Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Cancer Manifestations and Treatment Cancer Epidemiology Chapter 9 & 10

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Manifestations of Cancer  Clinical manifestations of cancer include:  Pain  Fatigue  Cachexia  Anemia  Leukopenia  Thrombocytopenia  Infection

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Pain  Little or no pain is associated with early stages of malignancy. Most occurs in late stages.  Influenced by fear, anxiety, sleep loss, fatigue, and overall physical deterioration.  It occurs as a result of the interaction among psychogenic, cultural, and physiologic components.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Pain Mechanisms:  Pressure  Obstruction  Invasion of sensitive structures like bone  Stretching of visceral surfaces  Tissue destruction  Inflammation with associated pain- inducing chemicals

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Pain  Adequate pain control is important therapeutic goal; based on continual evaluation of pain as reported by the individual.  Treatments include anti-inflammatory drugs, local anesthesia, and opiods (like morphine).

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Fatigue  Fatigue is the most frequently reported symptom of cancer and cancer treatment.  Subjective clinical manifestations, including:  Tiredness, weakness, lack of energy, exhaustion, lethargy, inability to concentrate, impaired intellectual performance, depression, mood swings, sleepiness, boredom, and lack of motivation.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Fatigue May be caused by a variety of mechanisms:  Disease processes – metabolic disturbances, neuromuscular dysfunction from circulating cytokines (TNF-alpha and interleukin-1), and side effects of treatment.  Secondary effects - sleep disturbance, chronic stress, age, psychosocial factors, level of activity, nutritional status, and environmental factors.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Cachexia  Most severe form of malnutrition.  Present in 80% of cancer patients at death.  Includes:  Anorexia, loss of appetite, early satiety, weakness, inability to maintain weight, anemia, taste alterations, and altered protein, lipid, and carbohydrate metabolism.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Cachexia

Cachexia  Leads to protein-calorie malnutrition and progressive wasting, similar to Kwashiorkor.  Altered carbohydrate metabolism causes a syndrome resembling diabetes mellitus.  Basal metabolic rate increases in some cancers, which accelerates weight loss.  This increase is caused by cytokines such as TNF-alpha (also called cachectin), IL-1, IL-6, and interferons.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Anemia  Anemia is a decrease of hemoglobin in blood.  Mechanisms:  Malnutrition, chronic bleeding and resultant iron deficiency, decreased secretion of erythropoietin, chemotherapy, and malignancies in the blood-forming organs.  Synthetic erythropoietin (Procrit) can increase hematocrit in cancer patients.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Leukopenia and Thrombocytopenia  Leukopenia – decreased leukocyte count; increases infection risk.  Thrombocytopenia – decreased platelet count; increases risk of hemorrhage.  Both caused by direct tumor invasion to the bone marrow.  Also triggered by chemotherapy, which is toxic to bone marrow, or radiation, which kills circulating leukocytes.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Infection  Most significant cause of complications and death in persons with malignant disease.  Infection may be caused by leukopenia, immunosuppression, or debility from advanced disease.  Risk increases when the absolute neutrophil and lymphocyte counts fall.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Paraneoplastic Syndromes  Symptom complexes that are not caused by the direct local effects of the tumor mass.  Most commonly caused by biologic substances released by the tumor, like hormones, or by an immune response triggered by the tumor.  Paraneoplastic syndromes are rare but significant because they:  May be the earliest symptom of an unknown cancer.  May represent serious and life-threatening problems.  May mimic progression and therefore interfere with appropriate treatment.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Cancer Treatment  Cancer is treated with:  Surgery  Radiotherapy  Chemotherapy  Combinations of these modalities.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Chemotherapy  Use of nonselective cytotoxic drugs that target vital cellular machinery or metabolic pathways critical to both malignant and normal cell growth and replication.  Targets any rapidly dividing cell.  Goal – eliminate enough tumor cells so the body’s defense can eradicate any remaining cells.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Chemotherapy  Single-agent chemotherapy –  Significant early response rates  Duration short lived because malignant cells develop resistance.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Chemotherapy Resistance

