[13] Chemotherapy Flashcards

1
Q

What does chemotherapy involve?

A

The use of pharmacological agents to kill tumour cells

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2
Q

What can chemotherapy be effective in treating?

A

Both primary tumours and metastatic spread

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3
Q

How does chemotherapy work?

A

It acts at different stages of the cell cycle, and exerts its effects primary by 3 different mechanisms;

  • Altering the chemistry of nucleic acids
  • Interfering with DNA or RNA synthesis
  • Disrupting mechanisms of cell devision
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4
Q

Are chemotherapy agents selective?

A

Most of the common agents act in a non-selective manner

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5
Q

What is meant by most chemotherapy agents acting in a non-selective manner?

A

They not only damage cancer cells, but affect normal dividing cells

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6
Q

What normal dividing cells are particularly affected by chemotherapy?

A
  • Hair follicles
  • Bone marrow
  • Gastrointestinal mucosa
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7
Q

What is the result of chemotherapy agents acting in a non-selective manner?

A

It produces side effects that limit the dose that can be administered and the recovery time before the next dose can be given

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8
Q

How is most chemotherapy given?

A

As a combination of drugs administered IV on an intermittent basis

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9
Q

On average, how often is an individual cycle of chemotherapy repeated?

A

Every 21-28 days

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10
Q

How many cycles does a typical course of chemotherapy consist of?

A

6

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11
Q

What is the purpose of intermittent dosing in chemotherapy?

A

Malignant cells have less capacity for repair than normal cells, and intermittent dosing exploits the fact that tumour cells recover from cytotoxic damage more slowly than normal cell populations

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12
Q

What does each sequential treatment cycle of chemotherapy allow?

A

Normal stems cells time to recover

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13
Q

What is the chemotherapy drug dose usually calculated from?

A

Surface area of patient, based on height and weight

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14
Q

What is pharmacodynamics?

A

The study of the effect that drugs have in the body

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15
Q

Why is pharmacodynamics significant in chemotherapy?

A

In terms of dose-limiting toxicity, which can be used to determine the maximum possible dose in an individual patient

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16
Q

What is pharmacokinetics?

A

The study of the effects that the body has on the drug

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17
Q

What can pharmacokinetics be modified by?

A
  • Renal and hepatic function

- Drugs clearance from the circulation

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18
Q

What is the result of the potential for modification of pharmacokinetics with chemotherapy?

A

Careful monitoring of the patient’s biochemistry, renal, liver, and bone marrow function is essential during chemotherapy treatment

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19
Q

What is the downside of chemotherapy?

A

It is highly toxic with the potential for life-threatening side effects

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20
Q

How is the potential for life threatening side effects of chemotherapy reduced?

A
  • Requires supervision from specialists

- Patients should have careful assessment prior to commencement of treatment, and prior to each cycle

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21
Q

What is a reliable predictor to tolerance of chemotherapy treatment?

A

Patient fitness

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22
Q

What is the result of poor fitness when having chemotherapy?

A
  • Will not tolerate chemotherapy as well

- Increased risk of adverse effects

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23
Q

How is the effects of poor fitness in chemotherapy patients combatted?

A

It is important to assess the patient’s performance status to determine patient suitability for chemotherapy and appropriate dosing of treatments

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24
Q

What is growth fraction?

A

The percentage of cells in a tumour mass that are actively dividing

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25
Q

Give an example of a cancer with a high growth fraction

A

Burkett’s lymphoma

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26
Q

What is the growth fraction in Burkett’s lymphoma?

A

50% (doubling time of 24 hours)

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27
Q

Give an example of a cancer with a low growth fraction?

A

Some adenocarcinomas

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28
Q

What is the growth fraction in some adenocarcinomas?

A

Immeasurable (doubling time of up to 200 days)

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29
Q

What can chemotherapy agents be divided into?

