Lesson 1: Foundations to Set the Stage
Focusing on Cellular Structure and Function
The Normal Cell Cycle
-The cell cycle refers to the ordered seres of processes of DNA replication and mitosis, or cell division
-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
During interphase:
Cell grows and DNA is replicated through the following three steps:
1: First growth phase (G1 or first gap)
2: Synthesis phase (S phase)
3:Mitotic Phse (M phase)
First Growth Phase (G1 or first gap)
-cells increase in size
-reproduce RNA
-“quality assurance” test that the cell will be ready to synthesis DNA
-Length of time is variable, can be from hours to days
Synthesis Phase (S phase)
-DNA replicates
-Results in the formation of identical pairs of DNA (chromatids)
-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
Major points of cell regulation are entry and exit from
-G1 checkpoint
-S Phase
-G2 checkpoint
-M phase
Restriction Point
-The transition from the resting phase into an actively dividing phase (G0-G1) is a point where cellular transformation can occur
-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 (Resting in G0 phase)
-Exceptions to this are those that are metabollically active, such as
-granulocytes
-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
Check points in the Cell Cycle: Keeping it All Under Control
-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
-These checkpoints monitor for DNA integrity and control progression through mitosis
Progression through the cell cycle is controlled through two proteins:
- cyclines (D, E, A, B)
- Cyclin-dependent kinases (CDKs)
-Cyclin-CDK complex allows the cell to progress through each phase of the cell cycle
Locations of proteins Cyclins (D, E, A, B) and CDKs
-(G0-G1) : Cyclin D and CDK 4/6
-Early S: Cyclin E and CDK 1/2
-Late S: Cyclin A and CDK 1/2
-G2: CDK 1/2 and cyclin A
-Before M: CDK 1 and Cyclin B
Inhibitory proteins
-prevent progression of the cycle when DNA damage is detected
-An example of an inhibitory protein is p53 (AKA TP53)
DNA Damage Checkpoints
-If DNA damage is present, cells are programmed to stop dividing or undergo apoptosis (programmed cell death)
-The retinoblastoma protein (Rb), p53, and p21 are some of the most well-understood inhibitory proteins (IP)
Inhibitory proteins p53
-Levels of this IP regulate several important target genes
-Will increase when DNA damage is present
-Protects against inappropriate signal proliferation
-sometimes called the “suicide gene”
M Phase Checkpoints
When the cells prepare to divide, the chromosomes line up in the mitotic spindle.
If the chromosomes are not properly aligned, division is not allowed to continue
Immunity
Cells of the Immune System
Pluripotent Stem Cell
-The cells of the immune system are created in the bome marrow from what is know as a _
-A stem cell that can differentiate into any cell type except for extraembryotic tissue, does not yet have a function
Myeolid Precursor Cells
Mature into:
-RBCS
-Plts
-WBCs (Granulocytes)
Lymphoid Precursor Cells
Mature into:
-Specialized WBCs called lymphocytes (Agranulocytes)
Lines of Defense: The Immune System’s Response to Attack
Consists of 2 types of immunity:
1: Innate
2: Adaptive
Innate Immunity
-First line of defense against a pathogen
-Does not retain memory of the entity
-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)
- Phagocytes
- Natural Killer Cells
- Granulocytes
- Macrophages
1.Cells that engulf and destroy invader - Cells that sense receptors on self and non-self to determine if they should kill or not
- Type of WBC that have granules (Neutrophils
Eosinophils – parasites
Basophils – release histamine to stimulate immune response) - Large phagocytic cells stimulated by infection
Adaptive Immunity
-Stimulated if innate immunity is insufficient
-leads to immune system memory
-Humoral immunity
-Cell-mediated immunity
-Regulatory T-cells
Humoral Immunity
-B-Cells
-Memory B-Cells
-Plasma act to produce immunoglobulins (Igs) or antibodies
B-Cell
-each one is programmed to make one specific antibody
-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
Plasma Cells
-some plasma cells will undergo apoptosis
-Some will go to the BM where they will continue to secrete antibodies sometimes for years
Cell-Mediated Immunity
Depends upon cytotoxic T cells and helper T cells and their cyokinds
-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
T-Cell
-Can only recognize antigens when they are presented to them by “presenting cells”
-Recognize phagocytized fragments of an antigen that are put on the surface of antigen-presenting cells
Helper T-Cells (CD4+)
-help other T-Cells by secreting chemicals
-Help B Cells to respond
-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
Cytotoxic T-Cells (CD8+)
-Directly kill cells for which they are activated to kill
-rapidly divide, become mature cells, and start killing antigens
Cytokines
-Secreted by lymphocytes
-Tasked with eliminating the antigen
-Multifunctional subsances having proinflammatory, anti-inflammatory, and regulatory functions in the immune system
Cytokines Include..
