Carcinogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells. It is characterized by a progression of changes on cellular and genetic level that ultimately reprogram a cell to undergo uncontrolled cell division, thus forming a malignant mass. Cell division is a physiological process that occurs in almost all tissues and under many circumstances. Under normal circumstances, the balance between proliferation and programmed cell death, usually in the form of apoptosis, is maintained by tightly regulating both processes to ensure the integrity of organs and tissues. Mutations in DNA that lead to cancer (only certain mutations can lead to cancer and the majority of potential mutations will have no bearing) disrupt these orderly processes by disrupting the programming regulating the processes. Carcinogenesis is caused by this mutation of the genetic material of normal cells, which upsets the normal balance between proliferation and cell death. This results in uncontrolled cell division Proto-oncogenes are genes that promote cell growth and mitosis, whereas tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. Typically, a series of several mutations to these genes is required before a normal cell transforms into a cancer cell. One of the first oncogenes to be defined in cancer research is the ras oncogene. Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known asLi-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer. A disregulation of the cell cycle components may lead to tumor formation. As mentioned above, some genes like the cell cycle inhibitors, RB, p53 etc., when they mutate, may cause the cell to multiply uncontrollably, forming a tumor. Epidemiology indices the data collection tools that aid in the measurement and evaluation of disease indicators and conditions; classification systems featuring numbered scales against which a specific population may be compared. The main types of cancer leading to overall cancer mortality each year are:• lung (1.3 million deaths/year)• stomach (803 000 deaths)• colorectal (639 000 deaths)• liver (610 000 deaths)• breast (519 000 deaths).
What causes cancer? Cancer arises from one single cell. The transformation from a normal cell into a tumour cell is a multistage process, typically a progression from a pre-cancerous lesion to malignant tumours. These changes are the result of the interaction between a persons genetic factors and three categories of external agents, including:• physical carcinogens, such as ultraviolet and ionizing radiation• chemical carcinogens, such as asbestos, components of tobacco smoke, aflatoxin (a food contaminant) and arsenic (a drinking water contaminant)• biological carcinogens, such as infections from certain viruses, bacteria or parasites. Some examples of infections associated with certain cancers:• Viruses: hepatitis B and liver cancer, Human Papilloma Virus (HPV) and cervical cancer, and human immunodeficiency virus (HIV) and Kaposi sarcoma.• Bacteria: Helicobacter pylori and stomach cancer.• Parasites: schistosomiasis and bladder cancer. Ageing is another fundamental factor for the development of cancer. The incidence of cancer rises dramatically with age, most likely due to a buildup of risks for specific cancers that increase with age. The overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective as a person grows older. Tobacco use, alcohol use, low fruit and vegetable intake, and chronic infections from hepatitis B (HBV), hepatitis C virus (HCV) and some types of Human Papilloma Virus (HPV) are leading risk factors for cancer in low- and middle-income countries. Cervical cancer, which is caused by HPV, is a leading cause of cancer death among women in low-income countries.
A cancer may be suspected for a variety of reasons, but the definitive diagnosis of most malignancies must beconfirmed by histological examination of the cancerous cells by a pathologist. Tissue can be obtained froma biopsy or surgery. Many biopsies (such as those of the skin, breast or liver) can be done in a doctors office.Biopsies of other organs are performed under anesthesia and require surgery in an operating room.The tissue diagnosis given by the pathologist indicates the type of cell that is proliferating, its histological grade,genetic abnormalities, and other features of the tumor. Together, this information is useful to evaluatethe prognosis of the patient and to choose the best treatment. Cytogenetics and immunohistochemistry areother types of testing that the pathologist may perform on the tissue specimen. These tests may provideinformation about the molecular changes (such as mutations, fusion genes, andnumerical chromosome changes) that has happened in the cancer cells, and may thus also indicate the futurebehavior of the cancer (prognosis) and best treatment.In pathology, grading is a measure of the progress of tumors and other neoplasms. Some pathology gradingsystems apply only to malignant neoplasms (cancer); others apply also to benign neoplasms. Theneoplasticgrading is a measure of cell anaplasia (lack of differentiation) in the sampled tumors arising fromthe hyperplasia of normal tissue.Pathology grading systems classify the microscopic cell appearance abnormality, deviations in their rate ofgrowth, degree of invasiveness and dissemination with the goal of predicting developments at tissue level (seealso the 4 major histological changes in dysplasia).Cancer is a disorder of cell life cycle alteration that leads (non-trivially) to excessive cell proliferation rates,typically longer cell lifespans and poor differentiation. The grade score (numerical: G1 up to G4) increases withthe lack of cellular differentiation - it reflects how much the tumor cells differ from the cells of the normal tissuethey have originated from (see Categories below). Tumors may be graded on four-tier, three-tier, or two-tierscales, depending on the institution and the tumor type.The histologic tumor grade score along with the metastatic (whole-body-level cancer-spread) staging are usedto evaluate each specific cancer patient, develop their individual treatment strategy and to predict theirprognosis. A cancer that is very poorly differentiated is called anaplastic.The most commonly used system of grading is as per the guidelines of the American Joint Commission onCancer. As per their standards, the following are the grading categories. • GX Grade cannot be assessed • G1 Well differentiated (Low grade) • G2 Moderately differentiated (Intermediate grade) • G3 Poorly differentiated (High grade) • G4 Undifferentiated (High grade)Grading systems are also different for each type of cancer.The Gleason system, named after Donald Floyd Gleason, used to grade the adenocarcinoma cells inprostate cancer is the most famous. This system uses a grading score ranging from 2 to 10. Lower Gleasonscores describe well-differentiated less aggressive tumors.Tumor-Host InteractionsTumors are surrounded by resident non-cancerous cells, connective tissue, and extracellular matrix.These components are known as the tumor stroma or microenvironment.
Tumor Microenvironment Introduction • The tumor microenvironment consists of four components: • Cancer cells • Non-cancer cells • Secreted soluble factors • Non-cellular, solid material • The actual composition of the tumor microenvironment is highly variable.Conditions within the tumor microenvironment • Low oxygen levels (hypoxia), acidic conditions (low pH), and low sugar (glucose) levels are common conditions in tumors. • Conditions within the tumor microenvironment affect both cancer cells and normal cells. • The tissue within and surrounding a tumor is often disorganized.Inflammatory Cells in Cancer • The immune system can inhibit or promote tumor growth. • Many cancers are associated with chronic inflammatory conditions that activate cells of the innate immune system. • Macrophages secrete factors that enhance tumor cell proliferation, invasion, and promote angiogenesis.Fibroblasts in Cancer • Fibroblasts are the predominant cells in the stroma. • Changes in fibroblast behavior are associated with tumor progression. • Matrix metalloproteinases (MMPs) produced by fibroblasts degrade the extracellular matrix. • MMPs are key players in cancer initiation, metastasis, and angiogenesis.The Tumor Stroma and Metastasis • Seed and Soil hypothesis: given tumor cells (seeds) can only colonize particular distant tissues (soil) that have a suitable growth environment. • Two key events must occur for site-specific metastasis to occur: 1) formation of a viable landing spot and 2) expression of appropriate genes in the tumor cells. • Tumor cells may invade foreign tissue but fail to colonize it. The reasons for this are unknown. These cells are considered dormant cancer cells.The T cell is the primary cell responsible for direct recognition and killing of tumor cells. T cells carry outimmunologic surveillance, then proliferate and destroy newly transformed tumor cells after recognizing TAAs.The T-cell response to tumors is modulated by other cells of the immune system; some cells require thepresence of humoral antibodies directed against the tumor cells (antibody-dependent cellular cytotoxicity) toinitiate the interactions that lead to the death of tumor cells. In contrast, suppressor T cells inhibit the immuneresponse against tumors.Cytotoxic T lymphocytes (CTLs) recognize antigens on target cells and lyse these cells. These antigens maybe cell surface proteins or may be intracellular proteins (eg, TAAs) that are expressed on the surface incombination with class I major histocompatibility complex (MHC) molecules. Tumor-specific CTLs have beenfound with neuroblastomas; malignant melanomas; sarcomas; and carcinomas of the colon, breast, cervix,endometrium, ovary, testis, nasopharynx, and kidney.Natural killer (NK) cells are another population of effector cells with tumoricidal activity. In contrast to CTLs,NK cells lack the receptor for antigen detection but can still recognize normal cells infected with viruses ortumor cells. Their tumoricidal activity is termed “natural” because it is not induced by a specific antigen. Themechanism by which NK cells discriminate between normal and abnormal cells is under study. Evidencesuggests that class I MHC molecules on the surface of normal cells inhibit NK cells and prevent lysis. Thus, thedecreased level of class I molecule expression characteristic of many tumor cells may allow activation of NKcells and subsequent tumor lysis.Macrophages can kill specific tumor cells when activated by a combination of factors, including lymphokines(soluble factors produced by T cells) and interferon. They are less effective than T-cell–mediated cytotoxicmechanisms. Under certain circumstances, macrophages may present TAAs to T cells and stimulate tumor-specific immune response.Dendritic cells are dedicated antigen-presenting cells present in barrier tissues (eg, skin, lymph nodes). Theyplay a central role in initiation of tumor-specific immune response. These cells take up tumor-associated
proteins, process them, and present TAAs to T cells to stimulate the CTL response against tumor. The presenceof dendritic cells in tumor tissues correlates with improved prognosis.Lymphokines produced by immune cells stimulate growth or induce activities of other immune cells. Suchlymphokines include IL-2, also known as T-cell growth factor, and the interferons. IL-12 is produced by dendriticcells and specifically induces CTLs, thereby enhancing antitumor immune responses.Regulatory T cells are normally present in the body and help prevent autoimmune reactions. They areproduced during the active phase of immune responses to pathogens and limit the strong immune responsethat could damage the host. Accumulation of these cells in cancers inhibits antitumor immune responses.Myeloid-derived suppressor cells consist of immature myeloid cells and their precursors. These cellsaccumulate in large numbers in cancers and potently suppress immune responses.Humoral ImmunityIn contrast to T-cell cytotoxic immunity, humoral antibodies do not appear to confer significant protection againsttumor growth. Most antibodies cannot recognize TAAs.metastatic diseaseSome cancer cells also acquire the ability to penetrate and infiltrate surrounding normal tissues in the localarea, forming a new tumor. The newly formed "daughter" tumor in the adjacent site within the tissue is called alocal metastasis.Some cancer cells acquire the ability to penetrate the walls of lymphatic and/or blood vessels, after which theyare able to circulate through the bloodstream (circulating tumor cells) to other sites and tissues in the body. Thisprocess is known (respectively) as lymphatic or hematogeneous spread.Metastasis occurs by four routes:
1. Spread into body cavities. This occurs by the seeding surface of the peritoneul, plural, pericardial or subarchnoid spaces. For example, carcinoma of the ovary spreads transperitoneally to the surface of the liver.2. Invasion of lymphatics. This is followed by the transport of tumor cells to regional nodes and ultimately to other parts of the body; it is common in initial spread of carcinomas.3. Hematogenous spread. This is typical of all sarcomas but it is the favored route in certain carcinomas (e.g. those originating in kidneys). Because of their thinner walls veins are more frequently invaded than arteries and metastasis follows the pattern of the venous flows.4. Transplantation. Mechanical carriage of fragments of tumor cells by surgical instruments during operation or the use of needles during diagnostic procedures.
Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response inthe host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancertherapy.Normal proteins in the body are not antigenic because of self-tolerance, a process in which self-reactingcytotoxic T lymphocytes (CTLs) and autoantibody-producing B lymphocytes are culled "centrally" in primarylymphatic tissue (BM) and "peripherally" in secondary lymphatic tissue (mostly thymus for T-cellsand spleen/lymph nodes for B cells). Thus any protein that is not exposed to the immune system triggers animmune response.Any protein produced in a tumor cell that has an abnormal structure due to mutation can act as a tumor antigen.Such abnormal proteins are produced due to mutation of the concerned gene. Mutationofprotooncogenes and tumor suppressors which lead to abnormal protein production are the cause of the tumorand thus such abnormal proteins are called tumor-specific antigens. Examples of tumor-specific antigensinclude the abnormal products of ras and p53 genes. In contrast, mutation of other genes unrelated to thetumor formation may lead to synthesis of abnormal proteins which are called tumor-associated antigens.Proteins that are normally produced in very low quantities but whose production is dramatically increased intumor cells, trigger an immune response. An example of such a protein is the enzyme tyrosinase, which isrequired for melanin production. Normally tyrosinase is produced in minute quantities but its levels are verymuch elevated in melanoma cells.Oncofetal antigens are another important class of tumor antigens. Examples are alphafetoprotein (AFP)and carcinoembryonic antigen (CEA). These proteins are normally produced in the early stages of embryonicdevelopment and disappear by the time the immune system is fully developed. Thus self-tolerance does notdevelop against these antigens.Abnormal proteins are also produced by cells infected with oncoviruses, eg. EBV and HPV. Cells infected bythese viruses contain latent viral DNA which is transcribed and the resulting protein produces an immuneresponse.Immunodiagnosis:Tumor Associated Antigens (TAAs) can help diagnose various tumors and sometimes determine the responseto therapy or recurrence. An ideal tumor marker would be released only from tumor tissue, be specific for agiven tumor type, be detectable at low levels of tumor cell burden, have a direct relationship to the tumor cellburden, and be present in all patients with the tumor. However, although most tumors release detectableantigenic macromolecules into the circulation, no tumor marker has all the requisite characteristics to provideenough specificity or sensitivity to be used in early diagnosis or mass cancer screening programs.Carcinoembryonic antigen (CEA) is a protein-polysaccharide complex present in colon carcinomas and innormal fetal intestine, pancreas, and liver. Blood levels are elevated in patients with colon carcinoma, but thespecificity is relatively low because positive results also occur in heavy cigarette smokers and in patients withcirrhosis, ulcerative colitis, and other cancers (eg, breast, pancreas, bladder, ovary, cervix). Monitoring CEAlevels may be useful for detecting cancer recurrence after tumor excision if the patient initially had an elevatedCEA and for refining estimates of prognosis by stage.α-Fetoprotein, a normal product of fetal liver cells, is also present in the sera of patients with primaryhepatoma, nonseminomatous germ cell tumors, and, frequently, ovarian or testicular embryonal carcinoma.Levels are sometimes useful for estimating prognosis or, less often, for diagnosis.β Subunit of human chorionic gonadotropin (β-hCG), measured by immunoassay, is the major clinicalmarker in women with gestational trophoblastic neoplasia (GTN)—a disease spectrum that includeshydatidiform mole, nonmetastatic GTN, and metastatic GTN (see also Gynecologic Tumors: GestationalTrophoblastic Disease)—and in about two thirds of men with testicular embryonal carcinoma orchoriocarcinoma. The β subunit is measured because it is specific for hCG. This marker is present in low levelsin healthy people. Levels are elevated during pregnancy.
Prostate-specific antigen (PSA), a glycoprotein located in ductal epithelial cells of the prostate gland, can bedetected in low concentrations in the sera of healthy men. Using an appropriate upper limit of normal, assayswith monoclonal antibodies detect elevated serum levels of PSA in about 90% of patients with advancedprostate cancer, even in the absence of defined metastatic disease. It is more sensitive than prostatic acidphosphatase. However, because PSA is elevated in other conditions (eg, benign prostatic hypertrophy,prostatitis, recent GU tract instrumentation), it is less specific. PSA can be used to monitor recurrence afterprostatic carcinoma has been diagnosed and treated.CA 125 is clinically useful for screening, diagnosing, and monitoring therapy for ovarian cancer, although anyperitoneal inflammatory process and some other cancers can increase levels.β2-Microglobulin is often elevated in multiple myeloma and in some lymphomas. Its primary use is inprognosis.CA 19-9 was originally developed to detect colorectal cancer but proved more sensitive for pancreatic cancer. Itis primarily used to judge the response to treatment in patients with advanced pancreatic cancers. CA 19-9 canalso be elevated in other GI cancers, particularly cancer of the bile ducts, and some benign bile duct andcholestatic disorders.CA 15-3 and CA 27-29 are elevated in most patients with metastatic breast cancer. Levels may also beelevated in other conditions. These markers are primarily used to monitor the response to therapy.Chromogranin A is used as a marker for carcinoid and other neuroendocrine tumors. Sensitivity and specificityfor neuroendocrine tumors can exceed 75%, and diagnostic accuracy is higher with diffuse than with localizedtumors. Levels can be elevated in other cancers, such as lung and prostate, and some benign disorders (eg,primary hypertension, chronic kidney disease, chronic atrophic gastritis).Thyroglobulin is produced by the thyroid and may be elevated with various thyroid disorders. It is primarilyused after complete thyroidectomy to detect recurrent thyroid cancer and to follow the response to treatment inmetastatic thyroid cancer.TA-90 is a highly immunogenic subunit of a urinary tumor–associated antigen that is present in 70% ofmelanomas, soft-tissue sarcomas, and carcinomas of the breast, colon, and lung. Some studies have shownthat TA-90 levels can accurately predict survival and the presence of subclinical disease after surgery formelanoma.Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating thepatients immune system to attack the malignant tumor cells that are responsible for the disease. This can beeither through immunization of the patient (eg. by administering a cancer vaccine, such asDendreons Provenge), in which case the patients own immune system is trained to recognize tumor cells astargets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case thepatients immune system is recruited to destroy tumor cells by the therapeutic antibodies.Antibodies are a key component of the adaptive immune response, playing a central role in both in therecognition of foreign antigens and the stimulation of an immune response to them. It is not surprising therefore,that many immunotherapeutic approaches involve the use of antibodies. The advent of monoclonalantibody technology has made it possible to raise antibodies against specific antigens such as the unusualantigens that are presented on the surfaces of tumors.Cancer immunotherapy:Monoclonal antibodies Brand Approval Antibody Type Target Approved treatment(s) name dateAlemtuzumab Campath 2001 humanized CD52 Chronic lymphocytic leukemia vascularBevacizumab Avastin 2004 humanized endothelial colorectal cancer growth factor epidermalCetuximab Erbitux 2004 chimeric growth factor colorectal cancer receptor
Gemtuzumab acute myelogenous Mylotarg 2000 humanized CD33ozogamicin leukemia (with calicheamicin) non-HodgkinIbritumomab Zevalin 2002 murine CD20 lymphoma (with yttrium-90 or itiuxetan ndium-111) epidermalPanitumumab Vectibix 2006 human growth factor colorectal cancer receptor Rituxan,Rituximab 1997 chimeric CD20 non-Hodgkin lymphoma MabtheraTrastuzumab Herceptin 1998 humanized ErbB2 breast cancer
The TNM Classification of Malignant Tumours (TNM) is a cancer staging system that describes the extentof cancer in a patient’s body. • T describes the size of the tumour and whether it has invaded nearby tissue, • N describes regional lymph nodes that are involved, • M describes distant metastasis (spread of cancer from one body part to another).he general outline for the TNM classification is below. The values in parentheses give a range of what can beused for all cancer types, but not all cancers use this full range.Mandatory parameters ("T", "N", and "M") • T (a, CIS,(0),1–4): size or direct extent of the primary tumor • N (0–3): degree of spread to regional lymph nodes • N0: tumor cells absent from regional lymph nodes • N1: regional lymph node metastasis present; (at some sites: tumor spread to closest or small number of regional lymph nodes) • N2: tumor spread to an extent between N1 and N3 (N2 is not used at all sites) • N3: tumor spread to more distant or numerous regional lymph nodes (N3 is not used at all sites) • M (0/1): presence of metastasis • M0: no distant metastasis • M1: metastasis to distant organs (beyond regional lymph nodes)Use of an "X" instead of a number or other suffix means that the parameter was not assessed.Some of the aims for adopting a global standard are to: • Aid medical staff in staging the tumour helping to plan the treatment. • Give an indication of prognosis. • Assist in the evaluation of the results of treatment. • Enable facilities around the world to collate information more productively.TNM Breast cancerThe T stages (tumour)TX means that the tumour size cannot be assessedT1 - The tumour is no more than 2 centimetres (cm) acrossT1 is further divided into 4 groups • T1mic - under a microscope the cancer cells can be seen to spread less than 0.1cm into surrounding tissue (microinvasion) • T1a - the tumour is more than 0.1 cm but not more than 0.5 cm • T1b - the tumour is more than 0.5 cm but not more than 1 cm • T1c - the tumour is more than 1 cm but not more than 2 cmT2 - The tumour is more than 2 centimetres, but no more than 5 centimetres acrossT3 - The tumour is bigger than 5 centimetres acrossT4 is divided into 4 groups • T4a - The tumour has spread into the chest wall
