Abstract
OBJECTIVE
To evaluate survival times for dogs with previously untreated, peripheral nodal, intermediate- or large-cell lymphoma treated with prednisone alone.
ANIMALS
109 client-owned dogs recruited from 15 institutions in the United States.
PROCEDURES
Dogs were treated with prednisone at a dosage of 40 mg/m2, PO, once daily for 7 days and at a dosage of 20 mg/m2, PO, once daily thereafter. Quality of life (QOL) was assessed by owners with a visual analog scale when treatment was started (day 0), 1 and 2 weeks after treatment was started, and every 4 weeks thereafter. The primary outcome of interest was survival time as determined by the Kaplan-Meier method. Factors potentially associated with survival time were examined.
RESULTS
Median overall survival time was 50 days (95% CI, 41 to 59 days). Factors associated with survival time included substage (a vs b) and immunopheno-type (B cell vs T cell). Owner-assigned QOL scores on days 0 and 14 were significantly positively correlated with survival time. When QOL score was dichotomized, dogs with day 0 or day 14 QOL scores ≥ 50 had significantly longer survival times, compared with dogs with day 0 or day 14 QOL scores < 50. No variables were predictive of long-term (> 120 days) survival.
CONCLUSIONS AND CLINICAL RELEVANCE
Results suggested that survival times were short for dogs with previously untreated, peripheral nodal, intermediate- or large-cell lymphoma treated with prednisone alone. Owner-perceived QOL and clinician-assigned sub-stage were both associated with survival time. Findings provide potentially important information for clinicians to discuss with owners of dogs with lymphoma at the time treatment decisions are made. (J Am Vet Med Assoc 2021;259:62–71)
Introduction
The most common form of naturally occurring lymphoma in dogs is multicentric, intermediate- or high-grade disease.1 Low-grade lymphomas are less common, are characterized by a slow growth rate and indolent biological behavior, and might not require treatment.1–3 Intermediate- and high-grade lymphomas are biologically aggressive, and affected dogs typically die within a few weeks if not treated.4
Chemotherapy protocols that involve concurrent or sequential administration of chemotherapeutic drugs are commonly used to treat dogs with lymphoma.5 In a 2013 survey6 of 110 veterinary oncologists and veterinarians with a special interest in oncology, 93% recommended protocols involving a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without L-asparaginase, to treat dogs with lymphoma, with most respondents recommending a 24- to 28-week protocol. Treatment strategies that include high-dose chemotherapy with7–9 or without10–12 autologous bone marrow transplantation, half-body radiation therapy,13,14 and chemoimmunotherapy15 have also been described but are infrequently used to treat dogs with lymphoma. Rabacfosadinea is an emerging, novel treatment option for this disease.16
Outcomes of dogs treated with commonly used, 6-month-long chemotherapy protocols incorporating cyclophosphamide, doxorubicin, vincristine, and prednisone have been well-described.13,17 Remission rates are reported to be high, with most dogs having survival times ranging from several months to several years,18 and most owners reported that treating their pet with chemotherapy was a worthwhile experience.19 In a survey by Mellanby et al20 of 25 dog owners whose pets with lymphoma were treated with chemotherapy, 23 (92%) responded they had no regrets about treating their pet with chemotherapy, and 20 (80%) indicated they would elect chemotherapy again in the future in the event they owned another dog with lymphoma.
Nevertheless, even though lymphoma in dogs is highly responsive to chemotherapy, many pet owners do not pursue treatment. This reluctance of owners to treat their pet with chemotherapy might reflect individual beliefs or previous experience with chemo-therapy, concerns about the potential for toxicoses, worries about actual or perceived stress on the pet, or the inconvenience of chemotherapy visits. Less than 2% of US dog owners hold pet health insurance policies,21 so financial costs may also have a substantial influence on the decision to use chemotherapy in pets. Finally, owner perception of a poor prognosis for their dog with lymphoma could play a role. In a survey of 78 owners of pets that did not have cancer, Williams et al22 found that 80% thought an increased life expectancy of 6 to 9 months was not sufficient to pursue treatment with chemotherapy. Unfortunately, many dogs with lymphoma treated with chemotherapy have survival times in this range,13,17 making this treatment unacceptable for many owners.
When chemotherapy is not elected for dogs with lymphoma, most veterinarians recommend treatment with prednisone.6 Glucocorticoids induce apoptosis or cell cycle arrest in lymphoid malignancies.23,24 The biological actions of glucocorticoids are mediated by glucocorticoid receptors, which are ligand-activated transcription factors belonging to the nuclear receptor superfamily.25 Compared with chemotherapy, treatment with prednisone as a single agent is lower in cost, less likely to result in toxicoses, and easier for owners to administer at home.
Despite the inclusion of prednisone in most multiagent chemotherapy protocols and the frequent use of prednisone as a single agent when chemotherapy is declined, there have to date been no controlled studies demonstrating the benefits of corticosteroids in dogs with lymphoma. Survival information for dogs with lymphoma treated with prednisone alone was first reported in 1968 by Brick et al.4 Survival times were 1 to 7.5 months, but that study4 was small and included cats (n = 8) and the prednisone dose and dosing schedule varied. In 1973, Squire et al26 re ported on a larger sample of dogs (n = 49). A response to prednisone, administered at a dosage of 2 mg/kg (0.9 mg/lb), PO, every 24 hours for 7 days and then at 1 mg/kg (0.45 mg/lb), PO, every 24 hours, was observed in 40% of the dogs, with a mean response time of 53 days. The response rate was similar (48%) in a 1984 study by Bell et al,27 but like the earlier report, both dogs (n = 32) and cats (3) were included. Also, animals were treated with prednisone (2 mg/kg/d) for only 2 weeks.
The purpose of the study reported here was to evaluate survival times for dogs with previously untreated, peripheral nodal, cytologically confirmed, intermediate- or large-cell lymphoma treated with prednisone as a single agent. A secondary objective was to evaluate factors potentially associated with survival time for dogs with lymphoma treated with prednisone alone.
