workshop 1- solid tumours

8/2/2019 Workshop 1- Solid Tumours

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Intro/Glossary

Cure

Removal of all cancerous cells from the body. Ideally, the patient will now have the

same life expectancy as someone who doesn't have cancer.

Remission

Reducing the cancer, even to below detectable levels. However, the cancer is not

completely removed, and may return at any time.

Adjuvant chemotherapy

Additional therapy given with the main method of treatment. For example, adjuvant

chemotherapy is chemotherapy given in addition to surgery (the main treatment).

Adjuvant therapy may also include radiation as well. All this is done to decrease the

chances of reoccurrence of cancer

Neo-adjuvant chemotherapy

Chemotherapy given BEFORE the main treatment, for example, chemotherapy may be

carried out to reduce the size of a tumour before surgery, which can reduce the

amount of tissue to cut, reduce the vasculature (that's a good thing, means you'd lose

less blood during surgery) and make it shrink away from healthy tissue to save that

tissue.

NOTE: Remember, chemo is more effective on the outer edge of solid tumours, which

causes the shrinkage.

Palliative chemotherapy

By this point, we know the cancer can't be cured, so chemo is given to reduce thetumour sizes to relieve symptoms. PLUS it can be used to extend life. Just remember,

we can't cure them by this point, make them more comfortable and live a bit longer.

TMN staging system

T= size of the initial tumour, higher the number, bigger it is

N= number of lymph nodes or extent of spread along lymph nodes, higher the number,

it's spread more throughout the lymphatic system

M= indicates if it has metastasized, where 0 is no, 1 is yes.

e.g. T2N1M0 means it's a medium sized tumour with little regional node infiltration and

no distant metastasis.

Metastasis

Bone (leads to bone pain)

Liver (leads to jaundice)

Brain (leads to mental changes)

Lungs (leads to difficulties in breathing)

Cancer cells are able to split off and travel around the body to for new tumours at

different sites of the body. There are four main sites they will go to, leading to a

common set of symptoms:

Disease templates

Breast cancer

The most common cancer in females. However, it does occur rarely in males. The

disease is also more common in older people, which is common for cancers.

Workshop 1- Solid tumours

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Age

Family history

Race

BRCA1 and BRCA2 double strand DNA repair mechanism genes are faulty in a

high number of cases. This mutation can be passed down, leading to somewomen developing breast cancer quite early in life

Early menarche (menstruating from a young age)

Not having children

Increased exposure to estrogen

Pathophysiology is common to most cancers, where the genetic material of cancerous

cells is damaged, leading to unregulated growth. However, there are some specific risk

factors:

Solid, hard

Irregular

Non-tender

Solitary

90% of the time, a small painless lump can be felt

10% of the time, stabbing or aching pain can occur

Sometimes, it can become tender, and a discharge can be seen

Regular screening is recommended

Very, very curable if picked up early

Signs and symptoms:

See above for symptoms if the cancer is advanced.

See common treatment goals

Mastectomy (removal of the breasts)

Note: may be just as effective as mastectomy in some cases

Radiation therapy (instead of surgery)

Non-pharmacological treatments:

Pharmacological treatments (see 'Mechanisms of action' and 'side effects' below for

details):

5-flurouracil

Epirubicin

Cyclophosphamide

Adjuvant therapy with FEC is common:

Notice how the above combo has two drugs which are not specific for any partsof the cell cycle, and 5-FU is specific for the S-phase. This makes them synergistic

as the treatment will work regardless of what stage the cells are in.

Early stage- focus on cure

Paclitaxel

Taxanes

Therefore, avoid use.

CAUTION: anthracyclines have cumulative cardiotoxicity. In other words, if you

used Epirubicin during adjuvant therapy, you can't use it again or anything else in

that family (like doxorubicin).

Late stage- focus on palliative care

Tamoxifen- a estrogen receptor antagonist. Normally, the estrogen

stimulates the growth of the tumour.

Endocrine therapy only if the cancer carries estrogen receptors

Misc

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Trastuzumab AKA Herceptin is only good for HER-2 positive cancers only

Long acting formulation + short acting for breakthrough pain

Also give laxatives to prevent constipation

Opioids like morphine are the gold standard

Paracetamol can work

NSAIDs can be useful for bone pain

Bisphosphonate for bone pain

Pain

Ondansetron plus dexamethasone

Nausea

Non-cancer

Prostate cancer

The most common cancer in males, again it is more common in older people. For

obvious reasons, it cannot occur in females.

