• Open Access

Efficacy of Maropitant in the Prevention of Delayed Vomiting Associated with Administration of Doxorubicin to Dogs

Authors


  • Dr Rau is presently affiliated with Carolina Veterinary Specialists, Greensboro, NC. This study was performed at Tufts University Cummings School of Veterinary Medicine, North Grafton, MA. Preliminary results of this study were presented at the 29th Annual Conference of the Veterinary Cancer Society, October 17, 2009, Austin, TX.

Corresponding author: Suzanne E. Rau, DVM, 501 Nicholas Road, Greensboro, NC 27409; e-mail: srau13@hotmail.com.

Abstract

Background: Vomiting, nausea, inappetence, and diarrhea are common delayed adverse effects of doxorubicin. Maropitant, a neurokinin-1 receptor antagonist, is known to prevent acute vomiting in dogs receiving cisplatin.

Objective: To evaluate the efficacy of maropitant in preventing delayed vomiting after administration of doxorubicin to dogs.

Animals: Fifty-nine dogs with cancer.

Methods: This randomized, double-blind, placebo-controlled study used a cross-over design. Dogs were randomized into 1 of 2 treatment groups. Group A received maropitant after the 1st doxorubicin, and placebo after the 2nd. Group B received placebo first, and maropitant second. Maropitant (2 mg/kg) or placebo tablets were administered PO for 5 days after doxorubicin treatment. Owners completed visual analog scales based on Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events to grade their pet's clinical signs during the week after administration of doxorubicin. Statistical differences in gastrointestinal toxicosis and myelosuppression between maropitant and placebo treatments were evaluated.

Results: Significantly fewer dogs had vomiting (P= .001) or diarrhea (P= .041), and the severity of vomiting (P < .001) and diarrhea (P= .024) was less the week after doxorubicin when receiving maropitant compared with placebo. No differences were found between maropitant and placebo for other gastrointestinal and bone marrow toxicoses.

Conclusions and Clinical Importance: Maropitant is effective in preventing delayed vomiting induced by doxorubicin. Its prophylactic use might improve quality of life and decrease the need for dose reductions in certain dogs.

Abbreviations:
NK1

neurokinin-1

VCOG-CTCAE

Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events

Doxorubicin chemotherapy is a standard component in many chemotherapy protocols for several tumor types, including lymphoma, osteosarcoma, and hemangiosarcoma.1–3 Nausea, inappetence, vomiting, and diarrhea are common dose-limiting adverse effects seen in dogs after doxorubicin chemotherapy treatment. Doxorubicin has gastrointestinal-related adverse effects that comprise 64% of all toxicoses experienced by dogs, with approximately 27% of dogs having some degree of gastrointestinal-associated adverse effects typically manifesting 3–5 days after treatment.4 The severity of these adverse effects might result in an unacceptable decline in a pet's overall quality of life, resulting in future dose reductions or even the preclusion of continued doxorubicin treatment.

Substance P has been identified as an important stimulatory neurotransmitter in the vomiting pathway that binds to neurokinin-1 (NK1) receptors.5 Maropitant,a an NK1 receptor antagonist, acts as a ligand for substance P receptors located in the emetic center of the brainstem, particularly the nucleus tractus solitarius.6 Blockade of substance P at the level of the emetic center has the potential to control vomiting resulting from a wide range of emetic stimuli, including chemotherapeutic agents.5

Maropitant proved effective in the prevention and treatment of acute vomiting events in dogs receiving cisplatin chemotherapy.7–9 Current guidelines from the American Society of Clinical Oncologists in 2006, however, advocate the use of NK1 receptor antagonists not only for acute emesis, but also delayed chemotherapy induced nausea and vomiting.10

The primary objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of maropitant in preventing vomiting in dogs after doxorubicin chemotherapy. If maropitant proves an effective preventative for gastrointestinal adverse effects, a protocol incorporating maropitant as a prophylactic measure after doxorubicin treatment might improve the quality of life and prevent the need for dose reductions in some dogs.