-Interferons (IFNs)
-Tumor necrosis factors
-Transforming GFs
-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
Benign Tumors
-encapsulated and grow in an orderly manner with smooth edges
-Do not invade neighboring tissue
-DO not metastasize to distant sites
-the cells well differentiated in that they look like the parent cell
Characteristics of Cancer Cells
-Malignant tumors are not encapsulated
-Cell structure is different from parent tissue (no as well differentiated)
-Cell division is uncontrolled
-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)
Proto-oncogene
-regulate normal cell growth and division
-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 __
Examples of oncogoenes
- 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)
-EGFR inhibitor therapies are known to cause cutaneous reactions
- Erb-B2 or HER2/neu (codes for an EGFR protein in the tyrosine kinase family and is associated with some breast cancers)
Tumor suppressor genes
-act like brakes in a car, slowing down or stopping cell growth and division
-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
p53
-“sucidie gene”
-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
Signal transduction steps
- Messages usually sent from outside the cell where the messenger (ligand) first binds to the cell receptor which extended through the cell membrane
- These receptors ae called receptor tyrosine kinases
- To send the message through the membrane, the receptor often has to join with another recetor to become active and t autophophorylate
- This is called dimerization and can be the following:
Dimerization
- Homodimerization: binding with the same type of receptor, such as an epidermal GF receptor (EGFR) 1 receptor with another EGFR
- Heterodimerization: binding with a different kind of receptor, such as EGFR1 binding with EGFR2
Protein tyrosine kinases phosphorylates
-turned on by giving up a phosphate molecule
-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
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
mitogen-activating protein kinase (Raf-1/MAPK) pathway
-shown to decrease the benefits of some cancer drugs
-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)
-transduction enzymes that activate Akt, leading to cell survival, increased cell proliferation, and growith
Neoadjuvant Treatment
-treatment given as a first step to shrink a tumor before the main treatment, usually surgery
-examples: chemo, radiation therapy, hormone therapy
Adjuvant therapy
-additonal cancer treatment given after the primary treatment to lower the risk that the cancer can recur
-Examples: chemo, radiation therapy, hormone therapy, targeted therapy, or biologic therapy
Dose density
-refers to the drug dose per unit of time
-reduction of time between treatments to achieve higher concentration than in a standard treatment plan
Dose intensity
-amount of drug delivered over time
-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
Alkylating Agent Subgroups
-Nitrogen mustards (cyclophosphamide{Cytoxin}, ifosfamide{Ifex}, bendamustine{Treanda})
-Platinum-based (cisplatin{Planitol}, carboplatin{Paraplatin}): do not possess an alkyl group
-nitrosoureas
Nitrosoureas
-subgroup of alkylating agents
-able to cross the blood-brain barrier (effective in treating some brain tumors, melanomas, lymphomas)
-Carmustine (BiCNU)
-Lomustine (CeeNu)
-Streptozocin (Zanosar)
-pulmonary monitoring recommended
Carboplatin (Paraplatin)
-Alkylazing agent
-possibility for a hypersensitivity reaction which is rash, urticaria, erythema, pruritis, rarely bronchospasm and hypotensision
-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
Cisplatin (Planitol)
-Alkylating agent
-nephrotoxic (IV hydration 2-3 L per day)
-severe N/V
-ovarian and testicular
Cyclophosphamide (Cytoxin)
-Alkylating agent)
-hemorrhagic cystitis (dysuria, hematuria, hemorrhage)
-DC treatment if hemorrhagic cystitis
-adequate hydration
Oxaliplatin
-Alkylating agent
-irritant and vesicant, extra caution with the IV site
-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
Intrathecal Chemotherapy
-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
-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
Chemotherapy-Induced N/V (CINV) Risk factors
-younger
-have a hx of low or no alcohol consumption
-are female
-hx of morning sickness
-prone to motion sickness
-have had chemo previously
Types of CINV
-Acute: occurring within 24 hours
-Delayed: from 24 hour – 5 days after
-Breakthrough: Occurring despite treatment
-Anticipatory: triggered by taste, odor, memories, visions, anxiety r/t chemo
-Refractory: occurring despite subsequent cycles when treatment failed in earlier cycles
Prevention/Treatment of hand foot syndrome
-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
-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
Nadir
-point at which blood cell counts are at their lowest following treatment
-typically, but not always, occurs 7-10 days after the cycle is administered
Neutropenia
-ANC of less than 500/mm3 or
-less than 1000/mm3 with the expectation that the count will drop below 500 in the next 48 hours
Neutopenia RF
-older than 65
-hx of neutropenia with previous chemo
-previous chemo or radiation
-hematologic malignancy, uncontrolled or advanced cancer, or lung cancer
Neutropenic Fever
-temp of 38.3 or greater one time
-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
