Role of the Pharmacist in Malignant Disease [COMPLETE] Flashcards
1
Q
What are alkylating agents?
A
Highly reactive compounds with an electrophilic alkyl group that can covalently link to nucleophilic groups in proteins such as DNA, RNA and proteins
2
Q
What are some examples of nitrogen mustard alkylating agents?
A
CYCLOPHOSPHAMIDE
MELPHALAN
Chlorambucil
Mechlorethamine
3
Q
Outline the mechanism of action of alkylating agents such as CYCLOPHOSPHAMIDE and MELPHALAN
A
- the chloride ion is displaced by the amine nitrogen to form a positively charged aziridinium ion
- The aziridinium ion will alkylate the N-7 of guanine as it is nucleophilic
- This forms a monoalkylated adduct
- The second chloride ion is then displaced by an amine nitrogen which forms another aziridinium ion which can alkylate N-7 of guanine completing the process of alkylation
4
Q
At which bases and postions can alkylation occur?
A
Guanine N-7 > Adenine N-3 > Adenine N-7 > Guanine N-3
5
Q
Which type of crosslink is associated with the antitumour potency of alkylating agents such as CYCLOPHOSPHAMIDE and MELPHALAN?
A
InTERstrand - crosslinks between to adjacent guanines of DIFFERENT DNA strands
6
Q
How does the formation of interstrand crosslinks give an antitumour effect?
A
Enzymes such as DNA helicase cannot seperate the DNA strands prior to replication and transcription. DNA damage is sensed by the cell -> checkpoint activation -> DNA cannot be repaired –> APOPTOSIS
7
Q
What factors need to be considered when considering route of administration of alkylating agents such as CYCLOPHOSPHAMIDE and MELPHALAN? (3)
A
Water solubility
Vesicant properties (BLISTERING AGENTS so should be kept away from the skin)
Rate of transformation to active intermediate (CYCLOPHOSPHAMIDE)
8
Q
How is CYCLOPHOSPHAMIDE converted into its active metabolite?
A
Undergoes microsomal Cytochrome P450 dependent metabolic activation in the liver
9
Q
What are the clinical uses of CYCLOPHOSPHAMIDE? (5 - BELLO)
A
Lymphoid tumours
Breast
Lung
Ovarian
Endometrial
10
Q
How is CYCLOPHOSPHAMIDE administered?
A
Oral or intravenous
11
Q
What are the clinical uses of MELPHALAN? (3 - MOB)
A
Multiple myeloma
Ovarian
Breast
12
Q
How is MELPHALAN administered?
A
oral or intravenous
13
Q
MELPHALAN is a phenylalanine derivative of which nitrogen mustard?
A
Mechlorethamine
14
Q
Are nitrogen mustard alkylating agents such as CYCLOPHOSPHAMIDE and MELPHALAN cell cycle specific?
A
NO
15
Q
What are the side effects of alkylating agents such as CYCLOPHOSPHAMIDE and MELPHALAN? (1 acute, 1 delayed)
A
Acute: Nausea and vomiting (level 3 to 4 : MODERATE TO HIGH)
Delayed: Bone marrow depression (DOSE LIMITING) - thrombocytopaenia and leukopaenia
16
Q
What is a dose limiting toxicity?
A
Side effect that is serious enough to prevent an increase in dose
17
Q
What are some specific toxicities associated with the use of CYCLOPHOSPHAMIDE? (2)
A
Alopecia
Haemmorhagic cystitis
18
Q
How can we reduce the risk of haemmorhagic cystitis in patients taking CYCLOPHOSPHAMIDE?
A
Use of MESNA - a organic sulphur compound the detoxifies urotoxic compounds derived from CYCLOPHOSPHAMIDE such as acrolein
19
Q
Why does the risk of acute myeloid leukaemia increase with taking alkylating agents like CYCLOPHOSPHAMIDE and MELPHALAN?
A
They are cytotoxic, mutagenic and carcinogenic
20
Q
Why is CISPLATIN described as an alkylating-like agent?
A
Forms adducts but doesn’t have an alkyl group so cannot alkylate
21
Q
Are CISPLATIN and transplatin both biologically active?
A
NO
22
Q
Describe the process of aquation after the administration of CISPLATIN?
A
Chloride ion in CISPLATIN is replaced by water after it enters the cell
23
Q
After aquation how does CISPLATIN interact with DNA?
A
The aqua ligand can be easily displaced so that platinum can bind to bases in DNA.
24
Q
What is the preferred base for platinum in CISPLATIN to bind to?
A
Guanine at N-7
25
When does crosslinking occur after the aquation process?
After BOTH chloride ligands have been replaced with water
26
Outline the mechanism of action of CISPLATIN?
1. CISPLATIN forms adducts with DNA to significantly alter its structure
2. It can crosslink DNA in several ways to interfere with cell division
Damaged DNA --> repair mechanisms activated --> repair is impossible --> APOPTOSIS
27
90% of intRAstrand crosslinks formed by CISPLATIN are...
1,2 GpG and ApG (guanine-guanine) and (adenine-guanine)
28
What other adducts/crosslinks are formed by CISPLATIN?
1,3 intRAstrand crosslinks
intERstrand crosslinks
monofunctional adducts
29
What are the clinical uses of CISPLATIN? (4 - SCOT)
Small cell lung cancer
Colerectal cancer
Ovarian cancer
Testicular cancer
30
How is CISPLATIN administered?
Intravenously as a short term infusion
31
What is the main ACUTE toxicity of CISPLATIN?
Severe nausea and vomiting (level 4 - 90% of patients)
32
What are some DELAYED toxicities of CISPLATIN? (4)
Ototoxicity
Peripheral neuropathy
Bone marrow depression - neutropenia
NEPHROTOXICITY (dose limiting)
33
What monitoring and supportive care is needed due to the nephrotoxic effect of CISPLATIN?
