Lymphoma is the most common neoplastic disorder in dogs, representing 83% of hematopoietic tumors and 24% of all tumors in dogs.1 The current standard treatment for dogs with intermediate- to large-cell lymphoma involves administration of a multiagent, CHOP-based protocol, yielding overall response rates of 85% to 95% and median survival times of 10 to 12 months. This is an improvement when compared with results for a doxorubicin-free protocol consisting of cyclophosphamide, vincristine, and prednisone, which provides a remission rate of 70% and a median survival time of 7.5 months.2
Doxorubicin's clinical utility must be weighed against its adverse effects, including bone marrow suppression, gastrointestinal upset, and cardiotoxicosis. Cardiotoxicosis is of particular concern because of its irreversible nature and high associated morbidity and mortality rates. In human patients, preexisting cardiac disease is a risk factor for doxorubicin-mediated cardiotoxicosis, and this is commonly assumed to apply to dogs as well.3 There are 2 categories of doxorubicin-associated cardiotoxicosis: arrhythmias and myocyte damage.3 Arrhythmias are typically characterized by ventricular premature contractions and supraventricular arrhythmias, although other abnormalities have been reported.4,5 Myocyte damage is cumulative in nature and is mediated through oxidative damage to the heart in conjunction with decreased free radical scavenging activity.3 In dogs receiving doxorubicin, between 7.4% and 17.7% develop ECG abnormalities, and between 2% and 4% develop congestive heart failure.4,6,7
In dogs for which doxorubicin is believed to carry a high risk of cardiotoxicosis, this risk may be mitigated through the use of cardioprotectants (eg, dexrazoxane) or alternative doxorubicin formulations (liposomal doxorubicin) or by substitution of an alternative drug. Dexrazoxane has been shown to be safe and well tolerated in dogs, and in humans, it decreases the risk of cardiomyopathy without significantly impacting the efficacy of doxorubicin treatment.3,8 However, it can be prohibitively expensive for many clients and is not readily available in all areas. Additionally, there are no clinical data showing that it protects dogs against the arrhythmogenic effects of doxorubicin. Liposomal doxorubicin has been investigated in dogs and was shown to have decreased cardiotoxicity, compared with standard formulations of doxorubicin, and epirubicin has provided outcomes similar to those associated with doxorubicin.9,10 As with dexrazoxane, however, availability and cost may be barriers to routine use of these products in veterinary patients. Thus, in most clinical settings, the most cost-effective and accessible strategy is to omit doxorubicin from the protocol and substitute mitoxantrone.
Mitoxantrone is an anthracenedione closely related to doxorubicin and with a similar mechanism of action, but with substantially less potential for cardiotoxicosis in dogs. Unlike doxorubicin, mitoxantrone does not undergo 1-electron reduction. This leads to decreased generation of free radical species and, consequently, decreased damage to cardiac myocytes.3 Mitoxantrone has been used in the maintenance phase of a CHOP protocol and is also effective as a single agent in treating dogs with lymphoma, with an overall response rate of 41% when used as a single agent.11,12 Additionally, a recent study13 showed that mitoxantrone and doxorubicin have equivalent efficacy in a first-line multidrug protocol for lymphoma in dogs. That study was a randomized, prospective clinical trial in which all dogs underwent uniform staging and treatment according to their group assignment. However, the study included only 22 patients in each treatment arm and may have been underpowered to detect small but clinically meaningful differences in outcome between treatment groups. The objective of the study reported here was to examine the efficacy of such a substitution in a larger group of patients. Specifically, we wanted to determine median overall and progression-free survival times for dogs with multicentric intermediate- to large-cell lymphoma treated with a standard CHOP-like protocol in which mitoxantrone was substituted for doxorubicin.
