Managing complications of chemotherapy (Proceedings)

Please be aware that these notes are not designed to be a complete reference. It is advisable to consult with an oncologist for current treatment recommendations prior to developing a therapeutic plan for your patient.

Chemotherapy can cause adverse effects in veterinary cancer patients. Because cytotoxic drugs target rapidly dividing cells, normal proliferating cells may be affected. Most commonly affected are the gastrointestinal epithelium, bone marrow, and active hair follicles. In addition, some agents cause unique toxicities. Organ dysfunction or mutations in MDR1 (gene coding for p glycoprotein) affect clearance of chemotherapy drugs and increase the risk of toxicity. It is important for veterinarians to know possible effects, how to prevent morbidity, and how to manage adverse effects. This lecture will focus on managing adverse effects of chemotherapy.

Extravasation Injury

Extravasation Injury

Injury to surrounding tissue due to leakage of a drug from vascular to interstitial space.

Prevention

Extravasation is a preventable complication of chemotherapy!

1. Know the toxicities (including potential for extravasation injury) of drugs BEFORE you give them.

2. Proper vein selection

a. Healthy, reasonably sized, accessible, not over joints or tendons

b. Not used for phlebotomy that day

c. No previous extravasation sites

d. Change to another vein if go through vein, vein "blows", no flashback, doesn't flush easily, or if any doubt of placement.

3. Proper administration techniques

a. Only competent technicians and clinicians with training in risk identification, prevention and management of extravasation, IV catheter placement and use of venous devices, and components of adequate documentation should administer IV chemotherapy.

b. Patient comfort essential: need appropriate number of trained restrainers, quiet room, comfortable positioning on mat or blanket, and sedation for fractious or restless patients.

c. Place appropriate IV catheter: use smallest gauge required, long enough that it will not slide out, consider whether a central or peripheral line is needed, consider the duration that the catheter will be in place. Butterfly catheters should not be used for vesicant drugs.

d. Tape catheter securely in a manner that allows visualization of insertion site.

e. Check for flashback and flush with >5 ml of saline (no heparin) to check patency (watch for bleb and palpate vein while flushing).

f. Chemotherapy agents should be diluted appropriately and administered at the proper speed. Some may be given by the "side arm" method.

g. Monitor patient and administration site closely.

h. Record date, site, drug.

i. Have extravasation management plan readily available and memorize initial steps.

Management of extravasation of common chemotherapy drugs

1. Aspirate back as much drug as possible BEFORE PULLING IV catheter. Pull catheter. Aspirate bleb.

2. Apply compress – cold for all drugs except warm for vinca alkaloids 15 min q4hr for 72 hrs.

3. Specific antidotes:

a. Vinca alkaloids: Infuse 1ml of 1% hyaluronidase for each ml of drug extravasated locally into extravasation site to help absorption of drug.

b. Doxorubicin (preliminary information): Treat with dexrazoxane (Zinecard). Canine dosing (Plumb Formulary): Give 3 consecutive IV doses at 24 hr intervals at a dose of 1000 mg/m2 x 2 days, then 500 mg/m2 day 3. Given IV over 15 minutes. Efective if given within 3-6 hours of extravasation.

One report in a cat: Single dose at 10X doxorubicin dose IV.

Possible side effects: Myelosuppression. Expensive.

Apply 90% DMSO topically to site q 6-8 hrs for 14 days. No occlusive dressings and WEAR GLOVES!

Role of resection of extravasated drug?

Other: E collar, surgical debridement if ulcer forms, antibiotics if open lesion.

Gastrointestinal Toxicity

Gastrointestinal toxicity may be acute (within 24 hours of chemotherapy administration) or delayed (>24 hours after chemotherapy). Acute gi toxicity (typically emesis) is due to direct irritation of the chemoreceptor trigger zone or free radical stimulation of enterochromaffin cells to release serotonin, which stimulates the CRTZ via vagal afferents. The mechanism of delayed gastrointestinal toxicity is not as well understood, but due to injury to dividing gastrointestinal epithelial cells. Vomiting, diarrhea, lethargy, and loss of appetite are noted. In cats, the most common toxicity is anorexia. Delayed gi toxicity usually resolves in 2-3 days with supportive care.

Gastrointestinal toxicity

*Vincristine is associated with a unique gi toxicity – paralytic ileus.

#Doxorubicin is associated with a unique gi toxicity – hemorrhagic colitis.

