Week 4 Flashcards
classes of chemo-induced N&V (CINV)
acute: occurring within first 24 hours after intiation of chemo
dealyed: occuring 24 hours to sevearl days 2-5) after chemo
breakthrough: occuring despite appropriate prohlyatic trtment
anticipatory: occuring before a treatment as a conditioned response to the occurence of CINV in previous cycle
refractory: recurring in subsequent cycles of therapy, excluding acticipatory CINV
patho of CINV
neuro transmitters associated w. CINV
neurotransmitters and receptors in cns and gi tract assocated w. CINV
Seretonin (5-HT3) and its receptor
substance P and the neurokinin-1 (NK-1) receptor
dopamine and its receptors
Patho of CNV
mchanisms of emetic response to chemo
Peripheral pathway
*5-HT3-mediated
*originates in GI tract
*activated in first 24hrs after chemo
*primarily associated w. acute emesis
Central pathway
*NK-1 receptor mediated
*occurs primarily in the brain
*thought to be predominantly involved in delayed CINV
principles of emesis control
Prevention is key
facots in choosing antiemetic
*emetic risk of therapy
*prior experience w. antiemetics
*pt factors
for chemo regimens w. multipk agents, anti emetic prophylaxis should be based on agent w. highest emetogenic risk
lifestyle measures may help alleviate CINV
Risk factors for developing CINV
age <50
emesis during pregnancy
history of cinv, prone to motion sickness
female sex
emetic potential of chemo theraoy
little or no previous alcohol use
trends for emetic risk of chemo meds
IV»_space; oral
emesis prevention- high emetic risk parenteral anticancer agents
note: scheduled ATC regardless if pt is experiencing CINV or not
*need at least 3 antiemetics
*dexamethasone,nk1 ra, and 5-ht3 RA have synergistic effects
Option 1 preffered:
Day1:
*Olanzapine
*Dexamethasone
*NK1-RA
*5-HT3
Day 2-4
*Olanzapine
Dexamethasone
**Aprepitant (nk1 ra)
**note: if Aprepitant IV is used, only given x1 dose on day 1. if Aprepitant PO is given on day 1, then it is also given on days 2 and 3
* you should never see aprepitant used IV on days 2 and 3
Option 2:
Day 1:
*olanzapine
*dexamethasone
*Palonsetron
Day 2-4:
*Olanzapine
Option 3:
Day 1:
*dexamethasone
*nk1 RA
*5-ht3 RA
Day 2-4
*dexamethasone
**Aprepitant (only use dondays 2,3 as PO if aprepitant PO was used on day 1)
Emesis prevention- Moderateemetic risk Parenteral anticancer agents
*need 2 antiemetic agents of different pathways
*up to 3 days
Option 1:
Day 1:
*dexamethasone
*5HT3
Day 2-3
*dexamethasone OR 5-HT3 RA
Option 2:
Day 1:
*olanzapine
*dexamethasone
*palonosetron
Day 2-3
*olanzapine
Option 3:
Day 1:
NK1 RA
Dexamethasone
5-HT3-RA
Day 2-3
*can be nothing
*if pt was on aprepitant PO day 1, would continue on day 2-3
*+/- dexamethasone
Emetic Prevention - low emetic risk
Parenteral anticancer agents
option 1: dexamethasone
option 2: metoclopramide
Option 3: prochlorperazine
option 4: 5-HT3 RA
Emetic PRevention: miminimal emetic risk
no routine ppx (unless pt start experiencing SS)
Emesis prevention
oral anticancer agents
High-moderate emetic risk
Low-minimal emetic risk
high-mod emetic risk
*5HT3 RA
Low to minimal emetic risk
*PRN recommened
Break through emesis treatment
*add one agent from a different drug class to the current regimen
*counsider routine, ATC adinistration rather than prn dosing(ex for pts on oral anti-cancer agents)
*consider antacid therapy if pt has dyspepsia
*palonesetron not used for breakthorugh emesis due to long 1/2 life (~40 hrs)
ex:
Olanzapine
5-HT3 RA
Prochlorperazine
dexamethasone
metaclopramide
scopolamine
lorazepam
dronabinol
anticipatory emesis treatment
prevention is key
avoid stong smells that precipitate symptoms
lorazepam is useful in anticipatory anxiety-related emesis
acupuncture
behavioral therapy
*guided imagery
*relaxtion
*hypnosis
*cognitive distraction
*yoga
*biofeedback
*Progressive muscle relaxation
*guided imagery
antimetic agents
Dexamethasone
indications:
MOA: mechanism in CINV unkown
AE:
*insomnia -> admin in morniing
*dyspepsia-> take w. food. consider adding h2 RA or PPO as clinically indicated
*hyperglycemia
*HTN
DDI:–
Pearls/considerations:–
antiemetic agents
5-HT3 RA
exs:
indications:
MOA:
AE:
DDI:
Pearls/considerations:
antiemetic agents
exs: ondansetron (1st gen), palonosetron, granistron(1st gen)
indications:
MOA: blockvagal nerve terminals and centrally in the chemo receptor trigger zone (medulla) seretonin, both peripherally (GI tract) on
AE: HEadache, constipation, qtc prolongation
DDI:
Pearls/considerations:
*ondansetron, Granistron are short acting and most effective in preventing acute CINV
*palonesetron is a 2nd gen, longer t1/2 ~40 hrs). not used for breakthrough nausea. effectivein preventing acute and delayed CINV
antiemetic agents
NK1 RA
exs:
indications:
MOA:
AE:
DDI:
Pearls/considerations:
antiemetic agents
exs:
*aprepitant
*Fosaprepitant
*rolaprepitant
*fosnetupitant(available in combo w. palonesetron)
*netupitant (available in combo w. palonosetron)
indications: *prevention of CINV, not treatment of breathrough nausea. most useful in preventing delayed cinv
MOA:Inhibits substance P/neurokinin 1 (augments 5HT3-RA and dexamethasone antiemetic activity
AE: Fatigue, GI upset, headache, hiccups
DDI: INHIBITS CYP3A4 AND CYP2C9 (Decrease dexamethasone dose to 8mg dail on days 2-4) (except for rolapitant)
Pearls/considerations:
rolapitant has extended half life (7days) sould not be administered <2 week intervals
