PowerPoint - Chemotherapy

Principles of
Wendy Blount, DVM
Indications for Chemotherapy
 Systemic or metastatic disease that is chemo responsive
• local control (surgery, radiation therapy) isn’t adequate
• Cure is rare (TVT is an exception)
• Remission or prolonged stable disease is likely
• Months to years
• Prepare owners for relapse that will ultimately be unmanageable
 Neo-adjuvant therapy
• Reducing size of large, localized tumor prior to surgery
 Dirty borders on localized tumor
 Increased survival time without decreasing quality of life
Metronomic Therapy
 Fewer side effects than high dose treatment
 Cyclophosphamide and piroxicam to prevent recurrence of
• Cyclophosphamide 10 mg/m2 PO SID or QOD
• Piroxicam 0.3 mg/kg PO SID or QOD
 Take care that the pet is not also on prednisone
 Low dose chlorambucil is also considered metronomic
Side Effects
 Make sure clients understand that chemo protocols for
animals are much less aggressive than for people
• Side effects are assumed to be present and possibly severe for
• Many pets who undergo chemotherapy have infrequent side
effects that are often mild
 Chemo drugs kill or harm cells that divide rapidly
• Gastrointestinal tract, bone marrow, skin and hair
 The most common side effects are gastrointestinal,
pancytopenias (mostly WBC) and changes in fur
 Dogs may be unable to reproduce after chemotherapy
Side Effects
GI Toxicity
 Direct damage to epithelial cells
• 3-5 days after chemo
 Direct stimulation of the chemoreceptor trigger zone
• 24-48 hours after chemo
 Both - inappetance, nausea, vomiting, diarrhea
• Can vary from a few soft stools to parvovirus-like disease
 Dispense Cerenia and Metronidazole at the first treatment
if you anticipate a problem with getting the meds on the
day needed
Side Effects
Bone Marrow Toxicity
 Direct damage to stem cells
 Neutrophils have shortest life, so they are affected first
 Then other WBC, platelets and RBC
 Delay chemo if Neutrophils <2,000/ul
• recheck CBC 3-7 days
 Antibiotic therapy if fever or neutrophils <1,000/ul
 GCSF (Neupogen®) if neutrophils <500/ul
 IV fluids and IV antibiotics only if septic
• Placing an IV catheter in an asymptomatic neutropenic dog can
result in infection or sepsis
Side Effects
Bone Marrow Toxicity
 Delay chemo if platelets <50,000, unless Tpenia is
thought to be caused by neoplasia
 If cytopenia, delay treatment by 3-7 days and reduce dose
by 20-25% when resumed
• Most chemo delay by 3-7 days
• Lomustine*, doxorubicin, cyclophosphamide*, chlorambucil
delay at least 7 days
CBC the day of and prior to every chemo dose
Draw from the jugular vein
Side Effects
Bone Marrow Toxicity Nadirs – recovery usually within 7
days (*these drugs longer)
 Not usually myelosuppressive – L-asparaginase
 4-6 days - methotrexate
 5-7 days - cytarabine
 7-10 days – doxorubicin*, mustargen, procarbazine
 10 days – mitoxantrone
 7-14 days – chlorambucil*, cyclophosphamide**
 14 days – carboplatin (cats 17-21 days)
 7-21 days – lomustine**
Side Effects
Hair Loss
 Fur might thin or change color, but complete hair loss is
 Fur loss is more common with non-shedding dogs such as
poodles and terriers
• Their fur continuously grows
 Cats may lose guard hairs or whiskers
 Be very careful to use kg not lb when converting body
weight to Body Surface Area.
