Malignant transformation may result from a gain in function as cellular proto-oncogenes become mutated (e.g. RAS), amplified (HER2) or translocated (BCR-ABL). However, these mutations are insuffiecient to cause malignant transformation by themselves. Alternatively there may be a loss of function of tumour suppressor genes such as PS53 that normally suppress growth. The genes most commonly affected can be characterized as those controlling cell cycle checkpoints, DNA repair and DNA damage recognition, apoptosis, differentiation, growth factor receptors and signalling pathways and tumour suppressor genes.
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| Oncogene pathways |
Tumour cells are usually not recognized and killed by the immune system. There are two main reasons:
- Failure to express molecules that are required for activation of cytotoxic or killer T lymphocytes.
- Tumours may actively secrete immunosuppressive cytokines and cause a generalized immunosuppression.
Angiogenesis
New vessel formation (angiogenesis) is stimulated by a variety of peptides produced both by tumour cells and by host inflammatory cells, such as bFGF, angiopoietin 2, VEGFs.
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| Angiogenesis in tumorcells |
Invasion and metastasis
Solid cancers spread by both local invasion and by distant metastasis through the vessels of the blood and lymphatic systems. Infiltration into surrounding tissues is associated with loss of cell-cell cohesion, which is medicated by active homotypic cell adhesion molecules (CAMs). Epithelial cadherin is expressed by many carcinomas.
AETIOLOGY AND EPIDEMIOLOGY OF CANCER
Genetic factorsAETIOLOGY AND EPIDEMIOLOGY OF CANCER
Germline mutations in the genes that predispose to the development of cancer maybe inherited and therefore present in all tissue.
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| Familial cancer syndromes |
Environmental factors
A wide range of environmental factors have been identified as being associated with the development of malignacy. Environmental factors interract with genetic predisposition.
Environmental/occupational
Ultraviolet light is known to increase the risk of skin cancer. Arsenical contamination of water supplies has been linked to high incidence of lung and colon cancers.
Infectious agents
Chronic persistent infection provides growth stimulation while many viruses contain transforming viral oncogenes. T-cell leukaemia is caused by infection with the retrovirus HTLV-1 (human T cell leukaemia virus) ans integration of the oncogene, TAX, nto the cellular genome. Hepatocellular carcinoma occurs in patients with hepatitis B and C infections.
Burkitt's lympphoma and nasopharyngeal carinoma are associated with the Epstein-Barr virus. EBV is also linked to Hodgkin's lymphoma. Patients with HIV infection or immunosuppression have an increased incidence of EBV-related lymphoma and herpesvirus 9 associated Kaposi's sarcoma.
The incidence of cervical cancer has increased among younger women in association with sexsually transmitted HPV types 16 and 18.
Baterial infection with Helicobacter Pylori predisposes to the development of gastric cancer and gastric lymphoma, while schistosoma japonicum infection predisposes to the development of squamous cell carcinomas in the bladder.
Medications
Oestrogens have been implicated in the development of vaginal, endometrial and breast carcinoma. Certain cytotoxic drugs given, e.g. Hogkin's lymphoma, are themselves associated with an increased incidence of secondary acute myelogenous leukaemie (AML), bladder and lung cancer. Androgens have been associated with both benign and malignant liver tumours.
Other factors include tabacco, alcohol, diet.
THE CLINICAL PRESENTATION OF MALIGNANT DISEASE
Asymptomatic detection through screeningTHE CLINICAL PRESENTATION OF MALIGNANT DISEASE
Most cancers start as focal microscopic clones of transformed cells and diagnosis only becomes likely once sufficient tumour bulk has accumulated to cause symptoms or signs. Genetic screening can be used to target screening to groups at most risk of developing cancer e.g. BRCA1 + and cancer.
An effective screening procedure should:
- be afforadable to the healthcare system
- be acceptable to all social groups so that they attend for screening
- have a good discriminatory index between benign and malignant lesion
- show a reduction in mortality from cancer
Cervical cancer: the smear test
Breast cancer: biplanar mammography
Colorectal cancer: faecal occult blood, colonoscopy (golden standard)
Prostate cancer: serum prostate-specific antigen (PSA)
Epithelilal ovarian cancer: serum CA125
The symptomatic patient with cancer
Patients may offer information of predisposing conditions and family history that alerts the clinician to the likelihood of a cancer diagnosis. Many present with a history of tumour site specific symptoms e.g. pain, mass, which readily indentify the primary site of the cancer. Some only seek medical attention when more systemic and nonspecific symptoms occur such as weight loss, night sweats, fever, fatique, recurrent infections and anorexia.
