Douglas H. Thamm
Key Points
· Client education handouts explaining side effects, how to manage them at home, and when to become concerned are useful.
· Identify and treat immediate side effects:
· hypersensitivity (allergic responses) and
· tissue damage from extravasation (drugs administered outside a vein).
· Identify and treat delayed side effects:
· questions to ask clients when handling phone calls about side effects,
· nausea/vomiting/diarrhea,
· neutropenia (low white blood cell count), and
· acute tumor lysis syndrome.
Introduction
Studies that have looked at clients’ opinions of medical treatment for cancer generally report a positive experience; most owners felt that the treatment was worthwhile, that it resulted in improvement in the well-being of their pet, and that quality of life during treatment was good.
Although uncommon, some side effects can have serious consequences for the pet and the owner. These include
· decreased quality of life,
· increased cost (hospitalization and treatment),
· delay or changes to future treatments, and
· reduced enthusiasm for continuing treatment.
It is the veterinary team’s job to make sure that clients understand the goals of therapy and the risks of side effects before treatment is started. The use of client education handouts explaining the potential side effects, how to manage them at home, and when to become concerned is encouraged. An example of such a handout is included at the end of this chapter (Appendix 8.1).
Even in practices where chemotherapy is not used, general and emergency/critical care practices may be called upon to deal with side effects from chemotherapy that has been given at another practice. Thus, a general familiarity with the identification and treatment of chemotherapy side effects is useful for most general practices.
Client Education
Owners may be very frightened by the idea of giving chemotherapy to their pet, based on experiences they may have had with a friend or family member. It is important to point out how cancer chemotherapy in animals differs from cancer chemotherapy in people (see Chapter 1 for more information). Most common veterinary chemotherapy protocols are made to have a low risk of side effects. In general, less than one in three animals will have an unpleasant side effect and only about 1 in 20 will have a significant side effect, one that requires hospitalization. Most pets will spend less than 72 hours in the hospital for the treatment of a serious side effect.
With effective treatment, the risk of a chemotherapy-associated death is less than 1 in 200. Should a serious side effect occur, doses can be reduced, drugs can be substituted, or other medications can be given to reduce the chance of further side effects. These changes are effective 90% of the time.
Why Side Effects from Chemotherapy Happen
Most cancer drugs work by damaging rapidly dividing cells. The most commonly encountered side effects, neutropenia (low white blood cell count) and digestive tract upset, generally occur as a result of “collateral damage” to rapidly dividing normal cells. The hope with chemotherapy treatment is to attack the tumor cells, which are among the most rapidly dividing and are also the cells that are least able to repair themselves. However, both bone marrow stem cells, which make new white blood cells, and gastrointestinal crypt cells, which provide the lining for the intestines, are rapidly dividing and thus are sensitive to the effects of chemotherapy. Additional acute effects that can happen and may require treatment, include allergic reactions and accidental drug extravasation (administration of drug outside a vein).
Hypersensitivity (Allergic Reactions)
Several cancer drugs are capable of causing immediate anaphylaxis or hypersensitivity reactions in patients. The most common drugs that can cause these reactions are asparaginase and doxorubicin. The shock organs of the dog are the intestinal tract and the skin, and these two organs are most severely affected during and immediately after administration. The lung is the shock organ in the cat.
Asparaginase can result in severe anaphylaxis, usually within 60 minutes of injection. Milder reactions can occur up to 24 hours following treatment. Therefore, animals should be monitored in the hospital for signs of anaphylaxis for 60 minutes following drug administration. The likelihood of these reactions increases with multiple asparaginase injections. If a hypersensitivity reaction to asparaginase does occur, it most commonly shows as facial swelling or development of hives. Occasionally, severe, acute collapse can occur.
Hypersensitivity reactions to doxorubicin can include itchiness, facial swelling, hives, reddening of the skin and the mucous membranes, head shaking, vomiting, restlessness, or difficulty breathing. These typically occur while the drug is being given. For this reason, it is helpful to note the color of the skin (the inside of the ear is a good spot to look) and mucous membranes before the treatment is started, and then check for increased redness several times during the doxorubicin administration.
If a mild or moderate hypersensitivity reaction occurs, stop drug administration and give diphenhydramine and dexamethasone sodium phosphate (SP). For very severe or life-threatening hypersensitivity reactions, epinephrinemay need to be given. See Table 8.1 for dosages and routes of administration for these medications. When the reaction improves, administration can be restarted at a slower rate. For animals that have previously had a hypersensitivity reaction, it usually can be prevented during subsequent treatments by pretreating with diphenhydramine and dexamethasone SP, 15–20 minutes before the chemotherapy drug is given.
