Flashcards in Oncology - Treatment of cancer Deck (64):
What is radiotherapy?
Radiotherapy uses ionising radiation to kill malignant cells. Unlike chemotherapy it is a local treatment, rather than systemic.
But like chemotherapy, radiotherapy cannot differentiate between malignancy and normal rapidly dividing cells and this causes side effects (mostly local in radiotherapy).
E.g. radiotherapy for prostate cancer produces radiation cystitis (frequency and dysuria) and radiation proctitis (diarrhoea and rectal bleeding)
What acute and late effects can occur in radiotherapy for breast cancer?
Acute effects - radiation inflammation, normally resolves when treatment is finished
Late effects - lymphadenopathy, due to fibrosis of the lymphatic ducts
What are the types of radiotherapy?
1) Teletherapy - external beam radiotherapy
- most common
2) Brachytherapy - source in or near to the tumour
3) Radioisotope therapy - ingestion/ injection of radioactive elements
- uncommon, e.g. radioactive iodine in treating thyroid cancer, radioactive strontium for boney secondaries, radioactive phosphorous for primary polycythaemia
What are the most common indications for brachytherapy?
In the UK, the most common indications are treating gynaecological and prostate cancers. There are various radionucleotides used, but radioactive Caesium is probably the most common.
How does radiotherapy damage DNA?
Radiation displaces orbiting electrons leading to ionisation of water molecules. This forms a hydroxyl free radical which damages DNA.
How does prostate brachytherapy work?
Steele pellets containing radioactive iodine are inserted under anaesthesia, via the anterior rectal wall or perineal approach, and remain permanently in place. With time, the decaying radioactive iodine gives off radiation that locally kills the prostate cancer. This accounts for less than 10% of all cancer radiotherapy.
What skin cancers respond best to external beam radiotherapy?
SCC and BCC are very sensitive to radiotherapy.
Malignant melanoma is best managed surgically and not with radiotherapy.
What is radiation measured in?
The rad was the old unit of radiation which has been replaced with Grays (Gy)
1 rad = 1 centiGray (cGy)
How is radiotherapy administered?
Radiotherapy is administered as a total dose given in specific fractions over a certain time frame. Usually, radiotherapy is given during week days.
Thus, a dose of 40Gy in 15 fractions over 3 weeks would be 2.6 fractions per day. Different dosing regimes have the same biologically equivalent doses of radiation by increasing the total fraction and giving it over longer periods of time.
What is the difference between curative and palliative radiotherapy?
The main difference between the two is the dose of radiation.
Curative treatments usually involve multiple high dose treatments (e.g. 60Gy/30 fractions/ 6 weeks). A single dose of 8Gy/ 1 fraction is a useful dose for palliation.
What is the concept of repair in radiobiology?
There is no cancer that cannot be cured with a large enough dose of radiation, but whilst this would kill the cancer cells it would also kill the patient. The way around this is to give smaller doses of radiation, often. Normal cells are damaged alongside cancerous ones when radiation is given. But because non cancerous cells have a greater capacity for repair (which can start after 4 hours or so) compared to cancerous cells, successive treatments (e.g. over 24 hours) deplete cancer cell numbers but give time for normal cells to repair.
What is the oxygen effect?
There needs to be sufficient levels of oxygen for radiotherapy to work. Radiosensitivity is highest when oxygen tension is at the level of arterial blood. Clinically, if you are treating a patient who is anaemic with a Hb of less than 10, you should give them a blood transfusion before radiotherapy.
What is the mechanism of action of alkylating agents?
Alkylating agents transfer an alkyl group to purine (adenine and guanine) DNA bases. Alkylating agents can either be bifunctional or monofunctional. Bifunctional alkylating agents form covalent bonds form between two different bases which introduces interstrand cross links. Monofunctional alkylating agents cannot cause cross links but form adducts. Both of these alterations inhibit DNA synthesis, so alkylating agents work best during the S phase of the cell cycle (phase specific agents). Examples of alkylating agents include mitomycin C, chlorambucil, and cyclophosphamide.
What side effects are associated with cyclophosphamide?
Transitional cell carcinoma
What is the mechanism of action of antimetabolites?
