chemotherapy in cancers
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CHEMOTHERAPY IN CANCER
MODERATOR DR SHEHTAJ KHAN
COMODERATOR PROF S A SIDDIQUI
PRESENTED BY : DR.YASHVEER SINGH
DATED 07/09/2015
CHEMOTHERAPY
• Systemic chemotherapy is the main treatment available for disseminated malignant diseases.
• Progress in chemotherapy resulted in cure for several tumors.
• Chemotherapy usually require multiple cycles.
Paul Ehrlich 1854 - 1915
• Father of Chemotherapy
• Nobel Prize 1908
HISTORICAL PERSPECTIVE
• Nitrogen mustards were a product of the secret war gas programs in both world wars
• In WWII, an explosion at Bar Harbor exposed seamen to mustard gas - they developed severe marrow and lymphoid hypoplasia
• Led to the use of these agents to treat Hodgkins and non-Hodgkins lymphomas at Yale in 1943
1965, The era of combination chemotherapy begins.
# POMP(Methotrexate,Vincristine,6MP,Prednisolone) regimen was able to induce long term remission in children with ALL# MOPP(Nitrogen Mustard,Vincristine,Procarbazine,Prednisolone) regimen successfully cured HL and NHL used by
Vincent DeVita and collegues in 1970
Currently, nearly all successful cancer chemotherapy regimens use this paradigm of multiple drugs given simultaneously, called combination chemotherapy or polychemotherapy.
The concept adjuvent Chemotherapy came out in 1972 when Emil Frei and collegues demonstrated chemotherapy given after surgical removal of osteosarcoma improves the cure rate.
In 1992 FDA approved Paclitaxal which become the blockbuster of Oncology drugs in present scenario
2004, FDA approved Bevacizumab, the first clinically proven antiangiogenic agent for colon cancer.
ANTICANCER DRUGS
• Cell Cycle Specific Drugs:
• Antimetabolites• Bleomycin peptide antibiotics• Vinca alkaloids
• Cell Cycle non-Specific Drugs:
• Alkylating agents• Antibiotics (Dactinomycin)• Cisplatin
Chemotherapeutic Agents
Effective for high growth-fraction-malignancies, such as hematologic cancers.
Effective for both low-growth (solid tumors) and high growth fraction malignancies
1. Alkylating agents:
• Major interaction: Alkylation of DNA
• Binds to nucleophilic groups on various cell constituents. Including DNA
• Primary DNA alkylation site: N7 position of
guanine (other sites as well) • Major Toxicity: bone marrow suppression
Chemotherapeutic Agents
CyclophosphamaideCarboplatinCisplatinOxaliplatinDacarbazine
Chemotherapeutic Agents2. Antimetabolites:
•Structurally related to normal compounds that exist within the cell.
•Interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis.
•Their maximal cytotoxic effects are in S-phase and therefore are cell-cycle specific.
5-FluoroUracilGemcitabineCyterabineMethotrexate
3. Microtubule Inhibitors:
• These are plant-derived substances .
• Cause cytotoxicity by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules.
• Vinca alkaloids inhibit microtubule polymerization and increase microtubule disassembly. The mitotic spindle apparatus is disrupted, and segregation of chromosomes in metaphase is arrested.
Chemotherapeutic Agents
Vinca AlkaloidsVincristine VinblastineVinorelbine
TaxanesPaclitaxelDocetaxel
4. Antineoplastic Antibiotics:
• Interacts with DNA, leading to disruption of DNA function.
• Also Inhibit topoisomerases (I and II) and produce free radicals.
• Cell-cycle nonspecific.
• Eg: Actinomycin D binds with double-stranded DNA and blocks the action of RNA polymerase, which prevents DNA transcription.
Chemotherapeutic Agents
BleomycinDoxorubicinDactinomycinDaunorubicin
5. Hormonal Agents:
• Commonly involves the use of glucocorticoids.• Direct antitumor effects are related to their
lympholytic properties;.• Glucocorticoids can inhibit mitosis, RNA synthesis,
and protein synthesis in sensitive lymphocytes.
