Workshop 1- Solid tumours

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 the tumour 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 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: Bone (leads to bone pain) Liver (leads to jaundice) Brain (leads to mental changes) Lungs (leads to difficulties in breathing)

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.

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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: 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 some women developing breast cancer quite early in life Increased exposure to estrogen Early menarche (menstruating from a young age) Not having children

Signs and symptoms: 90% of the time, a small painless lump can be felt Solid, hard Irregular Non-tender Solitary 10% of the time, stabbing or aching pain can occur Sometimes, it can become tender, and a discharge can be seen Very, very curable if picked up early Regular screening is recommended
See above for symptoms if the cancer is advanced.

See common treatment goals

Non-pharmacological treatments: Mastectomy (removal of the breasts) Radiation therapy (instead of surgery) Note: may be just as effective as mastectomy in some cases Pharmacological treatments (see 'Mechanisms of action' and 'side effects' below for details): Early stage- focus on cure Adjuvant therapy with FEC is common: 5-flurouracil Epirubicin Cyclophosphamide Notice how the above combo has two drugs which are not specific for any parts of 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. Late stage- focus on palliative care Taxanes Paclitaxel 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). Therefore, avoid use. Misc Endocrine therapy only if the cancer carries estrogen receptors Tamoxifen- a estrogen receptor antagonist. Normally, the estrogen stimulates the growth of the tumour. Trastuzumab AKA Herceptin is only good for HER-2 positive cancers only
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 Trastuzumab AKA Herceptin is only good for HER-2 positive cancers only Non-cancer Pain Opioids like morphine are the gold standard Long acting formulation + short acting for breakthrough pain Also give laxatives to prevent constipation Paracetamol can work NSAIDs can be useful for bone pain Bisphosphonate for bone pain Nausea Ondansetron plus dexamethasone

Prostate cancer
The most common cancer in males, again it is more common in older people. For obvious reasons, it cannot occur in females. It has been linked to: Age (old) Race (African Americans are more affected) Family history Symptoms are: 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 Population wide screening is not implemented, but there are some ways to diagnose prostate cancer: PSA assay has a low diagnostic value, some people without cancer have increased PSA, while people with cancer can have a low PSA Only carry it out if symptoms are present, or if the person has a high risk Digital Rectal Examination (DRE) has good diagnostic value, but people aren't very keen on having them. Can confirm cases quite easily and quickly Transrectal ultrasound Imaging allows points of interest to be mapped out and biopsied (with a needle) to check for cancerous cells, helps to grade the 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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Importantly, we need to know how hormones affect the tumour:

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) Non pharmacological treatments: 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) However, radiation is just as effective (external beam therapy, where radiation is fired at the prostate) It depends on what side effects the patient prefers At later stages, surgery to remove the testes (orchidectomy) can be performed (not very popular though) Plus old people are not candidates for this treatment, need to use a pharmacological treatment 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. Pharmacological treatments (advanced cancers): Goserelin injections- depot of goserelin injected monthly GnRH agonist, will attempt to over-stimulate the pituitary gland, and cause the receptors to desensitise to reduce the downstream production of testosterone Causes 'tumour flare', which causes an increase in symptoms arising from the tumour, plus hot flushes, decreased impotence and tender breasts Occurs because at the beginning of treatment, the GnRH receptors haven't desensitised, so there's a lot of testosterone being produced downstream Flutamide tablets- given daily for a short period of time 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) If non-responsive, need to focus on palliative care and maybe some other conventional chemotherapy drugs e.g. vincristine etc.
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conventional chemotherapy drugs e.g. vincristine etc. Surgery is not an option, because it's metastasized Make sure the chemotherapy agent is compatible with the patient

Colorectal cancer
Very common cancer overall in the population
Risk factors: 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) Signs and symptoms: Changes in bowel motions (chronic constipation) Weight loss Abdominal pain and cramps Malaena, tarry stools with blood Bloating Diagnosis: 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 Non-pharmacological treatments: Again, surgery is first line treatment for non-metastasized cancers, with adjuvant chemotherapy (FOLFOX) 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. Radiation is not as effective here Adjuvant therapy for local invasion of some tissues Radiation is more effective for rectal cancers Nutritional support to reverse weight loss Pharmacological treatments: FOLFOX (first line treatment): Folinic acid 5-Flurouracil Oxaliplatin Capecitabine (prodrug of 5-FU) if not responsive or at late stage Bevacizumab is an antibody which prevents the angiogenesis of metastatic growths, preventing them from growing Good for late stage cancers

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 tissues. Therefore, a complete cure is possible if the tumour is cut out, with some
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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 might not 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 Antimetabolites 5-flurouracil 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. Anthracyclines Doxyrubicin, epirubicin Not cell cycle specific Intercalates between bases in DNA to inhibit topoisomerase II and stabilise topoisomerase II once the DNA has been cut Can trigger apoptosis Also generates free radicals. However, this is not important to its action, but it results in some side effects Cumulative Cardiotoxicity WARNING: take care with people with ischemic heart disease Alkylating agents Cyclophosphamide Not cell cycle specific Binds to nucleophiles, the pyridine bases of DNA, causing alkylation, cross linking within or between strands of DNA Can also lead to apoptosis Side product, acrolein, is produced. It causes inflammation of the bladder Causes haemorrhagic cystitis (bleeding in bladder) Need to co-administer with Mesna and plenty if IV fluids to counter this Taxanes Paclitaxel 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) Vinca alkaloids Vincristine Also prevents mitosis by inhibiting microtubule formation by attaching to the actin subunit Attaches at a different site compared to taxanes Prevents the M phase
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 Prevents the M phase Platins Oxaliplatin Binds to DNA (crosslinking between strands) DNA becomes unusable Non-cancer agents Ondansetron Serotonin 5-HT3 receptor antagonist Antiemetic effect Dexamethasone Glucocorticoid Enhances the effect of Ondansetron

Side effects
General side effects and how to avoid them:

Extravasation (immediate effect) 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.
Nausea and vomiting (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 Mucositis and diarrhoea (delayed 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. Myelosuppression/neutropenia (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 Need to monitor blood cell counts weekly Worst suppression occurs 7-14 days after infusion 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 WARNING: must tell patients to look for symptoms of infection: Sore throat Pain on urination Feeling pretty shit But NO fever is present Hair loss and alopecia (delayed effect)
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 Hair loss and alopecia (delayed effect) Again due to hair follicles containing rapidly dividing cells Use a government subsidised wig or just buy a scarf Specific side effects have been listed with the specific drug

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