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General Therapeutic Principles of oncology

General Therapeutic Principles of oncology . Jamilah Alsaidan Msc. Outline. Describe etiology , risk factors of cancer Cancer statistics in Saudi Arabia Highlight diagnosis and screening of cancer Define cancer staging system Describe relative roles of available treatments

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General Therapeutic Principles of oncology

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  1. General Therapeutic Principles of oncology Jamilah AlsaidanMsc

  2. Outline • Describe etiology , risk factors of cancer • Cancer statistics in Saudi Arabia • Highlight diagnosis and screening of cancer • Define cancer staging system • Describe relative roles of available treatments • ( Chemotherapy, radiation, surgery) • Classify chemotherapeutic drugs and distinguish mechanisms and adverse effects • Identify certain medications ( and their rational for common malignancies)

  3. INTRODUCTION • Cancer is synonymous with the terms: • Neoplasm • Malignancy • Oncologic disease • Cancer is not a single disease, rather, it is a group of diseases characterized by uncontrolled growth and spread of abnormal cells.

  4. GENERAL THERAPEUTIC PRINCIPLES OF ONCOLOGY Common sites Lung, colon, lymphoma Males- Prostate Females- Breast The incidence of cancer and cancer related deaths can be affected by both age and ethnic background with the incidence greater in the elderly.

  5. Cancer statistics in Saudi Arabia • Between January 01 and December 31, 2007, the total number of cancer incident cases reported to the SCR was 12,309. • Overall cancer was slightly more among women than men. Cancers affected 5,982 (48.6%) males and 6,321 (51.4%) females. Cancer Incidence and Survival Report, Saudi Arabia ( Accessed Online 2011)

  6. GENERAL THERAPEUTIC PRINCIPLES OF ONCOLOGY • These abnormal cells : • Are often described as poorly differentiated or immature • cannot interact with other cells • cannot carry out the physiologic functions of their normal healthy mature counterparts • Have the ability to invade adjacent normal tissues and break away from the primary tumor (metastasize) and travel through the blood or lymph to establish a new tumor ( or metastases) at a new site.

  7. GENERAL THERAPEUTIC PRINCIPLES OF ONCOLOGY • A neoplasm is benign when it grows in an unregulated fashion without tissue invasion. • A neoplasm is malignant when it grows in unregulated fashion with tissue invasion.

  8. Etiology • Etiology Cancers arise from the transformation of a single normal cell. A certain initial “event” causes damage or mutation to the cell’s DNA.

  9. Basic Principles of Oncology Pharmacotherapy • Cancer at the molecular level: Two gene classes, oncogenes and tumor suppressor genes may play a major role in the origin of cancer. • Oncogenes ( Turn on Cancer) • Tumor Suppressor Genes ( Turn off Cancer) • Genetic alterations including chromosomal translocations, deletions, insertions, and point mutations of their normal counterparts- dysfunction- possible cancer.

  10. Basic Principles of Oncology Pharmacotherapy • In normal cells Proto-oncogenes code for proteins that stimulate cell division. Oncogenes arise from genetic alterations to Proto- oncogenes. • These oncogenes cause overgrowth of stimulatory proteins that lead to excessive proliferation or growth and ultimately a malignant transformation. • Tumor suppressor genes encode for proteins that control inappropriate cell division or growth. If these genes are lost, mutated or inactivated there will be elimination of the normal inhibition of cell division. • Tumor suppressor genes and proto- oncogenes together provide the stimulatory and the inhibitory signal that determine whether a cell will enter the life cycle to divide and grow.

  11. Basic Principles of Oncology Pharmacotherapy • These abnormal cells : • Are often described as poorly differentiated or immature • cannot interact with other cells • cannot carry out the physiologic functions of their normal healthy mature counterparts • Have the ability to invade adjacent normal tissues and break away from the primary tumor (metastasize) and travel through the blood or lymph to establish a new tumor ( or metastases) at a new site.

  12. Basic Principles of Oncology Pharmacotherapy • Another characteristic of cancer cells that differs from normal cells is that they often lack the normal cell-to- cell adhesion molecules called cadherins, and the cell to extracellular matrix molecules called integrins. • This allows the cancerous cells to break away from the primary tumor mass, move through the body and form metastatic sites.