Age (old)

Race (African Americans are more affected)

Family history

It has been linked to:

Generally little to no symptoms if locallised

Urgency and dribbling if it's starting to spread (the urethra passes through the

prostate gland, so if it's starting to grow, it will block it, so you can't piss as easily)

Can result in back pain plus other generalised symptoms if advanced

Symptoms are:

Only carry it out if symptoms are present, or if the person has a high risk

PSA assay has a low diagnostic value, some people without cancer have increased

PSA, while people with cancer can have a low PSA

Can confirm cases quite easily and quickly

Digital Rectal Examination (DRE) has good diagnostic value, but people aren't

very keen on having them.

Imaging allows points of interest to be mapped out and biopsied (with a

needle) to check for cancerous cells, helps to grade the cancer.

Transrectal ultrasound

Population wide screening is not implemented, but there are some ways to diagnose

prostate cancer:

Gleason score should be taken, which is where the cancer cells are checked to see if

they form glands (well differentiated cells) or not (undifferentiated cells).

Undifferentiated cells will cause a worse prognosis.

Importantly, we need to know how hormones affect the tumour:

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LH-RH (also known as GnRH or gonadotropin releasing hormone) will stimulate

the pituitary gland to release LH (Lutenizing hormone) and FSH (follicular

stimulating hormone)

LH and FSH will stimulate the testes to release testosterones which will stimulate

the prostate to grow, making the cancer worse

We need to target this pathway for a specific treatment (see below)

Surgery to remove the prostate is well recommended for a complete cure at early

stages (this is the main treatment, and what we're aiming for)

It depends on what side effects the patient prefers

However, radiation is just as effective (external beam therapy, where radiation is

fired at the prostate)

Plus old people are not candidates for this treatment, need to use a

pharmacological treatment

At later stages, surgery to remove the testes (orchidectomy) can be performed

(not very popular though)

Or for some patients, it's better for their life if they just waited and watched the

tumour carefully. This is because these people tend to be old, so it might not be

worth dragging them through treatment to make the rest of their lives miserable.

Non pharmacological treatments:

GnRH agonist, will attempt to over-stimulate the pituitary gland, and cause

the receptors to desensitise to reduce the downstream production of

testosterone

Occurs because at the beginning of treatment, the GnRH receptors

haven't desensitised, so there's a lot of testosterone being produced

downstream

Causes 'tumour flare', which causes an increase in symptoms arising from

the tumour, plus hot flushes, decreased impotence and tender breasts

Goserelin injections- depot of goserelin injected monthly

Non-steroidal testosterone receptor antagonist

Prevents testosterone from binding to the receptor, mainly to counteract

the tumour flare effect

Causes the same side effects as goserelin, but can also cause bone loss

(osteoporosis)

Flutamide tablets- given daily for a short period of time

If non-responsive, need to focus on palliative care and maybe some other

Pharmacological treatments (advanced cancers):

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Surgery is not an option, because it's metastasized

Make sure the chemotherapy agent is compatible with the patient

conventional chemotherapy drugs e.g. vincristine etc.

Colorectal cancer

Very common cancer overall in the population

Age is the main one (again)

Low fibre-high fat diet

Sedentary lifestyle

Hereditary (family history)

Inflammatory bowel conditions (especially Ulcerative colitus, Crohn's disease to a

lesser extent)

Risk factors:

Changes in bowel motions (chronic constipation)

Weight loss

Abdominal pain and cramps

Malaena, tarry stools with blood

Bloating

Signs and symptoms:

Most commonly, a barium enema can be used to check for growths

A colonoscopy may also be used

May be anemic, due to blood loss

A DRE can be used to rule out haemorrhoids as the cause of symptoms

Diagnosis:

Remove the tumour and surrounding tissue to make sure to remove all the

traces of cancer for a total cure

Colostomy will be performed just after the surgery, which is where one

part of the bowel will be open to the outside world to allow food in. Later

on, after the ends have healed, the GI tract is put back together.

Again, surgery is first line treatment for non-metastasized cancers, with adjuvantchemotherapy (FOLFOX)

Adjuvant therapy for local invasion of some tissues

Radiation is more effective for rectal cancers

Radiation is not as effective here

Nutritional support to reverse weight loss

Non-pharmacological treatments:

Folinic acid

5-Flurouracil

Oxaliplatin

FOLFOX (first line treatment):

Capecitabine (prodrug of 5-FU) if not responsive or at late stage

Good for late stage cancers

Bevacizumab is an antibody which prevents the angiogenesis of metastatic

growths, preventing them from growing

Pharmacological treatments:

Common treatment goals

Generally speaking, at earlier stages of cancer, the tumour is small, encapsulated (i.e.

cells are completely surrounded and cannot leave) and has not invaded any other

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tissues. Therefore, a complete cure is possible if the tumour is cut out, with some

adjuvant chemotherapy to make sure there aren't any cancer cells left.

