Transcript Cancer Chemotherapy

Cancer
Chemotherapy
Dr. Khdair
Al-Rawaq
Cancer
• It is basically a disease of cells characterized
by the shift in the control mechanism that
govern cell proliferation and differentiation.
Special Characteristics of Cancer Cells
•Uncontrolled Proliferation
•Dedifferentiation and loss of function
•Invasiveness (Spreading)
•Metastasis (spread of cancer from its primary site to other places in the bo
Management of Cancer
• Surgical
• Radiation
• Chemotherapy
• The neoplastic cell burden is initially
reduced either by surgery and /or
radiation followed by chemotherapy or
combination therapy.
Chemotherapy
Types of Therapis:
• Adjuvant: Additional treatment after the primary
treatment to lower the risk that the cancer will
come back.
• Neo-Adjuvant therapy :Treatment as a first step to
shrink a tumor before the main treatment.
• Concurrent therapy: When two or more therapies
are given together, such as chemotherapy and
radiation.
CANCERS WITH ESTABLISHED OR PROBABLE
BENEFIT FROM ADJUVANT CHEMOTHERAPY
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Breast cancer
Colorectal cancer
Osteosarcoma
Wilms' tumor
Stage II-III gastric cancer
Stage II-III non-small cell lung cancer
Stage III melanoma
The rationale of neoadjuvant therapy is
• The immediate exposure of local and possible
distant disease to effective chemotherapy,
avoiding the delay introduced by surgery and
recovery;
• Immediate in vivo assessment of chemotherapy
responsiveness of the primary tumor, and
therefore, of possible nodal or distant
micrometastatic disease;
• Bulk reduction of local disease to allow for a
subsequent less anatomically destructive
surgical procedure. In responding patients,
chemotherapy is carried out in a flexible number
of cycles to the best or complete response,
followed by definitive surgery.
CANCERS WITH ESTABLISHED BENEFIT FROM
NEOADJUVANT CHEMOTHERAPY
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Locally advanced breast cancer
Larynx cancer
Esophageal cancer
Bladder cancer
Anal cancer
Osteosarcoma
Soft tissue sarcoma
CANCERS WITH ESTABLISHED BENEFIT FROM
Concurrent Chemoradiation
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Larynx cancer
Esophageal cancer
Cervical carcinoma
PNS Carcinoma
Rectal Carcinoma
Chemotherapy
• It is the treatment of disease by chemicals
especially by killing micro-organisms or
cancerous cells.
• In popular usage, it refers to antineoplastic
drugs used to treat cancer or the combination
of these drugs into a regimen.
Cell Cycle
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G0 : A resting phase,the cell has stopped dividing.
G1 : Cells increase in size.
S : DNA replication occurs.
G2 : Gap between DNA synthesis and mitosis, the
cell will continue to grow.
• M : Cell growth stops ,and cellular energy is
focused on the orderly division into two daughter
cells.
Principles of cancer chemotherapy
1. Goal of treatment:
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The ultimate goal of chemotherapy is cure. i.e.
long term disease free survival.
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If cure is not attainable, then the goal becomes
pallitation i.e. alleviation of symptoms and
avoidance of life-threatening toxicity.
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Principles of cancer chemotherapy
2. Indications for treatment:
• Chemotherapy is indicated when neoplasms are
disseminated (Spread over a large area)and are not
cured by surgery.
• Chemotherapy is also used as a supplimental
treatment to attack micrometastasis following
surgery and radiation treatment.
CANCERS POTENTIALLY CURABLE
WITH CHEMOTHERAPY ALONE
1. Choriocarcinoma
2. Hodgkin's lymphoma
3. Non-Hodgkin's lymphoma (some
types)
4. Testicular cancer
5. Acute lymphoid leukemia
6. Acute myelogenous leukemia
7. Ovarian cancer
8. Small cell lung cancer
Principles of cancer chemotherapy
3. Tumor susceptibility and growth
cycle:
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Rapidly dividing cells are generally more sensitive
to anti cancer drugs. therefore the fraction of
tumor cells that are in replicative stage of their
cycle are most susceptible.