• T4b - The tumour has spread into the skin • T4c - The tumour is fixed to both the skin and the chest wall • T4d - Inflammatory carcinoma - this is a cancer in which the overlying skin is red, swollen and painful to the touchThe N stages (nodes)NX means that the lymph nodes cannot be assessed (for example, if they were previously removed)N0 - No cancer cells found in any nearby nodesN1 - Cancer cells are in nodes in the armpit but the nodes are not stuck to surrounding tissuesN2 is divided into 2 groups • N2a - there are cancer cells in the lymph nodes in the armpit, which are stuck to each other and to other structures • N2b - there are cancer cells in the lymph nodes behind the breast bone (the internal mammary nodes). These have either been seen on a scan or felt by the doctor. There is no evidence of cancer in lymph nodes in the armpitN3 is divided into 3 groups • N3a - there are cancer cells in lymph nodes below the collarbone • N3b - there are cancer cells in lymph nodes in the armpit and under the breast bone • N3c - there are cancer cells in lymph nodes above the collarboneThe M stages (metastases)M0 - No sign of cancer spreadM1 - Cancer has spread to another part of the body, apart from the breast and lymph nodes under thearm
Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiationtherapy or surgery. Most cancers are now treated in this way. Combination chemotherapy is a similar practicethat involves treating a patient with a number of different drugs simultaneously. The drugs differ in theirmechanism and side effects. The biggest advantage is minimising the chances of resistance developing to anyone agent.In neoadjuvant chemotherapy (preoperative treatment) initial chemotherapy is designed to shrink the primarytumour, thereby rendering local therapy (surgery or radiotherapy) less destructive or more effective.Adjuvant chemotherapy (postoperative treatment) can be used when there is little evidence of cancer present,but there is risk of recurrence. This can help reduce chances of developing resistance if the tumour doesdevelop. It is also useful in killing any cancerous cells which have spread to other parts of the body. This isoften effective as the newly growing tumours are fast-dividing, and therefore very susceptible.Palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase lifeexpectancy. For these regimens, a better toxicity profile is generally expected.All chemotherapy regimens require that the patient be capable of undergoing the treatment.Chemotherapy drugs are classified based on how they work. The main types of chemotherapy drugs aredescribed below: • Alkylating drugs kill cancer cells by directly attacking DNA, the genetic material of the genes. Cyclophosphamide is an alkylating drug. • Antimetabolites interfere with the production of DNA and keep cells from growing and multiplying. An example of an antimetabolite is 5-fluorouracil (5-FU). • Antitumor antibiotics are made from natural substances such as fungi in the soil. They interfere with important cell functions, including production of DNA and cell proteins. Doxorubicin and bleomycin belong to this group of chemotherapy drugs. • Plant alkaloids prevent cells from dividing normally. Vinblastine and vincristine are plant alkaloids obtained from the periwinkle plant. • Steroid hormones slow the growth of some cancers that depend on hormones. For example, tamoxifen is used to treat breast cancers that depend on the hormone estrogen for growth.
Alkylating agents cause cell death by interacting with DNA during cell synthesis. DNA is the component of cellscontaining all the genetic information the cell needs to grow, divide and function. The DNA is like the blue-print of livingcells and has a special helical ladder structure. Alkylating agents work by directly interacting with exposed DNA andadding alkyl groups. The resulting permanent DNA damage ultimately results in death of the cells.Cyclophosphamide (cycloblastin, endoxan) was the first clinically effective cancer chemotherapy agent and is the mostcommonly used alkylating agent. As well as its anti-tumour effects, it also has immunosuppressant activity as it alsodisrupts the function of lymphocytes (immune cells).Other alkylating agents include chlorambucil (leukeran), carmustine, lomustine and cisplatin. The latter is sometimesclassed as a platinum compound and has been responsible for the massive advances in the treatment of testicularcancer as well as being effective against a range of other cancers including lung, ovarian and head and neck cancers.Side effects of alkylating agentsAll alkylating agents depress bone marrow function and cause gastrointestinal disturbances such as nausea andvomiting. As bone marrow is responsible for the production of red blood cells, white blood cells and platelets when it isdepressed symptoms of anaemia, infection and bleeding respectively, may occur. Therefore regular monitoring ofbloodcounts is required during treatment. The frequency and severity of most adverse effects increase with increasing dose.Sterility and secondary malignancies have been reported with prolonged use of alkylating agents.Anti-metabolites are molecules that have very similar structures to true proteins within cells. They are therefore taken upby cells which cannot distinguish the drug from the real protein. Once inside the cell, anti-metabolites interact with DNA
and RNA like the normal protein would but due to slight variations in their properties prevent the cell processes fromcontinuing. Anti-metabolites therefore prevent normal proteins from binding in the cell and halt normal function anddivision. In other words, they mimic and interfere with the binding of real proteins. Once again this leads to programmedcell death (apoptosis).The molecules mimicked by anti-metabolites include folate, purine and pyrimidine. These agents seem to be particularlyimportant in DNA synthesis and cellularmetabolism in cancer cells.Folate antagonistsThese agents mimic folate and enter the cell. They inhibit an enzyme called dihydrofolate reductase which is needed inthe production of amino acids and purine nucleotides, the building blocks of DNA, RNA and key cellular proteins.Methotrexate is the main folate antagonist. It may be used in a variety of solid tumours and haematological malignancies.In addition its immunosuppressant properties may be utilised in the treatment of non-malignant conditions suchas rheumatoid arthritis and psoriasis.Side effects of folate antagonistsMethotrexate is very toxic at high doses, particularly to bone marrow and the digestive tract lining. Symptoms of toxicityinclude:•Bone marrow suppression, including bleeding, anaemia and increased risk of infection;•Nausea;•Anorexia;•Diarrhoea raging from mild to severe ulceration and bleeding.Methotrexate is often administered with leucovorin, which is an agent designed to reduce the anaemia and toxicity tonormal cells that often accompanies methotrexate therapy.Purine antagonistsPurine antagonists mimic the purines adenine and guanine, two of the bases that make up DNA. By mimicking thesemolecules, purine antagonists block DNA synthesis and prevent cell division. Examples of purine antagonists include 6-mercaptopurine (Puri-Nethol), 6-thioguanine, dacarbazine and fludurabine. Purine antagonists are used for the treatmentof acute leukaemias.Side effects of purine antagonistsThe side effects of 6-mercaptopurine are listed below which are similar to those seen with many other chemotherapeuticagents. They are rare in children.•Bone marrow suppression, resulting in increased bleeding and infection risk;•Mouth sores;•Skin rash/acne;•Mild nausea;•Abnormal liver function;•Hair loss.Anorexia, fever, fatigue/weakness and facial flushing can also occur with other purine antagonists than 6-mercaptopurine.Pyrimidine antagonistsPyrimidine antagonists mimic the pyrimidines cytosine and thymine, the other two bases making up nucleotides andDNA. By mimicking these molecules, pyrimidine antagonists block DNA synthesis and prevent cell division in a similarmechanism to purine antagonists.The pyrimidine antagonists include 5-fluorouracil (Efudix), cytarabine, capecitabine (Xeloda) and gemcitabine (Gemzar).5-Flurouracil has a major role in the treatment of gastrointestinal cancers. Capecitabine is an oral version of 5-
fluorouracil and is used in the treatment of metastatic colon cancer and metastatic or resistant breast cancer. Cytarabineis used to treat leukaemias, and gemcitabine is used in solid cancers such as ovarian or in combination with cisplatin totreat non-small cell lung cancer.Side effects of pyrimidine antagonistsAs 5-fluorouracil is active against dividing cells, it also kills healthy cells, which contributes to the following side effects:•Tiredness•Nausea and diarrhoea•Bone marrow depression that may lead to anaemia•Increased tendency to bruise•Mouth sores•Altered pigmentation of the skinThe side effects of capecitabine are similar, as it is converted to 5-fluorouracil once inside the body. Cytarabine may alsocause anorexia, fever and rash.