Antimetabolites are structurally similar to natural compounds and interfere with cellular enzymes. These agents inhibit the metabolism (usually synthesis) of compounds necessary for DNA, RNA or protein synthesis. This includes: (1) purine analogues, (2) pyrimidine analogues, (3) folic acid analogues, and (4) others, e.g. hydroxyurea. Most antimetabolites have their greatest effect during S phase.
- methotrexate: inhibits dihydrofolate reductase
- 5-FU: pyrimidine analogue inducing cell cycle arrest and apoptosis by blocking thymidylate synthase
- 6 mercaptopurine: decreasing purine synthesis
- cytarabine: pyrimidine antagonist
What are the side effects of methotrexate?
What is the mechanism of action of intercalating agents?
Intercalating agents interrupt the integrity of the DNA double helix. There exact mechanism of action is unknown, although anthracycline antibiotics intercalate into the major DNA groove between base pairs of the double helix and this action is non covalent with no base sequence specificity. Platinum agents also intercalate and form intrastrand links similar to alkylating agents.
1) Platins - e.g. cisplatin, carboplatin, oxaliplatin
2) Antibiotics - e.g. doxorubicin, bleomycin
What are the side effects of cisplatin?
What is the mechanism of action of the spindle poisons?
Antimicrotubule drugs can be divided into two groups, those that stabilise microtubules by inhibiting depolymerisation (e.g. taxanes) and those that are depolymerising agents that inhibit polymerisation of tubulin (e.g. vinca alkaloids). Spindle poisons inhibit the mitotic spindle function and therefore act during M phase of the cell cycle.
What are the side effects of the vinca alkaloids?
This includes vincristine and vinblastine.
Vincristine: peripheral neuropathy (reversible), paralytic ileus
What are the side effects of the taxanes?
The most clinically useful taxane is docetaxel which causes neutropaenia.
What is the mechanism of action of the topoisomerase inhibitors?
Topoisomerase prevents DNA strands from becoming tangled by cutting DNA and allowing it to wind and unwind. There are two classes of topoisomerase: topoisomerase type I breaks single strands of DNA, whilst topoisomerase type II breaks two strands of DNA. Topoisomerase type I inhibitors include topotecan and irinotecan. Type II inhibitors include etoposide and teniposide.
What cancers have a low sensitivity to chemotherapy?
Some tumours have an intrinsic resistance to chemotherapy which in part accounts for for the variable sensitivity of different cancer types to chemotherapy.
Kidney cancer, melanoma, adult brain tumours and prostate cancer generally have low sensitivity so chemotherapy is of limited use.
What causes resistance to chemotherapy?
Resistance to chemotherapy can be to one drug or a combination of drugs. The latter is normally caused by expression of efflux pumps on tumour cell membranes. The most commonly found pump in multi-resistant tumour cells is P-glycoprotein or the multidrug resistance protein (MDR).
Cytotoxic specific resistance occurs through a number of mechanisms - e.g. efficient DNA repair, reduced drug uptake, increased drug efflux, intracellular inactivation.
Name some examples of cancers were chemotherapy is used neoadjuvantly and adjuvantly
- Soft tissue sarcoma
- Locally advanced breast cancer
- Wilm's tumour
- Breast cancer
- Colorectal cancer
What is the role of stem cell repopulation in chemotherapy treatment?
Chemotherapy resistance can be overcome by escalating the dose of the cytotoxic agent. In many cases, the dose limiting toxicity (DLT) is myelosuppression and if this can be overcome doses may be doubled or more before the next DLT, which is often mucosal damage. Autologous (from the patient him/herself) and allogenic (from the donor) bone marrow transplantation helps with this. Prior to high dose chemotherapy, progenitor stem cells are harvested either from multiple bone marrow aspirations (BMT) or now more often from peripheral blood following growth factor stimulation (peripheral blood stem cell transplant) . These stem cells are immature haematopoietic cells capable of repopulating the bone marrow. The patient then receives the high dose chemotherapy and subsequently stem cells are reinfused. This technique is used frequently for haematological malignancies, neuroblastoma and myeloma.
What side effects are more common with the phase specific agents?
