Transcript
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• BASICS OF ONCLOLOGY
INTRODUCTION
Cancer- uncontrolled and abnormal spread of cells in the body .
Cancer is a collective term for 100 odd disordersLatin for “ crab “Around 15,00,000 new cases of cancer every year
DIFFERENT KINDS OF CANCERS
NORMAL CELL GROWTH AND DIVISION
Normal cell growth involves two steps
Cell division
Cell differentiation
CELL DIVISION:TWO TYPES
Meiosis- reproductive cells
Mitosis – somatic cells
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CELL CYCLE STAGES
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2
3
4
G1 phase
S phase
G2 phase
M phase
G1
S
G2M
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G1 PHASE
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2
3
Occurs before S and after M phase
G stands for gap
Cytoplasmic organelles multiply
G1
S
G2M
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S PHASE
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2
3
Occurs before G2 and after G1 phase
S stands for synthesis of DNA
Nuclear material (DNA) duplicated
G1
S
G2M
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G2 PHASE
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3
Occurs before M and after S phase
G stands for gap
Cytoplasmic organelle multiplication complete
G1
S
G2M
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M PHASE
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2
3
Occurs before G1 and after G2 phase
M stands for mitosis
Has 4 parts
• Prophase
• Metaphase
• Anaphase
• Telophase
G1
S
G2M
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G0 PHASE
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2
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Enters G0 phase through G1 phase
Quiet stage with no activity
No stimulus for multiplication
Lack of growth factors
G1
S
G2M
G0
COMPLETED,CELL CYCLE
5 phases :
G 1 phase – proteins for DNA synthesisS phase – DNA synthesisG2 Phase – proteins to arrange DNA M Phase – Two daughter cells from parent cellG0 phase – resting phase
TUMOUR
Tumour- Lump of abnormal cells
TUMOUR-TYPES
Two types :
Benign tumour – Tumour confined to a particular siteMalignant tumour – Tumour that invades and spreads to
other sites
TUMOURS-BENIGN VERSUS MALIGNANT
PresentAbsent Metastasis
No capsule,spread to nearby structuresLocalized,covered by a capsuleInvasion
RapidSlowRate of growth
Poorly differentiatedWell differentiatedDifferentiation
MalignantBenignCharacteristics
CHARACTERISTICS OF MALIGNANT TUMOURS
Invasion- local spread
Metastasis- distant spread
TYPES OF MALIGNANT TUMOURS
• Carcinomas – begin in the epithelium e.g skin
• Sarcomas- begin in the connective tissue e.g muscle , bone , fatty tissue .
CAUSES OF CANCER
Genetic
Environment
Viruses
GENETIC
Three types of genes :
Oncogene
Tumour suppressor gene
Protooncogene
ENVIRONMENTAL
Combination of various factors like-
Diet Tobacco Alcohol Drugs Chemicals Radiation
VIRUSES
HTLV virus –causes T cell leukemia in adults.
Hepatitis B virus causes Hepatocellular carcinomas
RISK FACTORS
Age
Tobacco
Diet
Chemicals
Ionising Radiation
Alcohol
Overexposure to estrogen
Family history
SPREAD OF TUMOURS
Direct
Lymphatic
Bloodstream
Within the body cavities
PRIMARY AND SECONDARY TUMOURS
Primary tumours– site where the tumour originally started
Secondary tumours- when the tumour breaks off from the original
site and spreads to other parts of the body
CANCER-SYMPTOMS
Thickening or lump in the breast or any other part of the bodyObvious change in a wart or moleA sore that does not healNagging cough or hoarseness Change in bowel or bladder habits Indigestion or difficulty swallowingUnexplained changes in weight – without any apparent cause Unusual bleeding or discharge
Prevention and Early Detection of Cancers
Cancer process is series of discrete cellular changes leading to progressively autonomous cellular processes: Cancer prevention & control possible
Primary prevention Secondary prevention
Secondary Prevention and Screening for Cancers
Effective screening available for breast, cervical, prostate, lung, skin and colon cancers
Screening Recommendations for Asymptomatic Normal-Risk Subjects
Cancer Recommended Screening
Breast cancer Breast Self Exam, Clinical Exam, Mammography
Cervical cancer Pelvic exam, PAP smear
Prostate cancer DRE, PSA
Colon cancer Sigmoidoscopy, Fecal occult blood test
Other Tests Used for Cancer Detection
Staging of Cancers
Concept of staging applies to most cancers except for leukemias
Solid tumor staging: Overall stage grouping (Roman numeral staging) TNM
Cervical and Ovarian cancers use FIGO staging Colon cancer use Duke’s staging Lymphoma use Ann Arbor staging
TNM Staging of Cancers