Anthracyclines are cytotoxic (cell killing) antibiotics that are also non-cell-cycle specific chemotherapyagents. They are probably amoung the most commonly used cytotoxic drugs. Many antracyclines also haveimmunosuppressant activity.Doxorubicin (adriamycin) is an example of an anthracycline medication which is used in a variety of cancersincluding affecting the breast, endometrium (lining of thewomb), ovary, testicle, thyroid, stomach, bladder, liver and lung, soft tissues and several childhood cancers.Epirubicin and mitozantrone are other examples of anthracycline medications.Side effects of anthracyclinesSide effects of anthracycline use include:•Myelosuppression (bone marrow suppression) especially of white blood cells, but also of red blood cells andplatelets. These side effects of chemotherapy can be minimised with red blood cell and platelet transfusions.In addition if you develop fever during treatment (febrile neutropenia) you must see a doctor for carefulmanagement;•Increased risk of infection and bleeding;•Toxicity to the heart which may lead to arrhythmias. Damage may become permanent after approximatelyone month of treatment especially if you have been previously exposed to these drugs. It is for this reasonthat doctors are often reluctant to prescribe anthracyclines if you have been treated with them in the past;•Severe local reactions, including tissue necrosis (death) or extravasation (leakage of drug outside the bloodvessels);•Secondary malignancies;•Radiation recall: The recurrence of skin damage from previous radiotherapy;•Alopecia (hair loss): This may be associated with significant effects on quality of life;•Nausea and vomiting;•Oral ulceration.Bleomycin is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Bleomycin refersto a family of structurally related compounds. When used as an anticancer agent, the chemotherapeuticalforms are primarily bleomycin A2 and B2. It works by causing breaks in DNA. The drug is used in thetreatment ofHodgkins lymphoma (as a component of the ABVD regimen), squamous cell carcinomas,and testicular cancer, as well as in the treatment of plantar warts  and as a means of effecting pleurodesisThe most serious complication of bleomycin is pulmonary fibrosis and impaired lung function. It has beensuggested that bleomycin induces sensitivity to oxygen toxicityThe mitomycins are a family of aziridine-containing natural products isolated from Streptomycescaespitosus or Streptomyces lavendulae. One of these compounds,mitomycin C, finds use asa chemotherapeutic agent by virtue of its antitumour antibiotic activity. It is given intravenously to treat uppergastro-intestinal (e.g.esophageal carcinoma), anal cancers, and breast cancers, as well as by bladderinstillation for superficial bladder tumours. It causes delayed bone marrow toxicity and therefore it is usuallyadministered at 6-weekly intervals. Prolonged use may result in permanent bone-marrow damage. It mayalso cause lung fibrosis and renal damage.Actinomycin D is primarily used as an investigative tool in cell biology to inhibit transcription. It does this bybinding DNA at the transcription initiation complex and preventing elongation by RNA polymerase. Because it can bind DNA duplexes, it can also interfere with DNA replication, although other chemicalssuch ashydroxyurea are better suited for use in the laboratory as inhibitors of DNA synthesis.Actinomycin D, marketed under the trade name Dactinomycin, is one of the older chemotherapy drugs, andhas been used in therapy for many years.
It is a clear, yellow liquid administered intravenously and most commonly used in treatment of a variety ofcancers including gestational trophoblastic neoplasia,Wilms tumor and rhabdomyosarcoma.
Vinca alkaloids act on a specific phase of the cell cycle called metaphase (M phase). They are another class of anti-tubulin agents (along with the taxanes) and work by binding tubulin and inhibiting the production of microtubules. Thishalts cell division and leads to cell death. Vinca alkaloids are used to treat both haematological (diseases of blood cellssuch as leukaemias) and non-haematological (solid organ) malignancies.There are four vinca alkaloids currently available namely vinblastine, vincristine, vindesine and vinorelbine (Navelbine).Side effects of vinca alkaloidsVinca alkaloids cause a number of the common side effects seen with chemotherapy such as:•Nausea and vomiting;•Hair loss;•Mouth sores;•Headache;•Constipation.Vinblastine also causes bone marrow suppression like many other agents, resulting in increased bleeding, infectionand anaemia risk. In addition, vinca alkaloids can damage nerves. For example, vincristine may cause numbness,sensory impairment, blurred or double vision and/or general weakness.Podophyllotoxin is a plant-derived compound which is said to help with digestion as well as used to producetwo other cytostatic drugs, etoposide and teniposide. They prevent the cell from entering the G1 phase(the startof DNA replication) and the replication of DNA (the S phase). The exact mechanism of its action is not yetknown.TaxanesTaxanes are cytotoxic agents that work on a protein called tubulin found in the cytoplasm of cells. Tubulin is needed forthe production of microtubules which are essential in cell division. Microtubules help separate chromosomes (agentscarrying our DNA) when cells divide. Taxanes are generally used when other chemotherapy regimens have failed. Theytend to be effective against ovarian, breast and lung cancers.Taxanes currently available in Australia include:•Paclitaxel (Anzatax, Taxol);•Nanoparticle albumin-bound paclitaxel (Abraxane); and•Docetaxal (Taxotere).Paclitaxel has been shown to have activity in a broad range of solid tumours.Docetaxal is very similar to paclitaxel in terms of mechanism of action, metabolism, and elimination. It is currentlyapproved as second line therapy for advanced breast cancer and non-small cell lung cancer (NSCLC).Nanoparticle albumin-bound paclitaxel is used for metastatic breast cancers. It binds the active component (paclitaxel) toa protein (Albumin) normally found in the blood. This increases the drugs solubility and avoids the use of other additives,associated with side effects, that normally act to increase the water solubility of the drug.Side effects of taxanesTaxanes cause bone marrow suppression like many other chemotherapeutic agents. The most common effect isneutropaenia, which increases the chance of infection. Other side effects include:•Nausea and vomiting•Diarrhoea;•Mouth sores;•Joint and muscle aches;
•Cisplatin is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas,some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas, and germ cell tumors. It wasthe first member of a class of anti-cancer drugs which now also includes carboplatin and oxaliplatin. Theseplatinum complexes react in vivo, binding to and causing crosslinking of DNA which ultimatelytriggers apoptosis (programmed cell death).Cisplatin is administered intravenously as short-term infusion in physiological saline for treatment of solidmalignacies.cisplatin has a number of side-effects that can limit its use: • Nephrotoxicity (kidney damage) is a major concern. The dose is reduced when the patients creatinine clearance (a measure of renal function) is reduced. Adequate hydration and diuresis is used to prevent renal damage. The nephrotoxicity of platinum-class drugs seems to be related to reactive oxygen species and in animal models can be ameliorated by free radical scavenging agents (e.g., amifostine). Nephrotoxicity is a dose-limiting. • Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies before and after treatment. • Nausea and vomiting: cisplatin is one of the most emetogenic chemotherapy agents, but this symptom is managed with prophylactic antiemetics (ondansetron, granisetron, etc.) in combination withcorticosteroids. Aprepitant combined with ondansetron and dexamethasone has been shown to be better for highly emetogenic chemotherapy than just ondansetron and dexamethasone. • Ototoxicity (hearing loss): unfortunately there is at present no effective treatment to prevent this side effect, which may be severe. Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as the aminoglycoside antibiotic class) may also cause ototoxicity, and the administration of this class of antibiotics in patients receiving cisplatin is generally avoided. The ototoxicity of both the aminoglycosides and cisplatin may be related to their ability to bind to melanin in the stria vascularis of the inner ear or the generation of reactive oxygen species. • Electrolyte disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the Cisplatin.Procarbazine is an antineoplastic chemotherapy drug for the treatment of Hodgkins lymphoma and certainbrain cancers (such as Glioblastoma multiforme). It is a member of a group of medicines called alkylatingagents.Asparaginase The rationale behind asparaginase is that it takes advantage of the fact that ALL leukemic cellsare unable to synthesize the non-essential amino acid asparagine, whereas normal cells are able to make theirown asparagine; thus leukemic cells require high amount of asparagine. These leukemic cells depend oncirculating asparagine. Asparaginase, however, catalyzes the conversion of L-asparagine to aspartic acid andammonia. This deprives the leukemic cell of circulating asparagine. The main side effect is an allergic orhypersensitivity reaction; anaphylaxis is a possibility. Asparaginase has also been associatedwith pancreatitis.RetinoidsRetinoids are drugs that are relatives of vitamin A. Retinoids control normal cell growth, celldifferentiation (the normal process of making cells different from each other), and cell death duringembryonic development and in certain tissues later in life. Retinoids effects on the cells are controlledby receptors on the nucleus of each cell (nuclear receptors).There are two major classes of retinoid nuclear receptors: retinoic acid receptors (RAR) and retinoid-X-receptors (RXR). There are also subtypes within each class. Each of these types of receptors has different
functions in different tissues. The different retinoid drugs work by binding to different receptors; which, in turn,affect cell growth and differentiation.Retinoids are relatively new types of anti-cancer drugs. They have been used alone or in combination to treat avariety of cancers such as skin cancers, cutaneous T-cell lymphoma, acute promyelocytic leukemia, lungcancer, breast cancer, ovarian cancer, bladder cancer, kidney cancer, and head and neck cancers. Retinoidshave also been used experimentally in an attempt to prevent certain types of cancer. There is ongoingresearch to determine their role in both cancer treatment and prevention.Retinoids have been associated with side effects such as skin problems (dryness, peeling, itching, sunsensitivity), reversible elevation in liver enzymes, temporary abnormal lipid levels, low thyroid levels(hypothyroidism), and headaches.