Chemotherapeutic agents have no ability to differentiate normal rapidly dividing cells from neoplastic cells. Predictable effects of chemotherapy on fast dividing cells (bone marrow, GIT epithelium, hair follicles etc) will be a consequence of inhibition of cell division and are more common with phase specific cytotoxics. In contrast, the consequences of slow growing cell types will occur most frequently with drugs that are not cell cycle specific such as alkylating agents that introduce DNA mutations resulting in secondary leukaemias and other tumours.
What are early side effects of chemotherapy?
Side effects of chemotherapy can be divided into 3 groups:
1) Early side effects - occur within hours
2) Delayed effects that occur within days, weeks or months but are generally manifested whilst the full course of chemo treatment is on going
3) Late effects that occur months or years after therapy has stopped
Early side effects include nausea and vomiting, anaphylaxis, extravasation and tumour lysis.
What causes nausea and vomiting during chemotherapy?
Vomiting is a central reflex initiated in the vomiting centre of the medulla that co-ordinates the contraction of the diaphragm and abdominal muscles with relaxation of the cardiac sphincter and muscles of the throat. There are four inputs into the vomiting centre:
(1) the labyrinths (e.g. motion sickness)
(2) the higher cortical centres (e.g. fear, anticipation)
(3) the vagus sensory input from the GIT particularly the small bowel
The chemoreceptor trigger zone (CTZ) is located in the area prostrema adjacent to the fourth ventricle where the blood brain barrier is relatively deficient and chemicals in the blood and CSF are sensed.
Chemotherapy mostly acts on the GIT causing serotonin release and acting via the vagus nerve. It also stimulates the CTZ via dopaminergic and muscarinic pathways.
Other than the emetogenicity of the chemotherapeutic agent, what risk factors are associated with nausea during chemotherapy?
Less than 50 years old
Concurrent use of opioids
Low alcohol intake
How should nausea and vomiting be managed in patients being treated with chemotherapy?
Acute vomiting within six hours of chemotherapy is best controlled by a combination of steroids and 5-HT3 receptor antagonists. Delayed vomiting occurring up to five days after chemo is best treated with steroids and dopamine antagonists. Anticipatory vomiting that occurs prior to chemo is best treated with BDZs (as this pathway acts through GABA).
What chemotherapy agents are particularly associated with anaphylaxis?
Risk of anaphylaxis with paclitaxel is so high that routine prophylaxis with steroids and anti-histamines is administered to all patients receiving it.
What is extravasation?
This is the inadvertent administration of chemotherapy into subcutaneous tissue. This leads to pain, erythema, inflammation and discomfort which if unrecognised and untreated can lead to tissue necrosis. Anthracyclines are especially likely to cause tissue damage.
What is tumour lysis syndrome?
Tumour lysis syndrome (TLS) is a potentially life threatening condition related to the treatment of high grade leukaemias and lymphomas. It can occur in the absence of chemotherapy but is usually caused by the introduction of combination chemotherapy. On occasion it can occur with steroid treatment alone. Awareness of this condition is crucial as prophylactic treatment can be given to prevent the deadly effects of TLS.
What causes tumour lysis syndrome?
TLS occurs due to the breakdown of tumour cells and subsequent release of chemicals from the cell. It leads to high potassium and high phosphate levels in the presence of low calcium. It should be suspected in ANY patient presenting with an acute kidney injury in the presence of high phosphate and high uric acid levels.
What prophylactic therapy should high risk patients receive?
Patients that are high risk should receive IV allopurinol or IV rasburicase immediately prior to, and during the first few days of chemo. Rasburicase is a recombinant version of urate oxidase, the enzyme that metabolises uric acid to allantoin. Allantoin is much more water soluble and so more easily excreted by the kidneys. Patients that are low risk should be given oral allopurinol during chemotherapy.
How is TLS graded?
Since 2004, TLS has been graded using the Cairo-Bishop scoring system:
1) Laboratory TLS = abnormality in two or more of the following occurring three days before, or seven days after the onset of chemotherapy
- 25% increase in uric acid, potassium, phosphate or DECREASE in calcium
2) Clinical TLS = laboratory tumour lysis syndrome plus one or more of the following:
- increased serum creatinine
- cardiac arrhythmia or sudden death
What are the common predictable delayed side effects of chemotherapy?
Hair loss and nail changes
Bone marrow suppression (myelotoxicity)
What agents are most responsible for hair loss?
