Principles of chemotherapy and radiation therapy

Question 1

What are the indications for chemotherapy

Answer 1

• Neoadjuvant therapy
• Eradicate micrometastasis
• Adjuvant therapy for local disease
• Treatment of measurable sensitive tumour
• Palliation
• Radiation therapy sensitizer

Question 2

What are the two main mechanisms of action for chemotherapy?

Answer 2

Cell cycle specific
• Interfere with cell cycle machinery
– Cell cycle non‐specific specific
• Damage DNA

Question 3

How does tumour size affect efficacy of chemo?

Answer 3

Governed by Gompertzian kinetics
– When smaller tumours are more sensitive to chemotherapy because they have more proliferating cells
• Conversely larger tumours have more none dividing or G0 cells
– Fewer sensitive cells within population
• Hence chemotherapy works best when tumour/ metastasis is small
• Problematic because of limit of detection of staging methods

Question 4

Aside from size, what else affects response to chemo?

Answer 4

ADME - absorption, distribution, metabolism, and excretion
– Duration of exposure to required concentration
– Transport into the cells
- Export from cell 
-  Vasculature
-  Uptake mechanisms
– Export from cell (pGP and other pumps)
• Cell cycle rates
• Resistance – intrinsic or acquired
• Dysregulated apoptosis
• Alterations in activating enzymes

Question 5

What are the two concepts in chemo resistance?

Answer 5

1. Goldie Coldman
   • Once detectable most tumours are heterogeneous
   • High likelihood that some of the cells will be resistant
   • Chemotherapy selects out sensitive cells
   • Therefore surviving resistant cells quickly make up majority of population
2. Stem cell
   • Chemotherapy kills daughter cells
   • Stem cell naturally resistant
   • Tumour proliferation rate great than chemotherapy kill due to required inter treatment interval.
   • Tumour grows

Likely to be a combination of these

Question 6

How can you aim to overcome chemotherapy resistance?

Answer 6

• Multidrug chemotherapy
– Maximise cell kill
– Broaden range of tumour cells which are sensitive to treatment
– Slow development of resistant population
– Maintain acceptable toxicity
• To do this
– Avoid overlapping toxicities
– Administer drugs as close to maximum tolerated dose as possible
– Use drugs known to have single agent efficacy

Question 7

What are the potential responses to chemotherapy?

Answer 7

• Complete remission (CR)
– No evidence of disease
– Getting harder to define due to new techniques
• Stage migration
– Extremely important to obtain

• Partial remission (PR)
– Usually 30% or greater reduction in size for 4 weeks
– RECIST – longest dimension measurement
– Implies resistance to treatment
– Large numbers of resistant cells increase the risk of development for further resistance

• Stable disease
– Neither PR or PD

• Progressive disease
– >20% increase in RECIST measurement at 4 weeks

Question 8

Outline alkylators

Answer 8

• Commonly used: Chlorambucil, Cyclophosphamide, Lomustine, Melphalan
• Broad mechanism of action:
Bind DNA, insert and alkyl group leading leading to a change in structure structure.
Transcription and replication are thus inhibited.
If the lesion is not repaired the cell undergoes apoptosis
• Cell cycle none‐specific

Question 9

Outline vinca alkyloids

Answer 9

• Commonly used:
Vincristine and Vinblastine
• Broad mechanism of action:
Either binds to or inhibits formation of microtubules thus preventing the formation mitotic spindle.
• Cell cycle specific

Question 10

Outline anti tumour anti biotics

Answer 10

• Commonly used:
Doxorubicin, Epirubicin, Actinomycin‐D, Mitoxantrone
• Broad mechanism of action:
1. Topoisomerase inhibition  DNA strand breaks
2. Intercalation with DNA  Prevents transcription
3. Free radical formation  DNA damage
• Cell cycle none‐specific

Question 11

Outline platinating agents

Answer 11

• Commonly used:
Carboplatin
• Broad mechanism of action: Platinum binds both within and between strands
- Inhibition of protein synthesis and cell death
• Cell cycle none‐specific

Question 12

Outline antimetabolites

Answer 12

• Commonly used:
Cytosine arabinoside, Methotrexate
• Broad mechanism of action: Different mechanisms both affect DNA production pathways
CA: Inhibits DNA polymerase, induces terminal differentiation
MT: Inhibits purine synthesis and thus DNA synthesis via inhibition of dihydrofolic acid reductase
• Cell cycle specific to S phase

Question 13

Outline L’aspariaginase

Answer 13

• Broad mechanism of action:
Malignant lymphocytes are dependent upon asparagine. Asparaginase destroys this leading to lymphocyte death.
• Cell cycle none‐specific
• Due to more rapid protein metabolism asparagine is replaced much more quickly in cats and this drug is therefore much less effective

Question 14

Outline hormone use in chemotherapy

Answer 14

Commonly used:
Prednisolone and Dexamethasone
• Broad mechanism of action:
Bind to cytoplasmic receptors and inhibit DNA synthesis

Question 15

Which drugs can penetrate the CNS?

