SACT and Targeted Therapy Toxicities - Notes

SACT and Targeted Therapy Toxicities - Notes

ILOs (Intended Learning Outcomes)

• Understand the toxicological mechanisms of chemotherapy, immuno-oncology (IO) agents, and targeted therapies.

  • Describe biological processes behind toxicities and their relation to drug mechanisms of action.

• Identify susceptibilities to toxicity.

  • Factors include genetics, age, and ethnicity-based influences.

• Apply pharmacogenomics to toxicities.

  • Recognize genetic factors in predicting and managing toxicities.

• Understand polypharmacy and drug interactions regarding toxicities.

  • Assess the impact of multiple treatments on toxicity risks.

• Suggest management strategies for toxicities.

  • Strategies include adjusting doses, changing regimens, and using secondary medications.

Chemotherapy Toxicities- happen bc chemo targets rapidly dividing cells.

• Common Toxicities: 1 in 2 chemo patients

  • Nausea and vomiting

  • Mucositis

  • Loss of appetite

  • Skin toxicity

  • Neuropathy

  • Fatigue

  • Alopecia

• Less Common Toxicities: rarer and often more serious

  • Anaphylaxis

  • Hypersensitivity reactions

  • Tumor lysis syndrome

  • Secondary malignancies

  • Fertility issues

  • Electrolyte disturbances

Toxicity Grading and Assessment- different scales to measure toxicity.

• Assess toxicities during the entire treatment cycle using various grading scales:

  • ECOG Performance Status

  • Karnofsky Performance Status

  • CTCAE Toxicity Grading Criteria

  • WHO Toxicity Grading

• Allows monitoring of improvement/deterioration over treatment cycles. can help to adjust treatmentr

Nausea and Vomiting (N&V)

• Types of N&V:

  • Acute: Within 24 hours post-chemotherapy.

  • Delayed: Occurs after 24 hours, may last up to 7 days.

  • Anticipatory: Occurs before the next chemotherapy cycle, often due to anxiety. know chemo has made you sick before, may feel sick going inro next cycle - pavlov dog kinda thing

  • Breakthrough: N&V despite standard treatment.

  • Refractory: Persistent symptoms despite additional medication.

• Causes:

  • Peripheral pathway: Involves GI tract, influenced by serotonin release.

  • Central pathway: Involves the brain's vomiting center; key substances include Substance P.

  • 2 pathways for n&v. go back over this

• Treatment Options:

  • Dopamine Antagonists: Prochlorperazine, Metoclopramide, Domperidone.

  • 5-HT3 Receptor Antagonists: Ondansetron, Granisetron.

  • Others: Cannabinoids, Antimuscarinics, Antihistamines, Substance P antagonists.

Diarrhea

• Causes:

  • Increased inflammation, permeability, and microbiome imbalance due to chemotherapy. direct death of cells that line the gut as they are fast growing- leads to lots of inflammatory activity in the gut. adding in extra damage- more angry cells, painful whoch can leasd to further damage - messes with microbiome - imbalance - if bad , can cause further damage.

• Treatment Options:

  • Antibiotics, Probiotics, Anti-inflammatories, Pain management, Nutritional support.

Mucositis- serious side effect

• Mechanisms of Injury:

  • Chemotherapy induces inflammation and epithelial cell damage, leading to ulceration.

  • dna damage from treatment , affects blood vessel and so tissue. try to fix themselves- 1-2 days where nothing happens, then immune system gets involved - starts to digest the tissue- been through chemo so cant replace these cells as too damaged from chemo. causes excessive inflammation, breaks down tissue even firther- over course of 2-10 days

  • can become life threatening as lose more barrier and risk of microbiome in bloodstream.

• Management:

  • Focus on mucosal healing and supportive care.

  • treatment options - on slide

Patient Factors Affecting Toxicity

• Intrinsic Factors:

  • Comorbidities, genetics

• Extrinsic Factors:

  • Polypharmacy, concurrent treatments.

  • Timing of administration affects chemotherapy efficacy.

  • treatment duration and dose , timing

  • polypharmacy

• timimng og chemo on efficascy- taking in morning vs afternon affects chances of survival in women of one particular drug- timing can affect treatment in specific groups.

