Chemotherapy Flashcards
High-dose methotrexate with CNS toxicity
- what are the stages?
- treatement options?
- early: hours/days, arachnoiditis
- subacute: days/weeks, encephalopathy
- chronic: months/years, progressive demyelinating encephalopathy
Treatment options:
- hold next IT
- leucovorin
- dextromethorphan
- hyperhydration
Vessicant/Irritant chemo and it’s management
- Vinca alkaloids: stop infusion, warm compress, hyaluronidase
- anthracycline: dexrazoxane/DMSO
- Dactinomycin:DMSO
- alkylating agents: sodium thiosulfate
Cold compress for: Anthracycline, antibiotics, alkylating agents
Warm compress for vinca alkaloids, taxanes, platin salts.
What is the Goldie Coldman hypothesis?
At any given time, a number of cells in a tumor are inherently drug resistant; this increases with tumor size. The best chance of cure is to use effective non-cross resistant chemotherapy in combination to maximize tumor kill.
General toxicities of chemo
Myelosuppression
- Immunosuppression
- Nausea/Vomiting
- Mucositis
- Alopecia
- Allergic reactions
- Extravasation
Mechanism of Methotrexate action
Inhibits DHFR:
Inhibits synthesis of purines + thymidine
Both cytotoxic + immunosuppressive
Methotrexate toxicity and management:
Primarily renal: related to drug concentrationand duration of exposure, myelosuppresion, mucositis, hepatic (elevated LFTs)
Mangement:
- hydration
- urinary alkalinization
- leukovorin
- measurement of levels
- carboxypeptidase (1U per 1uM MTX
Drugs that interact with methotrexate
PCP prophylaxis: Septra
Penicillins
Penems
PPIs
Fluoroquinolones
NSAIDs
Some macrolides
Acyclovir
6-MP
- mechanism
- metabolism
- toxicities
Incorporation into DNA as fradulentbase; Cytotoxicand immunosuppressive
Metabolized by TPMT -1/300 will have no functional TMPT –will need to use 25% of dose
TOXICITIES:
Early: rash, pancytopenia, stomatitis, oral lesions resembling thrush
Early/Delayed: hepatotoxicity(30%; 6TG>> 6MP), elevated LFTs
Cytarabine
- mechanism
- toxicities
Cytosine analogue, Cell cycle specific (S-phase)
Early: pancytopenia, fever, bowel necrosis, severe rash (<1%), conjunctivitis (use dexeye drops), nausea/vomiting with high dose
Cytarabine syndrome: flu-like syndrome 6-12 hours after IV cytarabine. Steroids as treatment + prophylaxis
Early/Delayed:neurotoxicity –onset at 5-7 days; cerebellar dysfunction, Sepsis –gram positive/strep viridans
TYPES OF ALKYLATORS
Nitrogen Mustards: cyclo, ifos, melphalan
Platinum compounds: cisplat, carbo, oxal
Nitrosureas: CCNU, BCNU
Others: Busulfan, Procarbazine, Dacarbazine, Thiotepa
Alkylators mechanism of action
Binding of alkyl group to DNA
Results in cross links –inter and intra strand —> APOPTOSIS
Cell cycle NON SPECIFIC
Oxazophorines
- acute side effects
1) Hemorrhagic cystitis: from accumulation of acrolein
- cyclo>1800, Ifos> 2000. Hydration and mesna
2) Nephrotoxicity: acute tubulopathy (ifos)
3) Neurotoxicity: Ifosphamide. 1-4d post. Somnolence, lethargy, hallucinations, coma, seizure. RF include renal/liver dysfunction, CNS rads, use of Cisplat. Treat with Methylene blue
Note: can be dialyzed
4) Cardiac: Cyclo >100mg/kg (BMT). within 14d, effusion, myocarditis, necrosis.
