Do Palliative Steroids Prolong Survival in Dogs With Multicentric Lymphoma ?

PICO question In dogs with naturally occurring multicentric B cell lymphoma does treatment with glucocorticoids alone extend survival time when compared to no treatment? Clinical bottom line  There is weak evidence, due to insufficient studies with untreated control groups, regarding the impact on survival of prednisolone treatment in dogs with multicentric lymphoma. From the papers identified from the search functions used for the clinical question remission in uncontrolled trials was reported following prednisolone treatment. Details of which can be found in other sections of this paper.

Proportional hazards regression models were used to assess relative risk of death and reported as Hazard ratios (HR) and 95% Confidence

PICO question
In dogs with naturally occurring multicentric B cell lymphoma does treatment with glucocorticoids alone extend survival time when compared to no treatment?

Clinical bottom line
There is weak evidence, due to insufficient studies with untreated control groups, regarding the impact on survival of prednisolone treatment in dogs with multicentric lymphoma.
From the papers identified from the search functions used for the clinical question remission in uncontrolled trials was reported following prednisolone treatment.Details of which can be found in other sections of this paper.
Intervals (CI).The numbers of dogs in each treatment group (chemotherapy including hydroxydaunorubicin, chemotherapy without hydroxydaunorubicin, prednisone alone and no treatment) was not stated for any of the lymphoma types.
 High Grade T and B cell lymphoblastic lymphomas (n= 36) with possible prednisolone only treatment.States that there is no evidence that prednisolone alone is better than no treatment (HR 0.50; 95% CI, 0.064-3.90;p=0.51).Centroblastic B cell lymphomas (n= 186).Risk of death of dogs treated with prednisolone alone similar to that with no treatment (HR 1.65;95%CI, 0.56-4.87;p=0.36). Immunoblastic B cell lymphomas (n= 57).Prednisolone only therapy associated with poorer survival than chemotherapy (HR 47.22 CI95% 2.67-834.74p=0.009) but 0 dogs in this group were were in the no treatment group. This paper also compared treatment to histological grade of lymphoma.The numbers of dogs in this part of the analysis was not stated.Survival following the different treatments (chemotherapy including hydroxydaunorubicin, chemotherapy without hydroxydaunorubicin or prednisone alone) was compared to that of dogs that received no treatment. Low grade lymphomas (n=81) were treated with chemotherapy including hydroxydaunorubicin, chemotherapy without hydroxydaunorubicin , prednisone alone and no treatment however the numbers in each group were not stated.However those treated with prednisone only had increased risk of death (HR 40.576.8-242.09P <0.001) compared to dogs receiving no treatment. Intermediate grade lymphomas (n=242): dogs treated with prednisolone only (HR 1.920.68-5.39p = 0.22) showed no significant difference from those not treated.Dogs treated with chemotherapy including hydroxydaunorubicin or chemotherapy without hydroxydaunorubicin , showed a reduced risk of death  High grade lymphomas (n=103) treated with prednisolone only (HR 1.63 95% CI 0.53-5.03p=0.39) showed no significant difference compared to chemotherapy including hydroxydaunorubicin, chemotherapy without hydroxydaunorubicin and no treatment) was not stated.
Based on this study prednisone only showed no advantage over no treatment for dogs with diffuse large centroblastic B cell lymphoma.Across all grades of lymphoma (including some T cell lymphoma dogs) treatment with prednisolone alone increased the risk of death but this increase was only significant when compared to chemotherapy treatment with or without hydroxydaunorubicin and not when compared to the no treatment group.

Limitations:
 The paper is a retrospective study assessing a wide variety of aspects of dogs with histologically confirmed lymphoma.The following dosage regimes were used: Cyclophosphamide 0.3mg/kg/day for 14 days followed by 14 days with no treatment Prednisolone 0.5mg/kg/day for 14 days followed by 7 days without treatment and the schedule then repeated.Chlorambucil 0.2mg/kg/day for 14 days followed by 14 days without treatment and the schedule then repeated.Prednisolone 0.5mg/kg/day for 14 days followed by chlorambucil 0.2mg/kg/day for 14 days and the schedule then repeated.

Study design: Descriptive case series
Outcome studied: Objective -Survival time in weeks

Main findings: (relevant to PICO question):
 6 dogs were given no treatment and mean survival time was 2.5 weeks and disease was extensive in 4 of the dogs.However grade was not mentioned.
 Prednisolone regime was administered to 6 dogs however one of these also received radiotherapy on one occasion.Survival time ranged from 1-7.5 months with a mean of 2.5 months. Of the 6 dogs and 2 cats that received prednisolone alone only 7 had a temporary reduction in node size.

