Principle of Oncology
Principle of Oncology
Principle of Oncology
• 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
Non-ionizing Radiation
• UV radiation is absorbed by DNA and induces DNA
damage
• human skin tumors: basal cell carcinoma, squamous
carcinoma, and melanoma
PHASE II ENZYMES
ALDH2
PHASE I ENZYMES
ADH3
CYP
Viral Carcinogen
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
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
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
“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
nodes
nodes
Sentinel lymph node biopsy
• Lymphoscintigraphy and gamma probe-guided
localization
“ultra staging”
Surgeon’s Role in Palliation
• 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
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
• Immunotherapy
• Differentiation Therapy
• Gene Therapy
Immunotherapy
Rationales
• Tumor cells have surface structures that are recognized by
effector.
Gene Therapy
• Transfection of genes producing cytokines
• Antisense oncogene
• Tumor suppressor gene therapy
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