Cancer Chemotherapy 1: Principles of Chemotherapy & Tumor Kinetics Dr. Syed Shariq Assistant Professor
Cancer Chemotherapy 1: Principles of Chemotherapy & Tumor Kinetics
Dr. Syed ShariqAssistant Professor
1. General Principles of Cancer Chemotherapy
2. Chemotherapy: Classical Drugs
3. Chemotherapy: Biologicals & Hormones
4. Chemotherapy: Novel Drugs & Prevention of Toxicity
• Etiopathogenesis
• General Principles of Chemotherapy
• Log Dose Kill – Chemotherapy Cycles
• Conventional Anticancer Agents
Alkylating Agents
Platinum Compouunds
General Principles of Cancer Chemotherapy
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
HistoryJust A century ago, there were NO cancer Drugs
World War II- Pearl Harbor: Mustard Gas
Severe marrow and lymphoid hypoplasia
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
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
Cancer : The Basics (Video)
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
Cell Cycle
4Cell
division
Mitosis
3
DNA
repair
G21
Cell
grows,
doubles
in size
G1
S
2Chromosome
duplication
G2/M checkpoint
G1/S
checkpoint
Effects of Cancer Chemotherapy
Apoptosis
Necrosis
Chemotherapy
• 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)
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
Route of Drug administration
• Enteral (Oral)
• Parenteral (IV, IM, SC)
• Local (IA, IP, IT)
Log kill Hypothesis
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
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
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
Conventional Anti- Cancer Agents
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
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
A = T G = C
Mustards react (alkyl group) with the N7 atom of purine bases (guanine)
Mechanism of action
A=C, A=G, T=C
1. Cross linkages
2. DNA Breakage
3. Mismatched Base pairing
4Cell
division
Mitosis
3
DNA
repair
G21
Cell
grows,
doubles
in size
G1
S
2Chromosome
duplication
G2/M checkpoint
G1/S
checkpoint
Metabolism
Cyclophosphamide 4 Hydroxy-
cyclophosphamide
Inactive Metabolites
Aldophosphamide
Phosphoramidemustard
Acrolein
CYPs
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
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
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
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
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
The Platinum Compounds
Platinum Coordinate Complexes
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
• 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
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
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
Questions !
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
Monitoring the Response
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
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
Terminology in chemotherapy