Anticancer Drugs & Immunosuppressants Flashcards
1
Q
Epidemiology of Cancer
—+ associated disease processes
— leading cause of the death in the U.S.
Nearly – deaths a day
–% of all deaths
Many causes of cancer are mediated by the environment
and lifestyle of a person
(3)
Multitude of theories on cancer pathophysiologic process
A
150
Second
1,500
25
Smoking
Obesity
Alcohol consumption
2
Q
Neoplasia
(4)
A
Process of altered cell differentiation and growth
- Uncoordinated
- Autonomous
- Lacks normal regulatory control
3
Q
Neoplasm
(2)
A
New growth
“Tumor”
4
Q
Cancer
A
Disease resulting from altered cell differentiation and growth
5
Q
Normal tissue renewal and repair
involves 2 components
A
Proliferation
Differentiation
6
Q
Cell cycle is orderly chain of events
(3)
A
Duplicate contents & divide
Genetic information is distributed to
“daughter cells”
Checkpoints for pauses or arrests in
proliferation
7
Q
— is hallmark characteristic of
cancer cells
A
Abnormal and rapid proliferation of
cells
8
Q
Cell Differentiation
Proliferating cells become
progressively more —
Cells have a specific set of …
As cells differentiate, their capacity
for — diminishes
— cells are hallmark
characteristic of cancer cells
A
specialized
structural,
functional, and life-expectancy
characteristics
proliferation
Undifferentiated
9
Q
Cell Growth Gone Wrong: Cancer
Unchecked growth that progresses toward limitless expansion
(3)
Causation – (2)
A
Abnormal and rapid proliferation
Loss of differentiation
anaplasia
genetic & external
10
Q
Carcinoma
A
Arise from the cells that cover external and internal body surfaces such as lung,
pancreatic, breast, and colon
11
Q
Sarcoma
A
Arise from cells found in the supporting tissues of the body such as bone, cartilage,
fat, connective tissue, and muscle
12
Q
Lymphoma
A
Arise in lymph nodes and tissues of the body’s immune system
13
Q
Leukemia
A
Cancers of the immature blood cells that grow in the bone marrow
14
Q
Invasion & Metastasis
Solid tumors secrete enzymes that …
Complete surgical removal difficult
Cancer cells may travel and “seed” into different body cavities
where they can …
A
break down proteins and
contribute to infiltration, invasion, and penetration of
surrounding tissues
proliferate and cause tumor growth (metastasis)
15
Q
Cancer cells may travel and “seed” into different body cavities
where they can proliferate and cause tumor growth (metastasis)
(3)
A
Blood vessel and lymphatic spread
Finely orchestrated; selected cells only
Angiogenesis
16
Q
–% o f b r e a s t c a n c e r p a t i e n t s d e v e l o p b o n e m e t a s t a s e s
A
7 0
17
Q
C u r r e n t b r e a s t c a n c e r t r e a t m e n t g u i d e l i n e s r e c o m m e n d
p o s t m e n o p a u s a l w o m e n w h o r e c e i v e c h e m o t h e r a p y a f t e r s u r g e r y f o r
e a r l y - s t a g e b r e a s t c a n c e r w i t h a h i g h r i s k o f r e c u r r e n c e s h o u l d a l s o
r e c e i v e
A
b i s p h o s p h o n a t e t r e a t m e n t a f t e r s u r g e r y
18
Q
a l s o i n d i c a t e d f o r t h e m a n a g e m e n t o f — f o r
m o s t p a t i e n t s w i t h s o l i d t u m o r s
A
m e t a s t a t i c b o n e d i s e a s e
19
Q
Metastasis & Use of Bisphosphonates in Cancer
(3)
A
Bone health maintenance
Reduce bone pain due to hypercalcemia
Reduction of bone metastasis (breast & prostate cancer)
20
Q
–% of breast and prostate cancer patients develop bone metastases
15-30% of other common solid cancers
A
70
21
Q
in women with early — cancer
reduce the risk of bone metastases and provide an overall survival benefit compared to
placebo or no bisphosphonates
A
breast
22
Q
n women with metastatic breast cancer and bone metastases