Table 8.1 Hypersensitivity drugs, routes, and dosages
|
Drug |
Dosage (mg/kg) |
Route |
|
Diphenhydramine |
3–4 |
Intramuscular |
|
Dexamethasone SP |
0.5–1 |
Intravenous |
|
Epinephrine |
0.001–0.01 |
Intravenous |
Extravasation
Several cancer drugs (doxorubicin, vincristine, vinblastine, actinomycin D) can cause tissue damage if accidentally given outside of a vein (extravasated). Administration of these drugs needs to be through a dedicated, perfectly placed (“first stick”) intravenous catheter (see Chapter 5 for additional information). Patients undergoing infusions of these tissue-irritant drugs should be constantly observed until completion of the infusion to ensure that the catheter remains functional and in place.
Most catheter leaks are noticed right away. A bleb or swelling appears immediately next to the catheter site. Some animals experience immediate discomfort and will squirm, cry out, or struggle. If an irritant drug is known to have been extravasated, stop the delivery. As much drug as possible should be aspirated back through the catheter, as well as through a series of 25-gauge needlesticks into the surrounding tissue, then withdraw the catheter. Following that, cold-packing 15–20 minutes four times per day is recommended for 48–72 hours. Prevent licking and chewing at all costs, through the use of an Elizabethan collar. Additionally, the application of 99% dimethyl sulfoxide (DMSO) topically every 8 hours for 2 weeks may forestall some of the effects.
While most catheter leaks are noticed right away, the skin ulceration may not appear for several days or even weeks. It has been demonstrated that doxorubicin can persist in the tissue for at least a month. If allowed, the pet will start licking at the catheter site. Then pain, swelling, inflammation, desquamation, and limping may occur and may continue to worsen for months.
Doxorubicin is a very commonly used cancer drug and is also an extremely potent tissue irritant (Figure 8.1). It is disheartening to realize that no currently applied procedures adequately prevent the devastating tissue damage that arises from doxorubicin extravasations. Surgical treatment, including immediate surgical removal of the affected tissues and, potentially, amputation may be required. The free-radical-scavenging drug dexrazoxane (Zinecard®; Pfizer, New York, NY), marketed for the prevention of doxorubicin-associated heart damage, may help minimize doxorubicin tissue damage. Intravenous administration of dexrazoxane at 10 times the dose of doxorubicin within 3 hours, and again at 24 and 48 hours after extravasation, may significantly reduce local tissue injury. Most veterinary clinics do not keep this drug in stock. If doxorubicin is used in your practice, it is recommended that a source of dexrazoxane (local human hospital or oncology clinic) be identified, so that it can be obtained quickly if needed.
Figure 8.1 Severe skin damage following accidental extravasation of doxorubicin in a dog. Months of nursing care, skin grafts, and, sometimes, amputation can be necessary to manage these types of injury.
More effective treatments for extravasation of drugs like doxorubicin continue to be explored. Interestingly, due to obvious similarities to some types of snakebite, a simple approach with a snakebite extractor kit has been applied to humans with extravasation injuries. In one study of human patients, three doxorubicin extravasations were encountered in a clinical setting between 1985 and 2002 (one every 6 or 7 years). Chemotherapy was immediately discontinued, and the catheter was removed. Then the specific area of extravasation was marked and surgically prepped, and X-shaped incisions, approximately 1 cm in length, were made through the full thickness of the skin. A clear snakebite extractor suction cup with a syringe was then applied directly over the incision. As the cup filled with serosanguinous fluid, it was emptied and reapplied until the drainage stopped. The area was dressed with sterile gauze and examined periodically. All three cases treated in this manner showed prompt and complete resolution within a week. A similar technique called the “modified Villalobos snakebite slit technique” is also reported to be a highly effective treatment in animal cancer patients.
Gastrointestinal Effects
While many pets receiving chemotherapy may experience 1–2 days of mildly decreased appetite, a few pets receiving chemotherapy (one in three or less) may have more unpleasant digestive side effects such as more prolonged loss of appetite, nausea/vomiting, or diarrhea. Most are mild and self-limiting; however, more severe episodes are sometimes seen.
Presenting Complaints
Most commonly, gastrointestinal effects are delayed, often 2–5 days following chemotherapy administration. Clinical signs can range from mild loss of appetite and slightly soft stools to severe vomiting or large amounts of watery or bloody diarrhea.
History
Careful medical and medication history helps to determine if the signs are likely to be associated with chemotherapy administration and to determine their severity. This information is often communicated over the phone and can be useful to determine whether a patient needs to be seen or can be managed at home (Table 8.2). Questions to ask include the following:
· What type of cancer does the pet have?
o Could the signs be related to the cancer rather than the treatment?