Creatinine clearance monitoring
Adequate hydration (IV fluids) to protect kidneys
34
What are the mechanisms of antitumour activity in topoisomerase inhibitors?
1. Inhibiting topoisomerase II
2. Binding to double stranded DNA
3. Formation of ROS
35
What are topoisomerases?
Enzymes the bind to single and double stranded DNA to form transient breaks so DNA can be unwound. The DNA backbone is resealed at the end. They are needed for the control of DNA supercoiling
36
What are the functions of topoisomerases?
Unwinding of DNA to allow enzyme access during replication and transcription
Separation of daughter chromosomes after replication
Maintaining supercoil structure
37
What is the difference between topoisomerase I and topoisomerase II?
Topoisomerase I breaks only ONE DNA strand. Topoisomerase II breaks BOTH DNA strands.
38
How does topoisomerase II work?
Cleaves BOTH strands of the DNA double helix
Transports another double helix through the break and then reseals cleaved strand
39
What are the anthracyclines?
Topoismerase inhibitors : DOXORUBICIN (hydroxydaunomycin), daunomycin and idarubicin
40
What is the main mechanism of action through which topoisomerase inhibitors such as DOXORUBICIN exert their antitumour effect?
1. Forms a stable ternary complex: drug-DNA-topoisomerase II
2. Stabilisation of intermediate --> DNA is covalently linked to topoisomerase II
3. DNA cannot be resealed
4. DNA double strand breaks
5. Repair is attempted by DNA repair enzymes
6. DNA cannot be repaired and multiple double strands broken
7. APOPTOSIS
41
What is essential for the formation of the drug-DNA-topoisomerase complex?
Daunosamine sugar (remember DOXORUBICIN is also called hydroxyDAUNOmycin)
42
How does the binding of toposiomerase inhibitors such as DOXORUBICIN to double stranded DNA cause antitumour activity?
Structural changes due to reversible intercalation of the planar aromatic ring of DOXORUBICIN into DNA and amino sugar being in the minor groove.
Stacked bases seperate and DNA double helix is partially uncoiled
43
What functional changes do the structural changes that occur after DNA intercalation by topoisomerase inhibitors such as DOXORUBICIN cause?
Inhibition of replication AND transcription --> CELL DEATH
44
How are ROS formed by anthracycline topoisomerase inhibitors such as DOXORUBICIN?
1. Quinone scaffold is reduced to give semiquinone and dihydroquinone
2. Semiquinone is an instable radical anion that is converted back to doxorubicin to release ROS as it reacts with oxygen to form SUPEROXIDE and HYDROGEN PEROXIDE
45
What does the formation of ROS by DOXORUBICIN lead to? (4)
DNA damage
Oxidation of proteins
Damage of cell membranes
APOPTOSIS
46
What can semi-quinone and ROS lead to cardiotoxicity?
semi-quinone, hydrogen peroxide and superoxide can reduce iron (III) to iron (II) which produces hydroxyl radicals which can damage cardiac tissue. The heart contains a low level of detoxifying enzymes
47
What are some toxicities related with the use of anthracyclines such as DOXORUBICIN? (4)
Alopecia
Myelosuppresion
Nausea and vomiting (Moderate 30-90%)
Cardiotoxicity (DOSE limiting)
48
What are the early and delayed cardiotoxicities caused by anthracyclines such as DOXORUBICIN?
Early: some transient ECG changes
Delayed: cardiomyopathy/congestivev heart failure which may take years to occur
49
What is the significance of cumulative lifetime dose when administering anthracyclines such as DOXORUBICIN?
Cumulative lifetime dose is related to cardiotoxicity and is calculated during treatment. Anthracycline treatment is STOPPED once maximum cumulative dose is reached.
50
What happens if DOXORUBICIN is administered alongside Herceptin (Trastuzumab)?
Risk of congestive heart failure increases and can occur below the calculated max. cumulative dose
51
When is cardiac monitoring recommended in administering anthracyclines such as DOXORUBICIN?
ALL patients: baseline and 3, 6 and 9 months
52
What are the clinical uses of DOXORUBICIN? (9)
BROAD spectrum of activity.
Breast
Bladder
Endometrium
Lung
Ovarian
Thyroid
Sarcoma
Lymphoma (Hodgkins and Non-Hodgkins)
Leukaemia
53
How is DOXORUBICIN (and all anthracyclines) administered?
Intravenously
54
What is ETOPOSIDE?
A plant alkaloid that also inhibits topoisomerase II by forming a ternary complex with DNA and topoisomerase II
55
What are the clinical uses of ETOPOSIDE ?
Testicular cancer
Small cell bronchial carcinoma
Often used in combination with other drugs
56
How is ETOPOSIDE administered?
Oral or IV
57
What are some toxicities of etoposide?
Alopecia
Hypotension
Myelosuppression
Nausea and vomiting
58
What are antimetabolites?
Antimetabolite drugs inhibit essential biosynthetic processes or incorporate into DNA and RNA to inhibit their normal function
59
What are antifolates?
Drugs that antagonise the actions of folic acid such as METHOTREXATE during the DNA and RNA synthesis (S phase of cell cycle)
60
What are the primary functions of folate in the body?
It is a cofactor for various methyltransferases needed for serine, methionine, thymidine and purine synthesis.
61
What effects do antifolates such as METHOTREXATE have on cell division?
Inhibit cell division by inhibiting DNA/RNA synthesis and repair and protein synthesis
62
What is the primary target of antifolates such as METHOTREXATE?
Enzyme DHFR (dihydrofolate reductase) which reduced dihydrofolate to tetrahydrofolate.
