PHCY 602 Fall 2024 Hematology-Oncology PDF

PHCY 602 – Hematology-Oncology Fall 2024 Introduction to Oncology Week 1 Wednesday Aug 21 Slide deck 1 John Rimoldi, Ph.D., Professor of Medicinal Chemistry and Environmental Toxicology Objectives Review cancer facts and trends and define common t...

PHCY 602 – Hematology-Oncology Fall 2024 Introduction to Oncology Week 1 Wednesday Aug 21 Slide deck 1 John Rimoldi, Ph.D., Professor of Medicinal Chemistry and Environmental Toxicology Objectives Review cancer facts and trends and define common terms and concepts used in oncology Evaluate general features of chemotherapy-oncology Interpret survival curves and understand-define clinical trial endpoints Classify cancer based on histological nomenclatures Calculate Body Surface Area (BSA) using Mosteller equation and use to calculate chemo dosages Define chemo treatment strategies Understand both TMN and summary staging terminology Identify racial and gender disparities in cancer Discriminate between genetic and environmental cancer links 2  Links to Resources MEDSCAPE Homework: Establish a MEDSCAPE account; you will need it and --its free! American Cancer Society Facts and Figures 2024 National Comprehensive Cancer Network American Society of Clinical Oncology National Cancer Institute 3 Go to Medscape CME/CE article below Do You Know Your ADCs: An Interprofessional Approach to Identifying and Managing Adverse Events of Antibody-Drug Conjugates https://www.medscape.org/viewarticle/1001403 There are 3 videos to view—each ~ 10 minutes. Review each video—answer pre-and post-questions. At the end, you will be asked to Save and Proceed –you can view your answers and the correct answers. Do not EARN CREDIT 4  Textbook Resource: FREE online GOTO: ACCESS Pharmacy Pharmacotherapy: A Pathophysiologic Approach, 11e Section 19 Oncologic Disorders Chapter 144 Cancer Treatment and Chemotherapy 5 Review Clinical Trial Endpoint Terminology and Definitions Clinical trial endpoints We will be using these terms throughout the oncology module. Here are two good sources – Read these documents! You should be able to interpret basic features of Kaplan-Meier (survival) curves and understand differences between major clinical trial endpoints. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651701/pdf/bh0501022.pdf https://www.fda.gov/media/71195/download https://www.youtube.com/watch?v=gBUcw1Jmyw0 (video tutorial-simple) 6 Clinical Trial Endpoints – Terms you should learn Define -Compare and contrast –Advantages/Disadvantages Overall Survival –gold standard Symptom Endpoints Disease-Free Survival Objective Response Rate Complete Response Progression-Free Survival or Time to Progression 7 Example: Overall Survival (OS) Assesses time from randomization(experimental vs. standard therapy) to death. measure of how long a patient diagnosed with cancer remains alive-usually 5-year OS. Advantages Disadvantages: Can you name a few? Primary endpoint ? Easily measurable ? Definitive results Eliminates researcher bias 8 Facts and Figures: Leading Causes Death US: 2023 (provisional) 9 Facts and Figures: Estimated New Cancer Cases and Deaths US 2024 10 Facts and Figures: Trends in Cancer Death Rates –US Males 11 Facts and Figures: Trends in Cancer Death Rates –US Females 12 Facts and Figures: Trends in Incidence Rates for Selected Cancers by Sex, United States, 1975 to 2019 Males Females 13 Facts and Figures: 5-Year Cancer Survival Rates (%) 1975-2019 14  Oncogenesis: Development of Cancer A, Factors contributing to the generation of the cancer cell. B, The effects of these factors on the cell. C, The pathologic outcome of A and B, with the progression from normal tissue to invasive carcinoma highlighted. Hyperplasia : a general term for an increase in the number of the cells of an organ or tissue causing it to increase in size. (Example-Benign Prostatic Hyperplasia, also known as prostate enlargement.) Dysplasia: an abnormality in the appearance of cells indicative of an early step towards transformation into a neoplasia. In situ carcinoma: Represents a final transformation of a dysplastic cell to cancer, though the cancer remains local and has not metastasized. (Example, Ductal Carcinoma in Situ -DCIS-Breast) Invasive Cancer: Cancer which has invaded beyond the original tissue layer and is also able to spread to other parts 15 of the body (metastasize). If left untreated it is almost always fatal.  Cancer classification Cancers are classified in two ways: 1. By the histological type: tissue in which the cancer originates. 