Paraneoplastic syndrome are indirect effects of cancer that are often associated with specific types of cancer and may be reversible with treatment of the cancer.
The coagulopathy of cancer may present with thrombophlebitis, deep venous thrombosis and pulmonary emboli, particularly in association with cancers of pancreas, stomach and breast.
Trousseau's Syndrome is a medical sign involving episodes of vessel inflammation due to blood clot (thrombophlebitis) which are recurrent or appearing in different locations over time.
Cachexia of advanced cancer is thought to be due to release of chemokines such as tumour necrosis factor (TNF) as well as the fact that patients have a loss of appetite.
Cancer-associated immunosuppression can lead to reactivation of latent infections such as herpes zoster and tuberculosis.
Serum tumours markers
Tumour markers are intracellular proteins or cell surface glycoproteins released into the circulation and detected by immunoassays. Values in the normal range do not necessarily equate with the absence of disease and a positive result must be corborated by histology as these markers can be seen in many benign conditions.
Cancer imaging
Radiological investigation by experts is required at various stages: at initial diagnosis and staging of the disease, during the monitoring of treatment efficacy, at the detection of recurrence and for the diagnosis and treatment of complication.
Biopsy and histological examination
The diagnosis of cancer may be suspected by both patient and doctor but advice about treament can usually only be given on the basis of a tissue diagnosis. This maybe ibtained by endoscopic, radiolocially-guided or surgical biopsy or on basis of cytology.
The degree of differentiation of the tumour has prognostic significance: generally speaking, more differentiated tumours have a better prognosis than pooly differentiated ones.
Tissue tumour markers. Immunocytochemistry, using monoclonal antibodies against tumours antigens, is very helpful in differentiating between lymphoid and epithelial tumours and between some subsets of there.
Fluorescent in sity hybridization (FISH) - look for characteristic chromosomal translocation, deletionss or amplification
Tissue microarrays - identify patterns of multiple genomic alteration and single nucleotide polymorphism
RNA assays - identify tissue of origin with prognostic and predictive relevance
PRINCIPLES OF CHEMOTHERAPY
Cytotoxic chemotherapy employs systemically administered drugs that directly damage cellular DNA (and RNA). It kills cells by promoting apoptosis and sometimes frank necrosis. Different cytotoxic drugs work at different stages in the cell cycle. There is a narrow therapeutic window between effective treatment of the cancer and normal tissue toxicity, because cytotoxic drugs are not cancer specific and the increased proliferation in cancers is not much greater than in normal tissues. The therapeutic effect on the cancer is achieved by a variety of mechanisms which seek to exploit differences between normal and transformed cells.Paraneoplastic syndrome are indirect effects of cancer that are often associated with specific types of cancer and may be reversible with treatment of the cancer.
The coagulopathy of cancer may present with thrombophlebitis, deep venous thrombosis and pulmonary emboli, particularly in association with cancers of pancreas, stomach and breast.
Trousseau's Syndrome is a medical sign involving episodes of vessel inflammation due to blood clot (thrombophlebitis) which are recurrent or appearing in different locations over time.
Cachexia of advanced cancer is thought to be due to release of chemokines such as tumour necrosis factor (TNF) as well as the fact that patients have a loss of appetite.
Cancer-associated immunosuppression can lead to reactivation of latent infections such as herpes zoster and tuberculosis.
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| Paraneoplastic syndrome |
Tumour markers are intracellular proteins or cell surface glycoproteins released into the circulation and detected by immunoassays. Values in the normal range do not necessarily equate with the absence of disease and a positive result must be corborated by histology as these markers can be seen in many benign conditions.
Cancer imaging
Radiological investigation by experts is required at various stages: at initial diagnosis and staging of the disease, during the monitoring of treatment efficacy, at the detection of recurrence and for the diagnosis and treatment of complication.
Biopsy and histological examination
The diagnosis of cancer may be suspected by both patient and doctor but advice about treament can usually only be given on the basis of a tissue diagnosis. This maybe ibtained by endoscopic, radiolocially-guided or surgical biopsy or on basis of cytology.
The degree of differentiation of the tumour has prognostic significance: generally speaking, more differentiated tumours have a better prognosis than pooly differentiated ones.
Tissue tumour markers. Immunocytochemistry, using monoclonal antibodies against tumours antigens, is very helpful in differentiating between lymphoid and epithelial tumours and between some subsets of there.
