Blue book Flashcards
What proportion of people are diagnosed with cancer in their lifetime?
1/3
What proportion of people die of cancer?
1/4
what percentage of cancer patients will be cured?
35-45%
What 4 things can be used to cure cancer?
o Chemo
o Radio
o Surgery
o Biological agents
What are the 4 commonest cancers?
lung, breast, prostate and gastrointestinal
What are the different classes of aetiological agents?
Inherited conditions Chemicals Physical Diet Drugs Infective Immune deficiencies
how do inherited conditions cause cancer and give examples?
characterised by specific genetic defects associated with an increased risk of one or more cancers. A germline deletion of one allele of a gene and subsequent mutation of the remaining allele leads to carcinogenesis.
Examples include neurofibromatosis, adenomatous polyposis coli, familial breast cancer (e.g. mutations in the tumour suppressor genes breast cancer susceptibility gene 1 (BRCA1) and BRCA2), and von-Hippel Lindau syndrome
How can chemicals cause cancer and give examples?
Many chemicals act as carcinogens by damaging cellular DNA and inducing mutations in oncogenes and tumour suppressor genes.
Carcinogenic chemicals include:
Cigarette smoke - carcinogens present in cigarette smoke cause specific mutations in the p53 tumour suppressor gene.
Aromatic amines - associated with bladder cancer
Benzene - leukaemia
Wood dust - nasal adenocarcinoma
Vinyl chloride - angiosarcomas
How can radiation cause cancer and give examples?
Radiation increases the risk of cancer by increasing DNA damage leading to the accumulation of mutations in tumour-suppressor genes and oncogenes.
The risk of tumour development is associated with:
Radiation source – for example, damage to DNA by UV light is thought to be pathogenic in skin cancers, including malignant melanoma.
Level of exposure - The dose received is critical to the incidence of tumour development.
Accumulation of a radioactive isotope in a particular tissue may lead to tumour formation, for example thyroid cancer and radioactive iodine.
How can diet cause cancer and give examples?
Many differing food substances have been implicated as causative agents through demographic studies e.g. association of colorectal carcinomas with low fibre diets in the West, and gastric carcinomas with smoked food in Japan. Many of the carcinogens are breakdown products of food (for example nitrosamines). Low fibre diets lead to an increased transit time through the bowel - thereby increasing exposure to carcinogenic substances.
How can drugs cause cancer?
Cytotoxic drugs induce DNA damage and are associated with an increased risk of malignancy. The effect is dose dependent and therefore of considerable importance in high-dose regimes.
Characteristic translocations may be induced by the topoisomerase inhibitors and lead to an acute leukaemia.
Give examples of infective causes of cancer.
HPV - Cervical and anal cancers are associated with sexual transmission of HPV.
Epstein Barr Virus - associated with non-Hodgkin’s lymphoma (NHL) and other lymphomas. The most common genetic abnormality - EBNA (Epstein Barr Nuclear Antigens); an 8:14 translocation
Hepatitis B virus - Infection is associated with hepatocellular cancer and leads to a greater than 100-fold increased risk.
Retrovirus - retroviruses can cause abnormal overexpression of oncogenes. In humans HTLV1 infection is associated with T-cell lymphomas.
Helicobacter pylori - mucosal associated lymphoid tissue (MALT) tumours. Eradication of the H. Pylori may lead to a regression of the tumour.
How can immune deficiencies cause cancer?
increasing evidence that the immune system is involved in tumour surveillance. Drugs causing immunodeficiency are associated with a higher risk of malignancy, as are infections that damage the immune system (for example HIV). Congenital abnormalities of the immune system, particularly T cell deficiencies, are also associated with an increased risk of tumours.
What are the common presenting symptoms in cancer?
Lumps - Breast lumps, Change in moles, Nodes, nodules and musculo-skeletal lumps
Bleeding - Haemoptysis, Rectal bleeding, Haematuria, Post-menopausal or irregular menstrual bleeding
Pain - Chest or abdominal pain, Headache.
Change in function - Change in bowel habit, new cough, dyspnoea, weight loss, fever, acute confusional state
What are other important factors in cancer?
Demographics - Age, Sex
Socioeconomics - Occupation and environmental exposures
Personal risk factors - Smoking, Family history, Ethnicity, Past medical history/ drugs/alcohol
How are most cancers staged?
TNM
T: Primary Tumour Tx Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ T1, T2, T3, T4 Increasing size and/or local extent of the primary tumour
N: Regional Lymph Nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1, N2, N3 Increasing involvement of regional lymph nodes
M: Distant/Organ Metastasis
Mx Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage 0 only in situ. No spread Stage 1 T1/T2. No spread Stage 2 T3/T4. No spread Stage 3 Any T, with N but M0 Stage 4 Any T and N, with M1
How is grade assessed in cancers?
Histologically, a tumour will have a grade, referring to the extent the tumour resembles normal tissue or has a bizarre appearance:
GX Grade of differentiation cannot be assessed
G1 Well differentiated: Similarities remain to normal tissue of the organ of origin
G2 Moderately differentiated
G3 Poorly differentiated: bizarre cells
Higher grades have a higher risk of recurrence locally and of being of higher stage including the development of secondaries.
What is the purpose of staging and grading?
indicate prognosis and the appropriate choice of treatment.
higher stage and grade - poorer the prognosis. communicated to the patient.
Determine the treatment choice - the higher the stage the more extensive the treatment has to be. ESP. lymph node metastases - problem in that these nodes need to be either removed or treated by radiotherapy or chemotherapy but is also a powerful indicator of probable systemic blood-borne metastases.