Based on
Extent of tumor (T) Extent of spread to lymph nodes (N) Presence of metastases (M)
TNM Staging of Cancers
Primary tumor (T)
Tx primary tumor cannot be evaluated
T0 no evidence of primary tumor
Tis carcinoma in situ
T1,2,3, 4 size and/or extent of tumor
TNM Staging of Cancers
Regional Lymph Nodes (N)
Nx regional LN cannot be evaluated
N0 no regional LN involvement
N1,2,3 involvement of regional LN (number and/or extent of spread
TNM Staging of Cancers
Distant Metastases (M)
Mx distant metastases cannot be evaluated
M0 no regional metastases
M1 distant metastases found
Staging of Cancers
Staging Definition
Stage 0 Carcinoma in situ
Stage I to III Higher numbers indicate more extensive disease: greater tumor size, and/or spread of cancer to nearby LN, and/or organs adjacent to primary tumor
Stage IV The cancer has spread to another organ
Clinical Use of Staging
Careful attempt to find out whether cancer has spread or not
Provides important guide to the diagnosis, prognosis and treatment of cancer
Grading of Cancers
Used to classify in terms of how abnormal cancer cells appear microscopically, what is outcome in terms of rate of growth, invasiveness and dissemination
Grading can be Numerical (grade 1 to 4) Descriptive (“high grade” or “low grade)
Grading of Cancers
American Joint Commission on Cancer grading
Gx grade cannot be assessed
G1 well differentiated (low grade)
G2 moderately differentiated (intermediate grade)
G3 poorly differentiated (high grade)
G4 undifferentiated (high grade)
Grading and Staging of Cancers
Stage - progress of tumor
Grade - appearance of tumor under microscope: Shows aggressiveness of a tumor
Prognosis of Cancers
Prediction of the future course and outcome of disease, and an indication of likelihood of recovery from that disease
Depends on the type, stage, grade of cancer Also will depend on patient’s age, general health and response to
treatment
Treatment Options
Surgery Radiation (incl: photodynamic therapy) Chemotherapy (incl: targeted molecular therapy & hormonal
therapies) Biological therapies (incl: immunotherapy and gene therapy)
Treatment Modalities
Primary modality –traditional or most effective therapy Neoadjuvant therapy Adjuvant therapy
Primary modality Primary modality Adjuvant RxAdjuvant RxNeoadjuvant Rx Neoadjuvant Rx
Role: to treat potential metastases or to shrink a
tumor so that it is easier to irradiate
Role: to treat microscopic residual disease and potential systemic metastases
Measures of Treatment Efficacy
Staging Definition
Partial response 50 % reduction in the size of tumor and no new areas of cancer
Complete response Absence of all signs and symptoms
Response rate Percentage of patients whose disease regressed after treatment
Complete response rate Percentage of patients who were fully treated - no signs and symptoms of disease present
Partial response rate Percentage of patients who were incompletely treated – 50 % reduction in size of primary tumor
5 year survival rate Percentage of patients still alive 5 years after treatment
Disease–free survival rate Percentage of patients who show no evidence of disease
Progression–free survival rate Percentage of patients whose disease is still present but has not grown
Time to progression Time (how long) for the disease to progress (worsen or relapse) following a particular treatment
Surgical Needs in Cancers
Preventive Diagnostic Staging Curative Debulking (Cytoreductive) Palliative Supportive Restorative (Reconstructive)
Surgical Needs in Cancer Diagnosis
FNAC Needle core biopsy Excisional / Incisional Biopsy Open surgical exploration
Surgical Methods in Cancer Therapy
Traditional Laser Cryosurgery Electrosurgery Laparoscopic surgery Stereotactic surgery
Complications of Surgery
After surgeryAfter surgery OthersOthersDuring surgeryDuring surgery
Bleeding Damage to internal organs / blood
vessels Reactions to anesthesia /
medicines Heart / Kidney toxicity
Pain Infection
PneumoniaBlood clotsSlow recovery of body functions
Radiation Therapy
Traditional Laser Cryosurgery Electrosurgery Laparoscopic surgery Stereotactic surgery
PRINCIPLES OF CANCER TREATMENT
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PRINCIPLES OF CANCER TREATMENT
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Chemotherapy
Radiotherapy
Surgery
Biologic therapy
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GOALS OF CANCER TREATMENT
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Cure
Control
Palliation
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GOALS OF CANCER TREATMENT
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Cure
Control
Palliation
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part 1 what is chemotherapy?
