principles of chemotherapy

General Principles of Cancer Chemotherapy

DR NILESH KATOLE, TYR, DEPT OF PHARMACOLOGY, LTMMC AND GH.

Chemotherapy • German chemist Paul Ehrlich- Coined

the term ‘‘chemotherapy’’

• Originally chemotherapy referred to treatment of disease with drugs or chemical

• but by mid 1950’s the term was only being used primarily in reference to drugs which were used to treat cancer.

Cancer :

• Diseases of cells that shows uncontrolled proliferation , anaplsia, invasivness and ability to metastasis .

• Due to Chromosomal abnormality and expression of oncogens .

• Second most common cause of death after cardiovascular disorders in world.

Current Treatment Modalities of Cancer

• Surgery

• Radiotherapy

• Chemotherapy, Immunotherapy, Gene therapy

Choice of therapy depends upon the • Location of tumour• Stage of tumour• General state of the patient.

• For solid cancers• 1/3 of patients can be cured,• Effective when tumor has not

metastasized

Chemotherapy : Historical perspective

• 1943 - During World War II , soldiers were exposed to nitrogen mustard gas and shows marked depletion in marrow and lymphoid cells.

• Based on this finding, Alfred Gilman and Louis Goodman from Yale university used Nitrogen Mustard to induced remission of Lymphoma in mice.


1948 - Sidney Farber showed that aminopterin, a folic acid analogue, developed by Y. Subbarao can induced remission in acute lymphoblastic leukemia. Latter more safer amethopterin ( Methotrexate ) was developed.


1950- Actinomycin D was developed as antibiotics, but found to be very toxic but have significant antitumour activity

1951 - Hitchings and Elion isolated 6-thioquanine and 6-mercaptopurine that inhibited purine metabolism, which are widely used for various cancer and as immunosuppressant.

• 1970’s - “Golden Age” of medical oncology.Development of effective combination chemotherapy regimens.

• New classes of drug developed - anthracyclines, platinum compounds .

• Cures achieved in some forms of cancer (lymphomas, leukemias, testis cancer).

• Significant responses in some common types of cancer (breast, stomach, small cell lung cancer)

•Effective use of chemotherapy to prevent recurrence in high risk breast cancer patients.


• Scientist continue to look for “the magic bullet” to eliminate cancer.

• Nowdays research is being focused on specific agents that interfere with cell division, as well as monoclonal antibodies, biologic modifiers, gene therapies, etc.


Goals of chemotherapy

To Cure• Wilm’s tumor, ALL, Testicular

cancer, Burkitt’s lymphoma, NHL

To Control • Prolong remission• Decreases rate of relapse

Palliation • Relive symptoms and improved quality of life

Types of chemotherapy

1. Primary Chemotherapy • Chemotherapy is main

modality of treatment • Can be single drug or

combination chemotherapy• e.g. Hematological

malignancy-• ABVD regimen for hodgkins

lymphoma.

2. Adjuvant Chemotherapy

• Combined with radiation or surgery.

• For advanced cancer• e.g. Ca breast After surgery

to remove microscopic foci.

Types of chemotherapy

3. Neoadjuvant chemotherapy

• Chemotherapy is given before surgery.

• Shrink a large cancerous tumour to make surgery easy.

• e.g. laryngeal carcinoma before surgery.

4. Concurrent chemotherapy

• Simultaneously with • Radiation.• mainly act as

radiation sensitizer, encourages the cancer cells to take radiotherapy.

• e.g.Head and neck CA, rectal CA, lung CA

Sensitivity of various tissues 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

Basic concepts of cancer cell growth

• Cell life cycle and drug

• Log kill hypothesis • Growth fraction

• Tumour burden

cell cycle and drugs G1 – L- Asparginase S – Methotrexate 6-Mercaptopurine 5-Fluorouracil

Mitomycin CHydroxyureaDoxorubicin

G2 – Bleomycin Etoposide,

Topotecan Daunorubicin

M – Vincristine Vinblastine Paclitaxel,

Docetaxel

• Cell kill by first order kinetics.

• A constant fraction of cells are killed by a given drug dose, not constant number.

• A constant percentage of the total number of cancer cells present in tumor will be killed with each course of chemotherapy.

• Hence repeated doses of chemotherapy must be used for total cells kill.