63
How does METHOTREXATE inhibit DHFR?
Has a very similar structure to dihydrofolate but a higher affinity (1000x) for DHFR. Competitive inhibitor
64
Outline the mechanism of action of METHOTREXATE.
1. Enters cells via the reduced folate carrier and membrane folate binding protein
2. Undergoes polyglutamation to become a potent inhibitor of DHFR
3. Inhibits DHFR to give lower levels of tetrahydrofolate
4. Less THF = less thymidylate which is needed for DNA synthesis
5. Growth arrest in rapidly proliferating cells and CELL DEATH
6. Polyglutamate tail is hydrolysed in the lysosome by GGH so methotrexate can leave the cell
65
Clinical uses for METHOTREXATE.
Breast
Head and neck
Acute lymphoblastic leukaemia
Lymphoma
Osteosarcoma
Choriocarcinoma
66
What toxicities are associated with METHOTREXATE?
Bone marrow suppression (LEUKOPAENIA)
Oral mucositis, stomatitis
67
What supportive care is needed for HIGH dose METHOTREXATE.
Pretreatment: hydration and alkalinisation (HCO3-) to protect kidneys given via IV drip 8-12 hours before treatment
Folinic acid (leucovorin) rescue for gut and bone marrow toxicity given 24 hours after treatment
68
What monitoring is required with METHOTREXATE? (3)
Serum methotrexate at 24 hours
FBC
Serum creatinine (every 2 months)
69
What are pyrimidine and purine antimetabolites?
Pyrimidine analogues that masquerade as pyrimidine to prevent it being incorporated into the DNA during S phase.
70
What is the role of thymidylate synthase?
It bind to dUMP and catalyses in conversion to dTMP via reductive methylation. Alongside this DIHYDROFOLATE is also generated.
71
What happens to 5-FU once it enters the cell?
It is converted to FdUMP.
72
What happens if FdUMP bind to thymidylate synthase instead of dUMP?
Methyl group donated to FdUMP however it can cannot undergo an elimination reaction to complete the methyl group donation. A stable ternary complex between 5-FU, TS and THF is formed. dUMP cannot bind to dTMP is not synthesised (and neither is DHF)
73
What are the two mechanisms of action of 5-FU?
Principle: inhibiting thymidylate synthase
Other: misincorporation of 5-FU metabolites into DNA and RNA
74
How does the misincorporation of 5-FU metabolites cause cytotoxicity?
fUTP is incorporated into RNA which disrupts normal RNA process and function leading to apoptosis.
75
What are the clinical uses of 5-FU? (BeNCH)
Head and neck cancer
Colon cancer
Breast cancer
76
How is 5-FU administered?
Intravenous injection - oral administration not reccomended due to unpredictable absorption from GI tract
77
How do plasma levels of 5-FU change after administration?
Peak plasma levels reached shortly after injection. half-life: 10-20 mins so rapid elimination
78
How are 5-FU levels maintained in the plasma?
Continuous infusion following intravenous bolus injection.
79
What are some toxicities of 5-FU?
Nausea and vomiting
Stomatitis
Bone marrow depression
Diarrhoea (DOSE LIMITING)
80
What enzyme metabolises 5-FU?
DPD - dihydropyrimidine dehydrogenase
81
What can happen to people taking 5-FU with an undetected DPD deficiency?
Accumulation of 5-FU --> life threatening toxicities can occur.
82
CAPECITABINE is another pyrimidine analogue. How is it administered?
Oral
83
What happens after CAPECITABINE is administered?
It is a prodrug.
1. converted to 5-DFCR by a carboxylesterase
2. 5-DCFR is the converted to 5-DFUR by cytidine deaminase found in liver AND in tumour
3. 5-DFUR is converted to 5-FU IN THE CELL by thymidine phosphorylase.
84
What are the clinical uses of CAPECITABINE?
Breast
Colorectal
85
Why is capecitabine considered more clinically important compared to 5-FU?
- Can be taken orally
- Tumour specificity - high levels of thymidine phosphorylase found in tumour tissue compared to normal tissue
86
What are the two types of microtubule poisons?
Vinca alkaloids
Taxanes
87
Name two vinca alkaloids?
VINCRISTINE
vinblastine
88
What is the principle mechanism of action of cytotoxicity in vinca alkaloids such as VINCRISTINE?
Depolymerise microtubules and disrupt their assembly.
89
Describe the mechanism of action of VINCRISTINE?
1. during mitosis highly dynamic microtubules are constatly polymerising and depolymerising
2. VINCRISTINE reversibly binds to to free αβ-tubulin heterodimers causing the microtubule to end (creation of kinetic cap)
3. This disrupts the balance between polymerisation and depolymerisation
4. Dissolution of microtubules destroys the mitotic spindle leads to mitotic arrest and CELL DEATH.
90
What are some clinical uses of VINCRISTINE?
Leukaemia
Lymphoma (H and NH)
Small cell lung cancer
Multiple myeloma
Can be used alone or in combination regimens
91
What are some toxicities associated with vinca alkaloids such as VINCRISTINE?
Peripheral neuropathy is the MAIN toxicity
Neutropenia (DOSE LIMITING)
92
What are the signs/symptoms associated with neuropathy following VINCRISTINE use?
Impaired sensation, movement, gland or organ function
Pain
Numbness
Paralysis
Loss of deep tendon reflexes
Ataxia
Motor dysfunction
93
Name two taxanes.
PACLITAXEL (taxol)
Docetaxel
94
Outline the mechanism of action of PACLITAXEL (taxol)
1. Stabilises microtubules so they cannot polymerise OR depolymerise
2. Interferes with microtubule dynamics and causes abnormal bundles of microtubules to form
3. Causes multi-polar divisions (spindles) to form in tumours leading to APOPTOSIS.
Action is concentration dependent.