A secondary endpoint of the study was to determine whether maropitant administration intensifies myelosuppression in dogs administered doxorubicin. Preliminary toxicity data for maropitant noted bone marrow hypoplasia in 8-week-old Beagles, though most of these dogs had concurrent diseases, including coccidia and parvovirus infection.11 This secondary objective was included to assess the safety of maropitant in dogs with cancer receiving doxorubicin.

Materials and Methods

Patient Selection

Dogs with cancer presenting to the Tufts Cummings School of Veterinary Medicine between June 2008 and December 2009 with the plan to receive a minimum of 2 doxorubicin treatments during the course of their chemotherapy protocol were candidates for the study. Dogs with a primary gastrointestinal tumor were disqualified from participation.

Other exclusion criteria included nausea, vomiting, or inappetence that occurred within 2 days before receiving a dose of doxorubicin. Dogs receiving concurrent medications with the potential for gastrointestinal toxicosis, such as prednisone or nonsteroidal anti-inflammatory drugs, were included only if they had received this medication for a minimum of 2 weeks before doxorubicin administration with no gastrointestinal adverse effects attributable to the medication observed by the owner. Dogs could not have received another medication classified as an antiemetic within 2 days before doxorubicin treatment. Owners were required to sign a study consent form confirming that their pet met the inclusion criteria and that they agreed to comply with rules and guidelines established by the study.

Treatment Protocol

Dogs received doxorubicin at a dose of 30 mg/m2 (25 mg/m2 if their weight was <10 kg). To reliably compare the response to maropitant versus placebo, dogs were required to receive the same dose of doxorubicin with both treatments.

Dogs receiving doxorubicin were randomized into 1 of 2 treatment groups. Group A received oral maropitant after their 1st doxorubicin treatment and a placebo after their 2nd doxorubicin treatment. Group B received an oral placebo after their 1st doxorubicin treatment and maropitant after their 2nd doxorubicin treatment. Both the investigators and clients were blinded to the treatment groups, with a designated technician controlling the randomization with a random numbers table. The random numbers table was created before the start of the study by the designated technician by a randomization program.b Maropitant (2 mg/kg PO) or a placebo control was given once daily for 5 consecutive days, beginning the day after treatment with doxorubicin.

An antiemetic of the clinician's choice was used as a rescue therapy for dogs who experienced >3 vomiting events within 24 hours or who vomited for >2 consecutive days (grade 2 or higher adverse event according to the Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events [VCOG-CTCAE]).12 The attending clinician and client were permitted to withdraw an animal from the study using their discretion on the basis of the welfare of the dog.

The study protocol was evaluated and granted approval by the Clinical Sciences Review Committee at the Tufts Cummings School of Veterinary Medicine.

Response and Toxicity Assessment

The response to either maropitant or placebo was evaluated using specific criteria, including the presence and severity of vomiting, diarrhea, nausea, inappetence, and lethargy. Owners were sent home with a notebook containing daily evaluation forms to be completed the week after doxorubicin (Fig 1). The forms asked owners to grade their pet's clinical signs on a visual analog scale. Marks on the scale corresponded to the VCOG-CTCAE, ranging from 0 (none) to 4 (life threatening) for factors including vomiting, diarrhea, nausea, appetite, and activity level.12

Figure 1.

 Example of daily evaluation form sent home and completed by the owner the week after doxorubicin treatment.

Indications of bone marrow toxicosis were recorded for each treatment group based on CBC obtained before and on day 7 after each administration of doxorubicin. Anemia, neutropenia, and thrombocytopenia were assigned a score by the VCOG-CTCAE.12

Statistical Analysis

Statistical analyses were performed to evaluate for differences in various gastrointestinal factors (vomiting, diarrhea, nausea, inappetence, and lethargy) between the maropitant and placebo groups.

A χ2-test was used to assess for any differences between the 2 groups in the proportion of dogs experiencing each gastrointestinal adverse effect.