reduce the risk of developing (3)
A
skeletal-related events (SRE), delay the median time to an
SRE, and appear to reduce bone pain compared to placebo or no bisphosphonat
23
Q
MOA: Bisphosphonates
(3)
A
Inhibit osteoclast
Reduce osteoclast genesis and
recruitment
Promoting osteoclast apoptosis
24
Q
Inhibit osteoclast
(2)
A
Attach to bony surfaces undergoing
active resorption
Bisphosphonates released during
resorption by osteoclasts impairs
ability of osteoclasts to form the
ruffled border, to adhere to the
bony surface
25
Tumor cells secrete:
parathyroid hormone related peptide (PTHrP) as the primary
stimulator of osteoclastogenesis
interleukin-6 (IL-6), prostaglandin E2 (PGE2), tumor necrosis
factor (TNF), and macrophage colony-stimulating factor (M-CSF)
increase RANK ligand expression, which directly acts on osteoclast
precursors to induce osteoclast formation and bone resorption
26
bone resorption process releases:
transforming growth factor-beta (TGF-β), which increase PTHrP
production by tumor cells as well as growth factors (eg, insulin-
like growth factors [IGFs], fibroblast growth factors [FGFs],
platelet-derived growth factor [PDGF], bone morphogenetic
proteins [BMPs]) increasing tumor growth
27
Symbiotic relationship further increases (2)
bone destruction and
tumor growth
28
Dental Concerns: Bisphosphonates
(3)
AntiResorptive-associated
OsteoNecrosis of the Jaw (ARONJ)
Medication Related ONJ (MRONJ)
Precipitated by extractions or
periodontal and implant procedures
29
AntiResorptive-associated
OsteoNecrosis of the Jaw (ARONJ)
---% on IV bisphosphonates
1-10
30
Medication Related ONJ (MRONJ)
(4)
Reduced levels of osteoclast
- Necrotic bone is maintained
- New bone deposited on necrotic bone
Includes Denosumab (Xgeva) &
Antiangiogenic Medications
31
Dental Concerns: Bisphosphonates
Risk factors:
Hx of bisphosphonates especially IV
Hx of Cancer
Corticosteroid therapy
Diabetes
Smoking
Alcohol use
Poor oral hygiene
Chemotherapuetic drugs
32
Median time to onset of MRONJ
was 15 to 16 months
63 (1.9%) on denosumab and 44
(1.3%) on zoledronic acid
developed MRONJ
Cumulative incidence increased
with longer duration of exposure
Dental extraction preceded
MRONJ event in --% of cases
63
33
Study on ONJ Risk
Prospective observational study assessed cumulative incidence of ONJ at 3 years in
metastatic bone disease pts from any malignancy receiving zoledronic acid
3,491 evaluable pts (breast 1,120; myeloma 580; prostate 702, lung 666, other 423)
between 2009-2013
2/3 of pts had a baseline dental exam
87 pts developed confirmed ONJ
cumulative incidence of ONJ --% at year 1, --% at year 2, and --% at year 3
Rates of 3-year confirmed ONJ highest in myeloma pts (4.3%)
Fewer total number of teeth, presence of dentures and any oral surgery at baseline were all
associated with a higher rate of ONJ
Conclusion: 1 in 40 patients on zoledronate for metastatic bone disease developed ONJ
Cancer type, and oral health effect risk
0.8
2.0
2.8
34
Non-Cancer Versus Cancer Indication
Low-risk for osteoporosis dosed bisphosphonates – 0.1%
ADA – “recommends that a patient with active dental or periodontal disease ...
should
be treated despite the risk of developing ARONJ, because the risks and consequences
of no treatment likely outweigh the risks of developing ARONJ.
35
Additional Considerations
(4)
Education
Avoid drug holidays
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 (Amoxil) or amoxicillin/clavulanic acid (Augmentin)
36
Non-Cancer Versus Cancer Indication
High-risk for oncologically dosed bisphosphonates – 2-18%
ADA – does not address
AAOMS – “...
procedures that involve direct osseous injury should be avoided.
