Aftershocks of chemotherapy: managing adverse effects (Proceedings)

The majority of cytotoxic chemotherapy protocols in common veterinary use are designed to have a low risk of adverse effects. In general, less than 1 in 4 animals will have unpleasant adverse effects and only approximately 5% will have a serious adverse event, leading to hospitalization. With appropriate intervention, the risk of a treatment-associated fatality is less than 1 in 200. Should serious side effects occur, doses can be reduced, drugs can be substituted, or additional medications dispensed to minimize the likelihood of further adverse effects. These changes are effective 90% of the time.

Even in practices where chemotherapy is not administered, referring and emergency/critical care practices are often called upon to deal with adverse effects resulting from cancer therapy that may have been administered at another clinic. Having a protocol in place for the treatment of these patients dramatically increases the likelihood of a good outcome should a serious adverse event be encountered.

The most commonly encountered adverse effects, neutropenia and gastrointestinal disturbance, generally occur as a result of "collateral damage" done to rapidly dividing cells by the cytotoxic agent. Both bone marrow stem cells and gastrointestinal crypt cells are rapidly dividing and thus sensitive to the antiproliferative effects of chemotherapy.

Neutropenia and sepsis

Neutropenia is a relatively common side effect of chemotherapy in companion animals and humans. In certain malignancies, bone marrow infiltration or other conditions can exacerbate myelosuppression. The severity of neutropenia and associated sepsis can be extremely variable, ranging from clinically silent to overwhelming and occasionally fatal.

Presenting complaints:

Many animals may be mildly or moderately neutropenic, yet show no outward signs of illness. Most companion animals have a relatively low risk of infection if their neutrophil count remains greater than 1,000/uL. It is important to remember that likelihood of infection and subsequent treatment decisions should be made based on absolute neutrophil count, not total white blood cell count.

Septic patients will typically present with vague, nonspecific signs of illness such as lethargy, weakness, and inappetance. They are often febrile, but a normal temperature does not rule out the presence of a serious or even life-threatening infection. An accurate medication history is very important, as the timing of the last chemotherapy treatment can help to determine if myelosuppression is likely. Neutropenia is likely to be seen 7-10 days after the administration of most chemotherapy drugs. Exceptions to this rule include vinblastine and paclitaxel, which can cause neutropenia as early as 4-5 days after administration, and lomustine (CCNU) and carboplatin, which can occasionally cause neutropenia as late as 2-3 weeks following administration.

Diagnostics:

Septic patients are often febrile, as mentioned above. Other physical abnormalities could include tachycardia, injected mucous membranes, slow or prolonged capillary refill, or weak pulses. Initial minimum database should include a CBC and platelet count with manual differential, serum biochemistry profile, and urinalysis. Common changes include neutropenia with or without a left shift or toxic changes, thrombocytopenia, hyper- or hypoglycemia, evidence of dehydration, or metabolic acidosis. Urinalysis may reveal a quiet sediment, however urinary tract infections cannot be ruled out as neutropenia can result in the absence of neutrophils in the urine. Many clinicians will empirically culture the urine of neutropenic, septic patients. A coagulation profile is indicated in an animal with unquestionable signs of septic shock, as varying degrees of disseminated intravascular coagulation can be seen and must be treated aggressively. In animals presenting with respiratory signs or with a history of vomiting prior to presentation, thoracic radiographs to identify a nidus of infection are indicated. Recent human studies suggest that there is no benefit to obtaining "screening" thoracic radiographs in the asymptomatic neutropenic, septic patient.

Treatment:

Asymptomatic patients with less than 1,000 neutrophils/uL can be managed on an outpatient basis. In these patients, the risk of nosocomial infection likely outweighs the benefit associated with hospitalization. A broad-spectrum oral antibiotic such as trimethoprim-sulfa (7.5 mg/kg BID), Clavamox® (13.75 mg/kg BID) or enrofloxacin (5-10 mg/kg SID) should be prescribed for a 5-7 day course, and the owner should be instructed to monitor the patient's temperature once or twice daily at home. If the patient becomes clinically ill or the temperature exceeds 103.5oC, hospitalization may be required. Patients with mild neutropenia (>1,000/uL) generally require no treatment.