· What drug was given most recently and how long ago?
o Intestinal signs would be rare in a dog that received chemotherapy 2 weeks ago, but would be much more likely in a dog that received chemotherapy 2–5 days ago.
· How many times has the patient vomited?
o A single episode of vomiting in a bright, eating patient is probably OK. Animals that have vomited more than three times in 24 hours, are vomiting every time they eat or drink (cannot keep anything down), or vomiting without eating or drinking (retching, dry heaving) should be evaluated by a veterinarian.
· Is he or she willing to eat and drink?
o Not wanting to eat for a day or two is often OK, but not drinking for any period of time can be very serious, as dehydration can result quickly. Animals that are not drinking should be evaluated in the hospital and might need fluid therapy.
· How severe is the diarrhea (if any)?
o Mild loose stool is probably OK. Dogs with severe watery or bloody diarrhea should be evaluated by a veterinarian.
· How are they acting?
o Bright, happy animals with mild signs can often be managed at home. Animals that are very weak, lethargic, or depressed should be evaluated in the hospital.
Table 8.2 When should an animal with gastrointestinal signs be seen?
|
Vomiting more than three times in a 24-hour period |
|
Vomiting every time they eat or drink (cannot keep anything down) |
|
Retching or dry heaving |
|
Unwilling to eat for more than 2 days: unwilling to drink for more than 18 hours |
|
Severe watery or bloody diarrhea |
|
Severe weakness, lethargy, or depression |
Treatment
Many animals with mild signs may respond to conservative therapy, for example, brief withholding of food and water followed by a bland, high-fiber diet over a short period of time. Oral antinausea medications like metoclopramide (Reglan®; UCB, Brussels, Belgium), prochlorperazine (Compazine®; GlaxoSmithKline, Research Triangle Park, NC), or maropitant (Cerenia®; Pfizer) can be prescribed for home use if vomiting is rare and the patient is bright and alert. Oral medications for diarrhea, such as loperamide (Imodium®; McNeil Consumer and Specialty Pharmaceuticals, Fort Washington, PA), metronidazole (Flagyl®; Pfizer), and/or tylosin (Tylan®; Elancon, Greenfield, IN), may be prescribed as well.
Animals that are weak, lethargic, dehydrated, or with severe signs should be hospitalized so that fluid, acid–base, and electrolyte disturbances can be addressed. These animals should be kept without food and water until vomiting resolves, and injectable antinausea drugs can be administered. Then, carefully rebuild the patient’s digestive tract with bland food and transfer to oral antinausea drugs after a patient has not vomited for 12–24 hours.
If hospitalization is necessary, most animals will need support for 24–72 hours. After this period of time, the intestinal cells have usually had sufficient time to regenerate, and the pet’s clinical signs should improve. Vomiting that persists longer than 72 hours indicates a reason to look for other causes, such as pancreatitis, foreign body, or tumor spread to the digestive tract.
Neutropenia and Sepsis
Neutropenia (decreased number of neutrophils, one of the white blood cells) is a relatively common side effect of chemotherapy in both pets and humans. Neutropenia and associated infections can be extremely variable, from clinically insignificant to overwhelming and occasionally fatal.
Presenting Complaints
Many animals may have mild to moderate neutropenia, yet show no outward signs of illness. Most pets have a low risk of infection if their neutrophil count remains greater than 1000/µL. It is important to remember that the likelihood of infection and treatment decisions should be made based on the absolute neutrophil count, not the percentage of neutrophils nor the total white blood cell count.
Septic animals typically present with vague, nonspecific signs such as lethargy, weakness, and poor appetite. They often have a fever, but a normal or decreased temperature does not rule out the presence of a serious or even life-threatening infection.
History
An accurate medication history is very important, as the timing of the last chemotherapy treatment can help to determine if neutropenia is likely. Neutropenia is most commonly seen 7–10 days after the administration of most chemotherapy drugs.
Diagnostics
As mentioned, septic patients usually, but not always, have a fever. Other physical abnormalities could include increased heart rate, injected mucous membranes, slow or prolonged capillary refill, or weak pulses. Initial minimum database should include a complete blood count (CBC) and platelet count with a manual differential, serum biochemistry profile, and urinalysis. The results of these tests will direct the veterinarian toward other necessary diagnostic tests and treatment.