A
  • Cell cycle independent

- Cell cycle dependent

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30
Q

What can chemotherapy agents that are cell cycle dependent be further subdivided into?

A
  • Phase non-specific

- Phase specific

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31
Q

What is meant by a chemotherapy agent being phase non-specific?

A

They are equally active against cells in all phases of the cell cycle except G0

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32
Q

What is meant by a chemotherapy agent being phase specific?

A

It is only active against cells in one phase of the cycle

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33
Q

How can if a chemotherapy is phase specific or phase non-specific be utilised clinically?

A

These features can be used to design drug regimen combinations and schedules that take advantage of individual drug characteristics

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34
Q

Where kind of cells does the normal process of tissue renewal involve?

A

Both actively proliferating and quiescent stem cells

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35
Q

What is true of the quiescent stem cells that are involved in normal tissue renewal?

A

They are in the G0 phase of the cell cycle

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36
Q

Why is it significant that quiescent stem cells involved in normal tissue renewal are in the G0 phase of the cell cycle?

A

Because most anti-cancer agents are not active against these cells

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37
Q

What is a single clonogenic malignant cell capable of?

A

Multiplying and ultimately killing the host

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38
Q

What does the fact that a single clonogenic malignant cell is capable of multiplying and ultimately killing the host imply?

A

That cure depends on total cell eradication of all malignant cells

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39
Q

Is it always the case that cure depends on total cell eradication in cancer?

A

No

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40
Q

Why is it not the always case that cure depends on total cell eradication of all malignant cells?

A

There is evidence that in some cancers, there is a host response that may augment chemotherapeutic cancer kill

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41
Q

What is the simplest model of tumour growth?

A

Exponential

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42
Q

When is the exponential model of tumour growth true?

A

Only for microscopic lesions with fewer than 10^9 tumour cells

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43
Q

What does the growth curve of a clinically palpable cancer follow?

A

A Gompertzian function

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44
Q

What is a Gompertzian function?

A

When the rate of growth slows as the tumour increases in size

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45
Q

Why does the rate of growth of a tumour slow as it increases in size?

A

Due to limits imposed by the tumour micro-environment

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46
Q

What is the result of larger volume cancers having smaller growth fractions?

A

They may be inherently less sensitive to phase-specific agents

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47
Q

What is the rationale for adjuvant chemotherapy?

A

Small or micrometases may be more sensitive to chemotherapy

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48
Q

What is the dose response for most chemotherapies?

A

Steep dose response

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49
Q

What is meant by a steep dose response to chemotherapy?

A

There is a greater cell kill demonstrated at higher drug doses

50
Q

Other than dose, what other factors might influence cell kill?

A
  • Dose intensity

- Density

51
Q

Is resistance to chemotherapy innate or acquired during treatment?

A

Can be either

52
Q

What features make it more likely that drug-resistance cells will be present?

A
  • Larger tumour mass

- Moe doublings occurring before treatment

53
Q

When can multi-drug resistance be observed in cancer cells?

A

After exposure to a single drug

54
Q

What are cancer cells that are multi-drug resistant after being exposed to a single drug usually susceptible to?

A
  • Alkylating agents

- Anti-metabolites

55
Q

What is multi-drug resistance associated with?

A

Increased expression of the membrane protein p-glycoprotein

56
Q

What is the function of p-glycoprotein?

A

Functions as an active pump transporting toxic alkaloids out of the cell

57
Q

How is the risk of resistance to chemotherapy minimised?

A

Anti-cancer drugs are often combined

58
Q

What are the different classes of chemotherapy?

A
  • Alkylating agents
  • Intercalating agents
  • Topisomerase I/II inhibitors
  • Antimetabolites
  • Tubulin binders
59
Q

What can alkylating agents be subdivided into?

A
  • Bifunctional alkylating agents

- Monofunctional alkylating agents

60
Q

Give an example of a bifunctional alkylating agent

A

Cyclophosphamide

61
Q

Give an example of a monofunctional alkylating agent

A

Dacarbazine

62
Q

How do bifunctional alkylating agents work?

