Principles of anti-cancer drug therapy Flashcards
Define chemotherapy
cytotoxic drugs used in cancer treatment
When is chemotherapy indicated? 6
- ) Primary treatment for disseminated disease (lymphoma and other haematopoietic tumours)
- ) Adjuvant therapy following surgery for highly metastatic tumours
- ) In certain tumours following incomplete resection (microscopic residual disease) Also consider radiation
- ) Neo-adjuvant chemotherapy
- ) Treatment of chemosensitive tumours not amenable to surgery or radiation
- ) Primary treatment for TVT (vincristine)
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
When is chemo contraindicated?
when surgery or radiation treatment is a more effective alternative
How can chemo be administered?
COMMONLY - IV, PO, SC (drug-dependent)
OTHER: intracavitary (mesothelioma and caicnomatosis with 5-FU or carboplatin) or intralesional (rarely)
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.
Define mesothelioma
cancer of cells that develop from the mesothelium which is the protective lining that covers the internal organs of the body.
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)
How do vinca alkaloids work?
inhibit microtubule formation and interfere with the G2/M phase and anti-metabolites act in the S phase
How do alkylating agents work?
not cell cycle specific (also anti-tumour antibiotics and platinum drugs)
When is chemo most likely to be effective?
when the disease burden is low (less effective for bulky disease)
When do you apply adjuvant chemotherapy?
following surgery, let the surgical wound heal (requires cell division) but then start chemo asap.
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)
Outline cytotoxic drug therapy
Use at the MTD (--> highest fractional kill) Multiple doses Pulse doses (often used with carefully selected inter-dose intervals)
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.
What are the principles of combination chemo?
USE DRUGS THAT ARE:
- ) are effective against the tumour individually
- ) different modes of action and don’t interfere with each other’s action
- ) act on different stages of the cell cycle
- ) don’t have overlapping toxicities
What combination chemotherapy protocols are commonly used to treat lymphoma in dogs and cats?
- ) COP-based (cyclophosphamide, vincristine, prednisolone)
- ) Doxorubicin-containing protocols (CHOP) e.g. Wisconsin-Madison protocol
- ) Modified LOPP protocol for TC lymphoma (lomustine, vincristine, procarbazine, prednisolone)
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
What are the stages of chemotherapy?
- ) Induction
- ) Maintenance
- ) Re-induction
- ) Rescue
Name 2 alternatives to conventional cytotoxic chemotherpay
- ) Metronomic chemotherapy/ continuous low dose chemotherapy
- ) Receptor tyrosine kinase inhibitors (RTKIs)
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.
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.
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
What drugs are resistant/sensitive to anti-cancer drugs?
Highly sensitive - lymphoma
Relatively resistant - pancreatic and renal carcinomas
What does drug penetration into tumour depend on? 2
tumour blood supply and natural barriers
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
When does multi-drug resistance occur?
when tumour cells become cross-resistant to unrelated compounds
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.
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)
What are AEs?
Give 4 examples
Adverse effects
EXAMPLES: Myelosuppression GIT toxicity Poor hair growth/whisker loss Drug extravasation
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
How should myelosuppression be managed?
- Monitor CBCs regularly - take prior to administration of each potentially myelosuppressive drug. Delay treatment if neutrophil count is < 210^9/l or platelets <110^9/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.
What AEs hav a major effect on QoL?
GIT toxicity (must be prevented where possible) Risk of bacterial translocation exists (esp if neutropenic)
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
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.
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)
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!
Prevention - chemo drug extravasation
Cleanly placed IV catheter
Tape in place securely
Flush with saline (0.9%) before and after drug admin.
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
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
Outline specific drug toxicities for CYCLOPHOSPHAMIDE
haemorrhagic cystitis (dogs, v rare in cats) - the metabolite acrolein is irritant to the bladder lining.
What is oxybutinin? Use?
an anti-spasmodic
may be given in cases of cyclophosphamide toxicity induced haemorrhagic cystitis
Outline specific drug toxicities for VINCRISTINE - 3
- Peripheral neuropathies (interference with microtubule formation)
- Ileus/constipation (cats)
- Skin sloughs (perivascular administration)
Outline specific drug toxicities for LOMUSTINE
Hepatotoxicity (especially dogs)
Nephrotoxicity
Outline specific drug toxicities for PLATINUM DRUGS
Nephrotoxic (especially cisplatin)
Vomiting (cisplatin, via CTZ)
Carboplatin (preferable)
Irritant (perivascular administration)
Outline specific drug toxicities in cats
DO NOT GIVE:
Cisplatin –> fatal pulmonary oedema
5-FU –> extreme neurotoxicity
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.
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
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)
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
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
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)
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
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.
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
Define RTKI
Receptor Tyrosine Kinase Inhibitor
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.
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).
Outline common drug indications - multiple myeloma
Melphalan and prednisolone (dogs)
Chlorambucil and pred (cats)
MST - approx 18 months in dogs, poorer in cats
Outline common drug indications - chronic lymphocytic leukaemia
Chlorambucil +pred (+/- vincristine)
MST - 1 year
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)
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.
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
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.
Outline common drug indications - anal sac carcinoma
Carboplatin Melphalan Mitoxntrone Toceranib Metronomic therapy
Can be used as adjunctive therapy +/- radiation as first line treatments
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
Outline common drug indications - thyroid carcinoma (dogs)
Doxorubicin - adjuvant to surgery
Outline common drug indications - polycythaemia ver
Hyrdoxycarbamide/hydroxyurea
Survival often > 1 year
Outline common drug indications - histiocytic sarcoma
lomustine - sole therapy in disseminated disease or as adjunct to surgery.