Hormonal therapy is one of the major modalities of medical treatment for cancer, others being cytotoxicchemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrinesystemthrough exogenous administration of specific hormones, particularly steroid hormones, or drugs whichinhibit the production or activity of such hormones (hormone antagonists). Because steroid hormones arepowerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormonescan cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs,such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.Hormonal therapy is used for several types of cancers derived from hormonally responsive tissues, includingthe breast, prostate, endometrium, and adrenal cortex.One effective strategy for starving tumor cells of growth- and survival-promoting hormones is to usedrugs which inhibit the production of those hormones in their organ of origin.Aromatase inhibitorsAromatase inhibitors are an important class of drugs used for the treatment of breastcancer in postmenopausal women. At menopause, estrogen production in the ovaries ceases, but other tissuescontinue to produce estrogen through the action of the enzyme aromatase on androgens produced bythe adrenal glands. When the action of aromatase is blocked, estrogen levels in post-menopausal women candrop to extremely low levels, causing growth arrest and/or apoptosis of hormone-responsive cancercells. Letrozole and anastrozoleare aromatase inhibitors which have been shown to be superior to tamoxifen forthe first-line treatment of breast cancer in postmenopausal women. Exemestane is an irreversible"aromatase inactivator" which is superior to megestrol for treatment of tamoxifen-refractory metastatic breastcancer, and does not appear to have the osteoporosis-promoting side effects of other drugs in this class.Aminoglutethimide inhibits both aromatase and other enzymes critical for steroid hormone synthesis inthe adrenal glands. It was formerly used for breast cancer treatment, but has since been replaced by moreselective aromatase inhibitors. It can also be used for the treatment of hyperadrenocortical syndromes, suchas Cushings syndrome and hyperaldosteronism in adrenocortical carcinoma.GnRH analogsAnalogs of gonadotropin-releasing hormone (GnRH) can be used to induce a chemical castration, that is,complete suppression of the production of estrogen and progesterone from the female ovaries, or completesuppression of testosterone production from the male testes. This is due to a negative feedback effect ofcontinuous stimulation of the pituitary gland by these hormones. Leuprolide and goserelin are GnRH analogswhich are used primarily for the treatment of hormone-responsive prostate cancer. Because theinitial endocrine response to GnRH analogs is actually hypersecretion of gonadal steroids, hormone receptorantagonists such as flutamide are typically used to prevent a transient boost in tumor growth.Hormone receptor antagonists bind to the normal receptor for a given hormone and prevent its activation. Thetarget recepetor may be on the cell surface, as in the case of peptide and glycoprotein hormones, or it may beintracellular, as in the case of steroid hormone receptors.Selective estrogen receptor modulatorsSelective estrogen receptor modulators (SERMs) are an important class of hormonal therapy agents which actas antagonists of the estrogen receptor and are used primarily for the treatment and chemoprevention of breastcancer. Some members of this family, such as tamoxifen, are actually partial agonists, which canactuallyincrease estrogen receptor signalling in some tissues, such as the endometrium. Tamoxifen is currentlyfirst-line treatment for nearly all pre-menopausal women with hormone receptor-positive breast cancer.
AntiandrogensAntiandrogens are a class of drug which bind and inhibit the androgen receptor, blocking the growth- andsurvival-promoting effects of testosterone on certain prostate cancers.Flutamide and bicalutamide areantiandrogens which are frequently used in the treatment of prostate cancer, either as long-term monotherapy,or in the initial few weeks of GnRH analog therapy
Interferons (IFNs) are proteins made and released by lymphocytes in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger theprotective defenses of the immune system that eradicate pathogens or tumors. IFNs have other functions: they activate immune cells, such as natural killer cells and macrophages; theyincrease recognition of infection or tumor cells by up-regulating antigen presentation to T lymphocytes; and theyincrease the ability of uninfected host cells to resist new infection by virus. Certain host symptoms, such asaching muscles and fever, are related to the production of IFNs during infection.Imidazoquinoline is the main ingredient of Aldara (Imiquimod) cream, treatment for actinic keratosis, superficial basal cell carcinoma, papilloma and external genital warts.Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for many cancers. This treatment is most effective for treating hematological malignancy; leukemia and lymphomasincluding hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, cutaneous T-cell lymphoma. Patients with recurrent melanomas receive recombinant IFN-α2bHematopoietic Growth Factors are a group of substances with the ability to support hematopoietic (blood cell) colonyformation in vitro. This group of substances includes erythropoietin, interleukin-3 and colony-stimulating factors (CSFs).Erythropoietin stimulates production of erythrocytes, or red blood cells. Interleukin-3 and CSFs can mature cells, haveoverlapping capabilities to affect progenitor cells (“parent” cells that will develop into a specific type of cell) of severalblood cell lines, and can also affect cells outside the hematopoietic system.HGFs are used to promote bone marrow proliferation in aplastic anemia, following cytotoxic chemotherapy, or following abone marrow transplant.
It is possible to take hematopoietic stem cells from one person and then infuse them into anotherperson (Allogenic) or into the same person at a later time (Autologous). If donor and recipient arecompatible, these infused cells will then travel to the bone marrow and initiate blood cell production.Transplantation from one person to another is performed in severe cases of disease of the bone marrow. Thepatients marrow is first killed off with drugs or radiation, and then the new stem cells are introduced.Before radiation therapy or chemotherapy in cases of cancer, some of the patients hematopoietic stem cellsare sometimes harvested and later infused back when the therapy is finished to restore the immune system.Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) areprocedures that restore stem cells that have been destroyed by high doses of chemotherapy and/orradiation therapy. There are three types of transplants: • In autologous transplants, patients receive their own stem cells. • In syngeneic transplants, patients receive stem cells from their identical twin. • In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.One reason BMT and PBSCT are used in cancer treatment is to make it possible for patients to receivevery high doses of chemotherapy and/or radiation therapy. To understand more about why BMT andPBSCT are used, it is helpful to understand how chemotherapy and radiation therapy work.Chemotherapy and radiation therapy generally affect cells that divide rapidly. They are used to treat cancer becausecancer cells divide more often than most healthy cells. However, because bone marrow cells also divide frequently, high-dose treatments can severely damage or destroy the patient’s bone marrow. Without healthy bone marrow, the patient isno longer able to make the blood cells needed to carry oxygen, fight infection, and prevent bleeding. BMT and PBSCTreplace stem cells destroyed by treatment. The healthy, transplanted stem cells can restore the bone marrow’s ability toproduce the blood cells the patient needs.In some types of leukemia, the graft-versus-tumor (GVT) effect that occurs after allogeneic BMT and PBSCT is crucial tothe effectiveness of the treatment. GVT occurs when white blood cells from the donor (the graft) identify the cancer cellsthat remain in the patient’s body after the chemotherapy and/or radiation therapy (the tumor) as foreign and attack them.BMT and PBSCT are most commonly used in the treatment of leukemia and lymphoma.To minimize potential side effects, doctors most often use transplanted stem cells that match the patient’s own stem cellsas closely as possible. People have different sets of proteins, called human leukocyte-associated (HLA) antigens, on thesurface of their cells. The set of proteins, called the HLA type, is identified by a special blood test.How is bone marrow obtained for transplantation? The stem cells used in BMT come from the liquid center of the bone, called the marrow. In general, the procedure for obtaining bone marrow, which is called “harvesting,” is similar for all three types of BMTs (autologous, syngeneic, and allogeneic). The donor is given either general anesthesia, which puts the person to sleep during the procedure, or regional anesthesia, which causes loss of feeling below the waist. Needles are inserted through the skin over the pelvic (hip) bone or, in rare cases, the sternum (breastbone), and into the bone marrow to draw the marrow out of the bone. Harvesting the marrow takes about an hour. The harvested bone marrow is then processed to remove blood and bone fragments. Harvested bone marrow can be combined with a preservative and frozen to keep the stem cells alive until they are needed. This technique is known as cryopreservation. Stem cells can be cryopreserved for many years. 1. How are PBSCs obtained for transplantation? The stem cells used in PBSCT come from the bloodstream. A process called apheresis orleukapheresis is used to obtain PBSCs for transplantation. For 4 or 5 days before apheresis, the donor may be given a medication to increase the number of stem cells released into the bloodstream. In apheresis, blood is removed through a large vein in the arm or a central venous catheter (a flexible tube that is placed in a large vein in the neck, chest, or groin area). The blood goes through a machine that removes the stem cells. The blood is then returned to the donor and the collected cells are stored. Apheresis typically takes 4 to 6 hours. The stem cells are then frozen until they are given to the recipient.