E.g. In breast cancer, if the patient has disease which involves the lymph nodes then the chance of metastatic disease is high and it is these patients who are predominantly treated with adjuvant chemotherapy.
In colorectal cancer, when lymph nodes are involved the risk of distant metastases is high and adjuvant chemotherapy has been shown to increase the cure rates.
How is imaging used in cancer treatment?
diagnosis, staging and treatment of cancer
non-invasively identify tumours, define their size and extent and detect metastatic disease is continuously improving
How is imaging used in diagnosing cancer?
Radiological investigation forms part of the initial assessment of almost all patients with cancer.
Many tumours have a characteristic radiological appearance but histology is required in most cases to make an accurate diagnosis.
CT or US are commonly used by radiologists to guide biopsies, under local anaesthesia, to provide an adequate specimen for histological or cytological diagnosis and may obviate the need for more invasive interventions.
How is imaging used in the staging of cancer?
Accurate staging requires precise definition of the anatomical extent of disease.
non-invasively
CT - standard imaging tool of chest and abdominal malignancies, supplemented by PET-CT. routinely in many types of cancer such as lung and oesophagus.
MRI - bone and soft tissue lesions, and regions where bone causes artefact in the CT appearances such as the pelvis or the posterior fossa of the brain.
How is imaging used in response assessment?
CT and MRI are used as reproducible techniques, accurately measuring changes in tumour dimensions.
chest radiography - monitor disease response when appropriate.
When comparing treatments in clinical trials it is vital to have a consistent and objective system for measuring response.
What is the RECIST system?
Complete Response (CR) No disease detectable radiologically
Partial Response (PR) All lesions have shrunk by at least 30%, but disease still present
Stable Disease (SD) Less than 20% increase in size or less than 30% decrease in size
Progressive Disease (PD) New lesions or lesions that have increased in size by more than 20%
How is imaging used in the follow up of cancer?
When detection of asymptomatic relapse has been shown to affect clinical outcome, (e.g. testicular tumours), further use of radiology for surveillance is justified. However, in most cancers, routine follow-up imaging is of no proven benefit.
How is imaging used in screening of cancer?
The use of screening mammography to detect breast cancer is now well established in the UK but the use of other radiological screening examinations has not proved effective (e.g. CXR to assess people at high risk of lung cancers, transvaginal ultrasound for ovarian cancer).
How does CT work and how is it used?
based solely on the X-ray attenuation of the tissues.
Section thicknesses of between 1 and 10 mm are used depending upon the application.
Oral contrast medium may be administered to outline the gastro-intestinal tract. Intravenous contrast medium is used to delineate vascular structures and to demonstrate tumour enhancement (thus increasing lesion detection, particularly in the liver).
The principal concern about CT is the dose of radiation involved - one additional cancer per 1000-2000 scans performed.
Always consider pregnancy before requesting scans or X-rays for women of child-bearing age.
How does MRI work and how is it used?
images of high soft tissue contrast in any cross-sectional plane.
now the gold standard for imaging neurospinal, rectal, prostate and musculoskeletal tumours, and is used for staging some subtypes of head and neck cancer.
Images can be reconstructed to examine a particular organ system, such as MR angiography of the cardiac vessels, or MR cholangiopancreatograms. Real-time MR is of increasing use in diagnostic work such as the assessment of breast masses.
no known toxicity
Most pacemakers electronically vulnerable to the effects. Metallic foreign bodies can also be a contraindication, prosthetic joints are sufficiently fixed in place so as not to be a problem. Most surgical manufacturers now try to use non-ferrous materials for this reason.
How does ultrasound work and how is it used?
reflection of high-frequency sound waves at soft tissue interfaces generates the ultrasound image.
no ionising radiation, is safe, widely available and inexpensive.
Used for:
detecting metastases in solid ‘visceral’ abdominal organs,
specialist applications such as duplex and doppler ultrasound are used to assess tumour blood flow. This can contribute to the characterisation of some neoplastic masses.
real-time guidance of biopsy and therapeutic interventional procedures.
less reliable for the serial measurement of lesions for response.
How does nuclear medicine work and how is it used?
Radioisotope-Iabelled pharmaceuticals are administered, and their distribution measured by γ-camera detection of emitted photons. Many isotopes are given intravenously, e.g. technetium (Tc99m DTPA) used for isotope glomerular filtration rate (GFR) whilst some are given orally, e.g. radioiodine. Bone scintography (bone scan) remains the principal investigation for detection of skeletal metastases.
How does PET scan work and how is it used?
detects high-energy photons emitted by short-lived radioisotopes chemically tethered to molecules such as glucose or somatostatin to form a tracer
produces functional images
differentiate malignant from benign pathologies,
Limited availability
usually merged with standard CT taken at the same time in order to map functional images to detailed anatomy.
The isotopes used have a short half-life in order to minimize radiation exposure to patients. The distance between production facility and clinical centre is therefore critical and the costs of manufacture and delivery of these agents is high.
FDG-18 PET-CT can identify otherwise occult metastases from some cancers. It is used in situations where radical treatment appears possible but has high mortality and/or morbidity.
What are tumour markers?
Tumour markers are substances produced either by, or in response to, tumour, and are present in blood or other tissue fluids and can be quantified.
A tumour marker should be both highly sensitive so that few people with the disease are missed and highly specific so that few people are falsely labeled as having the disease.
Define sensitivity in the context of tumour markers
The sensitivity of a marker describes its ability to detect those with a certain disease. If 100 people have the disease and the marker is elevated in only 95, its sensitivity is 0.95.
