Treatment of Cancer (chemo, radiotherapy and targeted biological therapies)

Question 1

what consists of ionising radiation?

Answer 1

high energy sources are gamma rays and x-rays
gamma rays = originate in cell nucleus of radioactive isotopes
x -rays = originate in electron fields or artificially produced by bombarding accelerating electrons to a target
(above no mass only packets of energy)

alpha and beta particles (mass and energy)

Question 2

difference between photoelectric effect and compton scattering

Answer 2

photoelectric effect = lower energy radiation (like seen in x rays and CT) is all absorbed by the atom based and is based on atomic number. the higher the atomic number the greater the absorption is.

with compton scattering in higher energy such as radiotherapy the incoming photon is scattered and reflected out. is independent of atomic number

Question 3

the mechanism of radiotherapy:

Answer 3

when radiation targets a molecule such as water/oxygen a free radical is formed. A free radical is a molecule with an unpaired electron that is highly reactive and can damage DNA by causing a single, double strand break or base mutation.

Question 4

types of radiotherapy

Answer 4

• external beam radiotherapy Dose per fraction 2-3 Gy
• stereotactic body RT or stereo active ablative RT (6-11 Gy) much higher dose)
• brachytherapy (pellets directly into a tumour) (follows inverse square law in which the tissues further away from the pellet receive inversely less radiation thus non-cancerous tissue is more protected
• brachytherapy in unsealed sources such as radioactive iodine which is taken as a pill and accumulates in certain places eg thyroid

Question 5

what is Gray

Answer 5

radiation dose
1 Gy is 1 J of energy absorbed per kg of matter

Question 6

radiotherapy can be split into..

Answer 6

radical treatment = curative
palliative treatment = alleviate symptoms
fractionated RT = given over several days

Question 7

applications of radical treatment

Answer 7

local and loco-regional treatment and early disease as with surgery
can be used alone, with surgery or with chemo

Question 8

advantages of radical radiotherapy

Answer 8

organ preservation
function preservation
cosmesis

Question 9

other applications of radiotherapy:

Answer 9

palliative =
pain: bone metastasis
bleeding = haemoptysis, tumour bleed

relief of obstruction in SVC, bronchial obstruction or spinal cord compression

adjuvant RT: to treat microscopic disease that is not seen on a imaging modality/macroscopic disease

Question 10

acute side effects of RT

Answer 10

skin = erythema, pruritus, desquamation
mucosa = mucositis
oesophagitis + dysphagia
lung = pneumonitis - cough and dyspnoea
liver - hepatitis
rectum = proctitis
haematopoietic = anaemia and leucopenia
systemic = lethargy
nerve = myelitis

Question 11

late/chronic side effects of RT

Answer 11

fibrosis occurring in many sites of body, telangiectasia, stricture + fistula,

radiation necrosis, growth retardation and asymmetry in bone

myelofibrosis

tumorigenesis

permanent nerve damage

Question 12

4 types of chemotherapy

Answer 12

• curative = cures the cancer permanently
• adjuvant = given after a local treatment such as surgery or radiotherapy
• neoadjuvant = given prior to a local treatment (shrinks the tumour)
• palliative = providing relief from symptoms

Question 13

4 classes of chemotherapy drugs

Answer 13

• Alkylating agents cause cross linking of DNA, damaging it and thus preventing protein synthesis. Examples include cyclophosphamide, cisplatin and dacarbazine
• anti-metabolites are designed to block DNA synthesis. Have similar structure but altered chemical groups —> errors —> apoptosis. Examples are 5 fluorouracil and methotrexate
• topoisomerase inhibitors inhibit enzymes from unwinding DNA, can’t be replicated. Example = etoposide
• anti-microtubule agents = hyper-stabilisation of microtubules = inflexible = blocks cell division. Example paclitaxel and vinblastine

Question 14

How can cancers become resistant to therapies

Answer 14

• change in sensitivity or binding affinity of target enzymes or receptors
• decreased drug accumulation due to increased expression of glycoprotein transporters or decreased permeability
• formation of drug-inactivating enzymes
• formation of reactive chemicals that trap anti cancer drug
• increased nucleic acid repair mechanisms
• reduced activation of pro-drugs

