CANCER MANAGEMENT BY CHEMOTHERAPY

Cancer management by chemotherapy

Definition

Chemotherpeutics are drugs that are used to treat cancer that inhibit the mechanisms of cell proliferation. They are therefore toxic to normally proliferating cells (ie bone marrow gastro intestinal eipithelium hair follicles

they may be used as primary neoadjuvant or adjuvant therapies

They can be

Cycle-specific: effective throughout the cell cycle

Phase-specific: effective during part of the cell cycle

, tumors susceptibility depends on the concentration of drug delivered, on cell sensitivity, cycling of tumour. Drugs are less effective in large solid tumours because of

• Fall in the growth fraction

• Poor drug penetrance into the centre


• Intrinsic drug resistance of sub-clones

What are chemotherapeutic drugs? chemotherapeutic or anticancer drugs include the following agents

  Alkylating agents

which divided into three main subgroups

Classic Alkylating agents

Nitrosoureas 

  DNA agents
miscellaneous

  Antitumour Antibiotic

  Antimetabolites agents

  Plant Alkaloids agents which subdivided into three main subgroups
Vinca alkaloids ,Epipodophyllotoxins ,Taxanes

  Miscellaneous agents

Topoisomerase inhibitor

Alkaylating agents

Classic alkylating agents like
Busulfan chlorambucil Cyclophosphamide Ifosfamide

Mechlorethamine as nitrogen mustard

Melphalan

MitomycinC

Trietbylene thiophosphoramide as thiotepa

Nitrosoure

Streplozocin Carmustine (BCNU) Lomustine (CCNU) Semustine(Me CCNU

Miscellaneous DNA·binding agents

Carboplatin Cisplatin Dacarbazine (DTICH ) examethylmelamine Procarbazine

Antitumor Antibiotics

Antibiotics

Bleomycin Dactinomycin (actinomycin D ) Daunorubicin Doxorubicin Plicamycin (mithramycin ) ldarubicin

Antimetabolities

folat analogues as Methotrexate

Purine analogues

Azathioprine Mercaptopurine Thioguanine Cladribine (2 Cd) Fludarabine Pentostati

Pyrimidine analogues

Capocitabine Cytarabine Floxuridine Gemcitabine

Ribonucleotide reductase inhibitors as Hydroxyurea

Plant Alkaloids

Vinca alkaloids like VanblastineVincristine Vindesine Vinorelbine

Epipodophyllotoxins like Etoposide Teniposide

Taxanes like Paclitaxel Docetaxel

Miscellaneous Agents like Asparaginase Estrumustine Milotane

Topoisomerase inhibitors

Indications for chemotherapy

• Primary treatment eg lymphoma

• Neo-adjunctive treatment to decrease tumour bulk before surgery

• Adjunctive treatment for prevention of recurrence

Advanced disease and palliation

• Maintenance treatment eg leukaemia

Important treatment in

• Haematological malignancy

• Germ cell tumours

• Ovarian cancer

• Small cell lung cancer

• Breast cancer locally advanced

Important neo-adjunct in

• Colorectal liver metastasis

Important adjunct in

• Colorectal cancer primaries Dukes' C stage

• Breast cancer

Methods of delivering chemotherapy

What are the Methods of delivery for chemotherapeutic agents

Intravenous
Oral
  Intra-arterial (eg HCC via the hepatic artery
Intramuscular
 Intrathecal
Intracavitary (eg intravesicular forTCC bladder) Intralesional

Doses are based on body surface area and are affected by hepatic metabolism renal excretion

  Efficacy of treatment for different tumours may be Improved by

Pulsed treatment

Combinations of drugs with different modes of action (synergy, reduces drug resistance) Alternating cycles and provides greater efficacy more than single agent therapy by three mechansims

it provides maximum cell kill within the range of toxicity for each drug that can be tolerated by the host

  it offers a broader range of caverage if resistant cell lines in a heterogeneous population

it prevents or delay the emergence of drug resistent cell lines , drugs with different mechanisms of action are combined to allow for additive or synergistic effects , combining cell cycle specific and cell cycle non specific agents may be especially advantageous

drugs with differing dose limiting toxic effects are combined to allow for each drug to be given at therapeutic doses , the treatment free interval between cycles is kept at the shortest possible time that allow for recovery of the most sensitive normal tissue
High dose treatment with subsequent replacement of normal tissues eg bone marrow transplant