95
What are some clinical uses for PACLITAXEL (taxol)
Lung
Ovarian
Breast
Head and Neck
Bladder
Prostate
Advanced Kapsosi's sarcoma (GI tract)
96
What is the prinicipal toxicity of PACLITAXEL?
Neutropenia
97
What are some other toxicities of PACLITAXEL (not NEUTROPENIA)?
Neurotoxicity
Nausea and vomiting
Alopecia
Myalgia
Hypersensitivity or anaphylaxis (TAXOL containing Cremphor EL to improve water solubiilty)
Asthenia
98
What is the mechanism of action of BLEOMYCIN?
Exact mechanism unknown but induces DNA strand breaks and may inhibit DNA polymerase
99
What are some clinical uses of BLEOMYCIN?
Hodgkins lymphoma
Squamous cell carcinomas
Testicular cancers
100
What are some common toxcities of BLEOMYCIN?
Alopecia
Fever
Rash
101
What is a less common but serious toxicity of BLEOMYCIN?
Pulmonary fibrosis - scarring of lung tissue causing serious breath issues
102
What are targetted therapies?
Interfere with specific targetted molecules needed for carcinogenesis and tumour growth
103
What are the benefits of targeted therapies of traditional chemotherapy?
Expected to be more effective
SHouldn't target all rapidly dividing cells so less harmful to normal cells
104
What are the types of targeted therapies?
1. Small molecules that target kinases e.g. IMATINIB (glivec)
2. Monoclonal antibodies e.g. TRASTUZUMAB
3. antibody-drug conjugates TRASTUZUMAB EMTANSINE
105
What is the role of HER2 receptor in cancer?
Stimulate cell growth, proliferation and tumour formation
High levels of HER2 in breast CANCER cells compared to normal breast tissue
106
What pathways does overexpression of HER2 activate?
Ras/Raf
PI3K/Akt
PLC/PKC
downstream pathways needed for abnormal proliferation and survival
107
What are the three mechanisms of action of TRASTUZUMAB (Herceptin)
Inhibits MAPK and PI3K/Akt pathways
HER2 degradation via ubiquitination
Antibody dependent cellulat cytotoxicity (ADCC) - attracts immune cells to cancer sites
108
What are the different types of monoclonal antibodies?
Murine
Chimeric
Humanised
HUman
109
What kind of antibody is TRASTUZUMAB?
humanised - derived from humans except for murine complementarity determining regions.
110
What are the clinical uses for TRASTUZUMAB?
HER2 positive breast cancer - adjuvant in early stages before surgery or if metastatic then combination or monotherapy
METASTATIC stomach cancer
111
How often is TRASTUZUMAB given?
ONCE every 3 weeks for up to a year .
2-3 hour infusion or subcutaneous injection
112
What are some side effects of TRASTUZUMAB?
Cardiomyopathy
Infusion related : flu like symptoms, tremor, nausea and diarrhoea
113
How can TRASTUZUMAB cause cardiomyopathy?
Reduction in neuregulin which is needed to activate cell survival pathways BUT is also needed to maintain cardiac function --> monitoring required
114
What are the mechanisms of resisatnce against TRASTUZUMAB? (4)
Inherent resistance - biomarkers used to identify who will show a response
Steric effects
Elevation of other tyrosine kinase receptors
Intracellular alterations in HER2 downstream signalling
115
What is IMATINIB used to treat?
Chronic myeloid leukaemia
Gastrointestinal stromal tumours
116
What is the mechanism of action of IMATINIB (Glivec)
Binds to the ATP binding site of BCR-ABL causing a self inhbiting conformation which blocks the tyrosine kinase domain and inhibits enzymatic of tyrosine kinase --> cell stops growing --> APOPTOSIS
117
What are the three phases of CML?
Chronic - mild symptoms, lower levels of blast cells (85% of patients)
Accelerated - disease progressing 10-20% blast cells
Blast phase (blast crisis) - > 20% blast cells , progresses rapidly, poor survival
118
How long will a person be on IMATINIB if they have CML?
Indefinitely
119
What are some side effects of IMATINIB?
Generally well tolerated
Nausea
Diarrhoea
Loss of appetite
Bone marrow suppression - neut, thrombocyt, anaemia
Severe congestive heart failure (RARE)
120
Are mechanisms of IMATINIB resistance well understood?
Primary - NO
Secondary - YES
- over 40 different mutations associated with resistance
more progressed disease = more likely for resistance to develop
121
HOw can resistance to IMATINIB in CML be delayed or prevented?
COMBINATION therapy????
Second generation TKIs such as dasatinib or nilotinib
Dose escalation
122
What are some hormone related cancers?
Estrogen:
Breast
Ovarian
Endometrial
Androgen:
Prostate
123
What is the role of estrogen in cell proliferation?
Estrogen binds to estrogen receptor.
Transcriptional activation and gene expression leading to the formation of proteins with roles in cell proliferation
124
How is estrogen synthesised pre and post menopause?
Pre-menopause in developing follicles in ovaries regulated by LH and FSH
Post menopause: from androgens in peripheral tissue including liver, adrenal galnds, breast and adipose tissue
125
What role does estrogen play in breast cancer?
Stimulates the proliferation of breast epithelial cells --> more cell division increases risk of replication errors which could cause abnormal cells with a large number of mutations so it can increase risk and potentially drive cancer proliferation
126
What is TAMOXIFEN?
A selective estrogen receptor MODULATOR that has antagonistic activity against oestrogen in some tissue and agonist activity in other tissue.
Inhibits ER in breast but activates ER in uterus and bone
127
Who is TAMOXIFEN mostly indicated in?