Limitations:
 The paper is a retrospective study but does not state how patients were identified or if any cases were excluded. Diagnosis was based on a combination of clinical signs (anorexia, depression, weight loss, anaemia and generalized lymphadenopathy) haematology results and a biopsy of tonsil or popliteal lymph node or bone marrow which would be acceptable assuming all patients had all three criteria assessed.This is not stated in the paper.Furthermore the paper does not state whether dogs had all or some of these symptoms and whether there was a difference in the presentation of dogs and cats. The paper does not specify the stage/sub stage of the cases reported except to state that the patients that had no treatment had widespread disease. Mean survival was reported rather than median which given the low numbers of cases is far from ideal. 1. Prednisone 2 mg/kg/day orally for 7 days followed by 1 mg/kg/day thereafter (n=49) 2. Prednisone as above plus cyclophosphamide 5 mg/kg/day orally for 7 days followed by 2.5 mg/kg thereafter (n=34) 3. Vincristine 0.03mg/kg intravenously on day 1 and 8.
Prednisone 2 mg/kg/day orally on days 1 and 8 followed by 1 mg/kg/day on days 9-21.Cyclophosphamide 5 mg/kg/day on days 15-21.6-mercaptopurine 5 mg/kg/day on days 15-21.Regime repeated every 30 days (n=25) Dogs that failed to respond to one regime were moved to treatment schedules 2 or 3 and then reported in that group

Study design: Non-randomised controlled trial
Outcome studied: Mean objective remission duration in days (number of days before regime failed to maintain complete remission (CR) or partial remission (PR) despite drug-induced toxicity.Survival measured as number of days from initial presentation until natural death or euthanasia in terminal disease.

Main findings: (relevant to PICO question):
 This study excluded 18 dogs that died or were euthanased due to advanced disease or an unsatisfactory response to therapy within 14 days of admission from the survival and remission duration data.
 Of the 49 dogs on prednisolone only 20 (41%) achieved complete remission with a mean objective remission time of 53 days (range 14-210 days).Remission induction rapid and usually reached its maximum at 7 days but was often partial within 72h.Partial remissions were not reported. In 34 dogs on schedule 2, 13 achieved complete remission with a mean objective remission time of 62 days (range 17-130 days).25 dogs had previously received prednisolone alone.7 that that had failed to achieve remission with prednisolone alone showed some sensitivity but the objective remission time is not stated.2 dogs failed to respond to schedule 2 despite achieving complete remission with prednisolone alone  In 19 dogs on schedule 3, 15 achieved complete remission with a mean objective remission time of 184 days (range 30-282 days).14 of these dogs had previously received prednisolone alone or schedule 2.  In 25 dogs on schedule 4, 19 achieved complete remission with a mean objective remission time of 136 days (range 18-300 days).None had received prior treatment  No severe side effects reported except in 1 dog which developed a gastric ulcer after several months of treatment. In several patients polyuria and polydipsia necessitated a reduction in dosage to 0.25-0.5 mg/kg/day. Increased appetite and mild signs of Cushing's syndrome were noted in several animals (number not stated)  9 dogs that failed to achieve remission on prednisolone alone were then treated with schedule 2. 7 of these dogs responded and 2 of these dogs failed to respond to schedule 2.  14 dogs that failed to respond to prednisolone alone or to schedule 2 were treated with schedule 3. Of these 12 achieved complete remission. Dogs on prednisolone alone were subsequently given chemotherapy if response was unsatisfactory or when refractoriness developed.

Limitations:
 Stage of lymphoma was defined as one of 4 stages (Stage 1 = one lymph node or one anatomic location  Stage 2 = involvement of multiple lymph nodes but limited to one side of the diaphragm  Stage 3 generalized involvement but limited to lymphoid tissue  Stage 4 involvement of any non-lymphoid tissue including viscera or blood or bone marrow nervous system etc.Viscera would normally be classed as stage 4 on the WHO system and the other areas would be as stage 5 on the WHO system Definition of Stage 3 in this study was generalised involvement but limited to lymphoid tissues i.e. lymph nodes, spleen, tonsils, thymus.In the current staging system this would be a group containing the survival times.However as there are no survival times given for this group we assume that most went onto get other treatments. Mean remission duration is provided rather than median.
Given the extremely wide range of 14-210 days this is far from ideal. No data on patients who did not get treatment as patients were recruited to be part of this study and given a treatment regime.