Materials and Methods
Case selection
Medical records databases of 12 referral institutions were queried to identify dogs with lymphoma treated with mitoxantrone between 2000 and 2015. Dogs were eligible for inclusion if a histologic or cytologic diagnosis of multicentric intermediate- to large-cell lymphoma had been made, a CMOP protocol (Appendix) was used for first-line treatment, and the dog had completed at least 1 cycle (4 weeks) of chemotherapy. Dogs were excluded if any chemotherapeutic drugs had been administered prior to initiation of the CMOP protocol (other than a single initial dose of l-asparaginase), radiation therapy was included as part of the lymphoma treatment, or doxorubicin was administered prior to substitution of mitoxantrone in the treatment protocol. Dogs that had received corticosteroids were eligible for inclusion if corticosteroids had been given for no more than 7 days before the first chemotherapy treatment. Medical records were reviewed by an investigator at each site, and data were recorded in a standardized abstracting form.
Control selection
A contemporaneous control group of dogs with lymphoma in which a CHOP protocol (with or without l-asparaginase) was used for first-line treatment was identified through a search of the medical records database of the Auburn University Veterinary Teaching Hospital. Other than the use of doxorubicin rather than mitoxantrone, the inclusion and exclusion criteria were identical to those for the case group. Adverse event data were not abstracted from medical records for the control group, and this group was used only for comparison of overall and progression-free survival times.
Medical records review
Medical records were reviewed to obtain information on signalment; body weight; lymphoma stage, substage, and immunophenotype; presence of hypercalcemia; reason for mitoxantrone substitution; mitoxantrone dosage; and inclusion of l-asparaginase in the initial treatment protocol. Records were also reviewed for clinical outcomes, including response to treatment, time to maximum response, progression-free survival time, overall survival time, cause of death, remission status at death or final follow-up, any chemotherapy-related adverse events, and any subsequent rescue protocols used.
Lymphoma stage was based on criteria published by the World Health Organization.14 Staging tests included a CBC, serum biochemical profile, urinalysis, 2- or 3-view thoracic radiography, abdominal ultrasonography, and cytologic examination of liver, spleen, and bone marrow aspirates. Staging was considered complete if all staging tests were performed; however, the selection of specific staging tests was at the discretion of the attending clinician and owner. Dogs were classified as substage a if they were generally otherwise healthy and as substage b if they had clinical signs attributable to their disease; assignment of substage was made by the attending clinician.
Hypercalcemia was defined as total serum calcium or ionized serum calcium concentration higher than the upper reference limit for the institution's laboratory. Immunophenotyping was performed by means of immunohistochemical or immunocytochemical methods, PARR, or flow cytometry, as available at each institution and at the discretion of the attending clinician and owner. Adverse events were characterized according to criteria set forth by the Veterinary Cooperative Oncology Group.15
Response to treatment was assessed by the attending clinician. Response criteria were based on recommendations set forth by the Veterinary Cooperative Oncology Group.16 In brief, complete remission was defined as the disappearance of all clinical evidence of disease. Partial remission was defined as a ≥ 30% decrease in but not complete resolution of measurable lesions. Patients that did not have a complete or partial response were considered to have no response to treatment. Relapse was defined as the recurrence of lymphoma. Progression-free survival time was defined as the time from the first chemotherapy treatment to progression, loss to follow-up, or death from any cause. Overall survival time was defined as the time from the first chemotherapy treatment to death.
Statistical analysis
Demographic characteristics were compared between the case and control groups with a 2-proportion z test (for categorical data), t test (for continuous data), or Mann-Whitney rank sum test (for body weight, which was not normally distributed). Median overall and progression-free survival times were estimated with the Kaplan-Meier method, and outcomes were compared between the 2 groups with the log-rank test. Dogs were censored from survival analyses if they were still alive and in remission at the time of final follow-up. Dogs that were lost to follow-up or died of an unrelated cause were included for calculation of progression-free survival time but were censored for calculation of overall survival time. Deaths of unknown cause were attributed to lymphoma. A commercially available computer software programa was used for statistical analyses. For all comparisons, values of P < 0.05 were considered significant. All statistical analyses were selected and performed by a single investigator (ANS).