Pre-menopausal women with early and advanced breast cancer
but can also be effective in perimenopause and post-menopause ER+ breast cancer
128
What is the mechanism of action of tamoxifen?
Tamoxifen is a prodrug.
Undergoes bioactivation in the liver by Cytochrome P450
Its active metabolite strongly binds to ER receptors.
It does not cause apoptosis byt inhibits transcription off genes needed for cell proliferation
129
How long is tamoxifen given for?
Tamoxifen is usually an adjuvant treatment used after surgery for 5 years
130
Side effects of tamoxifen.
Short term:
Hot flush
Irregular period
Vaginal bleeding or discharge
Long term:
Increased risk of endometrial cancer - agonist activity
Loss of cardiac suppresion: DVT, PE
131
Drugs that cancer can develop resistance to due to overexpression of Pgp drug efflux pumps?
PACLITAXEL
VINCRISTINE
IMATINIB
132
How does resistance to METHOTREXATE arise? (4)
1 Reduced uptake into cell due to down-regulation of Reduced Folate Carrier
2 Increased efflux due to ATP-driven efflux transporters such as MRP1, MRP2 and MRP3
3 Reduced retention due to increased expression of y-glutamyl hydrolyase so METHOTREXATE polyglutamate cannot be produced so not retained in cell
4 Overexpression of target DHFR
133
How can reistance to cisplatin develop?
Decreased influx
Increased efflux
Detoxification by forming adducts with antioxidants such as glutathione and metallothioneins
Increased nucleotide excision repair proteins
Increased DNA tolerance - some DNA polymerases can bypass intra-strand crosslinks
134
Chemotherapy regimen : FOLFOX
Use : colorectal cancer
Folinic acid
Fluorouracil (5-FU)
Oxaliplatin
135
Chemotherapy regimen : CHOP
Use : non-Hodgkin's lymphoma
Cyclophosphamide
Doxorubicin (Hydroxydaunomycin)
Vincristine (Oncovin)
Prednisolone
136
Chemotherapy regimen : BEP
Use: Testicular cancer
Bleomycin
Etoposide
Platinum (Cisplatin)
137
Chemotherapy regimen : FEC
Use: Breast cancer
Fluorouracil (5-FU)
Epirubicin
Cyclophosphamide
138
Chemotherapy regimen : ABVD
Use: Hodgkins Lymphoma
Adriamycin
Bleomycin
Cyclophosphamide
Dacarabazine
139
Chemotherapy regimen : XELOX
Use: Colorectal cancer
Capecitabine
Oxaliplatin
140
When is rituximab indicated for the treatment of non-Hodgkin's lymphoma?
When the CD20 antigen is present on lymphoma
Added to CHOP regimen.
141
Why are combination therapies used?
Different drugs with different mechanisms of action working on different parts of the cell cycle
142
Which part of the cell cycle do alkylating agents such as CYCLOPHOSPHAMIDE and MELPHALAN work?
Non-specific all parts
143
Which part of the cell cycles do microtubule poisons work?
M phase
144
Which part of the cell cycle do cytotxic anti
145
Describe pulsed therapy.
- Consistent time scale between each cycle
- Tumour cells rise before next cycles but overall decline in the number of cancer cells
- Use of combination therapy to minimise toxicity
- Normal cells given time to recover
146
What are the FOUR types of chemotherapy?
Curative - eliminating all of tumour mass
Palliative - symptom control but non-curative intent
Adjuvant - Given AFTER initial treatment such as non-debulking surgery (usually to clean up residual cells)
Neo-adjuvant - Given before other potential curable treatment (e.g. to shrink head and neck tumours so operating area is smaller)
147
What are the routes of administration for chmeotherapy?
IV
Oral
Subcutaneous
Intramuscular
Intrathecal - space around spinal cord
Intravesical - into bladder
Intrapleural - pleural cavity
148
What are some adjuvant treatments that may be given alongside traditional chemotherapy?
Hormone therapy
Targeted therapies (monoclonal antibodies, CAR-T)
Radiotherapy
Radiofrequency ablation
Laser treatment
HIFU (High intensity focused ultrasound)
Photodynamic therapy (skin)
Cryotherapy (Head and neck)
UV light treatment
149
How is dosing of cancer medication decided?
BSA
Calvert formula for CARBOPLATIN
Fixed doses
By weight
Weight ranges (paediatric)
National dose banding tables
150
Mostellar formular for BSA.
√[(height in cm * weight in kg) / 3600]
151
What is the Calvert formula?
Carboplatin dose (mg) = AUC (mg/ml x min) x [GFR (ml/min) + 25]
152
What is the Cockcroft and Gault formula?
(140-age) x weight (kg) x constant / serum creatinine
constant men: 1.23 women: 1.04
153
What are the advantages of national dose banding tables?
Improved medication safety
Reduced wastage
Reduced time to prepare chemotherapy
Shorter outpatient appointment
Saves personnel time
154
Why does combination therapy reduce the risk of specific side effects?
Different MoA so less likely for there to be an overlap
Can use lower doses of each drug compared to if they were used alone
155
What are the three phases of CINV?
Acute (day 1-4)
Delayed (day 5-7 onward)
Anticipatory (before chemo due to anxiety)
156
Which kind of chemotherapy agents are more likely to cause CINV?
Traditional therapies as they affect rapidly mutliplying cells including those in the gut mucosa whereas newer therapies are usually more specific
157
When is anticipatory nausea and vomiting more likely?
If person has cinv after the first cycle
158
What can uncontrolled nausea and vomiting lead to? (6)
Reduced quality of life
Dehydration
Hospital admission
Dose reduction - not getting next dose on time
Refusal of treatment
Superior Canal Dehiscence Syndrome
159
Who is more prone to chemotherapy induced nausea and vomiting? (5)
Women
If taking certain medications with high emetogenicity
30s-40s
History of sickness with other meds
If having radiotherapy
160
When are pre-chemotherapy antiemetics given?