Materials and Methods
Study design
The Canine Lymphoma Steroid Only trial was designed as a prospective, multicenter, observational study. An untreated control group was not included. The study protocol was approved by the Iowa State University Institutional Animal Care and Use Committee; the CHQLS completed by owners was approved by the Iowa State University Institutional Review Board. Cytologic confirmation of lymphoma, immunophenotyping, and prednisone was provided free of charge; dog owners were responsible for all other medical expenses. Written informed consent was obtained from all owners.
Study subject enrollment
Client-owned dogs with peripheral lymphadenomegaly and a suspected diagnosis of lymphoma were evaluated and recruited between April 2016 and September 2017 by 16 board-certified veterinary oncologists at 15 institutions in the United States. Only dogs with cytologically proven intermediate- or large-cell lymphoma that had not previously received any treatment were included. All cytologic diagnoses were confirmed by a single board-certified veterinary clinical pathologist (CJL) who was blinded to patient details such as signalment and presenting clinical signs.
Exclusion criteria
Dogs were excluded from the study if they had been treated with corticosteroids (PO or topically) in the 2 months prior to evaluation, had received any chemotherapeutic drugs, had an estimated life expectancy of < 3 days without treatment, or were known or suspected to have lymphoma involving the skin, gastrointestinal tract, or nervous system or had internal disease alone (eg, mediastinum, liver, or spleen) without peripheral lymph node involvement.
Diagnosis and staging
The diagnosis of lymphoma was made by means of cytologic examination of Wright-Giemsa–stained smears of samples collected via fine-needle aspiration of ≥ 1 enlarged peripheral lymph node. Intermediate-or large-cell lymphoma was diagnosed when > 50% of the cells consisted of intermediate-sized or large lymphocytes. Intermediate-sized lymphocytes were defined as cells with a nucleus 2 to 2.5 times the diameter of an RBC; large lymphocytes were defined as cells with a nucleus ≥ 3 times the diameter of an RBC.28
For dogs included in the study, immunopheno-type was determined by means of immunocyto-chemical staining. Peripheral lymph node specimens collected via fine-needle aspiration were applied to positively charged slides,b which were then air dried and stored at room temperature for up to 6 months. Slides were immunostained with monoclonal antibodies against CD3 and Pax5 by use of an automated stainerc and a standard protocol that included a series of alcohol washes, heat-induced epitope retrieval (30 minutes), and incubation with either anti-CD3d or anti-Pax5e antibodies. Secondary antibodies consisted of anti-mouse IgGf and anti-mouse IgGg for CD3 and Pax5, respectively. Control slides consisted of cytologic samples from dogs previously confirmed to have T- or B-cell lymphoma and were run as a single set of slides with each batch of study slides. Positive control slides were handled exactly the same way as study slides; negative control slides were treated with negative mouse serumh instead of the primary antibody. Positive CD3 immunoreactivity was considered supportive of T-cell lymphoma; positive Pax5 immunoreactivity was considered supportive of B-cell lymphoma. Background populations of immunopositive T or B cells were occasionally observed and interpreted as non-neoplastic background cells from nodal tissue. Dogs with predominant B-cell immuno-reactivity but an increased background population of T cells were considered to possibly have T-cell–rich, B-cell lymphomas. Immunoreactivity was evaluated in a blinded manner by a board-certified veterinary anatomic pathologist (DAK).
All dogs underwent a complete physical examination at the time of study enrollment. Staging tests (eg, clinicopathologic testing, diagnostic imaging, and cytologic examination of bone marrow) were not required for inclusion in the study; however, results were recorded when available. Dogs were classified as either substage a (having no clinical signs) or substage b (having gastrointestinal signs, respiratory signs, hypercalcemia [> 12 mg/dL], fever [> 39°C {103°F}], hyphema, or uveitis).
Prednisone protocol
All dogs were treated with the same formulation of prednisone.i Prednisone was administered PO by owners at a target dosage of 40 mg/m2 once daily for the first 7 days and then 20 mg/m2 once daily thereafter. The administered dose was calculated to the nearest 5 mg. Throughout the study, clinicians could increase or decrease the prednisone dosage at their discretion on the basis of perceived or real adverse effects or decreasing QOL.
QOL questionnaire and follow-up
To allow clinicians to track changes in the health status of dogs enrolled in the study, owners were asked to complete a CHQLS (Supplementary Figure S1, available at: avmajournals.avma.org/doi/suppl/10.2460/javma.259.1.62) at various times throughout the study. The prototype for the CHQLS was a cancer treatment questionnaire developed to assess QOL for dogs and cats enrolled in clinical studies for the antineoplastic drug toceranib phosphate.29 The CHQLS included 7 domains related to QOL. Each domain contained 3 related items phrased either positively or negatively, and each was scored on a scale from 1 to 5, with higher scores indicating increasing agreement with the statement. The questionnaire also included a global QOL assessment. For this assessment, owners were asked to mark an X on a 10-cm-long line to indicate their dog's overall QOL, with the left-hand limit labeled 0 (very poor) and the right-hand limit labeled 100 (excellent).
The CHQLS was completed by owners at the time of study enrollment (ie, day 0), 1 and 2 weeks after starting the prednisone protocol, and every 4 weeks thereafter. Because dogs were not required to return for repeated clinical examinations after study enrollment, owners were given the opportunity to complete follow-up CHQLSs electronically (ie, via email or fax) or verbally (ie, by telephone) or in a written paper format. After dogs enrolled in the study died or were euthanized, owners were asked to complete a final cancer treatment survey. The final cancer treatment survey consisted of 2 questions: the number of days prior to death or euthanasia that QOL was not acceptable and primary reason for euthanasia (eg, declining QOL, prednisone-related adverse effects, or financial considerations), with the question on primary reason for euthanasia presented as a multiple-choice question with an option for free-form responses.
Statistical analysis
All dogs with confirmed intermediate- or large-cell lymphoma were evaluated on an intent-to-treat basis. For the day 14 QOL analysis, dogs that died before assessment on day 14 were assigned a QOL score of 0. Survival time was defined as time from the first dose of prednisone until death or euthanasia (regardless of cause). Dogs still alive at the end of the study, dogs lost to follow-up, and dogs removed from the study (eg, withdrawn because of owner preference or because of initiating chemotherapy) were included in analyses until the last day follow-up information was collected, and then those dogs were censored.
