Introduction

Chemotherapy complications and side effects differ with each drug and can range from mild to severe. In human oncology, higher dosing and the use of multi-drug protocols can lead to more severe side effects. In veterinary oncology, we focus heavily on quality of life through treatment and therefore aim to reduce the risk of hospitalization or severe, life threatening complications. However, oncologic emergencies can arise, and a properly trained technician can not only reduce risks but could potentially reduce life-altering effects.

Chemotherapy Side Effects

Traditional chemotherapy does not discriminate between normal and cancerous cells. It targets rapidly dividing cells, and these include the normal cells in the bone marrow, hair follicles, and gastrointestinal tract. One acronym from human medicine: B.A.G.

Bone marrow suppression is common with use of most chemotherapeutic drugs and can be noted most during the nadir. This is when the blood cell with the shortest half-life, the neutrophil, has its count dip to its lowest point. While the nadir with many drugs falls in the range of 5–10 days after treatment, it is important to note that different chemotherapy drugs have different chemotherapy nadirs. Carboplatin for example has a nadir at 10–14 days post, but a second “double” nadir can be observed at 21 days post. For most chemotherapies, it is important to obtain a complete blood count (CBC) and temperature check at 7 days post to monitor myelosuppression that may occur. During the time of the chemotherapy nadir, though neutropenia is the most critical, thrombocytopenia and anemia may also be noted. Patients with severe neutropenia <1000 neutrophils/µL are at increased risk of sepsis which can lead to death. If a patient presents for a nadir check and is febrile with neutropenia, hospitalization with medical intervention is necessary. If the degree of neutropenia is moderate (1000–1500 neutrophils/µL) or the patient is symptomatic (febrile or lethargic), a preventative PO course of antibiotics may be prescribed to help reduce the possibility of sepsis. For future doses, a dose reduction or complete change of therapy may be indicated.

Alopecia (hair loss), though not life-threatening, can be extremely upsetting to the owner. Alopecia is most commonly noted in the constantly shedding breed dogs, such as poodles and bichon frises. Alopecia is not common with all chemotherapy drugs but is most noted with doxorubicin. Happily, any lost hair does grow back when treatment is completed, though it may grow back a different texture or color.

Gastrointestinal (GI) side effects make up the majority of the chemotherapy side effects that are noted by the owners at home. Most GI side effects are mild and can be self-limiting, but sometimes, if severe enough, medical intervention may be necessary to improve the patient’s quality of life. GI side effects most commonly include vomiting, diarrhea, lack of appetite or nausea. Most chemotherapy GI side effects are noted about 3–5 days post. If the owners note any side effects at home, food changes (NPO or a bland diet), the usage of anti-emetics, or anti-diarrhea medications can be used symptomatically, or in a preemptive manner for future treatments if the patient had a history of sensitivities. If the side effects are severe enough to decrease the quality of life of the patient, a dose reduction may be indicated for the next treatment. Though not all patients experience GI side effects, “white feet” breeds such as the herding dogs that express the MDR1 gene mutation may be more susceptible to chemotherapy-induced side effects. Thus, certain precautions may be made when treating such breeds as Australian Shepherds, Collies and even Long-haired Whippets.

Other side effects are less common but can occur with certain chemotherapy drugs. These may be drug- or species-specific and can be severe or even deadly without proper education and awareness. Doxorubicin-induced cardiotoxicity is mostly seen with cumulative doses in dogs, >200 mg/m². If a patient has cardio insufficiency, abnormal pulses, dilated cardiomyopathy or any atypical rhythms, such as ventricular premature contractions (VPCs), on an electrocardiogram, a cardiology consult with a board-certified cardiologist would be indicated before treatment of doxorubicin. Hepatotoxicity can occur with cumulative dosing of lomustine and therefore preemptive treatment with a liver protectant, such as Denamarin, would be recommended along with monitoring of the liver enzymes. Neurotoxicity can happen with the use of 5-fluorouracil (5-FU) in cats, and therefore is contraindicated and should never be used as it can cause death. Pulmonary toxicity is a fatal side effect with the use of Cisplatin in cats and is therefore contraindicated. Pulmonary fibrosis is a possible complication of Tanovea-CA1 and should be avoided in West Highland White Terriers and other terrier breeds. Neuropathy and gastrointestinal ileus may be noted with frequent vincristine treatments. Sterile hemorrhagic cystitis can occur with IV or long-term usage of oral cyclophosphamide so the use of a diuretic may be recommended to flush out the bladder to avoid this side effect. Asparaginase has the potential of anaphylactic reaction with multiple doses, so therefore, it is recommended to pre-treat with a steroid and antihistamine prior to administration and closely monitor for any symptoms for 24–48 hours post. Asparaginase treatment can also be associated with acute tumor lysis syndrome (ATLS). This is a rare syndrome that mostly affects higher grade lymphoma patients with a heavy tumor burden. The mechanism of asparaginase is to rapidly kill neoplastic cells, which leads to the release of the intracellular components. Patients who experience ATLS may exhibit symptoms hours, or even up to 7 days post administration. Due to the nature of the effects on the body, ATLS can be life threatening if immediate medical intervention is not taken. It is important to note that though ATLS is associated more with Asparaginase treatment in lymphoma/leukemia patients, any patient with a high tumor burden that receives chemotherapy treatment may be at risk.

