Chemotherapy and Immunotherapy: A Comparative Overview

ONS/ONCC Chemotherapy Immunotherapy Certificate Lesson 1: Foundations to Set the Stage Focusing on Cellular Structure and Function -The cell cycle refers to the ordered seres of processes of DNA replication and mitosis, or cell division The Normal Cell Cycle -Cell nucleus regulates these processes by gathering and processing complexes molecular information Interphase and Mitotic Phase Cell division produces two identical cells through these two major phases Cell grows and DNA is replicated through the following three steps: 1: First growth phase (G1 or first gap) During interphase: 2: Synthesis phase (S phase) 3:Mitotic Phse (M phase) -cells increase in size -reproduce RNA First Growth Phase (G1 or first gap) -"quality assurance" test that the cell will be ready to synthesis DNA -Length of time is variable, can be from hours to days -DNA replicates -Results in the formation of identical pairs of DNA (chromatids) Synthesis Phase (S phase) -which are attached a t the centromere -lasts 2-10 hours Mitotic Phase (M phase) -Replicated chromosomes are aligned, separated, and move into 2 new, identical daughter cells -takes about 30-60 minutes -G1 checkpoint -S Phase Major points of cell regulation are entry and exit from -G2 checkpoint -M phase -The transition from the resting phase into an actively dividing phase (G0-G1) is a point where cellular transformation can occur Restriction Point -During this time, cells pass through a transition phase known as a restriction point -Extracellular growth factors trigger reentry into G1, and GF are required to send the cells past the restriction point, or the point of no return G0 Phase (resting phase) -After mitosis, cells may enter back into the G1 phase or go into a resting phase, known as G0 -Most cells in the human body reside in G0 -Exceptions to this are those that are metabollically active, such as 1 / 13 -granulocytes -Exceptions to this are those that are (Resting in G0 phase) -and the epithelium of the GI tract Cell Cycling Time Amount of time from mitosis to mitosis Cell cycle video and image http://highered.mheducation.com/sites/0072495855/student_view0/chapter2/animation__how_the_cell_cycle_works.html -The cell cycle is carefully controlled through a series of checkpoints -Variation in duplication or distribution of chromosomes during cell division can alter the genetic information passed on to daughter cells, leading to cellular dysfunction and disease, such as cancer Check points in the Cell Cycle: Keeping it All Under Control -These checkpoints monitor for DNA integrity and control progression through mitosis 1. cyclines (D, E, A, B) Progression through the cell cycle is controlled through two proteins: 2. Cyclin-dependent kinases (CDKs) -Cyclin-CDK complex allows the cell to progress through each phase of the cell cycle -(G0-G1) : Cyclin D and CDK 4/6 -Early S: Cyclin E and CDK 1/2 Locations of proteins Cyclins (D, E, A, B) and CDKs -Late S: Cyclin A and CDK 1/2 -G2: CDK 1/2 and cyclin A -Before M: CDK 1 and Cyclin B -prevent progression of the cycle when DNA damage is detected Inhibitory proteins -An example of an inhibitory protein is p53 (AKA TP53) -If DNA damage is present, cells are programmed to stop dividing or undergo apoptosis (programmed cell death) DNA Damage Checkpoints -The retinoblastoma protein (Rb), p53, and p21 are some of the most well-understood inhibitory proteins (IP) -Levels of this IP regulate several important target genes -Will increase when DNA damage is present Inhibitory proteins p53 -Protects against inappropriate signal proliferation -sometimes called the "suicide gene" When the cells prepare to divide, the chromosomes line up in the mitotic spindle. M Phase Checkpoints If the chromosomes are not properly aligned, division is not allowed to continue Immunity Cells of the Immune System -The cells of the immune system are created in the bome marrow from what is know as a ___ Pluripotent Stem Cell -A stem cell that can differentiate into any cell type except for extraembryotic tissue, does not yet have a function 2 / 13 Myeolid Precursor Cells Mature into: -RBCS -Plts -WBCs (Granulocytes) Lymphoid Precursor Cells Mature into: -Specialized WBCs called lymphocytes (Agranulocytes) Consists of 2 types of immunity: Lines of Defense: The Immune System's Response to Attack 1: Innate 2: Adaptive -First line of defense against a pathogen -Does not retain memory of the entity Innate Immunity -Involves the following: (skin, mucous membranes, and normal flora of the skin and gut) (Cellular components such as phagocytes, natural killer cells, granulocytes, and macrophages) 1.Cells that engulf and destroy invader 1. Phagocytes 2. Natural Killer Cells 3. Granulocytes 4. Macrophages 2. Cells that sense receptors on self and non-self to determine if they should kill or not 3. Type of WBC that have granules (Neutrophils Eosinophils - parasites Basophils - release histamine to stimulate immune response) 4. Large phagocytic cells stimulated by infection -Stimulated if innate immunity is insufficient -leads to immune system memory Adaptive Immunity -Humoral immunity -Cell-mediated immunity -Regulatory T-cells -B-Cells -Memory B-Cells -Plasma act to produce immunoglobulins (Igs) or antibodies Humoral Immunity -each one is programmed to make one specific antibody B-Cell -Can recognize antigens whether they are freely circulating in the blood or attached to surface of a microbe -When dividing, can become plasma cells which will then begin secreting antibodies that are unique to that antigen -some plasma cells will undergo apoptosis Plasma Cells -Some will go to the BM where they will continue to secrete antibodies sometimes for years Depends upon cytotoxic T cells and helper T cells and their cyokinds Cell-Mediated Immunity -more effective against antigens within cells Regulatory T-cells AKA suppressor T-Cells regulate the immune response to prevent autoimmune reactions and limit inflammatory responses 3 / 13 -Can only recognize antigens when they are presented to them by "presenting cells" T-Cell -Recognize phagocytized fragments of an antigen that are put on the surface of antigen-presenting cells -help other T-Cells by secreting chemicals -Help B Cells to respond Helper T-Cells (CD4+) -rapidly divide, in an effort to stay ahead of the antigen dividsion -some will turn into effector cells, which secrete different kinds of cytokines -respond similarly to B-Cells -Directly kill cells for which they are activated to kill Cytotoxic T-Cells (CD8+) -rapidly divide, become mature cells, and start killing antigens -Secreted by lymphocytes Cytokines -Tasked with eliminating the antigen -Multifunctional subsances having proinflammatory, anti-inflammatory, and regulatory functions in the immune system -Interferons (IFNs) -Tumor necrosis factors -Transforming GFs Cytokines Include.. -Interleukins (IL -1, -2, -3, -4, -6, -8, -10, and -15) -These cytokines regulate antibody production and the functions of B and T cells as well as interact with antigen-presenting cells and NKCs -encapsulated and grow in an orderly manner with smooth edges -Do not invade neighboring tissue Benign Tumors -DO not metastasize to distant sites -the cells well differentiated in that they look like the parent cell -Malignant tumors are not encapsulated -Cell structure is different from parent tissue (no as well differentiated) -Cell division is uncontrolled Characteristics of Cancer Cells -Cells are loosely adherent without contact inhibition -Cells are able to invade neighboring tissue -Cells can migrate and metastasize to distant sites -Can stimulate the development of new blood vessels to supply the tumor (angiogenesis) -regulate normal cell growth and division Proto-oncogene 4 / 13 -large family of genes that code for proteins and enzymes that turn on the cell cyle Oncogene when mistakes in copies of DNA can occur, if a mutation occurs next to a proto-oncogene, it can "turn on" and become a ______ 1. EGFR or Erb-B1 (codes for an epidermal GF receptor in the receptor-tyrosine kinase family ad is associated with head and neck and colorectal cancers) Examples of oncogoenes -EGFR inhibitor therapies are known to cause cutaneous reactions 2. Erb-B2 or HER2/neu (codes for an EGFR protein in the tyrosine kinase family and is associated with some breast cancers) -act like brakes in a car, slowing down or stopping cell growth and division Tumor suppressor genes -in the presence of malignancies, they bind to DNA with intention