  13. Basic Principles of Oncology Pharmacotherapy • Another characteristic of cancer cells that differs from normal cells is that they often lack the normal cell-to- cell adhesion molecules called cadherins, and the cell to extracellular matrix molecules called integrins. • This allows the cancerous cells to break away from the primary tumor mass, move through the body and form metastatic sites.

  14. Basic Principles of Oncology Pharmacotherapy • Events that may induce alterations on the genetic level include occupational, lifestyle, and environmental factors, some medications and of course hereditary factors. • Another term used could be risk factors or carcinogens. Some are modifiable, that is a person can control their presence while others such as hereditary predisposition are not modifiable

  15. Basic Principles of Oncology Pharmacotherapy Carcinogens associated with an increased risk of cancer • Environmental: • Ionizing radiation ( radon gas emitted from soil containing uranium deposits) • Ultraviolet radiation Occupational • Asbestos • Chromium, Nickel, Vinyl chloride, Benzene • Associated Cancer • Leukemia, breast, lung, thyroid. • Skin melanoma • Lung, mesothelioma • Lung, liver

  16. Basic Principles of Oncology Pharmacotherapy Carcinogens associated with an increased risk of cancer • Lifestyle • Alcohol • Dietary Factors • Tobacco • Medical Drugs • Diethylstilbosterol • Alkylating agents • Estrogens • Cyclophosphamide • Associated Cancers • Esophagus, liver, stomach, oropharynx, larynx • Colon, Breast, Gall bladder • Lung, oropharynx, pharynx, larynx, esophagus, gall bladder • Breast, testes, ovary, and in offspring vaginal • Leukemia, bladder • Endometrial • Bladder

  17. Basic Principles of Oncology PharmacotherapyScreening • Because cancers are most curable with surgery or radiation before they have metastasized, early detection and treatment have obvious potential benefits • Early detection not possible for some cancers cause they don’t produce signs or symptoms until they have become large or have metastasized • Lack of effective screening methods for some cancers • Inaccessibility of some anatomic sites • For some cancers effective screening methods do exist • Incorporate education of the public

  18. Screening Guidelines for early detection of cancer

  19. Basic Principles of Oncology Pharmacotherapy Screening- Presenting Signs and Symptoms In Adults In Children Continued, unexplained weight loss Headaches with vomiting in the morning Increased swelling or persistent pain in the bones or joints Lump or mass in abdomen, neck, or elsewhere Development of a whitish appearance in the pupil of the eye Recurrent fevers not caused by infections Excessive bruising or bleeding Noticeable paleness or prolonged tiredness • Change in bowel or bladder habits • A sore that does not heal • Unusual bleeding or discharge • Thickening or lump in breast or elsewhere • Indigestion or difficulty in swallowing • Obvious changes in wart or mole • Nagging cough or hoarseness Adapted from tables 130-5 and 130-6, Pharmacotherapy, A pathophysiologic approach, 7th Edition

  20. Basic Principles of Oncology PharmacotherapyScreening • Loss of appetite and Pain also common symptoms • Warning signs of cancer in children differ and reflect the types of tumors more common in this patient population • Even with increased public awareness, the fear of a cancer diagnosis can deter people from seeking medical attention.

  21. Basic Principles of Oncology PharmacotherapyDiagnosis and staging • Diagnosis • MUST get tissue for pathologic diagnosis • Cytogenetics, Tumor markers ??????? • Lab • Complete blood cell count, electrolytes, renal & liver function • Radiology • X-rays, CT scans, MRI.

  22. Basic Principles of Oncology Pharmacotherapy Diagnosis and staging Staging (TMN) Refers to extent of disease and relative size of tumor. T: (0-4) =tumor size (primary) N: (0-3)= degree or regional lymph node involvement M: ( 0-3) = presence or absence of distant metastases Staging • Grading: Measures the extent to which tumor cells differ from their parent tissue • Grade 1= well differentiated cells, function most like parent tissue least malignant • Grade 4 =least differentiated cells, not like parent tissue most rapidly increasing in number