Extravasation

Chemotherapy extravasation is when the injection leaks out of the vessel and into the surrounding tissue. Extravasation can be avoided, but it is imperative to know which drugs are classified as vesicants, and what to do if it occurs. Prevention is key and with any good prevention strategy, knowledge is power. No one plans on chemotherapy extravasation, which is why it’s considered an oncologic emergency, but knowing what to do when it happens can help reduce the severity and may save a life. Unfortunately, most of the extravasation protocols that are in place are based on human medicine due to the lack of research in veterinary oncology.

Technician education is the first and foremost of importance when it comes to chemotherapy administration. Ensuring the staff is properly trained in intravenous catheter placement is crucial as a clean stick is required for any type of chemotherapy that is classified as an irritant or vesicant. It is recommended that the chemotherapy administration is supervised by a trained technician so therefore, if there is any possible extravasation, the proper steps to avoid detrimental tissue damage can begin immediately. A basic understanding of the patient’s temperament is also important. The use of pre-medications or sedation may be necessary to ensure the chemotherapy is given safely in patients who are not amendable to safe restraint for administration. A separate room or space where there is less commotion or distraction is recommended for any chemotherapy administration.

Signs of extravasation may be immediate or may arise days or even weeks after the injection. Immediate reactions may include pain at the site, swelling, erythema and inflammation. Severe delayed reactions can include ulcerating tissue necrosis.

Irritants include cyclophosphamide, gemcitabine, and carboplatin. Low vesicant potential drugs include mitoxantrone, 5-FU, dacarbazine and cisplatin. High vesicant potential drugs include mechlorethamine, vincristine, vinblastine, vinorelbine, and doxorubicin.

If any extravasation is noted, the first step is to stop the injection or infusion immediately and pull back as much of the drug as possible. One should NOT flush the catheter. The doctor should be alerted, and notation of the affected area should be made. If there is a bleb of drug, a needle aspiration may be performed to remove excess drug from the subcutaneous space. Note how much of the drug was obtained from the catheter, or from fine needle aspiration of the bleb. A marker should be used to outline the area of extravasation and treatment should start as soon as possible. At home care is similar to standard wound care, as it is crucial that the owner keeps the patient from licking at any extravasation site as it may delay healing, cause infection, or worsen the lesion overall.

For mild vesicant drug extravasation such as cyclophosphamide, cytarabine, carboplatin, and gemcitabine, a dry cold compression should be placed for 20–30 minutes, and then as needed for inflammation. Topical 90% DMSO may also help with carboplatin extravasation. DMSO can be applied to the skin surface every 8 hours for one week in conjunction with anti-inflammatory drugs if necessary.

For vinca alkaloid extravasation, a dry warm compress should be applied for 20–30 minutes at a time, for up to 4 times a day for the first 24–48 hours following the extravasation. Hyaluronidase is recommended to help absorb the drug. Human studies show that a 150 U/mL solution of hyaluronidase injected through the existing catheter helped reduce the extravasation severity. For every 1 ml of extravasated drug, 1 ml of hyaluronidase (150 U/mL) was given. Hyaluronidase can also be given subcutaneously, but ensure the needle is changed with every injection. If giving subcutaneously, inject 0.2 ml of the 150 U/mL hyaluronidase around the edge of the extravasation site.

For mechlorethamine extravasations, sodium thiosulfate can be injected into the local tissues. To be effective, this should be done immediately. For 10% sodium thiosulfate solution: mix 4 ml with 6 ml preservative-free sterile water for injection. If 25% sodium thiosulfate solution: Mix 1.6 ml with 8.4 ml of preservative-free sterile water for injection. Inject 2 ml for every 1 ml of vesicant extravasated through the existing line. Then consider injection 1 ml subcutaneously in 0.1-ml doses clockwise around the site. This can be repeated several times over the next 3–4 hours.

For doxorubicin extravasations, apply a dry cold compress immediately for 20–30 minutes at a time 4 times a day for the first 24–48 hours. Dexrazoxane should be administered as a separate intravenous infusion within 6 hours of the extravasation, but sooner administration yields better results. The dexrazoxane should be diluted as instructed, and then additionally diluted to a 1.3–5 mg/ml solution in either 0.9% sodium chloride or 5% dextrose injection. The dose is 1:10 of vesicant:dexrazoxane on day one. Then daily for two additional days. Triple doses have been more effective than a single dose. Surgical intervention may be necessary depending on the severity of the extravasation site. DMSO may be contraindicated in patients that are receiving or are going to receive dexrazoxane for extravasation treatment as a study in mice showed that the DMSO reduced the effectiveness of dexrazoxane. However, other reports in dogs indicate the usage of 90% DMSO without complication, but it is not recommended treatment option alone.

References

1.  Chemotherapy Extravasation Management. AAHA Home. www.aaha.org/aaha-guidelines/oncology-configuration/implementation-toolkit/chemotherapy-extravasation-management.

2.  Henry CJ, Higginbotham ML. Cancer Management in Small Animal Practice. Elsevier Mosby; 2010.

3.  MacDonald V. Chemotherapy: Managing side effects and safe handling. Can Vet J. 2009;50(6):665–668. www.ncbi.nlm.nih.gov/pmc/articles/PMC2684058. Accessed 28 July 2020.

4.  Washington State University VCPL—MDR1 Test. VCPL. vcpl.vetmed.wsu.edu.