Scheduling with continuous low dose

What are mode of actions indications and side effects of chemotherapeutic therapeutic agents

Classical alkylating agents

mode of action

. Act by forming covalent bonds with nucleic acids, proteins, nucleotides and amino acids
and so inactivate the enzymes involved in DNA production and protein synthesis or by direct damage to DNA the damage of DNA prevents cell division and if severe enough leads to apoptosis
they are cell cycle non specific agents meaning that they are able to kill cells in any phase of the cell cycle

Side effects and indications

classical alkylating agents

mustargen

indication Hodgkin's disease

NonHodgkin's lymphoma Chronic myelocytic leukaemia (CMl

chronic lymphatic leukaemia (Cl.L

side effects

Very toxic so rarely used
Vomiting

Bone-marrow depression

Cyclophosphamide

indications

many cancers including lymphoma breast lung ovary

side effects

Bone-marrow depression

Nausea and vomiting (mild unless high dose

Haemorrhagic cystitis (high doses) Pulmonary interstitial fibrosis

Chlorambucil

Chronic lymphatic leukaemia CLL

Non-Hodgkin's I.ymphoma (low grade ovary

side effects

Bone-marrow suppression Nausea, vomiting, diarrhoea Jaundice, pulmonary fibrosis

Melphalan

multiple myeloma

side effects

Bone-marrow depression Nausea and vomiting Diarrhoea Pulmonary fibrosis rash

Non-classical alkylating agents

mode of action

Act by causing cross-linkage of DNA strands

Cisplatin (C-DDP) (toxic to cycling and resting cells

indications

Ovary cancer Bladder cancer Lung cancer Oesophageal cancer Stomach cancerTestis cancerHead and neck cancer

side effects

Renal failure Electrolyte disturbance hypomahnesianas Peripheral neuropathy

Bone marrow depression

Ototoxicity

Carboplatin

Indications

Ovary cancer Lung cancer Seminoma

side effects

Less toxic analogue, but more marrow suppression

Anti-metabolites agents

mode of action

they are cell cycle specific agents that have their major activity during the S phase of the cell cycle they are structural analogues of naturally occurring metabolities involved in DNA and RNA synthesis therefore they
Act by interfering with purine or pyrimidine synthesis and hence interfere with DNA synthesis

Methotrexate (S-phase specific

Indications

Acute lymphocytic leukaemia (ALL) Breast cancer lung cancer

Side effects

Bone marrow depression

GI symptoms Stomatitis Renal failure Hepatic failure

5Fluorouracil (5-FU) (toxic to resting and cycling cells

Indications

Colon Breast stomach Oesophagus pancrease

side effects

Bone marrow depression

GI symptoms

Stomach Alopecia

Oesophagus Rash

Pancreas Palmar-plantar syndrome and cardiotoxicity with high-dose infusional treatments

Gemcitabine

indications

pancreas lung cancers

side effects

Nausea Flu like symptoms Oedema

Antitumour Antibiotics

mode of actions

they are the products of fermentation of microbial organisms and they are also cell cycle non specific
Act by interclating between base pairs and prevent RNA production and interfering with DNA synthesis There are several groups wirth differeing actions

Anthracycline antibiotics

mode of actions complex actions (not fully understood

Intercalate into DNA strands Bind membranes

Chelate metals - producing cytotoxic compounds Alkylating action.Produce free radicals

Doxorubicin

indications

Acute leukaemia lymphoma breast cancer small cell lung cancer sarcoma bladder cancer ovary cancer

wilm,s tumour neuroblastmoa

side effects

Bone marrow depression Nausea and vomiting Alopecia Cardiac dose dependent congestive heart failure

Epirubicin

indications

breast cancer

side effects

Doxorubicin analogue with less cardiac toxicity

Non anthracycline antibiotics

Mitozantrone

 indications in breast cancer

side effects

Bone marrow depression congestive heart failure Alopecia nausea and vomiting

Bleomycin

indications Lymphoma testicular cancer head and neck cancer

side effects

Bone marrow sparing pneumonitis and pulmonary fibrosis rash fever

Mitomycin C

indications

Breast cancer bladder cancer( intravesical) pancreatic cancer gastric cancer

side effects

Bone marrow depression renal failure (haemolytic - ureamic syndrome with tamoxifen ) stomatitis rash alopecia nausea and vomiting