Log kill hypothesis

1 log regrowth

3 log cell kill

Tumor regrowth after premature Cessation of Therapy.

Growth fraction Growth fraction is the percentage of actively dividing cells at any given point in time.

1. High growth fraction tumour : more sensitive to cycle-specific drugs.

e.g. 1. leukemia and lymphoma 2. Normal with tissues high growth fraction like bone

marrow, hair follicles, and intestinal

2. Low growth fraction tumour : Solid tumour e.g. carcinomas of the colon, lung cancer) are less responsive to cycle-specific drugs.

Tumour burden

• The tumor burden is the size of the tumor as determined by the number of cells present.

• Small tumor burden → more responsive

• Higher the tumor burden → probability of drug resistance.

• Cancer cells usually follows Gompertzian growth pattern.

Gompertzian Growth

Gompertzian Growth

It is model of cancer cell growth.

“Cell rapidly divide early in life, then plateaus.”

Significance :

1. Most anticancer drugs are ineffective in advanced cancers which have very low growth fraction.

2. Debulking procedures makes tumour again responsive to drugs by inducing remaining cells to divide.

Drugs Used in Cancer Chemotherapy

Alkylating Agents e.g. Nitrogen mustards , Nitrourea

Antimetabolites e.g. Folic acid analogue, Pyrimidine and Purine analogue

Natural Agents e.g. Vinca alkaloid, Taxens, Tecans.Antibiotics and enzymes

e.g. Dactinomycin, Daunorubicin , L-Asparaginase

Hormones and antagonists

e.g. Progestins , Estrogen, GnRH, Anti-estrogens

Miscellaneous agents

e.g. Hydroxyurea , Immunomodulators , Tyrosine kinase inhibitor, Biological Response Modifiers ,monoclonal antibody

Purine Synthesis Pyrimidine Synthesis

Ribonucleotides

Deoxyribonucleotides

DNA

RNA

Proteins

Enzymes Microtubules

6-Mercaptopurine6-ThioguanineMethotrexate → DHFR

5-Fluorouracil CytarabineGemcitabine

Hydroxyurea

EtoposideTopoisomerase II Inhibitor- DNA break

Antibiotics

L-Asparaginase

Vinca Alkaloids → prevent polymerizationTaxens →enhance polymerization

Antimetabolites

Alkylating agentsAlkylation→ Alter structure & function of DNA by cross linking and/or fragmenting DNA

MOA of some anticancer drugs

Alkylating agents CLASS DRUGS MAJOR USES

Nitrogen Mustards

Meclorethamine HL, NHL

Melphalan Multiple myeloma; breast, ovarian cancer

Chlorambucil ALL, CLL , HL, NHL,Multiple myeloma; Neuroblastoma;

Breast, Ovary, Lung cancer;Wilms’ tumor;

cervix, testis cancer;

CyclophosphamideIfosfamide

Etylenimine ThioTEPA Bladder, breast, ovarian cancer

Alkyl sulfonte- Busulfan CML

Nitrosoureas Carmustine Primary brain tumor;Melanoma, HL,NHL,

StreptozocinPancreatic insulinoma;

Malignant carcinoid

Triazine Dacarbazine Malignant melanoma;

CLASS DRUGS MAJOR USES

Folic acid analogue

Methotrexate ALL; choriocarcinoma breast, head, Lung cancer; osteogenic sarcoma; bladder ca

Pemetrexed Mesothelioma, lung cancer

Pyrimidine analogue

FluorouracilCapecitabine

Breast, colon, esophageal, stomach cancer.

Cytarabine AML, ALL, NHL Gemcitabine Pancreatic, ovarian, lung ca.

Purine analogue and related inhibitors

Mercaptopurine AML, ALL

Pentostatin Hairy cell leukaemia; CLL, small cell NHL.

Fludarabine CLL

Antimetabolites


Vinca alkaloids

Vinblastine HL, NHL, Testis cancer

Vinorelbine Non small cell lung cancer

Vincristine ALL, Neuroblastoma;Wilms’ tumor;

Taxanes Paclitaxel, Docetaxel

Metastatic ovarian, breast ca.

Epipodo-phyllotoxins Etoposide Testicular tumour, lung

cancer ,HL, NHL

Camptothecins Topotecan, Irinotecan Ovarian cancer; small-cell lung cancer; colon ca.

