Cancer Therapy Flashcards
Properties of cancer
Self-sufficiency in growth signals Insensitivity to anti-growth signals Tissue invasion and metastasises Evading apoptosis Sustained angiogenesis Limitless replicative potential
Types of cancer therapy
Neoadjuvant - administered before definitive treatment (surgery or radiotherapy) to shrink tumour and optimise outcomes
Adjuvant - given after treatment to reduce risk of disease recurrence
Palliative - designed to relive symptoms and improve quality of life
Options of cancer treatment
Traditional
- chemotherapy
- radiotherapy
- surgery
Novel therapies
- immunotherapy
- monoclonal antibodies
- checkpoint inhibitors
- radioimmunotherapy
- drugs targeting oncogenes
- signal transduction inhibitors
- anti-apoptotic agentsPrinciples of chemotherapy
Treatment of cancer with drug therapy
Interfere with essential step required for cell growth and proliferation
Damaged cancer cell unable to repair damage and initiate programmed cell death - apoptosis
Mechanisms of cancer cell resitance
Decrease uptake of drug Increase drug metabolism After drug targets Impair apoptotic pathway After cell cycle checkpoints Efflux pumps
Side effects of chemotherapy
Brain - chemo-brain - peripheral neuropathy - fatigue Hair - alopecia Heart/blood - neutropenic sepsis - cardiomyopathy - myelosuppression -> bleeding from low platelets, fatigue from anaemia and sepsis GI - vomiting - mucositis - diarrhoea - constipation Bladder - haemorrhagic cystitis Skin - PPE - rash - nail ridging/loss Reproductive organs - impaired fertility - decreased libido - premature menopause Kidneys - AKI - electrolyte disturbances Liver - deranged LFTs Lungs - pneumonitis - PE
Anti-emetics for chemotherapy
5HT receptor antagonists - ondansetron
- block receptors in GI tract and CNS tract
Dopamine receptor antagonist - metoclopramide
- act centrally by blocking the chemoreceptor trigger zone
Steroids - dexamethasone
Antihistamines - cyclizine
NK1 receptor antagonists - aprepitant
Antimuscarinics - hyoscine
Cannabinoids - nabilone
Benzodiazepines - midazolam, lorazepam
Features of tumour lysis syndrome
Tumour cell lysis -> hyperkalaemia
Release of DNA, phosphorus leads to Ca-Phos precipitation -> hypocalcaemia leading to arrhythmias
-> urate and Ca-Phos nephropathy
Release of purines, hypoxanthine, uric acid
- needs IV fluids, allopurinol and rasburicase
Features of immunotherapy
Uses immune system and its components to recognise, target and destroy cancer cells
Passive
- ex vivo
- activated cells or molecules that once found inside body compensate for missing or deficient immune functions
Active
- stimulates effector functions in vivo
- requires patient’s immune system to be able to respond upon challenge, stimulated and mediate effector functions
Types of immunotherapy
Passive - tumour-specific mAbs - cytokines - adoptive cell transfer Active - oncolytic viruses - checkpoint inhibitors - allogeneic whole cell vaccines - DC vaccines
Features of monoclonal antibodies
Bind to a certain antigen on cancer cell surface, blocking specific downstream signalling pathways and arresting cell proliferation
- HER2 inhibitors - Herceptin (Trastuzumab) in breast and gastric cancers
- VEGR (vascular epithelial growth receptor ) inhibitors - Bevacizumab in ovarian and bowel cancer
- EGFR inhibitor (epithelial growth factor receptor) - Cetuximab/Panitumumab in bowel cancer
Side effects of targeted therapies
Skin toxicity - acneform rash - dry skin Hair growth disorders Pruritis Nail changes Fatigue Myelosuppression Diarrhoea Nausea Hypertension Proteinuria GI perforation Delayed wound healing Arterial thromboembolic events Cardiac ischaemia Flu-like symptoms Abnormal LFTs Allergic reaction
Features of checkpoint inhibitors
Can be used as single agents or in combination
CTLA4 inhibitor
- Imipilumumab - used in melanoma
PD-1/PD-LI inhibitors
- Nivolumab, Pembrolizumab used in melanoma, lung and renal cancers
Features of side effects of checkpoint inhibitors
Inflammatory adverse reactions
Increased/excessive immune activity
Can present months following last dose
Most resolve after prompt therapy or withdrawal
Corticosteroids or alternate immunosuppression led to reversal in majority
Side effects of checkpoint inhibitors