Define specificity in the context of tumour markers
The specificity of a marker describes its ability to accurately define those who are disease free. If in 100 disease-free people the marker is negative in only 90 (i.e. there are 10 false positives) the specificity of the test is 0.90.
What are the different classses of tumour marker with examples?
Cell-surface glycoproteins - CEA, CA125, CA19.9
Oncofetal proteins - HCG, α-feto-protein (αFP)
Enzymesn - Acid phosphatase, Alkaline phosphatase, Lactate dehydrogenase, Neurone¬ specific enolase, Intermediate metabolites, 5-hydroxyindoleacetic acid, Vanillyl mandelic acid.
Hormones - Thyroglobulin, Antidiuretic hormone,
Adrenocorticotrophic hormone.
Immunoglobulins - Bence Jones Protein, Light Chains
Nucleic acids
Both DNA and RNA can be detected. These can be tumour specific (e.g. Philadelphia chromosome, oncogene mutations), or tissue-specific [e.g. the detection of tyrosinase expression (a melanocyte-specific gene) in blood]
What are the uses of tumour markers?
Screening - only certain high-risk groups have been identified in whom screening can be justified
Diagnosis - Most tumour markers are elevated in a broad spectrum of malignancies. Many are also elevated in benign conditions. helpful in some diagnostic situations. e.g PSA is highly tissue specific Very high levels of some tumour markers are more likely to be due to a particular malignancy, just as the specificity of any test can increase if the cutoff value is moved.
Prognosis - The rate of decline of a tumour marker following surgery or other treatments has been shown to relate to prognosis and may influence subsequent management.
Response - One of the most clinically useful features of tumour markers is their ability to indicate response to treatment. In a patient with an elevated tumour marker, a reduction in the level of that marker whilst receiving treatment is highly suggestive of a response.
Relapse
In a patient who has previously been demonstrated to be have high levels of markers when disease is active (‘marker positive’), subsequent increase in the level is highly suggestive of tumour relapse. However some cancers will not show a rise in marker levels at the point of relapse and therefore over-reliance on a persistently normal level is not advisable.
What are the negatives of tumour markers?
relatively expensive blood tests and are not substitutes for a careful history and examination. False positive results and the over diagnosis of quiescent tumours (e.g. low grade prostate cancer in the very elderly) can cause anxiety, inappropriate further investigation and harm.
What does the marker CEA show?
A cell surface antigen also expressed in a variety of normal tissues.
elevated in a wide variety of tumours but its common clinical use is in the setting of colorectal carcinoma.
The occurrence and degree of elevation is related to the clinical stage (4% in Dukes’ stage A, 65% with Dukes’ stage D). 98% of normal non-smokers have levels less than 5ng/ml. Elevated levels are also more common in people who smoke, or have inflammatory bowel disease, hepatitis, pancreatitis or gastritis.
What does the marker CA125 show?
Used as a marker in ovarian carcinoma, and is an antigen that is expressed on the surface of ovarian cells. It is not perfect in sensitivity and specificity: An elevated serum level has been found in 1% of normal women, 6% with benign conditions (pregnancy, endometriosis and pelvic inflammatory disease) and 82% of women with ovarian carcinoma. A level greater than 200 U /ml was not found in normal women or those with benign conditions. As with most markers its elevation is not specific for one tumour. Serum levels are also elevated in pancreatic (59%), lung (32%), colorectal (21%) and breast cancer (12%), usually where these are disseminated to the abdominal cavity.
What does the marker 5.3.3 Alpha Fetoprotein (αFP) show?
A glycoprotein produced by the normal foetal yolk sac, liver and intestines. It is undetectable in normal individuals after the first year of life. Its level is moderately elevated in hepatitis but high levels are also produced by hepatocellular carcinoma and cancers containing yolk sac elements (e.g. teratoma). High levels of αFP predict a poor prognosis in malignancy.
What does the marker 5.3.4 Human Chorionic Gonadotrophin (HCG) show?
A glycoprotein consisting of two subunits. HCG is elevated in patients with gestational trophoblastic disease (hydatiform mole, choriocarcinoma). There is also a specific elevation of the β-subunit in patients with non-seminomatous testicular cancers and some with seminoma. It is also raised in pregnancy!
What does the marker 5.3.5 Prostate Specific Antigen (PSA) show?
A protein produced by prostatic cells. Levels are raised in prostate cancers, but also with benign hypertrophy of the prostate – a near ubiquitous phenomenon as men age. The level may also be elevated by rectal examination, in prostatitis and in urinary tract infection.
PSA lacks sufficient sensitivity and specificity to act as an accurate screening test alone, although it is commonly used as a screening tool despite the equivocal evidence. It is used in monitoring response to hormonal and cytotoxic treatments, and in surveillance after radical treatment.
What can immunoglobulins show as a cancer marker?
Can be a measure of the paraproteinaemias (e.g. myeloma and Waldenstrom’s macroglobulinaemia) and occasionally non-Hodgkin’s lymphoma. They can be measured in the blood or their excretion can be measured as light chains in the urine (Bence-Jones protein), which occurs in 40-50% of all cases of myeloma.
What biopsy techniques can be used?
Fine needle aspiration cytology
Tru-cut needle biopsy – a piece of the tumour is sampled under local anaesthetic
Incisional biopsy- a piece of the tumour is sampled at surgery
Excisional biopsy- the whole of a mass is removed
How can surgery be used in cancer?
Curative intent:
30% of patients curable by surgical resection. requires localised disease, Adequate margins of clearance to minimise the risk of local tumour recurrence. may use (neo)adjuvant radiotherapy or chemotherapy -reduce the risk of local recurrence and, in some cases, allow the use of less radical surgery.
reduce bulk of residual disease:
long term benefit. e.g. ovarian cancer - significantly improves survival. only likely to be of benefit if there is effective therapy for the residual tumour.