Survival functions were calculated with the Kaplan-Meier product-limit method. The 95% CI was determined for survival time. Next, the importance of factors potentially associated with survival time was evaluated. Factors included substage (a vs b), immunophenotype (B cell vs T cell), and duration of clinical signs before enrollment (≤ 2 weeks vs > 2 weeks and ≤ 4 weeks vs > 4 weeks). The Kaplan-Meier product-limit method was used to estimate survival curves for each potential risk factor, and the Gehan-Breslow-Wilcoxon test was used to compare survival curves. This test was chosen over the log-rank test because it gives more weight to deaths at early time points, and it was expected that most patients would have relatively short survival times.
For owners’ global QOL assessments, a global QOL score from 0 to 100 was assigned by measuring from the left-hand limit to where the owner had placed a mark on the line. The Spearman rank correlation method was then used to determine whether scores assigned on day 0 or day 14 were associated with survival times. The QOL scores were subsequently dichotomized at the middle of the scale (< 50 and ≥ 50), and for both day 0 and day 14 scores, survival curves were compared with the Gehan-Breslow-Wilcoxon test. The relationship between having a QOL score < 50 or ≥ 50 on day 0 versus day 14 was evaluated with the Fisher exact test. The impact of day 0 and day 14 QOL scores on long-term survival, defined as survival > 120 days, was assessed with the Wilcoxon rank sum test.
For all tests, a 2-sided value of P < 0.05 was considered significant. All calculations were made with a computer software program.j
Results
Dogs
Between April 2016 and September 2017, 841 dogs with suspected or confirmed lymphoma were evaluated by the 16 investigators participating in the study. Seven hundred twenty-nine dogs were not enrolled for the following reasons: owners of 496 dogs elected to start chemotherapy, 122 dogs had confirmed or presumed involvement of excluded anatomic sites, 39 dogs were already receiving corticosteroids, owners of 32 dogs elected prednisone treatment but declined to participate in the study, owners of 29 dogs declined all treatments, and 11 dogs had an anticipated survival time of < 3 days. The remaining 112 dogs were tentatively enrolled in the study. However, during review of peripheral lymph node cytologic specimens, 3 of these dogs were excluded owing to inadequate sample cellularity or quality. The remaining 109 dogs met all criteria for enrollment and were included in the study.
Clinical findings
Median age of the 109 dogs included in the study was 8 years (range, 3 to 17 years), and median body weight was 26.8 kg (59 lb; range, 1.8 to 55.2 kg [4 to 121.4 lb]). There were 43 mixed-breed dogs, 8 Golden Retrievers, 8 Boxers, 5 Labrador Retrievers, and 5 German Shepherd Dogs. The remaining 40 dogs represented 27 other breeds with ≤ 4 dogs each. There were 59 (54%) males (54 castrated) and 50 (46%) females (48 spayed). According to the owners, clinical signs of lymph node enlargement, illness, or both were present for ≤ 2 weeks in 51 dogs, 2 to 4 weeks in 37 dogs, > 4 to 8 weeks in 8 dogs, > 8 to 12 weeks in 7 dogs, and > 12 weeks in 2 dogs before enrollment in the study. Duration of clinical signs was missing for 4 dogs. A complete diagnostic workup for staging was not required for enrollment, but on the basis of physical examination results, World Health Organization stage was at least stage II (enlargement of regional peripheral lymph nodes) for 6 dogs, stage III (generalized enlargement of the peripheral lymph nodes) for 52 dogs, stage IV (involvement of the liver, spleen, or both) for 46 dogs, and stage V (involvement of blood, bone marrow, or other organs) for 4 dogs. Staging information was not available for 1 dog. On the basis of clinician assessment, 62 (57%) dogs were classified as substage a at the time of enrollment, and 46 (42%) were classified as substage b. Substage information was missing for 1 dog. Of the dogs classified as sub-stage b, 43 had gastrointestinal signs, 5 had dyspnea, and 7 had hypercalcemia (some dogs had > 1 clinical sign). Median global QOL score for the dogs on day 0, as assessed by the owners with the visual analog scale on the CHQLS, was 74 (range, 0 to 100).
Cytologic findings
Cytologically, lymphoma cell size was intermediate to large in 9 dogs and large in 100 dogs. Immunophenotype was available for 108 of the 109 dogs; 88 (81%) had B-cell lymphoma, and 20 (19%) had T-cell lymphoma. One dog with cytologically confirmed stage III large-cell lymphoma was immuno-negative for both CD3 and Pax5. A PCR assay for antigen receptor rearrangement was performed with smears collected via fine-needle aspiration from an enlarged peripheral lymph node but did not confirm the presence of a clonal population of lymphocytes. One other dog with cytologically confirmed stage IV large-cell lymphoma was also immunonegative on immunocytochemical staining. However, the PCR assay for antigen receptor rearrangement with a B-cell primer amplicon showed a clonal band consistent with B-cell lymphoma.
Outcome
All dogs started prednisone treatment as planned. However, the prednisone dose or frequency of administration was decreased for 4 dogs because of adverse effects reported by the owners 13 to 119 days (median, 32 days) after treatment was started. Prednisone dose was increased in 25 dogs 10 to 122 days (median, 31 days) after treatment was started. Most often, owners perceived QOL to be better when their pets were receiving the initial higher prednisone dosage (40 mg/m2/d), compared with the lower maintenance dosage (20 mg/m2/d).
Median overall survival time for all dogs in the study was 50 days (95% CI, 41 to 59 days; range 3 to 660 days; Figure 1). One hundred seven (98%) dogs died (12/107) or were euthanized (95/107). Two (2%) dogs were censored, one at 306 days and the other at 660 days, because they were still alive at the time of analysis. Estimated probabilities that dogs would be alive 2, 4, and 6 months after starting prednisone treatment were 41%, 16%, and 7%, respectively.