• Considered cell-cycle nonspecific . • Resistance to a given glucocorticoid may develop
rapidly and typically extends to other glucocorticoids.
Chemotherapeutic Agents
PrednisoneTamoxifenEstrogensFlutamideNilutamideBicalutamide
• Antibodies that are made in the lab rather than by a person's own immune system.
• Directed at specific targets and often have fewer adverse effects.
• Designed to recognise and find specific abnormal proteins on cancer cells.
• Each monoclonal antibody recognizes one particular protein.
Chemotherapeutic Agents
Rituximab TrastuzumabCetuximabBevacizumab
6. Monoclonal Antibodies:
ETIOLOGY OF CANCER
• Carcinogenesis
– A cancer, is thought to develop from a cell in which the normal mechanisms for control of growth and proliferation are altered.
– Current evidence supports the concept of carcinogenesis as a multistage process that is genetically regulated
ETIOLOGY OF CANCER
Genetic and Molecular Basis of Cancer
• Two major classes of genes are involved in carcinogenesis: oncogenes and tumor suppressor genes
GOMPERTZIAN GROWTH• Growth rates are exponential at early stages of development
and slower at later stages of development
Biological growth follows this characteristic curve.Biological growth follows this characteristic curve.
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
Log kill hypothesis• According to the log-kill hypothesis, chemotherapeutic
agents kill a constant fraction of cells (first order kinetics), rather than a specific number of cells, after each dose
1. Solid cancer tumors - generally have a low growth fraction thus respond poorly to chemotherapy & in most cases need to be removed by surgery
2. Disseminated cancers- generally have a high growth fraction & generally respond well to chemotherapy
Log kill hypothesis:
Clinical Implications of Fractional Cell Kill
Pre chemo asssesment
• HISTORY• EXAMINATION• ROUTINE INVESTIGATIONS
CBC
RFT BS SE
LFT
ECG
URINE (R/M)
GOALS
Goals of treatment must be clearly defined
1.cure vs. palliation
2.acceptable toxicity
3.quality of life
MODES 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 given before surgery to shrink tumor and increase chance of successful resection– Example – Adriamycin, ifosfamide for osteosarcoma
MODES OF CHEMOTHERAPY
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
PALLIATIVE OR CURATIVE CHEMOTHERAPY
– metastatic cancers
Routes of administration of chemotherapy
Intrathecal, intraventricular in meningeal metastases from leukemia, lymphoma, breast cancer etc.
Intrapericardial — in malignant pericardial effusions
Intraperitoneal in ovarian cancer, colorectal cancer, mesothelioma.
Intra-arterial in liver cancer Isolated limb perfusion in melanoma Intravenous most common routeOral
Repeated intravenousadministration may lead toperipheral thrombo-phlebitisand venous inaccessibility. Inorder to avoid repeated venu‑puncture, increased accessand permit patient mobilityparticularly in continuousinfusion regimes, Port-a-cathwas developed forimplantation under the skinand central venous access
There is a wide variation in sensitivity of various cancers to chemotherapy
HighHigh IntermediateIntermediate LowLow
LymphomaLymphoma BreastBreast Head and neckHead and neck
LeukemiaLeukemia ColonColon ProstateProstate
Small Cell Lung cancerSmall Cell Lung cancer Non-small cell lung Non-small cell lung cancercancer
GastricGastric
Testicular cancerTesticular cancer PancreaticPancreatic
CANCER CHEMOTHERAPY: PRINCIPLES
1. Conventional chemotherapy targets have been the cell cycle, microtubules and DNA.
2. Combination chemotherapy improves responses over single agent, but dose intensity must be maintained.
PRINCIPLES FOR COMBINATION CHEMOTHERAPEUTIC REGIMENS
• Rationale:– minimize resistanceminimize resistance
– maximize synergy/additivitymaximize synergy/additivity
– avoid drugs of overlapping toxicityavoid drugs of overlapping toxicity
– biochemical considerationsbiochemical considerations
• Rationale:
– biochemical considerations:• addition of an agent to overcome drug resistance (eg
MDR inhibitor & vinca alkaloid)• cooperative inhibition (eg leucovorin & 5FU)• inhibition of drug breakdown (eg DPD inhibitor & 5FU)• rescue host from toxic effects of drug (eg leucovorin
following high-dose methotrexate)
CANCER CHEMOTHERAPY: PRINCIPLES
More is better, to a point!