Curative surgery for metastases:
some situations where surgical cure of distant metastases is possible e.g. solitary lung metastases from sarcomas or localized liver metastases from colon cancer. systemic therapy is almost always required in addition to the resection
Palliative surgery:
when an improvement in quality of life is considered likely and the risk of harm / likely length of hospital stay are considered acceptable. e.g. pinning of pathological fractures
Prevention of cancer:
surgical intervention can prevent cancer e.g. colectomy in patients with familial adenomatous polyposis coli or bilateral mastectomy
What is chemotherapy?
‘cytotoxic’ agents used in the systemic management of cancer. eradicate occult cancer cells. 60-70 % of cancer patients will require chemotherapy as a part of the treatment of their disease.
Hormonal and biological treatments can also play an important role.
Patients usually do not die as a result of local recurrence in the primary organ but as a result of systemic spread of the disease.
What is the mechansim of action for chemotherapy?
wide variety of mechanisms. Most agents target DNA either directly or indirectly.
preferentially toxic towards actively proliferating calls. Tumours which divide rapidly, with short doubling times, usually respond best to chemotherapy.
What are the different indications for chemotherapy?
Neoadjuvant - Pre-operative treatment of an operable tumour to make the tumour smaller, to allow less radical surgery, while at the same time treating occult micro metastases. aims to increase cure rates.
Primary - Initial chemotherapy for a tumour that is inoperable or of uncertain operability, to reduce tumour bulk. may increase cure rates.
Adjuvant - following surgery. treats the occult microscopic metastases which lead to relapse increases cure rates.
Palliative - alleviate symptoms and maybe prolong life. carefully balanced decision so that the patient’s quality of life is not made worse by the treatment. It may be justified to give second or third line chemotherapy if the disease remains chemo-sensitive
Curative - real chance of a cure even if there is metastatic disease at presentation. use of more intensive treatment associated with greater toxicity. only in select tumours
Prophylactic - Hormonal treatments may be given before overt malignancy appears. E.g. tamoxifen may be used for in-situ breast cancer before invasive carcinoma is recognised.
Why is chemo given as a combination of drugs?
- Different classes of drugs have different actions and may kill more cancer cells together by imparting several sub-lethal cell injuries than the sum of the cells they can kill when given individually (‘synergism’).
- There is less chance of drug-resistant malignant cells emerging.
- When drugs with different sites of toxicity are combined, dose can be maintained for each drug.
Single-agent chemotherapy may also be appropriate, especially in the palliative setting.
How long is a cycle of chemo and why?
given cyclically to allow normal cells to recover from the toxicity of treatment. The cells usually affected by chemotherapy at standard doses are haematopoietic stem cells and the lining of the GI tract, producing low blood counts (‘myelosuppression’) and mucositis. Giving the treatment every 3-4 weeks allows these cells to recover.
Theoretically any cycle of chemotherapy will only kill a proportion of the tumour cells. Therefore repeated cycles are required to get tumour clearance.
no advantage in giving endless cycles of chemotherapy, as this does not prevent resistance emerging and increases toxicity; many treatments are maximally effective after a 6-month course.
What is the optimal dose of chemo?
Conventional doses of drugs are those known to be effective against the particular malignancy and which, in the majority of patients, cause tolerable side effects. Many of these treatments can be given in an out-patient setting.
“High dose” treatments produce toxicity requiring specialized supportive care including bone marrow support with growth factors, or ‘rescue’ using the infusion of previously harvested blood stem cells or bone marrow. The toxicity of this treatment is justified only when long term survival or cure are possible, which is only the case in relatively few cancers, such as Hodgkins disease and Ewings Sarcoma.
when should maintenence treatment be used?
The use of prolonged chemotherapy to maintain a remission has little demonstrated advantage in solid tumours, as resistant clones soon develop and toxicity increases. In childhood leukaemia 18 months maintenance chemotherapy following the induction of a complete remission is central to modern treatment.
What routes can you take chemotherapy and why?
Orally - advantage of freeing the patient from lengthy hospital visits and invasive procedures. doesn’t necessarily reduce toxicity. regular review is almost always still required. cyclophosphamide, etoposide, capecitabine and tamoxifen are available orally. Variations in the levels of drug circulating based upon whether and when the drug is taken can be problematic
Systemically - Most given intravenously as bolus injection or short infusion. Some chemotherapy may be given as a continuous infusion via a central venous line, either peripherally placed or tunneled under the skin to reduce the chances of infection.
Regionally
• Intravesical. Chemotherapy is routinely given this way in the management of superficial bladder cancer. This has the advantage of producing high doses at the site of the tumour, with negligible systemic absorption and hence minimal systemic toxicity.
• Intraperitoneal. Chemotherapy may be administered directly into the peritoneal cavity in the context of tumours that spread trans-coelomically (e.g. ovarian cancer).
• Intra-arterial. Any tumour that has a well-defined blood supply is potentially suitable for intra-arterial chemotherapy (e.g. hepatic artery infusion for liver metastases). This allows higher doses to be delivered to the involved site and reduces systemic toxicity.
How is chemo dose calculated?
Body surface area (BSA): Routine cytotoxic chemotherapy doses are calculated according to the patient’s body surface area. The most commonly used formula is that of DuBois and DuBois,
Carboplatin, a commonly used chemotherapy drug, is the only one to have its dose calculated directly according to the renal function.
Some of the newer drugs, such as the monoclonal antibody trastuzumab, are calculated on body weight alone.