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CHEMOTHERAPY
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Use of drugs to kill multiplying cancer cells
Number of methods to target cancer cells
Combination of drugs to increase killing efficiency
First use of nitrogen mustards and folic acid inhibitors (1940s)
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BASIS OF CHEMOTHERAPY
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Most chemotherapy drugs work by impairing mitosis
Target fast dividing cancer cells
Other fast-dividing cells (hair and intestine) also targeted
Affect less differentiated tumor cells more (highly differentiated cells multiply slowly)
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part 2 what are the various chemotherapy groups?
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CHEMOTHERAPY GROUPS
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Anti-metabolite Drugs
Alkylating Drugs
Plant Alkaloids
Topoisomerase Inhibitors
Other Drugs
Hormones
Supportive Drugs
Not strictly chemotherapeutic agents
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CHEMOTHERAPY GROUPS
alkylating drugs
anti-metabolite drugs
plant alkaloids
cytotoxic antibiotics
taxanes
topoisomerase inhibitors
other drugs
immunosuppressants
immunostimulants
cytoprotective drugs
hormonal therapy
cyclophosphamide, ifosfamide, chlorambucil, melphelan, busulphan, lomustine, thiotepa, mesna
cytarabine, methotrexate, fludarabine, 5-FU, mercaptopurine
vincristine, vinblastine, vinorelbine, etoposide
doxorubicin, daunorubicin, epirubicin, idarubicin, bleomycin, mitomycin, mitoxantrone
paclitaxel, docetaxel
irinotecan, topotecan
carboplatin, cisplatin, oxaliplatin, dactinomycin, hydroxyurea, dacarbazine, procarbazine, l-asparaginase
azathioprine, cyclosporine
interferon-alfa
amifostine
tamoxifen, bicalatumide, megestrol
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CHEMOTHERAPY GROUPS
PURINES AND PYRIMIDINESPURINES AND PYRIMIDINES
NUCLEOTIDESNUCLEOTIDES
DNA
MITOSIS PROTEIN SYNTHESIS
anti-metabolites
alkylating agentsantibioticsnitrosoureasplatinum compounds
vinca alkaloidstaxanes
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part 3 anti-metabolite anti cancer drugs
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ANTIMETABOLITES
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Interfere with formation of key bio-molecules within cell (nucleotides)
Ultimately interfere with DNA replication
Mostly S-phase specific
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ANTIMETABOLITES*
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Anti-metabolites structurally similar to metabolites
But cannot be used by body in productive manner
• Folate Antagonists• Purine Antagonists• Pyrimidine Antagonists
• Folate Antagonists• Purine Antagonists• Pyrimidine Antagonists
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FOLATE INHIBITORS
Activated folic acid donates methyl groups to DNA nucleotidesActivating folic acid requires dihydrofolate reductase enzymeMethotrexate blocks DHFR and stops DNA replication
Activated folic acid donates methyl groups to DNA nucleotidesActivating folic acid requires dihydrofolate reductase enzymeMethotrexate blocks DHFR and stops DNA replication
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forms DNA
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dihydrofolateDHFR
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folic acid
methotrexatemethotrexate
tetrahydrofolateDHFR
dihydrofolate
transfers methyl group to purine precursor using thymidylate synthase
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• Folate Antagonists• Purine Antagonists• Pyrimidine Antagonists
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PURINE ANTAGONISTS
Purine bases: adenine & guaninePurine antagonists stop formation of adenine/guaninePurine antagonists get incorporated into DNA & cause errors
Purine bases: adenine & guaninePurine antagonists stop formation of adenine/guaninePurine antagonists get incorporated into DNA & cause errors
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6-mercaptopurine/6-thioguanine6-mercaptopurine/6-thioguanine
adenineadenine 6-MP6-MP
guanineguanine 6-TG6-TG
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3
replaced with
replaced with
• Folate Antagonists• Purine Antagonists• Pyrimidine Antagonists
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PYRIMIDINE ANTAGONISTS
Pyrimidine bases: cytosine, thymine and uracilPyrimidine antagonists stop formation of thyminePyrimidine antagonists get incorporated into DNA & cause errors
Pyrimidine bases: cytosine, thymine and uracilPyrimidine antagonists stop formation of thyminePyrimidine antagonists get incorporated into DNA & cause errors
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5-fluorouracil5-fluorouracil
uraciluracil
thyminethymine
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5-FU takes place of uracilTS cannot add methyl group to 5-FUThymine production stops
5-FU takes place of uracilTS cannot add methyl group to 5-FUThymine production stops
CH3
CH3 group added by TS enzyme
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4
thymidylate synthase
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Pyrimidine bases: cytosine, thymine and uracilPyrimidine antagonists stop formation of thyminePyrimidine antagonists get incorporated into DNA & cause errors
Pyrimidine bases: cytosine, thymine and uracilPyrimidine antagonists stop formation of thyminePyrimidine antagonists get incorporated into DNA & cause errors
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5-fluorouracil5-fluorouracil
uraciluracil thyminethymine
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5-FU5-FU
replaced with
PYRIMIDINE ANTAGONISTS
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part 4 alkylating anti cancer drugs
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ALKYLATING DRUGS
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Add alkyl groups to DNA structure (especially to guanine)