Natural Agents


Antibiotics

Dactinomycin (actinomycin D)

Choriocarcinoma; Wilms’ tumor; Rhabdomyosarcoma

Daunorubicin AML, ALL.

Doxorubicin Soft-tissue, osteogenic, and other

sarcoma; HL, NHL , AML, ALL.Breast, Genitourinary, Thyroid, lung,

stomach cancer; NeuroblastomaMitoxantrone AML, breast and prostate cancer

Bleomycin Testis, cervical cancer; HL, NHL

Mitomycin Stomach, anal, and lung cancer

Enzymes L-Asparaginase ALL

Antibiotics and enzymes

CLASS DRUGS MAJOR USESGlucocorticoides Prednisone ALL, CLL, HL, breast cancer,

multiple myeloma

Progestins Hydroxyprogesterone caproate,Medoxyprogesteroneacetate, Megestrol acetate

Endometrial, breast cancer

Estrogens Diethylstilbestrol, Ethinyl estradiol

Breast, prostate cancer

Anti-estrogens Tamoxifen, Toremifene, Breast cancer

Aromatase inhibitors

Anastrozole, Letrozole, Breast cancer

Androgens Testosterone propionate Breast cancer

Antiandrogen Flutamide , casodex Prostate cancer

GnRH analogue Leuprolide Prostate cancer

Hormones and antagonists


Substituted urea Hydroxyurea CML ; Polycythemia vera; Essential thrombocytosis

Differentiating agents Tretinoin, Arsenic trioxide

Acute Promyelocytic Leukemia

Protein tyrosine kinase inhibitor

Imatinib CML, GISTGefitinib Non-small-cell lung cancerSorafenib Hepatocellular cancer,

Renal cancerProteasome inhibitor Bortezomib Multiple myeloma

Immunomodulators Thalidomide Multiple myeloma

Lenalidomide Myelodysplasia , multiple myeloma

mTOR Inhibitors Temsirolimus, Everolimus

Renal cancer



Biological ResponseModifiers

Interferon-α, Interleukin 2

Hairy cell leukemia; Kaposi’s sarcoma; Melanoma; carcinoid; Renal cell; Ovary; Bladder; Mycosis fungoides;Multiple myeloma; NHL, CML

CD20 Rituximab B-cell lymphoma and CLL

CD52 Alemtuzumab B-cell CLL and T-cell lymphoma

CD33 Gemtuzumab Acute Myelocytic Leukemia

HER2/neu Trastuzumab Breast cancer

EGFR Cetuximab colorectal, pancreatic, breast ca.

VEGF Bevacizumab colorectal cancer


Dosage of chemotherapeutic agents

Dosage of chemotherapy are difficult: If the dose is too low, it will be ineffective , whereas excessive causes toxicity .

In most cases, the dose is adjusted for the patient's body surface area (BSA), a measure that correlates with blood volume.

The BSA is usually calculated with a mathematical formula using a patient's weight and height, rather than by direct measurement.

W is weight in kg, and H is height in cm.

• Standard doses –doses in which anticipate side effect are mild and no supportive therapy required

• High dose therapy – Increases in dosing amount, severe side effects are present. Supportive therapy is essential.

Large amounts of free drug in the serum not only increase efficacy of the drug but also facilitate penetration into the tumour cells.

Example :In AML , High-dose cytarabine (2000 to 3000 mg /m2 of BSA) have higher rates of relapse-free survival than standard dose of 100 to 400 mg /m2.

Dose intensification (DI) – higher than standard dose given in short interval

Achieved by

1. Increasing the dose of the chemotherapy per cycle (dose escalation)

2. Decreasing the time between the treatments (dose density)

Steep dose-response curve, meaning that relatively small increases in the chemotherapy dose will have a substantial effect on the number of tumor cells killed.

Principles of combination therapy

Combination therapy involves the use of two or more drugs proven effective against a tumor type.

Major advances in cancer treatment in the past 20 years.

RATIONALE OF COMBINATION CHEMOTHERAPY • Prevention of resistant clones.

• Cytotoxicity to resting and dividing cells. •

Biochemical enhancement or effect – Synergistic effect

Combination therapy is superior to single-drug therapy in terms of

• Higher tumor response rates

• Increased duration of remissions.