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Chemotherapy  Combination chemotherapy – synergistic use of several agents, each of which individually has an effect against a certain cancer process.  Primary rationale to this approach is to avoid single-agent drug resistance.  Allows use of lower doses of each drug so the harmful effects to normal cells may be reduced.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Chemotherapy  Principle of dose intensity – direct correlation between dose of a chemotherapeutic agent and killing of tumor cells (killing increases with increased dose). However, toxicity also increases.  Therapeutic index – the relative effective dose needed to kill cancer cells as compared to the dose that would be harmful to normal cells; generally quite low; limiting factor in use of chemotherapy.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Chemotherapy  Adjuvant chemotherapy – used after local treatment or removal of the primary tumor.  Useful in individuals who are at high risk for metastasis.  Prevents the growth of micrometastatic deposits that are not clinically detectable at diagnosis.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Radiation Therapy  Goals:  Eradicate cancer without excessive toxicity  Avoid damage to normal structures  Ionizing radiation damages the cancer cell’s DNA  May be used in conjunction with chemotherapy.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Surgery  Surgical therapy is used for nonmetastatic disease, for which cure is possible by removing the tumor, and as a palliative measure to alleviate symptoms caused by malignant masses.  Biopsy and lymph node sampling – often begins the treatment process, aids in staging the disease.  Sentinel nodes - lymph nodes that are first to receive drainage from any given location; sampling these allows less invasive tumor staging.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Surgery  Debulking surgery – majority of the tumor is removed, thereby allowing for increased success of adjuvant chemotherapy or irradiation. Used when tumor cannot be completely removed.  Palliative surgery – used to relieve current symptoms or prevent or delay anticipated symptoms as the tumor grows.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Surgery  Benign or premalignant growths – are surgically removed to prevent damage due to growth of tumor or progression to malignancy.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. ACTIVITY - Choices a. kills cancer cells left after surgery b. stimulates immune system c. specific antibodies against tumor antigens d. facilitates adjuvant chemotherapy or radiation e. direct application of ionizing energy

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. ACTIVITY 1. Radiation 2. Palliative surgery 3. Combination chemotherapy 4. Adjuvant chemotherapy 5. Debulking surgery

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. CHAPTER 10 Gene-Environment Interaction and Risk Factors  Cancer occurs in genes, but two-thirds of all cancers are caused by environmental/lifestyle factors interacting with genes.  Carcinogens - environmental agents that can cause cancer.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Epigenetics and Genetics  Epigenetics—change in genetic expression (phenotype) without DNA mutation (e.g., DNA methylation).  Usually involves factors that silence genes that should be active or activate genes that should be silent.  Genetics, epigenetics, and environmental factors interact to cause cancer.  Epigenetic processes can be influenced by environment/lifestyle including in utero.

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Tobacco Use  Cigarette smoke - most important cause of cancer.  Responsible for 30% of all cancer deaths in developed countries.  Associated primarily with squamous and small cell carcinomas of the lung and pulmonary adenocarcinomas.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Tobacco Use  Also linked to cancers of the lower urinary tract, upper respiratory and upper digestive tract, liver, kidney, pancreas, cervix, and myeloid leukemia.  Environmental tobacco smoke (ETS) or secondhand smoke has also been linked to lung cancer.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Diet  May account for 30% of the overall risk factors for cancer.  Xenobiotics - toxic, mutagenic, and carcinogenic chemicals in food. Examples:  Compounds produced in the cooking of fat, meat, or proteins (nitrosamines)  Alkaloids or mold by-products (including aflatoxin).

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Diet  May influence epigenetics.  Research ongoing regarding vitamin influence.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Diet  Foods that decrease cancer risk:  Fruits/vegetables; fiber; foods containing vitamins A, B6, C, D, E, and folate; whole grains; lycopene; legumes/nuts.  Foods that increase cancer risk:  Fat (especially large amounts of omega-6 fatty acids); high-glycemic-index carbohydrates; refined grain products; foods with high amounts of preservatives; alcohol; grilled, blackened foods; fried foods; high levels of calcium (≥2000 mg).

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Obesity  Correlates with high body mass index (BMI).  High BMI is associated with higher rates of death from esophageal, stomach, colorectal, liver, breast, gallbladder, pancreatic, prostate, kidney, and cervical cancers; non-Hodgkin lymphoma; multiple myeloma; and leukemia.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Weight and Cancer Risk

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Obesity  Proposed mechanisms:  Adipose tissue is an active endocrine and metabolic tissue.  In response to endocrine and metabolic signaling, adipose tissue releases free fatty acids.  Increased release of free fatty acids, resistin, TNF- α, and reduced release of adiponectin give rise to insulin resistance and causes chronic hyperinsulinemia.