Febrile or systemically ill patients should be hospitalized for 24-hour care. The first line of treatment for these patients is intravenous crystalloid therapy. Shock doses of fluids, or the addition of colloids should be considered in the hemodynamically unstable, critical septic patient. In the stable patient, a fluid rate of 1.5 times maintenance is reasonable after correction of any existing fluid deficit. It is quite common for fever and clinical status to improve significantly after several hours of fluid therapy. The second line of defense is appropriate antibiotic coverage. The most common organisms responsible for neutropenic sepsis are resident flora that are usually antibiotic-sensitive. Common bacteria include E. coli, Pseudomonas, Staph. epidermidis, and Staph. aureus. Thus, intravenous coverage for both gram-positive and gram-negative organisms should be employed. Typical drug combinations might include a penicillin/aminoglycoside combination such as ampicillin (22 mg/kg IV TID) and amikacin (10 mg/kg IV/IM/SQ SID) (assuming renal function is adequate) or first-generation cephalosporin/fluoroquinolone combination such as cefazolin (20 mg/kg IV TID) and enrofloxacin (5-10 mg/kg IV or IM SID). Antipyretics are almost never necessary, and may make interpretation of response to therapy difficult.

The majority of patients will respond rapidly to therapy, and neutrophil counts may rise very rapidly as well. The majority of animals will be afebrile within 12-24 hours, and can be discharged when they are afebrile and have greater than 1,000 neutrophils/uL. In patients that do not respond clinically during the first 48-72 hours, further diagnostics to identify a potential nidus of infection and to collect samples for bacterial culture and antibiotic sensitivity should be performed. Additional tests might include thoracic radiographs, abdominal ultrasound and echocardiography, and at least 2 sets of blood cultures. In those patients that do not respond rapidly, antibiotic coverage can be broadened while waiting for culture results. Anaerobic coverage may be broadened with the addition of metronidazole (25 mg/kg IV BID), and/or a second- or third-generation cephalosporin can be considered. Should protracted (>72h) neutropenia be encountered, a bone marrow aspirate may be useful (especially in patients with hematopoietic neoplasia where there is the possibility of infiltrative disease).

There is continued debate as to the clinical utility of recombinant human granulocyte colony-stimulating factor (G-CSF, Neupogen®). Some clinicians will routinely utilize G-CSF for febrile, neutropenic patients; others will utilize it in cases of severe neutropenia where neutrophil count is less than some arbitrary value (500/uL or 100/uL, for example). Others will utilize G-CSF only if neutropenia persists for longer than 72 hours. Although some human studies have suggested no benefit in terms of length of hospitalization or mortality rate if G-CSF is employed, a recent study showed that severely neutropenic (< 100/uL) patients had decreased duration of neutropenia and hospital stay compared to controls, although there was no significant difference in mortality. In the author's hands, G-CSF is almost never necessary.

Gastrointestinal effects

Although the majority of veterinary patients undergoing chemotherapy will tolerate treatment well, a small number may experience unpleasant gastrointestinal side effects such as nausea/vomiting or diarrhea. The majority are mild and self-limiting, however more severe episodes are occasionally encountered. Just as chemotherapy can target the rapidly dividing tumor cells and bone marrow precursors, the rapidly dividing gastrointestinal crypt cells are likewise susceptible to chemotherapy effects.

Presenting complaints:

There are certain drugs (cisplatin, for example) that have the potential to cause immediate nausea/vomiting due to the activity of the drug itself on the chemoreceptor trigger zone in the brain. During cisplatin administration, for example, most dogs will vomit during or after drug administration unless they are premedicated with an antiemetic such as butorphanol, ondansetron or maropitant. More commonly, damage to the GI mucosa can result in irritation and inflammation that can lead to vomiting and/or diarrhea, most commonly in the 2-5 day period following chemotherapy administration. Signs can range from mild inappetance and slightly soft stools to severe, intractable vomiting and profuse, hemorrhagic diarrhea. Animals with mild symptoms can often be managed at home with dietary modification and oral medications. Animals that are unable to keep water down, that are becoming depressed, dehydrated or lethargic, or animals experiencing severe hematochezia should be hospitalized.