Oxazophorines
- long-term effects
1) Infertility: cyclo > 19g/m2, Ifos> 60g/m2, busulfan > 600mg/m2
2) Renal: Ifos related. RF: age<4, cisplat use, dose > 60g/m2
3) Secondary malignancy
Platinum compounds
- acute toxicity
- nephrotoxicity
–> hydration and salt loading protective for kidneys
- ototoxicity
- neurotoxicity: parasthesia, numbness, glove and stocking distribution (reversible sensory neuropathy)
- All less for carbo but it is more myelosuppresive
- emetogenic
Anthracyclines
- RF for cardiac toxicity
- protective agent
RF: age (younger gets more), chest rads, cumulative dose (>300mg/m2)
- Dexrazoxane. Increased risk of SMN in Hodgkin’s
Dactino toxicity
Bleo toxicity
Dactino: emesis, myelosuppression, mucositis, extravasation, radiation recall. Veno-occlusive disease of the liver
Bleo: Not myelosuppressive. Skin toxicity, allergic reaction, fever, Raynaud’s, Pulmonary toxicity
RF for pumonary toxicity: total dose over 450 U (in adults), renal insufficiency, younger age (<8y), older age (>30y), smoking, concurrent radiation or oxygen
VincaAlkaloids
- mechanisms of action
- toxicities
MECHANISMS: Arrest cell division by tubulin binding and inhibiting microtubule polymerization. Impaired mitotic spindle formation. Specific for M phase (metaphase)
TOXICITIES:
- Neuropathy (constipation, jaw pain, foot drop, paraesthesia)
- Minimal myelosuppression with vincristine, some with others
- SIADH
- Extravasation burn
Epipodophyllotoxins
- mechanism of actin
- side-effects
MECHANISM: Inhibit topoisomerase II, cell cycle specific for S and G2 phases
TOXICITIES
- General: Myelosuppression
- Acute: Allergic reactions (use Etopophos)
- Chronic: Secondary leukemia – 11q23/MLL
Etoposide reactions: what are the next steps
- stop infusion
- treat anaphylaxis
- If minor reaction can consider pre-treating and trying Etop again at slow rate
- If major, switch to Etop-phos (needs SAP) with premeds
IrinotecanInduced Diarrhea
Immediate Onset
•Secondary to cholinergic properties
•Often accompanied by lacrimation, salivation, abdominal cramping, rhinitis
•Mean duration 30 minutes
•Responds to atropine
•If no response, treat as per delayed onset
Delayed Onset
•At >24 hours after exposure
•Predictors:
–Weekly administration
–Elevated Cr, Leukopenia
–Prior abdominopelvic RT
–Gilbert and Crigler-Najjarsyndrome
•Start loperamide at first sign
•Use octreotide if not controlled
•Cefpodoximeor cefixime for remainder of therapy* (to clear GI bacteria which convert SN38G back to active SN 38)
Rituximab side-effects
- Infusional reactions –75% of patients; lessen with subsequent doses. Pre med w/ antihistamine, antipyretic
- Transient hypotension. Slow infusion titrated up as tolerated over 4-6h
- 5-10% risk of serum sickness
- Hep B reactivation
- B cell depletion –persistent x 6 months; no major infx
- PML–progressive multifocal leukoencephalopathy; very rare (< 0.1%), JCvirus reactivationRituximab
Ch14.18
- target
- mechanism of action
- side-effects
Targets GD2 ganglioside
Mechanisms of action: Neutrophil + monocyte ADCC –augmented by GMCSF. Lymphocyte ADCC –augmented by IL-2. Complement activation
Side effects –significant infusionalreactions pain, fever, capillary leak, anaphylaxis
Pre-medications for Ch14.18
- Tylenol
- morphine
- Benadryl
- albumin
- ranitidine
- IV fluids
- consider hydroxyzine or certirizine
- consider gabapentin
Blinatumomab: BiTE
- mechanism of action
- administration
BiTE–bispecificT-cell engager. Molecule binds both CD19on B cells and CD3 on T cells. Kills by T cell cytotoxicity
Administration: Very short half life. Given by continuous infusion (over 4 weeks!)
Side effects: Infusional reactions, hypogamma, seizures, encephalopathy
Timing of different phases of emetogenicity
Acute: 1st dose of chemo. Last 24 hours post.
- Ondans/Granisteron, Dex, nabilone
Delayed: begins 24 hours after last dose. Lasts 7 d
- Dex, metaclopramide
Anticipatory: occurs within 24h prior to first dose
- Lorazepam
Which chemo requires extra hydration?
Ifos
Cyclo
Cisplat
MTX
Mucositis management
Oral care
–Good oral hygiene
–NaHCO3 mouthwash QID
–Avoid spicy, acidic, hard, hot foods
Pain control
–Low threshold for opioid analgesia
–Patients with moderate/severe symptoms may need morphine infusion
IV fluids +/-TPN
HSV prophylaxis +/-treatment
Determinants of CNS penetration
CNS blood flow
Drug properties: lipophilicity, molecular size, degree of ionization, free plasma concentration
Which chemos can be dialyzed?
Methotrexate
Platinum compounds
Oxazophorines
Which enzyme polymorphisms affect mercaptopurine metabolism?
TMPT
NUDT15
Which chemo causes SIADH?
Oxazophorines (Cyco/Ifos)
Vinca alkyloids
Carboplatin: Name 2 s/e not seen in Cisplat
Myelosuppression
Hypersensitivity reaction
Anthracycline mechanism of action
Intercalation of DNA
Topoisomerase II inhibition
Free radical damage
