Chemo

Question 1

Give a example of a molecular targeting drug

Answer 1

Bc-able tyrosine kinase inhibitor, imatinib (gleevec): Disease with a signature specific to it - drugs to target it specifically. Imatinib to argent cml . Agent to block catalytic part of receptor - cant signal down to grow cml cells.

• Magic bullet
• Rationally designed
targets and inhibitors
• Tumour selective
• More efficacious
• Fewer side effects

Question 2

What is the fractional cell kill hypothesis

Answer 2

Give bolus of chemo (arrow) - hits both. Tumour and rapidly dividing cells. Bone marrow cells are hit. All the cells dying, but then bm start to recover more quickly than cancer. Want to time next cycle when bm cells have recovered and tumour cells haven’t got back to original number. Also some bm cell reduction - but need supportive techniques to manage patient

Question 3

Describe classification of tumour according to chemo sensitivity

Answer 3

Highly Sensitive - May only need
chemo to cure
Lymphomas Germ cell tumours Small cell lung Neuroblastoma Wilm’s tumour

Modest Sensitivity - More common solid tumours. Not
going to be able to use chemo alone
- use in addition to surgery and radio
Breast Colorectal Bladder Ovary Cervix Lung

Low Sensitivity - Hav good targeted agents to renal cell
tumour - family members of imatinib
Prostate Renal cell Brain tumours Endometrial

Question 4

How do alkylating agents work

Answer 4

Bind to negatively charged sites on DNA molecule, which links a chain of carbon atoms to either side of the DNA in the double helix - this is called alkylation. The large side group which is attached impairs replication and is recognised as foreign and the section of DNA it is attached to is cleaved out, causing a single strand break. Alkylation at multiple points can cause DSB and lead to apoptosis of the cell.

Question 5

What is an issue with alkylating agents

Answer 5

Tumour cells can recognise the drug and pump it back out - no successful way to make sure gets into cell.

Also glutathione in cell can mop up the drug and neutralise it.

Question 6

How do platinum compounds work

Answer 6

Formation of platinated inter- and intrastrand adducts, leading to inhibition of DNa synthesis.The large side group which is attached is recognised as foreign and the section of DNA it is attached to is cleaved out, causing a single strand break. Can’t repair it.
G-G: 55%
G-A: 31%

Question 7

Name 2 antimetabolites

Answer 7

Methotrexate
5-Fluorouracil

Affects DNA synthesis

Question 8

When are antimetabolites used

Answer 8

Methotrexate:

• Haematological malignancies,
• Rheumatoid arthritis

5-FU:

• Common in oncology clinics
• Head and neck cancer
• Colorectal adenocarcinoma

Question 9

How does methotrexate work?

Answer 9

Methotrexate: inhibits dihydrofolate reductase - Critical in folate cycle. Dihydrofolate reductase catalyses conversion of dihydrofolate to the active tetrahydrofolate. Can’t form purines to make amino acids - the key carrier of one-carbon units in purine and thymidine synthesis - FOLATE CYCLE
- Methotrexate, therefore inhibits the synthesis of DNA by impairing purine synthesis

Question 10

How does 5-fu work

Answer 10

5-FU: Inhibit the enzyme thymidylate synthase which is necessary to the DNA synthesis pathway.

Question 11

What are spindle poisons?

Answer 11

Taxoids
Vinca alkaloids

Mitotic inhibitors - DNA damage and cell death
Once chromosomes are aligned at metaphase plate,
spindle microtubules depolymerize, moving sister
chromatids toward opposite poles
• Nuclear membrane re-forms and cytoplasm divides

Question 12

How do taxoids work?

Answer 12

Taxoids:
Promote spindle polymerisation (assembly) and prevent depolymerisation (disassembly): the cell becomes so rigid that it cannot divide

Question 13

How do vinca alkaloids work?