*for us of aprepitant TO PREVENT CINV, if IV formulation used, x1 dose onday 1. if PO formulation used, used on day 1 and then on days 2-3
antiemetic agents
Olanzapine
exs:
indications:
MOA:
AE:
DDI:
Pearls/considerations:
antiemetic agents
exs:
indications: useful in both prevention and treatment of cinv
MOA: blocks dopamine, 5HT3, muscarinic, and histmaine receptors
AE:
*SEDATION: -> admin at bedtime unless given as a premedication. consider lower dosing for elderly
*hyperglycemia
*fatigue
*qtc prolongation
DDI:
Pearls/considerations:
antiemetic agents
Dopamine antagonists
exs:
indications:
MOA:
AE:
DDI:
Pearls/considerations:
antiemetic agents
exs: proclorperazine
metoclopramide
promethazine
indications: most useful for breakthrough cinv
MOA: antagonizes dopamine in the chemoreceptor region
AE:
(phenothiazines)Prochlorperazine, Promethazine
*rowsiness
*constipation
*prochlorperazine( least chance of qtc prolongation
metoclopramide
*benzamines
*drowsiness
*diarrhea
*qtc prolongation
*tardive dyskinesia (avoid >12 weeks)
DDI:
Pearls/considerations:
*procloperazine has less risk fo rqtc prolongation
antiemetic agents
benzodiazepines
exs:
indications:
MOA:
AE:
DDI:
Pearls/considerations:
antiemetic agents
exs: LORZEPAM, ALPRAZOLAM
indications: most useful for anticiptaory CINV that has an anxiety component
MOA: anxiolyic
AE: sedation, dizziness
DDI:
Pearls/considerations:
*administer at night before or the morning of chemotherapy or both
antiemetic agents
Cannabinoids
exs:
indications:
MOA:
AE:
DDI:
Pearls/considerations:
antiemetic agents
Cannbinoids
exs: Dronabinol
indications: rarely used, only indicated in refractor disease
MOA: CB1 agonism supresses vomiting
*indirect activation of 5HT1A in raphe nucleus
AE:
sedation
euphoria, hallucinations
palpitation
flushing
cough
DDI:
Pearls/considerations:
*PO
antiemetic agents
scopolamine
exs:
indications:
MOA:
AE:
DDI:
Pearls/considerations:
antiemetic agents
exs:
indications:
MOA: anticholinergic
AE:
dry mouth
somnolence
blurred vision
DDI:
Pearls/considerations:
Cancer treatment induced diarrhea
incidence as high as 50-80%
most common offenders of cancer treatment induced diarrhea
fluorouracil
capecitadine
irinotecan
pertuzumab
abemaciclib
assessment of ctid
hx of citd
volume and duration of diarrhea
added risk factors
*fever
*orthostatic symptoms(dizziness)
*abdominal pain/cramping
*weakness
Irinotecan-induced diarrhea
can cause acute or delayed diarrhea
acute: due to cholinergic stimulation
*mean duration of symptoms is 30 min
*usually respond rapidly to atropine
delayed diarrhea: due to GI mucosal damage secondary to SN-38
*usually occur more than 24 hours after amdinistration
*noncumulative and occurs at all dose levels
mgt of CTID
non phar:
Iavoid foods that would aggravate the diarrhea
aggresive oral rehydration w. fluids that contain water, salt, and sugar
Pharm measures:
*loperamide-first line (4mg followed by 2 mg q4h or after every unformed stool . (not to exceed 16mg/d for CTID, MDD in regular circumstances is 8mg/d)
*diphenoxylate-atropine
*1-2 tabs q6hrs until control achieved (not to exceed 8 tablets/day
refractory CTID treatment options
octreotide
tincture of opium
probiotics
rule of C. diff and infection collitis
mucositis
SS
Complications
symptom: typically occurs within 5-14 days
complications:
decreased oral intake (poor nutritional status,
grade 3: severe oral pain
grade 4: requires parenteral or enteral nutrition
increase infection risk(gram+ oral flora, candida or fungal infections)
pain (may require opioids and pca administration)
mucositis vs stomatitis
mucositis: erythematous and ulcerative lesions of the mucose observed in pts treated w. chemo
can occur anywhere in gi tract
stomatitis: mucositis limited to the oral cavity
patho of chemo induced mucositis
five stage model of oral mucosisits
initiation- cellular damaged induced, reactive oxygen species formulations
primary damage resoinse
*activiation of p53 and nf-kb
sgnal aplifiation
ulceration- high risk for bacterial colonization
healing cessation from ongoing tissue damage
Risk factors for chemo induced mucositis
chemo
* melphalan
cisplastin+radiation
*high dose methotrexae
doxorubicin
busulfan
5-FU
pt factors:
smoking
poor oral hygeine
oral lesions at baseline
female sex
pretreamtent nutritional status
prevention of chemo induced mucositis
oral hygeine:
*avoid acidic or spicy foods
*burhs w. soft toothbrush twice daily; fossin gdaily
*swithc tabs to solutions o iv if hospitalized
*use nonalcoholic mouthwashes at least 4 times day
(ex NS or salt and soda
cryotherapy:
moa: local vasocinstriction-> less drug delivered to the oral mucose
*hold ice chips in their mouth for 30min before and/or during chemo
mgt of chemo induced mucositis
oral decontamination: bland mouthwash or oncology m outhwash. dexamethasone mouthwash for everolimus induced mucositis
pain control: 2% iscous lidocaine swish and spit, systemi opioids
palliation of dry mouth: artificial salive products or chewing gum to increase saliva production
nutritional supports: liquid or soft diet; tpn
oral candidiasis trt: nystatin oral solution or clotrimazole lozenge
*flucanozole 200 mg po x1 dose, then 100mg daily x 21 days
NEutropenia
neutropenia: absolute neutrophil count (ANC)<500 cells/mm3 or expected to decrease to <500 cells/mm3 in 48 hours
proound neutropenia: anc<100 CELLS/MM3
PROLONGED NEUTROPENIA: LASTIN LONGER THan 10 days
febrile neutropenia:
*single temp:>38.3 C orall or >38C over 1 hours