Prevention of Gastrointestinal Toxicity

1. Give appropriate doses of chemotherapy, diluted appropriately, and at the appropriate rate.

2. Reduce dose by 20-25% if significant gi toxicity.

3. Prophylactic antiemetic therapy is recommended for patients receiving emetogenic agents or with previous emesis/nausea following a drug.

a. Maropitant citrate (Cerenia) – substance P/neurokinin type 1 (NK-1) receptor antagonist – blocks central and peripheral activation of the emetic center. Dose in dogs only: 1 mg/kg SC 1 hour before chemotherapy agent. May sting. Only antiemetic licensed for dogs. No information available about use in cats. In humans, it is recommended that NK-1 antagonists be used with 5-HT3 antagonists.

b. Dolasetron and ondansetron (Anzemet and Zofran) – serotonin/5-hydroxytryptamine 3 (5-HT3) receptor antagonists – block receptors in gi tract and CRTZ. Give immediately before administration of chemotherapy if IV, 30 minutes prior if oral. Dolasetron (dogs/cats): 0.6-1 mg/kg IV slowly. Ondansetron (dogs): 0.1-1 mg/kg IV slowly or PO, (cats): 0.1-0.15 mg/kg IV slowly 15 minute before chemotherapy.

c. Metoclopramide (Reglan): dopamine (D2) receptor antagonist, 5-HT3 receptor antagonist, increases tone at lower esophageal sphincter and increases gastric emptying. 0.2-0.5 mg/kg PO or SC q8 hours at least 30 minutes before treatment. This drug is used for less emetogenic agents and patients may be sent home on this drug orally.

d. Butorphanol: mu opioid receptor antagonist, suspected to act at vomiting center. Has been used in dogs before cisplatin and streptozotocin at 0.2-0.4 mg/kg IM 20 minutes before administration.

Treatment of Gastrointestinal Toxicity

1. NPO

2. If the patient is acting normal and has self-limiting vomiting: water trial then bland diet trial. Consider metoclopramide 0.2-0.5 mg/kg PO q8 hours for nausea. (Maropitant citrate is also available as tablets for oral administration, but has not been evaluated for this use.)

3. If the patient is acting normal and has diarrhea that is not bloody or watery: bland diet, consider metronidazole 15 mg/kg PO q12 hours for colitis.

4. If the patient lethargic with gi signs, if vomiting and diarrhea are not self-limiting, or if the patient has watery or bloody diarrhea - admit to hospital for supportive care with intravenous fluids and medications:

a. Antiemetics

Metoclopramide: 0.2-0.5 mg/kg SC q8 hours or IV as a CRI at 1.1-2.2 mg/kg/day. Also for vincristine-induced ileus.

Maropitant citrate: 1 mg/kg SC q24 hours

If refractory:

Dolasetron (dogs/cats): 0.6-1 mg/kg IV slowly q12-24 hours

Ondansetron (dogs): 0.1-1 mg/kg IV slowly q8-24 hours; (cats) 0.1-0.15 mg/kg IV slowly q6-12 hours

b. H2 receptor antagonist: Famotidine 0.5-1 mg/kg IV slowly q12-24 hours

c. Antibiotic therapy if bloody vomit/diarrhea, neutropenic, or febrile – risk of sepsis

d. Enteral feeding tube if prolonged anorexia (rare)

Myelosuppression

Myelosuppressive drugs mainly affect the neutrophil count, but platelets may also be affected. The nadir for most drugs is 7 days after administration and neutropenia resolves in 2-3 days. Some drugs have variable nadirs (e.g. carboplatin, cisplatin, CCNU in cats) or can cause prolonged neutropenia (e.g. CCNU, carboplatin).

Myelosuppressive drugs

Prevention

1. Check CBC before administering myelosuppressive chemotherapy. Do not treat if <3,000 neutrophils/μL or <100,000 platelets/μL.

2. Double check chemotherapy doses. Note that some drugs require lower doses for small dogs or cats.

3. Check CBC at expected neutrophil nadir the first time patient receives each agent

a. If neutrophil count is <1,000 cells/μL, reduce subsequent doses of that drug by 20-25%.

4. If overdose, treatment with recombinant human granulocyte colony stimulating factor (rhG-CSF) is recommended (5 μg/kg q24 hours SQ for 3-5 days) starting 24 hours after treatment. Dogs and cats produce neutralizing antibodies to rhG-CSF, but should not be a problem with a short course of this drug.

Treatment

1. Usually none required.

2. For dogs, consider prophylactic antibiotics if neutrophil count <1,000 cells/μL. Options include clavamox 22 mg/kg PO q12 hours or sufadiazine-trimethoprim 15 mg/kg PO q12 hours for 5-7 days. Cats do not usually need prophylactic antibiotics. Owners can monitor rectal temperature.