-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
Cumulative dose
total amount of one antineoplastic agent given to the pt, adding up each time that the pt has received it
Cumulative lifetime dose
-“cumulative dose should not exceed…”
-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
Vesicants in PIVs
-Do not use IV in hand, wrist, AC areas
-Do NOT place the IV below a recent ventipuncture site used (<24 hours)
-Use a flexible IV catheter
When a vesicant extravasation occurs or is suspected, take the following steps:
- Immediately STOP administering the vesicant and IV fluids
- Disconnect the IV tubing from the IV device. Do not remove the IV device or noncoring port needle
- Attempt to aspirate residual vesicant from the IV device or port needling use a small (1-3 mL) syringe
- Remove the peripheral IV device or port needle
- Initiate appropriate management measures
Managing Non-DNA Binding Vesicant Extravasation
-Vinca Alkaloids (vincristine, vinblastine)
-Do not bind to DNA in healthy cells when they extravasate into tissue. Indirect effect on healthy tissue
-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(
Management of DNA-Binding Vesicant Extravasation
–Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin)
-Binds to DNA in healthy cells when they extravasate into tissue
-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
How targeted therapy and chemo differ
-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
-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)
Goals of targeted therapy
-disease cure when used as primary or adjuvant therapy
-improving overall response or increase disease-free survival when used in combination with conventional therapies
-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
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
targeted therapies work by doing the following
- blocking angiogenesis
- blocking signals inside or outside the cell
- delivering toxic substances to the cell
- stimulating the body’s immune system
BCR/ABL
-fusion protein tyrosine kinase formed with a gene translocation occurs between gene 9 and 22
-gene abnormality called the Philadelphia chromosome seen in CML and ALL
VEGF
this is the primary angiogenic factor produced by cells
mTOR
-target of rapamycin
-a protein that tells cells when to grow, divide, and survive
Two ways that angiogenesis inhibitors work
- some intergere with action of VEGF which stimulates n ew blood vessel formation
- others target their molecules that stimulate new blood vessel growth
Small Molecule Compound Targeted Therapies
-end in -ib
-targets located inside the cell because these gents are able to enter cells more easily
-intracellular
-most given orally
Monoclonal Antibody Targeted Therapy
- end in -mab
-relatively large in size and therefore usually cannot enter cells
-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
Immunotherapy works by
-stopping or slowing the growth of cancer cells
-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
Passive Immunotherapy
-initate an antitumor effect but do not result in any immunologic memory
-require repeated administration to be effective
-includes monoclonal antibodies and cytokines
Active Immunotherapy
-capitalize on the immune system’s ability to remember a foreign invade
-mount an immune response against the tumor and hopefully remember the cancer cells long after treatment has stopped
-includes cancer vaccines
Specific Immunotherapy
-capitalize on tumor markers to specifically target and kill cancer cells
-examples are mAbs and cancer vaccines
Nonspecific Immunotherapy
-do no target cancer cells alone but rather stimulate a large immune response
-given adjuvantly to other anticancer treatment drugs
-examples are cytokines, interleukins, and checkpoint inhibitors
Lesson 13: Safe Handling
Hierarchy of Hazard Controls aimed at reducing worker exposure
- Elinination of the Hazard
- Engineering Controls:
- Administrative Controls
- PPE:
- Elimination of the Hazard:
-highest level of protection from a hazardous exposure
-substitute a less toxic substance for the hazardous material
-not feasible with drug therapy
- Engineering Controls
-second highest level of protection
-use of machines or equipment that isolate or contain the hazard to reduce worker exposure
-Examples: biosafety cabinets and closed-system drug-transfer devices
- Administrative Controls
-third level of protection
-safe handling policies
-procedures
-work practices
-education and training of those responsible for HD handling
- PPE
-lowest form of protection
-consisting of garments that provide barriers to protect workers from HDs
-places the primary responsibility for protection on the worker
Donning PPE
- wash hands
- inspect gloves
- apply first pair of gloves
- put on gown with gloves inside cuff
- second pair of gloves over the cuff
- put on eye and face protection
Doffing PPE
- Remove outer gloves turning them inside out
- remove the gown
- remove the face shield
- properly dispose
5.remove inner gloves
- wash hands
True statements related to drug dose calculation and administration
-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 dose modification
-The AUC calculation is used for carboplatin dosing
-Children may metabolize drugs differently than adults; dose modifications are possible
What is a monoclonal antibody, and how is it different from chemo?