Nonrestorable teeth may be treated by removal of the crown and endodontic
treatment of the remaining roots. Placement of dental implants should be avoided in
the oncologic patient receiving IV antiresorptive therapy
37
Monocolonal Antibodies: Denosumab
Murine antibody that recognizes specific antigen
38
Humanised’
Murine Antibody:
(3)
induce a human anti-mouse antibody immune response
activate human immune effector mechanisms poorly
short t1/2 in humans
39
Toxicities – Infusion Reactions
Typical include (5)
within 30 minutes to two hours of initiation of drug infusion, symptoms may be
delayed for up to 24 hours
Premedication with (2) is indicated
fever, chills, nausea, dyspnea, and rashes
diphenhydramine and acetaminophen
40
Denosumab Risk of MRONJ
High Dose Denosumab :
Xgeva :
High prevalence (2-5% Osteonecrosis)
Bone cancer treatment - same prevalence as bisphosphonate
120mg every 4weeks
41
Low Dose Denosumab:
Prolia :
Rare Osteonecrosis
Weak evidence (case reports)
Osteoporosis treatment
60mg every 6months
42
Mechanism of MRONJ
Profound and prolonged inhibition of bone resorption with over-
suppression of bone remodeling (ie, low bone turnover), and infection are
the main mechanisms
43
Postulated that MRONJ is a form of avascular necrosis, possibly caused
by inhibition of angiogenesis.
In vitro experiments consistently demonstrate inhibition of angiogenesis by zoledronic
acid, and cancer patients treated with this agent have decreased circulating VEGF levels
Growing body of evidence linking MRONJ to antiangiogenic drugs, including
bevacizumab and orally active tyrosine kinase inhibitors.
44
Angiogenesis =
the development of new blood vessels
45
Angiogenesis = the development of new blood vessels
(3)
Key factor in the growth and metastasis of certain solid tumors
Solid tumors secrete proangiogenic factors, vascular endothelial growth factor (VEGF)
- stimulate new vessel development via downstream signaling pathways
Various inhibitors of angiogenesis have been developed and introduced into oncology
practice
46
Various inhibitors of angiogenesis have been developed and introduced into oncology
practice
(4)
monoclonal antibodies against VEGF (e.g., bevacizumab),
tyrosine kinase inhibitors (e.g., sorafenib, sunitinib),
mammalian target of rapamycin (mTOR) pathway inhibitors (e.g., everolimus)
immunomodulatory agents (e.g., thalidomide, lenalidomide).
47
Angiogenesis Inhibitor: Bevacizumab
Bevacizumab (Avastin)- humanized;
binds VEGF-A
(5)
Used in solid tumor cancers
Specifically recognize and bind to VEGF.
- Once bound, the complex is unable to activate the
VEGF receptor.
Most effective when combined with additional
therapies, especially chemotherapy.
- Do not necessarily kill tumors; they instead may
prevent tumors from growing.
Reduce formation of new blood vessels; reduce
nutrient delivery
Increases in bleeding and reduced wound healing
48
Note:
Association of ONJ with therapies that target angiogenesis is more
controversial
Especially monotherapy with an antiangiogenic agent
Risk for MRONJ more clearly established for use of
antiangiogenic
agents in patients ALSO receiving antiresorptive agents
49
International Task Force on Osteonecrosis of the Jaw
2015 systematic review and international consensus paper
For patients whose cancer management includes treatment with denosumab or IV
bisphosphonates, recommends
“a thorough dental examination with dental radiographs should be ideally completed prior
to the initiation of antiresorptive therapy in order to identify dental disease before drug
therapy is initiated”
“Any necessary invasive dental procedure including dental extractions or implants should
ideally be completed prior to initiation of [bisphosphonate] or [denosumab] therapy.”
50
American Society of Clinical Oncology (ASCO) – 2017
“All patients should have a dental examination and preventive dentistry before using a
Bone-modifying agent (BMA).”
“in the setting of invasive dental procedures, it is advisable, whenever possible to
delay the starting of therapy with BMA until the initial bone healing process of the
tooth socket bone has taken place”
“If an invasive manipulation of the bone underlying the teeth is clinically indicated
before starting BMA therapy...initiation of BMA therapy should be ideally delayed for
14 to 21 days to allow for wound healing, if the clinical situation permits.”