GI - diarrhoea - abdo pain - blood or mucus in stool - bowel perforation - peritoneal signs - ileus Skin - immune-related dermatitis - pruritus - dry skin - rash - Stevens-Johnson syndrome or toxic epidermal necrolysis Hepatic - immune related hepatitis - symptoms of hepatotoxicity Neuro - immune-related neuropathies - unilateral or bilateral weakness - sensory alterations - paresthesia - myasthenia gravis - Guillain-Barre syndrome Endocrine - hypophysitis - hypopituitarism - adrenal insufficiency - hypothyroidism Other - eosinophilia - angiopathy - myocarditis - temporal arteritis - vasculitis - blepharitis - conjunctivitis - episcleritis - uveitis - arthritis - polymyalgia rheumatica - nephritis - haemolytic anaemia - pneumonitis
Key points of radiotherapy
Use of high energy ionising radiation to treat, primarily, malignant disease
40% of all patients cured of cancer cured by radiotherapy
50% patients will benefit from receiving radiotherapy as part of cancer management
Given alone or in combination
Action of radiotherapy
Direction action
- DNA damage leads to cell death
Indirect action
- free radicals, DNA damage leading to cell death
Types of radiotherapy
External beam
Brachytherapy
- used as boost treatment o or primary for prostate and cervical
Systemic treatments
- radioactive substance injected or swallowed
Radiosensitisers
Make cells more sensitive to radiotherapy Temozolamide - oral chemo for GBM tumours Capecitabine - oral chemo for colorectal cancer Cisplatin - wide range of uses Cetuximabe - monoclonal antibody - given if prior cisplatin or cannot tolerate cisplatin 5FU - GI tract tumours
Features of radical radiotherapy
Intent to cure
Treatment duration
- 4-7 weeks
Small fields of irradiation
Features of palliative radiotherapy
Alleviate symptoms
1-10 daily treatments
Larger field of irradiation
Side effects of radiotherapy
Depend on area treated Fatigue N+V Erythema Lymphoedema Low blood counts Dysuria Radiation cystitis Hair loss Dysphagia Sore throat Oral mucositis Diarrhoea Sterility
Types of radiotherapy
External beam
Brachytherapy
- prostate and cervical
IMRT - intensity modulated radiotherapy
Systemic
- radioactive substances injected/swallowed
- iodine 131 radioisotope used for thyroid cancer
Radiosensitizers
Certain chemotherapies that make cells more sensitive to radiotherapy
- tamozolamide
Define radical radiotherapy
Radiotherapy used to treat cancer as part of curative strategy
- neoadjuvant
- adjuvant
- definitive
Define palliative radiotherapy
Symptom control - not aiming to cure Lower dose so reduced side effects Spinal cord compression Pain caused by bone mets SVCO
Side effects of radiotherapy
Depends on area treated Fatigue Hair loss Dysphagia, sore throat, oral mucositis Low blood counts N+V Erythema Cystitis Sterilisation Radiotherapy dermatitis
Late side effects of radiotherapy
Skin - pigmentation - necrosis - telangiectasia - ulceration Bone - necrosis - fracture Mouth - ulceration - xerostomia Eyes - cataracts Lung - fibrosis Hear - cardiomyopathy - pericadiafibrosis Gonads - infertility - menopause Bowel - strictures - ulcers
Radioresistant cancers
Melanoma
Renal cell cancers
Cancers predominantly only treated with chemotherapy
Mucosal surfaces
- Head and neck squamous cell
- Anus and rectal cancers
Types of cytotoxic chemotherapy
Alkylating agents - form covalent bonds with DNA to impede replication
- depression of bone marrow function, GI upset, increased risk of non-lymphocytic leukaemia
Antimetabolites - block one or more metabolic pathways involved in DNA synthesis
- pyrimidine analogues - fluorouracil
- purine analogues - tigouanine
- depression of bone marrow function, GI epithelial damage, nephrotoxicity, teratogenicity
Cytotoxic antibodies - prevent cell division by different mechanisms
- doxorubicin - prevents DNA unzipping
- dactinomycin - interferes with RNA polymerase
- bleomycin - degrades fully formed DNA
- N+V, myelosuppression, hair loss, fevers, muccositis, pulmonary fibrosis
Types of hormonal chemotherapy
Drugs antagonise or suppress hormonal action
o Glucocorticoids e.g. prednisolone, dexamethasone – inhibit lymphocyte proliferation
o Oestrogens and anti-androgens – used to suppress growth of prostate tumours
o Anti-oestrogens, e.g. Tamoxifen – competes at oestrogen receptors in breast cancer tissue, preventing oestrogen uptake and therefore reducing rate of tumour growth
