14- Treatment of cancer Flashcards
treatment modalities in cancer
radiotherapy
surgery
medical therapies
localised treatment
- surgery
- radiotherapy
systemic caner therapies
- Chemotherapies
- Hormones
- Immunotherapies
MDT treatment in cancer care
- Oncologists
- Surgeons
- Grading
o Radiologists
o Histopathologist - Medical doctors e.g. GI, resp
- Palliative care doctors
- Specialists nurses
Goals of treatment
- Curative (radical treatment)
o Aims to cure disease - Palliative
o If patients performance status is too poor for curative treatment
o Aims to improve symptom control and quality of life
define curative/primary treatment
Aims to cure the cancer i.e. eliminate all cancerous cells and results in “complete remission”
neo-adjuvant therapy
or pre-operative
- Radiation to shrink the tumour and make it easier to remove
- Sometimes inoperable tumours can be surgically removed after neo-adjuvant chemo
- In breast cancer neo-adjuvant chemo can sometimes reduce the tumour enough that a women can choose to have breast-conserving surgery (lumpectomy) instead of having whole breast removed (mastectomy)
- Goal is not to cure, but to give more option for treatment
Adjuvant therapy
- Given after primary treatment to reduce risk of reoccurring
- E.g. chemo given after curative
palliative therapy
- Non curative treatments such as chemotherapy, radiotherapy and surgery, to prolong life and reduce symptoms
- Given to patients with advanced cancer in hope of making patients more comfortable towards the end of life
maintenance therapy
- Is given to help keep cancer from coming back after initial treatment
- Prevent reoccurrence after patient is in remission
- E.g. late stage NSCLC-> often cannot be compleltley wipe out, but maintenance therpay can prolong patients life
treatment factors to consider
- Tumour
- Treatment
- Patient
tumour treatment factors
- Type- susceptibility of tumour to therapy
- Stage e.g. has it spread
treatment factors
- Availability of treatment
- Side effects vs benefits
Patient treatment factors
- Performance status (ECOG)
- How fit a patient is
- E.g. if a patient has HF, therefore radical surgery may not be feasible
- Patient wishes
Factors which influence treatment options
1) Co-morbidities (prognostic)
- Cardiopulmonary exercise testing
- Cardiac disease
- Lung disease
- Diabetes
- Heart failure
- COPD
- Cerebrovascular disease
- Dementia
- Liver disease
- Kidney problems
- Obesity
- HTN
2) Performance status
3) Patient choice
- Based on their understanding of their options and what they entail
patient co-morbidities
Co-morbidities
o Cardiopulmonary exercise testing
o Cardiac disease
o Lung disease
o Diabetes
o Heart failure
o COPD
o Cerebrovascular disease
o Dementia
o Liver disease
o Kidney problems
o Obesity
o HTN
why do co-morbidities affect treatment option
Available treatment may vary based on type and severity of comorbidity. Some oncologists may not recommend certain cancer treatments for patients with comorbid conditions due to a high risk of side effects and complications
e.g. chemotherapies may not be suitable if there is compromised kidney function -> could cause life-threatening toxicity
e.g. patient of chronic obstructive pulmonary disease may not be able to tolerate anesthesia required for thyroid cancer surgery, and hence would need a customized approach to cancer treatment.
what is used as a guide to which therapies would be suitable for a patient to give them the best outcomes
e.g. curative surgeries are very demanding on the body and if somebody has a poor performance status, may fair worse than somebody who is fit.
ECOG Performance status
- 0- fully active
- I- restricted in strenuous activity
- II- up and about 50%
- III- up and about <50%
- IV- bedbound
- V- dead
These scales and criteria are used by doctors and researchers to assess how a patient’s disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. They are included here for health care professionals to access.
What do patients want to know?
- What is the aim of the treatment
o Curative/neoadjuvant/adjuvant/palliative - Will the treatment work?
o Drug resistance
o Response rates - What does treatment entail?
o Duration of treatment
o Number of visits - What are side-effects?
