Chemo Flashcards
cancer is the ____ leading cause of death in the US
second
many causes of cancer are mediated by the environment and lifestyle of a person such as:
smoking, obesity, alcohol consumption
what is neoplasia and describe it
- process of altered cell differentiation and growth
- uncoordinated
- autonomous
- lacks regulatory control
what is a neoplasm
- new growth
- “tumor”
what is cancer
disease resulting from altered cell differentiation and growth
normal tissue renewal and repair involves what 2 components:
- proliferation
- differentiation
cell cycle is an orderly chain of events:
- duplicate contents and divide
- genetic information is distributed to daughter cells
- checkpoints for pauses or arrests in proliferation
what is a hallmark characteristic of cancer cells
abnormal and rapid proliferation
what happens in cell differentiation
- proliferating cells become progressively more specialized
- cells have a specific set of structural, functional and life expectancy characteristics
- as cells differentiate, their capacity for proliferation diminishes
- undifferentiated cells are hallmark characteristic of cancer cells
what makes cell growth lead to cancer
unchecked growth that progresses toward limitless expansion
- abnormal and rapid proliferation
- loss of differentiation: anaplasia
- causation- genetic and external
what is a carcinoma
arise from the cells that cover external and internal body surfaces such as lung, pancreatic, breast and colon cancer
what is a sarcoma
arise from cells found in the supporting tissues of the body such as bone, cartilage, fat, connective tissue, and muscle
what is a lymphoma
arise in lymph nodes and tissues of the bodys immune system
what is leukemia
cancers of the immature blood cells that grow in the bone marrow
how is invasion done by cells in solid tumors
secrete enzymes that break down proteins and contribute to infiltration, invasion, and penetrate of surrounding tissues
is complete surgical removal easy
no
cancer cells may travel and_______ where they ______
“seed” into different body cavities; can proliferate and cause tumor growth (metastasis)
describe cancer cells spreading
- blood vessel and lymphatic spread
- finely orchestrated, selected cells only
- angiogenesis
______ of breast cancer patients develop bone metastases
70%
what is the recommendation for current breast cancer treatment for postmenopausal women who receive chemotherapy after surgery for early stage breast cancer with a high risk of recurrence
bisphosphonates
bisphosphonates are also recommended for:
management of bone disease for most patients with solid tumors
what are bisphosphonates used for in cancer
- bone health maintenance
- reduce bone pain due to hypercalcemia
- reduction of bone metastasis (breast and prostate cancer)
_____ of prostate cancer patients develop bone metastases
70%
_______ of other common solid cancers develop bone metastases
15-30%
what is the bisphosphonate recommendation in women with early breast cancer
reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates
what is the bisphosphonate recommendation in women with metastatic breast cancer and bone metastases
reduce the risk of developing skeletal related events, delay the median time to an SRE, and appear to reduce bone pain compared to placebo or no bisphosphonate
what are the names of bisphosphonates
- clodronate
- pamidronate
- alebdronate
- ibandronate
- risendronata
- zolendronate
what bisphosphonate is the most potent
zolendronate
what is the MOA of bisphosphonates
- inhibit osteoclasts: attach to bony surfaces undergoing active resorption. bisphosphonates released during resorption by osteoclasts impairs the ability of osteoclasts to form the ruffled border, to adhere to the bony surface
- reduce osteoclast genesis and recruitment
- promoting osteoclast apoptosis
what do tumor cells secrete
- Parathyroid hormone related peptide- primary stimulator of osteoclastogenesis
- interleukin-6, prostaglandin E2, tumor necrosis factor, and macrophage colony stimulating factor
- increases RANK ligand expression which directly acts on osteoclast precursors to induce osteoclast formation and bone resorption
bone resorption process releases:
- TGF-B: increases PTHrP production by tumor cells and growth factors (IGFs, FGFs, PDGF, BMPs) increasing tumor growth
tumor cell and osteoclast symbiotic relationship further increases:
bone destruction and tumor growth
what are the dental concerns with bisphosphoantes and how are these issues precipitated
- ARONJ (anti resorptive associated osteonecrosis of the jaw)
- MRONJ
- precipitated by extractions or periodontal and implant procedures
what are the risk factors for dental concerns with bisphosphonates
- hx of bisphosphonates especially IV
- hx of cancer
- corticosteroid therapy
- diabetes
- smoking
- alcohol use
- poor OH
- chemotherapeutic drugs
median time to onset of MRONJ was:
15-16 months
dental extraction preceded MRONJ even in ____ of cases
63%
_______ patients on zolendronate for metastatic bone disease developed ONJ
1 in 40
low risk for osteoporosis doses bisphosphonates _____
0.1%
