Cancer Recap

Question 1

What is cancer

Answer 1

• Collection of diseases with shared features of uncontrolled cell division and invasion
• Can affect almost any organ/cell type
• Outcomes vary significantly - treatable to untreatable
• Different therapeutic approaches

Question 2

How do normal cells become cancer cells

Answer 2

1. Normal cell - undergoes multiple specific changes (known as mutations)
2. Uncontrolled cell division
3. Spread to surrounding and/or distant tissues

Question 3

Is a single mutation enough to cause cancer?

Answer 3

• A single mutation leading to a single acquired property such as increased proliferation is not enough to lead to cancer.
• A single cell has to be able to acquire (usually after multiple mutations) most or all of the hallmarks in order to progress to cancer.

Question 4

Where do mutations occur?

Answer 4

Occur in gene coding regions
- Point mutation
- Small insertions/ deletions

Question 5

Why do mutations occur?

Answer 5

• Alterations in transcription/splicing.
• Amplifications/deletions of chromosomal regions.
• Chromosomal translocations.
• Gains and losses of whole chromosomes.
• Changes in DNA modification e.g. DNA methylation.

Question 6

Risk factors for Cancer

Answer 6

• Lifestyle influences cancer progression
• UV and other radiation
• Viruses
• Chemicals: Smoking, Asbestos, Food
• Copying/repair errors: inherited susceptibility

Question 7

State the 6 hallmarks of cancer

Answer 7

1. Gains growth factor independence
2. Insensitivity to growth inhibitors
3. Proliferate without limit
4. Avoids apoptosis
5. Promotes angiogenesis
6. Invade and metastasis

Question 8

1. Gains growth factor independence

Answer 8

• Don’t require growth factors to stimulate cell division
• e.g. they gain an oncogene.
• Cancer cells are able to grow and divide uncontrollably

Question 9

2. Insensitivity to growth inhibitors

Answer 9

Alterations in cell cycle regulation:
- Loss of tumour suppressor genes (i.e. pRb)
- Upregulation of positive cell cycle regulators (i.e. CDC25 or cyclins)
- Cancer cells are able to bypass the normal mechanism that suppresses cell growth

Question 10

3. Proliferate without limit

Answer 10

• Cancer cells can rebuild their telomeres using the enzyme telomerase.
• Possess unlimited proliferative potential.

Question 11

4. Avoid apoptosis

Answer 11

Avoid programmed cell death

Question 12

5. Promote angiogenesis

Answer 12

Angiogenesis = formation of new blood vessels

Question 13

6. Invade and metastasize

Answer 13

• Cancer cells can invade nearby tissues
• Spread to other parts of the body

Question 14

Priorities in dealing with cancer: PET

Answer 14

• Prevention
• Early detection
• Total eradication

In most cases, these are unrealistic ideals

Question 15

Hierarchy of aims in cancer management (4)

Answer 15

1. Cure:
   eradicate tumour and metastasis
2. Remission/mitigation:
   significant reduction in tumour load
   increased survival
3. Symptomatic/pallation:
   treat secondary complications
   relief of symptoms
4. Terminal care:
   improve QoL
   optimise symptom control

Question 16

Modes of therapy - surgery

Answer 16

• For well-defined solid tumours
• In non-vital regions (e.g. mastectomy)
• Non-mutilating result
• Resection/reconstruction possible (e.g. gut)

Question 17

Modes of therapy - radiotherapy

Answer 17

• For diffuse but localised tumours (e.g. lymphoma)
• Vital organ/region (e.g. head and neck, CNS)
• Adjuvant therapy (e.g. post mastectomy)
• Palliation

Question 18

Modes of therapy - chemotherapy

Answer 18

• Adjuvant therapy following surgery or radiotherapy
• Neo-adjuvant therapy prior to surgery or radiotherapy
• Widely disseminated/metastasized
• Diffuse tumour e.g. leukaemia
• Some primary tumours (e.g. Hodgkin’s lymphoma)
• Palliation

Question 19

Rationale of chemotherapy

Answer 19

• Need to recognise features of tumour growth to understand the rationale of cytotoxic chemotherapy
• e.g. cell cycle time, growth fraction, number of cells - improtant for determining growth of tumour
• By the time tumours are clinically apparent, most are in the relatively slow phase of growth - chemo less likely to be effective

Question 20

When are tumours clinically apparent

Answer 20

~10^9 cells or more

Question 21

Chemotherapy combination

Answer 21

• Chemotherapeutic agents used in combo rather than single
• Should have minimal overlap in toxicity
• Treatment should be delivered on intermittent basis with shortest possible time between treatments
• Allow recovery of the most sensitive normal tissue

Question 22

Advantages of combo chemo

Answer 22

• More aggressive = Treatment remission
• multiple MoA = increased remission
• Note: also increased side effects

Question 23

Combined vs single agent therapy

Answer 23

New targeted treatment options
- e.g. tyrosine kinase inhibitors & mabs
- reignite competition over combination vs single agent

Question 24

Why are there SE to chemotherapy

Answer 24

• Cancer cells are rapidly dividing
• Chemotherapy drugs target rapidly dividing cells
• Most chemotherapy drugs are non-selective for cancer cells
• SE caused by impact of chemo on normal cells

Question 25

SE

Answer 25

• Myelosuppression
• Gastrointestinal tract and bladder (ulcers)
• Fertility; teratogenic action
• Skin and hair (alopecia)
• N+V

Question 26

Aims of minimising SE of chemo

Answer 26

Decrease
- Discomfort
- Morbidity and mortality

Increase
- Tolerable dose threshold and thus the dose that can be used

Question 27

Ways to minimise SE

Answer 27

Close monitoring
- FBC

Prevention used wherever possible
- Allowing for bone marrow recovery between treatments
- Administering stem cell GFs with chemotherapy to selectively enhance marrow proliferation

Question 28

Minimising SE of chemo that is nephrotoxic and bladder-toxic

Answer 28

• Forced diuresis is routinely given with these types of drugs
• This will reduce contact time and urine concentration
• Involved modest over hydration before therapy followed by a diuretic to maintain high urine output for at least 24 hours after therapy

Question 29

What is mannitol

Answer 29

• Diuretic
• Often given after cancer chemotherapy that is nephrotoxic and bladder-toxic