Diagnostics:

Careful medical and medication history should help to determine if the signs are likely to be associated with chemotherapy administration. In a severely affected animal, minimum database should include PCV/total solids, BUN/creatinine, electrolytes and urine specific gravity. A full CBC and serum chemistry profile is reasonable in these cases, and a CBC should also be performed in animals with significant hematochezia. If the patient has a protracted history of vomiting, thoracic radiographs are reasonable to rule out aspiration pneumonia. In an animal that is refractory to symptomatic therapy, further investigation (e.g. abdominal imaging) to rule out other causes for vomiting such as obstruction, pancreatitis, GI involvement with neoplasia, etc. should be considered.

Treatment:

Many animals with mild signs may respond to conservative therapy (e.g. brief NPO followed by bland, high-fiber diet and time). Oral antiemetics (e.g. metoclopramide 0.2-0.5 mg/kg PO or SQ TID, prochlorperazine 0.3 mg/kg PO or SQ TID) may be utilized if vomiting is infrequent and the patient is bright and alert. Oral medications for diarrhea such as kaolin/pectin may be used as well. The author favors the use of the opiate antidiarrheals such as loperamide (0.08 mg/kg PO TID) when necessary. Some animals with chemotherapy-associated diarrhea may respond to oral metronidazole (25 mg/kg daily) for 5 days. We will also prescribe metronidazole for any dogs with hematochezia.

Animals that are weak, lethargic, dehydrated, or with severe, refractory symptoms should be hospitalized so that fluid, acid-base and electrolyte disturbances can be addressed. These animals should be kept NPO until vomiting resolves, and parenteral antiemetics can be administered (See Table 1). Dehydration should be corrected over the first 8-12 hours, then patients can be maintained on a fluid rate of approximately 1.5 times maintenance. Some animals may be mildly or moderately hypokalemic – This should be corrected with potassium supplementation. Judicious re-feeding with bland food and transfer to oral antiemetics can typically start after a patient has been emesis-free for 12-24 hours.

Table 1: Commonly Used Antiemetics

For antiemesis in the inpatient, the author will often start ondansetron or maropitant, then consider adding prochlorperazine or metoclopramide as a constant-rate infusion if necessary. For very refractory vomiting cases, butorphanol or anti-inflammatory doses of corticosteroids may be added. The addition of an H2 blocker (e.g. famotidine 0.5-1 mg/kg IV or SQ) or proton pump inhibitor (e.g. pantoprazole 1 mg/kg IV) may be helpful in minimizing risks associated with continued vomiting/reflux esophagitis. The H2 blocker ranitidine may also have prokinetic and antiemetic activity due to concurrent inhibition of acetylcholinesterase activity.

If hospitalization is necessary, most animals will need support for 24-72 hours. After this period of time, the GI mucosal cells have usually had sufficient time to regenerate and the vomiting should subside. Vomiting persisting for longer than 72 hours should be an indication to rule out other disease.

References

Thamm DH, Vail DM. Aftershocks of cancer chemotherapy: managing adverse effects. JAAHA 43: 1-7, 2007.

Endicott M. Oncologic emergencies. Clin Tech Small Anim Pract. 2003;18(2):127-30.

Van de Wetering MD, de Witte MA, Kremer LC, et al. Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials. Eur J Cancer 2005;41(10):1372-82.

Berghmans T, Paesmans M, Lafitte JJ, et al. Therapeutic use of granulocyte and granulocyte-macrophage colony-stimulating factors in febrile neutropenic cancer patients. A systematic review of the literature with meta-analysis. Support Care Cancer. 2002;10(3):181-8.f