Treatment
Bright patients without a fever and with less than 1000 neutrophils/µL can usually be managed as outpatients. In these patients, the risk of a hospital-acquired infection probably outweighs the benefit of hospitalization. Treatment may be a 5- to 7-day course of a broad-spectrum oral antibiotic such as trimethoprim-sulfa or enrofloxacin. Instruct the owner to monitor the patient’s temperature once or twice daily at home. If the patient becomes clinically ill or the temperature exceeds 103.5°F, hospitalization may be required. Clinically normal animals with mild neutropenia (>1000/µL) generally require no treatment.
Febrile or systemically ill patients should be hospitalized for 24-hour observation and care. Intravenous fluid therapy is the first line of treatment for these patients. It is common for fever and clinical signs to improve significantly after several hours of fluid therapy.
The second line of defense is antibiotic treatment. Most bacteria that cause illnesses in septic veterinary cancer patients are sensitive to commonly used antibiotics. Intravenous coverage for both gram-positive and gram-negative bacteria should be used. Medications to reduce fever are rarely necessary, and may make the interpretation of response to treatment difficult.
Most patients respond rapidly to therapy, and neutrophil counts may also rise very rapidly. The fever breaks in most patients within 12–24 hours, and they can be sent home on oral antibiotics when they no longer have a fever and have neutrophil counts that are climbing.
Acute Tumor Lysis Syndrome
Acute tumor lysis syndrome is a life-threatening metabolic emergency associated with certain types of cancer. In acute tumor lysis syndrome, tumor cells break apart, releasing their contents into the bloodstream. The result is a dangerous alteration in the normal balance of serum electrolytes. The changes occur so quickly and can be so dramatic that rapid death can result.
Many factors contribute to the development of acute tumor lysis syndrome. Tumors that carry the highest risk of the development of acute tumor lysis syndrome are large and bulky, and are comprised of rapidly dividing cells. In addition, tumors that respond well to treatment are associated with acute tumor lysis syndrome because successful treatment may result in the death of a large number of cells all at once. Most often, the syndrome is associated with blood-based diseases, such as lymphoma and acute leukemia. Usually, acute tumor lysis syndrome develops after the administration of combination chemotherapy regimens, but it may also occur spontaneously or as a result of radiation or prednisone therapy. Patients with underlying kidney diseases are at a higher risk of developing acute tumor lysis syndrome. For example, a patient undergoing chemotherapy may experience nausea and vomiting, and may become dehydrated. Without optimal hydration, waste products build up and cannot be excreted in the urine fast enough. As a result, significant serum electrolyte imbalances can occur.
Treatment is aimed at prevention and supportive care. The main goal of treatment is to prevent renal failure and severe electrolyte imbalances. High-risk patients should receive chemotherapy or radiation therapy treatment on an inpatient basis to allow for close monitoring after therapy. Prior to initiating cancer therapy, a high-risk patient’s hydration status and electrolyte levels are to be carefully evaluated. If there are abnormalities, a treatment delay may be considered, although this may not always be an option. The effects of acute tumor lysis syndrome can be devastating, but sometimes the life of a patient with a high tumor burden is more at risk without cancer therapy. The risk assessment makes acute tumor lysis syndrome the more attractive outcome when compared with the likelihood of death, if the cancer remains untreated.
Appendix 8.1 Sample Chemotherapy Owner Handout
All of the chemotherapy protocols in common use for veterinary patients are designed to have a fairly low risk of causing unpleasant side effects. With most treatments, 70% of patients will have very little in terms of side effects, except for perhaps some slight tiredness or decreased appetite for 1–2 days following treatment. However, there are approximately 25% of patients that may experience some type of mild side effect and 5% that can experience a side effect severe enough to require hospitalization. We cannot usually predict which patients are likely to experience a serious side effect.
Most chemotherapy drugs work by targeting rapidly dividing cells. Although cancer cells are typically the most rapidly dividing and this is why they are preferentially killed, other rapidly dividing cells can be damaged as well. Cells lining the intestinal tract, cells in the bone marrow, and hair follicle cells are rapidly dividing cells, and damage to these cells is responsible for most of the side effects we encounter.
Digestive Tract
One of the side effects that can be seen with certain medications is digestive tract upset, in the form of unwillingness to eat/drink, nausea/vomiting, or diarrhea. In most cases, these signs are mild and will go away by themselves within a short period of time. These side effects are most commonly seen 2–5 days following a chemotherapy treatment.
Decreased appetite can occasionally be seen and is not worrisome if it persists for less than 48 hours. It is important, however, that your pet continues to drink. Unwillingness to drink water for more than 24 hours and prolonged, complete unwillingness to eat are problems that should be reported to your veterinarian.