A

By transferring an alkyl group to the purine bases of DNA, which forms covalent bonds between two different bases, resulting in interstrand or intrastrand cross links, therefore inhibiting DNA synthesis

63
Q

What are the purine bases of DNA?

A
  • Adenine

- Guanine

64
Q

What is the result of bifunctional alkylating agents acting by inhibiting DNA synthesis?

A

They act during the S phase of the cell cycle

65
Q

Can bifunctional alkylating agents act on more than one base?

A

Yes

66
Q

Are bifunctional alkylating agents more or less cytotoxic than monofunctional alkylating agents?

A

More

67
Q

How do monofunctional alkylating agents work?

A

They cannot form cross-links, but form adducts. This inhibits DNA synthesis

68
Q

What is the result of monofunctional alkylating agents acting by inhibiting DNA synthesis?

A

They act during the S phase of the cell cycle

69
Q

What is the disadvantage of monofunctional alkylating agents compared to bifunctional?

A

They are more mutagenic and carcinogenic than bifunctional

70
Q

What can intercalating agents be subdivided into?

A
  • Platinum compounds
  • Anthracyclines
  • Anthraquinones
71
Q

Give 3 examples of platinum compounds?

A
  • Cisplatin
  • Carboplatin
  • Oxaliplatin
72
Q

How do platinum compounds act as chemotherapy agents?

A

They intercalate and disrupt the steric integrity of the DNA double helix, but also form intrastrand adducts like those formed by alkylating agents

73
Q

Give 3 examples of anthracyclines

A
  • Doxorubicin
  • Danorubicin
  • Epirubicin
74
Q

How do anthracyclines work?

A

They intercalate into the DNA major groove between base pairs of the DNA double helix. This disrupts the steric integrity of the DNA helix, and blocks DNA replication

75
Q

Is anthracyclines action base specific?

A

No

76
Q

Why is anthracyclines action not base specific?

A

Because it’s action is non-covalent

77
Q

What is the main target for anthracyclines?

A

The enzyme topoisomerase II

78
Q

Give an example of a topoisomerase I inhibitor

A

Topetecan

79
Q

Give an example of a topoisomerase II inhibitor?

A

Etoposide

80
Q

What do topoisomerase enzymes do?

A

Prevent DNA strands from becoming tangled

81
Q

How do topoisomerase enzymes prevent DNA strands from becoming tangled?

A

By cutting DNA and allowing it to wind or unwind

82
Q

What does topoisomerase I do?

A

Breaks single-stranded DNA and relieves torsion

83
Q

In what phase of the cell cycle to topoisomerase I inhibitors act?

A

S phase

84
Q

What do topoisomerase I inhibitors do?

A

They precent the re-ligation step of the nicking-closing reaction, trapping topoisomerase I in a covalent complex with the DNA

85
Q

What does topoisomerase II do?

A

It breaks both strands of DNA, and allows the other strange to pass through the re-ligate

86
Q

What do topoisomerase II inhibitors cause?

A

Double-stranded DNA breaks

87
Q

What can anti-metabolites be divided into?

A
  • Anti-folates
  • Pyrimidine analogues
  • Purine analogues
88
Q

What are antimetabolites structurally related to?

A

Natural compounds

89
Q

What do antimetabolites do?

A

Inhibit the metabolism of compounds necessary for DNA, RNA, or protein synthesis

90
Q

When in the cell cycle are most anti-metabolites active?

A

During the S phase

91
Q

Give two examples of anti-folates

A
  • Methotrexate

- Ralitrexed

92
Q

Give 3 examples of pyramidine analogues

A
  • 5-FU
  • Gemcitabine
  • Cytosine arabinoside
93
Q

Give 2 examples of purine analogues

A
  • 6-metacaptopurine

- 6-thioguanine

94
Q

What can tubulin binders be subdivided into?