what is the ADA recommendation for non cancer patients
a patient with active dental or periodontal disease should be treated despite the risk of developing ARONJ because the risk and consequences of no treatment likely outweigh the risks of developing ARONJ
should drug holidays be given for bisphosphonates
no
what are the additional considerations for bisphosphonates
- education
- 0.2% chlorhexidine: rinse for 1 minute prior to dental treatment and continue rinsing twice daily for 7- days after treatment
- prophylactic antibiotics: no specific dose/agent recommendations: amoxicillin or augmentin
what is the ADA recommendation for cancer patients on bisphosphonates
- high risk for oncologically dosed bisphosphonates - 2-18%
- ADA not does address this
- but recommendation from AAOMS: procedures that involve direct osseous injury should be avoided. nonrestorable teeth may be treated by removal of the crown and endo treatment of the remaining roots. placement of dental implants should be avoided in the oncologic patient receiving IV antiresorptive therapy
what is the MOA of Denosumab (Xgeva and Prolia)
- RANKL is secreted by bone marrow cells and osteoblasts
- RANKL binds to RANK receptor on osteoclasts and promotes osteoclast differentiation and activity
- denosumab is a fully human monoclonal antibody that binds to RANKL
- bound RANKL cannot attach to RANK receptors, inhibiting activation of osteoclast
what is denosumab
murine antibody that recognizes specific antigen
what is a murine antibody
- induce a human anti-mouse antibody immune response
- activate human immune effector mechanisms poorly
- short half life in humans
- chimerized by substituting major portions of the human IgG molecule
what are the toxicities with infusion reactions
- typical include fever, chills, nausea, dyspnea, and rashes
- within 30 minutes to 2 hours of initiation of drug infusion, symptoms may be delayed for up to 24 hours
premed with what for infusion reactions?
diphenhydramine and acetominophen
describe the high dose denosumab risk for osteonecrosis and dosage
- high prevalence: 2-5% osteonecrosis
- Xgeva: bone cancer treatment - same prevalence as bisphosphonate
- 120mg every 4 weeks
describe the low dose denosumab risk for osteonecrosis and dosage
- rare osteonecrosis
- prolia: 60mg every 6 months
what is the mechanism of MRONJ
- profound and prolonged inhibition of bone resorption with over suppression of bone remodeling and infection are the main mechanisms
- postulated that MRONJ is a form of avascular necrosis, possibly caused by inhibition of angiogenesis
what is angiogenesis
the development of new blood vessels
- key factor in the growth and metastasis of certain solid tumors
what do solid tumors secrete
proangiogenic factors, VEGF
- stimulates new vessel development via downstream signaling pathways
what inhibitors of angiogenesis have been developed and introduced into oncology
- monoclonal antibodies against VEGF (bevacizumab)
- tyrosine kinase inhibitors (sorafenib, sunitinib)
- mammalian target of rapamycin pathway inhibitors (everolimus)
- immunomodulatory agents (thalidomide, lenalidomide)
what does bevacizumab do
- humanized
- recognizes and binds VEGF-A: once bound the complex is unable to activate the VEGF receptor
- reduce formation of new blood vessels, reduce nutrient delivery
- increase in bleeding and reduce in wound healing
when in bevacizumab used
in solid tumor cancers
bevacizumab is most effective when combined with: and why
additional therapies, especially chemotherapy
- does not kill tumors, they instead may prevent tumors from growing
association of ONJ with therapies that target angiogenesis is ______
more controversial
risk for MRONJ more clearly established for use of ________
antiangiogenic agents in patients also receiving antiresorptive agents
for patient whose cancer management includes treatment with denosumab or IV bisphosphonates the recommendation is:
- a thorough dental exam with xrays should be completed before the intitiation of antiresorptive therapy to identify disease before drug therapy
- any necessary invasive dental procedure including dental extractions or implants should be completed prior to initiation of therapy
what is the recommendation by american society of clinical oncology
- all patients should have dental exam and preventative dentistry before therapy
- in the setting of invasive dental procedures delay the starting of therapy with BMA until the initial bone healing process of the tooth socket has taken place
- if an invasive manipulation of the bony underlying the teeth is clinically indicated before starting BMA therapy, initiation of the BMA therapy should be ideally delayed for 2-3 weeks to allow for wound healing
cancer treatment therapy is based on ____-
severity of illness
what are the types of cancer therapy
curative
control
- palliative
what modalities are used in cancer treatment
- surgery
- radiation therapy
- chemotherapy
- hormonal therapy
- biotherapy
what are the different types of cancer chemotherapeutic agents
- neoadjuvant and adjuvant
- various mechanisms of action -> stop/slow proliferation
- reach microscopic cancer cells