palliative care
- For patients who’s condition cannot be cured
- Aims to reduced pain and distressing symptoms and prolong best quality life
- May receive palliative care alongside other therapies for treatment aiming for cure
- Does encompass end of life care – but is so much more
o Aim is to ensure optimal quality of life - Involves holistic approach
o Symptom management
o Psychological
o Social
o Spiritual support
End of life care
- People are considered to approaching rhe end of life when they are likely to die within the next 12 months
- A portion of palliative care directed towards the care of a person nearing end of life
- End of life difficult to predict
o Includes patients whose death is imminent (expected within a few hours and days) - Focus is on maintaining quality of life while offering services for legal matters
- Aim: patient dies with dignity
Best supportive/ enhanced
- ‘Prevention and management of the adverse effects of cancer and its treatments’
- Includes management of physical and psychological symptoms and side effects across the cancer experience from diagnosis through treatment and post treatment
- Involves
o Enhancing rehab
o Secondary cancer prevention
o End of life care
cytotoxic chemotherapy
- Treatment of disease with drugs
- Cytotoxic drugs- kills cells by targeting cell cycle
- Cannot distinguish between healthy and non healthy cells- targets rapidly dividing cells e.g. cancer cells
- Systemic therapy
Cytotoxic chemotherapy is different to:
- Hormone therapy
- Targeted therapy
- Immunotherapy
chemotherapy uses
Curative/radical
- Only works in some cancers e.g. leukaemia and lymphomas
- Induction: for remission
- Consolidation: prolongs remission
- Maintenance: long term remission
Neoadjuvant
- Chemo used to shrink tumour before surgery
Adjuvant
- In addition to treatment e.g. surgery/ radiotherapy
- Eliminated micro metastases
- Reducing risk of reoccurance
Combination
- Radio-sensitisation
- Makes cells more sensitive to radiotherapy
Palliative
- Extend life
- Improve symptoms
How is chemotherapy administered
IV
Orally
Others: IM, subcut, intrathecal, intracavitary (urinary bladder), topical
IV access
Options
- Cannulas
- Tunnelled central line
- PICC line
- Portacath
Benefits
- can stay in place much longer
- reduces risk of phlebitis
Mode of action of chemotherapies
- Exploits the fact that cancer cells divide faster than normal cells.
- Targets various aspects of cell cycle.
- Cancer cells often have mutations which cause reduced apoptosis even if detected as damaged in the cell cycle
cell cycle outline
- G1- cellular content replication
- S- DNA replication
- G2- checking stage
- M – mitosis (Prophase, metaphase, anaphase, telophase)
- G0- arresting phase
Classes of cytotoxic drugs
Cell cycle specific drugs
Antimetabolites
- Intervenes with S phase
- DNA replication
G2 phases
- Bleomycin
- Topoisomerase-1-inhibitors
M phases
- Plant derived -> block function of microtubules
- Cell division
- e.g.
Taxanes
Vinca alkaloid
Non cell cycles specific drugs
- Alkylating agents
- Platinum agents
Non cell cycles specific drugs
- Alkylating agents
- Platinum agents
classes of chemotherapy agents
Antimetabolites
Alkylating agents
Topoisomerase inhibitors
Mitotic inhibitors
Protein kinase inhibitors
antimetabolites
Prevent DNA replication (S phase of cell cycle), by replacing the natural building material needed for DNA and RNA synthesis
- pyrimidine antagonist
- purine antagonist
- folate antagonist
Pyrimidine antagonist
- MOA: inhibit thymidine synthase- preventing synthesis of thymidine nucleotides- halting DNA replication
- E.g. Gemcitabine (pancreatic, ovarian), 5-FU (colorectal, gastric, pancreatic), Cytarabine (lymphoma and leukaemia)
- Side affect: palmar-plantar eythrodysesthesia (PPE)
Purine antagonist
- MOA: inhibits enzymes used to produce pruine- preventing synthesis of adenosine and guanin
- E.g. 6-mercaptopurine and prodrug azathioprine (ALL). Fludarabine (low grade lymphomas)
- Thiopurine methyltransferase levels should be measured before prescribing -> deficiency in this enzyme can increase risk of toxicity
- Should not be used with allopurinol – myelosuppression and toxicity
Folate antagonists
- MOA: inhibit dihydrofolate reductase and thymidine synthase, preventing synthesis of thymine nucleotide
- E.g. methotrexate (lymphoma, leukaemia and choriocarcinoma)
- Side effects: hepatic and pulmonary fibrosis (should have baseline chest x-ray and pulmonary function test
Alkylating agents
Cause cross linking DNA and RNA strands -> leads to programmed cell death. Work on multiple phases of cell cycle -> main side effect is
- Cyclophosphamide
- platinum agents
- nitrogen mustards
Cyclophosphamide
- Uses: breast, ovarian, small cell lung cancer, leukaemia and lymphoma
- Side effects: bladder (haemorrhagic cystitis)and pulmonary toxicity , transitional cell cancers
Platinum agents
- E.g. Cisplatin, carboplatin, oxaliplatin
- Uses: ovarian, colorectal lung and bladder cancer
- Side effects: reversible peripheral neuropathy and nephrotoxicity (renal function should be closely monitored)
Nitrogen mustards
- E.g. Chlorambucil (Hodgkins and CLL) and melphalan (MM can cause PF and oedema)
topoisomerase inhibitors
Natural plant extracts which inhibit the topoisomerase family of enzymes- result in cell cycle arrest (inhibit cell divising during S and G2 phase). Common side effects: myleosuppresion, alopecia and mucositis