What are the immediate complications with chemotherapy?
Nausea/Vomiting - Most cause, which can normally be controlled to a tolerable level. Ondansetron used
Myelosuppression - kills haematopoietic progenitor cells - leucopenia and thrombocytopenia after 10 -14 days. counts return after 3-4 weeks. infection with a count less than 0.5 x 109/1 is significant.
Gastrointestinal
common. Oral mucositis, Diarrhoea, Constipation, paralytic ileus can develop due to autonomic neuropathy after platinum agents or vinca alkaloids.
Alopecia
rapidly dividing cell population at the hair follicle. reversible. use of a cold cap which reduces
Neurological
- Peripheral neuropathies. platinum drugs (particularly cisplatin), taxanes, and vinca alkaloids. principally affecting sensory nerves, may recover partially over a period of months
- Autonomic neuropathy.
- Central neurological toxicity. rare (ifosfamide-induced encephalopathy and 5-FU induced cerebellar toxicity).
- Ototoxicity. Cochlear damage rather than auditory nerve damage with cisplatin. permanent. Pre-existing high-tone hearing damage precludes the use of cisplatin.
Genitourinary
- Nephrotoxicity. cisplatin and ifosfamide. adequate renal function is required to reduce overall toxicity.
- Bladder toxicity. Cyclophosphamide and ifosfamide cause haemorrhagic cystitis
Cardiac
Doxorubicin and paclitaxel are both associated with acute arrhythmias. 5-FU may cause coronary artery spasm and therefore induce cardiac ischaemia.
Hepatic
transient rise of liver enzymes
Skin and soft tissue toxicity
- Extravasation.
- Palmar plantar erythema (Hand-foot syndrome).
- Photosensitivity. use of high-factor sun blocks.
- Pigmentation. Bleomycin leads to skin and nail pigmentation. It occurs in combination with pulmonary fibrosis
Others
• Myalgia and arthralgia. paclitaxel
• Allergic reactions. paclitaxel and docetaxel are associated with frequent hypersensitivity reactions
• Lethargy. General malaise and fatigue are common and frequently debilitating.
What are the long term complications of chemotherapy?
Second Malignancies - sub-lethal DNA damage that may induce a second malignancy. The most carcinogenic - alkylating agents and procarbazine.
Fertility
Most associated with a reduction in fertility. alkylating agents, render patients infertile at standard doses. Most patients who have high-dose treatments become infertile. Counselling of patients is required.
considered for sperm storage.
Pulmonary
Long-term pulmonary damage from fibrosis induced by drugs such as bleomycin and busulphan. High-dose or prolonged administration of most alkylating agents is associated with pulmonary fibrosis or pneumonitis.
Cardiac
cardiac fibrosis - predictable and dose-dependent. Younger patients are more susceptible
Psychological and social
prolonged effect on the patient’s psychology, adversely affecting quality of life. Employment, relationships, insurance, and social adaptation are also frequently compromised, particularly in young people.
What are the possible aetiologies of myelosuppression?
Treatment related - transient fall in the leukocyte and platelet count. nadir at 10 to 12 days. Recovery over a similar period. Higher doses more profound fall and more sustained. carboplatin cause relatively more thrombocytopaenia. also seen with biological therapies
Bone marrow infiltration - pancytopaenia. more common in haematological malignancies and breast, lung and prostate cancer. Successful anti-tumour therapy will lead to an improvement in the pancytopaenia.
Para-neoplastic syndromes - pancytopenia or falls in single haematopoietic lineages.
Other - Blood loss from a tumour can cause anaemia, usually iron deficient. Anaemia without iron deficiency can be due to chronic disease of any type. Anaemia due to repeated chemotherapy treatment is often macrocytic, but not megaloblastic. Other general medical causes also apply to these patients and should be included in the differential diagnosis.
How is myelosuppression investigated?
A transient nadir in blood counts following chemotherapy can be observed. However, prolonged or excessive degrees of suppression require investigation to exclude alternative causes such as marrow infiltration. Full evaluation includes a blood film, measurement of haematinics, bone marrow aspirate and trephine
How do you treat anaemia?
A haemoglobin level less than 10 g/dl may well impair quality of life and patients can potentially benefit from blood transfusion. The use of recombinant erythropoetin in preventing symptomatic anaemia can also be beneficial, and reduce risks of transfusion reactions and viral transmission.
How do you treat thrombocytopaenia?
- Platelet counts less than 10 x 109/L are associated with a significant risk of spontaneous bleeding such as intra cerebral haemorrhage, with a risk of irreversible disability. They are an urgent indication for platelet transfusion.
- Platelet counts between 10 x 109/L and 20 x 109/L are frequently supported with platelet transfusion, particularly in the presence of other complications such as infection.
- Platelet counts greater than 20 x 109/L, in the absence of spontaneous bleeding, do not routinely require platelet transfusion.
Repeated administration of blood products such as platelets is associated with the development of specific antibodies to blood cells including platelets. This manifests as a failure to increase platelet counts immediately after transfusion. This suggests the need for single donor (rather than pooled) or HLA matched platelets.
What are the clinical signs of thrombocytopaenia?
Clinical signs of significant thrombocytopenia include petechial haemorrhage, spontaneous nose bleeds, corneal haemorrhage and haematuria.
Conventional doses of chemotherapy rarely cause clinically important thrombocytopenia. The use of high dose chemotherapy is associated with prolonged thrombocytopenia requiring regular platelet transfusions.
