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Association between Body Condition Score and Cancer Prognosis in Dogs with Lymphoma and Osteosarcoma

Wiley
Journal of Veterinary Internal Medicine
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Background: In humans and rodents obesity appears to promote some cancers by increasing incidence, tumor aggressiveness, recurrence, and fatality. However, the relationship between obesity and cancer in dogs has not been thoroughly evaluated. Hypothesis/objectives: Whether body condition score (BCS) at the time of lymphoma (LSA) or osteosarcoma (OSA) diagnosis in dogs is predictive of survival time (ST) or progression-free interval (PFI). We hypothesized that an overweight body state at the time of cancer diagnosis would be associated with negative outcomes. Animals: Dogs with LSA (n = 270) and OSA (n = 54) diagnosed and treated between 2000 and 2010. Methods: Retrospective case review. Signalment, body weight, BCS, cancer diagnosis and treatment, relevant clinicopathologic values, and survival data were collected. Dogs were grouped by BCS (underweight, ideal, and overweight) and ST and PFI were compared. Results: Overall, 5.5% of dogs were underweight, 54.0% were ideal weight, and 40.4% were overweight at diagnosis. Underweight dogs with LSA had shorter ST (P = .017) than ideal or overweight dogs. BCS was not associated with ST for OSA (P = .474). Progression-free interval did not differ among BCS categories for either cancer. Conclusions and clinical importance: Obesity was not associated with adverse outcomes among dogs with LSA or OSA in this retrospective study; however, being underweight at the time of diagnosis of LSA was associated with shorter survival. More research is needed to elucidate the relationship between excessive body weight and cancer development and progression in dogs.
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Association between Body Condition Score and Cancer Prognosis in
Dogs with Lymphoma and Osteosarcoma
F.R. Romano, C.R. Heinze, L.G. Barber, J.B. Mason, and L.M. Freeman
Background: In humans and rodents obesity appears to promote some cancers by increasing incidence, tumor aggressive-
ness, recurrence, and fatality. However, the relationship between obesity and cancer in dogs has not been thoroughly evalu-
ated.
Hypothesis/Objectives: Whether body condition score (BCS) at the time of lymphoma (LSA) or osteosarcoma (OSA)
diagnosis in dogs is predictive of survival time (ST) or progression-free interval (PFI). We hypothesized that an overweight
body state at the time of cancer diagnosis would be associated with negative outcomes.
Animals: Dogs with LSA (n =270) and OSA (n =54) diagnosed and treated between 2000 and 2010.
Methods: Retrospective case review. Signalment, body weight, BCS, cancer diagnosis and treatment, relevant clinico-
pathologic values, and survival data were collected. Dogs were grouped by BCS (underweight, ideal, and overweight) and ST
and PFI were compared.
Results: Overall, 5.5% of dogs were underweight, 54.0% were ideal weight, and 40.4% were overweight at diagnosis.
Underweight dogs with LSA had shorter ST (P=.017) than ideal or overweight dogs. BCS was not associated with ST for
OSA (P=.474). Progression-free interval did not differ among BCS categories for either cancer.
Conclusions and Clinical Importance: Obesity was not associated with adverse outcomes among dogs with LSA or OSA in
this retrospective study; however, being underweight at the time of diagnosis of LSA was associated with shorter survival.
More research is needed to elucidate the relationship between excessive body weight and cancer development and progression
in dogs.
Key words: Lymphoma; Nutrition; Obesity; Osteosarcoma.
In people, obesity has been associated with increased
overall mortality from cancer,
1
increased aggressive-
ness and decreased response to treatment in some can-
cers,
2
and a higher rate of cancer recurrence.
3
Altered
concentrations of many hormones and a chronic,
low-grade inflammatory state characterize obesity.
4
Many of the biomarkers of obesityhyperinsulinemia;
increased concentrations of insulin-like growth factor-1,
leptin, sex hormones, and inflammatory cytokines; and
decreased concentrations of adiponectinhave been
demonstrated to promote tumor growth in people and
animal models.
5
Conversely, caloric restriction can slow
tumor progression and prevent metastasis in rodent
models.
5
These data suggest a role for nutrition and
calorie intake in the pathogenesis and progression of
cancer. To date, obesity has been associated with a
worse cancer outcome and sometimes a higher rate of
cancer recurrence in human cancers of the breast,
3
colon,
6
and prostate.
7
The data for other types of
cancers are less clear or lacking.
Spontaneously occurring cancer is widely reported to
be the most common cause of death in dogs; lifelong
prevalence in some breeds such as the Golden Retriever
exceeds 50%.
8
Overweight body condition is also com-
mon, with 3459% of all American dogs being over-
weight or obese.
911
Similarly, 1529% of dogs that
presented to the oncology service at 2 veterinary teaching
hospitals were obese (>20% over ideal body weight),
10,12
with another 21% overweight.
