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Cancer Chemotherapy 1: Principles of Chemotherapy & Tumor Kinetics Dr. Syed Shariq Assistant Professor

Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

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Page 1: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Cancer Chemotherapy 1: Principles of Chemotherapy & Tumor Kinetics

Dr. Syed ShariqAssistant Professor

Page 2: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

1. General Principles of Cancer Chemotherapy

2. Chemotherapy: Classical Drugs

3. Chemotherapy: Biologicals & Hormones

4. Chemotherapy: Novel Drugs & Prevention of Toxicity

Page 3: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

• Etiopathogenesis

• General Principles of Chemotherapy

• Log Dose Kill – Chemotherapy Cycles

• Conventional Anticancer Agents

Alkylating Agents

Platinum Compouunds

Page 4: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

General Principles of Cancer Chemotherapy

Page 5: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Cancer Chemotherapy

• Killing of cells

• Human cells

Antimicrobial Chemotherapy

• Killing of cells

• Foreign cells

Difficult to Identify difference between Self (Normal Body) cells & Cancer Cells

Therapeutic Index of anti-cancer drugs: Low

If an antibiotic leaves a few viable bacteria, the immune system can usually mop up

Page 6: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

HistoryJust A century ago, there were NO cancer Drugs

World War II- Pearl Harbor: Mustard Gas

Severe marrow and lymphoid hypoplasia

Page 7: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Chemotherapy

• Normal life for some patients with different types of tumors

• Total remission :25% patients

• Objective regression in 30–50% of patients treated for the first time with a chemical product.

• Tumors only responding to chemotherapy: 10–15%

• Increased recovery rates: An adjuvant in surgical therapy or radiotherapy

Page 8: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Sensitivity of cancers to chemotherapy:

High Intermediate Low

Lymphoma Breast Head and neck

Leukemia Colon Prostate

Small Cell Lung cancer Non-small cell lung cancer

Gastric

Testicular cancer Pancreatic

Page 9: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Cancer : The Basics (Video)

Page 10: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Chemicals, Viruses or Irradiation etc

MutationAcquired Inherited

Altered Gene Expression

Proto-oncogenes Oncogenesmyc, ras, sis, erbB

↓ Expression of Tumor Suppressor Genep53, Rb1

Unregulated cellProliferation

↓ Apoptosis

Primary Tumor

Invasive Tumor

Angiogenesis

Secondary Tumor

Metastasis

Metalloproteinases

Page 11: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Cell Cycle

Page 12: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

4Cell

division

Mitosis

3

DNA

repair

G21

Cell

grows,

doubles

in size

G1

S

2Chromosome

duplication

G2/M checkpoint

G1/S

checkpoint

Page 13: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Effects of Cancer Chemotherapy

Apoptosis

Necrosis

Page 14: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Chemotherapy

Page 15: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

• Major Chemotherapy Drug Groups available

S.No Name of the Group Remarks

1 Conventional chemotherapy agents

Small molecules (<1500 Daltons)

2 Targeted agents Small molecules - Inhibitors of “critical signaling pathways”

3 Hormonal therapies Sex hormones based

4 Biologic therapies Macromolecules with particular target (e.g., interferons and interleukins)

Page 16: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Calculating the dose

• Doses are individualized based upon a patient’s BSA (body surface area) (kg/m2)

• Drugs are given in cycles, usually at 3-4 week intervals

• Chemotherapy is often combined with surgery and/or radiation

Page 17: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Route of Drug administration

• Enteral (Oral)

• Parenteral (IV, IM, SC)

• Local (IA, IP, IT)

Page 18: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Log kill Hypothesis

Page 19: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Relationship of Fraction cell kill to Log kill

Cell Fraction killed Surviving Cell Fraction

Log Surviving Cell Fraction

Log Kill

.9 .1 -1 1

.99 .01 -2 2

.999 .001 -3 3

.999999999 .000000001 -9 9

Page 20: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Log kill hypothesis

1010

108

106

104

102

Can

cer

cells

Time

4 log kill

1 log Regeneration

Effective Killing= Log kill - Regeneration

No. of Cycles= Total cancer cellsEffective Killing

Cell Cycles

Page 21: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Exercise

The initial tumor burden is 1010 cells and the drug combination usedis known to give a log kill of 3. Assuming a 1 log re-growth per weekbetween treatments and that all the cells are sensitive, which of thefollowing treatment schedules would be expected to give a completecure (ignoring the fact that cancers don’t always behavepredictably)?