To evaluate the severity of gastrointestinal adverse effects for each dog, the maximum gastrointestinal toxicosis score for each factor was determined with the visual analog scales completed by the owner. When an owner marked a point on the scale that was between 2 toxicity grades, the toxicosis was assigned a value proportional to the placement of the mark. Therefore, it was possible to evaluate data both continuously, ranging from 0 to 4, as well as categorically, by rounding nonwhole number toxicity grades to the next highest grade. The Wilcoxon signed-rank test was used to assess for differences in the severity of gastrointestinal toxicosis between treatment groups.

Bone marrow toxicosis values were recorded for each treatment group based on CBC obtained before and on day 7 after administration of doxorubicin. Data were evaluated continuously by the blood count measurements for each parameter, as well as categorically by sorting each value into the appropriate VCOG toxicity grade. Differences in the severity of bone marrow toxicosis between the maropitant and placebo treatments were evaluated by the Wilcoxon signed-rank test.

For all of the gastrointestinal and bone marrow statistical tests discussed, factors with a P-value < .05 were considered significant.

Identical statistical analyses were performed to evaluate for any significant differences in gastrointestinal or bone marrow factors when comparing results from the 1st doxorubicin treatment to the 2nd. These additional analyses were performed to determine whether cumulative chemotherapy toxicity played a role for any factor evaluated.

Identical statistical analyses were also performed to assess for any significant differences in gastrointestinal toxicosis when comparing dogs that received maropitant after the 1st doxorubicin to those that received moropitant after the 2nd. This analysis was included to help determine whether gastrointestinal intoxication was more difficult to control if maropitant was withheld until after the 2nd treatment.

All statistical analyses were performed with a statistical software program.c

Results

Dog Population

A total of 59 dogs enrolled in the study, with 49 dogs reaching study completion. Of the 49 dogs completing the study, 24 dogs were randomized to group A, receiving maropitant after the 1st doxorubicin, and placebo after the 2nd. The remaining 25 dogs were randomized to group B, receiving placebo first and maropitant second. No significant differences were found between dog populations for factors such as age, weight, sex, and breed (Table 1).

Table 1.   Signalment and tumor types of the 49 enrolled dogs completing the study of the efficacy of maropitant in the prevention of delayed vomiting.
CharacteristicsNo. of Dogs
OverallGroup AGroup B
Age (years)
 Median (range)8 (3–13)8 (3–13)8 (3–13)
Sex
 Male castrated281216
 Female spayed21129
Weight
 <25 kg422
 >25 kg452223
Breed
 Mix1596
 Golden Retriever927
 Labrador Retriever440
 Mastiff303
 German Shepherd211
 Beagle211
 Other purebred1477
Tumor type
 Lymphoma251312
 Osteosarcoma1165
 Hemangiosarcoma624
 Soft tissue sarcoma (high grade)312
 Other neoplasia422

Of the 10 dogs that withdrew from the study, 3 dogs did so because of progression of their disease after the 1st doxorubicin treatment. Three additional dogs withdrew because of lack of owner compliance during the study. The remaining 4 dogs withdrew because of gastrointestinal or bone marrow toxicoses that required a dose reduction for the 2nd doxorubicin treatment. Of these 4 dogs with toxicosis, 3 were randomized to group B, receiving placebo after the 1st doxorubicin, while 1 was randomized to group A, receiving maropitant. All 4 dogs had signs of gastrointestinal intoxication, while 1 of the dogs in group B also experienced neutropenia.

Response and Toxicity

Overall, 4 dogs (8%) experienced vomiting when given maropitant for 5 days after doxorubicin treatment, compared with 17 (35%) who vomited when given placebo (P= .001) (Table 2). The vomiting in the maropitant-treated group was also significantly less severe for both categorically (P < .001) and continuously (P < .001) evaluated data. When results were analyzed categorically, the vomiting events in the 4 dogs in the maropitant-treated group were all classified as grade 1. In the placebo-treated group, 13 dogs had grade 1 vomiting, 3 had grade 2 vomiting, and 1 had grade 3 vomiting. When data were evaluated continuously, the mean vomiting grade for the 4 vomiting dogs was 0.6 (range 0.4–1) when treated with maropitant compared with a mean of 0.94 (range 0.3–3) for the 17 vomiting dogs in the placebo group. The median timing of vomiting events was 3 days postdoxorubicin, with 91% of dogs experiencing vomiting at 48 hours or more posttreatment.