ABVD
FFP: 81%
MOPP/ABV
FFP: 67%
ABVD
FFP: 65%
MOPP
FFP: 63%
SINGLE
AGENT
FFP: 20%
Advanced Hodgkin’s Disease
Careful Sequencing is CriticalDocetaxel Doxorubicin
Doc Dox
40 mg/m2 50 mg/m2
Dox Doc
50 mg/m2 70 mg/m2
Itoh et al. Study of Sequence Switching of AdministrationClin. Cancer Res 6:4082-4090, 2000
PLANNING DRUG DOSES AND SCHEDULES
• Doses - based on body surface area
- differ between children and adults
- adjusted for people who are elderly, have poor
nutritional status, have already taken or taking other medications, have already received or are currently receiving radiation therapy, have low blood cell counts, or have liver or kidney diseases
PLANNING DRUG DOSES AND SCHEDULES
• Schedule (Cycles)
- A cycle = one dose followed by several days or weeks without treatment for normal tissues to recover from the drug’s side effects
The number of cycles = based on the type and stage of cancer, and side effects
HEMATOLOGICAL CONSIDERATIONS FOR DOSE
SCHEDULING• Lifespan
– Platelet - 7-10 days
– Red blood cell - 120 days
– Neutrophils - 6-12 hours
• Time from Stem Cell to Mature Neutrophil
– ~7-10 days
DECIDING ON TREATMENT INTERVALS
• As short as possible
• Recovery of bone marrow
– Supplies mature cells for 8-10 days
– Onset 9-10th days
– Lowest (nadir) 14-18th days
– Recovery by day 21-28.
• Usual schedule is q21-28 days.
COMPLICATION OF CHEMOTHERAPY
• Every chemotherapeutic will have some deleterious side effect on normal tissue .
• E.G; Myelosuppression,nausea&vomiting,
Stomatitis,and alopecia are the most frequently observed side effects.
SIDE EFFECTS OF CHEMOTHERAPY
Mucositis
Nausea/vomiting
Diarrhea
Cystitis
Sterility
Myalgia
Neuropathy
Alopecia
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Renal failure
Myelosuppression
Phlebitis
Distinctive Toxicities of Some Anticancer DrugsToxicity Drug(s)
Renal Cisplatin,* methotrexate
Hepatic 6-MP, busulfan, cyclophosphamide
Pulmonary Bleomycin,* busulfan, procarbazine
Cardiac Doxorubicin, daunorubicin
Neurologic Vincristine,* cisplatin, paclitaxel
Immunosuppressive Cyclophosphamide, cytarabine, dactinomycin, methotrexate
Other Cyclophosphamide (hemorrhagic cystitis); procarbazine (leukemia); asparaginase* (pancreatitis)
*Less Bone marrow suppression – “marrow sparing”
Prevention or Management of Drug Induced toxicities
• The toxicities of some anticancer drugs can be well anticipated and hence be prevented by giving proper medications
E.g.
1.mesna is given to prevent hemorrhagic cystitis by cyclophosphamide
2.Dexrazoxane, is used to reduce the risk of anthracycline-induced cardiomyopathy
CRITERIA USED TO DESCRIBE RESPONSE ARE
• Complete response (complete remission)is the disappearance of all detectable malignant disease.
• Partial response : is decrease by more than 50% in the sum of the products of the perpendicular diameters of all measurable lesions.
• Stable disease : no increase in size of any lesion nor the appearance of any new lesions.
• Progressive disease : means an increase by at least 25% in the sum of the products of the perpendicular diameters of measurable lesions or the appearance of new lesions.
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