Results
Case (CMOP) group
Forty-four dogs met the criteria for inclusion in the study as case dogs. Case contributions were as follows: 7 each from University of California-Davis, University of Tennessee, and Colorado State University; 4 each from Auburn University, Purdue University, University of Georgia, and University of Illinois; 2 each from Veterinary Specialty Emergency Center and Mississippi State University; and 1 each from Georgia Veterinary Specialists, Loomis Basin Veterinary Clinic, and Charleston Veterinary Referral Center. There were 26 (59.1%) castrated males, 5 (11.4%) sexually intact males, and 13 (29.5%) spayed females. Median age was 10.3 years (range, 0.4 to 16.3 years). Median and mean body weights were 30 kg (66 lb) and 30.18 kg (66.4 lb), respectively (range, 6.5 to 94 kg [14.3 to 206.8 lb]). There were 9 Boxers, 8 mixed-breed dogs, 5 Labrador Retrievers, 3 Golden Retrievers, 2 Scottish Terriers, 2 Doberman Pinschers, and 15 additional breeds (1 dog/breed). Three dogs had stage II disease, 16 dogs had stage III disease, 12 dogs had stage IV disease, and 10 dogs had stage V disease; 3 dogs were unstaged. Of the dogs categorized as having stage III disease, 6 did not undergo complete staging and were noted to have disease of “at least stage III.” Similarly, 3 of the dogs categorized as having stage IV disease did not have bone marrow aspiration performed and were noted to have disease of “at least stage IV.” Twenty-one (47.7%) dogs were classified as substage a, and 13 (29.5%) were classified as substage b; substage was not reported for the remaining 10 (22.7%) dogs. Twenty (45.5%) dogs had B-cell lymphoma, 2 (4.5%) had T-cell lymphoma, and 22 (50%) did not have immunophenotyping performed. Four dogs (none of which had immunophenotyping performed) were hypercalcemic at the time of diagnosis. Twenty-three (52.3%) dogs received l-asparaginase at the start of chemotherapy.
With 3 exceptions, the reason for mitoxantrone substitution was cardiac abnormalities, with 10 dogs having > 1 cardiac abnormality listed. Twenty-two dogs had arrhythmias (ventricular [n = 11] or atrial [1] premature contractions, arrhythmogenic right ventricular cardiomyopathy [5], atrial fibrillation [2], sick sinus syndrome [1], ventricular tachycardia [1], and unspecified arrhythmia [1]). Seven dogs had poor cardiac contractility or low fractional shortening, 5 dogs had dilated cardiomyopathy, and 1 dog had subaortic stenosis, and in 1 dog, a diagnosis of congestive heart failure had previously been made. Fourteen dogs had other cardiac diseases (unspecified [n = 5], heart murmurs not further characterized [5], valvular degeneration or dysplasia [3], heartworm disease [1], and heart-based mass that persisted after remission of lymphoma [1]). One dog had pulmonary hypertension in addition to multiple other cardiac abnormalities, and another had pulmonary hypertension as the only reason for mitoxantrone substitution. For two dogs (both Doberman Pinschers), owners refused doxorubicin treatment owing to awareness of potential cardiotoxicosis, although neither dog had a documented cardiac abnormality.
Mitoxantrone was administered IV at a dose of 5 mg/m2 in 30 dogs, at a dose of 5.5 mg/m2 in 12 dogs, at a dose of 5.75 mg/m2 in 1 dog, and at escalating doses ranging from 5 to 7 mg/m2 in 1 dog. Nine dogs (20%) had adverse events (1 event/dog) during the course of chemotherapy that were either possibly or probably related to mitoxantrone administration. In 4 of these dogs, the adverse event was considered likely to be mitoxantrone related because the dogs experienced gastrointestinal upset within a week after mitoxantrone administration or were neutropenic approximately 1 week after mitoxantrone administration. In these dogs, adverse events consisted of grade 3 neutropenia (n = 1), febrile neutropenia for which grade was not recorded (1), grade 2 anorexia (1), and gastrointestinal upset that was not graded or further specified (1). In the remaining 5 dogs, there was no record of the timing of the adverse event in relation to mitoxantrone administration, or the adverse event was indistinguishable from clinical signs associated with uncontrolled lymphoma (ie, lethargy or fatigue). Therefore, adverse events in these 5 dogs were considered possibly mitoxantrone related. In these dogs, adverse events consisted of grade 2 neutropenia (n = 2), neutropenia for which grade was not recorded (1), grade 1 diarrhea (1), and lethargy for which grade was not recorded (1). In the latter 2 dogs, diarrhea and lethargy occurred following mitoxantrone administration, but these dogs were also noted to have concurrent progressive disease. In all 9 patients, recovery from the adverse event occurred with supportive outpatient treatment.