 Using lb will result in 2x chemotherapy dose
 If given PO, induce vomiting immediately
 This mistake is almost always fatal if given by injection
Have 2 staff members calculate the dose, and compare
A 60 lb dog is about 1m2 = 0.6cc vincristine, 15cc
doxorubicin, 40mg prednisone, 60mg CCNU, 200-250mg
cyclophosphamide (8-10 small tablets, 4-5 large tablets)
1 vial Elspar
Patient Care
 Chemotherapy patients should never be given MLV
vaccines (risk of post-vaccinal infection)
 Vaccinations with killed vaccines (rabies) should be fine
 Clients should be furnished with gloves to wear
• For administering chemo pills
• for cleaning up pet eliminations
• When sitting with animals during IV drips
 Always provide a written educational handout for each
drug given (http://wendybount.com)
Safe Handling
 Order liquid injectables rather than those that must be
• Doxorubicin, vincristine, vinblastine, carboplatin, mitoxantrone
 Have oral chemo doses professionally compounded
• Chemo gloves or double latex gloves
 Wear a respirator mask if you must reconstitute powders
• Cytosar-U, Actinomycin-D, dacarbazine (not Elspar)
 Inject bubbles out of the syringe prior to removing the
needle from the vial
 Put anything that touched the drug in biohazard disposal
Safe Handling
 Reconstitute drugs in a biological safety cabinet
• Have your local pharmacist do it for you
 Use venting devices or drug filters to avoid aerosolization
when withdrawing needle from the vial
 Wear an isolation gown, buttoned lab coat, etc.
 Wear eye protection
 Oncology nurses have higher incidence of
headaches and nausea
Skin irritation
Chromosomal, bone marrow and liver damage
Miscarriage and cancer
Keep Refrigerated
Vincristine, Vinblastine
Cytarabine once reconstituted
None are damaged by refrigeration
MDR-1 Deletion
White Feet – Don’t Treat
 Test for MDR1 deletion before giving these drugs to
collies: (form)
• Doxorubicin, D-actinomycin
• Vincristine, Vinblastine
 Do not give drugs that inhibit p-glycoprotein concurrently
• Comfortis or Trifexis
• Ca++ channel blockers (amioderone, diltiazem, verapamil,
• Azole antifungals
• Cyclosporin
• Lincosamides (azithromycin, clarithromycin, erythromycin)
IV Push Chemotherapy
 For drugs that are given IV quickly • Vincristine, mitoxantrone
 Flush butterfly catheter (19-22 gauge) with sterile fluid compatible
with the drug
• Place it on the glove envelope used as sterile field
 Predraw syringes – two 4-6cc fluid for flush, plus drug; remove
needles and place on sterile field
 Clip and gently clean the skin
 Assistant occludes and rolls the vein, to release when instructed
 Place butterfly catheter on clean stick, do not tape
 Flush/test, inject drug, flush/test
 Remove butterfly catheter and bandage leg
IV Drip Chemotherapy
 For drugs that are given IV slowly – more than a minute or
• Doxorubicin, mustargen, actinomycinD, carboplatin, (vinblastine)
 Attach buretrol and IV line to compatible IV fluid bag and
 Draw up chemo to be given
 Clip and gently clean the skin
 Place and secure IV catheter on clean stick
IV Drip Chemotherapy
 Trained trusted assistant sits with dog during drip
• If any problems, stop drip and then get help
 Run 20-50cc fluids into Buretrol and run into patient to test
line patency
• If problems, place another catheter
 Add chemo drug to Buretrol and qs to 2ml/minute
• e.g., vinblastine given over 10 minutes, qs to 20 ml
 Run 2-3 aliquots of 10-20cc IV fluids into the buretrol and
then into the patient, until fluid runs clear when drug is
 Remove IV catheter and bandage
Wicked Expensive Drugs
Mustargen (<$700 for a 4-pack)
Palladia and Kinavet (>$500 a month for medium dog)
Gleevex ($100 a pill)
Procarbazine (>$1000 last time I checked)
Doxil – liposomal doxorubicin – 20x cost of doxorubicin
Try Diamondback Pharmacy for all but TKIs
Try Medshoppe Pharmacy in Longview
for back ordered items
Alkylating Agents
Orally or by IV injection or drip
Efficacy not affected by route of administration
 Cyclophosphamide (Cytoxan®, Neosar®)
 Chlorambucil (Leukeran®)
 Lomustine, aka CCNU (Ceenu®)
 Melphalan (Alkeran®)
 Mustargen (Mustine®)
 Procarbazine (Matulane®)