Addition of alkyl groups causes three types of errors in DNA replication
Work best on slow-growing cancers
• Cyclophosphamide• Cisplatin, Oxaliplatin• Chlorambucil
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ALKYLATING DRUGS
1 Fragmentation of DNA strandsA
T
G
C
A
T
G
C
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T A
T
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T
G
C
A
T
G
C
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T A
T
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a
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T
G
C
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T
G
C
A
T A
T
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a
alkyl groups added
repair enzymes cut strand to repair error
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ALKYLATING DRUGS
2 Formation of cross-bridges in DNA strands (intra-strand adducts)
A
T
G
C
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T
G
C
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T A
T
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G
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G
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T
G
C
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T A
T
alkyl groups form ‘bridge’adducts
strands cannot separate from each other
a
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ALKYLATING DRUGS
2 Formation of cross-bridges in DNA strands (inter-strand adducts)
A
T
G
C
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G
C
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T A
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G
C
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T
G
C
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T A
T
alkyl groups form ‘bridge’adducts
strands cannot separate from each other
a
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ALKYLATING DRUGS
3 Wrong pairing of DNA strandsA
T
G
C
A
T
G
C
A
T A
T
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T
G
C
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T
G
C
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T A
T
a
a
A
T
G
T
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T
G
T
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T A
T
a
a
alkyl groups added
G pairs with T and causes DNA errors
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part 5 plant alkaloid drugs
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PLANT ALKALOIDS
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Derived from plants
Interfere with function of tubule spindles during mitosis
Two main families: vinca alkaloids and taxanes
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VINCA DRUGS
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Extracted from vinca group of plants
Prevent polymerization of tubulin to form microtubules
Induce depolymerization of formed microtubules
Cell cycle phase-specific for M phase
• Vinblastine• Vinpocetin• Vinorelbine
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ROLE OF SPINDLE FORMATION
polymerization separation
disassemblydaughter cells
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VINCA EFFECTS ON SPINDLE TUBULES
depolymerization prevents separation
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TAXANES
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Extracted from Pacific or European yew plants
Promotes stabilization of microtubules and inhibits disassembly
Cell cycle phase-specific for M phase
• Paclitaxel• Docetaxel
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TAXANES
stabilizes polymers prevents separation
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part 6 topoisomerase inhibitors
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TOPOISOMERASE ENZYMES
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2
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Two types: topoisomerase I and II
Function: unwind DNA strands during replication
Without ‘unwinding’ DNA strands undergo strain and break
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DNA TOPOLOGY
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TOPOISOMERASE ENZYMES
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2
Topoisomerase I: single strand break and linkage
Topoisomerase II: double strand break and linkage
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TOPOISOMERASE INHIBITORS
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2
Inhibit either TP I or TP II
Prevent unwinding, cause strain on strand, eventually strands break
• Topotecan• Irinotecan• Etoposide• Teniposide
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part 7 cytotoxic antibiotics
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CYTOTOXIC ANTIBIOTICS
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Anthracycline derivative antibiotics derived from streptomyces fungus
Multiple modes of action
Actions cell phase non-specific
• Doxorubicin• Daunorubicin• Dactinomycin • Bleomycin• Mitomycin C
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CYTOTOXIC ANTIBIOTICS
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2
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Intercalation of DNA strands to prevent separation during replication
Generation of free oxygen radicals
Blocks action of topoisomerase II enzyme
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COMBINATION CHEMOTHERAPY
Use of two or more drugs together to treat cancer
Objective- achieve maximum anti-tumour effect with minimal side effect
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ADVANTAGES OF COMBINATION CHEMOTHERAPY
Maximum therapeutic efficacy
Minimum resistance development
Minimum side effects
Synergism or additive effects possible
Avoidance of cumulative toxicity
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CHEMOTHERAPY DOSING
Dose – mg, per m2 , calculated according to BSA
Drug regimen- Strictly regulated scheme of drug administration.