Fluorescent in sity hybridization (FISH) - look for characteristic chromosomal translocation, deletionss or amplification
Tissue microarrays - identify patterns of multiple genomic alteration and single nucleotide polymorphism
RNA assays - identify tissue of origin with prognostic and predictive relevance
PRINCIPLES OF CHEMOTHERAPY
Toxicity to normal tissue can be limited in some instances by supplying growth factors such as granulocyt colony stimulating factor (G-CSF) or by the infusion of stem cell preparations to diminish myelotoxicity.
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| Effects of multiple courses of chemotherapy |
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| Cell cycle and chemotherapy drugs |
DNA damaging drugs
Alkylating agents act by covalently binding alkyl groups and their major effect is to cross link DNA strands, interfering with DNA synthesis and causing strand breaks.
Platinum compounds. Cisplatin, carboplain and oxaliplatin cause interstrand cross-links of DNA and are often regarded as non-classical alkylating agents.
Antimetabolites
Antimetabolites are usually structural analogues of naturally occurring metabolites that interfere with normal synthesis of nucleic acids by falsely substituting purines and pyrimidines in metabolic pathways.
Folic acid antagonists (methotrexate). This is structurally very similar to folic acid and binds preferentially to dihydrofolate reductase.
Pyrimidine antagonists. 5-Fluorouracil (5FU) acts by blocking the enzyme thymidylate synthase, which is essential for pyrimidine synthesis.
Arabinosides inhibit DNA synthesis by inhibiting DNA polymerase.
Purine antagonists
DNA repair inhibitors
Epipodophyllotoxins inhibit topoisomerase.
Cytotoxic antibodies. The anthracyclines act by intercalating adjoining nucleotide pairs on the same strand of DNA and by inhibiting topoisomerase II DNA repair.
Antitubulin agents
Vinca alkaloids. Drugs such as vincristine, vinblastine and vinorelbine act by binding to tubulin and inhibiting microtubule formation during mitosis.
Taxanes. Pacilitaxel and docetaxel bind to tubulin dimers and prevent their assembly into microtubules.
Side-effects of chemotherapy
The five most common side-effects are vomiting, hair loss, tiredness. myelosuppression and mucositis.
Extravasation of intravenous drugs. Cytotoxic drugs should only be given by trained personnel. They cause severe local tissue necrosis if leakage occurs outside the vein.
Nausea and vomiting. The severity of this common side effect varies with the cytotoxic and it can be eliminated in 75% of patients by using modern antiemetic (metoclopramide, domperiodone, 5-HT serotonin antagonist, dexamethasone). Drugs such as cyclizine, haloperidol and levomepromazine and benzodiazepines can be used to control persistent nausea.
Bone marrow suppression and immunosuppression. Anemia and thrombocytopenia are managed by red cell or platelet transfusions. The risk of infections can be ameliorated by the use of prophylactic antimicrobials.
Mucositis. Mucositis can be generalized throughout the intestinal tract when it can cause life-threatening diarrhea. Treatment is with antiseptic and anti-candidal mouthwash and if severe fluid and antibiotic support as the the mucosa is a portal for entry of enteric organisms. Palifermin, a recombinant keratinocyte derived growth factor, may ameliorate severe chemotherapy and radiotherapy induced mucositis.
Other toxicities
Cardiotoxicity. Usually associated with anthracyclines and can present as an acute arrhythmia during administration or cardiac failure due to cardiomyopathy after chronic exposure. The risk of anthracycline cardiomyopathy is also dependent on other treatments such as trastuzumab or radiotherapy as well as other cardiac risk factors such as hypertension, smoking and hypercholesterolemia. Cardiotoxicity can also be reduced by using analogue epirubin or by reducing peak drug concentrations through delayed release.
Neurotoxicity. Occurs predominantly with the vinca alkaloids, taxanes and platinum analogues.
Nephrotoxicity. Cisplatin, MTX and ifosfamide can cause renal damage. This can usually be prevented by maintaining an adequate diuresis during treatment.
Sterility and premature menopause. Some chemotherapy drugs (alkylating agents, anthracyclines, docetaxel) may cause gonadal damage resulting in sterility and in women the loss of ovarian estrogen production.
Secondary malignancies. Anticancer drugs have mutagenic potential and development of secondary malignancies, predominantly acute leukemia, is an uncommon but particularly unwelcome long-term side-effect.
Autologous stem cell transplantation
An autologous transplant is a type of transplant that uses the person's own stem cells. Haemopoietic stem cells are either collected from the patient's bone marrow, or more commonly by leucopheresis from the peripheral blood following stem cell mobilization from the marrow niche by the administration of the growth factor granulocyte colonystimulating factor (G-CSF).