of repairing or activating apoptosis -for it to be turned on it must be expressed or "opened" in the DNA helix so that it can be transcribed or copied -"sucidie gene" p53 -activates apoptosis when the cell is damaged beyond repair or too old to function -more than 50% of solid tumors, the gene is mutated and unable to perform its normal function Growth Signals -cancer cells are able to find their own growth signals making them self-sufficient Signal transduction -the communication or passage of a message telling the cell to do a biologic process, such as make a protein, divide, or make new blood vessels 1. Messages usually sent from outside the cell where the messenger (ligand) first binds to the cell receptor which extended through the cell membrane 2. These receptors ae called receptor tyrosine kinases Signal transduction steps 3. To send the message through the membrane, the receptor often has to join with another recetor to become active and t autophophorylate 4. This is called dimerization and can be the following: Dimerization 1. Homodimerization: binding with the same type of receptor, such as an epidermal GF receptor (EGFR) 1 receptor with another EGFR 2. Heterodimerization: binding with a different kind of receptor, such as EGFR1 binding with EGFR2 -turned on by giving up a phosphate molecule Protein tyrosine kinases phosphorylates -the message is now send via a "bucket bridage", or passing the message from one molecule to other signaling molecules until the message gets first into the cell nucleus -where it is transcribed Pathways 5 / 13 many pathways and crossalks signaling btw and among the different pathways, and they all have the power to control cell behavior in one way or another -shown to decrease the benefits of some cancer drugs mitogen-activating protein kinase (Raf-1/MAPK) pathway -decrease disease-free survival time in some pts mammalian target of rapamycin (mTOR) survival pathway -play a role in resistance to some chemotherapy agents in certain pts by keeping cells that have been exposed to chemotherapy from undergoing apoptosis -role in angiogenesis phosphoinositide 3-kinases (PI3K) Neoadjuvant Treatment -transduction enzymes that activate Akt, leading to cell survival, increased cell proliferation, and growith -treatment given as a first step to shrink a tumor before the main treatment, usually surgery -examples: chemo, radiation therapy, hormone therapy -additonal cancer treatment given after the primary treatment to lower the risk that the cancer can recur Adjuvant therapy -Examples: chemo, radiation therapy, hormone therapy, targeted therapy, or biologic therapy -refers to the drug dose per unit of time Dose density -reduction of time between treatments to achieve higher concentration than in a standard treatment plan -amount of drug delivered over time Dose intensity -smaller doses of chemotherapy given more frequently Relative dose intensity (RDI) -calculated by comparing the dose that the pt received to the planned dose of the standard regimen Oral Chemotherapy -greater challenge to adherence because the responsibility falls on the pt and caregiver Nonadherence -pt takes too few or too many pills Overadherence -when a pt believes a dose was missed or that "more is better", too much medication may be taken, leading to increased toxicity Factor affecting adherence -provider relationship -side effects -necessity -routinization -support -lifestyle fit -cost -medication knowledge -pill burden -regiment complexity Lesson 2: Alkylating Agents Alkylating Agents -function by causing a break in the DNA helix strand, causing interference with DNA replication, which results in cell death -Nitrogen mustards (cyclophosphamide{Cytoxin}, ifosfamide{Ifex}, bendamustine{Treanda}) Alkylating Agent Subgroups -Platinum-based (cisplatin{Planitol}, carboplatin{Paraplatin}): do not possess an alkyl group -nitrosoureas 6 / 13 -subgroup of alkylating agents -able to cross the blood-brain barrier (effective in treating some brain tumors, melanomas, lymphomas) Nitrosoureas -Carmustine (BiCNU) -Lomustine (CeeNu) -Streptozocin (Zanosar) -pulmonary monitoring recommended -Alkylazing agent -possibility for a hypersensitivity reaction which is rash, urticaria, erythema, pruritis, rarely bronchospasm