By the Numbers
When can we expect GI toxicity for chemotherapeutics? Usual nadir for myelosuppression?
GI - 2-5 days
Usual nadir - 7-10 days
Which chemotherapeutic can cause a sterile hemorrhagic cystitis?
Cyclophosphamide - alkylating agent, produces phosphoramide mustard and acrolein, interfering with DNA replications, RNA transcription and replication.
Which commonly used vinca alkaloid can cause peripheral neuropathy?
Vincristine - can present as hindlimb weakness, partial paralysis, ileus leading to constipation and abdominal pain.
MOA - binds to beta tubulin to block microtubule formation and prevent mitotic spindle formation, inhibits AA metabolism via glutamic acid utilization and prevents the purine synthesis, citric acid cycle, and urea formation.
Which long bone is most likely to be affected by a pathologic fracture? Which is least?
Most - femur
Least - radius
Chemotherapeutics can cause GI toxicity both centrally via stimulation of the CRTZ and directly. How does it affect the GI tract directly?
Rapidly dividing multipotent stem cells in the intestinal crypts can be damaged, leading to depletion of enterocytes and villous blunting. This can lead to poor nutrient absorption, diarrhea, and secretion of emetogenic factors resulting in nausea/vomiting.
Dogs <2500 cells/uL
Cats <2000 cells/uL
Clinical signs usually closer to <1000 cells/uL
Doxorubicin - Impairs topoisomerase II, intercalates with DNA base pairs, and generates free radicals to inhibit DNA/RNA/protein synthesis.
Name two chemotherapeutics that are fatal in cats.
5-FU - pyrimidine analog antimetabolite - converted to monophosphate and triphosphate metabolites to interfere with DNA/RNA synthesis. (neurologic signs)
Cisplatin - intra and interstrand DNA crosslinking to cause breaks, impair DNA replication, RNA transcription, and protein synthesis. (pulmonary edema)
Name some bloodwork abnormalities you might find in a dog suspected of tumor lysis syndrome.
Hyperkalemia, Hyperphosphatemia, Hypocalcemia, Azotemia
Name some paraneoplastic causes of hypercalcemia of malignancy and some cancers associated with hypercalcemia.
Paraneoplastic causes of HC - ectopic parathyroid hormone production (PTH), or PTH related peptide, extensive and multifocal lytic bone tumors, tumor associated prostaglandins (PGE1, PGE2) IL-1beta TGH-beta and RANKL(receptor activator of nuclear factor kappa beta ligand)
Cancers - T cell LSA, AGASACA, carcinomas of the prostate, mammary gland, liver, lung, multiple myeloma, primary bone tumors
What is the MST for canine splenic hemangiosarcoma with surgery alone and followed by a doxorubicin containing chemotherapy?
Adding chemotherapy - 125-162 days
Name two chemotherapeutics that can cause allergic reactions.
L-asparaginase - bacteria derived polypeptide protease.
Doxorubicin - histamine mediated hypersensitivity.
Taxanes (paclitaxel, ocetaxil) - cremaphor and polysorbate 80 used for solubility of the drug - histamine release, stimulation of basophils.
Carboplatin - double nadir possible at 10-14 and 21 days in dogs.
CCNU/lomustine can nadir between 7-28 days in cats.
What are some advantages and disadvantages to consider for autologous blood transfusions?
Advantages (Decreased transfusion reaction risk, decreased likelihood of TACO, prevention of transfusion induced hypothermia, immediately available compatible blood)
Disadvantages (hemolysis, coagulopathy, microembolism of air/fat, potential spreading of bacteria, potential malignancy spread)
Describe some mechanisms for neoplastic related hypoglycemia and name some cancers implicated in these mechanisms.
Mechanisms - inappropriate insulin secretion, secretion of insulin-like substances, accelerated glucose utilization of the tumor, failure of hepatic gluconeogenesis/glycogenolysis.
Cancers - Insulinoma, hepatocellular carcinoma, hepatoma, LSA, leiomyosarcoma, adenocarcinoma, hemangiosarcoma
What is the mean survival time for R atrial/auricular hemangiosarcoma without treatment? With a pericardectomy?
Pericardectomy MST - 52 days
Which chemotherapeutic can cause facial twitching, myoclonus, seizures, and acquired Fanconi's syndrome in cats?
Chlorambucil - aromatic nitrogen mustard derivative, alkylating agent - alkylation of DNA strands resulting in cross-linking and apoptosis.
Which chemotherapeutic can cause ototoxicity, cortical blindness, and nephrotoxicity in dogs?
Cisplatin - platinum antineoplastic - intra and interstrand DNA cross-linking that causes single and double stranded DNA breakage
What is the extravasation antidote for doxorubicin? for vinca alkaloids?
- Dose is 10x expected extravasation volume, administer within 3-6 hours, then again 24h, 48h
Vinca alkaloids - hyaluronidase - promotes diffusion through decreasing glycosaminoglycans locally
- Dose 1:1 for expected extravasation volume
Describe the progression of tumor lysis syndrome.
In response to therapy, large amounts of neoplastic cells undergo apoptosis. They release nucleic acids, potassium, phosphorus. Hypocalcemia follows as a result of the hyperphosphatemia. Nucleic acids are broken down and metabolized into xanthine and uric acid. Uric acid induces an AKI via renal vasoconstriction, impaired autoregulation, and mechanical damage via crystal formation. This can manifest as azotemia, cardiac arrhythmias, seizures, death.
What is the mean survival time for a dog with a pathologic fracture and gross metastasis detected treated with amputation alone?
MST - 133 days
Tanovea (rabacfosadine) - guanine nucleotide analogue
CCNU/Lomustine - unknown MOA,, believed to inhibit DNA, RNA, protein synthesis through alkylation and carbamoylation
Bleomycin - binds to DNA and ferrous iron to cleave DNA and cause cellular apoptosis
What class of chemotherapeutics has been documented to cause protein losing nephropathy?
Tyrosine Kinase inhibitors (tocerinab, mastinib) -
- Tocerinab - selective inhibits VEGFR2, PDGFR-beta, KIT via competitively inhibiting ATP binding, thereby preventing receptor phosphorlyation and subsequent downstream signal transduction
An oncology nurse suspects extravasation of a chemotherapeutic (doxorubicin vs. vinca in this case). Talk her through treatment to minimize injury to the patient.
1. Stop administration immediately
2. Withdraw as much of the drug as possible from the catheter
3. Doxo - ice pack, vinca - warm pack, applied quickly, then q6-8h for up to 10 days
3. Doxo antidote IV, vinca antidote or 0.9% NaCl SC/perilesionally
4. Treat any local reactions symptomatically (ABX, steroids, bandaging) E-collar for the next 10 days
5. Consider surgical debridement if severe
Describe how pulsus paradoxus occurs in dogs
Best appreciated in lateral recumbency, dogs can have weak pulses on inspiration and stronger pulses on expiration.
- In cases of PE, LV filling has already been limited by effusion on the heart wall. Combination of normal physiologic IVS shift during inspiration and pathological reduction in LV filling from PE results in reduced stroke volume during inspiration and weaker femoral pulses on palpation
- During expiration, thoracic pressure changes from negative to positive pressure, allowing improved LV filling and palpably stronger pulses