AND
ANC<500 cells/mm3 or expected to decrease to <500 cells/mm3 in 48 hours
consequences of neutropenia
dose reduction or treatment delayes
compromise clinical outcomes
longer hospital stays
increased treatment costs
decreased QOL
risk factors for febrile neutropenia
prior chemo or radiation
persistent neutropenia
bone marrow involvement by tumor
recent surgery and or open wounds
liver dysfunction (bilirubin >2.0 mg/dL)
renal dysfunction (Crcl <50 ml/min)
age> 64 years recieving ful chemo dos eintensity
primary prevention for febrile neutropenia
overall risk for neutropenia
High –>(regardless of pt risk factors) G-CSF recommended
intermediate risk (+>/1 risk factor) consider GCSF
Low (+>2 risk factors). GCSFs may be considered
note: G-CSF=granulocyte colony stimulating factor
pharm options for primary prevention for febril neutropenia
Filgastrim (category 1)
short -acting g-csf
start the next day or up to 3-4 days after completion of chemo
given daily until ANC recovery
pharm options for primary prevention for febril neutropenia
pegfilgastrim (category 1)
long acting g-csf
admin up to 3-4 days AFTER completion of chemo
singe administration!!
allow >/12 days between the dose of pegfilgastrim and the next cycle of chemotherapy
pharm options for primary prevention for febril neutropenia
Eflapegfilgastrim-xnst
(category 2A)
long acting c-csf
admin ~24hr after completion of chemo
single administration
do not admin 14 days before and 24 hrs after admin of chemo
treatment of febrile neutropenia
did pt recieve ppx g-csf? and which?
recieved filgastrim: continue filgastrim
recieved pegfilgastrim or eflapegfilgrastrim ppx: no additional g-csfs needed
if did not recieve ppx g-csf-> assess risk factors for infection-associated complication
risk factors for infection associated complications in establisehd febrile neutropenia
sepsis syndorme
age>65
ANC<100
neutropenia expected to be >10 days in duration
pneumonia or other clinically documented infctions
invasive fungal infection
hospitalization at the time of fever
prior episode of febrile neutropenia
secondary prevention for febrile neutropenia
(pt has hx of febrile neutropenia or dose limiting neutropenic event)
if pt has hz of prior use of g-csf-> consider chemo dose reduction or change in treatment regimen
if pt has no prior use of g-csf-> consider gcsf
Leukemia
Disease of bon marrow-> cancer of blood cells
acute vs chronic leukemia
acute
rapid onser
symptomatic (bleeding)
rapidly fatal if untreated
immature cells (blasts)
usually leukemia
chornic
*slowly progressive
*mos asymptomatic
*some survive years without trtment
*immature and matue cells
leukocystosis can occur in both phases
Histology differentiation of types of leukemia
Cancer can occur in the myeloid or the lymphoid white blood cells
when it occurs in the myeloid cells , it is called myelogenous leukemia
when it occurs in the lymphocytes , it is called lymphocytic leukemia
myeloid cells include granulocytes ( basophils, neutrophils, eosinophils), also platelets, and erythrocytes
Acute myeloid Lymphoma (AML) epidemiology
most common in adults aged 65-74. average age 68
most deadly leukemia in the US
risk factors for AML
increasing age
prior chemo= therapy related AML (t-AML)
ex: anthracyclines, alkylators (ex: cyclophosphamide, melhalan), topoisomerase inhibitors (etoposide)
prior pelvic radiation
cigarette smoking
radiation exposure
benzene exposure
pesticide exposure
Signs and sYmptons of AML
Anemia (fatigue and sob)
THOMBOCYTOPENIA (BLEEDING RISK)
NEUTROPENIA
ANC <500 or <1000 w. anticipated decrease to <500 w.in 48 hr
spontanous tumor lysis syndrome (TLS)
cns involvement rre(<3%) (somnolecense, headaches, consfusion
WBC count: 1/3 pts present w. pancytopenia, 1/3 w. wbc in normal limits, 1/3 w. elevated wbc
hyperleukocytosis: elevated wbc >/100,000/mcl
*poor prognosis
*increases risk of cns involvement
*very high risk of Tumor lysis syndrome
Patho of leukemia
hypercellular bone marrow
*immature blasts “outgrow” all other cells
*crowding results in cytopenias
* does not allow room for other cell lineages to grow
normal cellularity in marrow: 30-40%
sometimes these pts ca have 90-95% cellularity
hyperleukocytosis
oncologic emergency
8hyperviscosity syndrome (blood sludging)
*stumor, sob, vision changes
*can cause stroke, respiratory failure, cardiac ischemia, renal failure, retinal hemorrhage
management: hyroxyurea (hydrea)
*oral ribonucleitide reductase inhibitor
*used for count control
*used until clinically stable and ready to start induction chemo
*leukopheresis
dosing: package insert 50-100mg/kg/day
dosing heavily physician/pt specific
AE: nvd, risk for tumor lysis syndrome
LONG TERM: CUTANEOUS VASCULITIC ULCERATIONS
MUCOSITIS
ALOPECIA, HYPERIGMENTATION
diagnostic criteria of aml
WHO definition
> /20% blasts isolated on bone marrow biopsy (bmbx) or peripheral blood
cytogenitically definition: detection of cytogenetic abnormalities known to indicate AML, regardless of blast % on bmbx
Prognostic Markers
cytogenetics!!!; predicts abilility to obtain remission w. induction chemo with persons chromosomal make up aka karyotype, risk of relapse, and overall survivial
moelcular abnormalities
age
primary vs secondary aml
performance status
availability of stem donor
wbc at diagnosis
extramedullary disease (disease not in marrow)
FMS-Like Tyrosine Kinase (FLT3) mutations and effects of mutations
two types
*internal tandem duplication (ITD)
