Applied Therapeutics 1 Lec.1 Lecture Notes PDF

Therapeutics Fifth Stage Cancer chemotherapy & treatment Dr. Ali Al-Athari Cancer chemotherapy & treatment Cancer (neoplasm, tumor, or malignancy) is a group of diseases (more than 100 disease characterized by uncontrolled cellular growth, tissue infiltration, and spr...

Therapeutics Fifth Stage Cancer chemotherapy & treatment Dr. Ali Al-Athari Cancer chemotherapy & treatment Cancer (neoplasm, tumor, or malignancy) is a group of diseases (more than 100 disease characterized by uncontrolled cellular growth, tissue infiltration, and spread of abnormal cells (can't carry out normal physiological functions).  Cancer Prevention Most cancers are not curable in advanced stages. Both lifestyle modifications and chemoprevention agents may significantly reduce the risk of developing cancer. The Food and Drug Administration (FDA) has approved vaccines that can help prevent cancer. Available vaccines include those that prevent infection with human papillomavirus (HPV), responsible for cancers of the cervix, vulva, vagina, and anus and a vaccine that prevents hepatitis B viral infections, which can cause liver cancer. Additionally, medications, such as the selective estrogen receptor modulator (SERM) tamoxifen reduces the risk of breast cancer in premenopausal women, while raloxifene and the aromatase inhibitor (AI) exemestane reduce breast cancer in high-risk postmenopausal women. Because of possible long-term complications (eg, an increased risk of endometrial cancer with the use of tamoxifen) benefits versus risks needs to be weighed when making a recommendation. Note: Tamoxifen is a mixed agonist/antagonist; it is more agonistic in uterus than in breast. The steroid receptor co-activator 1 is more abundant in the uterus than in breast. Raloxifene is a SERM given orally that acts to block estrogen effects in the uterine and breast tissues, while promoting effects in the bone to inhibit resorption. This agent has been shown to reduce the risk of estrogen receptor– positive invasive breast cancer in postmenopausal women.  Smoking cessation is associated with a gradual decrease in the risk of cancer (e.g., lung, pharynx, mouth and esophageous), but more than 5 years is needed before a major decline in risk is detected. Proper sun protection, including minimizing sun exposure, using sunscreens with a sun protection factor (SPF≥15) on exposed areas, wearing protective clothing and sunglasses, avoiding tanning beds and sun lamps, can help in preventing the risk of skin cancer.  CARCINOGENESIS Carcinogenesis is the process by which normal cells are transformed into cancer cells. The exact cause of cancer remains unknown and is probably very diverse. It is thought that cancer develops from a single cell in which the normal mechanisms for control of growth and proliferation are altered. Evidence indicates that there are 4 stages in the cancer development process. Transformation  The first step, initiation, occurs when a carcinogenic substance encounters a normal cell to produce genetic damage and results in a mutated cell. The environment is altered by carcinogens or other factors to favor the growth of the mutated cell over the normal cell during promotion.(reversible process) Third, transformation (or conversion) occurs when the mutated cell becomes malignant Finally, progression occurs when cell proliferation takes over and the tumor spreads or develops metastases There are two major classes of genes involved in carcinogenesis, oncogenes and mutation of tumor suppressor genes (eg. p53 gene). Protooncogens are normal genes present in cells that converted by carcinogenic substances (eg. Smoking or radiation) into oncogene.  Tumor suppressor genes are normal genes which have protective effects against oncogenes. They inhibit inappropriate cellular growth and proliferation. Carcinogenic substances Chemicals, such as aniline and benzene, are associated with the development of bladder cancer and leukemia, respectively. Environmental factors, such as excessive sun exposure, can result in skin cancer, and smoking is widely known as a cause of lung cancer. Viruses, including HPV, Epstein-Barr virus, and hepatitis B virus, have been linked to cervical cancers, lymphomas, and liver cancers, respectively. Anticancer agents such as the alkylating agents (eg, melphalan), anthracyclines (eg, doxorubicin), and epipodophyllotoxins (eg, etoposide) can cause secondary malignancies (eg, leukemias) years after therapy has been completed. Note: The patient’s age, gender, family history, diet, and chronic irritation or inflammation may be considered to be promoters of carcinogenesis.  