and hypotensision Carboplatin (Paraplatin) -notify RN if itching, scratchy throat, difficulty breathing, rash -Blood count, particularly platelets, monitored because thrombocytopenia is a dose-limiting toxicity -Oral dosage: 1-5mg/kg/day -Alkylating agent Cisplatin (Planitol) -nephrotoxic (IV hydration 2-3 L per day) -severe N/V -ovarian and testicular -Alkylating agent) -hemorrhagic cystitis (dysuria, hematuria, hemorrhage) Cyclophosphamide (Cytoxin) -DC treatment if hemorrhagic cystitis -adequate hydration -Alkylating agent -irritant and vesicant, extra caution with the IV site Oxaliplatin -peripheral neuropathy is a dose-limiting side effect (exacerbated by cold temperatures) -avoid cold drinks and foods, wearing gloves and warm shoes -avoid breathing cold air -injects chemo directly into the subarachnoid space so it reaches the CNS -Often used to treat leukemia and lymphoma that has spread to the CNS since most IV chemo does not cross the blood-brain barrier Intrathecal Chemotherapy -only MTX and cytarabine via this route -IT hydrocortisone is often given at the same time to reduce inflammation -MUST be preservative free to avoid CNS irritation -younger -have a hx of low or no alcohol consumption -are female Chemotherapy-Induced N/V (CINV) Risk factors 7 / 13 -hx of morning sickness -prone to motion sickness -have had chemo previously -Acute: occurring within 24 hours -Delayed: from 24 hour - 5 days after -Breakthrough: Occurring despite treatment Types of CINV -Anticipatory: triggered by taste, odor, memories, visions, anxiety r/t chemo -Refractory: occurring despite subsequent cycles when treatment failed in earlier cycles -limit exposure of hands and feet to hot water -take cool showers -avoid exposure to sources of heat, such as using saunas or sitting in the sun -avoid activities that cause unnecessary force or friction on the hands or feet, such as running or aerobics Prevention/Treatment of hand foot syndrome -avoid contact with harsh chemicals used in detergents and household cleaning products -avoid activities that require you to press your hand against a hard surface -elevate your hands and feet when sitting or lying down -gently apply skin care creams to keep hands moist -wear loose-fitting, well ventilated shoes -point at which blood cell counts are at their lowest following treatment Nadir -typically, but not always, occurs 7-10 days after the cycle is administered -ANC of less than 500/mm3 or Neutropenia -less than 1000/mm3 with the expectation that the count will drop below 500 in the next 48 hours -older than 65 -hx of neutropenia with previous chemo Neutopenia RF -previous chemo or radiation -hematologic malignancy, uncontrolled or advanced cancer, or lung cancer -temp of 38.3 or greater one time Neutropenic Fever -temp of 38 lasting 1 hour Absolute Neutrophil Count - (%segs + %bands) x (WBC) / 100 Mucositis -inflammation of the mucous membrane lining the digestive tract from mouth to anus 8 / 13 -affects 40-100% of pts Stomatitis -specifically inflammatory conditions of the mouth Xerostomia -dryness of the mouth caused by damage to or dysfunction of the salivary glands Hypersensitivity Reaction (HSR) -body mounts an immunologic response to a foreign substance or antigen, resulting in local tissue injury IgE-mediated -immediate (within 5 minute) HSR, present like classic allergic reactions T-Cell--Mediated -Delayed hypersensitivity reactions, can occur any time after the immediate hypersensitivity window, even days or weeks Type 1 HSR early S/SX -pruritus -restlessness, agitation, anxiety, feeling of impending doom -fever, flushing, chills -urticaria (hives) -maculopapular rash -edema of hands, face, and feet -N/V -dyspnea, wheezing, bronchospasm -hypotension, cyanosis -circulatory and respiratory collapse Type IV HSR -pneumonitis -mucositis -contact dermatitis -granulomas -Graph vs host disease Lesson 7: Cumulative Dose total amount of one antineoplastic agent given to the pt, adding up each time that the pt has received it Cumulative dose -"cumulative dose should not exceed..." Cumulative lifetime dose -total amount of specific antineoplastic agents that can be safely given over the course of a pt's lifetime Extravasation -leak of a drug capable of causing tissue damage