o Adrenal hormone synthesis inhibitors (aromatase inhibitors) – used in post-menopausal breast cancer to inhibit sex hormone synthesis
o Progestogens – useful for endometrial neoplasms and renal tumours
o Gonadotrophin releasing hormone analogues/antagonists – act to inhibit gonadotrophin release, preventing its action on tumours and therefore inhibiting tumour growth in advanced breast cancers in pre-menopausal women and prostate cancers
o Somatostatin analogues – relieve symptoms of neuroendocrine tumours,
· Monoclonal antibodies – used for targeted treatment of specific cancers
o Can cause hypotension, chills and fevers, hypersensitivity
· Protein kinase inhibitors – inhibit protein kinases, e.g. tyrosine, which transduce growth signals in rapidly dividing cells
Managing side effects of chemotherapy
Nausea and vomiting
o Domperidone or metoclopramide in low level nausea and vomiting
o Serotonin antagonists (ondansetron) – better for severe nausea and vomiting
· Extravasation – inflammation caused by leak of white cells into tissue compartments. Seen as pain, redness, blotching and blistering, in serious cases can lead to skin necrosis
o Topical antidotes – e.g. Dimethyl sulfoxide
o Debridement and grafting depending on how damaged the skin becomes
· Bone marrow suppression
o Monitor neutrophil counts and admit for assessment of neutropenic sepsis if neutrophils drop below 0.5x109 cells/L
o Inform patients to go to A+E if they start to feel feverish or unwell during any chemo cycles
o Granulocyte Colony Stimulating Factor can be given to increase circulating volume of white cells if necessary
· Alopecia
o Hair may remain or grow back faster if head is kept cold
· Fertility – many chemotherapeutic agents lead to hypogametogenesis or infertility
o Counselling on this should be given before treatment starts
o Sperm/egg harvest and storage should be offered
o Most chemotherapeutic agents are teratogenic, therefore females should be counselled on contraception
If side effects are causing issues, reduce chemotherapy dose or wait longer between cycles
Types of radiotherapy
External beam – lasers emitting gamma radiation are fired at the tumour to damage cells, angled to avoid heathy tissues as much as possible
o Curative – given in short doses over a few weeks
o Palliative – large doses all at once to try to shrink tumour
o May be used alongside radiosensitisers – chemotherapy which stimulates the uptake of radiation into targeted tissues to help target radiotherapy further
o Side effects: tiredness, soreness/irritation, diarrhoea if near the rectum, cystitis if near the bladder, impotence, moist desquamation (especially under the breast, avoid by keeping skin clean and moisturised), lymphoedema (reduced drainage if lymph nodes are targeted) xerostomia if near salivary glands, risk of future cancer, nausea and vomiting, myelosuppression, pneumonitis if lung is affected
· Brachytherapy – radiation sources placed in or near the tumour
o Temporary
o Permanent – uses low-dose, long half-life sources
o Systemic – e.g. radioactive iodine taken orally to treat thyroid disease
Tumour markers
AFP (Alpha-fetoprotein) – liver cancers and germ cell tumours (e.g. testicular cancer)
· B2M (Beta-2-microglobulin) – myeloma, CLL and lymphoma
· Beta-hCG – choriocarcinoma (of trophoblast cells in uterus, e.g. malignant molar pregnancy) and germ cell tumours (e.g. testicular cancer)
· CA15-3 and CA27.29 – breast cancer
· CA19-9 – pancreas, gall-bladder, bile duct and gastric cancers
· CA125 – ovarian cancer
· Calcitonin – medullary thyroid cancer
· CEA (Carcinoembryonic Antigen) – colorectal cancer
· CgA (Chromogranin A) – neuroendocrine tumours
· Fibrin/fibrinogen in the urine – bladder cancer
· Immunoglobulin levels – myeloma
· LDH – melanoma, leukaemia and lymphoma
· PSA – prostate cancer
· Thyroglobulin – thyroid cancer
Features of the toxicity bear
Asparagine = neurotoxicity Cisplatin = ototoxic/nephrotoxic - tx = amifostine Vincristine = peripheral neuropathy Vinblastine = myelosuppression Bleomycin = pulmonary fibrosis Doxorubicin = cardiotoxic - tx = dexrozoxane Cyclophosphamide = nephro/bladder toxic - tx = mesna = SIADH effects - tx = democlocycline Methotrexate = neprhtoxic - tx = leucovorin = myelosuppression - tx = filgrastim