 Dacarbazine, (DTIC-Dome®)
 Dose: 200-250 mg/m2 PO or IV
• Can give in one dose, or divide into 3-5 daily doses
 Indications: LSA, leukemias, carcinomas, sarcomas
 Unique side effects:
1. Can cause sterile hemorrhagic cystitis (CIC)
• Can predispose to transitional cell carcinoma
• If not on prednisone, add furosemide 1 mg/lb given with each
cyclophosphamide dose
• Negative urine culture diagnoses CIC
• If cystitis, discontinue and replace with chlorambucil
• Give in the morning & encourage frequent bladder emptying
2. Give with food to prevent stomach upset
 Unique side effects:
• Rarely can cause pneumonitis
• Cleared by liver and kidneys – use with caution in pets with liver
or kidney disease
 Drug Interactions:
• Allopurinol an increase bone marrow toxicity
• Doxorubicin can increase cardiotoxicity
• Chloramphenicol, imipramine, phenobarbital, phenothiazines,
KI, thiazide diuretics and vitamin A can enhance toxicity
 Handling: Injectable is good for 14 days if refrigerated,
once mixed (label says 6 days)
 Dose: 15-20 mg/m2 PO SID or QOD x 4 days, repeat q3
• If sterile cystitis in response to cyclophosphamide occurs,
substitute chlorambucil 15 mg/m2 PO SID x 4 days
• 6-8 mg/m2 PO QOD for chronic therapy in dogs & cats
 Indications: leukemias, myeloma, indolent lymphomas
 Unique Side Effects: Liver toxicity, Pneumonitis
 Handling:
• Keep refrigerated
• Exterior coating is sweet – keep away from pets and children
 Dose: 60-70 mg/m2 PO, q3-4 weeks
• Doses of 90 mg/m2 are published, but Barton says she has
never given this high dose without sepsis
• Kevin Hahn uses 40 mg/m2 every 2 weeks
• Premedicate with diphenhydramine
 Indications: MCT, LSA Rescue, histiocytic sarcoma,
CNS tumors, canine skin lymphoma
 Unique Side effects:
1. Prolonged and cumulative myelosuppression
• No other chemo for 3-4 weeks
• First dose should have a 4 week treatment interval
• If subsequent doses show recovery by 3 weeks, interval can be reduced
to 3 weeks
 Unique Side effects:
2. Can cause hepatotoxicity
Serum panel prior to the first dose
Bile acids if significant liver disease is suspected
Choose another drug if bile acids significantly elevated
Check panel prior to third dose and every other dose thereafter
Discontinue if and when ALT climbs or albumin falls significantly
Often discontinued after 6-12 doses
SAMe and silymarin may mediate hepatotoxicity
3. Eliminated by the kidneys - Reduce dose in animals with
kidney disease; possible renal toxicity
4. Give with food to reduce stomach upset
5. Rare stomatitis , corneal ulcers or pneumonitis
 Indications: LSA rescue (DMAC), myeloma, sarcoma,
carcinoma, FIP
 Unique Side Effects:
• Pneumonitis, pulmonary fibrosis
• Use with caution with kidney disease – reduce dose by 50%
• neurotoxicity
 Drug Interactions:
• Kidney toxicity when used with cyclosporine
 Multiple Myeloma Protocol, with prednisone
• 0.1 mg/kg PO SID x 10 days, then 0.05 mg/kg PO QOD
• Prednisone 0.5 mg/kg PO SID x 10d, then QOD
 Or Pulse Therapy
• 7 mg/m2 PO SID x 5 days, repeat every 3 weeks
 Some add single dose cyclophosphamide –
• 200 mg/m2 IV
 Monitor globulins for response to therapy
• Also resolution of symptoms
• Lameness, bleeding diathesis, retinal lesions
 CLL for cats – 2 mg/m2 PO QOD + prednisone 20 mg/m2
 Any chronic melphalan therapy
• CBC q2 weeks x 2 times
• Then once a month
 Also comes as an injectable – different protocol
 Dose: 3 mg/m2 IV over 10 minutes
 Indications: LSA Rescue, intracavitary injections for
neoplastic effusions
 Unique Side Effects:
Urate stone formation in Dalmations
Hearing loss with
Liver toxicity
Peripheral neuropathy – weakness, ileus, constipation
GI ulceration
Sloughing if extravasated
 Drug Interactions: allopurinol dose may need to be
 Handling:
• Mix and administer immediately – it is inactive within an hour
• Draw up dose and dilute to 12 ml with saline
• Then give IV over 10 minutes
 Dose: 50 mg/m2 PO SID x 14 days
 Indications: LSA Rescue, GME, Brain tumors
 Unique Side Effects:
• Use with caution with liver disease, kidney disease, heart
disease, urate stones
• Nausea – give concurrently with Cerenia