A. 3 treatments at one week intervals

B. 8 treatments at two week intervals

C. 50 treatments at three week intervals

D. 5 treatments at one week intervals

E. none of the above

Page 22: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Conventional Anti- Cancer Agents

Page 23: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Conventional Chemotherapy

• Alkylating Agents

o Nitrogen Mustards

o Thiotepa, Busulfan

o Nitrosoureas, Mitomycin

o Procarbazine, Dacarbazine

• Platinum Complexes

o Cisplatin, Carboplatin

o Oxaliplatin

• Antimetabolites

o Methotrexate

o Purine Antagonists

o Pyrimidine Antagonists

• Anthracyclines

o Doxorubicin, Daunorubicin

o Idarubicin, Mitoxantrone

• Taxanes

o Paclitaxel, Docetaxel

o Nab-paclitaxel

• Topoisomerase II Inhibitors

o Etoposide

• Tubulin Interactive Agents

o Vincristine, Vinblastine

• Miscellaneous Agents

o Bleomycin

o Asparaginase

o Hydroxyurea

Page 24: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Alkylating Agents

S.No. Chemical Classes Names of agents

1 Nitrogen mustard derivatives

Cyclophosphamide, Mechlorethamine, chlorambucil, melphalan

2 Ethylene derivatives Thio-TEPA

3 Alkyl sulfonates Busulfan

4 Triazine derivatives Dacarbazine

5 Nitrosoureases carmustine, lomustine, semustine

Cell Cycle Non-Specific

Page 25: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

A = T G = C

Mustards react (alkyl group) with the N7 atom of purine bases (guanine)

Mechanism of action

Page 26: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

A=C, A=G, T=C

1. Cross linkages

2. DNA Breakage

3. Mismatched Base pairing

Page 27: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

4Cell

division

Mitosis

3

DNA

repair

G21

Cell

grows,

doubles

in size

G1

S

2Chromosome

duplication

G2/M checkpoint

G1/S

checkpoint

Page 28: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Metabolism

Cyclophosphamide 4 Hydroxy-

cyclophosphamide

Inactive Metabolites

Aldophosphamide

Phosphoramidemustard

Acrolein

CYPs

Page 29: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

ADRsAlopecia

Bone Marrow: MyelosupressionSecondary Leukemia

Skin: Powerful Vesicant

CVS: Cardiotoxic(Endothelial Injury HgeNecrosis)

Lungs: Depress Pulmonary Functions

GIT: Absorption – ModerateNausea and Vomiting

Liver: Hepatic DysfunctionBladder: Hge CystitisStarts: 24hrs- several weeks(t/t: Mesna,fluids, irrigation)SIADH

Mesna: Mercapto ethane sulfonic acid

Sterlity

Page 30: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Uses

• Anti cancer:Non Hodgkin’s Lymphoma

Other lymphomas

Breast, Ovarian

Solid Childhood tumors (Burkitt’s Lymphom)

• Immunosuppressant: Wegener’s Granulomatosis

Rheumatoid Arthritis

Nephrotic syndrome

Page 31: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

S.No Name of the Agent Side Effects/ Remarks Uses

1. Ifosfamide More Hge CystitisNeurotoxic, Myelosupression

SarcomaGerm cell testicular tumor

2. Melphalan Multiple Myeloma

3. Chlorambucil Only CLL

Page 32: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Alkyl Sulfonates

S.No Name of the Agent Side Effects/ Remarks Uses

1. Busulfan Powerful MyelosuppressionPulmonary fibrosis, Hyperpigmentation

CML

S.No Name of the Agent Side Effects/ Remarks Uses

1. Carmustin Hepatic veno occlusive diseasePulmonary fibrosisRenal failure

Highly lipophilicBrain tumor (Gliomas)

2. Lomustine

Nitrosoureas

Page 33: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Triazine derivatives