• Minimal chances of resistance.

Principles for selecting drugs for combination regimens

Active as single agents

Different mechanism of action

Different dose limiting toxicity

Used at optimal dose and schedule

Given at consistent interval

Different resistance mechanism Drugs with known synergistic biochemical interaction Cell kinetics scheduling: on basis of cell cycle specificity /

non specificity of drugs and phase of cycle at which drug exert toxicity.

Examples of combination therapy

vinblastin

Important drug combinations

REGIMEN CANCER DRUGS ABVD Hodgkin's Doxorubicin, Bleomycin, Vinblastine,

Dacarbazine CHOP-R NHL Cyclophosphamide,

Hydroxydaunorubicine, Vincristine, Prednisolone, Rituximab

VAMP AML Vincristine, Amethopterine, 6 MP, Prednisolone

FOLIFIRI COLON CANCER

5 FU, Leucovorin, Irinotecan,

WHO response scale to chemotherapy

1. Complete response – disappearance of disease on imaging test.

2. Partial response – size decrease of 50% or more from original tumor. No new lesions.

3. Stable disease – less than 50% response without actual progression of disease.

4. Disease progression – 25% increase in the size of the original tumor. Or new lesions developed.

Conditions when CytotoxicChemotherapy may be withheld

Infection

Previous chemotherapy given < 2 weeks

Leukopenia and thrombocytopenia

Severely debilitated patients

Pregnancy (1st trimester)

Major surgery < 2 weeks

Poor patient follow-up

Psychological problems

Not all patients can tolerate drugs, and not all drug regimens are appropriate for a given patient.

Choice of drug depends on following factor• Tumour type • General performance status of patient• Renal and hepatic function • Bone marrow reserve• Concurrent medical problems • Patient's willingness • Patient's physical and emotional tolerance for side effects

Choice of chemotherapeutic agent

2 major challenges to Chemotherapy

1. Toxic side effects 2. Drug resistance

Resistance to chemotherapeutic agents

Resistance constitutes a lack of response to drug-induced tumour growth inhibition

1. Primary resistance: No response from very first exposure.e.g. malignant melanoma, renal tumours.

2. Acquired resistance : During continuation of therapy .Due to adaption of tumour cells or due to mutation in one or more gene.

1. ↑ drug efflux via P-glycoprotein transporters e.g. doxorubicin, paclitaxel, vincristine, etoposide

2. Overexpression of the multidrug resistance protein 1(MRCP1) → ↑resistance to natural drugs e.g. vinca alkaloid, anthracyclins .

3. ↓ inward transport e.g. methotrexate

4. Insufficient activation of the drug (e.g. mercaptopurine , fluorouracil and cytarabine.

5. Increase in inactivation (e.g. cytarabine and mercaptopurine )

6. Increased concentration of target enzyme (methotrexate)

7. Rapid repair of drug-induced lesions (alkylating agents).

8. Altered activity of target proteins, for example modified topoisomerase II (doxorubicin).

Mechanism of resistance

• Use of combination drug therapy using different classes of drugs with different mechanism of action.

• With narrowest cycle intervals, necessary for bone marrow recovery.

• Drugs that reverse multidrug resistance include verapamil, quinidine, and cyclosporine .

Overcoming resistance :

• Rapidly multiplying cells

• Nausea & Vomiting

• Bone marrow depression

• Alopecia

• Gonads: Oligospermia, impotence, ↓ ovulation

• Foetus: Abortion, foetal death, teratogenicity

• Carcinogenicity

• Hyperuricemia

• Hazards to staff

Toxicity

Bone marrow suppressionCause by almost all anticancer drugs except Bleomycin, Vincristin and Asparginase.