  23. Basic Principles of Oncology Pharmacotherapy

  24. Basic Principles of Oncology Pharmacotherapy Treatment • Surgery: Oldest modality • Plays a major role in the diagnosis and treatment of cancer • Can reduce a tumor or totally remove it in early stages • Radiation: First used for cancer treatment in late 1800s • Is a mainstay in cancer management to this day • Receive treatment for multiple sites simultaneously • Effective for many kinds of cancer Surgery and Radiation are local treatments

  25. Basic Principles of Oncology Pharmacotherapy Treatment • Surgery and radiation can not treat completely if the cancer has metastasized, and usually cancer is diagnosed at late stages. • Thus to completely eliminate the cancer will need other modalities with localized treatment. This is where pharmacotherapy comes in.(Drug therapy) consisting of chemotherapy and biologic agents. Pharmacotherapy can be indicated as a primary, palliative, adjuvant, or Neoadjuvant treatment modality.

  26. Basic Principles of Oncology Pharmacotherapy Treatment  Pharmacotherapy: • Targets systemic malignancies such as leukemia that can not be cured with a localized modality • Chemotherapy and hormonal therapy can access the systemic circulation and can theoretically treat the primary tumor and any metastatic disease • therapies are currently considered in the broader sense of immunotherapy or “targeted therapies” • Systemic therapy is given either as adjuvant therapy to surgery or radiation, pre operatively, post operatively.

  27. Basic Principles of Oncology Pharmacotherapy Treatment • Micrometastases- cancer appears to be eliminated by surgery or radiation. However, there is recurrence of cancer. This implies that the primary tumor began to metastasize before it was removed. • These early metastases are too small to detect with current diagnostic tests and are known as micrometastases

  28. Basic Principles of Oncology Pharmacotherapy Treatment- Applications • Primary chemotherapy • 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 • Can be either curative or palliative, depending on specific type of tumor

  29. Basic Principles of Oncology Pharmacotherapy Treatment- Applications • Second line or salvage chemotherapy • Is administered after the tumor has become refractory to primary therapy or if the patient is unable to tolerate first line therapy • Chemotherapy is the primary treatment modality used for hematologic malignancies as well as a number of solid tumors that have metastasized at the time diagnosis or have recurred at metastatic sites after initial therapy.

  30. Basic Principles of Oncology Pharmacotherapy Treatment- Applications • Adjuvant therapy : is defined as the use of systemic agents to eradicate micrometastatic disease following localized modalities • Goal is to reduce subsequent recurrence rates and prolong long term survival • Neoadjuvant or Preoperative Setting • The goal is to make other treatment modalities more effective by reducing tumor burden and to destroy micrometastases • E.g. to shrink large tumors and make them more amenable to later surgery resection and possibly spare critical organs

  31. Basic Principles of Oncology Pharmacotherapy Treatment- Applications • Combined Modalities • The management of most types of cancer involves the use of combined modalities

  32. Basic Principles of Oncology Pharmacotherapy Treatment • Primary curative modality • Treatment with cytotoxic drugs, e.g. testicular cancer, leukemias • Palliative chemotherapy • Often solid tumors are not curable with chemotherapy alone, either because of the biology of the tumor or because of advanced disease at presentation • With palliative chemotherapy it is often possible to decrease tumor size or to retard growth enough to reduce untoward symptoms caused by the tumor.

  33. Basic Principles of Oncology Pharmacotherapy Treatment- • Factors that influence response to chemotherapy • 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 not heterogeneous; and some are resistant to chemotherapy. • The objective of successive chemotherapy courses is a further decrease in size of tumor mass. • Factors influence response: Dose intensity • schedule • drug resistance • tumor site • A patients performance status

  34. Tumor growth

  35. Basic Principles of Oncology Pharmacotherapy Treatment • Dose intensity: The chemotherapy dose per unit time over which treatment is given ( e.g., mg/m 2 /week) • Drug resistance might be overcome by escalating the dose intensity of drugs. This can be achieved by: • Increasing the dose of chemotherapy per cycle • Shortening the interval between cycles Unnecessary lengthening of the interval between successive courses or decreasing the dose can negatively affect treatment outcomes The dose intensity for most chemotherapy regimens is limited by the major dose related toxicity