from the vessel in which it is being administered into the surround tissue Irritant -causes inflammation, pain, and burning but rarely causes tissue necrosis Vesicants -causes blistering and significant pain and tissue damage and destruction, leading to tissue death -Do not use IV in hand, wrist, AC areas -Do NOT place the IV below a recent ventipuncture site used (<24 hours) Vesicants in PIVs -Use a flexible IV catheter 1. Immediately STOP administering the vesicant and IV fluids 2. Disconnect the IV tubing from the IV device. Do not remove the IV device or noncoring port needle When a vesicant extravasation occurs or is suspected, take the following steps: 3. Attempt to aspirate residual vesicant from the IV device or port needling use a small (1-3 mL) syringe 4. Remove the peripheral IV device or port needle 5. Initiate appropriate management measures 9 / 13 -Vinca Alkaloids (vincristine, vinblastine) -Do not bind to DNA in healthy cells when they extravasate into tissue. Indirect effect on healthy tissue Managing Non-DNA Binding Vesicant Extravasation -Treat with heat, elevation, and hyaluronidase local injection (spreads the vesicant through the tissue for faster metabolism of the vesicant agent) -Usually results in less tissue damage -Improves over a short period of time (days to weeks( --Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) -Binds to DNA in healthy cells when they extravasate into tissue Management of DNA-Binding Vesicant Extravasation -When not immediately treated with dexrazoxane, the vesicant remains in the tissue and invades adjacent healthy tissue -Likely to result in more tissue damage -Left untreated, extravasations become larger and deeper, worsening over time (weeks to months) Lesson 11: Targeted Therapy -targeted therapies act on specific molecular targets on or within the cells that are associated with cancer, whereas standard chemo act on all rapidly dividing cells -chemo has more SEs How targeted therapy and chemo differ -targeted therapy ae chosen and designed to interact with their target on or within the cells, whereas chemo were IDed becaused they kill cells -targeted therapies are often cytostatic (they block tumor cell proliferation) whereas chemo agents are cytotoxic (kill tumor cells) -disease cure when used as primary or adjuvant therapy -improving overall response or increase disease-free survival when used in combination with conventional therapies Goals of targeted therapy -controlling or stabilizing disease -maintaining or enhancing quality of life -decreasing the severity of toxicities from other therapies Receptor -molecule inside or on the surface of a cell that binds to a specific substance causes a specific effect in that cell Monomer molecule that can join with other identical monomers to form a structure called a polymer Ligand a substance that forms a complex with another biomolecule to exert a biologic effect Ligand Binding process by which the ligand attaches to a specific receptor site and activates that receptor, activating the signaling pathway Dimerization two monomers that are side-by-side on the surface of the cell are paired and activated by a ligand, which causes a series of signals 10 / 13 Kinase type of enzyme that adds chemicals called phosphates to other molecules such as sugars or proteins causing other molecules in the cell to become either active or inactive phosphorylation activation of a chemical process to initiate signaling 1. blocking angiogenesis 2. blocking signals inside or outside the cell targeted therapies work by doing the following 3. delivering toxic substances to the cell 4. stimulating the body's immune system -fusion protein tyrosine kinase formed with a gene translocation occurs between gene 9 and 22 BCR/ABL -gene abnormality called the Philadelphia chromosome seen in CML and ALL VEGF this is the primary angiogenic factor produced by cells -target of rapamycin mTOR -a protein that tells cells when to grow, divide, and survive 1. some intergere with action of VEGF which stimulates n ew blood vessel formation Two ways that angiogenesis inhibitors work 2. others target their molecules that stimulate new blood vessel growth -end in -ib Small Molecule Compound Targeted Therapies -targets located inside the cell