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Flashcards in Principles of anti-cancer drug therapy Deck (69):
1

Define chemotherapy

cytotoxic drugs used in cancer treatment

2

When is chemotherapy indicated? 6

1.) Primary treatment for disseminated disease (lymphoma and other haematopoietic tumours)
2.) Adjuvant therapy following surgery for highly metastatic tumours
3.) In certain tumours following incomplete resection (microscopic residual disease) Also consider radiation
4.) Neo-adjuvant chemotherapy
5.) Treatment of chemosensitive tumours not amenable to surgery or radiation
6.) Primary treatment for TVT (vincristine)

3

Give some examples of tumours where adjuvant chemotherapy following surgery for highly metastatic tumours may be used.

OSA
HSA
High grade STS
Grade 3 MCTs
Grade 2 MCT with high mitotic index

4

When is chemo contraindicated?

when surgery or radiation treatment is a more effective alternative

5

How can chemo be administered?

COMMONLY - IV, PO, SC (drug-dependent)
OTHER: intracavitary (mesothelioma and caicnomatosis with 5-FU or carboplatin) or intralesional (rarely)

6

Define carcinomatosis

Where multiple carcinomas develop simultaneously, usually after dissemination from a primary source. It implies more than spread to regional nodes and even more than just metastatic disease. The term is usually taken to mean that there are multiple secondaries in multiple sites.

7

Define mesothelioma

cancer of cells that develop from the mesothelium which is the protective lining that covers the internal organs of the body.

8

How do chemo drugs work?

Interfere with cell growth or division
Can affect different stages of the cell cycle
Some drugs are cell cycle specific, others aren't and can theoretically affect cells even in the resting (G0 phase)

9

How do vinca alkaloids work?

inhibit microtubule formation and interfere with the G2/M phase and anti-metabolites act in the S phase

10

How do alkylating agents work?

not cell cycle specific (also anti-tumour antibiotics and platinum drugs)

11

When is chemo most likely to be effective?

when the disease burden is low (less effective for bulky disease)

12

When do you apply adjuvant chemotherapy?

following surgery, let the surgical wound heal (requires cell division) but then start chemo asap.

13

What does the cell kill hypothesis state?

that tumour cell kill follows first order kinetics (a given dose of cytotoxic drug will kill a fixed percentage of the tumour population as opposed to a set number of tumour cells. Will not completely eradicate the tumour)

14

Outline cytotoxic drug therapy

Use at the MTD (--> highest fractional kill)
Multiple doses
Pulse doses (often used with carefully selected inter-dose intervals)

15

Is combination of single agent chemo usually more effective?

Combination (exceptions are vincristine in TVC and doxorubicin or carboplatin in OSA). Repeated use of a single agent is likely to select for resistant cells, whereas alternating drugs is less likely to cause selection pressure.

16

What are the principles of combination chemo?

USE DRUGS THAT ARE:
1.) are effective against the tumour individually
2.) different modes of action and don't interfere with each other's action
3.) act on different stages of the cell cycle
4.) don't have overlapping toxicities

17

What combination chemotherapy protocols are commonly used to treat lymphoma in dogs and cats?

1.) COP-based (cyclophosphamide, vincristine, prednisolone)
2.) Doxorubicin-containing protocols (CHOP) e.g. Wisconsin-Madison protocol
3.) Modified LOPP protocol for TC lymphoma (lomustine, vincristine, procarbazine, prednisolone)

18

How are cytotoxic chemotherapy drugs dosed?

MTD tends to correlate better with body surface area than body weight (and relates to metabolism). Most drugs are used on a mg/m2 basis.
BSA conversion charts
Obese animals - dose according to estimated lean body weight
Small dogs/cats - show increased toxicities when based on a mg/m2 basis - so dogs <10kg and cats are sometimes dosed on a mg/kg basis

19

What are the stages of chemotherapy?

1.) Induction
2.) Maintenance
3.) Re-induction
4.) Rescue

20

Name 2 alternatives to conventional cytotoxic chemotherpay

1.) Metronomic chemotherapy/ continuous low dose chemotherapy
2.) Receptor tyrosine kinase inhibitors (RTKIs)

21

Outline metronomic chemotherapy/continuous low dose chemotherapy

usually cytotoxic drug given alongside an NSAID
AIM = to slow growth by inhibiting angiongenesis via immunomodulatory effects, decreasing circulating Tregs and promoting anti-tumour immunity
No dramatic shrinkage, but stable disease/lack of progression.
Low dose cyclophosphamide most commonly
Similar survival times (canine HSA)
Can be used to delay time to recurrence in incompletely resected canine STS.