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Non proliferating cells (those are in Go phase)
usually survive the toxic effects of many of these
agents.
Principles of cancer chemotherapy
4. Cell cycle specificity of drugs:
• The normal and tumor cells differ in the number of
cells that are in various stages of the cycle.
• Chemotherapeutic agents that are effective only
against replicating cells are called cell cycle specific
(CCS) drugs.
• Others are said to be cell cycle non specific (CCNS)
drugs.
• The non specific drugs have more toxicity in
cycling cells and are useful against tumors that
have low percentage of replicating cells.
Principles of cancer chemotherapy
5. Tumor growth rate:
• The growth rate of most solid tumors in vivo is
initially rapid, but growth rate decreases as tumor
size increases. Because of unavailability of nutrients
and oxygen.
• By reducing the tumor burden through surgery or
radiation promotes the remaining cells growth
into active proliferation and increases their
susceptibility to chemotherapeutic agents.
Principles of cancer chemotherapy
6. Treatment regimens and scheduling:
•Drugs are administered on the bases of body surface
area.
•Destruction of cancer cell by chemotherapeutic agent
follows first order kinetics , i.e. given dose destroys
constant fraction of cells.(Log kill)
•Combine drug therapy is more successful than single
drug treatment.
•In combine therapy the drugs must have different
toxicities, Mechanism of action.
Chemotherapy scheduling and regimens:
The principles of choosing combinations of
chemotherapy are as follow:
• Each drug is active against the tumour as a single
agent.
• There are no clinically important drug interactions
between the agents.
• Combinations should avoid drugs of the same class
or those with similar modes of action.
• The drugs should have different dose-limiting
toxicities
•Drugs should have different mechanisms or patterns
of resistance
Principles of cancer chemotherapy
Effects of various treatments on the cancer cell burden:
Principles of cancer chemotherapy
Problems associated with chemotherapy:
• Resistance:
a) Inherent
b) Acquired
• Toxicities:
Effects on normal rapidly proliferating cells i.e.
Buccal mucosa, Bone marrow, GI mucosa, Hair.
Side Effects
Bone marrow suppression
• Anemia
• Neutropenia
• Thrombocytopenia
• Effects on GIT
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Nausea & Vomiting
Stomatitis & mucositis
Dysphagia
Constipation
Diarrhea
Side Effects
• Effects on skin:
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Skin dryness
Photosensetivity
Skin pigmentation
Hair loss
• Effects on reproductive system:
• Azospermia
• Amenorrhea
Side
Effects
• Effects on Cardiovascular System:
• Heart failure
• cardiomyopathy
• IHD
• Effects on CN system:
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Periphral neuropathy
Fit
Parasthesia
Loss of hearing
Side
Effects
• Effects on Respiratory System:
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Respiratory failure
Pulminary fibrosis
RDS
Chemical pneumonitis
• Effects on GU system:
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nephropathy
Haemoragic cystitis
Renal papillary necrosis
Renal fialure
Side
Effects
• Others
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Second Malignancies After Chemotherapy
Hepatic toxicity
Cataract
Electrolites imbalance
Teratogenicity in pregnancy
Hypersensetivity reactions
extravasation
ROUTES OF ADMINISTRATION
• Intravenous
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Most chemotherapeutic agents are available only in an
intravenous preparation, requiring venous access
• Oral
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A number of agents are available in oral form, making
intravenous access unnecessary.