*Tyrosine kinase domain(TKD) point mutations
promotes proliferation and blocks differentiation
associated w. worse prognosis, increased relapse rate and lower OS
associate w. leukocyosis and high percentage of blasts in bone marrow de novo AML
(ITD mutations associated w. worse survival/worse prognosis compared to tkd mutation)
Other molecular mutations for idh
ISOCITRATE dehydrogenase(IDH)
others being researched: RUNX1, TET2, spliceosome mutations
Risk stratification based on cytogenetics and molecular mutations
favorable risk: low risk of relapse if we get them into remission
intermediate risk
poor risk
*intermediate and poor risk pts are taken to transplants once they get to remission
AML treatment algorithm: agressive chemoTHERPAY
step 1: DETERMINE if pt is a candidate for aggresive chemo
(criteria for high-intensity induction chemo)
most pts<60
pts >/60 w.o significant co morbidities or end organ dysfunction (adeque renal, hepatic, and cardiac function
*adequate performance status
pts w. aggressive disease course (hyperleukocytosis, tumor lysis syndrome at presentation)
pts who are candidates for an allogenic stem cell transplant
AML treatment algorithm: agressive chemoTHERPAY
Step 2 : if pt is candidate for aggressive chemo, what is/are the regimen of choice
Cytarabine +Anthracycline (7+3) based regimen
for pts <60 yo.
cytarabine 100mg/m^2 IV daily continuous infusion x7 days
+daunorubicin 60 mg/m^2 x 3days OR idarubicin 12mg/m2/dx 3 days
for pts >/60
cytarabine 100mg/m^2 IV daily continuous infusion x7 days
+daunorubicin 60 mg/m^2 x 3days OR idarubicin 12mg/m2/dx 3 days
**note: pts >/65 have <50% complete remission rate (CR)
WBC phases oh 7+3 treatment for AML
days 1-7: chemo admin
*SE: n/v, GI, fatigue
WBC drop significantly
Days 8-24: cell count nadir and recovery
*side effects: fatigue, fevr/infection, high rbc and platelet transfusion requirmeent
days 25+ complete cell count recovery expected.
*d/c from hospital once ANC>500 and no longer platlet transfusion dependent
Additional induction regimens for AML
7+3 based regimens
*additional chemos and or tyrosine kinase inhibitors added to backbone of 7+3
exs:
FLT3-ITD or FLT3TKD positive
*Midostaurin
*50 mg BID w. food on days 8-21 of each cours of chemo (induction and consolidation)
*can cause nausea
*favorable/intermediate cytogenetics
*gemtuzumab ozogamicin (GO)
3mg/m^2 (max 4.5 mg) on days 1,4, and 7 of induction and day 1 of consolidation courses
*antibody drug conjugate.
no increase in survival seen in poor risk pts
Liposomal Daunorubicin +cytaribine (vyxeos)
*indication: 1st line treatment of treatment related/ secondary AML
*liposomal formulations
AML treatment algorithm: agressive chemoTHERPAY
Step 3: Analysis of treatment Response
Day 14 bmbx:
*Leukemia free state on day 14
Goal: <5-10% blasts, hypocellular (<10-20% cells)
complete remission/complete response n(CR) criteria: day 28+
*criteria for CR: <5% blasts and ANC>1000 ANDD platelets>100,000
complete remission w. incomplete count recovery (iCR)
*older pts w. prior MDS- residual dysplasia prevents full platelet recovery
AML treatment algorithm: agressive chemoTHERPAY
Step 4: Await countrecovery +/- G-CSF
response criteria in AML
complete remission/complete response n(CR) criteria: day 28+
*criteria for CR: <5% blasts and ANC>1000 ANDD platelets>100,000
complete remission w. incomplete count recovery (iCR)
*older pts w. prior MDS- residual dysplasia prevents full platelet recovery
*repeat bmbx to document complete remission
AML treatment algorithm: agressive chemoTHERPAY
Step5: Consolidation therapy
purpose:
favorable risk:
intermediate/poor risk
purpose: to eliminate remaining disease that was not eliminated during induction phase
favorable risk pts:
A) HiDAC: Hi dose cytarabine
*for those who recieved 7+3 based therapies
*gold standard consolidation therapy for AML
1.5-3 g/m^2 iv q12hrs x 6 doses q28 days x 3-4 cycles
b) other option: Liposomal daunorubicin+ cytarabine
Intermediate/poor risk
*stem cell transplant
*based on cytogenetics, molecular mutations
*usually, compete induction and 1+ cycle(s) if consolidation prior to transplant
AML treatment algorithm: non-agressive chemoTHERPAY
step 1: if pt is not a candidate for agressive chemo, what is/are the regimen of choice
“low intensity” chemo
*reserved for those unfit for intensive chemo or those w. significant comorbidities
a) HYpomethylating Agents (hma)+Venetoclax
*Azacitidine (Vidoza) 75 mg/m^2/dayx7 days q28 days-> can be subq or iv
**standard of care
*Decitabine (Dacogen): 20 mg/m^2/day IVx5 days q28 days
b) Low dose cytarabine (LDAC) +venetoclax
c)Ivosidenib +Venetoclax
*both agents given continuously
*only in IDH1 mutated pts
d) LDAC+ Glasdegib
Venetoclax interactions and dose reductions
immediatly when pt is on venetoclax, must consider other drugs pt is on to identify any DDI
HMA backbone dose: 400mg PO once daily
*strong cyp3a4 inhibitors (posiconazole/voriconazole): 100 mg once daily
*mod cyp3a4 inhibitors: isavuconazole, diltiazem, verapamil ) or pgp inhibiors (amiodarone, carvedilol) 200 mg once daily
LDAC backbone:
*strong cyp3a4 inhibitors (posiconazole/voriconazole): 150 mg once daily
*mod cyp3a4 inhibitors: isavuconazole, diltiazem, verapamil ) or pgp inhibiors (amiodarone, carvedilol) 300 mg once daily
Options for relapsed or refractory AML disease
clinical trial
can repeat intial induction regimen if response lasted >12 months
etc.