-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
-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
–
Should I avoid my grandchildren and other family members when I am getting treatment?
-it is perfectly safe for you to have contact with your loved ones while getting treatment
-Hugging, kissing, and spending time together while eating are all safe activities
-Safety with bodily fluids is necessary for the first 48 hours after receiving chemo
Can I be intimate with my partner during treatment?
-you should definiely check with your HCP first to be sure
-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
3 major phases of cell division:
Interphase
Mitotic phase
Cytokinesis
3 steps of interphase:
First growth phase (G1)
Synthesis phase (S phase)
Second growth phase (G2)
4 phases of mitosis:
Prophase
Metaphase
Anaphase
Telophase
Innate immunity:
Non-specific response, either:
- Barrier (skin, mucous membranes, flora of skin/gut)
- Cellular components (phagocytes, natural killer cells, granulocytes, macrophages)
Adaptive immunity:
Follows innate immunity if unsuccessful. Memory immunity, including:
- Humoral immunity (production of antibodies or immunoglobulins)
- Cell mediated immunity (dependent upon T cells)
- Regulatory T -cells (prevent autoimmune reactions and limit inflammatory responses)
Define mutations
Variations in the nucleotide sequence of a gene
3 main goals of treatment:
Cure
Control
Palliation
Define neoadjuvant therapy
Treatment is given prior to surgery to shrink the tumor
Define adjuvant therapy
Additional cancer treatment given after the primary treatment to lower the risk that the cancer reoccur
Define conditioning/preparative therapy
Treatments used to prepare a patient for stem cell transplantation
2 types of conditioning therapies:
Myeloablative
Nonmyeloablative
Define dose density
Drug dose per unit of time
Define dose intensity
Amount of drug delivered over time
How is relative dose intensity (RDI) calculated?
By comparing the dose that the patient ACTUALLY received to the planned dose of the standard regimen
How do alkylating agents work?
By causing a break in the DNA helix strand, interfering with DNA replication and causing cell death
3 subcategories of alkylating agents:
- Nitrogen mustards
- Platinum-based agents (do not possess an alkyl group but still termed alkylating agents as they work similarly)
- Nitrosoureas
Most common subcategory of alkylating agents:
Nitrogen mustards
Common alkylating agents:
Cyclophosphamide (Cytoxan)
Ifosfamide (Ifex)
Bendamustine (Treanda)
Common platinum-based agents:
Cisplatin (Platinol)
Carboplatin (Paraplatin)
What is unique about nitrosoureas agents?
Able to cross the blood-brain barrier; can be effective in treating some brain tumors
Common nitrosoureas agents:
Carmustine (BiCNU)
Lomustine (CeeNu)
Streptozocin (Zanosar)
Hypersensitivity can occur with late doses of:
Carboplatin
These agents are typically categorized as highly emetogenic:
- Alkylating agents
- Nitrosoureas
Pre-administration labs for alkylating agents and nitrosoureas:
BUN
Creatinine
CBC w/ diff
What is the medication Mesna used for?
Bladder protectant with administration of cyclophosphamide or ifosfamide
Instruct pts receiving __ to avoid exposure to cold air and consuming cold fluids for 3-4 days following treatment
Oxaliplatin
How do antimetabolites function?
By blocking DNA and RNA growth by interfering with enzymes needed for normal cell metabolism
Antimetabolites work in the _ phase.
S
What types of cells are best affected by antimetabolites?