After being treated with high-dose anticancer drugs and/or radiation, the patient receives the stem cells throughan intravenous (IV) line just like a blood transfusion. This part of the transplant takes 1 to 5 hours.The major risk of both treatments is an increased susceptibility to infection and bleeding as a result of the high-dosecancer treatment. Doctors may give the patient antibiotics to prevent or treat infection. They may also give thepatient transfusions of platelets to prevent bleeding and red blood cells to treat anemia. Patients who undergo BMT andPBSCT may experience short-term side effects such as nausea, vomiting, fatigue, loss of appetite, mouth sores, hairloss, and skin reactions.Potential long-term risks include complications of the pretransplant chemotherapy and radiation therapy, suchas infertility (the inability to produce children); cataracts (clouding of the lens of the eye, which causes loss of vision);secondary (new) cancers; and damage to the liver, kidneys,lungs, and/or heart.With allogeneic transplants, GVHD sometimes develops when white blood cells from the donor (the graft) identify cells inthe patient’s body (the host) as foreign and attack them. The most commonly damaged organs are the skin, liver,and intestines. This complication can develop within a few weeks of the transplant (acute GVHD) or much later (chronicGVHD). To prevent this complication, the patient may receive medications that suppress the immune system.Additionally, the donated stem cells can be treated to remove the white blood cells that cause GVHD in a process called“T-cell depletion.” If GVHD develops, it can be very serious and is treated with steroids orother immunosuppressive agents. GVHD can be difficult to treat, but some studies suggest that patients with leukemiawho develop GVHD are less likely to have the cancer come back. Clinical trials are being conducted to find ways toprevent and treat GVHD.
Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation inwhich functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount animmunologic attack. It can also take place in a blood transfusion under certain circumstances.Clinically, graft-versus-host-disease is divided into acute and chronic forms. • The acute or fulminant form of the disease (aGVHD) is normally observed within the first 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality.  • The chronic form of graft-versus-host-disease (cGVHD) normally occurs after 100 days.Classically, acute graft-versus-host-disease is characterized by selective damage to the liver, skin and mucosa,and the gastrointestinal tract. Newer research indicates that other graft-versus-host-disease target organsinclude the immune system (the hematopoietic system—e.g. the bone marrow and the thymus) itself, andthe lungs in the form of idiopathic pneumonitis. Chronic graft-versus-host-disease also attacks the aboveorgans, but over its long-term course can also cause damage to the connective tissue and exocrine glands.Acute GVHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane,severe diarrhea, abdominal pain, nausea, and vomiting. This is typically diagnosed via intestinal biopsy. LiverGVHD is measured by the bilirubin level in acute patients. Skin GVHD results in a diffuse maculopapular rash,sometimes in a lacy pattern.Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. If the GVHD is severe andrequires intense immunosuppression involving steroids and additional agents to get under control, the patientmay develop severe infections as a result of the immunosuppression and may die of infection.Intravenously administered corticosteroids, such as prednisone, are the standard of care in acuteGVHD and chronic GVHDThe Graft-versus-Tumor EffectOne of the reasons that cancer cells can grow, multiply, and spread is that the body does not recognizethem as diseased but accepts them as "self." Immune system cells transplanted from a normal donorcan often recognize cancer cells -- particularly those of leukemia patients -- as diseased cells and go towork eliminating them. This phenomenon is called the graft-versus-leukemia or graft-versus-tumoreffect, and it is one of the reasons that allogeneic transplants can be curative.This effect appears to be most powerful in diseases that progress slowly, like chronic leukemia,low-grade lymphoma, and in some cases multiple myeloma, but it is less effective in the rapidlygrowing acute leukemias. In some patients who relapse after transplant, the disease-killingcapability of the donors white blood cells can be harnessed again, by infusing the patient withmore of the donors white blood cells through donor lymphocyte infusion.
Febrile neutropenia is the development of fever, often with other signs of infection, in a patientwith neutropenia, an abnormally low number of neutrophil granulocytes (a type of white blood cell) in the blood.The term neutropenic sepsis is also applied, although it tends to be reserved for patients who are less well.Fever is actually caused by infection in 50% of cases, and bacteremia (bacteria in the bloodstream) may bepresent in as many as 20% of all patients with an absolute neutrophil count under 1.0.Febrile neutropenia can develop in any form of neutropenia, but is most generally recognized as a complicationof chemotherapy when this is myelosuppressive (suppresses the bone marrow from producing blood cells).Generally, patients with febrile neutropenia are treated with empirical antibiotics until the neutrophil count hasrecovered and the fever has abated; if the neutrophil count does not improve, treatment may need to continuefor two weeks or occasionally more. Guidelines issued in 2002 by the Infectious Diseases Society ofAmerica recommend the use of particular combinations of antibiotics in specific settings; mild low-risk casesmay be treated with a combination of oral co-amoxiclav and ciprofloxacin, while more severe casesrequire cephalosporins with activity against Pseudomonas aeruginosa (e.g. cefepime),or carbapenems(imipenem or meropenemSepsis is a potentially serious medical condition that is characterized by a whole-body inflammatory state(called a systemic inflammatory response syndrome or SIRS) and the presence of a known orsuspected infection. The body may develop this inflammatory response by the immunesystem to microbes in the blood, urine, lungs, skin, or other tissues. A lay term for sepsis is blood poisoning,more aptly applied to septicemia, below. Severe sepsis is the systemic inflammatory response, plus infection,plus the presence of organ dysfunction.Severe sepsis occurs when sepsis leads to organ dysfunction, such as trouble breathing, coagulation or otherblood abnormalities, decreased urine production, or altered mental status). If the organ dysfunction of severesepsis is low blood pressure (hypotension), or insufficient blood flow (hypoperfusion) to one or more organs(causing, for example, lactic acidosis), this is septic shock.Sepsis can lead to multiple organ dysfunction syndrome (MODS) (formerly known as multiple organ failure),and death. Organ dysfunction results from local changes in blood flow, from sepsis-induced hypotension (<90 mmHg or a reduction of ≥ 40 mmHg from baseline) and from diffuse intravascular coagulation, among otherthings.Sepsis can be defined as the bodys response to an infection. An infection is caused by microorganisms orbacteria invading the body and can be limited to a particular body region or can be widespread in thebloodstream. Sepsis is acquired quickest with infections developed in surgery and physical contact withsomeone with sepsis.Septic shock. Defined as sepsis with refractory arterial hypotension or hypoperfusion abnormalities in spite ofadequate fluid resuscitation. Signs of systemic hypoperfusion may be either end-organ dysfunction or serumlactate greater than 4 mmol/dL. Other signs include oliguria and altered mental status. Patients are defined ashaving septic shock if they have sepsis plus hypotension after aggressive fluid resuscitation (typically upwardsof 6 liters or 40 ml/kg of crystalloid).Leukocyte growth factors are natural molecules which are responsible for the proliferation anddifferentiation of normal blood stem cells. They can nowadays be massively produced by geneticengineering, however their cost remains high.First generationG-CSF (Neupogen™, Granocyte™) and GM-CSF (Leucomax™) growth factors comprisedthe first generation of leukocyte growth factors. Their prescription (at least in France) wasstrictly regulated.
It has been proven that they reduce the duration of leukopenia, but not its intensity, hencereducing the infectious risks related to such duration.Growth factors called colony-stimulating factors, which stimulate the production of white blood cells, aresometimes helpful.Bone marrow (or stem cell) transplantation is not used to treat neutropenia per se, but it may be recommendedto treat certain serious causes of neutropenia, such as aplastic anemia or leukemia.