targeted therapies in AML
FLT3 mutations (FLT3 ITD, FLT3 TKD)
A)FDA approved
*Midostaurin (Rydapt)->only used frontline. not used in refractory disease/relapse
*Gliteritinib-> only fda approved for relapsed/refractory flt3+ AML
IDH inhibitors:
a)FDA approved
*IVOSIDENIB-targets idh1- approved for newly diagnosed and relapsed/refractory disease
*ENASIDENIB- TARGETS idh2->approved for refractory/relapsed disease
Supportive care in AML
A)transfusions
*rbc transfusion if hgb<8g/dL
*plt transfusion if plt<10,000 mcL
b)infection ppx while neutropenic
I. Antiviral: HSV/VZV-acyclovir 400mg BID
II. antibacterial: ciprofloxacin 500mg BID or levofloxacin 500mg qd
III. invasive fungal(Asperigillus & mold (mucomycosis)
*posaconazole (covers mucoid)
*voriconazole (covers mold as well)
Tumor lysis syndrome
oncologic emergency
rapid tumor breakdown following chemotherapy
sudden release of intracellular potassium, phosphorous , uric acid
onset: 12-72 hrs post chemo
risk factors:
renal insufficiency
elevated uric acid, phosphorous, lactate dehydrogenase
dehydration
common tumor types: hematologic malignancies
associated w. large tumor burden, higher cell turnover, etc.
presentation of tls
metabolic disturbances hyperuricemia-> can crystalize and lead to irreversible kidney damage
hyperphosphatemia:calcium phophate precipitate inkidneys
hyperkalemia
hypocalceima
clinical manifestations:
**acute renal failure
*NVD
*hematuria
*CHF, cardiac dysrhtmias
syncope
seizures
death
TLS PPX
A)allopurinol
inhibits formulation of uric acid
dose: 300-600 mg/day
renal adjustment:
crcl 10-30: 200 mg/day
crcl: <10: 100 mg/dau
hydration
Rasburicase-> breaks down uric acid( usually used for treatment, not for ppx)
TLS management
Hyperuricemia
*IV hydration
maintain urine output >2.5L
*furosemide if unable to maintain urine output alone
*Rasburicase: 1.5-6 mg as single dose. can repeat q12-24hrs on repeat levels
*roswell dosing: 1.5 mg if pt<60kg, 3 if pt>60kg
*rasburicase can cause anemia in pts w. g6pd deficiency.
Hyperkalemia
*EKG-rule out active arrythmia
Sodium polystyrene sulfonate (kayexalate)
*insulin and glucose
*dialysis
Hyperphosphatemia
*phosphate binders (sevelamer, calcium acetate)
*dialysis
Hypocalcemia
*do not treat
Clinical pearls of chemo used in leukemia
Anthracyclines( daunorubicin, idarubicin, mitoxantrone)
*red in color: ink-light reddish urine
mitoxantrone: blue in color->blue green urine, sclera
*AE: myelosupression
cardiotoxicity
Cytarabine:
AE with HiDAC: neurotoxicity
*NEURO CHECKS REQUIRED pior to each dose
conjunctivitis
Gemtuzumab+Otogamicin (GO):
*mab-> infusion reactions( premedicate w. APAP, diphenhydramine, and methylprednisolone
hepatotoxic
BBW: VENO OCCLUSIVE DISEASE-> fatal disease that causes obstruction of blood veseels that lead into liver
*monitor LFTs, bilirubin, ascites, weight gain, hepatomegaly, amdominal pain
Low Intensity Chemo
*HMA backbones (Azacitidine)
AE: constipation-> standing bowel meds
low-mod emetogenicity, premedicate w. ondansetron
*Venetoclaax: AE: myelosupression
Myeloid Growth Factors
Granulocyte-colony stimulating Factor (G-CSF): Filgrastrim (Neupogen), filgastrim-sndz(Zarxio)
Granulocyte macrophage colony stimulating factor (GM-CSF): Sargramostim
indication in leukemia: may be used for severe infections in setting of neutropenia (i.e severe sepsis)
AE: bone pain (up to 50%)-> recommend loratidine ((due to histamine release of bone, causing the pain) or hydroxyzine
*feevr
Chronic Myeloid leukemia
etiology/pathogenesis
driven by acquired mutation that affects hemotopeitic stem cells
*philidlphia chromosome (Ph+) mutation creating MCR-ABL fusion onco gene, contains an active tyrosine kinase region which is responsible for cell proliferation, cell growth and survival
risk factors for cml
ionizing radiation
SS of CML
up to 50% of pts are asymptomatic
*splenomegaly >50% are present due to elevated platelets
anorexia
bone pain
purpura
unexplained weightloss
fatigue
Lab findings for cml
LEKOCYTOSIS - WBC>25 X 10^9/L
bone marrow findings
*hypercellularity(74-90%)
*increased erythropoeisis
*increased megakaryocytes
*minimal dysplasia
blasts<10%
*Ph+ chromosome
Phases of CML
chronic blast phase(CP): <10% blasts
etc.
goal: delay progression to AP/BP, eradicate philidelphia chromosome
Accelerated Phase: 10-19% blasts in peripheral blood and/or marrow
etc.