Thirty-six dogs (81.8%) had a complete response, and 8 (18.2%) had a partial response; overall response rate, therefore, was 100%. For 17 dogs, maximum response occurred after week 1 of the protocol; for 14 dogs, maximum response occurred after week 2 or 3 of the protocol; for 7 dogs, maximum response occurred after week 4 of the protocol; and for 2 dogs, maximum response occurred after week 6 of the protocol or later. Time to maximum response was not available for 4 dogs. Median progression-free survival time was 165 days (95% CI, 143 to 187 days; Figure 1). Median overall survival time was 234 days (95% CI, 165 to 303 days; Figure 2). Twenty-eight (63.6%) dogs received 1 or more rescue chemotherapy protocols following relapse; 6 of these dogs received at least 1 doxorubicin-containing rescue protocol. Ten dogs were censored from analysis of overall survival time, with a median time to censoring of 151 days. Four of these dogs were still alive, 4 were lost to follow up, and 2 died of unrelated cardiac causes while still in remission.
Kaplan-Meier curves of progression-free survival time for dogs with multicentric intermediate- to large-cell lymphoma treated with CMOP (n = 44; solid line) or CHOP (38; dashed line). Survival times for the 2 groups were not significantly (log-rank test; P = 0.998) different.
Citation: Journal of the American Veterinary Medical Association 254, 2; 10.2460/javma.254.2.236
Kaplan-Meier curves of progression-free survival time for dogs with multicentric intermediate- to large-cell lymphoma treated with CMOP (n = 44; solid line) or CHOP (38; dashed line). Survival times for the 2 groups were not significantly (log-rank test; P = 0.998) different.
Citation: Journal of the American Veterinary Medical Association 254, 2; 10.2460/javma.254.2.236
Kaplan-Meier curves of progression-free survival time for dogs with multicentric intermediate- to large-cell lymphoma treated with CMOP (n = 44; solid line) or CHOP (38; dashed line). Survival times for the 2 groups were not significantly (log-rank test; P = 0.998) different.
Citation: Journal of the American Veterinary Medical Association 254, 2; 10.2460/javma.254.2.236
Control (CHOP) group
Fifty-one dogs met the criteria for inclusion in the study as control dogs. There were 14 (27.5%) castrated males, 12 (23.5%) sexually intact males, 20 (39.2%) spayed females, and 5 (9.8%) sexually intact females. Median age was 8 years (range, 2 to 15.1 years). Median and mean body weights were 28 kg (61.6 lb) and 25.56 kg (56.2 lb), respectively (range, 3.8 to 47.6 kg [8.4 to 104.7 lb]). There were 9 Golden Retrievers, 8 Labrador Retrievers, 4 mixed-breed dogs, and 20 additional breeds (1 to 3 dogs/breed). Six dogs had stage III disease, 19 dogs had stage IV disease, and 26 dogs had stage V disease. Thirty-four (66.7%) dogs were classified as substage a, and 16 (31.3%) dogs were classified as substage b; substage was not reported for the remaining dog (2%). Thirty-two (62.7%) dogs had B-cell lymphoma, 3 (5.8%) had T-cell lymphoma, and 16 (31.4%) did not have immunophenotyping performed. Eleven (21.6%) dogs were hypercalcemic at the time of diagnosis. Thirty-two (62.7%) dogs received l-asparaginase at the start of chemotherapy.