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Obesity  Mechanisms (cont.):  High insulin levels promote the activity of insulin- like growth factor–1 (IGF-1), which regulates cell proliferation and inhibits apoptosis  Insulin promotes the synthesis and biologic availability of female and male sex hormones.  Adipose tissue cells produce steroid-hormone- metabolizing enzymes and are an important source of estrogens in postmenopausal women.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Alcohol Consumption  Chronic alcoholism is a strong risk factor for oral cavity, pharynx, hypopharynx, larynx, esophagus, and liver cancers  It is less strongly related to breast cancer and colorectal cancer; however, breast carcinogenesis can be enhanced with relatively low daily amounts.  Cigarette/alcohol combination increases a person’s risk for smoking-related cancers.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Ionizing Radiation  Health risks from ionizing radiation involve cancer and birth defects and eye maladies.  The most common cancers from ionizing radiation are acute leukemias (adults and children); thyroid and breast carcinomas.  Due to emissions from x-rays, radioisotopes, and other radioactive sources.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Ionizing Radiation  Exposure causes cell death, gene mutations, and chromosome aberrations.  Mutations in germ cells are heritable.  Increased use of diagnostic testing of concern.  CT scans provide 50 times more radiation to stomach than an x-ray.

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Ionizing Radiation  Bystander effects - chromosome aberrations and mutations may occur not only in the descendants of irradiated cells but in other cells not directly irradiated.  Low levels of radiation can induce bystander effects and genomic instability. Both findings appear to be associated with oxidative stress and cell-to-cell intercellular communication.

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Ultraviolet Radiation  Causes basal cell carcinoma, squamous cell carcinoma, and melanoma.  Principal source is sunlight.  Also overuse of tanning beds  Number 1 solar risk factor is sporadic exposure, resulting in burns.  Promotes skin inflammation and release of free radicals and TNF-alpha.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Ultraviolet Radiation  Skin carcinogenesis from UV light involves reactive oxygen species (ROS) (oxidative stress).  UV radiation is now known to cause specific gene mutations.

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Sexual and Reproductive Behavior  Sexually transmitted infection with high-risk types of HPV is required for the development of virtually all cervical cancers (99.7%).  Vaccines against the high-risk types of HPV prevent infection and subsequent cancer.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Physical Activity  Reduces the risk of breast and colon cancers and may reduce the risk of other cancers.  Decreases insulin and insulin-like growth factors  Decreases obesity  Decreases inflammatory mediators and free radicals  Increased gut motility

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Occupational Hazards  A substantial percentage of cancers of the upper respiratory passages, lung, bladder, and peritoneum are attributed to occupational factors.  Occupational carcinogenic agents include:  Dyes, rubber, paint, explosives, rubber cement, heavy metals, air pollution  Asbestos  Arsenic  Radon

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Occupational Hazards  Asbestos – increases risk of mesothelioma and lung cancer.  Arsenic – found in drinking water in some areas. Increases risk of skin, lung, and bladder cancers.  Radon – natural radioactive gas; primarily increases risk of bronchogenic lung cancer.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Occupational Hazards  Air pollution is a concern in regard to cancer because of inhalation of emissions, including arsenicals, benzene, chloroform, vinyl chloride, and acrylonitrile.  Indoor pollution is considered worse than outdoor pollution because of cigarette smoke, cooking fumes and radon gas.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. ACTIVITY - Choices a. Tobacco use b. Ionizing radiation c. UV radiation d. Diet e. Obesity f. Alcohol g. Sexual behavior h. Physical activity i. Occupational hazards

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. ACTIVITY 1. Includes air pollution exposure. 2. Causes alteration of hormones like insulin. 3. Harms cells directly and thru bystander effects. 4. Factor responsible for most cancer deaths. 5. Risk is due to transmission of viruses.

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. ACTIVITY 6. Risk is associated with xenobiotic intake. 7. Causes formation of reactive oxygen species. 8. Associated with throat and liver cancers. 9. An increase in this lessens cancer risk.