Hair loss with chemotherapy is both drug and dose dependent and is related to the frequency of cycle repetition. Hair loss from chemo is REVERSIBLE, with the hair growing back one to two months after completing chemotherapy. Doxorubicin and cyclophosphamide are the most common agents.
What nail changes are common in chemotherapy?
Again these are delayed but predictable complications. Onycholysis are nails that are brittle and prone to shredding. Onychomycosis is fungal infection of the nails.
A common physical sign in patients who have received chemotherapy are Beau lines, horizontal grooves or lines on the nail plate that indicate cycles or arrested nail growth with chemotherapy.
At what white cell or platelet count is the risk of myelosuppression most significant?
WCC <3.0 and/or platelet count is <150.
These values are the usual cut offs for administering a cycle of chemotherapy, but it can still be given at lower values in patients with haematological malignancy or if supportive therapy is planned. Myelosuppression is the dose limited toxicity of most chemotherapeutic agents. The main exceptions are vincristine, bleomycin, streptozotocin and asparginase which do not cause myelosuppression.
What agent most commonly causes anaemia? What symptoms are patients likely to experience? How is chemotherapy induced anaemia managed?
Anaemia is most troublesome with cisplatin since the nephrotoxicity of this agent may decrease EPO production from the kidneys in response to anaemia. The symptoms of anaemia include fatigue, lethargy and exertional dyspnoea with Hb levels in the range of 8-10g/dl. Reduced exercise capacity progresses to dyspnoea and tachycardia at rest and complications include cerebovascular (e.g. TIA) and cardiovascular (e.g. anigna) ischaemia as the Hb falls below 8g/dl.
Management of chemotherapy induced anaemia is with transfusion and in the case of cisplatin induced anaemia, at least, EPO may be beneficial.
What is neutropaenic sepsis?
Neutropaenia (neutrophil count <1) is the commonest dose limiting toxicity of chemotherapy. Neutropaenia most commonly manifests as infection, and neutropaenic sepsis is a medical emergency. Neutropaenic sepsis is defined as a fever of 38.0 or higher for at least two hours when the neutrophil count is below 0.5.
How should neutropaenic sepsis be managed?
If it is anticipated that a patient is at risk of having a neutrophil count <0.5 as a consequence of their treatment then they should be offered a fluoroquinolone.
- take cultures, CXR and urine dip to look for sources of infection
- antibiotics MUST be started immediately
- NICE recommend empiric antibiotic therapy using Tazocin
- following initial treatment patients should be re-assessed by a specialist and risk stratified to see if they can have therapy as an outpatient
- if patients are still febrile and unwell after 48 hours an alternative antibiotic such as meropenem is often prescribed +/- vancomycin
- if patients are not responding after 4-6 days the Christie guidelines suggest ordering investigations for fungal infections (e.g. HRCT) rather than just starting antifungal therapy
- there may be a role for G-CSF in selected patients
How should thrombocytopaenia associated with chemotherapy be managed?
This is the third consequence of myelosuppression (alongside anaemia and neutropaenia). It is a common side effect with chemotherapy, particularly with carboplatin, that rarely causes manifestations unless severe. Although petechiae and bruising do occur, major haemorrhage is very rare unless the platelet count falls below 20. At platelet counts below 10 there is appreciable risk of GI or cerebral haemorrhage and prophylactic administration of pooled platelets is needed.
What is gastrointestinal mucositis?
Mucositis is a common delayed complicated of chemotherapy. It is very common in patients receiving chemo-radiotherapy or radiotherapy alone for head and neck cancers. It is thought that chemotherapy and radiotherapy damage basal epithelial cells in the intestinal mucosa leading to apoptosis, atrophy and ulceration. Ulceration leads to bacterial and fungal infection, which activates macrophages and leads to further inflammation.Various therapies include sucking ice lollies, and mouthwash can provide symptomatic relief from mucositis. The time course for mucositis closely resembles that of neutropaenia, occuring 7-10 days after chemo.
What are idiosyncratic delayed side effects?
These delayed side effects are drug specific and are not immediately predictable from their mechanism of action. The organs most frequently affected are skin, nerves, heart, lungs and blood vessels.
What dermatological side effects can occur in chemotherapy?