How is neutropenia managed?
urgent broad-spectrum intravenous antibiotics.
may quickly lead to multi-organ failure associated with septic shock. warned about these potential hazards
Any pyrexia following chemo requires immediate review (within the hour)
Total white counts less than 1 x 109/L with an associated fever require immediate in-patient management with broad spectrum antibiotics. can present feeling non¬-specifically unwell. Severe infection with end-organ failure - supported with growth factors and admission to intensive care where appropriate.
look for source - Extensive cultures of blood, urine, sputum, throat etc. and a chest X-ray are take. but broad-spectrum cover is required.
Failure to respond to initial antibiotics within 48 hours requires a change to second-line broad-spectrum antibiotics. Persistent fever despite appropriate antibiotic treatment requires consideration of additional antifungal or antiviral agents. Atypical infections such as pneumocystis pneumonia (PCP) and systemic fungal or viral infections may occur.
Asymptomatic neutropenia may be closely observed without the need for antibiotics.
How can neutropenia be prevented?
Prophylactic antibiotics - not generally used but in certain conditions should be considered e.g. COPD
Dose modifications - curative chemotherapy such as Hodgkin’s disease and testicular cancer every effort is made to maintain dose intensity. palliative chemotherapy the balance will usually favour dose reduction.
Colony stimulating factors - may enable dose intensity to be maintained.
How do biological agents work?
Cells either gain mutations that promote cell growth or lose genes that control growth. Key molecules are cell surface growth factor receptors and their intracellular biochemical pathways, check point inhibitors controlling cell division in the nucleus and molecules involved in apoptosis and cell death in response to various insults to the cell. More recently, it has been shown that cancer cells can also develop mechanisms for subverting the host’s immune system, preventing their elimination by immune effector mechanisms.
Recent cancer drugs have been molecules targeting these specific pathways. As such, they have proved different from classical cytotoxic drugs, with very different side effects
Which cancers are most commonly hormone dependent?
those arising within tissues under hormonal control of normal cellular proliferation or survival. These include cancers of the prostate, breast and endometrium (sex hormones), and lymphocytic malignancies such as lymphoma, leukaemia and myeloma (corticosteroids).
How can hormonal treatments be used?
- To shrink primary tumours before (neo-adjuvant) or instead of surgery (primary medical therapy)
- To prevent or delay the growth of micro metastases following surgery (adjuvant therapy)
- To shrink established metastases and improve quality and duration of life (palliative therapy)
How can hormonal treatments work?
usually involve steroid hormones. Steroids interact with cytoplasmic protein receptors to form functional DNA transcription factors, affecting the transcription of multiple genes.
- Removing the source of a growth-promoting hormone
e. g. bilateral oophorectomy/bilateral orchidectomy - Hormone inhibitors
drugs that block the binding of hormones to their receptors in tumour cells. The best known is tamoxifen that acts (in part) as an anti-oestrogen. - Increasing hormones
Glucocorticoids in high concentration induce apoptosis in some malignant lymphoid cells.
Hormone supplementation is used in certain sex-hormone sensitive cancers with the aim of inducing negative feedback loops. may give direct inhibition of tumour growth via acting as an agonist of the progesterone receptor, but also produce negative feedback on the pituitary/gonadal axis. These drugs may also stimulate the appetite and are widely used in palliative medicine for that reason.
how is removal of hormone source different in pre and post menopausal women?
In pre-menopausal women, permanent ovarian ablation may be induced by radiotherapy. reversible “medical castration” is achieved by long-acting LHRH analogues (e.g. goserelin, leuprorelin) which, by receptor down-regulation in the pituitary, block LH and FSH production and, in turn, gonadal hormone output.
These techniques are unsuitable for postmenopausal women, for whom sex hormone production is mainly extra-gonadal, in fat and the adrenal glands.
The rate-limiting step in oestrogen synthesis is the conversion of androstenedione to oestrone by the enzyme aromatase. In postmenopausal women, androstenedione is secreted by the adrenal and aromatized in other tissues including fat and liver. This step is the target for aromatase inhibitors. New potent, specific aromatase inhibitors (anastrozole, exemestane, letrozole) are highly effective in clinical trials with greater efficacy and less toxicities.
What are the two types of anti androgen?
Steroidal anti-androgens (e.g. cyproterone acetate) have a dual action. In tumour cells they inhibit the androgen receptor, but in the hypothalamus they substitute for testosterone, so stimulate negative feedback inhibition with subsequent decrease in LHRH release.
Non¬-steroidal anti-androgens (e.g. bicalutamide) inhibit testosterone in both tumour cells and hypothalamus, so feedback inhibition is lost and serum testosterone levels rise.
“Maximum androgen blockade” describes the combination of a non-steroidal anti androgen with an LHRH analogue to prevent this effect and is used as a therapeutic strategy in prostate cancer.
When is hormone supplementation often used?
certain sex-hormone sensitive cancers with the aim of inducing negative feedback loops (e.g. oestrogens to down-regulate hypothalamic LHRH in prostate cancer) or tachyphylaxis (down-regulation) of receptors (e.g. high-dose oestrogens in breast cancer).
what are the different intentions of radiotherapy with examples?
curative potential - only if no distant metastatic spread. delivered as the sole treatment e.g. prostate cancer. commonly combined with chemotherapy to improve the efficacy of treatment
neo-adjuvant - reduce the risk of local recurrence e.g.of rectal cancer
adjuvant - reducing loco-regional recurrence, e.g. breast cancer.
palliation of symptoms and/or to control cancer growth when cure is not possible.
What are the different ways of giving radiotherapy?
photons/x-rays, electrons, radio-isotopes or protons. External beam radiotherapy using photons/x-rays is the most common form of radiotherapy used in the UK.