10
Obesity is associated
with increased risk of mast cell tumors,
10
mammary
tumors,
13
and transitional cell carcinoma of the bladder
in dogs
14
in retrospective and epidemiologic studies.
However, despite the large numbers of dogs with cancer
that are overweight and obese, the associations between
obesity and cancer survival and response to treatment
have not been thoroughly evaluated in dogs.
Perhaps more intuitive, underweight humans
15,16
and
cats
17
with cancer generally have shorter survival times
From the Department of Clinical Sciences, Cummings School of
Veterinary Medicine, Tufts University, North Grafton, MA
(Romano, Heinze, Barber, Freeman); Jean Mayer USDA Human
Nutrition Research Center at Tufts University, Boston, MA
(Mason). This project was completed at the Cummings School of
Veterinary Medicine at Tufts University. This manuscript was
presented as a research report at the 2015 ACVIM Forum in
Indianapolis, IN.
Corresponding author: C.R. Heinze, VMD, MS, DACVN,
Department of Clinical Sciences, Cummings School of Veterinary
Medicine, Tufts University, 200 Westboro Rd North Grafton, MA
01536; e-mail: cailin.heinze@tufts.edu.
Submitted October 7, 2015; Revised March 3, 2016;
Accepted April 21, 2016.
Copyright ©2016 The Authors. Journal of Veterinary Internal
Medicine published by Wiley Periodicals, Inc. on behalf of the Ameri-
can College of Veterinary Internal Medicine.
This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original
work is properly cited and is not used for commercial purposes.
DOI: 10.1111/jvim.13965
Abbreviations:
BCS body condition score
CHOP cyclophosphamide (C), doxorubicin (H=hydroxy
daunorubicin), vincristine (O=Oncovin
Ò
), and
prednisone (P)
LSA lymphoma/lymphosarcoma
MTR maximal treatment response
OSA osteosarcoma
PFI progression-free interval
ST survival time
J Vet Intern Med 2016;30:1179–1186
than ideal or overweight individuals. This same associa-
tion in dogs has not been reported in the literature.
There are also lingering questions about the “obesity
paradox”where overweight or even obese individuals
with certain chronic and acute diseases have longer sur-
vival times compared to ideal weight individuals, even
when the overweight state is a known risk factor for the
initial development of the disease. A well-known exam-
ple of this phenomenon can be seen in humans with
cardiovascular disease.
18
At this time, it is not clear
whether this phenomenon also exists for humans or
companion animals with cancer, but the preponderance
of the data at this time suggests the oppositethat obe-
sity is a risk factor for both the development of many
types of cancer and for a poorer prognosis.
1,2,5
The aims of this study were to determine whether
body condition score (BCS) at the time of diagnosis of
lymphoma (LSA) and osteosarcoma (OSA) is associated
with progression-free interval (PFI) and survival time
(ST). We hypothesized that an overweight or obese
body condition would be associated with a shorter ST
and PFI compared to ideal weight dogs and that under-
weight dogs would have shorter ST than ideal weight
dogs.
Materials and Methods
Case Identification
Medical records were reviewed retrospectively. Potential cases
were identified by searching the Cummings School of Veterinary
Medicine at Tufts University medical records database and the
oncology service case logs for dogs meeting initial inclusion crite-
ria. These criteria required a histologically or cytologically con-
firmed diagnosis of LSA or appendicular OSA, or presumptive
OSA based on radiographs and malignant clinical behavior (eg,
classic lytic bone lesion in a common location for OSA with or
without radiographic findings consistent with metastasis). These
specific cancer types were chosen based on a review of case logs
which suggested that adequate caseload was available. For all
dogs, a BCS and body weight recorded within 1 month of diagno-
sis and survival of at least 1 week postdiagnosis (to exclude cases
where euthanasia was elected at time of diagnosis) were required.
Another exclusion criterion was history of, or later development
of, a second primary malignant tumor, which could have altered
prognosis. Dogs with LSA that were categorized as stage 1
extranodal (except for gastrointestinal and cutaneous forms) were
also excluded because of their rarity (n =4) and highly variable
survival times compared to other types of LSA based on the
authors’ clinical experience. The record search was limited to cases
with diagnosis or treatment within the date range of January 1,
2000 to December 31, 2010; this assured the cases were recent
enough to reflect currently available diagnostics and treatments
(eg, chemotherapy protocols) with records still available for
review, but old enough that the vast majority would be deceased
for survival analysis.