Disseminated intravascular coagulation is a condition in which small blood clots develop throughoutthe bloodstream, blocking small blood vessels and depleting. The increased clotting depletes theplatelets and clotting factors needed to control bleeding, causing excessive bleeding. • There are a number of possible causes, including infection and surgery. • Excessive clotting is followed by excessive bleeding. • The number of clotting factors in the blood is measured. • The underlying disorder is treated.Disseminated intravascular coagulation (DIC) begins with excessive clotting. The excessive clotting is usuallystimulated by a substance that enters the blood as part of a disease (such as an infection or certain cancers) oras a complication of childbirth, retention of a dead fetus, or surgery. People who have a severe head injury orwho have been bitten by a poisonous snake are also at risk. As the clotting factors and platelets are depleted,excessive bleeding occurs.Symptoms and DiagnosisDIC that develops suddenly usually causes bleeding, which may be very severe. If the condition follows surgeryor childbirth, bleeding may be uncontrollable. Bleeding may occur at the site of an intravenous injection or in thebrain, digestive tract, skin, muscles, or cavities of the body.If DIC develops more slowly, as in people with cancer, then clots in veins are more common than bleeding.Blood tests may show that the number of platelets in a blood sample has dropped and that the blood is taking along time to clot. The diagnosis of DIC is confirmed if test results show diminished amounts of clotting factorsand large quantities of proteins that are produced when clots are broken up by the body (fibrin degradationproducts).TreatmentThe underlying cause must be identified and corrected, whether it is an obstetric problem, an infection, or acancer. The clotting problems subside when the cause is corrected.DIC that develops suddenly is life threatening and is treated as an emergency. Platelets and clotting factors aretransfused to replace those depleted and to stop bleeding. Heparin may be used to slow the clotting in peoplewho have more chronic, milder DIC in which clotting is more of a problem than bleeding.Thrombocytopenia (thrombopenia in short) is the presence of relatively few platelets in blood.Generally speaking, in human beings a normal platelet count ranges from 150,000 to 450,000 platelets permicroliter of blood.Often, low platelet levels do not lead to clinical problems; rather, they are picked up on a routine full bloodcount (or CBC, complete blood count). Occasionally, there may be bruising, particularly purpura in theforearms, petechia (pinpoint hemorrhages on skin and mucous membranes), nosebleeds and/orbleeding gums.Often occurs in Leukemia or myelodysplastic syndromeMedication-inducedThrombocytopenia-inducing medications include: • Direct myelosuppression • Valproic acid • Methotrexate • Carboplatin • Interferon • Isotretinoin
Infections are among the most common, potentially serious complications of cancer and its treatment.INFECTION DURING FEBRILE NEUTROPENIAIt has long been recognized that the incidence of infection is high in patients who develop a fever during neutropenia andthat empiric antimicrobial therapy is warranted in such patients.Neutropenia is defined as a neutrophil count of < 500/μL, although patients with a neutrophil count between 500 and1,000/μL in whom a decrease is anticipated are considered to be neutropenic. Patients with a neutrophil count < 100/μLare at greatest risk for infection, as are those with a rapid decrease in neutrophil count and those with protractedneutropenia.Bacteria Infections occurring during episodes of febrile neutropenia are caused predominantly by aerobic gram-negativebacilli (especially Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) and gram-positive cocci(coagulase-negative staphylococci, β-hemolytic streptococci, viridans streptococci, enterococci, and Staphylococcusaureus). In recent years, multidrug-resistant organisms have become more prominent.Fungi Fungal infections usually occur after a patient has received broad-spectrum antimicrobial therapy and/or steroids.The most common fungal pathogens are Candida species (predominantly C albicans and C tropicalis)and Aspergillus species. Less common are Fusarium, Scedosporium, and Zygomycetes infections (see also section on“Fungal infections”).Viruses Viral infections occurring during neutropenia are caused predominantly by herpesviruses and respiratory viruses.The herpesviruses include herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), andEpstein-Barr virus (EBV). The respiratory viruses include adenovirus, respiratory syncytial virus, parainfluenza virus,influenza A and B viruses, metapneumovirus, and rhinovirus (see also section on “Viral infections”).Signs and symptomsThe most remarkable aspect of the febrile, neutropenic patient is the lack of physical findings. This is due to theneutropenia and the absence of an inflammatory response at the infection site. The patient may have only a fever with orwithout chills or rigors. Even if the patient has pneumonia, there may be few respiratory symptoms. Likewise, a perirectalabscess may be relatively asymptomatic.DiagnosisAn initial evaluation and diagnostic work-up of any fever in a neutropenic patient should begin immediately but should notdelay the initiation of empiric therapy (see below). A complete history (exposures, past infections, rashes, cough,abdominal pain, diarrhea) should be taken and a physical examination (skin lesions, exit site and tunnel of right atrialcatheter, oropharynx, abdomen, perineum) should be performed.Diagnostic workup should include:• at least two sets of blood cultures: one from a peripheral vein and one from each port of a central venous catheter. Iffever persists in the face of negative cultures, blood cultures for fungi and acid-fast bacilli should be considered.• culture of any drainage from a catheter exit site• stool examination for Clostridium difficile and other bacterial/protozoal agents• urine culture and urinalysis• chest radiograph
• aspiration or biopsy of any skin lesions.CT If indicated by signs or symptoms, CT scans of the brain (followed by lumbar puncture), chest, abdomen, and pelviscan be performed.Laboratory tests Determination of serum transaminases, CBC, and serum creatinine is also recommended. Otheruseful serologies include Aspergillus galactomannan, beta-D-glucan, Coccidioides antibody panel, and histoplasmosisantigen, depending on the region.Pneumocystis pneumonia (PCP) or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus (which had previously been erroneously classified as a protozoan) Pneumocystis jirovecii.The disease PCP is relatively rare in people with normal immune systems, but common among people withweakened immune systemsThe diagnosis can be confirmed by the characteristic appearance of the chest x-ray which shows widespreadpulmonary infiltrates, and an arterial oxygen level (pO2) strikingly lower than would be expected fromsymptoms. The diagnosis can be definitively confirmed by histological identification of the causative organismin sputumor bronchio-alveolar lavage (lung rinse).Antipyretics (literally "against the fire") are drugs that reduce fever ibuprofen and aspirin, which are used primarily as pain relievers. Non-steroidal anti-inflammatorydrugs(NSAIDs) are antipyretic, anti-inflammatory, and pain relievers. There is some debate over the appropriateuse of such medications, as fever is part of the bodys immune response to infection.
Pathophysiology of Nausea and VomitingThe vomit center receives input from four major areas: the GI tract, the chemoreceptor trigger zone,the vestibular apparatus, and the cerebral cortex. (The center also has intrinsic chemoreceptors thatcan modulate, stimulate, and repress nausea.) 2,3 Each of these four areas responds to certain typesof stimuli, modulated by specific neurotransmitters that bind specific receptors. Understanding howthese areas modulate nausea and vomiting helps us tailor specific therapies for specific problems.The GI tractAs the primary source of toxin absorption is the gut, the effect of the GI tract on the vomit center is complex.Stimulation of the gut chemoreceptors and stretch receptors triggers nausea and vomiting via vagal nerveafferents and afferent fibers associated with the sympathetic nervous system. Serotonin, acetylcholine,histamine, and substance P are major neurotransmitters involved in stimulating these receptors.Chemoreceptors in the gut appear to be major mediators of the toxic effect of certain chemotherapeuticagents, such as cisplatin, even when such drugs are given intravenously via binding to 5HT 3 receptors. Inaddition to being a neurotransmitter that stimulates nausea, acetylcholine also increases gut motility and gutsecretion. Histamine mediates transmission of nausea via the vagus nerve. Substance P binds neurokinin 1receptors in the gut (and directly in the vomit center in the brain). 4,5The chemoreceptor trigger zone (CTZ)The CTZ senses chemicals in the blood. The CTZ is particularly sensitive to increasing blood levels ofpotentially toxic substances. If a toxic substance is detected, nausea is experienced and the vomit reflexinitiated - hopefully before more toxin is absorbed. It is easy to understand the evolutionary advantage ofsuch a failsafe. The brain detects an "alien" chemical. By itself, this is not so unusual - we have lots ofpeculiar non-self chemicals floating around in our bloodstreams. However, if the concentration of a chemicalis rapidly rising, this could constitute a threat to our health - better to expel any residual substance in thestomach; better safe than dead. Two major neurotransmitters are involved - dopamine, acting onD2 receptors, and serotonin, acting on 5HT 3 receptors. Different toxin responses are mediated throughdifferent neurotransmitters. Opioid-related nausea appears to be most related to stimulation of D 2 receptors.Understanding this has helped with selective blockage of specific receptors in specific disorders.The vestibular apparatusMotion and body position are sensed through the vestibular apparatus. Motion sickness, such as carsickness and seasickness, are mediated through the vestibular apparatus, as are inner-ear diseases, suchas Menieres disease. The vestibular apparatus may once have served as a sensor for certain neurotoxins(such as alcohol) that can produce disequilibrium. Stimulation of the vestibular apparatus by alcohol mayprovide a survival advantage in keeping our species from, literally, drinking ourselves to death. Stimulus ofthe vestibular apparatus is mediated largely through histamine and acetylcholine receptors.The cerebral cortexThe cerebral cortex and associated structures in the limbic system modulate complex experiences such astaste, sight, and smell as well as memory (involved in anticipatory nausea) and emotion. Discreteneuropathways are less well understood. However, higher cortical effects are still important and can beextremely powerful in stimulating and suppressing nausea and vomiting.Chemotherapy-induced nausea and vomiting can be broadly categorized as acute(occurring within 24 hours of therapy), delayed (persisting for 6–7 days after therapy), oranticipatory (occurring prior to chemotherapy administration). Breakthrough and refractorynausea and vomiting describe the symptoms of uncontrolled emesis.The 5-HT3-receptor antagonists, regarded as the ‘gold standard’ in antiemetic therapy, are thefirst-line treatment for moderately and highly emetogenic chemotherapy
A class of drugs called 5-HT3 antagonists are the most effective antiemetics and constitute the single greatestadvance in the management of nausea and vomiting in patients with cancer. These drugs block one or more ofthe nerve signals that cause nausea and vomiting. During the first 24 hours after chemotherapy, the mosteffective approach appears to be blocking the 5-HT3 nerve signal. Approved 5-HT3 inhibitorsincludedolasetron, granisetron, and ondansetron (Zofran). The newest 5-HT3 inhibitor, palonosetron, alsoprevents delayed nausea and vomiting, which occurs during the 2–5 days after treatment. Since some patientshave trouble swallowing pills, these drugs are often available by injection, as orally disintegrating tablets, oras transdermal patchs.
