based on
• technical abilities of the surgeon or
availability of a surgical team
• adequacy of adjuvant and neoadjuvant
therapies
• biological behavior (local and systemic) of
the disease
Surgeon’s Role in Primary Therapy
• 90% of curable solid tumors require
surgical resection alone or in combination
with other modalities.

• The role of a surgeon is to remove the

malignant tumor completely with an
appropriate margin.

• The extent of the required margins varies

with type and location of the tumor.
Surgeon’s Role in Primary Therapy

• On evidence of high risk of regional

lymphatic spread, the regional lymph nodes
usually are resected along with the primary
tumor
- Therapeutic lymph node dissection
- Prophylactic lymph node dissection
- Lymphatic mapping and sentinel node
biopsy
 Sentinel lymph node biopsy
• Restrict node biopsy to one or a very small number of

nodes

• Metastases will travel first from the primary tumor site

to the sentinel lymph node (SLN), and only

subsequently move on to the remaining regional lymph

nodes
 Sentinel lymph node biopsy
• Lymphoscintigraphy and gamma probe-guided

localization

• Blue dye localization

• The SLN identified by the presence of blue staining

and/or radiotracer uptake

• Therapeutic node dissection is performed only in

patients whose SLN is positive.

• Allow the pathologists to focus on the one or two
nodes most at risk for metastasis for detailed
pathologic exam.

• H&E: one tumor cell in 10,000 normal cells.

• IHC: one tumor cell in 100,000 normal cells.

• RT-PCR: one tumor cell in 1 million normal

lymphocytes.

“ultra staging”
 Surgeon’s Role in Palliation

• A primary carcinoma that is surgically

nonresectable or that already has metastasized.

• Symptoms such as intestinal obstruction, pain, or

bleeding.

• Surgical bypass or resection

- to enhance affected patients’ quality of life
- to improve the clinical situation to allow other
measures of cancer treatment to be used.
 Resection of Visceral Metastasis
1. Type of primary tumor
2. Interval between primary diagnosis and metastasis
3. Number and location of metastases
4. Technical feasibility of a clear margin of resection
5. Performance status of patients
6. Ability to treat further with additional therapies

Isolated pulmonary metastasis: Wilms’ tumor, osteogenic sarcoma,

soft tissue sarcomas, colorectal carcinoma, breast carcinoma

Isolated liver metastasis: colorectal cancer and carcinoid tumors

 Surgeon’s Role in
Patients Receiving Other Therapies

• To provide route for long-term nutritional

support

• To provide route for frequent blood

sampling and IV drug administration

• To remove pleural fluid or ascites for

symptomatic relief or for diagnosis
 Surgeon’s Role in
Patients Receiving Other Therapies
• To evaluate post-treatment tumor status

• To manage complications such as

opportunistic infections, local tissue
slough from leakage, bowel obstruction
or fistula

• To manage second primary malignant

tumors
 Surgeon’s Roles in Clinical Trials

• Participation in the development of good

clinical research trials that incorporate
surgical resection with other modes of
therapy

• Monitoring the quality of surgical resection

in these studies

• Referring appropriate patients into clinical

trials
 Basic Principles of Oncology
• Cancer Epidemiology
• Cancer Biology
• Surgical Therapy
• Radiotherapy
• Chemotherapy
• Biologic Therapy
 Radiation Oncology
• Ionizing radiation is part of the treatment for 60
percent of patients.

• With radiation, tumors can be destroyed while

anatomy is preserved.

• Concurrent medical problems have less influence

on radiation therapy than on surgical or
chemotherapy.

• Radiation can, however, have immediate and

delayed side effects on normal tissues.
 Physical Basis of Radiation
• Ionizing particles interact with cellular molecules

• Relies on transfer of energy created by secondary charged

particles (usually electrons)

• Charged particles are directly ionizing: directly disrupt the

molecular structure and produce chemical/biological
changes (electrons, protons, neutrons)

• Electromagnetic radiation are indirectly ionizing: they are

absorbed in tissue and give up energy to inflict the damage
(X-ray, gamma ray).

• External beam vs. Brachytherapy

Radiobiology
 External Beam Irradiation
• Dual-energy linear accelerators generate:
– Low energy megavoltage x-rays (4-6 MeV)
– High energy x-rays (15-20 MeV)
– Photon energy

• Photon therapy advantages

– Skin sparing
– Penetration
– Beam uniformity
 Brachytherapy

• Radioactive source in direct contact with tumor

– Interstitial implants, intracavitary implants or surface
molds
• Greater deliverable dose
• Continuous low dose rate
• Advantage for hypoxic or slow proliferators
• Shorter treatment times
• Gamma rays
 Brachytherapy

• Limitations
– Tumor must be accessible
– Well-demarcated
– Cannot be only modality for tumors with high
risk of regional lymph node metastasis
 Combined Modalities
• Surgery and XRT complement each other
• Surgery – removes gross tumor (bulky tumors are more
difficult to control with XRT)
• XRT – effective for microscopic disease, better with
exophytic tumors than ulcerative ones (Surgical failures
may leave subclinical disease)
• Combining treatments counteracts limitations
• Pre or Post-operative XRT
 Preoperative XRT
• Advantages
– Unresectable lesions may become resectable
– Extent of surgical resection diminished
– Smaller treatment portals
– Microscopic disease more radiosensitive (blood supply)
– Decreased risk of distant metastasis from surgical
manipulation?