Appraisal, application and reflection
There is limited data on this topic with papers reporting findings in relatively small numbers of dogs.
Unfortunately the paper that most closely answers the clinical question (Mortier et al., 2012) was only available as an abstract and therefore could not be fully reviewed.This study suggested that dogs could achieve remission for up to 210 days on prednisolone alone (median of 32 days).This is similar to the findings of Brick et al. (1968) and their reported survival times of 1-7.5 months with a cyclical administration of prednisolone (0.5 mg/kg/day for 14 days followed by 7 days without treatment and with a schedule repeat).Squire et al. (1973) also reported remission times of 14-210 days with administration of 2 mg/kg/d for 7 days, then 1 mg/kg/d thereafter in 20 dogs (41%) who achieved remission for a mean of 53 days (range 14-210 days).In the latter paper they excluded patients who failed to survive 14 days so their median remission time is likely to be lower than their reported mean suggests.In addition

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 As this was a retrospective study, patients were allocated to a particular treatment option based on clinician and owners preference.It is not clear from the paper if cases from particular practices or regions had differing treatment regimes.There is no reporting of the dose of prednisolone used for the prednisolone alone group or any reporting of the chemotherapy doses used.Similarlythere is no reporting of the numbers of dogs in each treatment group within each category.This reflects the focus on survival for the group as a whole rather than in respect of differing treatment regimes.2.Tozon (2006) Population: Dogs with lymphoma diagnosed by cytology Sample size: 39 dogs Intervention details: 13 dogs on differing chemotherapy regimes: COP protocol (n=6), COPA protocol (n=4) doxorubicin (n=2) and methylprednisolone (n=1).Drug doses and duration were not stated Study design: Descriptive case series Outcome studied: Occurrence of different cyto-morphological diagnoses and how sex, clinical stage and treatment choice affects first remission time (days) and survival time (days) of patients undergoing differing regimes of treatment.Veterinary Evidence ISSN:2396-9776 Vol 3, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v3i1.96next review date: 02 Feb 2020 p a g e | 5 total pages:

12 Main findings: (relevant to PICO question):
Cytomorphological analysis was similar to previous reports with high malignant lymphoma in 25 dogs, intermediate grade lymphoma in 13 dogs and low malignant lymphoma in 1 dog.There is no information on outcome in 26 dogs and it is not clear if they received any treatment.13 dogs were treated these comprised 6 dogs with high grade, 6 dogs with intermediate and 1 dog with low grade.Details on which treatment each dog received are provided but the numbers in each subgroup are two small to draw any further information on the survival times associated with each lymphoma type.
Brick (1968) Only one patient out of 39 received prednisolone alone.Authorsdo not state how cases were selected or give any inclusion or exclusion criteria for this study Veterinary Evidence ISSN:2396-9776 Vol 3, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v3i1.96nextreviewdate: 02 Feb 2020 p a g e | 6 total pages: 123.Brick (1968) Paper does not state the survival time of 1 dog that also received radiation therapy and does not state which of the 6 dogs and 2 cats did not get a reduction in node size.There is no indication if location or grade of disease affected this finding. Regime is not continuous prednisolone as usually recommended in current veterinary practice across the world.

Search Outcome Database Number of results Excluded -not relevant to PICO question Excluded - No survival data reported Excluded - Reviews and letters Excluded - not in English or not available Total relevant papers
(Valli et al., 2013)do not report overall survival time however it can be assumed that this is longer than remission time.The single relevant case reported byTozon et al. (2006)survived 240 days with Stage 3a lymphoma.The most recent publication(Valli et al., 2013)suggests that there is no benefit of treatment with prednisolone alone in a number of histological types and grades of lymphoma.Clearly more research is required to review survival times of dogs with lymphoma who are given no treatment of any sort and comparing them to those receiving a standardised regime of prednisolone without prior other treatments and no further treatment of any sort being applied at a later date.DOI: http://dx.doi.org/10.18849/ve.v3i1.96next review date: 02 Feb 2020 In vitro studies,  T cell lymphoma or wrong location of B cell lymphoma,  No treatment reported  Only chemotherapy or other treatments reported  No survival data reported  Reviews of other reported literature  Letters to editor  Conference proceedings with no abstract available  Available in English Inclusion: Correct species, B cell lymphoma with group treated with prednisolone alone and survival data reported in any form Veterinary Evidence ISSN:2396-9776 Vol 3, Issue 1 DOI: http://dx.doi.org/10.18849/ve.v3i1.96next review date: 02 Feb 2020 p a g e | 11 total pages: 12