Answer 13

Vinca Alkaloids: Prevent spindle polymerisation (assembly) in the first place, which stops cell cycle

Question 14

What are the indications for chemo

Answer 14

Use: Cancer, rheumatoid arthritis. Administered depending on performance status, clinical stage, prognostic factors and molecular diagnostics
Aim is different in different malignancies

Question 15

What is predicted response based on?

Answer 15

predicted response is also different within the same
cancer based on:
– performance score
– clinical stage
– prognostic factors or score (often involving biological factors)
– Molecular or cytogenetic markers

Question 16

How are multiple drugs used together?

Answer 16

For many types of cancer, chemotherapy regimen will
consist of a number of different drugs - combination
chemotherapy – usually given an acronym. A drug may be given as a single agent.

Question 17

What are the routes of administration for chemo?

Answer 17

– IV is the most common – bolus, infusional bag, continuous pump
infusion
– PO convenient, dependent on oral bioavailability
– SC convenient in community setting
– Into a body cavity – bladder, pleural effusion
– Intralesional - directly into a cancerous area – consider pH
– Intrathecal - into the CSF – by lumbar puncture or omaya reservoir
(directly into ventricles)
– Topical -medication will be applied onto the skin
– IM rarely

Question 18

Describe the use of IV lines

Answer 18

Repeated cycles - can damage veins. So end to
use central lines - can be Hickman line - needle
goes into chest but tuned under skin and going
to scc under clavicle - tunnelling helps to
prevent infection - macrophages in the skin to
combat this. Patients can wear a pump on the
belt. A pic line plastic tube going into larger vein
in arm - connected to a pump, worn under
elastic stocking, can go home with this. Only
inpatients of theyre having treatment for
leukaemia, teratoma, sarcoma, bm transplant.
Not usual on oncology wars

Question 19

What are the side effects of chemo

Answer 19

Affects dividing cells - alopecia (all body hair - can grow back on chemo as well), mucositis (mouth and gut - diarrhoea, GI bleed, sore mouth/throat - get secondary infections), bladder (inflammation - cystitis), nausea and vomiting (acute or delayed - can be controlled), sterility, skin toxicity (if doesn’t go into vein properly - necrotic, if feet gets sore don’t take), cardio-toxicity (myopathy or arrhythmias), lung toxicity (Bleomycin drug for testicular tumours but can cause pulmonary fibrosis and worse with oxygen - carry cards) and haematological toxicity (most frequent cause of death - die from neutropenic sepsis, decreased white cells)

Question 20

What are the adverse effects of chemo

Answer 20

• Acute renal failure - often multifactorial – hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules

• GI perforation at site of tumour – reported in lymphoma
Patch of lymphoma covering pne particular area of stomach. This melts away, can leave a perforation.
Peritonitis - patients will die of this. If risk of perforation, get them in hospital, fed artificially. If they get
a perforation you can manage conservatively

• Disseminated intravascular coagulopathy eg onset within a few hours of starting treatment for acute myeloid leukaemia - can die of this

Question 21

Describe vomiting as a side effect of chemo

Answer 21

• Multifactorial but includes direct action of
chemotherapy drugs on the central
chemoreceptor trigger zone
• Patterns of emesis
– acute phase 4 - 12 hours
– delayed onset, 2 - 5 days later
– chronic phase, may persist up to 14 days

Question 22

Describe alopecia as a side effect of chemo

Answer 22

• Hair thins at 2 - 3 weeks
• May be total
• May re-grow during therapy
• Marked with doxorubicin, vinca alkaloids, cyclophosphamide
• Minimal with platinums
• Help sometimes with scalp cooling

Question 23

Descrube skin irritation as a side effect of chemo

Answer 23

• Local
– Irritation and thrombophlebitis of veins
– extravasation

• General
– bleomycin
• hyperkeratosis
• hyperpigmentation
• ulcerated pressure sores
– busulphan, doxorubicin, cyclophosphamide,
actinomycin D
• Hyperpigmentation

Hand foot syndrome. If your feet get sore stop taking
tablets?? But there is overcompliance for chemo/
patient education