3. If febrile or clinical for sepsis (lethargy, loss of appetite), admit to hospital for IV fluids and IV broad spectrum antibiotics based on culture and sensitivity (if available) or empirical use of clinician's preferred combination, for example ampicillin 22 mg/kg IV q8 hours slowly with enrofloxacin 5 mg/kg IV q12 hours (dogs), dilute and give slowly (can cause blindness in cats, so limit to 5 mg/kg/day)).

Allergic Reactions

L-asparaginase can cause a type I hypersensitivity reaction. Signs include facial swelling, erythema, urticaria, panting, agitation, vomiting, diarrhea, dyspnea, tachypnea, weakness, collapse, and hypotension.

Prevention

1. Administer by subcutaneous route.

2. After first dose, premedicate with diphenhydramine 2 mg/kg IM 20 minutes before L-asparaginase. Monitor patient for allergic reaction 30 minutes after treatment.

3. If a patient has an allergic reaction, that patient should not receive L-asparaginase again.

Treatment

1. Depends on severity

2. Dexamethasone sodium phosphate 0.5 - 2 mg/kg IV

3. Diphenhydramine 1-2 mg/kg IM or slow IV (dog), IM only (cat)

4. Intravenous fluids at 90 ml/kg/hr (dog), 50 ml/kg/hr (cat)

5. Epinephrine if severe (Dilute 1 ml of 1:1,000 solution in 9 ml of 0.9% NaCl. Give 0.1 ml/kg of1:10,000 solution.)

Doxorubicin can cause an allergic-type reaction due to stimulation of mast cell degranulation during administration. Signs are similar to those described for L-asparaginase. This is not a true allergic reaction.

Prevention

1. Administer at appropriate rate - no faster than 1 mg/minute or over 10-15 minutes for small dogs or cats.

2. If allergic reaction with previous dose, premedicate patient with diphenhydramine 2 mg/kg IM and dexamethasone SP 0.5 mg/kg SQ 20-30 minutes prior to subsequent doses and administer at slower rate.

Treatment

1. Stop infusion.

2. Reaction is usually not as severe as with L-asparaginase.

3. Dexamethasone sodium phosphate 0.5 - 2 mg/kg IV

4. Diphenhydramine 1-2 mg/kg IM or slow IV (dog), IM only (cat)

Cardiac Toxicity

A unique cumulative toxicity of doxorubicin. Typically seen at doses of 180-240 mg/m2 . Free radical damage occurs because cardiac myocytes have less production of catalase. Initially results in cardiac arrhythmias and decreased contractility. Progresses to dilative cardiomyopathy and congestive heart failure weeks to months after treatment.

Prevention

1. Echocardiogram prior to doxorubicin for breeds at risk for DCM and dogs with cardiac abnormalities (heart murmur, arrhythmia, cardiomegaly). Do not treat dogs with myocardial dysfunction.

2. Limit total lifetime cumulative dose to <180-240 mg/m2. Weigh risk versus benefit if giving >150 mg/m2 and echocardiogram patients receiving further doses.

3. Substitute non-cardiac toxic agents (mitoxantrone, actinomycin-D) after 150 mg/m2.

4. Dexrazoxane (Zinecard) – 10 mg for every 1 mg of doxorubicin given IV <30 minutes before doxorubicin. Free radical scavenger, not helpful once cardiac injury present. Not used routinely in veterinary oncology.

Treatment

Do not administer further doxorubicin. Consult with cardiologist.

Hemorrhagic Cystitis

A unique toxicity of cyclophosphamide. Acrolein, a metabolite, causes direct injury to bladder urothelium.

Prevention

1. Give furosemide (2 mg/kg PO, IV, or SC) with cyclophosphamide, reduces risk from 9% to 1%.

2. Give in morning to avoid acrolein in bladder overnight.

3. Give water ad lib and encourage frequent urination for 24 hours after cyclophosphamide.

4. If a dog develops hemorrhagic cystitis, cyclophosphamide should not be administered again. Often chlorambucil is substituted.

Treatment

Urinalysis and culture and sensitivity to check for bacterial cystitis, treat if present. Hemorrhagic cystitis is self-limiting, but may take weeks or months to resolve. Treat with NSAIDs or prednisone for anti-inflammatory and analgesic affects. Oxybutynin hydrochloride (0.2 mg/kg PO q8-12 hours) has been recommended for straining and pollakiuria. Consult with oncologist.

Cats Are Not Small Dogs

1. ***Do not administer to cats***

a. Cisplatin - fatal pulmonary edema

b. 5-fluorouracil - fatal neurologic signs

2. Some toxicities are not observed clinically in cats

a. Cyclophosphamide – hemorrhagic cystitis

b. Doxorubicin - documented histopathologic changes, but cardiotoxicity is not seen clinically