1 hour before chemotherapy and for each day of chemotherapy
161
Antiemetics used in nausea and vomiting
Dopamine D2 antagonists - Domperidone , metoclopramide
5HT3 antagonists - Ondansetron
Neurokinin-1 receptor antagonists - Aprepitant
Dexamethasone
162
What is the pre-treatment for chemotherapy regimens where there is a minimal risk (<10%) of emesis?
No routine prophylaxis
163
What is the pre-treatment for chemotherapy regimens where there is a low risk (10-30%) of emesis?
Start 1 hour before chemotherapy
Metoclopramide 10-20mg QDS or dexamethasone 6mg BD
164
What is the post chemotherapy treatment for chemotherapy regimens where there is a low risk (10-30%) of emesis?
START ON THE DAY AFTER CHEMOTHERAPY FINISHES
Metoclopramide 10-20mg QDS OR domperidone 10mg tds PRN for THREE DAYS
165
What is the pre-treatment for chemotherapy regimens where there is a moderate risk (30-90%) of emesis?
Start 1 hour before chemotherapy Dexamethasone 8mg OD oral or IV
Ondansetron 8mg or another 5HT3 antagonist
Metoclopramide 10-20mg QDS OR domperidone 10mg tds
166
What is the post chemotherapy treatment for chemotherapy regimens where there is a moderate risk (30-90%) of emesis?
START ON THE DAY AFTER CHEMOTHERAPY FINISHES
Dexamethasone 8mg OM for 2-3 days
Metoclopramide 10-20mg QDS OR domperidone 10mg tds for THREE days
167
What is the pre-treatment for chemotherapy regimens where there is a high risk (>90%) of emesis? NO APREPITANT
Start 1 hour before chemotherapy Dexamethasone 6mg BD oral or IV
Ondansetron 8mg or another 5HT3 antagonist
Metoclopramide 10-20mg QDS OR domperidone 10mg tds
168
What is the post chemotherapy treatment for chemotherapy regimens where there is a high risk (>90%) of emesis? NO APREPITANT
START ON THE DAY AFTER CHEMOTHERAPY FINISHES
Dexamethasone 8mg OM for 2-3 days
Metoclopramide 10-20mg QDS OR domperidone 10mg tds for THREE days
169
When is aprepitant used for CINV?
High risk of emesis (>90%)
Patient is on an anthracycline and cyclophosphamide or cisplatin ≥ 70mg/m2 or if aprepitant is indicated in trust guidelines
170
How is aprepitant added on to anti-emetics used pre-chemotherapy?
Single day treatment:
Aprepitant 125mg po or fosaprepitant 150mg IV 20-30 mins ON DAY ONE
Mutiple day treatment:
DAY ONE : Aprepitant 125mg po or fosaprepitant 150mg IV 20-30 mins ON DAY ONE
Subsequent days : Aprepitant 80mg PO for TWO DAYS of chemotherapy
171
How is aprepitant added on to anti-emetics used post-chemotherapy?
Aprepitant 80mg po for TWO DAYS
172
How is emotogenic risk calculated for combination regimens.
If drugs in the same category combined, then regimen is classified at higher risk e.g. two drugs with low risk would be moderate risk together
If drugs are from different categories, emetic risk is based on the most emetic drug e.g. one high risk drug and one moderate risk combination would be high risk overall
173
High emesis risk drugs (5 IV, 1 oral)
IV
Cisplatin ≥ 70mg/m2
Anthracyclines (-rubicin) AND cyclophosphamide used in combination
Cyclophosphamide > 1500mg/m2
Doxorubicin > 60mg/m2
Dacarbazine
oral
Procarbazine
174
Moderate risk emesis drugs (6 IV)
IV
Cisplatin < 70mg/m2
Cyclophosphamide < 1500mg/m2
Doxorubicin < 60mg/m2
Etoposide > 120mg/m2
Melphalan > 100mg/m2
Methotrexate > 250mg/m2
175
Low risk emesis drugs (4 IV)
IV
Doxorubicin (liposomal)
Etoposide
Fluorouracil (5-FU)
Methotrexate < 250mg/m2
176
Minimal emesis risk drugs (4 IV, 2 oral)
IV
Bleomycin
Rituximab
Trastuzumab
Vincristine
Oral
Melphalan
Methotrexate
177
What are the two types of cancer treatments that can cause diarrhoea?
Conventional chemotherapy - due to affect on gut mucosa
Immunotherapy - Inflammation related diarrhoea
178
What cancer treatments are most commonly associated with diarrhoea?
Capecitabine
Irinotecan
TKIs (imatinib)
immunotherapy
179
What is the treatment for immunotherapy associated diarrhoea?
Steroids and immediate hospital admission
180
What is the treatment for chemotherapy (non-immunotherapy) associated diarrhoea? (4)
Loperamide and/or codeine
Octreotide - somatostatin analogue that reduces intestinal motility if loperamide is ineffective or grade 3-4 diarrhoea (hospitalisation)
Atropine given prophylactically for IRINOTECAN regimens
Oral rehydration
181
What is mucositis?
Damage to the mucosal lining of the GI tract
182
What are the main cytotoxic inducers of mucositis? (3)
Fluorouracil (5-FU) continuous infusion
Capecitabine
High dose methotrexate
183
What are the issues associated with mucositis? (3)
Infection risk
Decreased oral intake
Pain
184
Chemotherapy induced mucositis prophylaxis.
Good oral hygiene
Soft toothbrush
Corsodyl/nystatin mouthwash to prevent infection
185
How is mucositis treated? (4)
DIfflam mouthwash
Sucralfate
Lignocaine
Paracetamol
186
How does sucralfate protect in mucositis?