Idiosyncratic delayed toxicities:
- hyperpigmentation (esp. 5-FU and bleomycin)
- hand and foot syndrome: painful redness, scaling or shredding of the skin of the palms and soles may occur with continuous infusion of 5-FU
- radiation recall: erythematous reaction of skin in a previous radiation field (can occur when radiotherapy was decades ago, gemcitabine most common)
What is the most common cardiovascular side effect of chemotherapy and what agents cause it?
Dose related dilated cardiomyopathy is the most common side effect of chemotherapy seen with the anthracyclines. This usually presents with heart failure within 8 months of the last anthracycline dose. Diuretics improve symptoms and early use of ACEi can increase LV ejection fraction. Prognosis is poor.
What is the most common neurological side effect of chemotherapy?
Peripheral neuropathy is the most frequent neurotoxicity of chemotherapy. It is commonly seen with the vinca alkaloids, taxanes and platinum derivatives. The longest nerves are affected most, so it presents as a symmetrical sensory loss over the feet and hands. This may progress to worsening paraesthesia, loss of tendon reflexes and eventually motor loss. Features usually improve over several months following cessation of chemotherapy.
Other neurological toxicities include:
- autonomic neuropathy: abdominal pain, constipation, paralytic ileus, urinary retention, bradycardia
- acute encephalopathy most commonly associated with ifosfamide: confusion, agitation, seizures, somnolence and coma
- cerebellar toxicity: most common in cytarabine therapy
- ototoxicity: most common with cisplatin
What pulmonary side effects occur with chemotherapy?
Chronic pulmonary toxicity and fibrosis occurs with a number of cytotoxics and the outcome is generally poor. Bleomycin is the most common culprit and the risk increases with dose. The cardinal symptom of drug induced pulmonary toxicity is dyspnoea associated with non productive cough, fever, fatigue and malaise. Symptoms usually develop over 6 weeks to months. CXR shows diffuse interstitial shadowing most commonly at the bases and occasionally pleural effusions. Lung function tests show a reduced transfer factor for carbon monoxide and restrictive defect.
What hepatic side effects can occur with chemotherapy?
Many cytotoxics cause elevated serum transaminases and bilirubin, and fatty infiltration and cholestasis may occur as the toxic effect progresses.
Hepatic veno-occlusive disease (VOD) results from the blockage of venous outflow in the small centrilobular hepatic vessels following damage to cells in the area of the liver surrounding the central vein. This rare side effect occurs with high dose chemotherapy often as part of stem cell transplantation. The clinical features are painful hepatomegaly, ascites, peripheral oedema, marked elevations in serum enzymes and bilirubin and hepatic encephalopathy.
How does chemotherapy affect male and female fertility?
Differentiating spermatogonia actively proliferate and are therefore highly susceptible to cytotoxic agents. Sertoli cells, Leydig cells and later stage germ cells (spermatocytes onwards) do not proliferate, they are not susceptible to chemotherapy. Sperm counts take about 2 months to decline following chemo. Testosterone production only decreases significantly with testicular radiation. Men due to start chemo should be offered sperm storage.
Gonadal toxicity is different in women, because somatic cells not germ cells proliferate. Chemotherapy reduces the number of primordial follicles, if this number decreases significantly then primary amenorrhea occurs. This risk is increased in older women who have fewer follicles remaining. As in men, alkylating agents are the main culprits.
How long should a women wait after having chemotherapy before getting pregnant?
Many cytotoxics are teratogenic in murine models, but information in humans is limited. All alkylating agents are toxic during the first trimester but no increased risk in the second or third. Methotrexate is abortive during early pregnancy. Most clinicians advise a two to five year gap before pregnancy following chemotherapy.
What determines the risk of secondary malignancies following chemotherapy? What agents are most likely to cause secondary malignancy?
Many cytotoxic agents are genotoxic. The risk of inducing malignancy depends not only on the cytotoxics administered but also on the initial cancer diagnosis, with the greatest risk in patients with Hodgkins disease where the second malignancy rate is 10-15% after 15 years. Two forms of secondary leukaemia following chemotherapy are widely recognised. Alkylating agents are carcinogenic with acute laeukaemias occurring in up to 5% three to five years after exposure and associated with chromosome deletions. Alkylating agents also increase the risk of solid tumours.