Point two: MDR-1 gene is responsible for glycoprotein that is involved in drug efflux

Question 15

Difference between primary and secondary drug resistance

Answer 15

Primary = tumour shows resistance from the start, never responds to treatment
Secondary = occurs later in tumour development

Question 16

What other cells with a high growth fraction are affected by chemotherapy

Answer 16

Bone marrow
Hair follicles
GI mucosa
skin
Nails

Question 17

Common side effects of chemotherapy:

Answer 17

• decreased WBC, RBC and platelets
• alopecia
• stomatitis or mucositis
• nausea or vomiting
• extravasation = leakage of intravenous drugs into surrounding tissues

Question 18

What are some of the limitations of conventional cytotoxic therapies

Answer 18

Lack of specificity
Toxicity of chemotherapeutic agent
Lack of effectiveness
Lack of individualisation

Question 19

Normal role of EGFR and pathway under normal conditions and what happens in cancer

Answer 19

Epidermal growth factor receptor is activated by ligands such as EGF and transforming growth factor. This causes it to form a homodimer or heterodimer that are now active. Dimerisation stimulates intrinsic auto phosphorylation of tyrosine residues. This elicits downstream activation of other proteins. Cascade of signal transduction begins leading to DNA synthesis and proliferation.

In cancer mutations (somatic) lead to over expression of EGFR or over activity —> uncontrolled cell division
Seen in squamous cell carcinoma of lung, anal cancers, glioblastoma and epithelial tumours of head and neck

Question 20

What drugs can be used to target EGFR

Answer 20

• monoclonal antibody inhibitors. Cetuximab is a monoclonal antibody that blocks the extracellular ligand binding domain so pathway is not initiated
• small molecule kinase inhibitors such as gefitinib which inhibit tyrosine kinase which is not able to activate itself and signalling cascade is halted

Question 21

How do immune checkpoint inhibitors work and examples of PD-1 inhibitors and PD L1 inhibitors

Answer 21

Immune checkpoints are molecules that turn up a signal or turn down a signal in the immune system
Programmed cell death 1 protein and its ligand PD L1.
PD1 is located on immune cells such as T cells, NK, B lymphocytes, macrophages, dendritic cells and monocytes. When PD L1 binds to PD1 activity of immune cells is inhibited. In cancer PD L1 is upregulated so cancer cells are able to evade immune system

PD1 inhibitors = permbrolizumab
PD L1 inhibitors = atexolizumab

Question 22

What is an example of another protein located on T cells that inhibits its activity in cancer + example of an inhibitor of this protein

Answer 22

Cytotoxic T. Lymphocyte associated protein 4 (CTLA-4)

Monoclonal antibodies can attach to protein and stop it from working thus boosting immune response to cancer cells

CTLA-4 inhibitor = ipilimumab

Question 23

What stimuli any turn on an angiogenic switch in tumour cells

Answer 23

Oxygen deprivation

Inflammation
Oncogenic mutations
Mechanical stress

Question 24

What pro-angiogenic paracrine factors do tumour cells secrete

Answer 24

Angiogenin
VEGF
Fibroblast growth factor FGF
Transforming growth factor

Question 25

What strategies can be used to prevent angiogenesis in tumour cells

Answer 25

Antibodies directed against VEGF, or VEGFR
Soluble VEGF/VEGFR hybrids
Tyrosine kinase inhibitors

Question 26

Major adverse effects cell signalling therapy (EGFR inhibitors)

Answer 26

Papulopustular rash across face and torso
Diarrhoea
Vomiting
Nausea
Fatigue
Dehydration

Question 27

How do many patients develop resistance to EGFR inhibitors

Answer 27

Through mutation of T790M
MET oncogene

Question 28

Common SE of immune checkpoint inhibitors

Answer 28

Can allow Immune system to attack some normal body organs

Fatigue
Nausea
Loss of appetite
Skin rash
Itching

Question 29

Common side effects of angiogenic inhibitors

Answer 29

Bleeding
Hypertension
Rash or itchy skin
Diarrhoea
Fatigue
Low blood count