L6 - Principles of systemic anticancer treatment Flashcards
What are the SIX possible approaches to cancer management?
Surgery Radiotherapy Chemotherapy Endocrine therapy Targeted therapy Immunotherapy
What are the main TWO goals when CURING cancer?
Destroy all cancer cells
Prevent recurrence
What are the main FOUR goals when CONTROLLING cancer?
Shrink tumour
Prevent tumour from growing & spreading further
Improve quality of life
Possibly prolong life
What are the main TWO goals when providing cancer PALLIATION?
Reduce & relieve cancer symptoms
Improve quality of life
What are the SEVEN types of chemotherapy/cytotoxic treatment?
Alkylating agents
Anthracyclines
Antimetabolites
Vinca alkaloids
Taxanes
Platinum compounds
Antibody-drug conjugates
What are the THREE types of non-cytotoxic treatment?
Endocrine therapy
Targeted therapy –> tyrosine kinase inhibitors
Immunotherapy –> monoclonal antibodies (checkpoint inhibitors)
What is adjuvant chemotherapy?
Given after surgery to reduce risk of relapse
What is neoadjuvant chemotherapy?
Given to shrink tumour enough to allow curative/less invasive surgery
What is palliative chemotherapy?
Given to relieve cancer symptoms, improve quality of life, possibly prolong life
When is chemotherapy most effective?
Proliferating cells, in M-phase (ie. when cells are dividing)
What are FIVE ways in which chemotherapy works?
Prevent cell replication
Inhibits synthesis of new DNA strands
Blocks formation of nucleotides necessary to create new DNA
Stops mitosis & cell division
Causes cell damage which leads to apoptosis
Why is chemotherapy typically given in 2/3 week cycles?
Timespan for neutrophils to come back up to safe levels for next chemotherapy cycle
What is chemotherapy dosing based on?
Body surface area (BSA)
BSA = square root [ (height cm x weight kg) / 3600 ]
When are dose modifications for chemotherapy doses (when calculated by BSA) needed?
Performance status, age, frailty
Kidney/liver function
Toxicity during cycles –> adjust dose for next cycle
Which cell cycle phase do taxanes work in?
M-phase (mitosis)
How do taxanes work?
Bind to microtubules & stabilise their structure
- -> Prevent anaphase
- -> Prevent cell division
What are examples of taxanes?
Docetaxel
Paclitaxel
What are examples of antimetabolites?
Cytarabine
Methotrexate
Gemcitabine
Fluorouracil (5FU)
Capecitabine
Which cell phase do antimetabolites work in?
S-phase (synthesis of DNA)
How do antimetabolites work? (general)
Substitute themselves for essential metabolites
–> Prevent DNA & RNA synthesis
What are examples of folate antagonists? (antimetabolites)
Methotrexate
Pemetrexed
How does methotrexate work? (antimetabolite)
Inhibits conversion of folic acid –> folinic acid by dihydrofolate reductase
Folinic acid needed for DNA replication
How does pemetrexed work? (antimetabolite)
Inhibits multiple enzymes involved in folate metabolism (inc. dihydrofolate reductase like methotrexate)
When is it preferred to give folic acid over folinic acid?
Smaller methotrexate doses
When is it preferred to give folinic acid over folic acid?
Larger methotrexate doses
Why is folinic acid important if methotrexate is being used?
Co-factor for DNA replication –> causes apoptosis when inhibited
If not supplemented following methotrexate administration, deficiency can cause mucositis, neutropenia etc.
How does fluorouracil (5FU) work? (antimetabolite)
Pyrimidine analogue (actual nucleotide found in DNA) --> "Fraudulent nucleotide" inhibits thymidylate synthetase, enzyme essential in DNA synthesis
What is the prodrug of fluorouracil (5FU)?
Capecitabine
How does folinic acid work with fluorouracil (5FU)?
Increases 5FU toxicity/efficacy –> stabilises complex with thymidylate synthetase
What are examples of anthracyclines?
Doxorubicin
Epirubicin
What cell phase do anthracyclines work in?
NON-phase specific
How do anthracyclines work?
Intercalation of base pairs in DNA double helix
- -> Alkylation of DNA by free radicals
- -> DNA strand breaks by inhibition of topoisomerase II (unwinding enzyme)
- -> No transcription allowed
- -> Inhibit DNA replication
What are examples of alkylating agents?
Cyclophosphamide
Ifosfamide
What cell phase do alkylating agents work in?
NON-phase specific
How do alkylating agents work?