Response to treatment could be evaluated for 38 of the 51 dogs. The remaining dogs underwent initial follow-up at their primary care clinic, and their remission details could not be reliably attained. However, they were retained in the group for purposes of survival analysis. Thirty-five (92.1%) had a complete response and 2 (5.3%) had a partial response, for an overall response rate of 97.4%. One dog had no response (stable disease). Adverse event data were not abstracted for the control dogs. Median progression-free survival time was 208 days (95% CI, 122 to 294 days; Figure 1). Median overall survival time was 348 days (95% CI, 287 to 409 days; Figure 2). Eight dogs were censored from analysis of overall survival time, with a median time to censoring of 486 days. Four of these dogs were lost to follow-up, 2 were still alive at the time of final follow-up, and 2 died of unrelated causes (details unknown, but both dogs were reported to be in remission at the time of death).
Kaplan-Meier curves of overall survival time for dogs with multicentric intermediate- to large-cell lymphoma treated with CMOP (n = 44; solid line) or CHOP (38; dashed line). Survival times for the 2 groups were not significantly (log-rank test; P = 0.492) different.
Citation: Journal of the American Veterinary Medical Association 254, 2; 10.2460/javma.254.2.236
Kaplan-Meier curves of overall survival time for dogs with multicentric intermediate- to large-cell lymphoma treated with CMOP (n = 44; solid line) or CHOP (38; dashed line). Survival times for the 2 groups were not significantly (log-rank test; P = 0.492) different.
Citation: Journal of the American Veterinary Medical Association 254, 2; 10.2460/javma.254.2.236
Kaplan-Meier curves of overall survival time for dogs with multicentric intermediate- to large-cell lymphoma treated with CMOP (n = 44; solid line) or CHOP (38; dashed line). Survival times for the 2 groups were not significantly (log-rank test; P = 0.492) different.
Citation: Journal of the American Veterinary Medical Association 254, 2; 10.2460/javma.254.2.236
Group comparisons
The CMOP and CHOP groups did not differ significantly with respect to sex distribution, body weight, distribution of stage or substage, presence of hypercalcemia, or immunophenotype distribution. Dogs in the CHOP group were significantly (P = 0.023) younger than those in the CMOP group.
Progression-free survival time for dogs in the CMOP group was not significantly (P = 0.998) different from that for dogs in the CHOP group (median, 165 and 208 days, respectively; Figure 1). Additionally, overall survival time for dogs in the CMOP group was not significantly (P = 0.167) different from that for dogs in the CHOP group (median, 234 and 348 days, respectively; Figure 2). Percentages of dogs in the CMOP group with complete and partial responses (36/44 [81.8%] and 8/44 [18.2%], respectively) were not significantly different from the percentages of dogs in the CHOP group with complete and partial responses (35/38 [92.1%] and 2/38 [5.3%], respectively).
Discussion
Results of the present study suggested that for dogs with multicentric intermediate- to large-cell lymphoma, treatment with CMOP was as effective as treatment with CHOP. A complete or partial response was reported for all 44 dogs treated with CMOP, which compared favorably with the 97.4% (37/38) response rate for the dogs treated with CHOP and with previously reported response rates with CHOP of 85% to 95%.1 Additionally, the median progression-free survival time of 165 days and median overall survival time of 234 days for dogs treated with CMOP were not significantly different from median times (208 and 348 days, respectively) for dogs in the contemporaneous control population treated with a standard CHOP protocol. Post hoc power analysis suggested that a study the same size as the present study would be adequately powered to detect an approximate 1.8-fold difference in overall or progression-free survival time. To demonstrate statistical significance for the approximately 1.2-fold difference in progression-free survival time in the present study, a total of 558 patients would be required.