Goal: control wbs, bring back to CP an avoid progressin to BP
blast phase (BP): >.20% blasts in peripheral or in bone marrow
Goal : survive induction, bridge to allogeneic stem cell transplant
Treatment of CML
Targeted therapy-Tyrosine Kinase Inhibitors (TKIs)
1st gn: Imatinib (Gleevec)
2nd gen: Dasatinib (Sprycel), Nilotinib
3rd Gen: Bossutinib, Ponatinib
STAMP inhibitor: Asciminib, binds to a different place on TKI
oral admin
now condiered a chronic disease state managed w. TKI’s
Responses to therapy in CML
hematologic response: looking at peripheral blood counts
cytogenic response: bmbx, number of Ph+ metaphases remaining
molecular response: how much kinase is in blood
*how we currently monitor response
Tyrosine Kinase Inhibitors
Imatinib (Gleevac)
moa:
dose:
AE:
AE mgt:
Pearls/considerations:
Tyrosine Kinase Inhibitors
moa: selective inhibitor of bcr-abl TYROSINE KINASE
*also inhibits c-kit and plt derived growth factor receptor
dose:400 mg daily
AE: edema/ fluid retention, myalgias, hypophosphatemia, NVD
AE mgt: diuretics, supportive care. consider checking EF if pleaural/pericardiac. for myalgias, calcium supplementation
Pearls/considerations:
*high doses >400 mg not recommended as initial therapy
* developed resistance, lead to development of later gen TKIs
Tyrosine Kinase Inhibitors
Dasatinib (Sprycel)
moa:
dose:
AE:
Pearls/considerations:
Tyrosine Kinase Inhibitors
Dasatinib
moa:
dose: 100 mg daily
AE:
*pleural/ pericardial effusions, bleeding risk, pulmonary arterial HTN
AE mgt:
*pulmonary htn: d/c
*fluid retention, edema, ascites: diuretics, supportive
Pearls/considerations:
*standard oc care
*second gen,
*cns penetration
Tyrosine Kinase Inhibitors
Nilotinib
moa:
dose:
AE:
Pearls/considerations:
Tyrosine Kinase Inhibitors
moa:
dose: 300 mg
AE: elevated pancreatic enzymes, indirect hyperbilirubinemia, qtc prolongation, cv events
AE mgt:
*qtc prolongation: ecg@baseline, 7 days after intiation, and periodically. corect for hypokalemia and hypomagnesemia.
elevatd lft: consider dose reduction or d/c
*peripheral arterial occlusive disease: d/c
Pearls/considerations:
*qtc prolongation
*2nd gen mgt
Tyrosine Kinase Inhibitors
Bosutinib
moa:
dose:
AE:
Pearls/considerations:
Tyrosine Kinase Inhibitors
moa:
dose:
AE:
*Diarrhea manageable w. loperamide, hepatotoxicity, headache, rash
AE mgt:
*hepatotoxicity: hold until recovery, then dose reduce or d/c
*diarrhea: hold until recover, loperamide
Pearls/considerations:
*3rd gen
How to choose which tki to use
SoKal score: calculates relative risk calculation
intermediate-high risk
Category 1 recommendation: *2nd or 3rd gen TKI
low risk:
*Imatinib or 2nd gen
monitoring cml
color chart:
red: tki resistance disease
*evaluate pt compliance and ddi.
*CONSIDER MUTATIONAL ANALYSIS
recommendation: switch to alternate tki and evaluate for allogenic hct
yellow: possible tki resistance
recommendation: switch to alternate tki, continue same tki (other than imatinib) or increase imatinib dose to max of 800mg and ocnsider evaluation for allognic hct
light green: tki sensitive disease
recommendation: if optimal, continue same tki, if not optimal, share decision making w. pt
green: continue same tki
mutation profiles for CML clinical pearl
Asciminib and Ponatinib are only tki that cover BCR-ABL T315I mutation
T315I mutation is resistant to other TKIs.
Tyrosine Kinase Inhibitors
Ponatinib
moa:
dose:
AE:
Pearls/considerations:
Tyrosine Kinase Inhibitors
moa:
dose:
AE: elevated pancreatic enzymes, HTN, skin toxicity, thrombotic events
AE mgt:
hepatotoxicity: hold until recover, then dose reduce or d/c
*ischemic reactions: d/c
elevated lft: hold until recovery
Pearls/considerations:
*3rd gen
*reserved for pts who failed atleast 2 tki, or have T315I mutation
*BBW: vascular occlusion, hepatotoxicity, HF
Tyrosine Kinase Inhibitors
Asciminib
moa:
dose:
AE:
Pearls/considerations:
Tyrosine Kinase Inhibitors
moa: STAMP inhibitor
dose:
AE:
Pearls/considerations:
trt of pts who have previously recieved 2+ tkis or have T31FI mutaion
TKI common class side effects
myelosupression
transminitis
hepatotoxicity
electrolyte changes
CV events
TKI DDI
imatinib-cyp3a4 substrate and inhibitor
Dasatinib, bosutinib, poatinib-cyp3a4 substrate
nilotinib: cyp3a4 substrate and inhibitor, also 2cb, 2c9, and 2d6
TKI food drug interactions
dasitinib- needs acidic environment for absorption (no ppis or h2 blockers)
nilotinib and asciminib: admin on empty stomach. 2 hrs before eating or 1 hr after
tki dose adjustment for organ impairment
imatinib: dose adjust for renal and hepatic
nilotinib, bosutinib, ponatinib- dose adjust for hepatic
Acclerated phase/blast crisis treatment
Goal: return pt to chronic phase
all tkis have been shown to induce favorable response rates
current recommendations:
Dasatinib, niltinib, or bosutinib
omacetaxine can be considered in cass of disease progression
blast crisis:
TKI +/- chemo followed by allogenic HSCT
*chemo chosen on subtype of the disease
what s the prostate
surrounds urethra
produces seminal fluid that nourishes and transports sperm
composed of acinar secretory calles arranges in a radial shape surrounded by a foundation of supporting tissue
95% of prostate cancer cases are caused by adenocarcinoma
epidemiology of prostate cancer
most diagnosed cancer in males
2nd most common diagnosed cancer in US
5 year relative survivial from 2012-2018: 96.8%
for most pts. prostate cancer is a slow growing or indolent disease
risk factors for prostate cancer
Race: african amerians more common, less common in asians. incidence higher in US and scandanavian countries
Age:most ppl dagnosed 65-74. Median age of diagnosis: 67
Family hx: increase in men w. family hx of prostate cancer
*familial predisposition
*BRCA-2 mutations a.w 2-6 fold increase in risk
*lynch syndrome 2-5.8 fold increase in risk
Lifetime risk of prostate cancer
*16% of one first degree raltive vs 8% if no family hx
screning for prostate cancer
different organizations have different screening protocols
usually involves prostate -specific antigen
often determined by pts age and life expectancy