• Neurotoxicity – seizures, ataxia
• Peripheral neuropathy – ileus, constipation, stumbling
• stomatitis
 Drug Interactions:
• Potentiates activity of CNS depressants
• anticonvulsants, opiates, sedatives, antihistamines, antihypertensives,
tricyclic antidepressants
• Serious hypertension if given with sympathomimetics
• Phenylpropanolamine
• Avoid foods high in tyramine – aged cheese, yogurt, bananas
 Contraindications: any of the above drugs
 Handling: OK to compound into capsules, but liquids
must be oil based
 Dose: 800-1000 mg/m2 IV over 5-8 hours q2-3 weeks
• Pretreat with Cerenia
• Pretreat with dexamethasone to prevent phlebitis
• Pretreat with opiate to prevent pain on IV infusion
 Indications: LSA Rescue, ST sarcoma, melanoma
 Unique Side Effects:
• Serious extravasation injury, like Actinomycin D
• Hepatoxicity and nephrotoxicity - use with caution with hepatic
or renal disease
• Photosensitivity
• Dilute to prevent pain on IV infusion (D5W or saline)
 Contraindications: not for use in cats, as there is no
evidence cats can metabolize it in the liver
 Handling:
• Keep refrigerated
• Use within 8 hours of reconstituting at room temperature and 72
hours if refrigerated
• I do not use this drug, as it is causes severe injury on
extravasation and I can not have a tech sit with a dog for 5-8
hours to manage an IV drip. It may work well in a practice with
ICU supervision.
Antitumor Antibiotics
by intravenous drip
 Doxorubicin (Adriamycin®)
 Mitoxantrone (Novantrone®)
 Actinomycin-D, dactinomycin (Cosmegen®)
 Bleomycin
 (Doxycycline)
• Decreases metalloproteinases, which break down
intracellular matrix allowing tumor invasion
• Antioangiogenic effects
Doxorubicin – “Red Death”
 Dose: 20-30 mg/m2 IV over 20 minutes, q2-3 weeks
• Premedicate with diphenhydramine and Cerenia
• 1 mg/kg if less than 15 kg
 Indications: LSA, leukemia, carcinomas, sarcomas
 Unique Side Effects:
• Severe necrosis leading to amputation or death due to
cardiotoxicity if extravasated
• More likely to cause GI signs and malaise than the other drugs
in CHOP protocols
• Often the last drug to lose effectiveness in CHOP
• Toxicity can be somewhat cumulative – may need to reduce
dose with time
• Prolonged myelosuppression – check CBC at 10 days post Tx
Doxorubicin – “Red Death”
 Unique Side Effects:
• Hypersensitivity – allergy to one brand may not be to others
• Cardiotoxicity
• Acute cardiotoxicity – cardiac arrest during or several hours after
• Cumulative cardiotoxicity precludes further use of doxorubicin
• can occur as low as 90 mg/m2 total dose
• 6% of dogs with 5+ doses
• Nephrotoxicity in cats
• monitor BUN, creat, phos
• Urinalysis - casts
• Increased toxicity in dogs with MDR-1 Deletion
• Reduce dose by 30%
Doxorubicin – “Red Death”
 Drug Interactions:
• Actinomycin-D and Ca channel blockers increase cardiotoxicity
• Diltiazem
• Verapamil
• Cyclophosphamide, cyclosporine increase doxorubicin levels
• Phenobarbital & glucosamine may reduce doxorubicin levels
 Contraindications:
• Myocardial failure
• echocardiogram prior to giving doxorubicin to Dobermans, Great Danes
and Boxers or if heart murmur
• Dogs and Cats with renal failure
• Dogs with MDR-1 deletion (reduce dose by 30%)
Doxorubicin – “Red Death”
 Handling:
• refrigerate and protect from light
• Irritating to the skin – wash well if exposed
 Special Client Communications:
• Prior permission to take immediately to surgery if extravasated
• Warn of cardiotoxicity – acute and cumulative
Doxorubicin – “Red Death”
 Lifetime Total Dose:
• should not exceed 180-200 mg/m2, unless cardioprotective
drugs are given
• Check echocardiogram prior to each dose >150 mg/m2
• Should never exceed 240 mg/m2, or cardiotoxicity is likely
 Liposomal doxorubicin (Doxil)
• Reduces cumulative cardiotoxicity
• Can be used after total lifetime doxorubicin dose has been
• Cost is 20x that of native doxorubicin
 Overcoming resistance with dacarbazine (see LSA
Rescue Handout)
Doxorubicin Extravasation
 Some believe you should take the dog right to surgery and
cut out the red stuff
 Give Zinecard (dexrazoxane) 150-300 mg/m2 IV within 2-3