Table 2.   Results of statistical analyses for incidence of various gastrointestinal factors for the 49 dogs completing the study.
FactorNo. (%) Exhibiting Sign: Maropitant versus PlaceboNo. (%) Exhibiting Sign: 1st versus 2nd Doxorubicin
MaropitantPlaceboP-Value1st Doxorubicin2nd DoxorubicinP-Value
Vomiting4/49 (8%)17/49 (35%).0019/49 (18%)12/49 (25%).46
Diarrhea16/49 (33%)26/49 (53%).04117/49 (35%)25/49 (51%).10
Nausea18/49 (37%)14/49 (29%).3912/49 (25%)20/49 (41%).085
Inappetence25/49 (51%)17/49 (35%).1016/49 (33%)26/49 (53%).041
Lethargy29/49 (59%)26/49 (53%).5425/49 (51%)30/49 (61%).31

Additionally, significantly fewer dogs experienced diarrhea when given maropitant compared with placebo (P= .041). Sixteen dogs (33%) had diarrhea while receiving maropitant versus 26 (53%) with diarrhea while receiving placebo. The diarrhea events were significantly less severe with administration of maropitant (P= .024) when analyzed categorically, though not when signs of toxicoses were evaluated continuously (P= .061). When receiving maropitant, 14 dogs had grade 1 diarrhea, 1 had grade 2 diarrhea, and 1 had grade 3 diarrhea. In the placebo-treated group, 18 dogs had grade 1 diarrhea, 7 had grade 2 diarrhea, and 1 had grade 3 diarrhea. The median timing of diarrhea events was 4 days postdoxorubicin, with 95% of dogs experiencing diarrhea at 48 hour or more after treatment.

No statistically significant differences were found in the incidence or severity of nausea, inappetence, or lethargy between the maropitant and placebo treatments.

Forty-one of the 49 dogs (84%) had CBC performed both before and at day 7 after both administrations of doxorubicin and could be included in statistical analyses evaluating bone marrow toxicosis. There were no significant differences found in the degree of anemia (continuous data, P= .16; categorical data, P= .5), neutropenia (continuous data, P= .73; categorical data, P= .82), or thrombocytopenia (continuous data, P= .23; categorical data, P= .14) after doxorubicin when receiving maropitant compared with placebo (Figs 2–4).

Figure 2.

 Box and whisker plot of neutrophil counts for 41 dogs at 7 days after doxorubicin administration, placebo versus maropitant.

Figure 3.

 Box and whisker plot of hematocrit values for 41 dogs at 7 days after doxorubicin administration, placebo versus maropitant.

Figure 4.

 Box and whisker plot of platelet counts for 41 dogs at 7 days after doxorubicin administration, placebo versus maropitant.

Differences in gastrointestinal and bone marrow toxicoses between the 1st and 2nd administrations of doxorubicin, regardless of which study drug a dog received, were also evaluated. Of all the factors assessed, only inappetence was found to be significantly higher after the 2nd doxorubicin treatment, having both an increased incidence (P= .041) and severity (categorically P= .025; continuously P= .021). Sixteen dogs (33%) experienced inappetence after the 1st administration of doxorubicin compared with 26 dogs (53%) after the 2nd administration of doxorubicin. Of the 16 dogs with a decreased appetite after the 1st administration of doxorubicin, categorical grading was grade 1 (n = 5), grade 2 (n = 5), grade 3 (n = 4), grade 4 (n = 2). This is compared with the 26 dogs with a decreased appetite after the 2nd administration of doxorubicin: grade 1 (n = 8), grade 2 (n = 9), grade 3 (n = 5), grade 4 (n = 4). When reported continuously, the mean inappetence grade for the 16 inappetent dogs after the 1st administration of doxorubicin was 2.09 (range 1–4) compared with a mean of 2.09 (range 0.25–4) for the 26 inappetent dogs after the 2nd administration of doxorubicin.