22

Outline RTKIs

Interfere with aberrant signalling through cell surface receptors in cancer cells and have effects inhibiting angiogenesis, reducing proliferation and promoting apoptosis.
Dosed daily or EOD or MWF
Tumours may not shrink dramatically, but stable disease/lack of progression may be achieved
Toceranib and mastinib licensed for treatment of canine MCT.

23

List what factors affect the success of anti-cancer drug therapy?

Tumour type
Penetration of drug into tumour
Development of drug resistance
Multi-drug resistance

24

What drugs are resistant/sensitive to anti-cancer drugs?

Highly sensitive - lymphoma
Relatively resistant - pancreatic and renal carcinomas

25

What does drug penetration into tumour depend on? 2

tumour blood supply and natural barriers

26

How does tumour drug resistance develop?

Various mechanisms:
decreased drug uptake
increased drug removal from cell
decreased drug activation
increased drug inactication
increased/altered drug targets
use of alternative pathways
increased DNA repair

27

When does multi-drug resistance occur?

when tumour cells become cross-resistant to unrelated compounds

28

What is multi-drug resistance associated with?

increased expression of multi-drug resistance gene (MDR1), leading to increased p-glycoprotein (Pgp) expression, which pumps cytotoxic drugs such as vinca alkaloids and doxorubicin out of the cell. MDR1 gene can be activated by glucocorticoids and these drugs can induce resistance to vinca alkaloids/doxorubicin.

29

What should you do if resistance occurs?

switch to drugs that the tumour has not been exposed to before - preferably combinations of drugs with different mechanisms of action (rescue therapy)

30

What are AEs?
Give 4 examples

Adverse effects

EXAMPLES:
Myelosuppression
GIT toxicity
Poor hair growth/whisker loss
Drug extravasation

31

Outline myelosuppression due to cytotoxic drugs

BM haematopoietic SCs are affected by many anti-cancer drugs --> neutropenia and thrombocytopenia.
Neutropenia = dose-limiting toxic effect of many agents
Neutrophil nadir = drug-dependent, mostly at 7 days after dose (10-14 days for carboplatin)
Platelet nadir = usually occurs 10 days post-treatment

32

How should myelosuppression be managed?

- Monitor CBCs regularly - take prior to administration of each potentially myelosuppressive drug. Delay treatment if neutrophil count is < 2*10^9/l or platelets <1*10^9/l but patient appears well, give prophylactic ABs (e.g. TMS)
- If neutropenic and pyrexic/sick = URGENT! Give BS ABs (e.g. enrofloxacin and potentiated amoxicillin), barrier nurse, treat GI signs, IVFT.

33

What AEs hav a major effect on QoL?

GIT toxicity (must be prevented where possible)
Risk of bacterial translocation exists (esp if neutropenic)

34

How should GIT toxicity AEs be managed? 3

VOMITING: bland diet, gut protectants (H2 blockers, sucralfate, omeprazole), anti-emetics (maropitant, odansetron)

DIARRHOEA: bland diet, metronidazole for immunomodulatory effects (especially for colitis post-doxorubicin), possibly symptomatic tx (sulphasalazine, loperamide), IVFT (severe cases)

ANOREXIA: maropitant if nauseous, appetite stimulants (cyproheptadine, mirtazapine), feeding tubes

35

How else can chemo drugs cause vomiting and nausea?

Direct action on the CRTZ
EXAMPLES = platinum drugs (particularly cisplatin), dacarbazine, Actinomycin D, doxorubicin.
Prophylactic anti-emetics should be given (maropitant, odansetron) prior to the chemo drug.

36

Outline hair loss due to chemo drugs

Complete alopecia is rare, but hair thinning/ slow regrowth post-clipping can occur.
Extensive hair loss can occur in some breeds (OESD, Beardies, Poodles, some terriers)

37

Why is chemo drug extravasation undesirable?

Many of the IV chemo drugs are irritant or vesicant if extravasated (vincristine, vinblastine and doxorubin especially).
= serious complication ,can result in severe tissue damage, even resulting in amputation so avoid!

38

Prevention - chemo drug extravasation

Cleanly placed IV catheter
Tape in place securely
Flush with saline (0.9%) before and after drug admin.

39

Treatment - chemo drug extravasation

Leave catheter in place and attempt to withdraw as much as possible (aspiration)
Doxorubicin = apply ice packs, give dexrazoxane IV
Vincristine = apply hot compress, inject hyaluronidase locally.