hrs of extravasation through a different IV catheter
 Repeat at 24 and 48 hours
 Zinecard can near 100% protection from slough and acute
fatal cardiotoxicity
 Ice pack 15 minutes every 6 hours for 48 hours
 Apply DMSO 99% to area 2x extravasation q6hrs x 14
Doxorubicin is a double edged sword
Mitoxantrone – “Blue Thunder”
 Dose: 5-6.5 mg/m2 IV every 2-3 weeks
 Indications: LSA, carcinomas, hemangiopericytoma
• Safer for cats with renal failure than doxorubicin
• Combining with dacarbazine (DTIC) may increase effectiveness
for rescue therapy
 Unique Side Effects:
Use with caution in hepatic disease
Jaundice, renal failure
Irritation if extravasated
Green-blue urine for up to 5 days
Mitoxantrone – “Blue Thunder”
 Drug Interactions:
• Increased dose of allopurinol may be needed
• Enhanced cardiotoxicity if previous doxorubicin, daunorubicin or
radiation therapy
• Precipitates in contact with heparin
 Contraindications: myocardial failure, though
cardiotoxicity not yet reported in dogs as in people
 Dose: 0.5-1 mg/m2 IV over 20 minutes, q2-3 weeks
• Premedicate with diphenhydramine and Cerenia
 Indications: LSA Rescue, OSA
 Unique Side Effects:
Necrosis if extravasated
GI ulceration or stomatitis
Increases uric acid – avoid in urate stone formers
Possible hepatotoxicity – monitor liver enzymes every 2-3 doses
Cardiotoxicity – echo after 4-6 doses
 Drug Interactions:
• Additive cardiotoxicity with doxorubicin
 Contraindications:
• hepatic dysfunction
• Dogs with MDR-1 deletion (reduce dose by 30%)
 Handling: use immediately and discard unused portion
Platinum Drugs
by intravenous drip
 Carboplatin (Paraplatin®)
 Cisplatin
 Dose:
300-350 mg/m2 IV over 15 minutes q3 weeks in dogs
180-260 mg/m2 IV over 15 minutes q3-4 weeks in cats
Has been given intratumorally for nasal planum SCC in cats
Intracavitary for mesothelioma
 Indications: carcinomas (not TCC), sarcomas, OK for
 Unique Side Effects:
• Anorexia or vomiting at 2-4 days
• Used cautiously if hepatic or renal disease
• Hearing impairment
 Drug Interactions:
• increased nephrotoxicity and ototoxicity of aminoglycosides
• Increased likelihood of MLV vaccine induced disease
 Handling:
• dilute in D5W, saline or sterile water
• Once reconstituted, use within 8 hours
• Black precipitate will form if it comes into contact with aluminum
Vinca Alkaloids
by intravenous injection or drip
 Vincristine (Oncovin®)
 Vinblastine (Velban®)
 Dose: 0.5-0.75 mg/m2 IV push
 Indications: LSA, leukemias, thrombocytopenia, TVT
 Unique Side Effects:
• Peripheral neuropathy - ileus, constipation, dropped hocks
• Slough if extravasated (not as severe as doxorubicin)
• Infiltrate with dexamethasone or DMSO
Rare severe GI side effects in cats
Reduce dose by 50% if icteric (cats with LSA can be)
Use with caution with liver or musculoskeletal disease
Reduce dose by 25-30% in MDR1 deletion dogs
 Drug Interactions:
• Toxicities increased by drugs that inhibit p-glycoprotein
• Comfortis or Trifexis
• Ca++ channel blockers (amioderone, diltiazem, verapamil,
• Azole antifungals
• Cyclosporin
• Lincosamides (azithromycin, clarithromycin, erythromycin)
 Contraindications: severe liver disease
 Handling: keep refrigerated
 Dose: 2-2.2 mg/m2 IV over 10 minutes
• Nausea, pallor, vomiting if given too fast
 Indications: LSA, MCT, carcinomas
• Developed to avoid vincristine associated neuropathy (dogs)
 Unique Side Effects:
• More myelosuppressive than vincristine
• The rest like vincristine
• Nausea, vomiting for 24 hours
 Drug Interactions/Contraindications: same as
 Handling: keep refrigerated
 Cytarabine, cytosine arabinoside (Cytosar-U®)
 Methotrexate
 5-Fluouracil
 Dose: 200 - 300 mg/m2 IV drip over 4 hours or SQ
divided q1 hour x 4
• Premedicate with Cerenia
 Indications: leukemias, CNS LSA, feline renal LSA
 Unique Side Effects:
• More myelosuppression with IV administration
• stomatitis, conjunctivitis
• Rare liver toxicity
 Drug Interactions:
• May decrease absorption of digoxin for several days
• May decrease efficacy of gentocin
 Handling:
• good for 17 days after reconstituting if refrigerated
• hazy solution should be discarded.