Mucositis is a medical term that is used to refer to mouth sores, oral mucositis, or esophagitis. It can range in severityfrom a red, sore mouth and/or gums to open sores that can cause a patient to be unable to eat. The lining of the entiregastrointestinal tract (mouth, throat, stomach, and bowel) is made up of epithelial cells, which divide and replicate rapidly.Imagine this: if you bite your lip, the tissue is often able to heal by the next day because of this rapid growth.Chemotherapy and radiation therapy kill not only cancer cells, but other rapidly dividing cells as well, including the liningof the entire gastrointestinal tract. This article will discuss the effects on the lining of the mouth and throat (this lining iscalled the mucosa).Oral mucositis leads to several problems, including pain, nutritional problems as a result of inability to eat, andincreased risk of infection due to open sores in the mucosa. It has a significant effect on the patientÃ•s quality oflife and can be dose- limiting (requiring a reduction in subsequent chemotherapy doses).Signs and symptoms of mucositis include: Red, shiny, or swollen mouth and gums Blood in the mouth Sores in the mouth or on the gums or tongue Soreness or pain in the mouth or throat Difficulty swallowing or talking Feeling of dryness, mild burning, or pain when eating food Soft, whitish patches or pus in the mouth or on the tongue Increased mucus or thicker saliva in the mouthWho gets mucositis?Over forty percent of patients who receive chemotherapy will develop some degree of mucositis during the courseof their treatment. Patients receiving radiation to the head, neck, or chest areas, and patients who undergo bonemarrow or stem cell transplant, are even more likely to develop mucositis. Certain chemotherapy agents are morelikely to cause this side effect (Table 1), as is total body irradiation, often used for bone marrow transplants.Table 1: Chemotherapy agents known to cause mucositisAlemtuzumab (Campath) Bleomycin (Blenoxane) Asparaginase (Elspar)Cyclophosphamide Cytarabine (Cytosar-U) Busulfan (Myleran,(Cytoxan) Busulfex)Docetaxel (Taxotere) Doxorubicin Capecitabine (Xeloda) (Adriamycin)Fluorouracil (5-FU) Gemcitabine (Gemzar) Carboplatin (Paraplatin)Gemtuzumab ozogamicin Hydroxyurea (Hydrea) Daunorubicin(Mylotarg) (Cerubidine)Idarubicin (Idamycin) Interleukin 2 Epirubicin (Ellence) (Proleukin)Lomustine (CeeNU) Melphalan (Alkeran) Etoposide (VePesid)Mitomycin (Mutamycin) Mitoxantrone Irinotecan (Novantrone) (Camptosar)Oxaliplatin (Eloxatin) Paclitaxel (Taxol) Methotrexate (Rheumatrex)Pentostatin (Nipent) Procarbazine Mechlorethamine (Matulane) (Mustargen)Topotecan (Hycamtin) Trastuzumab Pemetrexed (Alimta) (Herceptin)Vinblastine (Velban) Vincristine (Oncovin) Thiotepa (Thioplex)Tretinoin (Vesanoid)Chemotherapy often causes hair loss otherwise known as Alopecia. This is because the cells in the hair folliclesgrow fast and chemotherapy damages fast growing cells. (see what is chemotherapy). Hair loss is not permanentand it will grow back once your treatment has ended. Not all drugs cause hair loss - Some just cause thinning and
others cause dramatic hair loss including the body hair and eye brows. Furthermore, different people havedifferent tolerances to the drugs.
Malnutrition:The World Health Organization defines malnutrition as "the cellular imbalance between supply of nutrients andenergy and the bodys demand for them to ensure growth, maintenance, and specific functions.In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterised by loss of lean bodymass, muscle wasting, and impaired immune, physical and mental function. Cancer cachexia is also associated withpoor response to therapy, increased susceptibility to treatment-related adverse events, as well as poor outcome andquality of life.Indications for nutritional support:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1434612/?page=1A feeding tube is a medical device used to provide nutrition to patients who cannot obtain nutrition byswallowing.asogastricA nasogastric feeding tube, or "NG-tube", is passed through the nares (nostril), down the esophagus and intothe stomach. Gastric feeding tubeA gastric feeding tube (or "G-tube," or "button") is a tube inserted through a small incision in the abdomen intothe stomach and is used for long-term enteral nutrition. One type is the percutaneous endoscopicgastrostomy (PEG) tube. It is placed endoscopically: the patient is sedated and an endoscope is passedthrough the mouth and esophagus into the stomach. The position of the endoscope can be visualized on theoutside of the patients abdomen because it contains a powerful light source. A needle is inserted through theabdomen, visualized within the stomach by the endoscope, and a suture passed through the needle is graspedby the endoscope and pulled up through the esophagus. The suture is then tied to the end of the PEG tube thatwill be external, and pulled back down through the esophagus, stomach, and out through the abdominal wall.The insertion takes about 20 minutes. The tube is kept within the stomach either by a balloon on its tip (whichcan be deflated) or by a retention dome which is wider than the tract of the tube.Gastric tubes are suitable for long-term use; they last about six months, and can be replaced through anexisting passage without an additional endoscopic procedure. The G-tube is useful where there is difficulty withswallowing because of neurologic or anatomic disorders (stroke, esophageal atresia, tracheoesophagealfistula), and to avoid the risk of aspiration pneumonia. It is also used when patients are malnourished andcannot take enough food by mouth to maintain their weight, such as with mitochondrial disease and short bowelsyndrome.Feed preparationsVarious nutritionally complete pre-packaged feeds are available: • Standard enteral feeds: • These contain all the carbohydrate, protein, fat, water, electrolytes, micronutrients (vitamins and trace elements) and fibre required by a stable patient. • "Pre-digested" feeds: • These contain nitrogen as short peptides or free amino acids and aim to improve nutrient absorption in the presence of pancreatic insufficiency or inflammatory bowel disease. • The fibre content of feeds is variable and some are supplemented with vitamin K, which may interact with other medications.
Parenteral nutrition (PN) is feeding a person intravenously, bypassing the usual processof eating and digestion. The person receives nutritional formulas that contain nutrients suchas salts, glucose, amino acids, lipids and added vitamins. It is called total parenteral nutrition or totalnutrient admixture (TPN or TNA) when no food is given by other routes.Parenteral nutrition is indicated to prevent the adverse effects of malnutrition in patients who are unable toobtain adequate nutrients by oral or enteral routes. Other indications are short gut syndrome, high-outputfistula, prolonged ileus, or bowel obstruction.The nutrient solution consists of water and electrolytes; glucose, amino acids, and lipids; essential vitamins,minerals and trace elements are added or given separately. Previously lipid emulsions were given separatelybut it is becoming more common for a "three-in-one" solution of glucose, proteins, and lipids to be administeredThe preferred method of delivering PN is with a medical infusion pump. A sterile bag of nutrient solution,between 500 mL and 4 L, is provided. The pump infuses a small amount (0.1 to 10 mL/hr) continuously in orderto keep the vein open. Feeding schedules vary, but one common regimen ramps up the nutrition over one hour,levels off the rate for a few hours, and then ramps it down over a final hour, in order to simulate a normalmetabolic response resembling meal time. This should be done over 12 to 24 hours rather than intermittentlyduring the day.Chronic PN is performed through a central intravenous catheter, usually through the subclavian or jugularvein with the tip of the catheter at the superior vena cava without entering the right atrium. Another commonpractice is to use a PICC line, which originates in the arm, and extends to one of the central veins, such as thesubclavian with the tip in the superior vena cava.
Organ toxicity of oncological therapy:Cardiotoxicity:The anthracyclines are perhaps the most notorious offenders. Acute reactions include chest discomfort and shortness ofbreath consistent with a myopericarditis. Toxicity can also develop months after the last chemotherapy dose and typicallypresents as new onset heart failure with left ventricular systolic dysfunction. Late reactions are seen years afterpresentation as new-onset cardiomyopathy, often in patients who were treated for childhood neoplasms. 5-Fluorouracil,its prodrug capecitabine, and trastuzumab, a tumor-specific antibody, have also been associated with cardiotoxicity.Nephrotoxicity is one of the most common kidney problems and occurs when your body isexposed to a drug or toxin that causes damage to your kidneys. When kidney damage occurs,you are unable to rid your body of excess urine, and wastes. Your blood electrolytes (such aspotassium, and magnesium) will all become elevated.Nephrotoxicity can be temporary with a temporary elevation of lab values (BUN and/or creatinine). If theselevels are elevated, these may be due to a temporary condition such as dehydration or you may be developingrenal (kidney failure). If the cause of the increased BUN and/or creatinine levels is determined early, and yourhealthcare provider implements the appropriate intervention, permanent kidney problems may be avoided.Chemotherapy drugs such as: Cisplatin, Carboplatin, Carmustine, Mitomycin, high-dose Methotrexate.• Biologic therapy such as Interleukin-2, or Interferon Alfa.HepatotoxictyToxic liver injury can reproduce virtually any known pattern of injury, including necrosis,steatosis, fibrosis, cholestasis, and vascular injuryAlkylating agents e.g. chlorambucil, cyclophosphamideAntimetabolites: 6-mercaptopurine (6-MP), methotrexate.The antitumor antibiotics include doxorubicin, daunorubicin, mitoxantrone, bleomycin,mitomycin, mithramycin (plicamycin),and dactinomycin.NeurotoxicityNeurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy.Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome withgrowth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases therisk of neurotoxicity. Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheralneuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or evencoma. In this article we describe the neurological adverse effects of the most commonly used chemotherapeutic agents.The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity.These drugs are widely used for various malignancies such as ovarian and breast cancer, and haematological cancers.Chemotherapy-induced neuropathy is clearly related to cumulative dose or dose-intensities. Patients who already haveneuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxicchemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy.Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily known for their central neurotoxic sideeffects. Central neurotoxicity ranges from acute toxicity such as aseptic meningitis, to delayed toxicities comprisingcognitive deficits, hemiparesis, aphasia and progressive dementia.Pulmonary toxicity:Pulmonary (lung) toxicity occurs when you are exposed to a chemical or an agent that causesdamage to your lungs. You may develop a mild or severe form of pulmonary toxicity. Pulmonarytoxicity may be described as:• A form of lung fibrosis or pneumonitis (inflammation of the lung)• A form of non-heart related pulmonary edema (swelling in your lungs)
• A sudden onset or occurrence of being overly sensitive (hypersensitive) to your chemotherapy or radiation therapyAntitumor antibiotics - Such as bleomycin and mitomycin are the most common drugs thatcause pulmonary toxicity. Your risk may increase if you are over 70 years of age, and had priorradiation to your chest area.• Antimetabolites- such as methotrexate - have been known to cause pulmonary toxicity.• Alkylating agents - such as busulfan have been known to cause pulmonary toxicity• Nitrosoureas - such as BCNU or carmustine have been known to cause pulmonary toxicity• Vinca Alkaloids - such as vincristine sulfate - may cause pulmonary toxicity if used in combination with mitomycin