WEEK 6 - SACT and Targeted Therapy Toxicities Flashcards
(26 cards)
What factors contribute to a patient’s susceptibility to specific toxicities
Inc. genetics, age, and ethnicity-based influences
- Intrinsic
- Factors you can’t control
- e.g. Genetics, Age
- Genetics: drug repsonse, PK - Extrinsic
- External factors
- e.g. Lifestyle (smoking, alcohol, stress)
- can affect how well respond to chemo - Treatment duration and Dose
- Treatment timing
- Humans are circadian organsims, body rleis on clock
- Diff levels of hormones are present in diff. amoutns at diff. times of day
- Changes can affect how chemo / RT work - Co-morbidities
- Cancer usually a disease of old age
- Expect pt may have many other diseases = challenge
- Other conditions can increase risk of SE
- Need to treat cancer, manage toxicities + other conditions - Poly-pharmacy
- If pt has co-morbidities = going to be taking many other meds = need to consider this
Chemotherapy: Grading and Assessment
Gradingi Scales:
- WHO Toxicity Grading
- ECOG Performance Status
- Karnofsky Performance Status
- CTCAE Toxicity Grading Criteria
How Scale is Useful:
- Pt Toxicity SE is given a number
- No. allows monitoring (improvement/ deterioration) between cycles
- Can determine mgmt.
- e.g. pt with multiple low grades toxicities in comparison to pt with one high grade toxicity
List Chemotherapy SE and Treatments
3 SE Categories
Common:
- GI effects: N&V, diarrhoea, constipation
- Mucositis
- Bone marrow toxicity
- Alopecia / hair loss
- Skin toxicity
- Fatigue
- Neuropathy
Occur after treatment started
Acute Toxicities:
- Anaphylaxis
- TLS
- Hypersensitivity
- Doesnt happen often, if occurs = STOP treatment
Less Common:
- Renal / hepatic impairment
- Fertility issues
Nausea and Vomitting
Cause, 5 Types of N&V, Treatment
Cause:
2 Pathways
1. Chemo acting Centrally (on CNS)
- Chemo crosses BBB
- Enters brain + induces N&V
2. Chemo acting Peripherally
- Chemo effects gut
- Gut lining destroyed = release of factors
- Factors stimulate N&V from brain
Types of N&V:
1. Acute – within 24hrs
2. Delayed – after 24hrs up to a week
3. Anticipatory – learned response i.e. had chemo before made you sick = thought of having chemo makes you sick
4. Breakthrough – when pt is on anti-emetics but still experiencing N&V
5. Refactory – tried many things but no help / pt still experiencing N&V
Treatment:
- Anti-emetics
- Target central or/and peripheral pathway
Diarrhoea Cause
- Direct death of cells lining the lower gut (SI and LI)
- Death of cells cause chronic inflammation which causes more death
- painful +
- Further damage = death and changes to microbiome
- inbalanced microbiome = bacteria dependent on microbiome will change
- bacteria may die, balance between good and bad bacteria change
- More bad bacteria growing also causes damage through toxins etc.