Serum panel/lytes and urinalysis
every 3 months minimum on chemo patients
Tyrosine Kinase Inhibitors
by mouth – covered under lymphoma
 Palladia®
 Kinavet®
 Gleevex®
by mouth or by injection
 Prednisone
 Dexamethasone
by mouth or by injection
 Piroxicam (Feldene®)
• Cancer cells express cyclo-oxygenases that form
• Prostaglandins of the E2 series inhibit NK cells
• NK cells kill cancer cells
• COX-2 inhibitors and other COX inhibitors inhibit
formation of the PGE2 series
• They remove inhibition of NK cells by cancer cells
 Deramaxx®
 Previcox®
Piroxicam – COX inhibitors
 Dose: 0.3 mg/kg PO SID to QOD
• Little data, but some believe any COX inhibitor is just as good
• Carprofen (Rimadyl®), meloxicam (Metacam®), Zubrin®,
Oncior®, etc.
• No studies of antineoplastic effects in cats
 Indications:
• carcinomas, sarcomas
• Generally not LSA or MCT because those are on pred
 Unique Side Effects:
• Positive side effects – antipyretic, anti-inflammatory, analgesic
• Inhibits platelet aggregation like aspirin
Piroxicam – COX inhibitors
 Unique Side Effects:
• GI ulceration
• Renal papillary necrosis – monitor especially in cats
• peritonitis
 Drug Interactions:
• do not give with corticosteroids or furosemide
• Displaces protein bound drugs to increase toxicity –
aminoglycosides, anticoagulants, sulfas, phenytoin
 Contraindications: serious toxicity when NSAIDs used
with methotrexate
 L-Asparaginase (Elspar®)
 MOA:
• To make a cancer drug, some fundamental difference between
cancer cells and normal cells must be defined and exploited
• Lymphoproliferative tumors require huge amounts of asparagine
to support tumor growth, and lack L-asparaginase synthetase
• Asparaginase is an enzyme that breaks down asparagine
• Tumor cells become depleted and rapidly die
 Dose: 10,000 U/m2 SC, IM, IV (max dose 1 vial)
• Pretreat with diphenhydramine
 Indications: Lymphoma, MCT
• When bone marrow is compromised , bulky disease or ALL
• Works only 2-3 times in most cases
 Unique Side Effects:
IV administration increases risk of anaphylaxis
Induction of hepatic encephalitis in patients with liver failure
Rare coagulopathy or hepatotoxicity
Hyperglycemia and dysregulation in diabetics
Thyroid suppression for 4 weeks
 Drug Interactions:
• Reduced efficacy of methotrexate (wait 48 hours)
• Occasional marrow suppression when given with vincristine
 Contraindications: history of pancreatitis
 Handling:
no special handling is necessary as other chemo drugs
Keep refrigerated
Once reconstituted, good for 8 hours – 14 days
Discard turbid solutions
Dilute with D5W or sodium chloride – volume not crucial
Avoid shaking vigorously – becomes foamy and difficult to inject
 Ruthanne Chun, BS, DVM, DACVIM(Oncology)
UW Madison School of Vet Med, Madison, WI
 Plumb Veterinary Drug Handbook, 7th edition

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