51
Cancer Treatment
Goal of therapy based on severity of illness
(3)
Curative
Control
Palliative
52
Multiple modalities utilized
(5)
Surgery
Radiation therapy
Chemotherapy
Hormonal therapy
Biotherapy
53
--- care for clinical manifestations and/or treatment adverse reactions
Supportive
54
Chemotherapy Agents
Multiple cancer chemotherapeutic agents
(4)
Adjuvant vs. neoadjuvant
Various mechanisms of action
slow/stop cell proliferation
Reach ‘microscopic’ cancer cells
55
Adverse reactions limit use
(3)
GI disturbances (N/V/D)
Hair loss
Bone marrow suppression
(anemia, increased infection risk)
56
Antineoplastic Medications
(5)
Cytotoxic drugs
Hormones
Monoclonal antibodies (MABs)
Protein Kinase Inhibitors
Miscellaneous
>100 various agents
57
Cytotoxic drugs
(4)
Alkylating agents
Antimetabolites
Cytotoxic antibiotics
Plant derivatives
58
Alkylating Agents
(4)
Directly damage cell DNA
- Impairs replication & 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
59
Alkylating Agents
(6)
Nitrogen Mustards:
Platinum Compounds:
Nitrosoureas: (brain tumors)
Alkyl sulfonates:
Triazines:
Ethylenimines:
60
Nitrogen Mustards:
cyclophosphamide (Cytoxan®), chlorambucil, ifosfamide, melphalan
61
Platinum Compounds:
cisplatin, carboplatin, oxaliplatin
62
Nitrosoureas: (brain tumors)
streptozocin, carmustine (BCNU), and lomustine
63
Alkyl sulfonates:
busulfan
64
Triazines:
dacarbazine (DTIC) and temozolomide (Temodar®)
65
Ethylenimines:
thiotepa and altretamine (hexamethylmelamine)
66
Noteworthy: Platinum Compounds – Cisplatin, 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
Regardless of the mechanism, apoptosis
results in secondary damage to peripheral
nerves
67
Oxaliplatin associated:
pain triggered by
exposure to cold liquids
Cold-induced perioral paresthesias – 95%
Cold-induced pharyngolaryngeal dysesthesia – 92%
Dyspnea – 40%
Muscle cramps – 34%
Jaw stiffness – 34%
Dysphagia – 30%
Visible fasciculations – 30%
Voice changes – 6%
Ocular changes – 0.7%
68
Antimetabolites are structurally related to
normal compounds that exist
within the cell
69
Antimetabolites interfere with DNA and RNA growth by
substituting for
or competing with the normal building blocks of DNA and RNA
i.e. the availability of normal purine or pyrimidine nucleotide precursors
May either by inhibiting the synthesis of normal nucleotides or compete with them in
the formation of DNA or RNA
70
Their maximal cytotoxic effects are in
S-phase
Synthesis – DNA replicates, yielding two separate sets
71
Antimetabolites
Folate antagonists:
Pyrimidine antagonists:
Purine antagonist:
=== Inhibit precursors to DNA synthesis
methotrexate, pemetrexed
5-Fluorouracil (5FU), Cytarabine, gemcitabine
Mercaptopurine, Fludarabine
72
Methotrexate
(2)
Antineoplastic; immunosuppressant (psoriasis; RA)
Target S-phase (DNA replication), inhibit rapid proliferating cells
- Bone marrow and intestinal epithelium
- Myelosuppression risk for hemorrhage and infection
73
Methotrexate
Dental Note: oral mucositis
(3)
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
74
Cytotoxic Antibiotics
(2)
Bind to and break DNA inside cancer cell to keep them from growing
and multiplying
Oral Mucositis
75
Cytotoxic Antibiotics
Groups:
Anthracyclines: (4)
Other: (3)
Doxorubicin, daunorubicin, epirubicin, idarubicin.
bleomycin, plicamycin, mitomycin.
76
Mitotic Inhibitors
Groups include:
Vinca Alkaloids: (2)
Taxanes: (2)
Work in M-Phase to prevent cell division
Vincristine, Vinblastine
Paclitaxel, Docetaxel
77
Example: Vincristine
Derived from Madagascar periwinkle
MOA: bind β tubulin & block its polymerization with α tubulin into
microtubules
Cell division arrests in metaphase
Absence of intact mitotic spindle, chromosomes
cannot align, disperse throughout the cytoplasm
Apoptosis
Toxicity-
Peripheral neuropathy-numbness, tingling
Neurotoxicity may also be persistent, deep aching and burning pain that mimics a
toothache
78
Side Effects: Cell Replication Inhibition
(4)
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)
79
Impairment of bone marrow (myelosuppression)
suppressing white blood cells, red blood cells, and platelets
GET LABS THE DAY BEFORE ANY PROCEDURE
WBC >2000
ANC >2000
Platelets >75,000
80
Oral Complications Common to Chemotherapy & Radiation
(7)
Oral mucositis (20-40%):
Infection:
Xerostomia/salivary gland dysfunction:
Functional disabilities:
Taste alterations:
Nutritional compromise:
Abnormal dental development:
81
Oral mucositis (20-40%):
inflammation and ulceration of the mucous membranes
can increase the risk for pain, oral and systemic infection, and nutritional compromise.
