WEEK 3 - Radiotherapy and drug radiotherapy combinations Flashcards
(21 cards)
Radiotherapy (RT) background info
- Can be part of a pt’s treatment at any stage (e.g. from early disease to pallative care)
- Can be used as treatment in many diff. cancers
What are the 3 types of RT
- External RT
- X ray (most common)
- diff. beams of radiation produced as accelartor arm moves around pt
- ISSUE: dose targets tumour AND surrounfing normal tissue = TOXICITY - Proton therapy (more specific)
- dose enters tumour tissue BUT some is delivered to normal cells as well
- X ray (most common)
- Internal RT (brachytherapy)
- Place RT inside pt at specific point
- Molecular RT (radiopharmaceutical)
- Use pharmaceuticals that deliver radioactive isotope to specific site in body
NOTE:
- internal / external = need to know tumour location
- molecular = need to know tumour biology
X-ray advantages / disadvantages
Advantages:
- Uses multiple beams / diff radiation = minimises dose to normal tissue
Disadvantages:
- Signifcant radiation dose to normal tissue
- Diff. to treat tumouts clos to radio-sensitive critical organs
- Risk of SE + radiation indcued cancers
What are the advantages of proton therapy over x-ray
External RT
- Reduces toxicity / amount of dose entering normal tissue
- no exit dose, smaller entry dose - Can treat tumours close to critical organs
- ↓ risk of toxicities and secondary cancer
- PREFFERED method for CHILDREN / young adults
NOTE: both still deliver dose to normal cells
- but proton only hits regions required, x ray has exit doses and hits normal tissue
How does internal RT work
Place source of RT inside pt at specific point
- Implant seed of radioactivity directly into tumour (iodine 125 seed)
- Iodine emits low energy gamam rays as it decays (over 60 days)
- as it decays radioactivity ↓ - Rays can only travel specific length within tumour = ↓ SE
- Radioactivity causes cell death
How does molecular RT work and list the 6 methods (targeted RT)
Use pharmaceuticals that deliver radioactive isotope to specific site
Inject radioactivity (isotope) into pt
- diff. isotiopes emit diff. RT (e.g. beta or alpha particles), travel diff. lengths, and have diff half lives
What are the 6 approaches (use):
1. Radioactive element that uses a natural transporter
2. Small molecule
3. Peptide
4. Antibody
5. Nano construct
6. Microspheres
NOTE: requires knowledge of tumour biology = targeted therapy
- to know why RT will acummulate in tumour
- how to dleiver RT to tumour site only
How does radioactive element RT work
molecular RT
Use radioactive isotope that uses natural transporter to get into / accumulate in tumour site
- use transporter we know is present within that specific tumour
Example:
Radium-223- chloride
- high energy alpha emitter = cause direct DNA damage
- RT is localised, only causes damage within tumour
- used in bone tumours / metastases
- is a calcium analogue
- emits calcium
How does small moleculer RT work
molecular RT
Tag radioisotope to small molecule that we know targets a specific molecule within the tumour
- gives specifc binding
Example:
- Radioactive bound PSMA
- PSMA is highly expressed on prostate cancer
- Small moleucle recognises PSMA = radioactivity delivered only to PSMA expressing tissue
How does peptide RT work
molecular RT
Attach radioactive isotope to a peptide that binds to a site within the tumour
Example:
- Peptide will recognise its receptor (found on specific tumours)
- I have tumour expressing high levels of this receptor the protein will bind and deliver RT
How does RT work
inc, direct and indirect RT
RT induces DNA damage directly or indirectly
- Directly = high energy RT
- directly ionsises DNA
- Indirectly = low energy RT
- e.g. x-rays
- ionises water molecules around DNA = OXIDATIVE STRESS = free radicals
- if pt has hypoxia (↓ O2) = resistant to RT as damage is ↑ by O2 presence
Once DNA is damaged:
- causes SSBs, DSBs, lesions in DNA
- DNA repair is attempted if repair fails = cell death
- DNA has non-repairale damage = cell death
AIM: cause tumour cell death through DNA damage
RT Side effects
- Tiredness
- Skin reactions
- e.g. sore, red or darker - Hair loss (in treated area)
- Difficulty eating
- if have RT for head or neck - Bone marrow and blood cells
- if have widespread RT - Emotional SE
- Bowel / Bladder changes
- N&V
- Weight loss
- Pain
- Changes in sexual function
- Brain RT: headaches, seizures
- Chest RT: heart probelms, breast changes
NOTE: SE vary and not everyone may exp.