Metastases A metastasis is a growth of the same cancer cell found at some distance from the primary tumor site. The presence of metastasis at diagnosis usually is associated with a poorer prognosis than the patient with no known metastatic disease. Usually, once distant metastases have occurred, the cancer is considered incurable. Cancers spread usually by two pathways: hematogenous (through the bloodstream) or through the lymphatics (drainage through adjacent lymph nodes). The usual metastatic sites for solid tumors are the brain, bone, lung, and liver.  PATHOPHYSIOLOGY Tumor Origin Tumors may arise from the 4 basic tissue types: epithelial (carcinoma), connective (ie, muscle, bone, & cartilage) (called sarcoma), lymphoid, or nerve tissue. Adenocarcinomas arise from glandular tissue (eg. Lung, breast, colon, …). Malignancies of the bone marrow or lymphoid tissue, such as leukemias or lymphomas, are named differently. The suffix -oma is added to the name of the cell type if the tumor cells are benign (eg. Lipoma). Precancerous cells have cellular changes that are abnormal but not yet malignant and may be described as hyperplastic or dysplastic. Tumor Characteristics Tumors are either benign or malignant. Benign tumor Benign tumors often are encapsulated, localized, and indolent; they seldom metastasize; and they rarely recur once removed. Malignant tumors are invasive and spread to other locations even if the primary tumor is removed. Malignant tumor The cells no longer perform their usual functions, and their cellular architecture changes (anaplasia).  TREATMENT Desired Outcome Chemotherapy may be given to cure cancers, or it may be given to help control the symptoms of an incurable cancer (also known as palliation). Palliative care consists of pharmacologic and nonpharmacologic treatments and is most effective when initiated at the time of other treatments, improving quality of life. Treatment of cancer The three primary treatment modalities of cancer are surgery, radiation, and pharmacologic therapy. Non pharmacological therapy of cancer Surgery is useful to gain tissue for diagnosis of cancer and for treatment, especially those cancers with limited disease. However, when cancer is widespread, surgery may play little or no role, but radiation therapy localized to specific areas may palliate symptoms. Radiation plays a key role not only in the treatment and possible cure of cancer but also in palliative therapy. Together, surgery and radiation therapy may provide local control of symptoms of the disease.  Pharmacological therapy of cancer Adjuvant therapy: Systemic therapies that administered after surgery (surgery can remove all macroscopic but not all microscopic disease) to destroy microscopic malignant cells. The goals of adjuvant chemotherapy are to decrease the recurrence by eliminating microscopic malignant cells of the cancer and to prolong survival. Neoadjuvant chemotherapy: Chemotherapy that is given before surgical resection of the tumor to decrease the tumor burden to be removed and make the surgery easier to perform because the tumor has shrunk away from vital organs or vessels. Dosing of Chemotherapy Chemotherapeutic agents typically have a very narrow therapeutic index. The doses of chemotherapy must be given at a frequency that allows the patient to recover from the toxicity of the chemotherapy; each period of chemotherapy dosing is referred to as a cycle. Each cycle of chemotherapy may have the same dosages; the dosages may be modified based on toxicity; or a chemotherapy regimen may alternate from one set of drugs given during the first, third, and fifth cycles to another set of different drugs given during the second, fourth, and sixth cycles.  The dose density of chemotherapy refers to shortening of the period between cycles of chemotherapy. Administration of dose-dense chemotherapy regimens often used when goal of therapy is cure and it requires the use of colony-stimulating factors (eg, filgrastim or granulocyte– colony stimulating factor [G-CSF]) to be administered to shorten neutropenia duration & severity. When a chemotherapy regimen is used as palliation (to control symptoms), the dosages of chemotherapy may be decreased based on toxicity or the interval between cycles may be lengthened to maintain quality of life. Factors that affect chemotherapy selection and dosing are age, concurrent disease states (e.g., Renal failure, heart disease), and performance status (assessed through specific scales). Combination Chemotherapy The principles of using combination therapy are to use: Agents with different pharmacologic actions Agents with different organ toxicities (e.g., Anthracyclines (eg, doxorubicin) have the potential to cause cardiac toxicity; Microtubule-targeting agents (eg, vincristine) are associated with various forms of neurotoxicity; Alkylating agents (eg, melphalan) are associated with secondary malignancies. Agents that are active against the tumor and ideally synergistic when used together Agents that do not result in significant drug interactions. When two or more agents are used together, the risk of development of resistance may be lessened, but toxicity may be increased. ‫‪Note :‬‬ ‫اﻟﺻور اﻷﺗﯾﺔ ﻟﻼطﻼع‬