• Disadvantages
– Decreased wound healing
– Decreased safe dose (45 Gy in 4.5 weeks eradicates
subclinical disease in 85% to 90% of patients)
 Postoperative XRT
• Advantages
– Better surgical staging
– Greater dose can be given safely (60 to 65 Gy in 6 to 7
weeks)
– Total dose can be based on residual tumor burden
– Surgical resection is easier
– Tissue heals better
• Disadvantages
– Distant metastasis by manipulation?
– Delay in postoperative treatment if healing problems
(poorer results if delayed more than 6 weeks)
 Basic Principles of Oncology
• Cancer Epidemiology
• Cancer Biology
• Surgical Therapy
• Radiotherapy
• Chemotherapy
• Biologic Therapy
 Principles of Chemotherapy
Skipper
• A single cancer cell can grow into a lethal tumor mass.
• The rate of tumor growth (tumor doubling time) slows
with increasing tumor burden in the later stages of tumor
growth.
• Most chemotherapeutic agents exhibit log cell kill
kinetics, and the same increment of log cell kill is seen
with subsequent doses.
• Tumor burden is inversely related to curability by
chemotherapeutic agents.
Determinants of Response to Chemotherapy
Micrometastatic disease
Rates of recurrence, disease-free survival, and overall
survival

Measurable tumor
Change in summed tumor mass
• Complete response Total disappearance of tumor at
least 4 weeks
• Partial response Minor 25-50 percent reduction
Major >50 percent reduction
• Tumor progression > 25 percent increase or new lesions
• Stable disease No change or change less than 25
percent
 Mechanisms of Drug Resistance

1. Tumor cells reside in sanctuary sites inaccessible to drugs

2. “pseudoresistance” incomplete absorption, rapid

excretion, or fails to be converted to its active form

3. Genetic and biochemical background of cancer cells

spontaneous mutation = 1 of every 106 to 107 cells
multidrug resistance (MDR) gene
Classification of Chemotherapeutic Agents
• Non-cell cycle-specific and cell cycle-specific (phase-
specific)
• Drug combinations are based on the complementary effects
of phase-specific agents on rapidly dividing cells,
and non-cell cycle-specific agents on dividing and non-
dividing cells

Alkylating agents Antimetabolites

Plant alkaloids Antibiotics
Miscellaneous
 Neoadjuvant Chemotherapy
• Use of chemotherapy prior to definitive surgery or
radiation therapy

• Intent is to improve both local and distant control

of disease in order to provide greater organ
preservation and overall survival

• Chemotherapy in neoadjuvant setting benefits

from drug delivery to a tumor with vasculature not
damaged by surgery or radiation
 Neoadjuvant Chemotherapy
Advantages
– To downstage locally advanced tumors, allowing a safer
resection that spared surrounding normal tissues.
– Tumor responsiveness can be monitored while grossly
present; agents that produce an initial major response will be
continued postoperatively.
– Immediate treatment of possible micrometastatic disease.

Disadvantages
– Unsuccessful chemotherapy can delay locoregional
interventions, and tumor progression may preclude safe
resections or require sacrifice of additional normal
surrounding structures.
– May confuse pathologic staging of resected tissues,
complicating future treatment decisions and prognosis.
Concomitant Chemoradiotherapy
• Simultaneous use of chemotherapeutic agent and
radiation therapy

• Intent is systemic control through elimination of

micro-metastases and improved local control
based on the concepts of additivity and synergy
 Adjuvant Chemotherapy
• The use of regional or systemic chemotherapy
after locoregional tumor elimination.

• To eliminate residual micrometastatic disease in

patients with moderate-to-high risk for local or
distance recurrence.

• Response can be evaluated only by monitoring

rate of recurrence, disease-free survival, and
overall survival.
 Basic Principles of Oncology
• Cancer Epidemiology
• Cancer Biology
• Surgical Therapy
• Radiotherapy
• Chemotherapy
• Biologic Therapy
 Biologic Therapy

• Immunotherapy

• Differentiation Therapy

• Inhibitors of Signal Transduction Pathways

• Gene Therapy
 Immunotherapy
Rationales
• Tumor cells have surface structures that are recognized by
effector.

• Tumor cells will be susceptible to lysis or growth

inhibition by one or more effector mechanisms.

• Augmentation of relevant effector mechanisms will

decrease the incidence of tumors or metastases.

• Restoration of depressed effector activity will decrease the

incidence of tumors or metastases.
 Immunotherapy
1. Active specific immunotherapy (cancer vaccines).
• Allogeneic vaccines
• Autologous vaccines
• Oncolysate vaccines
• Recombinant vaccines

2. Passive specific immunotherapy.

• Monoclonal antibodies specific to tumor antigens
• Immunotoxins

3. Active nonspecific immunotherapy.

• BCG
• Recombinant cytokines: IFN-α-2b

4. Passive nonspecific immunotherapy (adoptive immunotherapy).

• Lymphokine-activated killer (LAK) cells
• Tumor-infiltrating lymphocytes (TIL)
Differentiation Therapy
• all trans retinoic acid in acute promyelocytic leukemia

Small-Molecule Inhibitors of Signal Transduction

Pathways
• Tyrosine kinase inhibitors
• Farnesyl :Protein transferase inhibitors
• Cyclin-dependent kinase inhibitors
• Angiogenesis inhibitors

Gene Therapy
• Transfection of genes producing cytokines
• Antisense oncogene
• Tumor suppressor gene therapy
Good Luck on Your Exams