Secondary acute leukaemia also occurs in patients treated with topoisomerase II inhibitors. These leukaemias occur early following treatment, and are associated with translocations.
What endocrine therapies are used to treat breast cancer?
Breast cancers that express oestrogen receptors are sensitive to circulating levels of hormones. By blocking the effect of these hormones it may be possible to treat the cancer.
1) Luteinizing hormone releasing hormone receptor agonists, (LHRH agonists) such as goserelin cause downregulation of pituitary LHRH receptors, and via a decrease in LH and FSH, also reduce plasma oestradiol.
2) Tamoxifen binds to oestrogen receptors and prevents oestradiol binding
3) Aromatase inhibitors such as anastrazole bind to an d inhibit the aromatase enzyme in peripheral tissues, including adipose tissue, which converts androstenedione and testosterone and other androgens into oestradiol
LHRH agonists and Tamoxifen are used in the neoadjuvant, adjuvant and palliative setting in pre menopausal women. Aromatase inhibitors are used in post menopausal women, usually for patients whose disease has advanced with Tamoxifen.
What endocrine therapies are used to treat prostate cancer?
1) LHRH agonists cause downregulation of pituitary LHRH receptors and via a decrease in LH to a reduced serum testosterone and tissue dihydrotestosterone
- adverse effects are impotance, loss of libido gynaecomastia and hot flushes
- tumour flare, an increase in tumour size which can cause symptoms such as increase in bone pain and spinal cord compression, can occur with initial use of the drugs due to an initial increase in testosterone. An anti-androgen such as bicalutimide, cyproterone and flutamide should be prescribed for a few weeks before LHRH agonists
2) Anti-androgens - block and prevent testosterone from attaching to the receptor in prostate cancer cells
- adverse effects cause hepatotoxicity, gynaecomastia, diarrhoea and abdominal pain
What is the role of passive specific immunotherapy in treating cancer?
Passive immunotherapy with monocloncal antibodies is established for breast cancer and NHL. Monoclonal antibodies are produced by a single clone of B cells and may be humanised to reduce their immunogenicity.
- Retuximab - antiCD20 used in low grade and follicular Hodgkins lymphoma
- Trastuzumab - antibody against Her2, overexpressed in 30% of breast cancers; cardiotoxic when given with anthracyclines
What active specific immunotherapy is used in cancer treatment?
Active cellular immunotherapy involves the harvesting and ex vivo activation (in the test tube) of lymphokine-activated killer (LAK) cells and is an experimental treatment for renal cancers and melanoma. Other trial active immunotherapies include tumour vaccines.
What is non specific immunotherapy?
Global stimulation of the host cellular immune system in order to promote tumour rejection is the basis of using BCG, which is administered intrathecally to prevent recurrence of superficial bladder cancers, interferons and interleukins.
What interferons can be used in cancer therapy?
IFN alpha is licensed for use and may work by enhancing the expression of HLA by tumour cells leading to increased recognition and lysis by cytotoxic T cells and NK cells. Only IFN alpha is used in the treatment of cancers, including hairy cell leukaemia, chronic myeliod leukaemia, melanoma, renal cancer and Kaposi's sarcoma. The adverse effects of IFN are flu like symptoms, fatigue and myelosuppression.
How is interleukin-2 used to treat cancer?
IL-2 is a cytokine produced predominantly by activated CD4+ helper T cells that have been stimulated by antigen. It acts as an autocrine growth factor and in response to IL-2, CD4+ T cells differentiate into one of two T helper subsets. The Th1 pathway is essentially cell mediated immunity, with the activation of macrophages, NK cells, cytotoxic T cells and prolonged inflammatory response. The Th2 pathway is essentially the humeral pathway, with the production of cytokines which promote B cell growth and production of antibodies. IL-2 causes growth and proliferation of activated T cells thus expanding tumoricidal LAK cells and may be used to treat melanoma and renal cell cancers. Adverse effects of IL-2 are fluid retention, multi-organ dysfunction and bone marrow and hepatic toxicity.
What tyrosine kinase inhibitors are used to treat cancer?
E.g. Imatinib is an oral tyrosine kinase (bcr/Abl gene product) is used to treat CML. Erlotinib is used in non small cell lung cancer and targets EGFR.