Add alkyl groups to nucleic acids, proteins, amino acids, nucleotides
- -> Crosslink DNA strands (“extra ladder rungs”)
- -> Prevent strand separation & unwinding
- -> Widespread cell damage –> apoptosis
What are examples of platinum compounds?
Cisplatin
Carboplatin
Oxaliplatin
What cell phase do platinum compounds work in?
NON-phase specific
How do platinum compounds work?
Add alkyl groups to nucleic acids, proteins, amino acids, nucleotides
- -> Crosslink DNA strands (“extra ladder rungs”)
- -> Prevent strand separation & unwinding
- -> Widespread cell damage –> apoptosis
What cell phase do platinum compounds work in?
NON-phase specific
Because cisplatin is highly emetogenic, nephrotoxic & ototoxic, what else needs to be given along with its administration?
Fluids –> lots to flush drug through while minimising adverse effects
Monitor
Although carboplatin is more tolerable than cisplatin (less emesis/nephrotoxicity/ototoxicity), what does it have a higher risk of?
Myelosuppression (decreased bone marrow activity)
Neutropenia (low WBC)
Thrombocytopenia (low platelets)
What formula is used to calculate carboplatin dosing?
Calvert formula –> based on CrCl, since carboplatin is almost exclusively excreted renally
What is the main way of excretion of carboplatin
Renal excretion
Which sort of cancer is oxaliplatin indicated for?
GI cancers. eg. colorectal
Although oxaliplatin has the safest side profile compared to cisplatin & carboplatin, what does it have a higher risk of?
Cold-induced neuropathy
- Tingling etc. even when touching cold things, drinking cold drinks
Caution, esp. few days after chemo
Adverse effects of chemotherapy are split into what phases?
Immediate
Early onset
Late onset
What are TWO types of immediate adverse effects of chemotherapy?
Extravasation
Hypersensitivity reactions
What are SEVEN types of early onset adverse effects of chemotherapy?
Haematological
Gastrointestinal –> mucositis, constipation, diarrhoea, nausea & vomiting
Dermatological –> eczema, psoriasis, SJS
Nephrotoxicity, hepatotoxicity
Myalgia (esp. with taxanes)
Neuropathy
Alopecia
What are FIVE types of late onset adverse effects of chemotherapy?
Cardiac toxicity (esp. with anthracyclines)
Pulmonary toxicity
Neurotoxicity (esp. with vinca alkaloids)
Loss of fertility
Secondary malignancies –> most cytotoxic drugs are carcinogenic, since many cause DNA damage
What is haematological toxicity? (early onset)
Most frequent toxicity –> may be dose-limiting
What are the THREE types of haematological toxicity?
Neutropenia –> neutrophils
Thrombocytopenia –> platelets
Anaemia –> RBCs
What is thrombocytopenia?
Low platelets
What does thrombocytopenia result in?
Increased bleeding risk –> low platelets means clotting decreased
How can thrombocytopenia be treated?
Platelet infusion
What is anaemia?
Low haemoglobin in RBCs
What are TWO common symptoms of anaemia?
Fatigue
Shortness of breath
How can anaemia be treated?
RBC transfusion (epoetin alfa)
Why is neutropenia most dangerous?
Occurs relatively quickly (short neutrophil lifespan)
Increased susceptibility to infection
May cause delay/dose reductions
How can neutropenia (not febrile) be treated or prevented?
G-CSF
- Filgrastim
- Pegfilgrastim
What is the difference between filgrastim & pegfilgrastim?
Pegylated version increases molecule size
- -> Harder to metabolise/break down
- -> Longer half-life & duration of action
- -> Reduced dosing frequency
Filgrastim preferred in shorter chemo cycles eg. 1-2 weekly –> cleared fast enough for next dose
Pegfilgrastim required at least 14 days before next chemo cycle
Why are G-CSF treatments not used in acute myeloid leukaemia?
Neutrophils come from the myeloid line –> in leukaemia, there are too many WBC.
G-CSF stimulates blood cell growth –> may increase risk of blood cancer
What temperature is considered febrile neutropenia?
38.3°C & low neutrophil count < 0.5 x 10⁹/L
How can febrile neutropenia be treated?
[guidelines]
Empiric antibiotics
G-CSF –> if no improvement after 48 hours
What investigations are involved in a “septic screen”?
Blood cultures
Midstream urine sample
Chest xray
What are the THREE phases of chemo-induced nausea & vomiting
Acute onset
Delayed onset
Anticipatory
Which FOUR chemotherapy drugs have HIGH emetogenic risk?
Cisplatin
Dacarbazine
Anthracycline/cyclophosphamide combination
High-dose cyclophosphamide
Which FOUR chemotherapy drugs have MODERATE emetogenic risk?
