Principles of chemotherapy and radiation therapy Flashcards
What are the indications for chemotherapy
- Neoadjuvant therapy
- Eradicate micrometastasis
- Adjuvant therapy for local disease
- Treatment of measurable sensitive tumour
- Palliation
- Radiation therapy sensitizer
What are the two main mechanisms of action for chemotherapy?
Cell cycle specific
• Interfere with cell cycle machinery
– Cell cycle non‐specific specific
• Damage DNA
How does tumour size affect efficacy of chemo?
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
Aside from size, what else affects response to chemo?
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
What are the two concepts in chemo resistance?
- 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 - 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
How can you aim to overcome chemotherapy resistance?
• 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
What are the potential responses to chemotherapy?
• 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
Outline alkylators
• 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
Outline vinca alkyloids
• 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
Outline anti tumour anti biotics
• 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
Outline platinating agents
• 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
Outline antimetabolites
• 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
Outline L’aspariaginase
• 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
Outline hormone use in chemotherapy
Commonly used:
Prednisolone and Dexamethasone
• Broad mechanism of action:
Bind to cytoplasmic receptors and inhibit DNA synthesis
Which drugs can penetrate the CNS?
- Prednisolone
- l’asparaginase
- Cytosine arabinoside
- CCNU
- Methotrexate
Outline metronomic chemotherapy
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
How do receptor tyrosine kinase inhibitors work?
• 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
What are the TKIs on the market?
• 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
What are the possible s/e with RTKIs?
• 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
What is the theory behind immunotherapy?
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
What are the indications for external beam radiation therapy?
Loco‐regional disease
- Tumours not amenable to surgery
- Post surgical incomplete excision
- (Pre‐surgery surgery as neoadjuvant therapy)
- Palliation for radioresponsive tumours
- Pain relief
How does radiation kill?
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
Outline fractionation in radiotherapy
• 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
What are the commonly used fractionation protocols?
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