82
Infection: viral, bacterial, and fungal
from myelosuppression, xerostomia, and/or damage to mucosa from chemotherapy or radiotherapy
83
Xerostomia/salivary gland dysfunction: dry mouth d/t thickened, reduced, or absent salivary flow
(2)
increases the risk of infection and compromises speaking, chewing, and swallowing
persistent dry mouth increases the risk for dental caries
84
Functional disabilities: impaired ability to eat, taste, swallow, and speak
due to mucositis, dry mouth, trismus, and infection.
85
Taste alterations:
changes in taste perception of foods, ranging from unpleasant to tasteless
86
Nutritional compromise:
eating difficulties due to mucositis, dry mouth, dysphagia, and loss of taste
87
Abnormal dental development:
altered tooth development, craniofacial growth, or skeletal
development in children secondary to radiotherapy and/or high doses of chemotherapy before age 9
88
Taste Alterations - Chemotherapy
Common occurrence following
chemotherapy administration
Lasts 3-4 weeks post-treatment
Commonly associated with:
(7)
Cisplatin
Cyclophosphamide
Doxorubicin
5-Fluorouracil
Methotrexate
Paclitaxel
Vincristine
89
---% of the patients reported taste alterations during
at least one assessment time, and 14.6% reported at all
assessment times during the study period
69.9%
90
Other Complications
Neurotoxicity:
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 (vinca alkaloids; platinum compounds)
91
Bleeding:
oral bleeding from the decreased platelets and clotting factors
92
Radiation caries:
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
93
Osteonecrosis:
blood vessel compromise and necrosis of bone exposed to high
-dose radiation therapy; results in decreased ability to heal if traumatized
94
Disease States for Immunosuppression
Autoimmune, collagen, connective tissue and inflammatory disorders
Systemic Lupus erythematosus
Rheumatoid arthritis
Chronic active hepatitis
Inflammatory bowel disease
Glomerulonephritis
Nephrotic syndrome
Myasthenia gravis
...among others...
Organ or tissue transplantation
Prevent rejection
95
Target of Immunosuppression
Inhibit mononuclear cells
(lymph and blood cells)
96
Immunosuppressants
(3)
T-cell Inhibitors
T-cell and B-cell inhibitors
Corticosteroids = Glucocorticoids
97
T-cell Inhibitors
(4)
Cyclosporine (Sandimmune)
Tacrolimus (Prograf; FK506)
Sirolimus (Rapamune)
Everolimus (Zortress)
98
T-cell and B-cell inhibitors
(3)
Azathioprine (Imuran)
Leflunomide (Arava)
Mycophenolate (Cellcept)
99
Corticosteroids = Glucocorticoids
(2)
Prednisone, dexamethasone, prednisolone, etc
Will cover – 4/19 – Adrenal Cortex – Dr. Knell
100
T-Cell Inhibitors
(3)
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
101
Cyclosporine – Side Effects
(4)
Gingival hypertrophy
Infection risk
(immunosuppressant)
Hypertension/Kidney Impairment
- Avoid NSAIDs and Bactrim
DRUG INTERACTIONS!!!
102
Gingival hypertrophy
(2)
May be additive with CCBs (nifedipine,
amlodipine)
Case reports suggest tx’d with 2-week
course metronidazole (750mg po TID)
while cyclosporine continued
103
Drug Interactions
(7)
Cimetidine (Tagamet)
Clarithromycin (Biaxin)
Erythromycin
Corticosteroids
Fluconazole (Diflucan)
Itraconazole (Sporanox)
Ketoconazole (Nizoral)
104
T-Cell and B-Cell Inhibitors
MOA:
inhibit purine (azathioprine
and mycophenolate) and
pyrimidine (leflunomide)
nucleotide synthesis for lymphocyte
production (T and B)
Prevent and treat rejection of organ
and bone marrow transplants; RA
105
T-Cell and B-Cell Inhibitors
Dental Notes
(2)
Antacids and PPIs can reduce effectiveness
of mycophenolate
Risk for infection increased while taking