Cells with high division rates
Common side effects of antimetabolites:
Myelosuppression
GI toxicities
Photosensitivity
Hand-foot syndrome
Common antimetabolite drugs:
Azacitidine
Capecitabine
5-FU
Cytarabine
Decitabine
Methotrexate
The institute for Safe Medication Practices recommends what route of administration for vincristine?
IV piggyback via gravity
Anthracycline antitumor abx work by:
Interfering with enzymes necessary for DNA to replicate in ALL phases of the cell cycle
The two major classifications of antitumor antibiotics are:
Anthracyclines
Non-anthracyclines
Common anthracycline antitumor abx:
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
The antitumor abx _ is not an anthracycline, but has anthracycline-type properties.
Mitoxantrone
Common non-anthracycline antitumor abx:
Actinomycin D
Mitomycin C
Bleomycin
Monitoring necessary with doxorubicin:
Vesicant –> extravasation
Cardiac function
Lifetime dose tracking (cardiotoxicity)
Lifetime dose of doxorubicin should not exceed:
550 mg/m^2
What cardiac protectant medication can be administered prior to doxorubicin?
Dexrazoxane
Significant side effects of doxorubicin are:
Cardiotoxicity
N/V
Mucositis
Diarrhea
Severe myelosuppression
Hepatic impairment
Secondary cancers
Monitoring necessary with bleomycin:
Pulmonary toxicity
Hypersensitivity reactions (esp. in lymphoma patients)
Cutaneous reactions
Lifetime dose tracking (pulmonary toxicity)
Pulmonary fibrosis is possible when the lifetime dose of bleomycin exceeds:
400 units
What 6 patient characteristics make CINV more likely?
- Younger than 50 years
- Hx of low alcohol intake
- Female gender
- Hx of morning sickness during pregnancy
- Prone to motion sickness
- Previous chemotherapy
Types of CINV:
Acute
Delayed
Breakthrough
Anticipatory
Refractory
Define acute CINV
Occurring within 24 hours of chemotherapy
Define delayed CINV
Occurring from 24 hours to 5 days after treatment
Define breakthrough CINV
Occurring despite treatment
Define anticipatory CINV
Triggered by taste, odor, memories, visions, or anxiety related to chemotherapy
Define refractory CINV
Occurring during subsequent cycles when treatment failed in earlier cycles
Highly emetogenic chemo (HEC) causes CINV in more than _% of patients
90
Moderately emetogenic chemo (MEC) causes CINV in patients % to % of the time
30-90
Patients on low-potential emetogenic chemo develop CINV % to % of the time
10-30
Minimal-risk emetogenic chemo causes CINV less than _% of the time
10
Common IV HEC drugs include:
Carmustine
Cisplatin
Cyclophosphamide
Dacarbazine
Mechlorethamine
Streptozosin
Common IV MEC drugs include:
Carboplatin
Cytarabine
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Ifosfamide
Irinotecan
Oxaliplatin
Common low-potential IV emetogenic chemo drugs include:
5-FU
Cytarabine
Docetaxel
Etoposide
Gemcitabine
Methotrexate
Mitomycin C
Mitoxantrone
Paclitaxel
Pemetrexed
Common minimal-risk IV emetogenic chemo drugs include:
Bleomycin
Bevacizumab
Bortezomib
Busulfan
Cetuximab
Fludarabine
Trastuzumab
Vinca alkaloids
The 2 most important neurotransmitters involved in vomiting are:
- Serotonin
- Substance P
Describe the peripheral pathway of CINV
Primarily occurs in the GI tract
Associated with acute CINV
Neurotransmitter –> serotonin
Describe the central pathway of CINV
Primarily occurs in the brain
Associated with delayed CINV
Neurotransmitter –> Substance P
Common serotonin 5-HT3 antagonists used for CINV:
Dolasetron
Granisetron
Ondansetron
Palonosetron
Common neurokinin-1 antagonists used for CINV:
Aprepitant
Fosaprepitant
Common steroids used for CINV:
Dexamethasone
2 types of therapies that commonly have cutaneous reactions:
- EGFR inhibitor therapies
- Antimetabolites
Most-common cutaneous reaction seen with 5-FU and Capecitabine:
Palmar-plantar erythrodysesthesia AKA hand-foot syndrome
Antimetabolites that commonly cause cutaneous reactions:
5-FU
Capecitabine (Xeloda)
Define myelosuppression
Bone marrow activity is decreased, resulting in fewer RBCs, WBCs and platelets
If severe: myeloablation
The most common dose-limiting toxicity of chemotherapy
Myelosuppression
Define nadir, and when does it occur?