A
  • Vinca alkaloids

- Taxanes

95
Q

Give 2 examples of vinca alkaloids

A
  • Vincristine

- Vinblastine

96
Q

How do vinca alkaloids work?

A

By binding to the tubulin dimer and preventing the assembly of microtubule filaments, therefore interfering with the functinon of the mitotic spindles and preventing cell division during the M phase of the cell cycle

97
Q

Give 2 examples of taxanes

A
  • Paclitaxel

- Docetaxel

98
Q

How do taxanes work?

A

Binding to tubulin as a polymerised molecule, and preventing the disassembly back into dimeric form

99
Q

What stage of the cell cycle do taxanes act in?

A

M phase

100
Q

Give 3 examples of antibodies used in the treatment of cancer

A
  • Rituximab
  • Bevaxizumab
  • Trastuzumab
101
Q

How do antibodies work in cancer?

A

By binding to cell surface proteins expressed in target tissue. High-affinity binding prevents the normal ligand from attaching, and therefore inhibits the normal activation of the receptor. This diminishes the intracellular signals that drive cellular processes, such as angiogenesis and cell growth

102
Q

Give 3 examples of kinase inhibitors used in chemotherapy

A
  • Imatinib
  • Erlotinib
  • Lapatinub
103
Q

How do kinase inhibitors work in chemotherapy?

A

They are small molecules which bind to the intracellular domains of a cell surface receptor and prevent activation of the intracellular signals that drive cellular processes

104
Q

What can the adverse effects of chemotherapy be classified based on?

A

The time of onset

105
Q

When are early effects of chemotherapy seen?

A

During treatment, or within the first few weeks of its completion

106
Q

When do intermediate effects of chemotherapy occur?

A

Several weeks to months after completion of treatment

107
Q

What are the late effects of chemotherapy?

A

Months to years after treatment

108
Q

Are late effects of chemotherapy common?

A

No, they are rare

109
Q

What are the categories of side effects of chemotherapy?

A
  • Cardiovascular
  • Respiratory
  • Gastrointestinal
  • Neurological
  • Urogenital
  • MSK
  • Skin
  • Other
110
Q

What are the cardiovascular side effects of chemotherapy?

A
  • Cardiomyopathy
  • Acute coronary syndrome
  • Arrhythmias
  • Heart failure
111
Q

What are the respiratory side effects of chemotherapy?

A
  • Pulmonary fibrosis

- Pleuritic pain

112
Q

What are the gastrointestinal side effects of chemotherapy?

A
  • Nausea and vomiting
  • Gastritis and oesophagitis
  • Constipation
  • Diarrhoea
  • Stomatitis
  • Hepatic dysfunction
113
Q

What are the neurological side effects of chemotherapy?

A
  • Focal neurological signs
  • Ototoxicity
  • Sensory neuropathy
  • Motor neuropathy
  • Memory changes
  • Personality changes
114
Q

What are the urogenital side effects of chemotherapy?

A
  • Cystitis
  • Nephropathy
  • Premature gonadal failure
  • Amenorrhoea
115
Q

What are the MSK side effects of chemotherapy?

A
  • Arthralgia
116
Q

What are the skin side effects of chemotherapy?

A
  • Rashes
  • Hair loss
  • Hypersensitivity
  • Hand-foot syndrome
  • Photosensitivity
  • Skin hyperpigmentation
117
Q

What are the other side effects of chemotherapy?

A
  • Anaemia
  • Pancytopenia
  • Thrombocytopenia
118
Q

What is extravasation?

A

When during administration the drug leaks into into the surrounding SC tissue

119
Q

What is the consequence of extravasation of chemotherapy?

A

Local inflammatory reaction at the infusion site

120
Q

What are the clinical features of the inflammatory reaction caused by extravasation of chemotherapy?

A
  • Pain

- Redness