No statistically significant differences were found in the incidence or severity of any gastrointestinal sign of intoxication when comparing dogs that received maropitant after the 1st doxorubicin to those that received moropitant after the 2nd administration.

Discussion

The results of this study support that maropitant is effective in preventing delayed vomiting associated with administration of doxorubicin. Both the incidence and severity of vomiting were significantly decreased when dogs were treated prophylactically with maropitant compared with placebo. The prophylactic use of maropitant can improve the quality of life and eliminate the need for dose reductions in certain dogs.

An unanticipated finding was that significantly fewer dogs experienced diarrhea when treated with maropitant, and that these episodes were also significantly less severe when toxicosis was assessed categorically. Substance P and NK1 receptors have been detected in the central nervous system and peripheral tissues, including the entirety of the gastrointestinal tract in rats and humans.13–17 Substance P regulates smooth muscle contractility, epithelial ion transport, vascular permeability, and immune function in the human gastrointestinal tract.18–20 Substance P activation leads to the release of cytokines and chemokines, as well as other neuropeptides that modulate diarrhea, inflammation, and motility associated with the pathophysiology of several intestinal disease states.13,18,21,22 NK1 receptor antagonists in mice and humans block substance P binding to the NK1 receptor and interrupt the inflammatory cascade that initiates and maintains the intestinal lesions in inflammatory bowel disease.18,23–26

Based on these findings, one possible hypothesis is that substance P plays a similar role in diarrhea associated with chemotherapy in dogs. By blocking the NK1 receptors and preventing the binding of substance P in the gastrointestinal tract, maropitant might have reduced the incidence and severity of diarrhea in dogs in the present study. Further studies are required to explore this theory.

Signs suggestive of nausea were not significantly decreased during prophylactic treatment with maropitant. One possible explanation is that nausea remains difficult to evaluate in dogs and that more dogs experienced nausea than were reported in this study.

Overall, an increased incidence and severity of inappetence was found after the 2nd doxorubicin treatment when compared with the 1st. This finding might have been the result of the cumulative effects of the chemotherapy protocols on dogs. Additionally, it might have been more difficult to control inappetence in dogs in group B that did not receive maropitant until after their 2nd doxorubicin treatment. Human oncology patients have nausea and vomiting resulting from chemotherapy that becomes more difficult to control at subsequent cycles when not adequately controlled after the initial treatment.27,28 Although this theory was not statistically supported in the present study, the study was not sufficiently powered for this assessment. Because data were no longer paired for this particular analysis, additional dogs would be needed to adequately address this question.

Preliminary safety data for maropitant showed an increased risk of bone marrow hypoplasia when administered to a small group of 8-week-old Beagles.11 Therefore, it seemed prudent to evaluate for any exacerbation of bone marrow toxicosis when maropitant was administered to immunosuppressed dogs. In the present study, there was no evidence of increased myelosuppression in dogs with cancer receiving maropitant with concurrent chemotherapy treatments.

Limitations of this study include the somewhat subjective method of recording signs of gastrointestinal toxicosis by the owners. With a visual analog scale that corresponded to the VCOG-CTCAE, an attempt was made to keep the results as objective as possible. Additionally, because the same owner was evaluating each dog during both the maropitant and placebo weeks, some observer bias was minimized.

Footnotes

aCerenia, Pfizer Animal Health, New York, NY

bResearch Randomizer, Social Psychology Network, Middletown, CT

cStatsDirect Statistical Software, StatsDirect Ltd, Cheshire, Wales, UK

Acknowledgments

The authors thank Drs Holly Burr, Carol DeRegis, Meredith Gauthier, Nathan Lee, and Chantal Tu for their contribution to patient accrual for the study.

Funding for this study was provided by Pfizer Animal Health's 2008 Oncology Resident Grant program.

Conflict of Interest: At the time this study was conducted, none of the authors had a relationship with Pfizer Animal Health. Subsequently, Dr Barber has participated in the Experts Leading Industry Through Education (ELITE) program and accepts honoraria for providing continuing education to veterinarians regarding toceranib phosphate.

Ancillary