How does radiotherapy work/ science behind? (just read - long)
generated and delivered by a linear accelerator
X-rays penetrate deep into body tissue whilst sparing the over-lying skin
produce secondary electrons and free radicals which cause DNA damage to both cancer cells and normal cells
Normal cells can often repair the DNA damage and therefore survive
cancer cells commonly have defective DNA repair pathways and are unable to repair radiotherapy induced DNA damage
balance of killing cancer cells without causing irreversible damage to the surrounding normal tissues
The dose of radiation is expressed in the unit Gray.
commonly delivered as a series of small doses called fractions rather than as a single large dose. The number of fractions and the dose (Gy) given in each fraction depends on the treatment intent. Radical/curative treatments require large doses of radiotherapy overall. The total dose is then divided into multiple small fractions
What is a common palliative radiotherapy dose?
Palliative radiotherapy, which is primarily given to alleviate symptoms, is delivered in a smaller number of fractions and to a lower total dose. Commonly used palliative schedules are 8Gy in 1 fraction, 20Gy in 5 fractions or 30Gy in 10 fractions
What are the tumour kill and toxicity dependent on?
- treatment issues, for example: the total dose, the total volume treated, dose per fraction and overall treatment time,
- co-morbidities (such as diabetes and inflammatory bowel disease), smoking,
- Intrinsic radio-sensitivity of the cancer cells (seminoma and Hodgkin’s disease are highly radiosensitive and respond well to low doses of radiation whereas cancers such as a glioblastoma multiforme are relatively radio-resistant to even high doses of radiotherapy), tumour hypoxia, tumour re-population and additional treatment such as chemotherapy.
What is concurrent chemotherapy and what does it do?
Chemotherapy given to patients during their radiotherapy treatment is called concurrent chemotherapy and is thought to act as a radiosensitiser, which means it increases the sensitivity of the cells to radiation. This improves the efficacy of the radiotherapy treatment without having to significantly increase the dose of radiotherapy. Concurrent chemoradiotherapy regimens are associated with increased radiation-related side effects, in addition to the expected side effects of the chemotherapy drugs.
What are GTV, CTV and PTV on radiotherapy planning?
The tumour is delineated on each CT slice it appears on, this is called the Gross tumour volume (GTV).
A margin is then added for microscopic disease spread (the clinical target volume (CTV) - which may include adjacent nodal groups).
further margin is added to allow for minor daily variations in patient and tumour position, this is called the planning target volume (PTV).
A radiotherapy plan is then created that conforms to this shape, thereby treating the tumour whilst avoiding as much normal tissue as possible
What are the acute side effects of radiotherapy?
develop during treatment, usually after the first 5-10 fractions. increase during treatment and hit a peak in the first few weeks after treatment. generally reversible but must be managed appropriately, t
Acute side-effects of radiotherapy are due to damage of normal tissue and the ability of normal cells to repair the damage also explains why the acute side effects usually completely resolve once treatment has finished.
Such side effects included a localised skin reaction, oral mucositis and diarrhoea.
What are the late side effects of radiotherapy?
Develop at least 3 months after radiotherapy and sometimes manifest years later. often irreversible and may worsen over time. difficult to treat and require multi-disciplinary management, including surgery.
Long-term toxicity occurs as some of the damage to normal cells cannot be repaired and partly due to the development of fibrosis and blood vessel damage within the irradiated tissue. e.g. lung fibrosis, skin atrophy and infertility.
Radiotherapy itself is carcinogenic and there is a risk of a second malignancy. The risk increases over the decades after treatment and depends on the treated volume and dose.
for women receiving radiotherapy for breast cancer, there is an excess absolute risk from radiotherapy of 2 to 4 cases per 10,000 person years. The risk is significantly greater for younger patients treated for a good prognosis cancer.
Radiotherapy is also teratogenic and therefore must be avoided in any woman who is pregnant.
What is brachytherapy?
radiation treatment where radiation sources are placed within or close to the tumour. It allows the delivery of a localised high radiation dose to a small tumour volume, increasing the chance of tumour control, whilst minimizing the dose to surrounding normal tissue. The commonest cancers to be treated with brachytherapy are prostate cancer, gynaecological cancers, oesophageal cancer and head and neck cancers.
What are the two main types of brachytherapy?
- Intracavity: the radioactive material is placed inside a body cavity such as the uterus and cervix.
- Interstitial: where the material is put into the target, such as the prostate.
When are radioisotopes used?
A radioisotope is an unstable form of a chemical element, which emits radiation when it decays and is another method of radiation delivery. The most commonly used form is radioactive iodine, I-131, which is used in the management of the most common forms of thyroid cancer. The iodine is preferentially taken up by and concentrated in any remaining thyroid tissue, normal or malignant, where it emits radiation as it undergoes radioactive decay, ablating the thyroid cells. As there are few other tissues in the body that take up iodine this is a way to selectively deliver radiation. The patient will need to remain in the lead lined room until the level of radiation they are emitting is low enough to be safe to others, which is usually around four days.
Define quality of life
- The subjective evaluation of life as a whole.
- Patients’ appraisal of and satisfaction with their current level of functioning compared with what they perceive to be possible or ideal.
- Physical, mental and social well-being, not merely the absence of disease or infirmity (WHO).
What aspects are important to consider in assessing a patients quality of life?
- Physical functioning. This includes performance of self-care activities, functional status, mobility, physical activities, and ‘role activities’ such as work or household responsibilities.
- Disease and treatment-related symptoms. This includes specific symptoms from the disease such as pain, shortness of breath or side effects of drug therapy such as nausea, vomiting, hair loss.