Question 24

Describe mucositis with chemo

Answer 24

• Gastrointestinal tract epithelial damage
• May be profound and involve whole tract
• Most commonly worst in oropharynx
• Presents as
– sore mouth/throat
– diarrhoea
– G.I. bleed

Question 25

Describe cardio toxicity as an adr of chemo

Answer 25

• Cardio-myopathy
– doxorubicin ++ (> 550 mg/m2)
– high dose cyclophosphamide
– mortality approx. 50%

• Arrhythmias
– cyclophosphamide
– etoposide
alkylating agents do this

Question 26

Describe lung toxicity as an adr of chemo

Answer 26

• Bleomycin
– pulmonary fibrosis
– beware concurrent radiotherapy

• Mitomycin C, cyclophosphamide,
melphalan, chlorambucil
– pulmonary fibrosis

Bleo. Effective at cutting testicular tumours. But can get lung toxicity - fibrosis that
gets worse esp if you give oxygen. Lungs get a reaction, short of breath, give o2 , but
not good. So patients have to carry cards for life. Reactions can happen quite late
after event

Question 27

Describe the haematological toxicity of cancer therapy

Answer 27

• Most frequent dose limiting toxicity
• Most frequent cause of death from toxicity
• Different agents cause variable effects on
degree and lineages
– Neutrophils
– platelets

All aspects of bld count can be affected. wcc most significant. - neutropenia - sepsis quickly - die.

Question 28

What does dose for a specific patient depend on

Answer 28

Dose needs to be altered for the individual patient based on
– their surface area and/or body mass index
– drug handling ability (eg liver function, renal function… dependent on the metabolism and
excretion routes)
– general wellbeing (performance status and comorbidity)

Question 29

What does treatment phasing (eg over a period of time) need to take into account

Answer 29

• Treatment phasing needs to take into account the balance between:
– growth fraction
– the ‘cell kill’ of each cycle of the chemotherapy regimen
– marrow and GI tract recovery before next cycle
– how tolerable is the regimen – both short term organ toxicity and physical side effects and
long term damage causing late effects

• Hence…way up the role and dose of chemotherapy for every cancer patient
individually and always remember the aim of the treatment

Question 30

What causes variability in the PK of chemo

Answer 30

• Abnormalities in absorption
– N+V, compliance, gut problems
Diarrhoea - affect absorption

• Abnormalities in distribution
– Weight loss, reduced body fat, ascites etc
Ascites due to cancer- drugs stay in fluid - toxicity over longer period of time

• Abnormalities in elimination
– Liver and renal dysfunction, other meds

• Abnormalities in protein binding
– Low alb, other drugs

Question 31

What are important DDIs for chemo

Answer 31

• Other drugs may increase plasma levels of the
chemotherapy drug (and therefore side effects)

– Vincristine and itraconazole (a commonly used antifungal) leads
to more neuropathy
– Capecitabine (oral 5FU) and warfarin
– Methotrexate – caution with prescribing penicillin, NSAIDs
– Capecitabine and St Johns Wort, grapefruit juice

Question 32

How are patients monitored during chemo

Answer 32

• Response of the cancer
– Radiological imaging
– Tumour marker blood tests
– Bone marrow/cytogenetics

• Drug levels
– Eg Methotrexate drug assays taken on serial days to ensure
clearance from the blood after folinic acid rescue

• Checks for organ damage
– Creatinine clearance
– Echocardiogram

Question 33

How do drugs get from “bench to bedside”

Answer 33

ss

Question 34

What are some new targeted therapies

Answer 34

• Chemotherapy is the treatment of cancer with drug therapy –
traditionally this applies to cytotoxic drugs
• Over the years more classes of drugs have been introduced to treat
cancer..
– Hormones
– Now… targeted drug therapy eg
• Monoclonal antibodies
• Drugs inhibiting angiogenesis
• Drugs targeting gene expression
• Signal Transduction inhibitors
• Drugs interfering with the apoptotic pathways
• Drugs interfering with cell cycle control
• Cytokines
• Immunotherapy