Forms a white layer over the mucosa after gargling and swallowing
187
Why is lignocaine used in mucositis?
Numbs mouth but this means person can damage mouth without feeling it
188
What may be required in severe cases of mucositis?
Stronger analgesics (Morphine)
Dose reductions
189
What is palifermin?
A truncated growth factor that stimulates the growth of cells lining the gastrointestinal mucosa specifically in people with haematological malignancies being treated with radiotherapy as part of stem cell transplant
190
What chemotherapy agents can cause alopecia? (5)
Cyclophosphamide
Taxanes
Vinca alkaloids
Anthracyclines
Methotrexate
191
Describe chemotherapy induced alopecia
Gradual loss and will reverse at the end of treatment
May not lose all hair
192
What advice would be given to a person who may experience alopecia caused by chemotherapy?
No pharmacological treatment is available
Avoid dyeing, perms, plaits, heat etc
193
What is scalp-cooling?
Effective but very uncomfortable method to reduce alopecia.
Hat put on soaking wet hair a few hours before chemotherapy. Tubes of very cold water and insulation so scalp is cold enough for capillaries around hair follicles to constrict and come away from the scalp so less drug reaches follicles
194
What cancer is scalp-cooling commonly used in?
Breast - highest risk of alopecia in regimen and usually affects women
195
Why can patients with CNS disease not undergo scalp cooling?
Brain cancer or metastasis - constricting blood supply could prevent chemotherapy reaching site of cancer in the CNS
196
What is extravasation?
When patient is cannulated but the parenteral fluid goes into surrounding subcutaneous tissue instead of the vein which can cause damage
Can occur during or a few hours after treatment
197
What are the three categories for extravasation?
Vesicants (further split into DNA binding and non-DNA binding)
Irritants
Non-vesicants
198
What is the difference between DNA binding and non DNA binding vesicants?
Non-DNA binding agents cause damage but are metabolised and excreted faster whereas DNA binding agents bind to DNA so they are not quickly metabolised and flushed out after extravasation
199
What are some DNA binding vesicants? (1)
Anthracyclines : DOXORUBICIN
200
What are some non-DNA binding vesicants? (2)
Paclitaxel
Vincristine
201
What are some irritants? (extravasation) (8)
Fluoruracil
Etoposide
Irinotecan
Liposomal doxorubicin
Melphalan
Methotrexate
Cisplatin
Oxaliplatin
202
What are some non-vesicants? (extravasation)
Bleomycin
Cyclophosphamide
Monoclonal antibodies (Trastuzumab)
203
Why does extravasation needed to be treated immediately?
Can cause tissue necrosis
204
How would you manage extravasation ? (general -4)
Stop infusion
Leave cannula in
Aspirate about 20-30ml of blood to remove leftover chemo
Mark area
205
How would you manage extravasation with non-DNA binding agents?
HEAT - promotes circulation so it can enter body to be metabolised
206
How would you manage extravasation with DNA binding agents?
COLD - constricting blood flow to help minimise normal cell damage
207
What lab test results would be needed whilst a patient is on chemotherapy? (6)
FBC
Renal function
Hepatic function
Cardiac function
Us and Es
Tumour biomarkers - e.g. CVA in colorectal cancer
208
What are some signs of bone marrow suppression? (6)
Unexplained bleeding
Unexplained bruising
Sore throat (INFECTION)
Fever (INFECTION)
Fatigue (Anaemia)
Breathlessness (Anaemia)
209
What is the threshold for neutropenic sepsis?
Absolute neutrophil count of 0.5 x 10^9 or lower AND
temperature over 38 with any symptoms/signs of sepsis
210
What is the threshold for febrile neutropenia?
Absolute neutrophil count of 0.5 x 10^9 or lower AND
temperature over 38 BUT NO symptoms/signs of sepsis
211
What are the signs of sepsis? (4)
Confusion
Blue grey, pale skin
Rash that doesnt fade
Breathing issues
212
What should be done to chemotherapy if a person's neutrophil count is too low?
Delay
213
What is the treatment if a patient is neutropenic?
Immediate hospital admission
Broad spectrum antibiotics (pip-taz, gentamicin)
GCSF?
214
What is GCSF?
Recombinant human granculocyte colony stimulating factor - stimulates the production of neutrophils
Filgrastim , lenograstim
215
What is GCSF used for?
Reducing the duration of neutropenia and incidence of febrile neutropenia
216
What is primary prophylaxis using GCSF?
Used when patient is on a curative regimen with docetaxel - offset drop in neutrophils by using GCSF on day 4-5. This means next cycle can be given on time as they do not have to come to hospital between cycles due to neutropenia
217
What is secondary prophylaxis using GCSF?
When docetaxel is being as palliative treatment (lower dose) . Patient experiences neutropenia in the first cycle then GCSF is given as prophylaxis in case neutropenia occurs again.
218
Who may be given GCSF?
Patients reieving cytotoxic chemotherapy (especially anthracyclines such as DOXORUBICIN and DOCETAXEL)
After stem cell therapy
219
What is thrombocytopaenia?
Reduced platelet count
220
What are some drugs that may require dose reductions/delays in treatment due to thrombocytopenia?
carboplatin
gemcitabine
221
What may be given to patients on chemotherapy experiencing thrombocytopaenia?
Platelet transfusion (temperary solution)
Pools of platelets used in severe cases
But withdrawal of treatment and cessation of antiplatelets is usually enough
222
What can be used to treat anaemia caused by chmeotherapy?
Iron tablets
Blood transfusion if Hb is critically low however if patient becomes transfusion dependent leading to iron overload as iron is not cleared quickly enough after haemolysis
223
What chemotherapy drugs are commonly associated with renal impairment?