However, in later stages, palliative care is more important, trying to reduce the sizes of

the tumour and distant metastasis. A multitude of drugs can be given, and surgery is

less important because it wouldnt achieve a cure.

Also, we have to weigh up between treating the cancer and preserving the life quality

of the patient. For example, if the person is old and has advanced cancer, then it mightnot be worth giving them chemotherapy because it would severely reduce their life

quality without much of an impact on the life expectancy. See prostate cancer for more

examples.

Mechanisms of action

Specifically targets the S-phase of the cell cycle (because it stops DNA

replication)

Pyridine analogue which gets incorporated into the growing DNA strand.Because it has a fluorine on the 5 position, it stops any more nucleotides

from being added to the molecule, stopping synthesis of DNA.

5-flurouracil

Antimetabolites

Not cell cycle specific

Can trigger apoptosis

Intercalates between bases in DNA to inhibit topoisomerase II and stabilise

topoisomerase II once the DNA has been cut

Cumulative Cardiotoxicity

WARNING: take care with people with ischemic heart disease

Also generates free radicals. However, this is not important to its action,

but it results in some side effects

Doxyrubicin, epirubicin

Anthracyclines

Not cell cycle specific

Can also lead to apoptosis

Binds to nucleophiles, the pyridine bases of DNA, causing alkylation, cross

linking within or between strands of DNA

Causes haemorrhagic cystitis (bleeding in bladder)

Need to co-administer with Mesna and plenty if IV fluids to counter

this

Side product, acrolein, is produced. It causes inflammation of the bladder

Cyclophosphamide

Alkylating agents

Anti-mitotic agent, inhibits microtubule formation by attaching to the actin

subunit

Prevents the M phase (where they build microtubules to split the genetic

material between nuclei)

Paclitaxel

Taxanes

Also prevents mitosis by inhibiting microtubule formation by attaching to

the actin subunit

Attaches at a different site compared to taxanes

VincristineVinca alkaloids

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Prevents the M phase

Binds to DNA (crosslinking between strands)

DNA becomes unusable

Oxaliplatin

Platins

Serotonin 5-HT3 receptor antagonist

Antiemetic effect

Ondansetron

Glucocorticoid

Enhances the effect of Ondansetron

Dexamethasone

Non-cancer agents

Side effects

General side effects and how to avoid them:

Fluid from infusion can seep out into surrounding tissues

Incredibly dangerous as some drugs are vesicants (blistering agents)

May be caused by poor circulation (due to incorrect line site, use a central

line, which has good flow compared to a peripheral line)

Patients must be told to report discomfort or pain at the infusion site so it

can be stopped and an antidote can be administered.

Extravasation (immediate effect)

Caused when the drug is detected by the chemoreceptor zone in the brain,

triggers nausea and vomiting

Ondensetron and Dexamethasone are commonly used

Nausea and vomiting (immediate effect)

Will also damage oral linings as well as the rest of the GI tract, leading to

diarrhoea

Occurs because the mucus membranes contain rapidly dividing cells, and

they too are affected by treatment

Good oral health and nystatin (anti-fungal drug) are given to prevent oral

issues, while loperamide (anti-diarrhoeal) will be given for GI symptoms.

Mucositis and diarrhoea (delayed effect)

Reduced white blood cells and platelets, leading to increased bleeding or

susceptibility to infections

Again, the bone marrow contains rapidly dividing cells, leading to a

shortage in these cells

Worst suppression occurs 7-14 days after infusion

Need to monitor blood cell counts weekly

If neutrophils are very low, they must be put into isolation

gCSF (granulocyte Colony-Stimulating Factor) can be given to stimulate

white blood cells to grow

Sore throat

Pain on urination

Feeling pretty shit

But NO fever is present

WARNING: must tell patients to look for symptoms of infection:

Myelosuppression/neutropenia (delayed effect)

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Again due to hair follicles containing rapidly dividing cells

Use a government subsidised wig or just buy a scarf

Hair loss and alopecia (delayed effect)

Specific side effects have been listed with the specific drug

workshop 1- solid tumours

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