Seek specialist advice
Anti-inflammatory doses of dexamethasone IV and topical steroid creams might be useful, provided there are no other contraindications

40

Outline specific drug toxicities for DOXORUBICIN

Cardiotoxicity (dogs)
Dysrhymthmias can occur during administration (rarely a problem if given slowl)
Chronic toxicity - more significant, more likely to occur at cumulative doses >180,g/m^2 --> DCM
Mast cell degranulation can occur (rare) during administration --> wheals, urticarial, puritis,oedema, V+D, dyspnoea or hypovolaemic shock.
Nephrotoxicity (cats)
Vesicant - if injected perivascularly
GI - colitis

41

Outline specific drug toxicities for CYCLOPHOSPHAMIDE

haemorrhagic cystitis (dogs, v rare in cats) - the metabolite acrolein is irritant to the bladder lining.

42

What is oxybutinin? Use?

an anti-spasmodic
may be given in cases of cyclophosphamide toxicity induced haemorrhagic cystitis

43

Outline specific drug toxicities for VINCRISTINE - 3

- Peripheral neuropathies (interference with microtubule formation)
- Ileus/constipation (cats)
- Skin sloughs (perivascular administration)

44

Outline specific drug toxicities for LOMUSTINE

Hepatotoxicity (especially dogs)
Nephrotoxicity

45

Outline specific drug toxicities for PLATINUM DRUGS

Nephrotoxic (especially cisplatin)
Vomiting (cisplatin, via CTZ)
Carboplatin (preferable)
Irritant (perivascular administration)

46

Outline specific drug toxicities in cats

DO NOT GIVE:
Cisplatin --> fatal pulmonary oedema
5-FU --> extreme neurotoxicity

47

Outline specific drug toxicities in herding dog breeds

Increased sensitivity to vinca alkaloids (e.g. vincristine) and doxorubicin.
EXAMPLES = collies, shetland sheepdogs, australian sheepdogs, long haired whippets
WHY = mutation in MDR1 gene --> impaired excreteion
Homozygotes worse than heterozygotes
Use substrates that don't go via the pump such as cyclophosphamide and prednisolone for lymphoma.

48

Mechanism of action - ALKYLATING AGENTS
Cell cycle specific?
Examples

They substitute an alkyl group for a H+ ion in the DNA causing cross-linkage and breaking of DNA strands --> interference with DNA replication and transpriction.

NOT cell cycle specific.

EXAMPLES = cyclophosphamide, lomustine, melphalan,chlorambucil, procarbazine, dacarbazine

49

Mechanism of action - MITOTIC SPINDLE INHIBITORS
Cell cycle specific?
Examples

Bind to tubulin and prevent normal assembly of the microtubules. Causes arrest of mitosis in metaphase.

YES cell cycle specific - affects G2/M phase

EXAMPLES = vincristine, vinblastine, vinorelbine, taxanes (e.g. paclitaxel)

50

Mechanism of action - ANTI METABOLITES
Cell cycle specific?
Examples

Mimic normal substrates used in nucleic acid metabolism - either inhibit enzymes OR lead to the production of non-functional molecules, thus interfereing with DNA synthesis.

YES cell cycle specific

EXAMPLES = cytosine arabinsoide/cytarabine, methotrexate, hydroxycarbamide (hydroxyurea), 5-FU, gemcitabine, azathioprine

51

Mechanism of action - ANTI TUMOUR ANTIBIOTICS
Cell cycle specific?
Examples

Several mechanisms of action to prevent DNA and RNA synthesis:
Inhibition of topoisomerase 2 (helps untangle DNA)
Breaking of DNA strands
Cross-linking of DNA base pairs
Free radical oxidative damage (Doxorubicin)

NOT cell cycle spefic

EXAMPLES = doxorubicin, epirubicin mitoxantrone, actinomycin-D

52

Mechanism of action - PLATINUM COMPOUNDS
Cell cycle specific?
Examples

Work similarly to alkylating agents - the platnium compound causes inter and intrastrand crosslinks in the DNA, interfering with DNA synthesis and trasncription

YES cell cycle specific

EXAMPLES = carboplatin, (cisplatin)

53

Mechanism of action - CORTICOSTEROIDS
Cell cycle specific?
Examples
Adverse effects

Not classed as a cytotoxic drug. Cause apoptosis of lymphoid and mast cells.

NOT cell cycle specific

EXAMPLES = prednisolone, dexamethasone

ADVERSE EFFECTS: PD, PU, polpyphagia, excessive panting, mm weakness, slow wound healing, immunosuppression

54

Mechanism of action - L-ASPARAGINASE
USE?
Adverse effects.

Enzyme that breaks down L-asparagine

USE = Tx of lymphoma/leukaemia since neoplastic lymphoid cells can't sythesise L-asparagine (lack L-aspargine synthetase), rely on an extracellular supply for protein synthesis and die in the presence of L-asparaginase. Normal cells can synthesise L-Asparagine de novo.