2. By the primary site, or the location in the body where the cancer first developed. From a histological standpoint there are hundreds of different cancers, which are grouped into six major categories: Carcinoma Sarcoma Myeloma Leukemia Lymphoma Mixed Types 16 Cancer classification: Malignant Carcinoma- cancer of epithelial cells (e.g., lung, breast, prostate, and colon) Sarcoma – cancer of connective tissue (muscle and bones) Myeloma- cancer of plasma cells of bone marrow. Leukemia – cancer of bone marrow. Lymphoma-cancer of lymphatic tissue 17 Cancer nomenclature: histological prefixes 18 Not all tumors (-omas) are malignant NCI tumor categories 19  Body Surface Area and Chemo Dosage of chemotherapeutics in units of mg/m2 Body Surface Area (BSA) is believed to be a more accurate measure that eliminates “adipose” effects. Criticized for not taking into account inter-patient variation in pharmacokinetics and PGx. Mosteller formula, 1987 Example: (Rimoldi) Weight= 210 lbs (95.2 kg) ; height = 74 inches (188 cm) Rimoldi BSA of 2.22 m2 The commonly accepted 50th percentiles for BSA are 1.94 m 2 for adult men and 1.69 m2 for adult women Mosteller RD. Simplified Calculation of Body Surface Area. N Engl J Med. 1987, 317, 1098. 20 BSA used to calculate dosage of oncology drugs (oral or IV) A physician orders 40 mg/m2 of a drug PO once daily. How many mg of drug would you need for an adult patient weighing 88 kg with a height of 150 cm? Round to 80 mg 21 General Features in Oncology Conventional options for treatment are available… 22 Illustrated in The Pillars of Cancer Care 23 General Features in Oncology But advanced technologies are here.. or on the horizon Molecular Biology Reports (2023) 50:9663–9676. https://doi.org/10.1007/s11033-023-08809-3 24  Chemotherapy Treatment -Definitions Neoadjuvant Chemotherapy delivered BEFORE the main treatment, to help reduce the size of a tumor or kill cancer cells that have spread. In many cancers, its used to downstage select patients with malignant tumors, thereby rendering the primary tumors and metastases resectable in some cases. Adjuvant Chemotherapy delivered AFTER primary treatment which attempts to eliminate micrometastasis; given to prevent a possible cancer recurrence. First line chemotherapy Chemotherapy determined to have the best probability of treating a given cancer. This may also be called standard therapy. Second line chemotherapy Chemotherapy that is given if a disease has not responded or reoccurred after first line chemotherapy. In some cases, this may also be referred to as salvage therapy. Palliative Chemotherapy aimed at improving or managing symptoms. Curative Elimination of all known tumor mass (Complete and Durable Response) 25 General Features in Oncology Chemotherapeutics act at various stages of cell cycle G0 26  General Features in Oncology Chemotherapeutics generally have a narrow therapeutic window ◼ Relationship Between Dose, Therapeutic Effect and Toxic Effect. ◼ The Therapeutic Window is Narrow for Most Cancer Drugs. ◼ TI=Therapeutic Index ◼ Toxic dose/effective dose ◼ TI of 3 or greater = safer drug 27 General Features in Oncology Chemotherapy produces adverse effects (off-target) Alopecia Mucositis Pulmonary fibrosis Nausea/vomiting Cardiotoxicity Diarrhea Cystitis Local reaction Sterility Renal failure Myalgia Myelosuppression Neuropathy Phlebitis 28 Chemotherapy-Induced Effects and Therapeutic Mitigation: –pre or -post chemo. Nausea and Vomiting (CINV) 5HT3 receptor antagonist (-setron class) Dexamethasone NK1 receptor antagonist (-pitant class) Peripheral Neuropathy (CIPN) No FDA approved therapies… yet (duloxetine?) Bone-Loss (CIBL) Bisphosphonates Neutropenia (CIN) and Febrile Neutropenia (CIFN) Neutrophil Enhancers Thrombocytopenia (CIT) Platelet Enhancers Anemia (CIA) Erythropoietin Stimulating Agents (ESA) 29 General Features in Oncology Drug resistance to chemotherapy-intrinsic or acquired “In its simplest definition, cancer therapy operates as a three- component system: (i) a therapy; that targets (ii) a population of cancer cells; within (iii) a particular host environment. The pharmacological properties of the therapy, together with intrinsic and acquired physical and molecular parameters of cancer cells and extrinsic environmental factors, result in the spectrum of clinical responses.” Drug resistance can be categorized as intrinsic or acquired resistance based on the time when it is developed. Intrinsic resistance exists before drug treatment while the acquired resistance is induced after therapy, each occurring in about 50% of cancer patients with drug resistance. READ ME: A view on drug resistance in cancer-Nature 2019 30  General Features in Oncology Oral anticancer drugs