• Intraperitoneal Therapy
• Intrathecal
• Leptomeningeal seeding and/or free tumor cells in the
cerebrospinal fluid (CSF) most commonly occur with acute
lymphocytic, and myelogenous leukemia, lymphomas, and
carcinomas
ROUTES OF ADMINISTRATION
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Intraventricular Therapy
Intra-arterial Therapy
primary and metastatic to the liver
Intravesical therapy
BCG for T1 Ca Bladder
Wafers eluting BCNU
surgically implanted into resection sites have been
used as part of multimodality therapy for gliomas
• Intrapleurally
• for sclerosis of malignant pleural effusions
Chemotherapeutic Agents
• Cell Cycle Specific Drugs:
• Antimetabolites
• Bleomycin peptide antibiotics
• Vinca alkaloids
Effective for high
growth-fractionmalignancies,
such as
hematologic
cancers.
• Cell Cycle non-Specific Drugs:
• Alkylating agents
• Antibiotics (Dactinomycin)
• Cisplatin
Effective for both
low-growth (solid
tumors) and high
growth fraction
malignancies
Drugs according to cell-cycle effects
Cell cycle Agents
Cell cycle nonspecific Nitrogen mustards, aziridines,
nitrosoureas, alkyl alkane
sulfonates, nonclassic alkylating agents,
anthracyclines,
actinomycins, anthracenediones
Cell cycle specific
S Bleomycin, antimetabolites, camptothecins,
epipodophyllotoxins
G2 Bleomycin, epipodophyllotoxins
M Vinca alkaloids, taxanes
Chemotherapeutic Agents
Chemotherapeutic Agents
1. Alkylating agents:
Cyclophosphamaide
Carboplatin
Cisplatin
Oxaliplatin
Dacarbazine
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Major interaction: Alkylation of DNA
Binds to nucleophilic groups on various cell
constituents. Including DNA
These drugs react with carboxyl, sulfhydryl, amino,
hydroxyl, and phosphate groups of cellular
constituents.
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Primary DNA alkylation site: N7 position of
guanine (other sites as well)
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Major Toxicity: bone marrow suppression
Chemotherapeutic Agents
2. Antimetabolites:
5-Fluoro Uracil
Gemcitabine
Cyterabine
Methotrexate
•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.
Chemotherapeutic Agents
Vinca Alkaloids
Vincristine
Vinblastine
Vinorelbine
Taxanes
Paclitaxel
Docetaxel
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
4. Antineoplastic Antibiotics:
Bleomycin
Doxorubicin
Dactinomycin
Daunorubicin
• 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
Prednisolone
Tamoxifen
Estrogens
Flutamide
Nilutamide
Bicalutamide
5. Hormonal Agents:
• Commonly involves the use of glucocorticoids.
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Direct antitumor effects are related to their
lympholytic properties;.
• Glucocorticoids can inhibit mitosis, RNA synthesis,
and protein synthesis in sensitive lymphocytes.
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Considered cell-cycle nonspecific .
• Resistance to a given glucocorticoid may develop
rapidly and typically extends to other
glucocorticoids.
Chemotherapeutic Agents
Rituximab
Trastuzumab
Cetuximab
Bevacizumab
Interleukin
Interferone
imatinibe
6. Targeted therapy:
• Biologic response modifiers (e.g., interferon ‫خ‬±
and interleukin 2,) antibodies, and targeted
agents of several types. In addition, gene
therapy and antisense approaches
• Antibodies or molecules 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
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Rituximab
Trastuzumab
Cetuximab
Bevacizumab
Three types of monoclonal A-bodies:
1. Trigger the immune system to attack and kill cancer
cells. E.g. Rituximab (Mabthera)
2. Stop cancer cells from taking up proteins
E.g. Trastuzumab (Herceptin).
3. Carry cancer drugs or radiation to directly to cancer
cells These are called conjugated MABs.
E.g. Ibritumomab (Zevalin)
CANCER CHEMOTHERAPEUTIC DRUGS WITH
RADIATION SENSITIZER PROPERTIES
• 5-Fluorouracil
• Gemcitabine
• Cisplatin, carboplatin
• Paclitaxel
• CPT-11, topotecan
• 5-bromodeoxyuridine, 5iododeoxyuridine