what are the adverse reactions of chemo agents that limit use
- GI disturbances
- hair loss
- bone marrow suppression: anemia, increased infection risk
what are the main antineoplastic medications
- cytotoxic drugs: alkylating agents, antimetabolites, cytotoxic antibiotics, plant derivatives
- hormones
- monoclonal antibodies
- protein kinase inhibitors
- miscellaneous
describe alkylating agents
- directly damage cell DNA: impairs replication and transcription = cell death
- work in all phases of the cell cycle: can be used in many different cancers
- due to affect on DNA, big impact on bone marrow: bone marrow suppression- reduce blood cell production. highly immunosuppressant
- toxicity related to cumulative dose: mucosal damage- oral mucosal ulceration. GI disturbance, sterility, acute non lymphocytic leukemia
what are the types of alkylating agents and names
- nitrogen mustards: cyclophosphamide, chlorambucil, ifosfamide, melphalan
- platinum compounds: cisplatin, carboplatin, oxaliplatin
- nitrosoureas (brain tumors): streptozocinm, carmustine (BCNU) and lomustine
- alkyl sulfonates: susulfan
- trizaines: dacarbazine and temozolomide
- ethylemimines: thiptepa and altretamine
describe the side effect associated with cisplatin and oxaliplatin
- neurotoxicity
- drugs enter into the dorsal root ganglion and binds to DNA causing apoptosis
- platinum compounds form intrastrand adducts and interstrand crosslinks altering tertiary structure of DNA. this promotes alterations in cell cycle kinetics, leading to an attempt of differentiated postmitotic dorsal root ganglion neurons to re-enter cell cycle, which leads to the induction of apoptosis
- apoptosis results in secondary damage to peripheral nerves
what are the side effects of oxaliplatin
- pain triggered by exposure to cold liquids
- cold induced paresthesias
- cold induced pharyngolaryngeal dysethesia
- dyspnea
- muscle cramps
- jaw stiffness
- dysphagia
- visible fasculations
- voice changes
- ocular changes
what are antimetabolites and what do they do
- S- phase specific
- antimetabolites are structurally related to normal compounds that exist within the cell
- antimetabolites interfere with DNA and RNA growth by substituting for or competing with the normal building blocks of DNA and RNA: may either by inhibiting the synthesis of normal nucleotides or compete with them in the formation of DNA or RNA. ie the availability of normal purine or pyrimidine nucleotide precursors
- their maximal cytotoxic effects are in the S phase; where DNA replicated, yielding two separate sets
what are the folate antagonists that are antimetabolites
- methotrexate, pemetrexed
what are the pyrimidine antagonists that are antimetabolits
5-fluorouracil, cytarabine, gemcitabine
what are the purine antagonists that are antimetabolites
- mercaptopurine
- fludarabine
describe methotrexate and what it does
- antineoplastic, immunosuppressant (psoriasis; RA)
- target S- phase (DNA replication), inhibit rapid proliferating cells
- bone marrow and intestinal epithelium
- myelosuppression risk for hemorrhage and infection
what is the dental note for methotrexate
- oral mucositis
- oral pain, erythema, difficulty opening the mouth
- DNA cycle specific agents are most stomatotoxic
- methotrexate, etoposide known to be secreted into the saliva
- further increasing stomato toxicity potential
what do cytotoxic antibiotics do
- bind to and break down DNA inside cancer cell to keep them from growing and multiplying
what are the groups of cytotoxic antibiotics
- anthracyclines: doxorubicin, daunorubicin, epirubicin, idarubicin
- other: bleomycin, plicamycin, mitomycin
cytotoxic antibiotics have a potential to generate:
hydrogen peroxide and free radicals that are non cell cycle specific
- irreversible cardiomyopathy d/t doxo- and daunorubicin
- bleomycin typically associated with lung toxicities
what drugs are associated with oral mucositis
- methotrexate
- 5FU
- cytarabine
-doxorubicin - etoposide
- bloemycin
what do mitotic inhibitors do and what are the groups
- work in M-phase to prevent cell division
- groups include: vinca alkaloids: vincristine, vinblastine
- taxanes: paclitaxel, docetaxel
what is vincristine derived from, MOA and toxicity
- derived from madagascar periwinkle
- MOA: binds beta tubulin and block its polymerization with alpha tubulin into microtubules: cell division arrests in metaphase, absence of intact mitotic spindle, chromosomes cannot align and disperse in cytoplasm. apoptosis
- toxicity: peripheral neuropathy- numbness, tingling
- neurotoxicity may also be persistent, deep aching and burning pain that mimics a toothache
what are the side effects of cell replication inhibition
- primarily GI tract, bone marrow, oral cavity
- mucositis painful inflammation along GI: develops within 1-week of chemotherapy initiation
- stomatotoxic (toxic effects on the oral tissues)
- impairment of bone marrow (myelosuppression): suppressing white blood cells, red blood cells, and platelets
- WBC should be greater than 2000
- ANC should be greater than 2000
- platelets should be greater than 75,000