Most serious toxicity and often limit dose of chemotherapy

• Granulocytopenia• Agranulocytosis• Thrombocytopenia• Aplastic anemia• Lymphocytopenia • immunosppression

Drug causing severe myelosuppression

Carmustin

Cytarabine

Daunorubicine

Paclitaxel

Alkylating agents

AntimetabolitesComplications :• Opportunistic infections • Bleeding

Gastrointestinal toxicity Drugs Nausea and vomiting Carmustin,cisplatin,cyclophosphamide,dacarb

azine,cytarabine,lomustine,thiotepaStomatitis Capecitabine,5

FU,methotrexate,mercaptopurineDiarrhea Irinotecan, 5FUConstipation VincristineAnorexia, taste change,etc

Dermatological toxicity DrugsAlopecia Cyclophosphamide, Ifosfamide

Vincristin ,Methotrexate , Paclitaxel, Local necrosis- extravasation Dactinomycin, Doxorubicin, vinca alkaloid

Hyperpigmentation of skin

General toxicity of cytotoxic drugs

Toxicity DrugsNeuropathy Oxaliplatin,Paclitaxel, Cytarabine,5FU,Renal toxicity Cisplatin, Ifosfamide, MethotrexateHemorrhagic cystitis Cyclophosphamide, IfosphamideHepatotoxicity Asparginase, Cytarabine,

Mercaptopurine,Thioguanine, MethotrexateCardio toxicity Daunorubicin, Doxorubicin,Epirubicine,

Mitoxantrone,Transtuzumab, BevacizumabPulmonary toxicity Bleomycin, Melphalan, Chlorambucil,

Busulphan,Infertility Alkylating agentsHypersensitivity reaction Asparginase, Platinum compound, etoposide

General toxicity of cytotoxic drugs

Drugs Use Filgrastim (G-CSF) 1. Prevent neutropenia,

2. Increases neutrophil count, 3. prevent infection.Sargramostim (GM-CSF)

Amifostine1. Cisplatin induced

nephrotoxicity,2. Prevent radiation induced

xerostomia Oprelvekin (IL-11)

1. Prevent thrombocytopeniaThrombopoietin

Toxicity amelioration and supportive care

Drugs UseFolinic acid Methotrexate toxicity

Mesna Cyclophosphamide induced cystitis

Dexrazoxane Doxurubicine /Daunorubicine cardiotoxicity

Ondansetron, Dexamethaone, Lorazepam Vomiting

Allopurinol, Alkalization of urine Hyperuricaemia

Hydration , Bisphosphonates Hypercalcaemia

Toxicity amelioration and supportive care

The practice of cancer medicine has changed dramatically over the years from palliative → curative.e.g. Wilms tumour, Ewing sarcoma, Choriocarcinoma, Hodgkins disease, testicular cancer can be cured with chemotherapy.

Adjuvant chemotherapy and hormonal therapy can extend life and prevent disease recurrence following surgical resection of localized breast, colorectal, and lung cancers.

Current status and future trend of chemotherapy

Increasingly used in autoimmune diseases like rheumatoid arthritis (methotrexate and cyclophosphamide), Crohn's disease (6-mercaptopurine), organ transplantation (methotrexate and azathioprine) etc.

As part of multimodal treatment of locally advanced head and neck, breast, lung, and esophageal cancers, thereby allowing for more limited surgery and even cure in these formerly incurable cases

Toxicities of Cytotoxic drugs have become more manageable with the development of better supportive therapy like G-CSF, IL-11 to restore bone marrow function


Newer target molecules or monoclonal antibody are not likely to replace cytotoxics in the future. Rather, both will be used in combination.

e.g. For instance, monoclonal antibodies or small targeted molecules, used as single agents against solid tumors, produce low response rates and modest benefits; however, in combination with cytotoxics they are dramatically effective .


Bevacizumab plus irinotecan, fluorouracil, and leucovorin (IFL) for metastatic colorectal cancer.

The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo,

Molecular Testing to Select Patients for Chemotherapy

Molecular tests are increasingly employed to identify patients likely to benefit from treatment and those at highest risk of toxicity

Pre-treatment testing has become standard practice for following tumours 1. Estrogen receptor –breast cancer- transtuzumab

2. B cell non Hogdkins lymphoma- Rituximab (CD20)-

3. EGFR- for colorectal cancer- to use Cetuximab

Gene therapy : approaches for cancer management

• The future may see the development of agents which could induce differentiation in tumour cells, rendering them non-neoplastic.

• By inhibiting an abnormal oncogene product but not the normal equivalent.

• By using antisense oligonucleotides to inhibit translation of an abnormaloncogene messenger RNA.

• By introducing MDR-1 gene into bone marrow cells and rendering them less susceptible to myelosuppressant drugs.

Thank you

principles of chemotherapy

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