The point at which blood cell counts are at their lowest following a treatment cycle.
Typically occurs 7-10 days following cycle
NCCN defines neutropenia as an ANC < _/mm^3
500
Risk factors for developing neutropenia include:
65 years old
Hx of neutropenia with previous chemotherapy
Hx of chemotherapy or radiation treatment
Hematologic malignancy
Uncontrolled/advanced cancer
Lung cancer
Define neutropenic fever
Fever of 101 F or greater one time
OR
Fever of 100.4 F lasting one hour or longer
ANC calculation
(% polys + % bands) x (WBC)/100
Normal WBC count
4,500-10,000
Normal neutrophil count
54%-62% of WBC
An ANC of less that _ is considered a risk for infection
1,000
Define thrombocytopenia
Low platelet count
Symptoms of thrombocytopenia
Petechiae or easily bruising
Headaches
Hypotension and tachycardia
Prolonged bleeding (gums, menstruation)
Define anemia
Deficiency of RBC or hemoglobin in the blood
Symptoms of anemia
Dyspnea
Fatigue
Dizziness
Headaches
Acute diarrhea lasts:
1-2 days and resolves on its own
Persistent diarrhea lasts:
2-4 weeks
Chronic diarrhea lasts:
4 weeks
Common constipation-causing agents:
Vinca alkaloids (vincristine and vinorelbine)
Thalidomide
Lenalidomide
Bortezomib
Define mucositis
Inflammation of the mucous membranes lining the digestive tract from mouth to anus
Define stomatitis
Inflammatory conditions of the mouth specifically
AKA oral mucositis
Define xerostomia
Dryness of the mouth caused by damage to or dysfunction of the salivary glands
Common diarrhea-causing agents:
Irinotecan
5-FU
Paclitaxel
Dactinomycin
Capecitabine
Hypersensitivity reaction (HSR) versus anaphylaxis
HSR- localized tissue injury; generalized
Anaphylaxis- severe inflammatory response; systemic; caused by histamine release
Immediate HSR can occur:
Within 5 minutes of start of infusion to 6 hours following infusion
Delayed HSR can occur:
Days or weeks after immediate HSR window
Risk factors for HSR and anaphylaxis:
Administration of a known HSR causing agent
Hx of allergies
Hx of hypersensitivity or anaphylaxis
Premedications not ordered/administered
First thing to do if a HSR occurs:
STOP THE INFUSION IMMEDIATELY
Define cumulative dose
Total dose of an antineoplastic agent or radiation after repeated exposure to the treatment
Define single dose
Recommended dose of one antineoplastic agent given at a single point in time
Define course dose (AKA divided dose)
Recommended dose of one antineoplastic agent given over a defined period of time
Define extravasation
Leak of a drug capable of causing tissue damage from the intended vessel into the surrounding tissue or unintended sites
Agents classified as irritants can cause:
Inflammation
Pain
Burning
** Rarely cause tissue necrosis comparable to vesicants
Agents classified as vesicants can cause:
Blistering
Significant pain
Tissue damage and destruction
**Lead to tissue death
Define infiltration
Leakage of non-vesicant/non-irritant solutions into surrounding tissue
Common plant alkaloids:
Etoposide
Docetaxel
Paclitaxel
Vinblastine
Vinorelbine
Vinca alkaloids are ALL administered (1) and should NEVER be administered (2), as this will result in patient death
- Intravenously
- Intrathecally
How does hormone therapy work?
