1. Applied therapeutics

2.  Cancer (neoplasm, tumor, or malignancy) is not a single disease; rather, it is a group of diseases characterized by uncontrolled growth and spread of abnormal cells.  Cancer cells do not respond to the normal processes that regulate cell growth, proliferation, and survival, and they cannot carry out the physiologic functions of their normal differentiated (mature) counterparts.  Often, cancer cells are described as poorly differentiated or immature.

3.  Cancers arise from the transformation of a single normal cell. An initial “event” causes damage or mutation to the cell's DNA.  These events may include lifestyle, environmental, or occupational factors, as well as some medical therapies (e.g., cytotoxic chemotherapy, immunosuppressive therapy, or radiation therapy) and hereditary factors.  Currently, cigarette smoking is probably the most significant single factor that contributes to the development of cancers.  In addition, approximately one-third of expected cancer deaths are thought to result from preventable causes, such as physical inactivity, obesity, nutrition, and other lifestyle factors.

4.  Standardized screening tests can help identify disease in asymptomatic individuals (screening) or help diagnose a disease in symptomatic individuals (early detection).  Ideally, a screening test should be quick and simple to maximize compliance with screening recommendations.  The cancer screening tests recommended meet four basic requirements: (a) there must be good evidence that the test is effective in reducing morbidity or mortality (e.g., effective treatment must be available for the screened disease); (b) the benefits of the test should outweigh its risks; (c) the costs of the test should be in balance with its presumed benefits; and (d) the test should be practical and feasible within the existing health care setting.

5.  The histologic diagnosis of a tumor is the most important determinant of how a malignancy will be treated. This is because a tumor's histologic classification influences its natural history, pattern of progression, and responsiveness to treatment.  A surgical biopsy or excision of the primary tumor, followed by a microscopic and a biochemical evaluation by a pathologist, can provide the most accurate histologic diagnosis.  The stage of the cancer, as well as the histologic diagnosis, significantly influences both the treatment and prognosis. Staging is the process that determines the extent or spread of the disease.

6.  Cancer can have a profound effect on the patient's quality of life and his or her ability to tolerate appropriate therapy. For example, patients with malnutrition secondary to anorexia, mechanical obstruction, or pain may not tolerate some therapies because of significant physical debility.  Tumor involvement of the liver, kidneys, or lungs also can complicate therapy by causing significant organ dysfunction and metabolic disturbances.  In addition, compression or obstruction could produce a “mass effect” by impairing normal organ or tissue function and causing pain or other uncomfortable physical effects.  Life-threatening physical effects that require immediate intervention include obstruction of the superior vena cava, spinal cord compression, and brain metastases.

7.  Surgery ; is the oldest modality available to treat patients with cancer.  Radiation therapy ; can be used to eradicate localized tumor masses. Not all cancers are sensitive to the lethal effects of radiation, so this modality has limited application in the treatment of some cancers  Cytotoxic Chemotherapy.  Endocrine Therapy.  Angiogenesis Inhibition.  Biologic Response Modifiers.

8.  The era of cytotoxic chemotherapy can be traced to World War II, when an explosion of mustard gas produced bone marrow and lymphoid hypoplasia in seamen exposed to the gas. This incident led to the use of alkylating agents (derivatives of mustard gas) in the treatment of Hodgkin disease and other lymphomas.

9.  In the clinical setting, tumor cells do not always decrease predictably with each successive course of chemotherapy.  This is because the growth fraction of human tumors is not 100% and because the cell population is heterogeneous and some are resistant to chemotherapy.

10.  Dose Intensity ; is defined as the chemotherapy dose per unit time over which treatment is given (e.g., mg/m 2 /week).  Schedule Dependency ; The schedule of chemotherapy administration is an important determinant of response. It influences dose intensity largely by affecting toxicity.  Drug Resistance ; can occur de novo in cancer cells or develop during cell division as a result of mutation.  Tumor Site ; The cytotoxic effects of chemotherapy agents are related to the time the tumor is exposed to an effective concentration of the agent.  Pharmacogenetics ; Antitumor activity and adverse effects of chemotherapy agents are associated with the presence of genetic polymorphisms that can affect the metabolism and disposition of drug.