now represent a main component of cancer treatment “The growing use of oral chemotherapy is obvious and calls for investments in supporting patients in managing medication adherence and adverse events.” Link: National trends in the use of oral chemotherapy over 13 years “As the pace of drug development has recently accelerated, the development of oral agents has also increased. In the last 3 years alone (2019–2021), the FDA approved 44 new cancer therapies, of which 27 (61%) were oral anticancer agents.” Link: Oral Chemotherapy Metric Performance in Quality Oncology 31 Practice Initiative Practices: Updated Trends and Analysis  General Features in Oncology Cancer Staging is critical Staging describes the extent or spread of disease at the time of diagnosis. Proper staging is essential in determining treatment options and in assessing prognosis. It is used to gauge cancer extent and severity. Two staging systems generally used TNM Summary 32 The Summary Staging System (4 main types) More general of a system for staging In situ is early cancer that is present only in the layer of cells in which it began. Localized is cancer that is limited to the organ in which it began, without evidence of spread. Regional is cancer that has spread beyond the original (primary) site to nearby lymph nodes or organs and tissues. Distant (metastatic) is cancer that has spread from the primary site to distant organs or distant lymph nodes. 33 5-year survival rates by stage at diagnosis 34  The TNM Staging System (T) The size of the tumor and/or whether it has grown to involve nearby areas. (N) The absence or presence of regional lymph node involvement (M): absence or presence of distant metastases Once the T, N, and M are determined, a stage of 0, I, II, III, or IV is assigned, with stage I being early stage cancer and stage IV being the most advanced. Stage 0 is generally considered non-invasive 35 Relationship between TNM and Summary Staging Systems Stage 0 = Carcinoma in situ Stage I=Localized Stage II=Localized or Regional Stage III=Regional Stage IV=Distant 36 Racial Disparities in Cancer Death Rates (1975-2020) 37 Racial/Ethnic Disparities in Cancer Research Two tendencies were observed across oncological studies: lack of racial/ethnic information and overrepresentation of Caucasian/White samples/individuals. These results clearly indicate a need to diversify oncological studies to other populations along with novel strategies to enhanced race/ ethnicity data recording and reporting. 2018 -Analysis of Racial/Ethnic Representation in Basic/Applied Cancer studies 38 Factors Contributing to Cancer From the inside: Genetics Germline mutations From the outside: Dose and Exposure Somatic mutations Food and diet (Adiposity) Carcinogens (e.g., Tobacco-Smoking) Radiation (UV, X-ray, radon) Infectious Diseases 39 Cancer has a genetic component… 40  …But not entirely Most cancers are due to mutations that occur specifically within the group of the cells or the tissues that have cancer (somatic) and are not due to an inherited, genetic, germline susceptibility. The vast majority of cancer (about 90 percent) occur by chance due to what we call "sporadic mutations," and it's only five percent to 10 percent that are due to genes that we're born with. Lu, C. et al. Patterns and Functional Implications of Rare Germline Variants across 12 Cancer Types. Nat. Commun. 6:10086 doi: 10.1038/ncomms10086 (2015). 41 Cancer has a strong environmental component. Most cancers are neither “purely genetic” or “purely environmental” Lynch and de la Chapelle. N Engl J Med. 2003;348:919-932. Chernobyl Disaster: 1986 a catastrophic nuclear accident --explosion and fire released large quantities of radioactive particles into the atmosphere (137-Cs). APC is a autosomal dominant disorder, purely genetic—formation of polyps in large intestine—transforms to malignant. 42  Most cancers have both genetic and environmental components Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common known hereditary cause of colon cancer. BRCA1/BRCA2 are tumor suppressor genes; defects-mutations in these genes lead to defective protein products; correlated with increased risk of breast cancer. 43 Forward Looking: Example NABPLEX question A 42 year old female with no significant past medical history is diagnosed with breast cancer that will require Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide). Which of the following adverse effects are significantly associated with this regimen and require monitoring? Select all that apply. A. Cardiomyopathy B. Extravasation C. Hyperthyroidism D. Hemorrhagic cystitis E. Myelosuppression 44