- Topoisomerase I inhibitors
- Topoisomerase II inhibitors
Topoisomerase I inhibitors
- MOA results in breakdown of single stranded DNA
- E.g. Irinotecan (colorectal, pancreatic, SCLC) and topotecan (cervical, ovarian and SCLC)
- Side effects: pneumonitis
Topoisomerase II inhibitors
- MOA results in breakdown of double stranded DNA
- E.g. Etoposide (testicular cancer and leukaemia)
Mitotic inhibitors
Vinka alkaloids
Taxanes
Mitomycin C17
Bleomycin
Anthracyclines
Vinka alkaloids
- MOA: binding on B-tubulin units and preventing microtubule polymerisation- prevents spindle formation and the cell cycle arrests
- E.g. vincristine, binblastine and vinorelbine
- Solid tumours and lymphomas
Taxanes
- MOA: bind polymerised microtubules and cause hyperstabilisation of the microtubule structure
- Lack of microtubule depolymerisation oprveenting chromosomal separation -> cell cycle arrest
- Side effects: nail changes
- E.g. docetazel and paclitazel (breast, ovarian and gastric cancers)
Mitomycin C17
- MOA: alkylating DNA strands cauding DNA damage and preventing further DNA replication
- E.g. previously used in bladder cancer
- Side effects: haemolytic uraemic syndrome, myelosuppression, cardiomayothapy
Bleomycin
- MOA: bind to emtallic ions forming cmplees rhat generate ROS- oxidative damage to DNA strands, halting cell cycle in G2 phase
- E.g. testicular cancer and Hodgkins lymphoma
- Minimal impact on myelosuppression, but associated with mucositis
- Side effects: PF
Anthracyclines
- MOA: formation of free radicals causing oxidative DNA damage and stabilisation of topoisomerase II DNA compels – preventing DNA synthesis
- Sdie effects: myelosuppression, alopecia, cardiomyopathy
- Ues: breast cancer and Non-hod
- E.g. doxorubicin, epirubicine and idarubicine
protein kinase inhibitors
Prevent PK from phosphylating target proteins _. Prevent cell division. Each PKI named after the enzyme is inhibits
- BCR-ABL tyrosine kinase inhibitors
- EGFR tyrosine kinase inhibitors
- Brunton kinase inhibitors
- Multiple receptor kinase inhibitors
main chemo side effects
- Hair loss
- Brain (not due to chemo, but combination of cancer, treatment and anxiety)
o Mood changes
o Poor conc
o Fatigue - Pulmonary toxicity
- Cardiotoxicity
- Hepatotoxicity
- Nephrotoxicity
- Bladder toxicity
- GI
o Taste change
o Ulcers- mucositis
o Poor appetite
o Weight loss
o Diarrhoea
o Constipation - Dry skin/ nail changes
- Loss of libido
- Sterility
- Peripheral neuropathy
- Ototoxicity
- Bone marrow toxicity -> pancytopenia
o Anaemia
o Infection- neutropenic sepsis
o bleeding
BCR-ABL tyrosine kinase inhibitors
- Imatinib -> CML, ALL
- Side effects- neurotoxicity, hepatotoxicity, nephrotoxicity
EGFR tyrosine kinase inhibitors
- Erlotinib and gefitinib -> lung cancer
- Side effects -> skin toxicity (folliculitis), PF, diarrhoea
side effects of chemotherapy occur because
Tissue which divides quickly will also be damaged
Cells commonly affected.
- Hair follicles -> hair loss
- Gastrointestinal cells
- Skin and nail cells
- Germ cells
- Bone marrow cells
Brunton kinase inhibitors
- Ibrutinib – CLL- prevents B cell proliferation
- Cardiotoxicity, hepatotoxicity, myleosupression
chemo man
chemo drug resistance
- Cancers can become less sensitive after exposure to chemotherapy due to mutations – like bacterial resistance
- E.g. if chemo kills majority of cells and leads to clinical remission, but resistant drugs live on and grow
o Often resistant to other drugs- multi- drug resistance
Combination chemotherapy
- Most treatments use a combination of drugs
- Targets different parts of the cell cycle, therefore affecting all cells in different stages of cell cycle
- Principles of drugs
o Must be effective against that tumour type
o Differing mechanism of action
o Different part of cell cyle targeted
o Not susceptible to same mechanism of resistance
o Differing side effect profiles
Tumour pathophysiology and reaction to chemotherapy
A tumour is made up of many of the same mutated cells, but at different stages in the cell cycle. It can be divided into:
- Compartment A
o Cells currently undergoing cell division
o This is called the Growth fraction
Because the number of cells that are undergoing division determines that rate at which tumours grow
o Susceptible to chemotherapy because cytotoxic drugs can itnervent with the cell cycle
- Compartment B
o Cells not currently dividing – but with the right stimulus are able to divide
o E.g. in Cell arrest- G0
o Not susceptible to chemotherapy, but may enter the cell cycle to divide, after chemotherapy has destroyed all of compartment A- therefor ethe tumour can continue to grow- THIS IS A PROBLEM
- Compartment C
o Cells which contribute to bulk of tumour but will never be able to enter cell cycle to divide
o Not really a problem because not dividing, therefore will not be contributing to tumour growth
Cancer cells do not actually go through the cell cycle faster than other healthy cells. However if you look at the proportion of cell types in a tumour, a much higher proportion will be in Compartment A- meaning they are actively dividing -> quicker rate of tumour growth
Tumours with a high proportion of Compartment A cells (in the growth fraction) are
more responsible to chemotherapy.
Tumours with larger Growth fraction
- Leukaemia
- Germ cell tumours
Tumours with low growth fraction
- Most solid tumours
- More resistant to chemotherapies
