Pre-reading -Oncology.pdf

Topic : Oncology Overview Guest lecturer Dr Siow Tian Rui MBBS, MRCP, FRCR (Clinical Oncology) Dr. Siow is a Senior Consultant at the Division of Radiation Oncology, National Cancer Centre Sing...

Topic : Oncology Overview Guest lecturer Dr Siow Tian Rui MBBS, MRCP, FRCR (Clinical Oncology) Dr. Siow is a Senior Consultant at the Division of Radiation Oncology, National Cancer Centre Singapore. He sub-specialises in Hepato- Pacreato-Biliary, Upper Gastrointestinal, Colorectal, and Thoracic- oncology. Dr Siow is also an Adjunct Assistant Professor with SingHealth-Duke NUS Medical School. Learning outcomes Upon completing the pre-readings and the lecture, you should be able to 1. Explain the pathophysiology of benign & malignant tumour 2. Describe the common symptoms, investigations, diagnosis & staging of cancers 3. Discuss the mechanisms of tumour spread & metastasis 4. Compare the basic concepts underpinning the various cancer therapy -chemotherapy, hormonal therapy, radiation therapy & targeted therapy and immunomodulatory therapy Study resources VanMeter, K. C., & Hubert, R. J. (2014). Gould's Pathophysiology for the Health Professions (5th Ed.). Philadelphia, PA: Saunders. Cp 20: Neoplasms and cancer Huether, S. E., & McCance, K. L. (2020). Understanding Pathophysiology (7th Ed.). New York: Elsevier Health Sciences. Cp 9: Biology, clinical manifestations and treatment of cancer Hammer, G. D., & McPhee, S. J. (2019). Pathophysiology of Disease: An Introduction to Clinical Medicine (8th Ed). McGraw Hill Professional. Cp 5: Neoplasia Asperheim, M. K., & Favaro, J. (2012). Introduction to pharmacology (12th Ed.). St. Louis, MO: Saunders. Cp 21: Antineoplastic drugs 5 Jan 2022 Pre-readings Neoplasm or tumour: Cellular growth that no longer responds to normal genetic controls. The cell continues to reproduce, without need for them to reproduce. This excessive growth deprives other cells of nutrition o Benign tumour- tissue name + oma (e.g., lipoma – benign tumour of fatty tissue) o Malignant tumour– known as cancer. tissue name + carcinoma (e.g., adenocarcinoma) o Tumour of connective tissue – tissue name + sarcoma (e.g., liposarcoma) The general characteristics of benign & malignant tumours are summarized in Table 1. The specific characteristics depends on: o Type of cell from which the tumour arises o Unique structure and growth pattern Table 1: The general characteristics of benign & malignant tumours (VanMeter KC, 2014, p550) Benign tumours Malignant tumours Cells Similar to normal cells Varied in size & shape with large Differentiated nuclei Fairly normal mitosis Many undifferentiated Mitosis increased and atypical Growth Relatively slow Rapid growth Often encapsulated and expand No capsule, cells do not connect with each other Spread Localized & does not spread Infiltrate & invade into surrounding tissue Metastasizes to distant sites through blood & lymph vessels Systemic rare Often present effects Life Only in area where pressure effect is Yes (by tissue destruction & tumour threatening critical (e.g., brain) spread) Fig 1. Characteristics of benign & malignant neoplasms (VanMeter KC, 2014, p551) 5 Jan 2022 Carcinogenesis Process whereby normal cells are transformed into cancer cells Process varies greatly with respect to time Cancer is a multifactorial disease because of: o Environmental effects o Change in gene expression (heredity) o Infection in some cases (e.g., cervical and hepatic cancers) Risk factors for cancer o Genetic factors: Oncogenes that regulate all growth o Viruses: Oncoviruses alter host cell’s DNA. o Radiation: UV rays, X-rays and gamma rays, Radioactive isotopes o Chemicals (natural or synthetic products) : Organic solvents, Asbestos, Heavy metals, Formaldehyde, Chemotherapy agents o Biological factors: Chronic irritation and inflammation o Age: increasing age o Diet: natural substances, additives or processing methods o Hormones Pathophysiology of cancer Defining cancer- An enlarging space-occupying mass composed of more primitive or dysplastic cells. Normal organization, growth inhibition, contact controls and cell-cell communications are absent The expanding mass compresses nearby tissue  necrosis & area of inflammation around the tumour Metathesis- malignant cells do not adhere to each other & often break loose from the mass, infiltrating into adjacent tissue Malignant cells release o enzyme collagenase  protein & cells breakdown destruction of adjacent tissue & systemic effects (e.g., altered serum Ca2+) o growth factor stimulate angiogenesis  promote tumour development Inflammation and loss of normal cells lead to progressive reduction in organ integrity and function The diagnostic workup of cancer Blood tests: o Generally low