clinical presentation of prostate cancer
localized
*asymptomatic generally
locally invasisive
*urrerteral dysfunction
*urinary frequency
*urinary hesitancy
*dribbling or decreased urinary stream
*incomplete bladder emptying
advanced disease
*back pain
cord compression
lower-extremeity edema
pthologic factors
anemia
weightloss
prognostic factors
PSA
A)protate specific antigen
*gycoprotein produced by prostate epithelial cells
*specific for prostate, not for cancer
(if pt ha bph, psa can be high)
*can be reduced by 5-alpha reductase inhibitors)
normal range </4, some pts with psa 2.5-4 still develop prostate cancer
PSA velocity may be another predictor of prostate cancer risk
general prognostic factors of prostate cancer
prostate specific antigen (PSA)
tumor size and extent of primary tumor
histologic grade(gleason score)
Prognostic factors
tumor size and extent of primary tumor
localized tumore: excellent long term prognosis
locally advanced cancer: 5 year survival is very good
metastatic disease: not curable, median survival shortened
staging system for prostate cancer
TNM: tumor, node, metastasis
Tumor (T): clinical staging to determine size
Node (N): presence and extent of regional lymph node involvement
Metastasis: presence and extent of metastasis
Prognostic factors
Histologic grade-Gleason score
gleason score
*describes how cancer cells look under a microscope
pathologist gets biopsy of tissue and assigns a score to 1st and second most predominnant tissue
score ranges 1-5
closest to 1: low grade tumor cells; looks similar to normal cells
closest to 5: high grade tumor cells; mutated so much they barely look like normal cells
both numbers are added, to give a score. total score between 2-10.
Gleason score group
gleason scores 2-4 tend to be less agressive,
gleason scores 7-10 tend to be more agressive
Goals of therapy for prostate cancer
localized disease:
cure
control disease and symptoms
decrease morbidity and mortality
advanced/ metastatic disease
*palliation
*improved qol
*prolong survival
factors to consider for prostate cancer treatment
pt comorbidities
pt symptoms
recurrence risk
pt life expectancy (expected survivial
disease stage
** for localized and regional disease, treatment approach is based on RISK STRATIFICATION rther than stage
Local prostate cancer disease recurrence risk stratification
Recurrance Risk: Very low
expected survival
1) <10 years
* initial therapy: observation
2) 10-20 years
*initial therapy: Active surveillance
3) >/20 years
*initial therapy:
Prostate cancer treatment
gold standard: Androgen Deprivation therapy (ADT) for advanced prostate cancer
testosterone is the driving force of prostate cancer
surgical castration: bilateral orchiectomy
!!!Medical Castration:
*LHRH agonists+/- antiandrogen
*LHRH antagonist
intent is to lower levels of testosterone
prostate cancer treatment
LHRH agonists
moa: mimics endogenous LHRH, causing sustained release of LH and FSH. release of lh and fsh would normally cause production of testosterone. howevere, sustained release causes negative feedback loop, decreasing the amount of testosterone produced.
ex: Leuprolide (Trelstar), Goserelin (Zoladex)
LHRH agonist adverse effects
acute: tumor flare (due to short term increase in testosterone due to LH an FSH), hot flashes, erectile dysfunction, edema, gynecomastia, injection site reaction
Long term: osteoporosis, clinical fracture, insulin resistance, increased risk of diabetes, CV events, alteration in diabetes
moa of initial tumor flare in prostate cancer
cause by a surge in lh/fsh release, causing increased testosterone production.
SS: increased bone pain (if metastatic) or increased urinary SS
resolves after 2 weeks
starting a first gen anti androgen before admin of LHRH agonist and continuing for 2-4 weeks frequently used to mitigate tumor flare.
baseline bone mineral density test bfore starting longterm ADT (calcium and vit. D supplementation
LHRH antagonists
moa: binds to GnRH receptors in on cells in pituitary gland, dramatically reducing LH/FSH resulting reduced production of testosterone to castrate levels
ex:Degarelix
Relugolix
advantage: much faster drop in testosterone levels
castration levels seen in 7 days or less compared to 28 days w. lhrh agonists. no tumor flare and thus no antiandrogen needed
cons: less flexible indosing schedule, high cost
anti androgens in prostate cancer
moa: inhibits anrogen uptke and/orbinding in target tissues. specifcally, a competitice inhibitor for the binding of DHT and testtosterone
first gen:
bicalutamide
flutamide
nilutamise
second gen:
apalutamide
enzalutimaide
darolutamide
2nd gen more potent
ade: diarrhea, gynecomastia, elevated lft, hot fashes
monitoring: lfts monthly
combined androgen blockade in prostate cancer
lhrh agonist or antagonist +anti androgen
contraversial
associated w. more ADE
Castration sensitive prostate cancer therapy options
ADT+ abiraterone or Apalutamide or Enzalutamide
ADT w. docetaxel x6 cycles +abiraterone or darolutmidde
*use din high volume castration sensitive metastatic prostate cancer
choice of regimen invoes discussion w. pt about potential toxicities of abiraterone and docetaxel as well as cost of treatment
castration resistant prostate cancer
serum testosterone <50 ng and disease progression
nccn recommendation: continue adt and maintain castrate levels while adding therapies
therapy base don whether pt has non metastatic m0 or metastatic m1 disease
treatment for nometastatic m0 CRPC
M0-> continue AT to maintain castrate tstosterone
if PROSTATE DOUBLES >10 MONTHS
A) MONITOR or
2) other secondary hormone therapy
id prostate doubles <10 months
a) apalutamide
b)enzalutamide
secondary hormone therapies for castration resistant prostate cancer CRPC
continue ADT to maintain castarte levels of testosterone and add:
2nd gen antiandrogen
*apalutamide for m0 and PSADT </10 months
darolutamide for m0 and PSADT </10 months
enzalutamide for m0 and PSADT </10 months and M1
androgen metabolism inhibitor
abiraterone w. prednisone or methylprednisolone
etc.