S.No Name of the Agent Side Effects/ Remarks Uses

1. Dacarbazine Malignant Melanoma

Methylhydrazine

2. Procarbazine Risk of Acute Leukemia: 5-10%Disulfiram like reaction

Hodgkin’s Lymphoma

Page 34: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

The Platinum Compounds

Platinum Coordinate Complexes

Page 35: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Mechanism of Action

Enters the cell:

Cu+ Transporter- CTR1

Chloride Moiety Replaced by Water

Charged & highly reactive molecule

Aquated Specie React with DNA and Proteins

Page 36: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

• Before use: Inactivated by Aluminum: Needles

To prevent Renal Toxicity: Chloride Diuresis (NS)

• Uses: Testicular Cancer (Combinational Therapy)

Ovarian Cancer

Cancers of Bladder, Head and Neck, Cervix

Radio sensitizer: Lung, esophageal cancers with radiotherapy

Page 37: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

ADRsCNSSensory and motor NeuropathyOtotoxicity: Tinnitus

Bone Marrow: Mild to Moderate Myelosupression

CVS: Rare Cardiotoxic

GIT: Nausea and VomitingInitially: 5HT3 ReceptorCorticosteroidLate: NK1 receptor

Kidneys: NephrotoxicityStarts: 24hrs- several weeks(t/t: Amifostin, fluids)

Electrolyte imbalance: Hypocalcemia, hypomagnesemia, hypokalemia, Hypophosphatemia

Anaphylactic- like Reaction:Facial edema, bronchoconstriction, Hypotension

Page 38: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

S.No Name of the Agent Side Effects/ Remarks Uses

1. Carboplatin Less ADRsMore Hypersensitivity Rxn

Ovarian cancerLung cancer

2. Oxaliplatin Peripheral neuropathy Colorectal Cancer

Typical anti-emetic regimenDexamethasone 12 mg po day 1 then 8 mg po daily x 3 daysPalonosetron 0.25 mg IVP day 1Aprepitant 125 mg po day 1 then 80 mg po days 2 – 3

Page 39: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Questions !

Page 40: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Terminology in ChemotherapyType of therapy

Induction

Consolidation

Intensification

Maintenance

Adjuvant

Neoadjuvant

Palliative

Salvage

Dose of Agent & Timing Objective of treatment

High dose at start of TT Complete Remission

High dose after induction Increase cure rate or prolong remission

High dose after remission (with same or different agent)

Increase cure rate or prolong remission

Low dose for long time after remission

Delaying re-growth of residual tumor

High dose for short time after surgery or chemotherapy

Destroy residual cells (Tumor not clinically visible)

High dose for short time before surgery or chemotherapy

Shrink the tumor

Control symptom or prolong life- Where cure is unlikely

High dose (After failure or recurrence)

Potentially curative

Page 41: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Monitoring the Response

Page 42: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Types of Chemotherapy

• Primary Chemotherapy - chemotherapy is used as the sole anti-cancer treatment in a highly sensitive tumor types– Example – CHOP for Non-Hodgkins lymphoma

• Adjuvant Chemotherapy – treatment is given after surgery to “mop up” microscopic residual disease– Example – Adriamycin, cyclophosphamide for breast cancer

• Neoadjuvant chemotherapy – treatment is give before surgery to shrink tumor and increase chance of successful resection– Example – Adriamycin, ifosfamide for osteosarcoma

• Concurrent chemotherapy – treatment is given simultaneous to radiation to increase sensitivity of cancer cells to radiation– Example – Cisplatin, 5-fluourouracil, XRT for head and neck

tumors

Page 43: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Gompertzian growth model

Initial tumour growth is first order, with later growth being much slower

Smaller tumour grows slowly but large % of cell dividing

Medium size tumour grows more quickly but with smaller growth fraction

Large tumour has small growth rate and growth fraction

Page 44: Cancer Chemotherapy 1 · 1. General Principles of Cancer Chemotherapy 2. Chemotherapy: Classical Drugs 3. Chemotherapy: Biologicals & Hormones 4. Chemotherapy: Novel Drugs & Prevention

Terminology in chemotherapy