  36. Basic Principles of Oncology Pharmacotherapy Treatment- Factors that influence response to chemotherapy • Schedule dependency: The schedule of chemotherapy administration is an important determinant of response. • It influences dose intensity largely by affecting toxicity. • In some circumstances, changing the administration schedule can reduce the toxicity sufficiently to allow patients to receive higher total doses or more frequent courses of therapy, thereby increasing the dose intensity • E.g., IV bolus vs. frequent IV infusion or continuous IV infusion

  37. Basic Principles of Oncology Pharmacotherapy Treatment • Drug Resistance: • Biochemical resistance to chemotherapy is the major impediment to successful treatment with most cancers • Resistance can occur de novo in cancer cells or develop during cell division as a result of mutation • Possible Mechanisms of anti- cancer cells drug resistance include: • Proficiency in repair of DNA • In drug activation • In drug inactivation • In cellular uptake of drug • In efflux of drug (multidrug resistance) • Alterations in target enzymes (DHFR, topoisomerase)

  38. Basic Principles of Oncology Pharmacotherapy Treatment • Tumor site: • The cytotoxic effects of chemotherapy agents are related to the time the tumor is exposed to an effective concentration of the agent (i.e., concentration X time [C×T]). • The dosage regimen, including the dose, infusion rate, route of administration, lipophilicity, and protein binding, can influence the concentration-time product. • Tumors located in sites of the body with poor drug penetration may not receive a sufficient concentration of medication to eradicate cancerous cells.

  39. Basic Principles of Oncology Pharmacotherapy Treatment • Patients performance status • Specific patient factors such as presence of genetic polymorphisms affect antitumor activity and adverse effects of chemotherapy agents. • E.g., a prodrug that needs to be metabolized to the active form by a glucuronidating enzyme. • Patients with decreased activity of this enzyme experience accumulation of drug and are at increased risk for potential side effects.

  40. Basic Principles of Oncology Pharmacotherapy Treatment

  41. Basic Principles of Oncology Pharmacotherapy Treatment

  42. Basic Principles of Oncology Pharmacotherapy Treatment

  43. Basic Principles of Oncology Pharmacotherapy Treatment

  44. Basic Principles of Oncology Pharmacotherapy Treatment Figure 60.1 Summary of the mechanisms and sites of action of some chemotherapeutic agents useful in neoplastic disease. From Goodman and Gilman, The pharmacological Basis of Therapeutics, 12th Edition

  45. Basic Principles of Oncology Pharmacotherapy Treatment Figure60–2. Cell cycle specificity of antineoplastic agents. From Goodman and Gilman, -The pharmacological Basis of Therapeutics

  46. Basic Principles of Oncology PharmacotherapyCell cycle specificity • S-Phase: DNA synthetic phase • M-Phase: Formation of mitotic spindle, Mitosis , most vulnerable part of the cell cycle • Leukemias and lymphomas have high percentage of proliferating cells, and are the neoplasms most susceptible to chemotherapeutic measures. • Slowly growing tumors with a small growth fraction (e.g., carcinomas of the colon or non small cell lung cancer ) are less responsive to cycle specific drugs • More effective are agents that inflict high levels of DNA damage (e.g., alkylating agents) or those that remain at high concentrations inside the cell for extended periods of time (e.g., fluoropyrimidines)

  47. Basic Principles of Oncology Pharmacotherapy Treatment –cell cycle specificity • Works on reproducing (non-resting) cells • There will always be some cells still alive • Schedule dependent • Usually (but not always) as infusion • Works on all cells • Dose Dependent • Bolus (probably better but not always) or infusion Specific Non specific

  48. Basic Principles of Oncology Pharmacotherapy Treatment -Toxicity and other adverse effects • Toxicity targets rapidly dividing cells: • Narrow therapeutic range and distinctive toxicity • Bone marrow/myelosuppression (WBC, RBC, PLTs) • Mucus membrane and skin (esophagitis, diarrhea and alopecia) – • Nausea and vomiting via CTZ

  49. Basic Principles of Oncology Pharmacotherapy Treatment -Toxicity and other adverse effects • Other adverse effects • Promalignant • Extravasation • Hypersensitivities • Gonadal effects ( hypogonadism, sterility) • Organ-Drug specific ( lungs, heart)

  50. Basic Principles of Oncology Pharmacotherapy Treatment -Toxicity and other adverse effects

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