Kaplan-Meier curve of survival time for 109 dogs with previously untreated, peripheral nodal, intermediate- or large-cell lymphoma treated with a standardized protocol of prednisone as a single agent. Median overall survival time was 50 days (95% CI, 41 to 59 days). Circles represent censored data.
Citation: Journal of the American Veterinary Medical Association 259, 1; 10.2460/javma.259.1.62
Declining QOL attributable to lymphoma was the most commonly reported reason for electing euthanasia (90/95 [95%]); 4 of 95 (4%) dogs were euthanized for likely nonlymphoma conditions (congestive heart failure, severe chronic diarrhea, tooth root abscess, and unknown cause), and 1 (1%) owner reported adverse effects of prednisone as a reason for euthanasia. Median QOL score for dogs at the time of euthanasia was 5 (range, 0 to 80). Owners reported QOL was not acceptable for 0 to 10 days (median, 3 days) before electing euthanasia.
Substage assigned by the clinician at the time of enrollment (day 0) was significantly (P = 0.005) associated with survival time. Median survival time was significantly (P = 0.005) longer for the 62 dogs with substage a (median, 60 days; 95% CI, 47 to 72 days) than for the 46 dogs with substage b (median, 36 days; 95% CI, 21 to 49 days; Figure 2). The QOL score on day 0, as assessed by the owner, was significantly positively correlated with survival time (r = 0.43; P < 0.001; Figure 3). The 78 dogs with a day 0 QOL score ≥ 50 had a significantly (P < 0.001) longer survival time (median, 60 days; 95% CI, 48 to 70 days) than did the 27 dogs with a day 0 QOL score < 50 (median, 26 days; 95% CI, 7 to 43 days; Figure 4). Day 14 QOL score was also significantly positively correlated with survival time (r = 0.37; P < 0.001). The 80 dogs with a day 14 QOL score ≥ 50 had a significantly (P < 0.001) longer survival time (median, 64 days; 95% CI, 53 to 74 days) than did the 19 dogs with a day 14 QOL score < 50 (median, 13 days; 95% CI, 0 to 33 days). Dogs with a QOL score < 50 on day 0 were significantly (P < 0.001) more likely to have a QOL score < 50 on day 14 (relative risk, 3.85) than were dogs with a QOL score ≥ 50 on day 0. Immunophenotype was significantly (P = 0.009) associated with survival time. Median survival time for the 20 dogs with T-cell lymphoma was 90 days (95% CI, 67 to 109 days), compared with 39 days (95% CI, 28 to 49 days) for the 88 dogs with B-cell lymphoma (Figure 5). Duration of clinical signs prior to study enrollment was not significantly associated with survival time (Table 1).
Kaplan-Meier curves of survival time for the dogs in Figure 1 grouped as substage a (no clinical signs; n = 62; dashed line) or substage b (gastrointestinal signs, respiratory signs, hypercalcemia, fever, hyphema, or uveitis; n = 46; solid line). Information on substage was not available for 1 dog. Survival time for dogs classified as substage a (median, 60 days; 95% CI, 47 to 72 days) was significantly (P = 0.005) longer than survival time for dogs classified as substage b (median, 36 days; 95% CI, 21 to 49 days). Circles represent censored data.
Citation: Journal of the American Veterinary Medical Association 259, 1; 10.2460/javma.259.1.62
Scatterplot of global QOL scores (range, 0 to 100) assigned with a visual analog scale by the owners of dogs in Figure 1 on the day of study enrollment (day 0) versus survival time. There was a significant (r = 0.43; P < 0.001) positive correlation between day 0 QOL score and survival time.
Citation: Journal of the American Veterinary Medical Association 259, 1; 10.2460/javma.259.1.62
Kaplan-Meier curves of survival time for the dogs in Figure 1 grouped on the basis of an owner-assigned global QOL score ≥ 50 (n = 78; solid line) or < 50 (27; dashed line) on the day prednisone treatment was started (ie, day 0). Circles represent censored data.
Citation: Journal of the American Veterinary Medical Association 259, 1; 10.2460/javma.259.1.62
Kaplan-Meier curves of survival time for the dogs in Figure 1 grouped on the basis of immunophenotype as having B-cell lymphoma (n = 88; solid line) or T-cell lymphoma (20; dashed line). Circles represent censored data.
Citation: Journal of the American Veterinary Medical Association 259, 1; 10.2460/javma.259.1.62
Results of univariable analysis of factors potentially associated with survival time for 109 dogs with previously untreated, peripheral nodal, intermediate-or large-cell lymphoma treated with a standardized protocol of prednisone as a single agent.
| Variable | Survival time (d) | |||
|---|---|---|---|---|
| No. of dogs | Median | 95% CI | P value | |
| Substage* | 0.005 | |||
| a | 62 | 60 | 47-72 | |
| b | 46 | 36 | 21-49 | |
| Day 0 QOL score† | < 0.001 | |||
| < 50 | 27 | 26 | 7-43 | |
| > 50 | 78 | 60 | 48-70 | |
| Day 14 QOL score† | < 0.001 | |||
| < 50 | 19 | 13 | 0-33 | |
| > 50 | 80 | 64 | 53-74 | |
| Immunophenotype‡ | 0.009 | |||
| B cell | 88 | 39 | 28-49 | |
| T cell | 20 | 90 | 67-109 | |
| Duration of clinical signs§ | 0.97 | |||
| < 2 wk | 51 | 50 | 36-63 | |
| > 2 wk | 54 | 51 | 37-63 | |
| Duration of clinical signs§ | 0.11 | |||
| < 4 wk | 88 | 40 | 30-50 | |
| > 4 wk | 17 | 74 | 50-95 | |
Substage was assigned by the attending veterinarian at the time of study enrollment as substage a (no clinical signs) or substage b (gastrointestinal signs, respiratory signs, hypercalcemia, fever, hyphema, or uveitis); information on substage was not available for 1 dog.
A global QOL score was assigned by owners using a visual analog scale (range of potential scores, 0 to 100).
Immunophenotype could not be determined for 1 dog.