Some animals can develop nausea, which can lead to vomiting. Vomiting is not a cause for undue concern if it occurs less than three times. Should your pet vomit, withhold food and water for approximately 12 hours, to give the digestive tract a “rest.” Then slowly reintroduce water first. If no vomiting occurs several hours after water is given, then a bland food can be offered in small amounts. This may consist of boiled chicken or lean ground beef mixed with starch like rice, pasta, or potatoes. We may sometimes prescribe oral antinausea medications that can be given to relieve mild nausea, inappetance, or vomiting. Repeated vomiting, vomiting after every meal (“can’t keep anything down”), or repeated nonproductive retching (dry heaving) should be reported to your veterinarian. Animals that experience these effects will need to be evaluated for dehydration, and may need hospitalization for intravenous fluids and antinausea medications.
You may also see diarrhea as a side effect of certain chemotherapy drugs. This can range from mild soft stools or increased frequency of defecation, to profuse, watery diarrhea that may contain blood. Mild diarrhea in a bright, eating pet can be treated with the bland diet described above. Some oral medications can also help to resolve diarrhea. Severe, watery diarrhea, blood in the stool, or diarrhea associated with lethargy, weakness, depression, or unwillingness to drink should be brought to the attention of your veterinarian.
White Blood Cells
If the rapidly dividing cells in the bone marrow have been affected by the chemotherapy, a low white blood cell count can develop. This side effect is most commonly seen 7–10 days after chemotherapy is given. We check the white blood cell count prior to each and every chemotherapy treatment, to insure that it is not too low for another treatment to be safely given. Occasionally, the white blood cell count may dip low enough that we need to delay a treatment for a few days. Such a brief delay will not affect the overall success of your pet’s chemotherapy protocol.
It is uncommon for the white blood cell count to drop low enough that an increased susceptibility to infection is a concern. However, if your pet has a very low white blood cell count and is eating and drinking normally, does not have a fever, and is otherwise acting normally, we will often prescribe a broad-spectrum antibiotic for you to give at home. We would then recommend that your pet’s temperature be taken once or twice per day to ensure that they are not developing a fever. Taking a pet’s temperature is easy. A standard glass or digital thermometer that you buy at the store is used. If a glass thermometer is used, make sure to shake it down well first. Lubricate the thermometer with a small amount of Vaseline or K-Y jelly, and insert it approximately one half inch into the rectum. For a glass thermometer, it should be left in place for approximately 2 minutes. Most digital thermometers will beep when the temperature is recorded. A normal dog or cat’s temperature at home should be between 100 and 102°F. If your pet’s temperature is higher than 103°F or they show signs of weakness, lethargy, depression, or unwillingness to eat, please call. Hospitalization may be necessary.
If your pet has a low white blood cell count and has a fever, or is depressed, lethargic, or not eating, hospitalization for intravenous fluids, antibiotics, and very careful monitoring is recommended. Most animals will improve rapidly with this treatment, and hospitalization is rarely necessary for more than 72 hours. They are ready to go home when their temperature has become normal and their white blood cell count is no longer in a dangerously low range.
If serious side effects are seen after a treatment, we always try to make changes to the treatment protocol, so that they are much less likely to happen again. Some of the changes may include decreasing the dose of chemotherapy given for subsequent treatments, adding some medications to help prevent adverse effects, or switching to an entirely different drug. It is always our goal to make it so that serious side effects are not encountered more than once.
Additional Reading
Bronden LB, Rutteman GR, Flagstad A, Teske E. 2003. Study of dog and cat owners’ perceptions of medical treatment for cancer. Vet Rec 152:77–80.
Laing EC, Carter RF. 1988. Acute tumor lysis syndrome following treatment of canine lymphoma. J Am Anim Hosp Assoc 24:691–6.
Mahoney JA, Bergman PJ, Camps-Palau MA, Hull TL. 2007. Treatment of doxorubicin extravasation with intravenous dexrazoxane in a cat. J Vet Intern Med 21:872–3.
Mellanby RJ, Herrtage ME, Dobson JM. 2003. Owners’ assessments of their dog’s quality of life during palliative chemotherapy for lymphoma. J Small Anim Pract 44:100–3.
Thamm DH, Vail DM. 2007. Aftershocks of cancer chemotherapy: Managing adverse effects. J Am Anim Hosp Assoc 43:1–7.
Vickery KR, Thamm DH. 2007. Successful treatment of acute tumor lysis syndrome in a dog with multicentric lymphoma. J Vet Intern Med 21:1401–4.
Villalobos A. 2006. Dealing with chemotherapy extravasations: A new technique. J Am Anim Hosp Assoc 42:321–5.