Study Design
A chart review was performed for each case that met inclusion
and exclusion criteria, and data were collected on the dogs’ cancer
diagnosis, type and duration of treatment, and survival time. Sig-
nalment data, BCS, and body weights (within 1 month of diagno-
sis and the last available weight and BCS prior to death) were also
collected. Specific clinicopathologic parameters known or sus-
pected to correlate with prognosis for LSA (ie, albumin, calcium,
and whether hematocrit or PCV was within the reference range) or
OSA (ie, alkaline phosphatase) were also recorded. Dogs were
considered hypoalbuminemic or hypercalcemic if their albumin or
total calcium values were below or above the laboratory reference
range at the time of cancer diagnosis, respectively. Likewise, dogs
were considered anemic if their packed cell volume or hematocrit
was below the laboratory reference range at the time of diagnosis.
Cases were categorized by the World Health Organization classifi-
cation system
19
by location (ie, generalized/multicentric including
hepatic and splenic, alimentary/gastrointestinal, cutaneous/skin,
thymic/mediastinal, other), stage (I-V), and immunophenotype
(B- or T-cell) for LSA and by location (forelimb versus hindlimb)
and presence of metastasis at the time of diagnosis for OSA. Sub-
stage a or b was assigned to LSA cases either based on record
notation at the time of presentation or on the basis of clinical
signs at the time of diagnosisdogs that were presented for weight
loss, poor appetite, gastrointestinal signs, etc. were retroactively
assigned substage b, whereas those that were clinically ideal except
for enlarged lymph nodes or organomegaly were assigned substage
a. For LSA, not all dogs underwent full staging (eg, bone marrow
aspiration was rare), so the stages recorded represent the minimum
stage confirmed in each dog.
The treatment regimen and the date that treatment began were
recorded and the date of the first treatment was used to calculate
the timing of the maximal treatment response (MTR) for LSA.
The most common treatment regimens for canine lymphoma are
referred to as “CHOP-based protocols”. These protocols are
combination chemotherapy protocols that include cyclophos-
phamide (C), doxorubicin (H =hydroxydaunorubicin), vincristine
(O=Oncovin
Ò
), and prednisone (P). Initial treatment regimens were
recorded from the medical records and categorized as CHOP-
based, lomustine, excisional surgery, radiation therapy, corticos-
teroids alone (palliative), or a combination of treatment modalities
(including investigational therapies employed in clinical trials). The
MTR was recorded along with the timing of the MTR (whether or
not complete remission was achieved within 6 weeks as is typical
for chemotherapy-sensitive LSA cases in our hospital), and indi-
cated the highest degree of treatment response (complete clinical
remission, partial remission, stable disease, progressive disease)
achieved. For OSA, treatments were categorized as surgery alone,
surgery plus chemotherapy, radiation therapy plus chemotherapy,
or radiation therapy alone (palliative). The PFI for both cancers
was defined as the time from diagnosis until disease progression
was recorded. Overall ST was calculated as time from diagnosis to
death.
Weight change from diagnosis to death, or from postamputa-
tion (the first available weight in the record after amputation, typi-
cally in the first 12 days postsurgery) to death for dogs with OSA
that had an amputation, was calculated as a percentage, and then
categorized into the following groups: loss of 10% body weight,
loss of <10% body weight, no change (within 1% of diagnosis or
postamputation weight), gain of <10% body weight, or gain of
10% body weight.
After the initial record review, referring veterinarians were con-
tacted to provide any essential missing information. Cases with
inadequate data on treatment response and progression were
included in the survival analysis only.
Data Analysis
The primary variables of interest were BCS at time of diagnosis,
overall ST, and PFI. The MTR and its timing were secondary
endpoints for LSA only. For analysis, cases were assigned
BCS categories as follows: BCS <4/9 were considered underweight,
4/9 BCS <6/9 were considered ideal, and BCS 6/9 were
1180 Romano et al
considered overweight. All analyses were conducted across these
BCS categories. For overall survival analysis, the outcome was
death caused by any cause. For those subjects still alive during the
study, survival time was calculated for the date of last follow-up
and right censored. If the date of death was unknown or the dog
was lost to follow-up, the case was censored based on the last
known date that the dog was alive. Survival analysis and analysis
of PFI were conducted by Kaplan-Meier curves and Cox propor-
tional hazards models to determine the effect of individual vari-
ables (univariate) on the endpoints. Chi-square analysis was
performed to compare categorical data among subgroups of the
study population. Independent variables that were significant at
the level of P.10 were then included in multivariate analyses by
linear regression analysis and stepwise (backward) estimation. For
the multivariate analyses, the 4 dogs that were confirmed alive
were excluded. When the linear regression showed significance for
a variable that had more than 2 categories, Kruskal-Wallis one-
way ANOVA was used along with the Dwass-Steel-Critchlow-
Fligner test for posthoc comparison. All analysis was performed
with commercial statistical software,
a,b
with a P<.05 considered
statistically significant. All data are presented as median (range) as
many of the data were not normally distributed.