because these gents are able to enter cells more easily -intracellular -most given orally - end in -mab -relatively large in size and therefore usually cannot enter cells Monoclonal Antibody Targeted Therapy -extracellular or transmembrane -man made version of antibodies that are designed to attack a very specific target on cancer cells -usually from mice Lesson 12: Immunotherapy -stopping or slowing the growth of cancer cells Immunotherapy works by -stopping cancer from spreading to other parts of the body -helping the immune system recognize cancer cells and increase its effectiveness at eliminating cancer cells -initate an antitumor effect but do not result in any immunologic memory Passive Immunotherapy -require repeated administration to be effective -includes monoclonal antibodies and cytokines 11 / 13 -capitalize on the immune system's ability to remember a foreign invade Active Immunotherapy -mount an immune response against the tumor and hopefully remember the cancer cells long after treatment has stopped -includes cancer vaccines -capitalize on tumor markers to specifically target and kill cancer cells Specific Immunotherapy -examples are mAbs and cancer vaccines -do no target cancer cells alone but rather stimulate a large immune response Nonspecific Immunotherapy -given adjuvantly to other anticancer treatment drugs -examples are cytokines, interleukins, and checkpoint inhibitors Lesson 13: Safe Handling 1. Elinination of the Hazard 2. Engineering Controls: Hierarchy of Hazard Controls aimed at reducing worker exposure 3. Administrative Controls 4. PPE: -highest level of protection from a hazardous exposure 1. Elimination of the Hazard: -substitute a less toxic substance for the hazardous material -not feasible with drug therapy -second highest level of protection 2. Engineering Controls -use of machines or equipment that isolate or contain the hazard to reduce worker exposure -Examples: biosafety cabinets and closed-system drug-transfer devices -third level of protection -safe handling policies 3. Administrative Controls -procedures -work practices -education and training of those responsible for HD handling -lowest form of protection 4. PPE -consisting of garments that provide barriers to protect workers from HDs -places the primary responsibility for protection on the worker 1. wash hands 2. inspect gloves Donning PPE 3. apply first pair of gloves 4. put on gown with gloves inside cuff 12 / 13 5. second pair of gloves over the cuff 6. put on eye and face protection 1. Remove outer gloves turning them inside out 2. remove the gown 3. remove the face shield Doffing PPE 4. properly dispose 5.remove inner gloves 6. wash hands -the AUC calculation incorporates renal function as part of the equation -Pts who have had previous radiation therapy or chemo are considered special populations with regard to a potential need for True statements related to drug dose calculation and administradose modification tion -The AUC calculation is used for carboplatin dosing -Children may metabolize drugs differently than adults; dose modifications are possible -mAbs are agents that are derived from human or mouse antibodies or a combination of the two -mAbs search out proteins on the cells surface -mAbs recognize and bind to specific anatigens on the cells surface What is a monoclonal antibody, and how is it different from chemo? -natural killer cells and/or cytotoxic proteins of the immune system recognize and destroy the marked tumor cells -mAbs can also directly induce cell death as well -One of the biggest differences is that mAbs cause harm only to those cells that are marked or binded -it is perfectly safe for you to have contact with your loved ones while getting treatment Should I avoid my grandchildren and other family members when -Hugging, kissing, and spending time together while eating are all I am getting treatment? safe activities -Safety with bodily fluids is necessary for the first 48 hours after receiving chemo -you should definiely check with your HCP first to be sure Can I be intimate with my partner during treatment? -traces of chemo may be present in vaginal fluid for up to 48 hours after treatment -use of a barrier is recommended for this reason for at least the first 48 hours 13 / 13