what are the oral complications to chemotherapy and radiation
- oral mucositis
- infection
- xerostomia/salivary gland dysfunction
- functional disabilities
- taste alteration
- nutritional compromise
- abnormal dental development
- neurotoxicity
- bleeding
- radiation caries
- osteonecrosis
describe oral mucositis as a side effect of chemotherapy and radiation
- 20-40% prevalence
- inflammation and ulceration of the mucous membranes
- can increase the risk for pain, oral and systemic infection, and nutritional compromise
describe infection as a side effect of chemotherapy and radiation
- viral, bacterial and fungal
- from myelosupresion, xerostomia, and/or damage to mucosa from chemotherapy or radiotherapy
describe xerostomia/salivary gland dysfunction as a side effect of chemotherapy and radiation
- dry mouth d/t thickened, reduced, or absent salivary flow
- increases the risk of infection and compromises speaking, chewing and swallowing
- persistent dry mouth increases the risk for dental caries
describe functional disabilities -as a side effect of chemotherapy and radiation
- impaired ability to eat, taste, swallow, and speak
- due to mucositis, dry mouth, trismus and infection
describe taste alterations as a side effect of chemotherapy and radiation
changes in taste perception of foods, ranging from unpleasant to tasteless
describe nutritional compromise as a side effect of chemotherapy and radiation
eating difficulties due to mucositis, dry mouth, dysphagia and loss of taste
describe abnormal dental development as a side effect of chemotherapy and radiation
- altered tooth development, craniofacial growth, or skeletal development in children secondary to radiotherapy and/or high doses of chemotherapy before age 9
how long do taste alterations occur after treatment and what meds are they commonly associated with
3-4 weeks
- cisplatin
- cyclophosphamide
- doxorubicin
- 5Fluorouracil
- methotrexate
- paclitaxel
- vincristine
describe neurotoxicity as a side effect of chemotherapy and radiation
- persistent, deep aching and burning pain that mimics a toothache but no dental or mucosal source can be found
- side effect of certain classes of drugs
describe oral bleeding as a side effect of chemotherapy and radiation
from decreased platelets and clotting factors
describe radiation caries as a side effect of chemotherapy and radiation
lifelong risk of rampant dental decay that may begin within 3 months of completing radiation treatment if changes in quality or quantity of saliva persist
all chemotherapy agents are _____
immunosuppressive
what are the disease states for immunosuppression
- autoimmune, collagen, connective tissues and inflammatory disorders: SLE, RA, chronic active hepatitis, IBS, glomerulonephritis, nephrotic syndrome, myasthenia gravia
-oran or tissue transplantation: prevent rejection
what is the target of immunosuppression
- inhibit mononuclear cells (lymph and blood cells)
- acquired immune system
what are the immunosuppressants
- T-cell inhibitors: cyclosporine, tacrolimus, sicrolimus, everolimus
- T cell and B cell inhibitors: azathioprine, leflunomide
- mycophenolate
- corticosteroids = glucocorticoids: prednisone, dexamethasone, prednisolone
what are T-cell inhibitors and what do they do
- downstream inhibit helper and killer T cell activation
- actively attack/destroy any invading/invaded cell (each T cell is specific to virus/bacteria/protein
- to prevent and treat rejection of organ and bone marrow transplants; RA; psoriasis
what are the cyclosporine side effects
- gingival hypertrophy
- infection risk
- hypertension/kidney impairment (avoid NSAIDs and bactrim)
- drug interactions
for gingival hypertrophy from cycloporine what is the tx suggested
2 week course of metronidazole (750mg PO TID) while cyclosporine continued
what are the drug interactions with cyclosporine and tacrolimus
- cimetidine
- clarithromycin
- erythromycin
- corticosteroids
- fluconazole
- itraconazole
- ketoconazole
what is the drug interaction between cyclosporine and tacrolimus AND cimetidine
cimetidine increases cyclosporine concentrations and/or decrease its clearance
what is the drug interaction between cyclosporine and tacrolimus AND clarithromycin
acute renal failure and 2-3 fold increase in tacrolimus serum concentrations after 9 doses of clarithromycin
what is the drug interaction between cyclosporine and tacrolimus AND corticosteroids
toxic effects of prednisone and/or cyclosporin if agents combined
what type of drug is cyclosporine
t cell inhibitor
what is the drug interaction between cyclosporine and azoles
serum cyclosporine concentrations increase as much as tenfold in transplant patients following initiation of azole antifungal agents
what is the MOA of T-cell and B-cell inhibitors and what do they do
- inhibit purine (azathioprine and mycophenolate) and pyrimidine (leflunomide) nucleotide synthesis for lymphocyte production
- prevent and treat rejection of organ and bone marrow transplants; RA
what are the dental notes for T-cell and B-cell inhibitors
-antacids and PPIs can reduce the effectiveness of mycophenolate
- risk for infection increased while taking