Attempts to add, block, or remove hormones from the body to interrupt cancer cell division
LHRH agonists MOA
Produce an initial increase in LH and FSH, which can cause a flare. Then lower testosterone made by testicles and estrogen & progesterone made by ovaries
*Prostate cancer
*Estrogen receptor-positive, premenopausal metastatic breat cancer
LHRH antagonists MOA
Directly inhibits pituitary from releasing LH and FSH
*No tumor flare
Most common type of breast cancer
Hormone receptor (HR)-positive breast cancer
Aromatase inhibitors MOA
Block the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body
**Less estrogen is available to stimulate growth of HR-positive breast cancer cells
2 types of aromatase inhibitors
- Steroidal (irreversible)
- Nonsteroidal (reversible)
3 aromatase inhibitors
Anastrozole
Letrozole
Exemestane
Common side effects of aromatase inhibitors (AI):
Fatigue
N/V*
Weakness
HA*
Insomnia
Dizziness
Hot flashes*
Weight gain*
Higher cholesterol
Increased sweating*
Bone/joint pain*
Selective ER downregulators (SERDs) MOA
Binding to and degrading ER
Common SERD
Fulvestrant
Selective ER modulators (SERMs) MOA
Blocking and downregulating ERs
*Can function as ER agonists, antagonists, or mixed agonist-antagonists
*Can activate or block estrogen
Common SERMs
Tamoxifen
Raloxifine
Bazedoxifine
Antiandrogens MOA
Keeps androgens from binding to androgen receptors found in prostate cancer cells (and in some other tissue cells)
Androgen synthesis inhibitors MOA
Stop the adrenal glands from producing androgens
Common androgen synthesis inhibitors
Ketoconazole
Aminoglutethimide
Abiraterone acetate
CYP17 inhibitors MOA
Inhibit the key enzyme that catalyzes biosynthesis of androgens from all sources
Common CYP17 inhibitors
Abiraterone
Orteronel
Adrenolytic agents MOA
Suppress testicular and adrenal steroidogenesis, rapidly reducing testosterone levels
Define receptor
Molecule inside/on surface of a cell that binds to a specific substance and causes a specific effect in that cell
Define monomer
Molecule that can be bonded to other identical molecules to form a polymer
Define ligand
Molecule that binds to a receptor to exert a biologic effect
Define ligand bonding
Process by which ligand attaches to specific receptor site and activates receptor, activating the signaling pathway
Define dimerization
2 monomers that are side-by-side on cell surface are paired and activated by a ligand, which causes a series of signals
Define kinase
Enzyme that adds phosphates to other molecules, causing other molecules in the cell to become either active or inactive
Define phosphorylation
Activation of a chemical process to initiate signaling
Targeted therapies work by:
- Blocking angiogenesis
- Blocking signals inside or outside the cell
- Delivering toxic substances to the cell
- Simulating the body’s immune system
__ has been described as a way to “fire up the immune system’s response to cancer”
Immunotherapy
Immunotherapy works by the following 3 ways:
- Stopping or slowing the growth of cancer cells
- Stopping cancer cells from spreading to other parts of the body
- Helping the immune system recognize cancer cells and increase its effectiveness at eliminating cancer cells
What sets immunotherapy apart from traditional chemotherapy?
Highly specific
Trained to remember cancer cells
Immunotherapy categories:
Passive
Aggressive
Specific
Nonspecific
Passive immunotherapy MOA
Administered to initiate an antitumor effect
*Do not result in any immunologic memory
Examples of passive immunotherapy
Monoclonal antibodies
Cytokines
Active immunotherapy MOA
Mount an immune response against tumor
*Should remember cancer cells long after treatment has stopped
Examples of active immunotherapy
Cancer vaccines
Specific immunotherapy MOA
Target tumor markers or tumor-associated antigens (TAAs) to kill cancer cells
Examples of specific immunotherapy
mAbs
Cancer vaccines
Nonspecific immunotherapy MOA
Stimulate a large immune response
*Given adjuvantly to other anticancer treatment drugs
Examples of nonspecific immunotherapy
Cytokines, interleukins, checkpoint inhibitors
2 different ways that immunotherapies work against cancer:
- Triggering the immune system to destroy cancer cells
- Boost immune system’s ability to fight cancer
6 main types of immunotherapy
- Monoclonal antibodies
- Immune checkpoint inhibitors
- Cancer vaccines
- Nonspecific immunotherapies
- Adoptive cell therapy (CAR T-cell therapy)
- Oncolytic virus therapy
mAbs MOA
Mark cancer cell surface receptor/antigen to make the cell visible to the immune system to destroy
Different types of mAbs used in treatment of cancer
Naked mAbs
Conjugated monoclonal antibodies
Bispecific monoclonal antibodies
mAbs ending in “-ximab” source
Chimeric human-mouse
mAbs ending in “-zumab” source
Humanized mouse
mAbs ending in “-umab” source
Fully human
mAbs ending in “-omab” source
Murine mouse
Immune checkpoint inhibitors MOA
Prevent cancer cells from turning off T cells –> allows T cells to infiltrate a tumor and stop it from growing
Immune checkpoint inhibitors initially cause tumors to swell, making it appear as if the tumor is growing. This is called _
Pseudoprogression
2 main types of cancer vaccines
Preventative/prophylactic
Treatment/therapeutic
Nonspecific immunotherapies MOA
Stimulating the immune system in a general way, hopefully leading to a better immune response against cancer cells
Adoptive cell therapy MOA
T cells collected from patient
T cells grown in laboratory
This increases amount of T cells able to kill cancer cells or fight infections
T cells given back to patient to help immune system
Oncolytic virus therapy MOA
Naturally occurring or genetically engineered virus that can infect and kill a cancer call without harming normal cells
Common side effects of immunotherapies
Fatigue
Diarrhea
Colitis
Musculoskeletal pain
Dermatitis
Common treatment for immunotherapy side effects
Corticosteroids
Results of immunotherapy agents most commonly occur between __ after starting therapy
12-16 weeks
Hierarchy of controls when controlling workplace hazards
Elimination
Substitution
Engineering controls
Administrative controls
PPE
4 different types of medication dosing:
- Fixed doses
- Weight-based doses
- Body surface area (BSA) doses
- Area under the curve (AUC) doses
G1
first growth phase (or first gap)
2
How many cells are produced each time a cell divides?