11.  Combination chemotherapy provides broader coverage against resistant cell lines within the heterogeneous tumor mass.  Several principles provide the basis for selecting the agents to be included in a chemotherapy regimen: Only agents with demonstrable single-agent activity against the specific type of tumor should be used in combination therapy. All agents in the regimen should have different mechanisms of action. Agents should not have overlapping toxicities so that the severity and duration of acute and chronic toxicities are minimized. All agents in the regimen should be used in their optimal dose and schedule.

12.  Primary chemotherapy is defined as first-line treatment and, in the case of leukemia, it is referred to as induction chemotherapy.  Choice of primary chemotherapy is governed by observations made from clinical trials that demonstrate that a given regimen has the highest known activity against the tumor.

13.  Some patients may have unrecognized micro- metastases or residual disease after primary treatment.  These patients have a high probability of disease recurrence, even though the primary treatment may have successfully removed all visual evidence of the primary tumor.  To eradicate any undetectable tumor, the patient could receive systemic therapy after initial curative surgery (or radiation therapy).  Systemic chemotherapy administered after primary therapy is referred to as adjuvant chemotherapy.

14.  Neoadjuvant chemotherapy is the therapy given before the primary treatment in patients who present with locally advanced tumors (e.g., large tumors or those that are impinging on surrounding vital structures) that are unlikely to be cured with primary surgery or radiation therapy.  The objective is to reduce the tumor mass with neoadjuvant therapy (chemotherapy or hormonal therapy), thereby increasing the likelihood of eradication by subsequent surgery or radiation.

15.  Systemic;  Systemic chemotherapy is most commonly administered by the IV route, either as a bolus injection (generally <15 minutes), a short infusion (15 minutes to several hours), or a continuous infusion (lasting 24 hours to several weeks). Some systemic chemotherapy agents can be administered by the oral route, whereas other agents can be administered by the intramuscular or subcutaneous route.

16.  Regional;  Although chemotherapy was initially developed for systemic use, techniques have been developed to locally administer agents to specific sites of the body affected by the tumor.  Regional or local chemotherapy allows high concentrations of agents to be achieved at the site of the tumor while reducing systemic exposure and subsequent toxicity.  On the other hand, undetectable metastases at distant sites may not be exposed to the chemotherapy, allowing continued growth of the tumor mass.

17.  Endocrine therapy can be used to treat several common cancers, including breast, prostate, and endometrial cancers, which arise from hormone- sensitive tissues.  These tumors grow in response to endogenous hormones that trigger growth signals by binding to specific receptors located on a cell membrane or within the cytoplasm of a cell.  Current endocrine therapies inhibit tumor growth by blocking the receptors or by eliminating the endogenous hormone feeding the tumor.

18.  By understanding the mechanisms by which cancer cells exhibit unregulated growth and immortality, and possess the ability to invade tissues and metastasize, it has been possible to design drugs that inhibit these processes.  The EGFR, HER2/neu, and VEGF signaling pathways can be blocked by monoclonal antibodies that inhibit receptor tyrosine kinase activation by binding to the extraceullar domain.

19.  Angiogenesis, the main process for new blood vessel formation postnatally, occurs during wound healing and disease states such as cancer.  It occurs through remodeling, migration, and proliferation of pre-existing blood vessels.  These factors trigger cell proliferation and secretion of such factors as MMP, collagenase, and tissue plasminogen activators.  Sunitinib and sorafenib, which are both small molecule inhibitors, act as antagonists at several locations along the signaling pathways that promote angiogenesis.

20.  Biologic response modifiers used to treat cancers include proteins (vaccines), antibodies (monoclonal and polyclonal), and growth factors.  These agents can be used to kill cancer cells or to booster the host's defense mechanisms.  The first recombinant cytokine to become available for the treatment of cancer was interferon- α.  This interferon affects tumor cells through several different mechanisms, including (a) a direct antiproliferative effect; (b) an immunomodulatory effect on natural killer cells, T cells, B cells, and macrophages; (c) an induction of tumor cell antigens; and (d) a differentiating effect on tumor cells. Interferons also possess antiangiogeneic effects.