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CHEMOTHERAPY SIDE EFFECTSMyelosuppression
Leucopenia
Thrombocytopenia
Anemia
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GI SIDE EFFECTS
Acute or delayed
Can cause dehydration
Treated by antiemetic agents
Gastritis
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GI SIDE EFFECTS
Anorexia-loss of appetite
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SIDE EFFECTS
Alopecia-loss of hair
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OTHER SIDE EFFECTS
Mutagenecity and carcinogenecity
Infertility
Nephrotoxicity
Cardiotoxicity
Neurotoxicity
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OTHER DRUG THERAPIES
Surgical therapy
Hormonal therapy
Biologic therapy
Molecular targeted therapy
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HORMONAL THERAPY
Therapy using hormones for tumours
Hormones modify growth of some hormone dependent cancers
Hormones used-glucocorticoids,progestins,estrogen analogues etc.
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SOME HORMONAL THERAPIES
Prolactin secreting tumoursDopamine agonistsProstate cancerGonadotropin analogues
Breast cancerEstrogen receptor antagonist, progestational agents
Leukemias,LymphomasGlucocorticoidsCancersHormonal therapy
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SIDE EFFECTS
• Fluid retention• Weight gain• Hot flashes • Interrupted menstrual periods • Impotence
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BIOLOGIC therapy
• Stop , control, or suppress processes that permit cancer growth.
• Boosts killing power of immune system cells,such as T cells, NK cells & macrophages
• Prevents cancer cells from spreading to distant parts of the body
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BIOLOGIC THERAPY TYPES
• Nonspecific Immunomodulating agents- BCG vaccine, Levamisole• Cytokines- Interleukins,Interferon, Colony stimulating factors• Monoclonal antibodies • Cancer vaccines
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NON SPECIFIC IMMUNOMODULATING AGENTS
• Stimulate or indirectly augment the immune system .
• BCG vaccine – used in superficial bladder cancer
• Levamisole- restores depressed immune function
• Used along with 5 – fluorouracil chemotherapy in the treatment of colorectal cancer .
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CYTOKINES
• Interferons – CML, Melanoma
• Interleukins- metastatic kidney cancer and metastatic melanoma
• Colony stimulating factors – Haemopoeitic growth factors e.g G-CSF(filgrastim), GM-CSF ( sargramostim) - increase WBCs
• Erythropoietin
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MONOCLONAL ANTIBODIES
• Monoclonal antibodies –antibodies produced by a single type of cell and are specific for a particular antigen
• Act against cell growth factors , thus interfering with growth of cancer cells
• Examples – Rituximab, Trastuzumab.
• Cancer vaccines – help the body reject tumours and prevent cancer from recurring
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SUPPORTIVE THERAPY
• Use of medicines to counteract the untoward effects of chemotherapeutic drugs
Types of supportive therapies :
• Antiemetics – to counteract nausea and vomiting
• Haemopoietic growth factors like G-CSF , GM-CSF, Epoeitin – to counteract myelosuppression
• Analgesics – for cancer pain.
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CLINICAL TRIALS
• Scientific study of how a medicine or a treatment works in people
Carried out in 4 phases –
• Phase 1 - side effects , pharmacokinetics ,in about 12 patients
• Phase 2 - dose –ranging , efficacy. 50-300 patients
• Phase 3 - comparing efficacy & safety of new drug with standard treatment 250-1000 patients
• Phase 4 - to detect adverse effects missed out in earlier phases. Post marketing studies
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• Open• Uncontrolled• Controlled• Randomized• Double –blind• Single-blind
CLINICAL TRIALS
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