mitosis
the process of cell division
interphase
The time when a cells grows and replicates DNA in preparation for cell division.
G1
most important checkpoint in cell division
cell division
Phases of include synthesis phase, G1, G2, M phase
Chemotherapy and immunotherapy
These treatments are ALL developed to target specific points in the cell division process.
cyclins and cyclin-dependent kinases
Progression through the cell cycle is controlled by these two proteins:
pluripotent
_____ stem cells are created in the bone marrow and can differentiate into any type of cell (except embryonic tissue).
undifferentiated
Is a pluripotent stem cell differentiated or undifferentiated?
myeloid, lymphoid
for hematology a pluripotent stem cell divides producing cells from either _ or _ lineage
myeolid
This type of precuros or pre-cell matures into red blood cells, platelets, and white blood cells.
lymphoid
this type of stem cell or pre-cell matures into specialized WBCs called lymphocytes.
immunotherapy
the use of the body’s own immune system to treat cancer
B, T
These two letters make up the two types of lymphocyte cells.
Alkylating agents
Classification
Break DNA helix strand, thereby interfering with DNA replication
Altretamine (Hexalen)
Alkylating Agent
PO
Ovarian CA
Side effects- nausea, vomiting, skin rash, hypersensitivity reaction, diarrhea
Dose limiting – neuro-toxicity, peripheral neuropathy, myelosuppression
Bendamustine (Treanda/Bendeka)
Alkylating agent
IV
CLL or Indolent NHL
Side effects- pyrexia, nausea, vomiting, skin reactions, TLS, hepatotoxicity, vein irritation
Dose limiting – myelosuppression
Irritant and vesicant properties
infusion reactions likely to occur in 2nd or subsequent infusions
Busulfan (IV busulfex: PO Myleran)
Alkylating Agent
IV or PO
CML and Stem cell prep
Side effects – profound tachycardia, HTN, chest pain, hyperpigmentation, alopecia, infertility, confusion, suizures, mucositis, nausea, vomiting, insomnia, hyperglycemia, blurred vision, secondary malignancy, VOD (now sinusoidal obstruction syndrome)
seizure prophylaxis
central line only for IV
Carboplatin
Alkylating agent
IV
Ovarian CA
Side effects – neutropenia, nausea, vomiting, hypersensitivity, mild alopecia, skin rash
Dose Limiting – thrombocytopenia
Irritant
AUC dosing
Chlorambucil (Leukeran)
Alkylating agent
PO
CLL, HL, NHL
Side effects – infertility, nausea, vomiting, secondary malignancy, hyperuricemia, pulmonary fibrosis, seizure
Dose Limiting – myelosuppression, skin reactions
empty stomach
caution in pts with seisure history and within 1 month of radiation or other cytotoxic therapy
Cisplatin
Alkylating agent
IV
Ovarian, Testicular, Bladder
Side Effects – severe acute and delayed CINV, ototoxicity, hyperuricemia, hypersensitivity, electrolyte abnormalities, peripheral neuropathy
Dose Limiting – nephrotoxicity, myelosupression
Mannitol and hydration to prevent nephrotoxicity
check creatinine prior to dose
nausea up to 6 days after dose
Cyclophosphamide (Cytoxan)
Alkylating agent
IV, PO