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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.
Chemotherapy : Historical perspective
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.
Chemotherapy : Historical perspective
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.
Chemotherapy : Historical perspective
• 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.
Chemotherapy : Historical perspective
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
CLASS DRUGS MAJOR USES
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
CLASS DRUGS MAJOR USES
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
CLASS DRUGS MAJOR USES
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
Miscellaneous agents
CLASS DRUGS MAJOR USES
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
Miscellaneous agents
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
Current status and future trend of chemotherapy
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 .
Current status and future trend of chemotherapy
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