The retrospective nature of the present study brought with it some expected limitations, including lack of randomization and blinding, incomplete staging for some dogs, a lack of immunophenotyping for some tumors, and incomplete reporting of adverse events. Although we did not find a significant difference in the percentages of dogs with B- and T-cell lymphoma, a large percentage of dogs in each group did not have immunophenotyping performed, and significant differences between groups may have been identified if immunophenotyping had been performed for all study patients. Given that immunophenotype is a well-established prognostic factor for treatment outcome for dogs with lymphoma, this was a weakness of our study.1
A related limitation of the present study was that the method of immunophenotyping varied. In particular, some dogs had immunophenotype determined by means of PARR alone. Immunocytochemistry, immunohistochemistry, and flow cytometry are all methods to assess cell surface antigen expression and, therefore, immunophenotype. In contrast, PARR, which tests for rearrangement of T- or B-cell receptor loci, is more correctly a test of clonality rather than immunophenotype. In some cases, T cells may rearrange their B-cell loci or vice versa, leading to erroneous conclusions when PARR is used for immunophenotyping. Indeed, PARR and immunohistochemistry have been shown to agree 69% of the time when used for immunophenotyping of canine lymphoma, whereas flow cytometry and immunohistochemistry have 94% agreement.17 However, PARR has sensitivities of approximately 67% and 75% for detection of B- and T-cell lymphomas, respectively, and has been reported as an acceptable method for immunophenotyping by other authors.17–20 Additionally, it has the advantage of not requiring viable cells or a tissue biopsy specimen, making it more practical in some dogs and in some clinical scenarios.
Another limitation of the present study was that some dogs received l-asparaginase as part of the chemotherapy protocol and some did not. The addition of l-asparaginase to a CHOP protocol has been shown to have no influence on duration of first remission, median survival time, or overall response rate21 and, therefore, should not have significantly affected the outcomes of the present study. The addition of l-asparaginase has also been investigated in a cyclophosphamide, vincristine, and prednisone protocol and similarly was not found to increase the likelihood of remission or to prolong the progression-free interval.22 Both of these studies21,22 support omission of l-asparaginase from first-line treatment and suggest that its omission does not affect treatment outcome. However, it is not clear whether the study investigating CHOP with or without l-asparaginase was adequately powered to detect a difference between the 2 groups, because a power analysis was not reported. Another study23 suggests an improvement in response rate (although not remission or survival time) when combining l-asparaginase with first-line treatment, but that study used doxorubicin as a single agent, rather than as part of a multiagent chemotherapeutic protocol, and was not randomized. Considering the conflicting evidence and lack of adequately powered trials, we cannot say conclusively that use of l-asparaginase in dogs in the present study had no effect on outcome.
Inclusion of cases from multiple institutions represented another limitation of the present study because of differences in evaluation methods, methods for determining remission status, and definitions of relapse; the lack of standardization for cardiac assessment; and the possibility of protocol variation. No single institution contributed more than 7 cases, and to accrue the maximum possible number of cases, the multicenter nature of the study was judged necessary despite the additional limitations it introduced. A contemporaneous control group was used, rather than published historical controls, to improve the amount of data that could be gleaned from medical records and to allow better comparison between study and control patients regarding known prognostic factors. Importantly, the 2 study groups were found to be statistically similar in all examined demographic variables except age.
Median age of the CMOP group was higher than that of the CHOP group in the present study (10.3 vs 8 years). Several possible considerations relate to this observed difference. First, the CMOP group was nearly completely composed of dogs with underlying heart disease, which may have resulted in selection bias for an older population. Second, young age has been reported as a poor prognostic indicator for dogs with lymphoma.24 This may have contributed to shorter median overall and progression-free survival times for the CHOP group, although the median overall survival time was within the 10- to 12-month range reported for most studies. Finally, because older dogs may be more likely to have comorbid conditions, patients in the CMOP group may have had additional disease processes affecting their survival times.
Progression-free survival time provides a more meaningful assessment of a chemotherapeutic protocol's effectiveness than does overall survival time because the latter can be influenced by a variety of factors, including use of multiple subsequent rescue protocols and variable owner criteria for euthanasia. Nevertheless, both progression-free and overall survival time are frequently assessed and reported in the veterinary literature, and overall survival time may be of interest to clinicians and clients alike. In the present study, however, overall survival times for dogs in the CMOP group might have been shortened because, for most of these dogs, their cardiac disease would have precluded the use of doxorubicin for rescue therapy.
