ONCO-Basics

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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

6

CELL CYCLE STAGES

1

2

3

4

G1 phase

S phase

G2 phase

M phase

G1

S

G2M

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G1 PHASE

1

2

3

Occurs before S and after M phase

G stands for gap

Cytoplasmic organelles multiply

G1

S

G2M

8

S PHASE

1

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

1

2

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

1

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

1

2

3

4

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)


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


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


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

1

2

3

4

Chemotherapy

Radiotherapy

Surgery

Biologic therapy

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GOALS OF CANCER TREATMENT

1

2

3

Cure

Control

Palliation

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GOALS OF CANCER TREATMENT

1

2

3

Cure

Control

Palliation

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part 1 what is chemotherapy?

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CHEMOTHERAPY

1

2

3

4

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

1

2

3

4

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

1

2

3

4

5

6

7

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

1

2

3

Interfere with formation of key bio-molecules within cell (nucleotides)

Ultimately interfere with DNA replication

Mostly S-phase specific

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ANTIMETABOLITES*

1

2

Anti-metabolites structurally similar to metabolites

But cannot be used by body in productive manner

• 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

2

forms DNA

1

dihydrofolateDHFR

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folic acid

methotrexatemethotrexate

tetrahydrofolateDHFR

dihydrofolate

transfers methyl group to purine precursor using thymidylate synthase

5


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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

1

6-mercaptopurine/6-thioguanine6-mercaptopurine/6-thioguanine

adenineadenine 6-MP6-MP

guanineguanine 6-TG6-TG

2

3

replaced with

replaced with


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PYRIMIDINE ANTAGONISTS

Pyrimidine bases: cytosine, thymine and uracilPyrimidine antagonists stop formation of thyminePyrimidine antagonists get incorporated into DNA & cause errors


1

5-fluorouracil5-fluorouracil

uraciluracil

thyminethymine

3

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

2

4

thymidylate synthase

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1

5-fluorouracil5-fluorouracil

uraciluracil thyminethymine

2

5-FU5-FU

replaced with

PYRIMIDINE ANTAGONISTS

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part 4 alkylating anti cancer drugs

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ALKYLATING DRUGS

1

2

3

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

A

T A

T

A

T

G

C

A

T

G

C

A

T A

T

a

a

A

T

G

C

A

T

G

C

A

T A

T

a

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

A

T

G

C

A

T A

T

A

T

G

C

A

T

G

C

A

T A

T

a

A

T

G

C

A

T

G

C

A

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

A

T

G

C

A

T A

T

A

T

G

C

A

T

G

C

A

T A

T

a

A

T

G

C

A

T

G

C

A

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

A

T

G

C

A

T

G

C

A

T A

T

a

a

A

T

G

T

A

T

G

T

A

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

1

2

3

Derived from plants

Interfere with function of tubule spindles during mitosis

Two main families: vinca alkaloids and taxanes

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VINCA DRUGS

1

2

3

4

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

1

2

3

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

1

2

3

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

1

2

Topoisomerase I: single strand break and linkage

Topoisomerase II: double strand break and linkage

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TOPOISOMERASE INHIBITORS

1

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

1

2

3

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

1

2

3

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

ONCO-Basics

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