Hb and erythrocytes count o Measure blood cell levels during chemo or radiation treatment, such as thrombocytopenia, erythrocytopenia and leukopenia Tumour markers o Substances, enzymes, antigens or hormones produced by some neoplastic cells (e.g., carcinoembryonic antigen for colon cancer, -fetoprotein for hepatocellular cancer) o Use for screening, diagnosis or monitoring clinical course o can be found in the blood, urine, stool, tumour tissue, or other tissues or bodily fluids Radiographic, ultrasound, MRI, CT o Visualizing changes in tissues or organs 5 Jan 2022  o May incorporate radioisotopes Histological & Cytological tests o For screening, diagnosing and monitoring o Require biopsy or cell sample o Determine degree of differentiation and tumour type most dependable confirmation of malignancy Effects of tumour Local effects Systemic effects Pain Weight loss and cachexia o May be absent until very late o Contributed by anorexia, pain, stages stress and to demands on o Occurs when tumour is well the body from tumour cells advanced Anaemia o Severity depends on tumour o Due to blood loss at tumour type site or reduce Hb synthesis Obstruction from nutritional deficits. o when tumour compresses a duct Severe fatigue or passageway (e.g., digestive o Caused by inflammatory tract or bronchi) changes, cachexia, anaemia, o Blood supply or lymphatic flow & stress of treatment schedule may be restricted o Psychological factors Tissue necrosis and ulceration Effusions o May lead to bleeding or infection o Inflammation causes fluid around the tumour build-up in body cavities. Frequent Infections o Due to resistance declines Paraneoplastic syndrome o Tumour cells release substances that affect neurological function or blood clotting, or may have hormonal effects. The spread of tumour: Carcinoma in situ: A group of abnormal cells that remain in the place where they first formed. Also called stage 0 disease. Tumour progresses from in situ via three basic mechanisms Invasion Local spread Tumour cells grow into adjacent tissues E.g., Uterine carcinoma invades the vagina Metastasis Spread to distant sites when tumour cells invade vein or lymphatic vessel Lungs and liver are common secondary sites E.g., Carcinoma of the colon spreads to the liver. Seeding Spread of cancer cells in body fluid or along membranes, usually in body cavity E.g., ovarian cancer to peritoneum cavity 5 Jan 2022  Fig 2. Spread of malignant tumour. Example of carcinoma of the cervix (VanMeter KC, 2014, p554) 5 Jan 2022 Tumour staging A cancer classification process at the time of diagnosis. It describes the extent of disease and provide a basis for treatment and prognosis TMN system: o Size of primary tumour (T) o Involvement of regional lymph nodes (N) o Spread (metastasis) of tumour (M) Treatment of cancer Basic treatment measures are surgery, chemotherapy, immunotherapy, or radiation or a combination of them. The treatment can be curative or palliative (to reduce manifestation & complications related to the cancer and to prolong life) Adjuvant therapy – additional prophylactic (preventive) treatment to manage potential micrometastases (e.g., chemo & radiation therapy after apparent complete removal of localized breast tumour) A cure for cancer is defined as a 5yr survival without recurrence after diagnosis and treatment 5 Jan 2022 Surgery Therapy of choice for solid tumour- for removal of tumour and surrounding tissue Removal of adequate surrounding tissue may result in changes in function. Radiofrequency ablation (RFA) - Performed by interventional radiologist who uses CT scan and US to guide insertion of needle & electrodes into the tumour, killing the malignant cells using heat in the form of radio waves Radiation therapy Ionizing radiation consists of electromagnetic waves such as X-rays or gamma rays (from radioactive substances like radium or cobalt) or high energy penetrating particles (electrons, protons) May be used alone (e.g., lymphoma) or combined with other therapies, or used as an adjuvant therapy prior to surgery to shrink tumour Mechanism o Causes mutations or alterations in target DNA  preventing mitosis or causing immediate cell death. o Damages blood vessels, cutting off blood supply to tumour cells o Inflammation, necrosis and scar tissue along the pathway of radiation Most effective in rapidly dividing cells (radiosensitive) : skin & mucosa (epithelial), bone marrow, gonads Some types of cancers are radioresistant. Methods of administrating radioisotope o External sources—cobalt machine ▪ Radiation for a short time to specific site in the body o Seeding the radioisotope and internally inserted at the tumour site (e.g., cervical cancer) o Internally inserted at tumour site via brachytherapy (implanting