How to treat oedema in brain if have brain tumour
RT and steroids
- pt may have swelling in brain
- Steroids isnt cancer treatment, but targets swelling = solve SE
- if steroid contraindicated = Avastin (anti-angiogenic)
What 6 chemo agents are often used with RT
- Cisplatin
- Cetuximab
- ONLY USED if cisplatin is NOT tolerated
- has same positive effects when used in RT for head/neck
- Targets EGFR
- More expensive
- No extra benefit if use RT, cetuximab and cisplatin - 5-FU
- Carboplatin
- Mitimycin C
- Gemcitabine
Combination:
- Enhances RT response
- Reduces recurrence rates
- Need to consider tolerance and toxicity - Late effects are considered more benficial than toxic
What is the MoA of Cisplatin
- Causes monofunctional adducts in DNA and intrastrand cross links
= changes / damage - Cisplatin adducts AND RT adducts causes complex damage = ↓ chance of repair
- If tumour cells less likely to repair = unable to tolerate damage in replication = cell death
What is the MoA for Anti-metabolites
e.g. 5-FU and Gemcitabine
Inhibits body’s normal metabolic process
- breaks in DNA strands from RT makes it easier for metabolite to enter DNA
- presence of metabolites in DNA + RT damage = more compelx damage
- tumour less likely to repair = cell death
5-FU
- Inhibits thymidylate synthase
- Depletes pool of nucletodie triphosphates
- Incorporation of 5-FU into DNA / RNA adds to cytotoxicity
- Radiosensitisation ↑ with the amount of 5-FU in DNA
Gemcitabine
- Depelets deoxynucleoside triphosphates
- Gemcitabine is incorproated into DNA = ↑ cytotoxicity
- ↑ radiosensitisation
MoA and the Benefits of Temozolomide and RT in Glioblastoma (brain tumour)
MoA:
- Causes adducts in DNA (called 06- methylguanine)
- In normal cells: MGMT would repair adduct = get guanine on the DNA back
- If cell lacks MGMT = no repair
Benefits:
- Improves OS (compared to RT alone)
- Reduces tumour cells ability to repair DNA-lesions
- Identify patients with ↓ MGMT expression (a methylated promoter)
- drug is given to them = good response
NOTE:
- no benefit if given to unmethylated promoter
What 5 cancer types use chemo-radiotherapy as treatment standard
- Lung
- Head and neck
- Cervix
- Bladder
- Anal / rectal
How can RT be enhanced via direct inhibition of DNA repair
Via molecular targeted therapies
When enzymes repair cytotoxic / RT induced damage = poor treatment response
- Inhibit repair = ↑ cell death = ↑ therapeutic response
- Can use small molecule inhibitors combined with treatments inducing DNA damage
Can inhibit:
- ATM
- MRN complex (involved in DSBs)
- PARP (involved is SSBs)
How do PARP inhibitors (PARPi) enhance DNA damaging effects from chemo/RT
An enzyme repair inhibitor
PARP = nuclear enzyme
- has important role in base excision repair
- PARP inhibiton = good target
- amplifies DNA damage
- induces cell death - RT induces SSBs that PARP would normally repair
- Inhibitibg PARP prevents repair of SSBs = become DSBs = lethal = cell death
PARPi can be used in combination with DNA damaging agent
- tumour cells unable to repair damage
- ↑ cell death
How do Checkpoint inhibitors enhance DNA damaging effects from RT
a.k.a. immune interactions
Combine RT with drugs that target / inhibit immune resposnes
- e.g. antibodies
- e.g. immune checkpoint inhibitors
- e.g. PD-L1, PARP, CD40
- RT / cytotic treatment trigger immune system e.g. upregulate PD-L1
- programmed death ligand 1 - PD-L1 causes immune evasion + poor prognosis in cancer
MoA of PD-L1 inhibitor
- Inhibtior + RT = tumour cells unable to turn off T cells
- Active T cells = anti-tumour effect
- Improved response
What is therapeutic ratio
Balancing pros and cons of RT treatment
- i.e. how much benefit agaisnt tumour vs toxicity in tumout
Determined as the ratio of dose modification for tumour: normal tissue
- >1 - treatment more beneficial than toxic
- <1 – treatment more toxic than beneficial
NOTE:
- Combining treatment increases toxicity
- Consider long term effects, mgmt, risks
- Do NOT want to ↑ risk of late effects
- e.g. late toxicity arising years after RT
- late DNA damage (irreversible)