Vinca alkaloids

mode of actions
plant alkaloids are derived from plants such as the periwinkle plant , vinca rosa eg vincristine or vina alkaloid or the root of mandrake podophyllum peltatum eg etoposide
Act by inhibiting mitosis by preventing or impaired mitotic spindle formation in the M - phase specific bythat blocks microtubule polymerization binding tubulin in the S phase we must remember that intrathecal administration of vinca alkaloids is fatal

Vincristine

indications

Acute leukaemia lymphoma neuroblastoma wilm,s tumour rhabdomosarcoma

side effects Highly vesicant neuropathy bronchospasm

Vinblastin

indications

testis hodgkins lymphoma choriocarcinoma

side effects

Highly vesicant bone marrow depression bronchospasm abdominal pain and ileus mimic acute abdomen
peripheral neuropathy

Vinorebline

indications

breast cancer lung cancer

side effects

Highly vesicant bone marrow depression abdominal pain and constipation local phlebitis

Taxanes

mode of action

Act by inhibiting mitosis through stabilisation of microtubules

Docetaxel

indications

breast cancer ovarian cancer

side effects

Allergic reaction severe neutropenia alopecia peripheral oedema myalgia peripheral neuropathy

Paclitaxel

indications

Ovary cancer breast cancer lung cancer

side effects

Anaphylaxis severe neutropenia sudden total alopecia myalgia peripheral neuropathy

Topoisomerase inhibitors

Irinotecan

Colorectal cancer

Side effects

Cholinergic syndrome

Profuse diarrhoea may be life threatening

What are side effects of chemotherapy in general

Acute complications

• Nausea and vomiting

• Diarrhoea or constipation

• Mucositis

• Alopecia

• BM suppression

• Cystitis

• Phlebitis

• Renal and cardiac toxicity

Chronic complications

• Carcinogenesis especially alkylating agents which cause leukaemias.Risk proportional to dose

• Pulmonary fibrosis

• Infertility

What are the mechanisms of drug resistance in tumours

Several tumour factors influence tumour

 Cell kill tumours are heterogenous and the tumours cells are genetically unstable and tend to mutate to form different cell clones this has been used as an argument for giving chemotherapy as soon as possible in treatment in order to reduce the likelihood of resistant clones emerging tumour size is another important variable the greater the tumoue size the larger the heterogencity and according to the Gompertizian model cancer cells initially grow rapidly then the growth slows down owing to hypoxia and decreased nutrient supply because of the larger proportion of cells dividing smaller tumours may be more chemosensitive

Multiple mechanisms of chemotherapy resistance have been identified

 Cells may exhibit reduced sensitivity to drugs by virtue of their cell-cycle distribution

For example, cells in Go phase are resistant to drugs active in the S phase

This phe­nomenon of kinetic resistance is usually temporary, and if the drug level can be maintained, all cells will eventually pass through the vulnerable phase of the cell cycle

 Altemativally, tumor cells may exhibit pharmacologic resistance, when the failure to kill cells is due to insufficient drug concentration

This may occur when tumor cells are located in sites where effective drug concentrations are difficult to achieve (such as the central nervous system) or can be due to enhanced metabolism of the drug after its administration decreased conversion of the drug to active fonn, or a decrease in the intracellular drug level due to increased removal of the drug from the cell associated with enhanced expression of P-glycoprotcin

The protein product of the multidrug resistance gene I (MDR· 1

Other mechanisms of resistance include decreased affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect,
For drug- sensitive cancers, another factor limiting optimum killing is proper dosing

 A dose reduction of 20% because of drug toxicity can lead to a decline in the cure rate by as much as 50%

On the other hand, a twofold increase in dose can be associated with a tenfold  increase in tumor cell kill

 

General mechanism of Drug Resistance

Cellular and biochemical mechansim

Decreased drug accumulation by

 • Reduced drug uptake

increased drug effulx

altered intracelluar trafficking of drug

Altered gene expression by

DNA mutation amplification or deletion

altered transcrition posttranscription processing or translation

• Increased concentrations of target enzymes to minimise the effects of enzym

• DNA repair mechanisms eg melanoma cells

• Mutations coding for cell pumps which extrude the drug

• Salvage pathways

• Drug inactivation

tags:chemotherapy,cancer,management