Information on duration of clinical signs was missing for 4 dogs.
We attempted to identify variables that might predict long-term survival (ie, survival > 120 days after starting prednisone treatment); however, clinical and cytopathologic factors seemed inconsistent among dogs surviving > 120 days. Long-term survivors did have significantly (P = 0.027) higher day 0 QOL scores (median, 89; interquartile [25th to 75th percentile] range, 68 to 100), compared with scores for dogs that survived ≤ 120 days (median, 72; interquartile range, 47 to 94), but there was substantial overlap between groups. Long-term survivors also had significantly (P = 0.045) higher day 14 QOL scores (median, 84; interquartile range, 74 to 93), compared with scores for dogs that survived ≤ 120 days (median, 76; interquartile range, 52 to 90), but there was similar substantial overlap between groups.
Discussion
In the present study, median survival time was 50 days for dogs with previously untreated, peripheral nodal, cytologically confirmed, intermediate- or large-cell lymphoma treated only with prednisone. Although long-term survival (ie, survival > 120 days) was possible, the probability that dogs would be alive 6 months after starting prednisone treatment was only 7%. To our knowledge, the present study represented the largest prospective study to evaluate outcome of dogs with lymphoma treated only with corticosteroids. However, our findings were consistent with anecdotal information published in textbooks and small case series.4,26,27,30–33
Notably, results of the present study might not be applicable to dogs with other less common anatomic forms of lymphoma such as those involving the gastrointestinal tract, skin, or nervous system. Also, we excluded dogs with an anticipated survival time of < 3 days; therefore, our findings do not provide information on the use of corticosteroids in emergency or critical situations.
There were a number of other important limitations to the present study. Staging tests were not required for inclusion in the study. Because 46 of 108 (43%) dogs were categorized as substage b, mostly because of gastrointestinal signs, incomplete staging might have led to the inclusion of some dogs with gastrointestinal lymphoma. Historically, dogs with gastrointestinal lymphoma generally perform poorly when treated with chemotherapy, and a similar lack of benefit could exist for corticosteroids alone.34
The lack of a control population that did not receive any treatment was an important limitation of the present study. Because of this lack of a control population and the lack of dogs receiving other treatments, our results do not provide information on results that can be expected for dogs that do not receive any treatment or for dogs that receive other treatments for canine lymphoma.
Perhaps the most important limitation of the present study was that the diagnosis was not confirmed by means of histologic examination. Most lymphomas in dogs are diffuse, intermediate- or large-cell lymphomas, and cytologic examination of these types of lymphomas is often adequate for diagnosis.35 None of the dogs in the present study had cytologic findings consistent with small-cell or low-grade lymphoma. Nevertheless, lymphoma in dogs is an extremely heterogeneous disease encompassing a number of subtypes with differing malignancy,36,37 and for both B-cell and T-cell lymphoma, the various subtypes show significant discrepancies in biological behavior. In the present study, median survival times for dogs with either B-cell (median, 39 days; 95% CI, 28 to 49 days) or T-cell (median, 90 days; 95% CI, 67 to 109 days) lymphoma were relatively short, suggesting tumors had subtypes with more aggressive biological behavior. The duration of clinical signs before the diagnosis of lymphoma was made was not associated with survival time, and estimated 6-month survival probability was only 7%, suggesting that dogs with small-cell or low-grade lymphoma were not included. Still, some dogs with low-grade T-cell lymphoma could have been included, and these dogs might have had prolonged survival times as a result of the natural course of their disease, rather than a result of treatment.3 Histologic examination could have provided classification and architectural information. But, ultimately, the PCR assay for antigen receptor rearrangement, flow cytometry, gene expression profile analysis, and analysis of other biomarkers would have been ideal to best characterize the population in the present study.37
The primary outcome of interest in the present study was survival time, and we did not examine the response or remission rate. The Veterinary Cooperative Oncology Group discourages reporting survival time or response rate when reporting the outcome of dogs with peripheral nodal lymphoma because of confounding variables such as subjective variation in tumor measurements, owners’ willingness to pursue additional treatments, and owner influence on timing of euthanasia.38 Instead, progression-free survival time calculated on the basis of tumor measurements during serial examinations has been suggested to allow consistent comparisons between chemotherapy protocols. However, we do not believe these recommendations are applicable to our study. Our goal was to determine survival time for a population of dogs that would not necessarily be reexamined for repeated measurements, similar to what is routinely done in practice when owners decline treatment beyond prednisone. We believe this was a robust, clinically relevant objective.
In the present study, global QOL score, as assessed by dog owners, was positively correlated with survival time. The CHQLS we used included scoring for 7 domains, 2 general health questions, and a global QOL question measured on a visual analog scale. For the study reported here, we chose to examine only whether the global QOL score (scored on a scale from 0 to 100) was associated with survival time. Lavan39 has suggested that a single overarching QOL assessment posed to owners can by itself accurately reflect the QOL of dogs. In a recent study by Giuffrida et al,40 the Canine Owner-Reported QOL Questionnaire and its factors (vitality, companionship, pain, and mobility) had moderate to strong correlations with global QOL scores measured on a visual analog scale (r = 0.49 to 0.71). Visual assessment scales have also been used in other studies to examine owner perceptions of their pet's QOL following bilateral enucleation,41 parotid duct transposition,42 cranial cruciate ligament repair,43 chemotherapy for pulmonary carcinoma,44 and electrochemotherapy or gene therapy for various tumors.45 Similar to our findings in dogs, QOL at diagnosis is predictive of overall survival time for people with aggressive lymphoma.46 In that study,46 people with a QOL score ≤ 50 at baseline had shorter survival times than did people with a QOL score > 50 at baseline (92 vs 121 months).