Answer 15

• Prednisolone
• l’asparaginase
• Cytosine arabinoside
• CCNU
• Methotrexate

Question 16

Outline metronomic chemotherapy

Answer 16

Low dose ongoing therapy thought to:
1. Reduce neo‐angiogenesis
2. Reduce numbers of regulatory immune cells protecting the tumour
Most protocols use a combination of cyclophosphamide and a NSAID
Several studies:
1. MST with metronomic chemotherapy similar to with adjuvant doxorubicin in splenic HSA
2. DFI in incompletely excised STS is longer with surgery followed by metronomic therapy than surgery alone
– BUT likely to be shorter than if a further surgery or RT were pursued

Question 17

How do receptor tyrosine kinase inhibitors work?

Answer 17

• Competitive inhibition of ATP phosphorylation in
growth pathway
– Drugs not entirely specific for particular receptor
– Receptor not specific to particular cell
• Therefore side effects are potentially unpredictable
– Greatest therapeutic margin
• Receptors are over expressed
• Receptors are over active – e.g constant activation in
the presence of an ITD

Question 18

What are the TKIs on the market?

Answer 18

• Toceranib (Palladia)
– Inhibits
– Perhaps less specific for KIT therefore possibly a wider range of target diseases
• Masitinib (Masivet)
– Inhibits
– Perhaps more specific and therefore fewer off target
effects than other TKI’s

Question 19

What are the possible s/e with RTKIs?

Answer 19

• Side effects
– Not entirely predictable
– Diarrhoea, vomiting, anorexia and GI bleeding are possible with both
• Masitinib specific side effects effects
– Protein losing nephropathy and haemolytic anaemia (both rare)
• Moderate neutropaenia more common with Toceranib
• Most side effects resolve with cessation of treatment and supportive treatment

Question 20

What is the theory behind immunotherapy?

Answer 20

Tumours commonly invoke regulatory immune elements to protect them
– Higher levels of T‐regs and MDSC associated with poorer survival in studies performed
• Immunotherapy has to break this tolerance and stimulate the immune system
• It also needs sufficient time to develop the response
• The goal is to invoke a cytotoxic T cell response

Question 21

What are the indications for external beam radiation therapy?

Answer 21

Loco‐regional disease

1. Tumours not amenable to surgery
2. Post surgical incomplete excision
3. (Pre‐surgery surgery as neoadjuvant therapy)
4. Palliation for radioresponsive tumours
5. Pain relief

Question 22

How does radiation kill?

Answer 22

depositing energy in or near DNA molecules
– This leads to breaks in DNA strands
– Cells undergo undergo apoptosis apoptosis when damage cannot be repaired when cell reaches cell cycle checkpoint
– Repair pathways mainly active in cycling cells
Therefore rapidly proliferating cells are radiation
sensitive

Question 23

Outline fractionation in radiotherapy

Answer 23

• Fractionation allows higher doses by breaking up the dose over time which allows for repair of normal tissues.
– Late responding tissues are more affect by dose size.
• The total treatment period is limited by accelerated repopulation in the tumour population.
– Acute side effects are also more severe (relative to dose) if treatment is given more rapidly.
• Cells in certain phases of the cell cycle are more sensitive.
Fractionation means more tumour cells are exposed to radiation when sensitive due to redistribution.
• Fractionation also allows for reoxygenation of the tumour which enhances radiation efficacy

Question 24

What are the commonly used fractionation protocols?

Answer 24

Palliative intent protocols
8 – 9 Gy ‐ Once weekly for 4 weeks

Definitive protocols
4 Gy or less 3 to 5 days per week for 4 weeks

Pain relief
1 ‐ 3 fractions 8 – 9 Gy

Question 25

What are the common acute side effects of treatment?

Answer 25

Acute Radiation Induced Dermatitis
– 95% affected
– Starts from around 3 weeks into treatment resolves after 4‐6 weeks
– Hair loss common
– Varies from erythema, sebhorrhea to moist desquamation
– Infection with yeasts and bacteria common complicating factors
• Mucositis/Colitis/Anusitis
– Similar time frame as above
– Mild to moderate discomfort eating and halitosis
• Keratoconjunctivitis

Question 26

What are the common chronic side effects of tumours

Answer 26

• Typically at least 6 months after treatment
• Alopecia and leukotrichia
• Skin fibrosis and poor wound healing
• Keratoconjunctivitis and dry eye
• Small increase increase in the rate of de novo tumours
• Degenerative brain lesions

Question 27

Outline photodynamic therapy

Answer 27

• Useful for treating superficial local disease
– Feline nasal SCC
1 A. photosensitiser photosensitiser is administered administered systemically systemically or more commonly commonly applied applied locally.
2. A particular wavelength of light is used that causes excitation of the photosensitiser
3. Photosensitiser interacts with O2 leading to reactive oxygen species
4. The ROS cause inflammation, vascular stasis and eventually necrosis and apoptosis

Question 28

What are common s/e of TKIs?

Answer 28

the most common adverse events relate to the GI tract, including loss of appetite, diarrhoea, and occasionally vomiting. The administration of an antacid, particularly omeprazole, may be beneficial in mitigating the risk of GI ulceration, particularly in the setting of MCT. Inappetence is a relatively common side effect and typically responds to standard antinausea therapies (metoclopramide, ondansetron, maropitant) or the addition of low-dose (0.5 mg/kg) prednisone

Less common - hypertension, PLN, hepatotoxcity, neutropaenia