Peripheral neuropathy- platinum compoinds floating all aroinf - can do things to immune system , peripheral neurones and microglia - can throw cells out of balance. if cells die , disturbs environment of othrt surrounding cells, lots of extra k , na , ca etc

although peripheral neutones etc are not rapidly dividing cells, they can still, be partially harmed by these medications, as they bind to macromolecules not dna- so can still attach to theur proteins etc. - ownslide of this is thay they are v sensitive tio their environment - loss of balance can lead to inflammation , and the wrong firing of peripheral neurones spo can get peripheral neuropathy - v painful

treatment if platinum induced perioheral neuropathy- slide

selecive uptake inhibs

pharmacological and non pharmacological stratefies

keepinf patieny mobile and exercise can help- but often difficult . within reason for pt

patient factors affectibg chemo induced peripheral neuropathy

• age

• genetics - can test to se if pt likely to be at risk

• comorbidities

• alcohol

intrinsic and extrinsic factors- on slide

cardiotoxicity of doxorubicin- mechamism

complex with iron and mess around with lipids, gets im way of dna -

can lead to degradation of lipids, can mess around w mitochondria , can target topo- tjhen habe problems with smooth ER, whic will then mess around w calcium - muscle tissues are sensitive to calcium dysregulation- leads to cardiotoxixity

overview slide

treatmentof cardiotoxitiy ftom doxo

• can sometomes occur up to 6 months after trestment - premeptively work with thos and give prophylactic cardioprotective medication

• regulate amount of iron

• act on pathways tol work against excessive ca signalling

• various strategies to use - on slides

Lots of pt factors that affect doxo cardiotox

in slides

Immunotherapy Toxicity- therapy that targets the immune sustem to help

block inflammation thay helps the tumour, or help the inflammation that attacks the tumour

types of immunotherapy

depends on the type of immune cells involveds in the cancer

tip the scales so bodys defence works harder than cancers attack

pd1 inhibs- pics to show moa

mabs against pdl1

ici induced colitis- immune checkpoinnt inhib

healthy gut - lots of immune presence here - adding pdl1 inhib gices v v upregulated immune system - in attack mode , so as well as attackng tumour can also attackm and break down tissue

treartment if this

different grades of colitis -

infliximab - dampens immune system back down- bc cant reverse dose of chemo that has already gome into person

pt factors affecting ici induced colotis

• lifestyle

• age, sex

• genetics

pt factors affecting immune related adverse events- on slide= lots of potntial, targets.

patient factors can also affect response to ici therapy

• Common Side Effects: on slide

• red blobs indicate severity, blue indicate incidence

  • Central neurologic disorders (hypophysitis, thyroid dysfunction, colitis).

  • Peripheral neurologic disorders, myocarditis, skin, and liver toxicities.

• Management:

  • Monitor for autoimmune reactions and provide symptomatic treatments.

Targeted Therapy Toxicity

• Common Side Effects:

  • Skin issues, hypertension, slow wound healing, and liver problems.

  • issies w blood pressure

  • high temp

  • diarrhoea

  • Specific toxicities vary by drug class (e.g., anti-angiogenic vs. signal transduction inhibitors). cardiotoxicitie ]s etc.

• Management strategies include dose adjustments and symptomatic treatments.

BRAF and MEK inhibs

normal pathway in healthy cell- get growth factor, it binds to a receptor tyrosine kinase, and causes cascade of phosphorylation events that converge on transcription which causes proliferation and survival. ome of the maon patheays that orchestrates growth and division - is derranged in cancer- allows cancer to acquire hallmarks.

in melanoma- the braf gets mutated to a different amino acid - point mutation - change in single base which changes codon - this then changes the amino acid in a certain position in that protein- means that that protein no longer needs the growth factor to bind to the receptor , the receptor to bind to its one above- in order to signal - so it just signals all the time at a higher rate without any stimulation - so cells grow out of control.

drugs that block braf and the one below it (its workers) to stop this from happenig.

Side effects of these inhibitors-

mechanism- drug tries to block in cancer cells- when have normal cell, this can overstimulate the pathway whihc can lead to lots of issues with over zealius inflammatory responses and issues in the skin.

one od the main ways these drigs can do thos is IRF1- can get switched on too ,much and induce other nasty factors tha cayse strong inflammation in the skin and more likely to haooen in the skin.

Patient factors in braf and mek inhibitors- use slides.

diffweent patient groups have different mutations. - shown on slide.

Toxicity Deep Dives

1. Nausea and Vomiting:

   • Importance of understanding and managing chemotherapy-induced emesis.

   • Advances in controlling symptoms.

2. Gastrointestinal Toxicity:

   • Diarrhea: Significant management strategies are needed, especially for drugs like Irinotecan.

   • Constipation: Mostly caused by vinca alkaloids; managed symptomatically.

3. Bone Marrow Toxicity:

   • Understand leukopenia, thrombocytopenia, and the implications for treatment.

4. Renal Toxicity:

   • Nephrotoxic drugs like Cisplatin; require hydration and monitoring of renal function.