Cisplatin
High dose methotrexate
224
How is risk of renal impairment associated with chemotherapy managed?
IV fluids
Baseline tests and subsequent tests throughout treatment
225
What cancer treatment is associated with live impairment ?
Trastuzumab emtansine
226
What cancer treatments can cause transient rises in LFTs but not true liver impairment?
Methotrexate
Gemcitabine
Vincristine
227
How is liver impairment due to cancer treatment managed?
Withhold treatment
Caution with supportive care or regular medications known to be metabolised in the liver
228
What is tumour lysis syndrome?
Tumour lysis syndrome is a metabolic condition caused by the break down of malignnat cells
229
What are the metabolic disturbances associated with tumour lysis syndrome?
HYPERuricaemia
HYPERphosphataemia
HYPERkalaemia
HYPOcalcaemia
230
Why is TLS associated with the first cycle of chemotherapy?
Untreated cancer is tumour at its largest --> exposed to chemo --> lots of cells lysed and intracellular contents released into bloodstream
231
What can TLS lead to?
renal damage
arrhythmia
seizures
death
232
Which cancers are associated with TLS?
- High proliferation rate and tumour burden
- More common in haematological compared to oncological
- non-Hodgkins lymphoma, acute myeloid leukaemia, Burkitt's lymphoma
233
Who is at higher risk of TLS?
Older patients
Patient with impaired renal function
234
How is TLS managed?
Prophylaxis: Allopurinol 300mg OD started before chemotherapy
Prophylaxis AND treatment: rasburicase IV
Manage hyperkalaemia
Dialysis???
235
When would rasburicase be contraindicated? (ref. anaemia lecs)
Patients with G6PD deficiency (definite risk)
236
Why does trastuzumab lead to cardiotoxicity?
Affects HER-2 receptors on the myocardium
237
What monitoring is needed for patients on trastuzumab due to risk of cardiotoxicity?
Cardiac monitoring baseline and every 3 months
238
What is a MUGA scan?
Multiple gated acquisition scan - uses nuclear medicine to measure ejection fraction
239
How do anthracyclines cause cardiotoxicity?
anthracyclines such as doxorubicin release ROS which reduce iron release hydroxyl radicals that can damage cardiac tissue
240
How can we prevent cardiotoxicity from anthracyclines?
- Do not exceed maximum cumulative lifetime dose
- Using slow infusion instead of bolus - slower release reduces the number of radicals produced
- Using liposomal formulations
- Using cardiac medications : ACEi, ARB, BBs
- Dexrazoxane
241
What are the risks of using slow infusions for anthracylines?
They are DNA binding vessicants --> longer infusion time increases risk of extravasation
242
From LVEF monitoring results when would we avoid or withdraw treatment?
Avoid trastuzumab if LVEF < 50% or drops by 10% over the course of treatment
Avoid anthracyclines if LVEF < 60%
243
How does cyclophosphamide cause haemmorhagic cystitis?
Releases acrolein when metabolised which can irritate the lining of the bladder
244
What is MESNA used for?
Prevention and treatment of haemmorhagic cystitis by binding to acrolein in the kidney
245
When is MESNA always given?
Patients receiving cyclophosphamide dose of 1g/m2 or more
All patients on ifosfamide
246
What formulations of MESNA are available?
IV or oral (if small traces of blood in urine can take oral tablets home)
247
What are the symptoms of peripheral neuropathy?
Change in sensation
Increased sensitivity
Pain
Numbness
Pins and needles
Muscle weakness
Difficulty handling small objects (e.g. buttons)
Issues with balance and coordination
Constipation and bloating
248
What agents are commonly associated with peripheral neuropathy?
Vinca alkaloids
Taxanes
Platinum agents
Capecitabine
249
How is peripheral neuropathy due to chemotherapy managed? (4)
Treat symptoms
Pyridoxine 50mg PO
TENS
Acupuncture
Gabapentin or pregabalin (severe cases)
250
What is plantar-palmar erythema?
Skin reaction to chemo that feels like neuropathy but with cracking on palms and soles of feet
251
What are some ways to manage plantar-palmar erythema?
- Dose reduction of chemotherapy depending on severity
- Urea cream
-Fragrance free moisturiser
Loose fitting, comfy clothes and shoes
- Avoiding extremes of temp so no very hot or cold baths
- Pat dry
- Use rubber gloves when washing dishes
- STAY HYDRATED
252
Pain management categories
Non opioids: Paracetamol, NSAIDs, aspirin
Weak opioids: Codeine, tramadol, low dose morphine
Strong opioids: morphine, fentanyl, hydromorphone, buprenorphine
Adjuvants: antidepressants, anticonvulsants, antispasmodics, muscle relaxants
253
WHO pain ladder?
Step 1 (mild pain) : Non opioid +/- adjuvants
Step 2 (moderate pain): Weak opioid +/- Non opioid +/- adjuvants
Step 3 (severe pain): strong opioid +/- Non opioid +/- adjuvants
254
Why may steroids be used in malignant disease? (5)
Treating cancer alongside chemotherapy (R-CHOP)
Reduce inflammation - immunotherapy associated diarrhoea
Reduce immune response
Relieve sickness - dexamethasone
Stimulant appetite (low doses)
255
What is PCP?
Pneumocystis Pneumonia is a fungal lung infection caused by Pneumocystis jirovecii can occur in patients on chemo especially for haematological cancers
256
PCP prophylaxis
Co-trimoxazole
Pentamidine isetionate
Dapsone
Atovaquone
257
PCP treatment
Co-trimoxazole
Pentamidine isetionate
Dapsone with trimethoprim
Clindamycin with primaquine
Atovaquone
