Cancer Manifestations and Treatment Cancer Epidemiology Chapter 10 & 11

Clinical Manifestations of Cancer Clinical manifestations of cancer include: Pain Fatigue Cachexia Anemia Leukopenia Thrombocytopenia Infection

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.

Pain Mechanisms: Pressure Obstruction Invasion of sensitive structures like bone Stretching of visceral surfaces Tissue destruction Inflammation with associated pain-inducing chemicals

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).

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.

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.

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.

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.

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.

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.

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.

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.

Cancer Treatment Cancer is treated with: Surgery Radiotherapy Chemotherapy Combinations of these modalities.

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.

Chemotherapy Single-agent chemotherapy – Significant early response rates Duration short lived because malignant cells develop resistance.

Chemotherapy Resistance

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.

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.

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.

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.

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.

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.

Surgery Benign or premalignant growths – are surgically removed to prevent damage due to growth of tumor or progression to malignancy.

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

ACTIVITY 1. Radiation 2. Palliative surgery 3. Combination chemotherapy 4. Adjuvant chemotherapy 5. Debulking surgery

CHAPTER 11 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.

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.

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.

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.

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).

Diet May influence epigenetics. Research ongoing regarding vitamin influence.

Diet Foods that decrease cancer risk: Foods that increase 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).

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.

Weight and Cancer Risk

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.

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.

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.

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.

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.

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.

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.

Ultraviolet Radiation Skin carcinogenesis from UV light involves reactive oxygen species (ROS) (oxidative stress). UV radiation is now known to cause specific gene mutations.

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.

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

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

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.

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.

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

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.

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.