In addition to owner-assigned QOL scores on days 0 and 14, we assessed whether clinician-assigned sub-stage was associated with survival time. Substage b has been shown to be a strong negative prognostic factor for dogs with lymphoma treated with chemo-therapy,10,17 but a lack of established criteria for assigning clinical substage has resulted in potential ambiguity, as emphasized in a 2014 survey.47 The visual analog scale used to measure global QOL in our study was simple and might be helpful when discussing expectations with owners of dogs with lymphoma who are considering treatment with only prednisone. It is worth noting that 3 of the 4 factors significantly associated with patient survival time in the present study were manifestations of patient QOL, and it is not possible to determine which of these factors, if any, was most important. However, the fact that most patients in the present study were euthanized emphasized the importance of owner-perceived QOL in the euthanasia decision-making process.
Along with substage, T-cell immunophenotype has previously been shown to be a strong negative prognostic factor in dogs with lymphoma undergoing chemotherapy.48,49 In the present study, immunophe-notype was predictive of survival time, but in contrast, dogs with the T-cell phenotype survived longer than did dogs with the B-cell phenotype. This difference could have been due to a lack of statistical power owing to the relatively small number of dogs with T-cell lymphoma. A previously unrecognized clinical benefit of corticosteroids in dogs with T-cell lymphoma treated with prednisone alone, without cytotoxic chemotherapeutics, could have also been a factor. Greater suppression of the blastogenic response to T-cell mitogens than to B-cell mitogens has been demonstrated, implying that T cells may be more sensitive to the effects of corticosteroids.50 Finally, it is possible that some dogs with low-grade disease were included in the group of dogs with T-cell lymphoma, resulting in longer survival times. However, in the present study, survival times for dogs with T-cell lymphoma (median, 90 days; 95% CI, 67 to 109 days) were relatively short, compared with what would be expected for dogs with low-grade disease,18 and none of the dogs had cytologic findings suggestive of low-grade disease.
Owing to the design of the present study, which did not include determination of response rate or involve repeated lymph node measurements, we do not have a firm understanding of the specific effect or effects prednisone might have been having on these dogs. Prednisone effects might include a lymphocytolytic benefit or mitigation of clinical signs. In vitro, prednisone has dose-dependent inhibitory effects on the proliferation of various canine lymphoid malignancies.51 Compared with common chemotherapeutics such as vincristine, cyclophosphamide, and doxorubicin, however, corticosteroids exhibited the least activity.51 The biological actions of glucocorticoids are mediated by glucocorticoid receptors, and a previous study25 found that lower numbers of glucocorticoid receptors per cell contributed to a poorer treatment response in neoplastic lymphoid cells. Recently, prednisone resistance was found to be associated with decreased glucocorticoid NR3C1α gene expression in biopsy specimens obtained from dogs with high-grade lymphoma after treatment with prednisone was started.52 Interestingly, in that study,52 clinical resistance to prednisone was observed a median of 68 days after initiation of prednisone treatment,52 which was similar to the median survival time for dogs in the present study.
The standardized prednisone dosage used in the present study was based on the experience of the investigators rather than on data collected in controlled clinical studies. Discrepancies in corticosteroid dosages used in regimens to treat lymphomas in people are common.53 The use of a different prednisone dosage in the present study might have yielded different results, and future studies addressing prednisone dosage can be considered. Toxicoses related to prednisone were rarely reported by owners in the present study, and the prednisone dosage was reduced because of perceived adverse effects in only 4 dogs. Nonetheless, our results suggested that survival time for dogs with lymphoma treated with prednisone alone would be relatively brief, so consideration should be given to tapering the dosage when the benefit seems marginal or toxicoses seems to outweigh benefit.
Most veterinary oncologists consider chemo-therapy protocols incorporating cyclophosphamide, doxorubicin, vincristine, and prednisone to be the standard of care for the treatment of dogs with lymphoma. Use of prednisone as a single agent has potential advantages for clients that decline chemo-therapy, including low cost, no risk of myelosuppression, and ease of oral administration. However, treatment with prednisone prior to initiating cytotoxic chemotherapy has been reported to have negative effects on remission rate and survival time,18,54,55 al though why this might be the case is not completely understood.52,56,57 Nevertheless, the potential negative effects of starting treatment with prednisone alone prior to starting cytotoxic chemotherapy should be discussed with owners at the time treatment decisions are being made.
In conclusion, results of the present study suggested that survival times are brief for dogs with previously untreated, peripheral nodal, intermediate- or large-cell lymphoma treated with prednisone alone. A poor QOL related to the underlying disease, not to the prednisone treatment, was most often cited by owners as the reason for electing euthanasia. Nevertheless, there is growing acceptance that a treatment can be valuable if it improves patients’ subjective well-being, even if it does not meaningfully impact other outcomes used to quantify success in cancer therapy, such as overall survival time.40 Findings of the present study may help clinicians when discussing potential treatment with owners of dogs with lymphoma.
Acknowledgments
Funded by Merial and the Iowa State University College of Veterinary Medicine.
Dr. Johannes has been a paid consultant and speaker for Elanco and QBiotics. The remaining authors declare that they had no conflicts of interest.
Presented in part at the Veterinary Cancer Society Annual Conference, Portland, Ore, October 2017.
The authors thank Drs. Mary Davis, Carrie DeRegis, John Chretin, Shawna Greene, Michael Lucroy, and Sarah Gillings for contributing case data and thank Dr. Leslie Fox for assistance in the institutional animal care and use committee approval process.
Footnotes
Tanovea-CA1, Elanco, Greenfield, Ind.
Shandon ColorFrost Plus microscope slides, Thermo Fisher Scientific, Waltham, Mass.
Bond automated stainer, Leica Biosystems, Buffalo Grove, Ill.
LN10, PA0122, mouse monoclonal, Leica Biosystems, Buffalo Grove, Ill.
IEW, PA0552, mouse monoclonal, Leica Biosystems, Buffalo Grove, Ill.
PowerVision Poly-HRP anti-mouse IgG, PV6114, Leica Biosystems, Buffalo Grove, Ill.
PowerVision Poly-AP anti-mouse IgG, PV6110, Leica Biosystems, Buffalo Grove, Ill.
PA0996, Leica Biosystems, Buffalo Grove, Ill.
Prednisone, HIKMA Pharmaceuticals, Amman, Jordan. Distributed by West-Ward Pharmaceuticals, Eatontown, NJ.