device at the site) (e.g., oral tumours). o Instill radioisotope in a solution into a body cavity (e.g. pleural cavity). o Given orally (e.g., 131I for thyroid cancer) o Radioisotopes may be given by injection for specific tumours. Adverse effects of radiation o Bone marrow depression ▪  leukocytes—increase risk of infection (pneumonia & septicaemia) ▪  erythrocytes—fatigue, tissue breakdown ▪  platelets—excessive bleeding, hemorrhage o Epithelial cell damage: damage to blood vessels (vasculitis) and skin (inflamed as if sun burn), hair loss (alopecia), oral mucosa (ulceration or dry mouth), mucosa of digestive tract (nausea, vomiting & diarrhea, melena, hematemesis), o Infertility with abdominal radiation o Nonspecific fatigue and lethargy: can lead to mental depression Chemotherapy Use a combination of 2-4 antineoplastic drugs in following classifications o Antimitotics o Antimetabolites o Alkylating agents 5 Jan 2022  o Antibiotics Useful for generalized cancer & most effective against rapidly producing cells and on small tumour mass. Applied in repeated dose in cycles (may repeat at weekly or monthly interval) Mechanism: Drugs interfere with protein synthesis and/or DNA replication at different points in the tumour cell cycle (Fig 4.3) Fig 3. Effects of chemotherapy ABVD on tumour cell cycle (VanMeter KC, 2014, p562) Adverse effects of chemotherapy o Bone marrow depression ▪ Limiting factor with chemotherapy & need monitoring by blood test before each treatment ▪ Nadir-the point of lowest cell count (neutropenia or leukopenia) o Nausea: direct chemical stimulation of the emetic center in brain. o Epithelial cell damage: hair loss (alopecia) & breakdown of skin and mucosa (stomatitis & diarrhea) o Damage to specific areas with some antineoplastic drugs ▪ Fibrosis in the lungs ▪ Damage to myocardial cells ▪ Kidney damage 5 Jan 2022 Long term side effect of chemotherapy Source: https://www.healthline.com/health/cancer/effects-on-body (Updated Dec 2019) https://i0.wp.com/images- prod.healthline.com/hlcmsresource/images/topic_centers/Chemo_Effects_Pinterest_crop.jpg?w=1155&h=7854 5 Jan 2022 Targeted Therapy (https://www.cancer.gov/about-cancer/treatment/types/targeted- therapies/targeted-therapies-fact-sheet) A cornerstone of precision medicine- a form of medicine that uses information about a person’s genes and proteins to prevent, diagnose, and treat disease. Also called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or “rational drug therapy” Drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. Targeted therapies differ from standard chemotherapy in several ways: o Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells. o Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells. o Targeted therapies are often cytostatic (that is, they block tumour cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumour cells) o Tends to be better tolerated (less adverse side effects) than standard chemotherapy. Types of targeted therapy o Hormone Therapy ▪ Glucocorticoid (e.g., prednisone). The functions use to  mitosis and  erythrocyte counts  appetite and sense of well being  inflammation & swelling around the tumour ▪ Sex hormone (e.g., Estrogen for prostate cancer) ▪ Hormone blocking agent (e.g., Tamoxifen as estrogen blocking agent in breast cancer)- Act to block receptors for growth promoters on cancer cells o Signal transduction inhibitors o Angiogenesis inhibitors: Inhibit the stimulus for growth of blood vessels o Gene expression modulators o Immunotherapy (detail in subsequent section) o Cancer vaccines and Biological therapies for cancer are sometimes considered as targeted therapies because they interfere with the growth of specific cancer cells 5 Jan 2022 Immunotherapy (https://www.cancer.gov/about-cancer/treatment/types/immunotherapy) Immunotherapy is a type of biological therapy, which involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Mechanisms: boost patient’s natural immune system to fight the cancer o Stopping or slowing the growth of cancer cells o Stopping cancer from spreading to other parts of the body o Helping the immune system work better at destroying cancer cells Types of immunotherapy o Monoclonal antibodies ▪ Use as targeted therapy to block an abnormal protein in cancer cell ▪ -umab drug (e.g., Nivolumab, Atezolizumab) o Non-specific immunotherapies ▪ interferon ▪ interleukins o Cytokines o Oncolytic virus therapy- ▪ Uses genetically modified viruses to kill cancer cells. ▪ Inject T-VEC directly into melanoma o T cell therapy or adoptive cell transfer ▪ A treatment that boosts the natural ability of patient’s T cells to fight cancer. o Cancer vaccines ▪ Cancer prevention vaccine: human papillomavirus (HPV) vaccine ▪ Cancer treatment vaccine 5 Jan 2022