- Psychological functioning. Including emotional distress, anxiety or depression (that may be secondary to the disease).
- Social functioning. For example family interactions, time with friends, recreation activities.
5. Others. Additional considerations in the evaluation of QL may include: Spiritual or existential concerns. Cognitive function. Sexual functioning and body image. Satisfaction with health care.
What sort of tumours should screening programmes find?
Tumours should ideally:
• Be curable when detected early in the majority of the patients.
• Be relatively common.
• Have a long pre-invasive or non-metastatic stage.
• Be able to be detected by relatively simple tests.
• Be distinct from benign lesions.
What sort of tests should screening programmes use?
- Be able to detect cancer at an early enough stage to implement effective treatment.
- Be sensitive – i.e. be able to distinguish tumours clearly and give a low false negative value (i.e. not miss actual cases).
- Be specific – i.e. would not give false positive results
- Be well tolerated, hence improving compliance.
- Be easy to administer or perform.
- Be inexpensive.
- Be well publicised in order to ensure high uptake amongst the target population.
What are the potential advantages to screening?
- Reduction of mortality by detecting early disease that is curable.
- Less radical treatment hence reducing morbidity.
- Saving on health service resources by increased cure rates.
- Reassurance given by a negative test.
What are the potential disadvantages to screening?
- Increased length of anxiety and morbidity if no effective intervention is possible.
- The over-investigation of false positive cases with associated morbidity.
- Over-treatment of borderline cases that do not require treatment.
- False reassurance from a false negative result.
- Possible harmful effects of the screening test.
- Cost of screening a large population.
What are two effective ways to make screening programmes better?
- Limit the screening to “at-risk” populations. This improves the overall sensitivity and specificity. It also often allows more effective targeting of the test which increases compliance. The resource implications are also favourable if an at-risk group and their characteristics can be identified.
- Develop an effective infra-structure, for example through primary health care teams, support groups and through work places to increase awareness and uptake of at-risk populations.
How does the cervical cancer screening work in the UK?
This is the most effective screening programme to date. All women aged between 25 and 64 are offered screening. Women aged 25 to 49 are invited for “cervical smears” (cytological assessment of collected specimens) every three years. After that they are invited every five years. This is particularly successful because of the relatively long pre-¬invasive period during which early detection can occur, and for which an effective treatment can be offered.
Issues: Screening of both at-risk patients (that is those with a strong family history) and the general population, with CA125 and trans-vaginal ultrasound, is being studied.
How does the Breast cancer screening work in the UK?
Regular mammography is offered to all women between the ages of 50 and 70 every 3 years.
The ability of mammography to reduce mortality remains controversial. Screening for younger patients who are at increased risk, such as those with a family history should be considered as part of a package of care, including screening if appropriate, after referral to a breast cancer service.
How does the Colorectal cancer screening programme work in the UK?
men and women are offered bowel screening, using faecal occult blood (FOB), every two years from 60 to 69. The English programme is being extended to 74; older patients can request a screening kit.
At risk patients, such as those with ulcerative colitis, a strong family history or a previous primary tumour should be screened within their existing management plan including regular colonoscopies.
What are the issues with implementing a prostate cancer screening programme?
There is no organised screening programme for prostate cancer but an informed choice programme, ‘Prostate Cancer Risk Management’ has been introduced. This provides information for patients about the pros and cons of having a PSA test performed.
Men are often diagnosed with prostate cancer later in life. Many of these tumours would never progress during the remainder of the man’s natural life and the majority of men diagnosed would die with, rather than of, their prostate cancer. There is therefore a significant risk of over-treatment with the associated risks and harms.
What does palliative care do?
- Provides relief from pain and other distressing symptoms
- Integrates physical, psychological, social and spiritual care
- Affirms life and regards dying as a normal process
- Neither hastens nor postpones death
- Helps patients live as actively as possible until death
- Offers support to help the family/carers during the patient’s illness and into bereavement.
What are important principles in symptom management?
A diagnosis of the cause of the symptom is an essential step towards effective symptom management. Symptoms may be caused by:
• The disease itself
• The treatment
• A concurrent disorder
Any reversible causes should be identified and treated if possible. Good palliation may include treatments to modify the disease itself, as well as medicines to control symptoms.
pharmacological and non-pharmacological treatments. Attention to detail is paramount; symptoms and their cause may change daily.
What is advanced care planning?
a voluntary process of discussion and review to help an individual who has capacity to anticipate how their condition may affect them in the future and, if they wish, set on record choices about their care and treatment
What are the different forms of formal ACP?
- Advance statement of wishes to inform subsequent best interest judgments
- Advance decisions to refuse treatment which are legally binding if valid and applicable
- Appointment of Lasting Powers of Attorney for ‘Health and Welfare’ and/or ‘Property and Affairs’.
What is pain?
what the patient says hurts”. Pain is a total personal experience with physical, psychological, social and spiritual dimensions.
How should you assess pain?
- Onset & duration
- Site & radiation
- Character
- Temporal factors
- Exacerbating factors
- Relieving factors
- Severity
- Associated symptoms
- Effects on sleep, work, mood
- Current treatment
- Treatments tried and results
- Understanding of illness
- Expectations
What are the common types of pain in cancer?
occurs in about 80% of patients
Bone pain visceral pain Headache/ICP neuropathic infection
What are the features of bone pain and how should you treat it?
Features - Either a dull ache over a large area or well localised tenderness over the bone. Often worse on weight bearing or with movement.
Treatment NSAIDS (e.g. diclofenac 50mg tds), radiotherapy and bisphosphonates (e.g. pamidronate infusion).