Allogenic stem cell transplantation
Conventional ablative allogenic transplants
The transplantation of donor haemopoietic cells gets combined with myeloablative chemotherapy with or without radiotherapy with the dual effects of treating the malignancy as well as causing temporary immunosuppression that allows the graft 'to take'. Donors are usually fully matched at the major HLA antigens. Complications include graft-versus-host disease, immunosuppression both from conditioning therapy and the immunosuppressive drugs. All patients receive prophylactic antibacterial, antifungal and antiviral drugs.
Non-myeloablative allogenic stem cell transplantation
This method allows patient to have less intensive chemotherapy before transplantation with allogenic haematopoetic stem cells. This approach may be recommended for a variety of reasons including age, type of disease, other medical issues.
BIOLOGICAL THERAPIES
Interferons
Interferons are naturally occurring cytokines that mediate the cellular immune response. They are both antiproliferative and stimulate humoral and cell-mediated immune responses to the tumour that can result in an antitumour effect.
Alpha-interferon (INF-a): melanoma, renal cell carcinoma
Side effects: flu-like symptoms, fatigue.
Interleukins
Interleukin 2, a recombinant protein, is used to activate T-cell responses, often in conjunction with interferon-stimulated B-cell activation.
Used for melanoma, renal cell carcinoma
Side-effects: toxicity is common, acutely this includes the capillary leak syndrome with hypotension and pulmonary edema, while autoimmune thyroiditis and vitiligo occur later.
Immunotherapy
Certain antigens that are specific to cancer cells, have been used as tumour vaccines together with manipulation of the immune system to overcome tolerance.
Bacille Calmette-Guerin (BCG) - Bladder cancer
Immunomodulatory drugs (IMIDs) thalidomide, lenalidomide
IMID have antiangiogenic functions as well as affecting cytokine production, tumours/stromal interactions and T-cell co-stimulatory functions.
Used in myeloma, chronic lymphocytic leukaemia (CLL), myelodysplastic syndrome (MS) and other solid tumours.
Proteasome inhibitors
Proteasome inhibition leads to apoptosis in cancer cells.
Bortezomib - myeloma, types of NHL
TARGETED THERAPIES
Monoclonal antibodies
Monoclonal antibodies bind only to cancer cell-specific antigens and induce an immunological response against the target cancer cell.
Side-effects: hypersensitivity to the foreign protein and specific cross-reactivity
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| Monoclonal antibodies |
Many cancer cells are transformed by the activity of the protein products of oncogenes that signal growth by phosphorylation of tyrosine residues on the intracellular portion of growth factor receptors. Inhibitors of it have pharmacokinetic advantages.
Examples
Imatinib (tyrosine kinase inhibitor) - chronic myeloid leukemia and GIST
Lapatinib (Her2 inhibitor) - breast cancer
Sunitinib & Sorafenib (tyrosine kinase inhibitor) - metastatic renal cancer
Erlotinib & Gefitinib (tyrosine kinase inhibitor) - lung cancer
Vemurafenib (kinase inhibitor) - melanoma
RADIOTHERAPY
Radiation causes single- and doublestrand DNA breaks, inducing apoptosis of cells as they progress through the cell cycle and through the generation of short-lived free radicals, particularly from oxygen, which damage proteins and membranes. The radiation dose is measured in Gray (Gy).
Types of radiation therapy
External beam (or teletherapy) from a linear accelerator source produces X-rays. The energy is transmitted as photons and is the most commonly used form of radiotherapy.
Fractionation is the delivery of the radiation dose in increments separated by atleast 4-6 hours to try exploit any advantage in DNA repair between normal and malignant cells.
Hyperfractionation is when more than one fraction per day is given.
Brachytherapy is the use of radiation sources in close contact with the tissue to provide intense exposure over a short distance to a restricted volume.
Systemic radionuclides (e.g. iodine-131) can be administered by intravenous or intracavitary routes to provide radiation targeted to particular tissue uptake via surface antigens or receptors.
Combination chemoradiotherapy
The local efficacy of radiotherapy can be increased by the simultaneous but not serial addition of chemotherapy.
Side-effects of radiotherapy
Early radiotherapy side-effects are associated with general systemic disturbance (anorexia, nausela, malaise, mucositis, alopecia, myelosuppression)
Later side-effects occur from months to years later. Late effects reflect both the loss of slowly proliferating cells and a local endartritis which produces ischaemia and proliferative fibrosis.
Secondary malignancies appear 10-20 years after the cure of the primary cancer.
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