Mucositis Cause
- Damage caused by DNA DNA-damaging agent (e.g. chemo, RT)
- Damage effects blood vessels and tissue cells in mucosa
- Latent period occurs
- cells realise they are damaged, stop and try fix themselves (0-2 days)
- Immune system starts producing factors which digest damaged tissue
- E.g. NF-kB, macrophages
- Damaged cancer cells don’t have ability to regenerate to fill gaps = gaps in vessels and tissues
- Macrophages stimulate cells to divide and fill gap of wound but as cells have been damaged by chemo = unresponsive to signals from macrophages
- results in excessive inflammation = further breakdown of tissue (2-10 days)
- Breakdown of mucosa = all of microbiome / bacteria can get past barrier and into blood
- Becomes life threatening if loose all of barrier + microbiome is able to enter blood
- Cells eventually recover (adducts dissaper, drug broken down etc.) = cells repair + rpelace damage
- takes up to 3 weeks
- but if having chemo every 4 weeks = problem (just recoverd + about to induce problem again)
Diarrhoea and Mucositis Treatment
- Antibiotics
- Pro-biotics
- Anti-oxidants
- Mucosal barrier regulators
- Anti-inflammatories
- Hormones
- Pain killers
- Nutrition replacement
What is the MoA of Platinum compounds
A type of chemotherapy
Platnium compound binds to DNA covalently
- can also bind to macromolecules = SE
- as compound is given IV = in circulation = starts binding to other parts of body
SE of Platinum Compounds: Peripheral Neruopathy
As compound is given IV = in circulation = starts binding to other parts of body
OFF-TARGET EFFECTS:
- Immune system
- activates immune cells + alters function of immune cells
- Release of pro-inflammatory cytokines - neuronal inflammation
- Microglia
- Release TNFa = activate immune cells = nerunal inflammation
- Peripheral Neurons
- binds to mtDNA
- degrades axons + loss of peripheral sensory = pain
- chelates calcium
- affects Ca2+, Na, K levels (↑) = throws cells out of balance (homeostasis)
How to manage SE of Peripheral Neruopathy
Pharmacology:
- if have changes in signalling due to change in microbiome = use drugs that are selective uptake inhibitors
- use drugs that force things lost to be produced
- Gabapentin (useful for pain)
Non-pharmacological:
- Cryotherapy
- if make environment colder = can stop all damage and inflammation brought through by blood flow
- flow is frozen
- Accupuncture
- Exercise + keeping pt mobile / moving as much as possible
- if not moving and damage is peripheral (in feet) = not being flushed away
Explain the role of patient-specific genetic factors in predicting and managing Peripheral Neuropathy
- Older age (>65) = 2x ↑
- African ethnicity = 2x ↑
- Germline variants
- if have SBF2 mutation = more likely to acquire this SE
- test for mutation
- Co-morbidities
- had prior neuropathy, uncontrolled diabtes, obesity
- all ↑ risk
- Lifestyle (can be controlled to ↑ SE)
- smoking (affects peripheral flow)
- alcohol use
- inactive
- vitamin D, B12 deficient
- Pertuating factors (depression)
- make SE worse
What is the MoA of Doxorubicin Cardiotoxicity
A type of Chemo
- Dox forms complex with iron = lipid peroxidation occurs
- Dox can cause epigeneitc changes = dysregulate + damage mtDNA = apoptosis = cardiotoxicity
- Dox affect Topo-2 = calcium dysregulation
- Affect smooth endoplasmic reticulum = calcium dysregulation = muscles affected = cardiotoxity in heart
NOTE:
- Whilst doing this still doing its intedned function in cancer cells
How to manage Cardiotoxicity of Doxorubicin
Cardiotoxicity can be latent
- occur up to 6 months after treatment completion = hard to detect
- Give treatment whilst on Dox. to prevent it from happening
- once it happens / have symptoms = damage has already been done - Regulate amount of iron
- Dox. forms compelx with iron = lipid affected - Activate pathways that prevent mtDNA death
- Activate pathways against excessive Ca2+ signalling
Explain the role of patient-specific genetic factors in predicting and managing Cardiotoxcity
Intrinsic / Non-modficiable
- Age = ↑ (<21 or >65)
- Gender
- African ethncity = ↑ risk
Comorbidities
- Diabetes control ↑
- Dyslipideemia, obesity, high cholesterol = ↑ (more lipid for dox to bind)
- Hpt. and CVD disease = ↑
Polypharmacy
- If take mediciation beneficial to heart ↓
- Other medications ↑
NOTE:
Can save pt from worse cardiotoxicity if potentially wait for hypt, CVD, diabetes etc. to get under control before starting next cycle
Immunotherapy
What it is, Example, SE,
WHAT:
- Therapy that is targeting the immune system to help against cancer
2 Methods:
1. Block inflammtion that helps tumour
2. Help inflammation in body that attacks tumour
Example:
- PD-L1 (immune checkpoint inhibitor)
- make T-cells become more active to attack tumour cells
- Vaccine, cytokine therapy
SE:
(as we are altering normal immune function)
- Vomitting
- Pancreatitis, Colitis, Myocarditis, Hepatitis
- Anaemia
- Skin
- AKI
- Thyrodid dysfucntion
Driven by immune sytsem attacking part of body it shouldnt
What is the aim of Immunotherapy
AIM:
- tip balance between immune cells towards tumour rejection immune cells
- e.g. supress tumour progression cells
- T regs supress normal immune T cells
- MDSCs supress natural M1 macrophage attack
- M2 macrophages produce growth factors like eGF to help tumour cell growth - e.g. add mor tumour rejection cells
What is the MoA of Imunne Checkpoint Inhibitor (ICI) induced colitis
- Have helathy gut microbiome with normal interactions ongoing
- many antigen presneting cells (injest food with bacteria), PD-1 and PD-L1 interactions, T cells = normal
- If add ICI = immune system in stomach is upregulated
- Immune system starts to attack + brek down tissue in colon
- loosing barrier
- Causes inflammation = more damage
- Microbiome may be absorbed into bloodstream = sepsis etc.