Prism 5, GraphPad Software, San Diego, Calif.
Abbreviations
| CHQLS | Canine health quality-of-life survey |
| QOL | Quality of life |
References
- 1. ↑
Valli VE, Kass PH, San Myint M, et al. Canine lymphomas: association of classification type, disease stage, tumor sub-type, mitotic rate, and treatment with survival. Vet Pathol 2013;50:738–748.
- 2.
Martini V, Marconato L, Poggi A, et al. Canine small clear cell/T-zone lymphoma: clinical presentation and outcome in a retrospective case series. Vet Comp Oncol 2016;14(suppl 1):117–126.
- 3. ↑
Flood-Knapik KE, Durham AC, Gregor TP, et al. Clinical, histopathological and immunohistochemical characterization of canine indolent lymphoma. Vet Comp Oncol 2013;11:272–286.
- 4. ↑
Brick JO, Roenigk WJ, Wilson GP. Chemotherapy of malignant lymphoma in dogs and cats. J Am Vet Med Assoc 1968;153:47–52.
- 6. ↑
Regan RC, Kaplan MS, Bailey DB. Diagnostic evaluation and treatment recommendations for dogs with substage-a high-grade multicentric lymphoma: results of a survey of veterinarians. Vet Comp Oncol 2013;11:287–295.
- 7. ↑
Frimberger AE, Moore AS, Rassnick KM, et al. A combination chemotherapy protocol with dose intensification and autologous bone marrow transplant (VELCAP-HDC) for canine lymphoma. J Vet Intern Med 2006;20:355–364.
- 8.
Willcox JL, Pruitt A, Suter SE. Autologous peripheral blood hematopoietic cell transplantation in dogs with B-cell lymphoma. J Vet Intern Med 2012;26:1155–1163.
- 9. ↑
Warry EE, Willcox JL, Suter SE. Autologous peripheral blood hematopoietic cell transplantation in dogs with T-cell lymphoma. J Vet Intern Med 2014;28:529–537.
- 10. ↑
Chun R, Garrett LD, Vail DM. Evaluation of a high-dose chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med 2000;14:120–124.
- 11.
Sorenmo K, Overley B, Krick E, et al. Outcome and toxicity associated with a dose-intensified, maintenance-free CHOP-based chemotherapy protocol in canine lymphoma: 130 cases. Vet Comp Oncol 2010;8:196–208.
- 12. ↑
Burton JH, Garrett-Mayer E, Thamm DH. Evaluation of a 15-week CHOP protocol for the treatment of canine multicentric lymphoma. Vet Comp Oncol 2013;11:306–315.
- 13. ↑
Rassnick KM, McEntee MC, Erb HN, et al. Comparison of 3 protocols for treatment after induction of remission in dogs with lymphoma. J Vet Intern Med 2007;21:1364–1373.
- 14. ↑
Williams LE, Johnson JL, Hauck ML, et al. Chemotherapy followed by half-body radiation therapy for canine lymphoma. J Vet Intern Med 2004;18:703–709.
- 15. ↑
Regan D, Guth A, Coy J, et al. Cancer immunotherapy in veterinary medicine: current options and new developments. Vet J 2016;207:20–28.
- 16. ↑
Thamm DH, Vail DM, Post GS, et al. Alternating rabacfosa-dine/doxorubicin: efficacy and tolerability in naive canine multicentric lymphoma. J Vet Intern Med 2017;31:872–878.
- 17. ↑
Garrett LD, Thamm DH, Chun R, et al. Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogs with lymphoma. J Vet Intern Med 2002;16:704– 709.
- 18. ↑
Marconato L, Stefanello D, Valenti P, et al. Predictors of long-term survival in dogs with high-grade multicentric lymphoma. J Am Vet Med Assoc 2011;238:480–485.
- 19. ↑
Brønden LB, Rutteman GR, Flagstad A, et al. Study of dog and cat owners’ perceptions of medical treatment for cancer. Vet Rec 2003;152:77–80.
- 20. ↑
Mellanby RJ, Herrtage ME, Dobson JM. Owners’ assessments of their dog's quality of life during palliative chemotherapy for lymphoma. J Small Anim Pract 2003;44:100–103.
- 21. ↑
Burns K. Pet health insurance helping more pet owners afford optimal care. J Am Vet Med Assoc 2014;244:1348–1353.
- 22. ↑
Williams J, Phillips C, Byrd HM. Factors which influence owners when deciding to use chemotherapy in terminally ill pets. Animals (Basel) 2017;7:18.
- 23. ↑
Distelhorst CW. Recent insights into the mechanism of glucocorticosteroid-induced apoptosis. Cell Death Differ 2002;9:6–19.
- 24. ↑
Greenstein S, Ghias K, Krett NL, et al. Mechanisms of glucocorticoid-mediated apoptosis in hematological malignancies. Clin Cancer Res 2002;8:1681–1694.
- 25. ↑
Matsuda A, Tanaka A, Muto S, et al. A novel NF-kappaB inhibitor improves glucocorticoid sensitivity of canine neoplastic lymphoid cells by up-regulating expression of glucocorticoid receptors. Res Vet Sci 2010;89:378–382.
- 26. ↑
Squire RA, Bush M, Melby EC, et al. Clinical and pathologic study of canine lymphoma: clinical staging, cell classification, and therapy. J Natl Cancer Inst 1973;51:565–574.
- 27. ↑
Bell R, Cotter S, Lillquist A, et al. Characterization of glucocorticoid receptors in animal lymphoblastic disease: correlation with response to single-agent glucocorticoid treatment. Blood 1984;63:380–383.
- 28. ↑
Raskin RE. Hemolymphatic system. In: Raskin RE, Meyer DJ, eds. Canine and feline cytology. 3rd ed. St Louis: Elsevier, 2016;91–137.
- 29. ↑
Lynch S, Savary-Bataille K, Leeuw B, et al. Development of a questionnaire assessing health-related quality-of-life in dogs and cats with cancer. Vet Comp Oncol 2011;9:172–182.