ADVERSE EFFECTS = L-asaparaginase is a foreign protein --> possible allergic/anaphylactic reactions. Give anti-histamine prior to a second dose. Treat AEs with antihistmaine/dexamethasonne IV. Expensive.

55

How do NSAIDs work?

Anti-cancer effects are incompletely understood - they are thought to involve COX-2 inhibition. Inhibit angiogenesis, promote apoptosis, anti-inflammatory, analgesic

EXAMPLES = prioxicam, meloxicam, firocoxib

USE = in continuous low dose chemotherapy protocols/ metronomuc protocols, often alongside low dose cyclophosphamide. For the Tx of many tumours (TCC of bladder, prostate carcinoma)

AE = gastric ulceration, renal toxicity

56

Define RTKI

Receptor Tyrosine Kinase Inhibitor

57

RTKI - mechanism of action
Examples
Adverse effects

MECHANISM: interfere with cell-signalling through cell-surface receptors known as RTKs, which are normallu involved in cell growth, proliferation and survival. Cancer cells may overexpress TKs (--> amplified signalling) or may carry a genetic mutation --> aberrant receptors that are consititutively activated.

EXAMPLES = 2 drugs licencsed for treatment of non-resectable/metastatic grade 2 or 3 canine MCTs = mastinib and toceranib. Inhibit signalling through KIT receptors. About 40% canine MCTs have KIT mutations but these drugs are also effective in MCTs without KIT. ALso have effects through other RTKs

ADVERSE EFFECTS = GIT effects common (V, D, weight loss, sometimes GI haemorrhage), myelosuppression (usually mild), proteinuria. ALso with toceranib --> mm cramping and hypertension. Depigmentation can occur.

58

Outline common drug indications - lymphoma

Vincristine, Cyclophosphamide, Prednisolone, Doxorubicin
(lomustine/vinc/procarb/pred for canine TC lymphomas)

Multi-agent therapy is 1st line of treatment (COP or CHOP for BC).

Median survival is 1 year for multicentric high grade BC lymphoma in dogs (shorter for high grade TC).

59

Outline common drug indications - multiple myeloma

Melphalan and prednisolone (dogs)

Chlorambucil and pred (cats)

MST - approx 18 months in dogs, poorer in cats

60

Outline common drug indications - chronic lymphocytic leukaemia

Chlorambucil +pred (+/- vincristine)
MST - 1 year

61

Outline common drug indications - OSA

Carboplatin or doxorubicin (cisplatin)

Adjuvant chemotherapy significantly increases survival after amputation (few moths with surgery alone, to 8-11 months)

62

Outline common drug indications - HSA

Doxorubicin single agent OR combined with cyclophosphamide (AC) +/- vincristine (VAC)
Metronomic cyclophos + NSAID

Adjuvant chemo significantly increases MST after splenectomy from 3 to 6 months. Also useful with metastases.

63

Outline common drug indications - MCT (high grade or metastatic)

Vinblastine/lomustine + pred
Vinblastine _ cyclophos + pred
Chlorambucil + pred
Mastinib
Toceranib

Used in adjuvant setting following surgery or radiotherapy or sometimes as sole therapy for high grade tumours.

Mastinib - licensed for non-resectable grade 2 or 3 KIT mutation + MCT,
Toceranib - non-resectable metastatic recurrent grade 2/3

64

Outline common drug indications - TCC of bladder/urethra

NSAIDs alone
Metronomic chloramb. + NSAID
Mitoxantrone + NSAID
Vinblastine
Carboplatin
Gemcitabine
Doxorubicin

Complete responses are rare - PR or stable disease more common, drug therapy improves clinical signs and prolongs survival.

65

Outline common drug indications - anal sac carcinoma

Carboplatin
Melphalan
Mitoxntrone
Toceranib
Metronomic therapy

Can be used as adjunctive therapy +/- radiation as first line treatments

66

Outline common drug indications - mammary carcinoma

Doxorubicin +/- cyclophosphamide (AC) - can be used in the adjuvant setting in cats or in gross disease.

FAC in dogs (5-FU, doxorubicin, cyclophosphamide) - limited evidence for efficacy in dogs

67

Outline common drug indications - thyroid carcinoma (dogs)

Doxorubicin - adjuvant to surgery

68

Outline common drug indications - polycythaemia ver

Hyrdoxycarbamide/hydroxyurea
Survival often > 1 year

69

Outline common drug indications - histiocytic sarcoma

lomustine - sole therapy in disseminated disease or as adjunct to surgery.

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