Carboplatin
Epirubicin
Irinotecan
Oxaliplatin
Which FOUR chemotherapy drugs have LOW emetogenic risk?
Docetaxel
Paclitaxel
Fluorouracil
Methotrexate
Which TWO chemotherapy drugs have MINIMAL emetogenic risk?
Vinorelbine
Vincristine
What FOUR drugs are used for HIGH emetic risk with chemotherapy?
Aprepitant
Olanzapine –> dopamine receptors also targeted by antipsychotics
Dexamethasone
Ondansetron
What TWO drugs are used for MODERATE emetic risk with chemotherapy?
Dexamethasone
Ondansetron
What TWO drugs are used for LOW emetic risk with chemotherapy?
Dexamethasone
Ondansetron
Which TWO types of emesis does dexamethasone work on?
Acute onset
Delayed onset
Which TWO types of emesis does aprepitant work on?
Acute onset
Delayed onset
[only for highly emetic chemo]
Which ONE type of emesis does ondansetron work on?
Acute onset
Which TWO types of emesis does olanzapine work on?
Acute onset
Delayed onset
Which ONE type of emesis does lorazepam work on?
Anticipatory –> helps calm patient down
Usually if have had bad experiences with chemo before –> psychological
Which chemotherapy drugs usually cause diarrhoea?
Capecitabine
Irinotecan
Less commonly fluorouracil, docetaxel
What is the THREE step treatment plan for chemotherapy-induced diarrhoea?
Loperamide (higher doses than normal)
Codeine
Octreotide (continuous SC infusion)
–> usually nil by mouth when on chemo –> total parenteral nutrition may be needed to reduce malnutrition
How do monoclonal antibodies work? (TWO ways)
Stimulate patient’s immune system to destroy target
Prevent growth by blocking target
What is the most common ADR with monoclonal antibodies?
Infusion-related –> allergic
What are the THREE types of immune checkpoint inhibitors?
PD-1 inhibitors –> nivolumab, pembrolizumab
PD-L1 inhibitors –> atezolizumab
CTLA-4 inhibitors –> ipilimumab
What does it mean when the Death Star is firing at Alderaan?
Tumour cells destroying normal cells. Activity not inhibited
What does it mean when Admiral Ackbar is telling the Rebels about the Death Stars deflector shield?
Tumour cells have mechanisms to stop T cells from attacking them
How does PD-1 & PD-L1 work?
PD-1 (T cell) usually binds to PD-L1 (normal cell) & this inactivates T cells –> do not attack
Tumour cells able to express PD-L1 –> T cell inactivated & tumour cell free to replicate/grow
What does it mean with Han, Luke & Leia?
Deflectors shields need to be brought down by them on the forest moon of Endor
Checkpoint inhibitors
How do checkpoint inhibitors work?
Block binding of PD-1 & PD-L1
- -> T cell not inactivated by tumour cell
- -> T cell can continue attacking tumour cells
What does it mean when the Millenium Falcon destroys the Death Star’s exhaust port?
T cell attacking & destroying tumour cell
What are the TWO main adverse effects of immunotherapy & TWO less common ones?
Immune-related adverse effects
Fatigue
Less common: nausea, low blood counts
What are FIVE examples of immune-related adverse effects?
Hormonal effects –> eg. initial hyperthyroidism flare then persistent hypothyroidism
Hepatitis, nephritis
Pneumonitis –> breathlessness, cough
Colitis –> diarrhoea
Skin rash, itch
What are the grades for immune-related adverse effects?
1: Mild
2: Moderate
3: Severe
4: Life-threatening
How are the different grades of immune-related adverse effects managed?
1: Treat symptomatically; continue with checkpoint inhibitors
2: Withhold checkpoint inhibitor, start prednisone. Resume checkpoint inhibitor when symptoms return to grade 1
3 & 4: Permanently discontinue checkpoint inhibitor, start higher prednisone dose
If ADRs not resolved with prednisone, consider infliximab or mycophenolate (for hepatitis)
How are other immune-related adverse effects (eg. hypothyroidism & hyperthyroidism) managed?
Hypothyroidism: levothyroxine
Hyperthyroidism: watch & wait –> generally initial flare followed by persistent hypothyroidism
What does hypercalcaemia as a complication of cancer lead to?
Drowsiness
Confusion
Osteoporosis
Risk of cardiac arrhythmias
How is hypercalcaemia as a complication managed?
Rehydration –> fluids
Zoledronic acid, pamidronate
Why is zoledronic acid preferred over pamidronate for hypercalcaemia?
100x more potent
Less frequent administration
Shorter duration of infusions