- 30. ↑
Moore AS, Frimberger AE. Usefulness of chemotherapy for the treatment of very elderly dogs with multicentric lymphoma. J Am Vet Med Assoc 2018;252:852–859.
- 31.
MacEwen EG, Patnaik AK, Wilkins RJ. Diagnosis and treatment of canine hematopoietic neoplasms. Vet Clin North Am 1977;7:105–118.
- 32.
Vail DM, Pinkerton M, Young KM. Canine lymphoma and lymphocytic leukemias. In: Vail DM, Thamm D, Liptak J, eds. Withrow and MacEwen's small animal clinical oncology. 6th ed. St Louis: Elsevier, 2019;688–714.
- 33. ↑
Vail DM. Hematopoietic tumors. In: Ettinger SJ, Feldman EC, Cote E, eds. Textbook of veterinary internal medicine expert consult. 8th ed. St Louis: Elsevier, 2017;2065–2077.
- 34. ↑
Rassnick KM, Moore AS, Collister KE, et al. Efficacy of combination chemotherapy for treatment of gastrointestinal lymphoma in dogs. J Vet Intern Med 2009;23:317–322.
- 35. ↑
Ponce F, Marchal T, Magnol JP, et al. A morphological study of 608 cases of canine malignant lymphoma in France with a focus on comparative similarities between canine and human lymphoma morphology. Vet Pathol 2010;47:414–433.
- 36. ↑
Sayag D, Fournel-Fleury C, Ponce F. Prognostic significance of morphotypes in canine lymphomas: a systematic review of literature. Vet Comp Oncol 2018;16:12–19.
- 37. ↑
Aresu L. Canine lymphoma, more than a morphological diagnosis: what we have learned about diffuse large B-cell lymphoma. Front Vet Sci 2016;3:77.
- 38. ↑
Vail DM, Michels GM, Khanna C, et al. Response evaluation criteria for peripheral nodal lymphoma in dogs (v1.0)—a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet Comp Oncol 2010;8:28–37.
- 39. ↑
Lavan RP. Development and validation of a survey for quality of life assessment by owners of healthy dogs. Vet J 2013;197:578–582.
- 40. ↑
Giuffrida MA, Cimino Brown D, Ellenberg SS, et al. Development and psychometric testing of the Canine Owner-Reported Quality of Life questionnaire, an instrument designed to measure quality of life in dogs with cancer. J Am Vet Med Assoc 2018;252:1073–1083.
- 41. ↑
Hamzianpour N, Smith K, Dawson C, et al. Bilateral enucleation in dogs: a review of owner perceptions and satisfaction. Vet Ophthalmol 2019;22:566–576.
- 42. ↑
Rhodes M, Heinrich C, Featherstone H, et al. Parotid duct transposition in dogs: a retrospective review of 92 eyes from 1999 to 2009. Vet Ophthalmol 2012;15:213–222.
- 43. ↑
Innes JF, Bacon D, Lynch C, et al. Long-term outcome of surgery for dogs with cranial cruciate ligament deficiency. Vet Rec 2000;147:325–328.
- 44. ↑
Polton G, Finotello R, Sabattini S, et al. Survival analysis of dogs with advanced primary lung carcinoma treated by metronomic cyclophosphamide, piroxicam and thalidomide. Vet Comp Oncol 2018;16:399–408.
- 45. ↑
Milevoj N, Tozon N, Licen S, et al. Health-related quality of life in dogs treated with electrochemotherapy and/or inter-leukin-12 gene electrotransfer. Vet Med Sci 2020;6:290–298.
- 46. ↑
Thompson CA, Yost KJ, Maurer MJ, et al. Quality of life at diagnosis predicts overall survival in patients with aggressive lymphoma. Hematol Oncol 2018;36:749–756.
- 47. ↑
Barber LG, Weishaar KM. Criteria for designation of clinical substage in canine lymphoma: a survey of veterinary oncologists. Vet Comp Oncol 2016;14(suppl 1):32–39.
- 48. ↑
Brodsky EM, Maudlin GN, Lachowicz JL, et al. Asparaginase and MOPP treatment of dogs with lymphoma. J Vet Intern Med 2009;23:578–584.
- 49. ↑
Rebhun RB, Kent MS, Borrofka SA, et al. CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma. Vet Comp Oncol 2011;9:38–44.
- 50. ↑
Cohn LA. The influence of corticosteroids on host defense mechanisms. J Vet Intern Med 1991;5:95–104.
- 51. ↑
Pawlak A, Rapak A, Zbyryt I, et al. The effect of common antineoplastic agents on induction of apoptosis in canine lymphoma and leukemia cell lines. In Vivo 2014;28:843–850.
- 52. ↑
Hanot CC, Mealey KL, Fidel JL, et al. Development of prednisone resistance in naive canine lymphoma: longitudinal evaluation of NR3C1alpha, ABCB1, and 11beta-HSD mRNA expression. J Vet Pharmacol Ther 2020;43:231–236.
- 53. ↑
Moreno A, Colon-Otero G, Solberg LA Jr. The prednisone dosage in the CHOP chemotherapy regimen for non-Hodgkin's lymphomas (NHL): is there a standard? Oncologist 2000;5:238–249.
- 54. ↑
Price GS, Page RL, Fischer BM, et al. Efficacy and toxicity of doxorubicin/cyclophosphamide maintenance therapy in dogs with multicentric lymphosarcoma. J Vet Intern Med 1991;5:259–262.
- 55. ↑
Dobson JM, Gorman NT. Canine multicentric lymphoma 2: comparison of response to two chemotherapeutic protocols. J Small Anim Pract 1994;35:9–15.
- 56. ↑
Schuetz JD, Silverman JA, Thottassery JV, et al. Divergent regulation of the class II P-glycoprotein gene in primary cultures of hepatocytes versus H35 hepatoma by glucocorticoids. Cell Growth Differ 1995;6:1321–1332.
- 57. ↑
Altuvia S, Stein WD, Goldenberg S, et al. Targeted disruption of the mouse mdr1b gene reveals that steroid hormones enhance mdr gene expression. J Biol Chem 1993;268:27127–27132.