How to manage ICI-Induced Colitis
Grade SE (5 Grades)
- if pt is grade 3-4 = manage properly to avoid grade 5 (death)
USE: Infliximab
- dampens immune system
- contradicts immunotherapy which overactivates immune system
Explain the role of patient-specific genetic factors in predicting and managing ICI-Induced Colitis
Lifestyle
- Alcohol
- Smoking
- Body weight
Intrinsic / Non-modficiable
- Age
- Gender
- Genetics
Comorbidities
- Diabetes control ↑
- GI issues = ↑
- Enodcrine issues, pre-exisiting autoimmune disease = ↑
- Pre-exisiting psoriasis = better repsonse
- as immune system is already active against this disease
Polypharmacy
- Drugs affecting immune response = ↑ risk
- e.g. steroid use within 3 mths
- Change / swap immunosupressants
- If give ICI with RT = better response
What are the SE of targeted therapy
- Skin issues
- BP changes
- Liver issues
- High temp.
- Diarrhoea
- Cardiotoxicities (from some not all therapies)
- e.g. Hypt, HF, ACS, QT prolongation, LV systolic dysfunction
- e.g. anti-angiogenic agents - change how blood vessels formed = why see changes in hpt.
What is the MoA of targeted therapies: BRAF and MEK (inhibitors)
In normal and cancerous cells
In healthy cell:
- Have GF which binds to receptor tyrosine kinase (RTK)
- Binding causes cascade of phosphorylation events
- i.e. BRAF→ MEK → ERK activated
- Activation causes inactivation of retinoblastoma (Rb) protein
- Lack of protein aids proliferation and survival
NOTE: this pathway is the main pathway controlling growth and division = why we see it most commonly altered in cancers
b) In Melanoma:
- BRAF gets mutated into BRAF V600E (a diff. amino acid)
- This single change = protein no longer needs GF to bind to RTK
- BRAF can have constant signalling at higher rate = acquire cancer hallmarks
= constant proliferation (without stimulation from GF) + survival
c) Addition of Inhibitors in Melanoma
- Drugs that inhibit specifically the mutated BRAF V600E
- Drugs that inhibit process below BRAF e.g. MEK inhibitors, ERK inhibitors and CDK4/6 Inhibitors
- Inhibitions = Proliferationa and survival can’t occur
What are the SE from BRAF and MEK inhibitors
- Skin effects (rash, dry)
- Fatigue, headache, pyrexia
- Cough, dyspnea
- Oedema
- GI: N&V, diarrhoea, constipation, abdominal pain
- Cardiac toxicity
Explain the MoA of BRAF and MEK inhibitor induced SE
Inhibitor:
- Inhibitor will block BRAF in cancer cell due to presence of mutated version
- But WT / normal version can be affected
- IRF1 can be switch on if BRAF or MEK inhibitor is used
- Overactivation of IRF1 = induction of CCL2, CXCL10, IFIT2 etc.
- Factors cause strong inflammation to be induced in skin
Explain the role of patient-specific genetic factors in predicting and managing BRAF / MEK inhibitor skin SE
- Mutation can vary within diff. patient groups
- e.g. gender, age