Second generation antiandrogen therapies
Apalutamide (Erleada)
moa
dosing
ADE
considertions/pearls
Second generation antiandrogen therapies
moa: nonsteroidal androgen receptor inhibitor, binds dirctly to androgen receptor preventing androgen translocation, dna binding, and transcription. causes decreased prolifration of tumor cells and increased apoptosis leading to decreased tumor volume
dosing 240 mg once daily w. or w.o food
ADE: fatigue, htn
considertions/pearls
*ci in pts w. seizures
Second generation antiandrogen therapies
Darolutamide
moa
dosing
ADE
considertions/pearls
Second generation antiandrogen therapies
moa
dosing
ADE
considertions/pearls
no increase risk in seizures
renal dosing
Second generation antiandrogen therapies
Enzalutamide
moa
dosing
ADE
considertions/pearls
Second generation antiandrogen therapies
moa
dosing
ADE
considertions/pearls
*increased risk of seizures
treatment of m1 CRPC
no prior docetaxel/ no prior hormone therapy
MOST PROSTATE CANCERS ARE ADENOCARCINOMAS. IF HISTOLOGY IS UNKOWN, TREAT AS IF ADENOCARCINMOMA.
no prior docetaxel/ no prior hormone therapy
preffered regimens
*abiraterone
docetaxel
enzalutamide
cirtain circumstances:
radium 223 for symptomatic bone metas.
sipuleacual
treatment of m1 CRPC
prior hormone therapy/no prior docetaxel/
preferred: docetaxel
treatment of m1 CRPC
prior docetaxel/ no prior hormone therpay
preferred: abiraterone
cabazitaxel
enzalutamide
treatment of m1 CRPC
prior docetaxel and prior novel hormone therapy
preferred regimend:
docetaxel rechallange, cabazitaxel
summary of treatment of m1 crpc 1st line
if pt has viseral metas (liver, lung, adrenal, peritoneum,brain (consider docetaxel if pt has not recieved it and pt is fit for chemo
no viseral metas.: treat based on prior therapy
symptomatic bone metas: radium 223
asymptomatic or minimally symptomatic, no liver metas, life expectancy> 6 months.. consider sipuleucal-T
chemo therapy agents for m1 prostate cancer
Docetaxel
moa:
dose:
ade:
considerations/ pearls
chemo therapy agents for prostate cancer
moa:microtubule inhibitot
dose: dose+prednisone
ade:
*alopecia, myelosupression, peripheral neuropathy, hypersensitivity reaction (premidcate before)
considerations/ pearls:
cause hepatic impairment
chemo therapy agents for m1 prostate cancer
Abiraterone (Zytiga)
moa:
dose:
ade:
considerations/ pearls
chemo therapy agents for prostate cancer
moa: inhibits CYP17. responsible for androgen biosynthesis in many diff tissues, inhibits formtion of testosterone precursors
dose:
ade:hypokalemia, diarrhea, edma, htn, hepatotoxicity
considerations/ pearls:
give w. steroids to prevent hypokalemia due to mineralcorticoid excesscaused by drug long term.
prednisone can increase glucose
*monitor lft, K+, po4, bp on monthly basis
chemo therapy agents for m1 prostate cancer
Abiraterone
moa:
dose:
ade:
considerations/ pearls
chemo therapy agents for prostate cancer
moa:
dose:
ade:
considerations/ pearls:
*pt must always recieve w. steroid
therapy agents for m1 prostate cancer
radium-223
moa:
dose:
ade:
considerations/ pearls
chemo therapy agents for prostate cancer
moa:
dose:
ade:
considerations/ pearls
only used in pt w. bone metas. ONLY and no visceral metas.
not used in combo w. chemo
chemo therapy agents for prostate cancer
Sipulecual T (provenge)
moa:
dose:
ade:
considerations/ pearls
chemo therapy agents for prostate cancer
moa: dendritic cell vaccine designed to enhance t cell immune response to prostatic acid phosphatase
cells exposed to PAP fused with GM-CSF).
dose:
ade:infusion reactions
considerations/ pearls
$100,000 per dose
second line therpiaes for m1 pc
if prir chemo, consider hormone therpay
*cabazitaxel
cabazitxel/ carboplatin
LU-177-PSMA-617
other trtments
*pembralizumab
radium 223 bone metastesis
etc.
chemo therapy agents for prostate cancer
cabazitaxel
moa:
dose:
ade:
considerations/ pearls
chemo therapy agents for prostate cancer
moa: microtubule inhibitor
dose:
ade:*febrine neutropenia
considerations/ pearls
2nd line if pt still has disease progression
*pt must be on prednisone
supportive care in prostate cancer
adt associted w. increase risk of bone fracture
*baseline dexa scans
*calcium 1000-1200 mg daily and vit. 400-800 iu
bone metas.: must give bone modifying agents
*Zolendronic acid, denosumab (at doses didfferent than in osteoporosis