It is important that a potential protocol modification (in this case, the substitution of mitoxantrone for doxorubicin) be well tolerated. In the present study, 9% (4/44) of dogs experienced adverse events that were considered likely sequelae of mitoxantrone administration, and all of these were mild, with all dogs recovering with outpatient supportive treatment. An additional 11% (5/44) of dogs had adverse events that were possibly related to mitoxantrone administration, yielding a conservative estimated adverse event rate of 20% (9/44). Although it is possible that mild adverse events may have been underreported, adverse events severe enough to warrant hospitalization were unlikely to have been overlooked, and no dog in the CMOP group required hospitalization because of an adverse event. Information on adverse events was not abstracted from medical records for dogs in the CHOP group, and therefore, a direct comparison could not be made regarding the tolerability of mitoxantrone versus doxorubicin in this study. However, previously published studies8,25,26 of single-agent doxorubicin treatment report adverse event rates ranging from 5.5% to 64.8%, and 9.4% of dogs receiving CHOP required hospitalization. Therefore, the tolerability of mitoxantrone in our study, particularly in regard to adverse events severe enough to warrant hospitalization, compared favorably with that of doxorubicin and CHOP as reported in the existing literature.
In the present study, response rates, progression-free survival times, and overall survival times were not significantly different between the group of dogs treated with CMOP and the contemporaneous control group of dogs treated with CHOP. Additionally, the CMOP protocol was well tolerated. An adequately powered prospective randomized study would be needed to confirm that the protocols are equal in efficacy, but such studies can be difficult to perform in veterinary medicine. The present study, despite its limitations, was the largest to date examining CMOP as a first-line treatment for dogs with lymphoma. Together with the data published by Wang et al,13 our findings supported the use of CMOP in dogs in which doxorubicin would carry an unacceptable risk.
Acknowledgments
Presented in poster form at the 34th Annual Conference of the Veterinary Cancer Society, St Louis, October 2014.
The authors thank the following individuals for contribution of cases: Laura D. Garrett, DVM; Rebecca E. Risbon, VMD; John M. Thomason, DVM, MS; Susan A. Kraegel, DVM; Rebecca C. Regan, DVM; and Kerry C. Rissetto, DVM, MS.
ABBREVIATIONS
| CHOP | Cyclophosphamide, doxorubicin, vincristine, and prednisone |
| CI | Confidence interval |
| CMOP | Cyclophosphamide, mitoxantrone, vincristine, and prednisone |
| PARR | PCR assay for antigen receptor rearrangement |
Footnotes
SigmaPlot for Windows, version 12.0, build 12.2.0.45, Systat Software, San Jose, Calif.
References
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Appendix
Chemotherapy protocol administered to dogs with multicentric intermediate- to large-cell lymphoma in a study examining substitution of mitoxantrone for doxorubicin.
| Week | ||||||
|---|---|---|---|---|---|---|
| Drug | Dosage | 1 | 2 | 3 | 4 | 5 |
| l-asparaginase | 400 U/kg (182 U/lb) or 10,000 U/m2, SC | X | ||||
| Vincristine | 0.5–0.7 mg/m2, IV | X | X | |||
| Cyclophosphamide | 250 mg/m2, PO, over 2–4 d | X | ||||
| Doxorubicin* | 30 mg/m2 (25 mg/m2 or 1 mg/kg [0.45 mg/lb] for dogs weighing < 15 kg [33 lb]), IV | X | ||||
| Mitoxantrone* | 5–7 mg/m2, IV | X | ||||
| Prednisone | 2 mg/kg (0.9 mg/lb; wk 1), 1.5 mg/kg (0.68 mg/lb; wk 2), 1 mg/kg (wk 3), and 0.5 mg/kg (0.23 mg/lb; wk 4), PO, q 24 h | X | X | X | X | |
A CBC was performed during week 5. Weeks 1 through 5 were repeated, with the omission of l-asparaginase and prednisone, for a total of 4 cycles. At clinician discretion, some patients did not receive l-asparaginase, received the last 2 cycles of treatment on an every-other-week rather than weekly basis, or had week 3 of each cycle omitted.
Either doxorubicin or mitoxantrone was administered.