Results
LSA
Two hundred and seventy dogs with LSA were
included in this study (Table 1). The most common
breeds represented were mixed breed (58/270, 21.5%),
Golden Retriever (37/270, 13.7%), Labrador Retriever
(21/270, 7.8%), and German Shepherd (14/270, 5.2%).
LSA types (locations) included 227/270 (84.1%) multi-
centric, 20/270 (7.4%) mediastinal, 15/270 (5.6%) gas-
trointestinal, 6/270 (2.2%) cutaneous, and 2/270 (0.7%)
other. One dog did not have staging reported in the
medical record and review of the record did not allow
for retroactive assignment of stage; for the rest of the
cases there were 11/269 (4.1%) stage I, 7/269 (2.6%)
stage II, 59/269 (21.9%) stage III, 98/269 (36.3%) stage
IV, and 94/269 (34.8%) stage V. Immunophenotyping
was not available for 132 dogs; of the cases with typing
available, 85/138 (61.6%) were B-cell and 53/138
(38.4%) were T-cell. At diagnosis, 165/270 (61.1%)
dogs showed signs of systemic illness, with 127/270
(47.0%) reporting decreased appetite.
The BCS distribution for the dogs at diagnosis was
1 (1 dog), 22.5 (3), 33.5 (12), 44.5 (48), 55.5 (100),
66.5 (59), 77.5 (29), 8 (9), and 9 (9). Over half of the
dogs (130/237, 54.9%) lost weight between diagnosis
and death, but adequate information was often not
available in the medical record to allow more detailed
evaluation of the temporal associations of that weight
loss with treatment or disease progression; weight
change as a percentage of original body weight ranged
from 30.9 to 37.9% (median =loss of 2.4%) with
50/236 (21.2%) losing 10% of initial body weight.
From the first BCS to the final, the proportions of dogs
categorized as underweight and overweight increased
numerically, whereas those categorized as ideal weight
decreased (Table 1).
Two hundred and sixty-eight dogs (99.3%) received
some form of cancer treatment; treatment regimens
included CHOP-based chemotherapy (217/268, 81.0%),
lomustine chemotherapy (13/268, 4.9%), palliative ster-
oids alone (6/268, 2.2%), or other [32/268, 11.9%in-
cluded radiation therapy, high-dose cyclophosphamide,
MPD-01 (derived from a Japanese mushroom), thera-
peutic vaccination, and combinations of the other pro-
tocols]. The maximal treatment response recorded was
complete remission for 158/259 (61%) dogs, partial
remission for 61/259 (23.6%) dogs, stable disease for
28/259 (10.8%) dogs, and progressive disease for 12/259
(4.6%) dogs. These data were not available for 11 dogs.
There was no difference in whether dogs achieved com-
plete remission by 56 weeks or the MTR among dogs
of different BCS categories.
Progression-Free Interval. Two hundred and seven
(76.7%) cases had documented progression of their dis-
ease with a median PFI of 132 days (71,137 days);
data on PFI for the remaining cases were unavailable.
For underweight dogs, median PFI was 99 days (35
257 days); for ideal weight dogs, median PFI was
141 days (91,137 days); for overweight dogs, median
PFI was 143 days (71,108 days). Body condition score
category at diagnosis was not associated with PFI
(P=.150). The presence of anemia (P=.030), hypoal-
buminemia (P=.007), and the type of treatment
(P<.001) was associated with PFI on univariate analy-
sis, as was substage (P<.001) and immunotype
(P=.003). On multivariate analysis, only substage and
immunophenotype were independent variables; dogs
with substage b (showing clinical illness) had shorter
PFI than dogs with substage a (P=.004) and dogs with
B-cell lymphoma had longer PFI than dogs with T-cell
(P=.026). No significant interaction between substage
and immunophenotype was identified (P=.06).
Survival Time. Only 4 dogs (1.5%) were known to be
alive at the time of analysis. Two hundred and sixteen
dogs were known to be deceased; of these, 26 dogs died
and 190 dogs were euthanized. Fifty-four dogs were lost
to follow-up and censored by the last known date that
they were alive. The median ST for dogs with LSA was
218 days (73,720 days). For underweight dogs, median
ST was 176 days (15623 days); for ideal weight dogs,
median ST was 219 days (93,720 days); for overweight
dogs, median ST was 225 days (range, 72,737 days).
On univariate analysis, underweight dogs had a signifi-
cantly shorter ST (P=.017, Fig 1) compared to the
ideal and overweight groups, but there was no signifi-
cant difference in survival between ideal weight and
overweight dogs. There was no difference in ST among
BCS categories on multivariate analysis.
Stage (P<.001), substage (P<.001), and
immunophenotype (P=.010) were associated with ST
on univariate analysis; dogs with substage b or T-cell
LSA had shorter survival compared to substage a or
B-cell LSA, respectively. The presence of anemia
(P=.004) and hypoalbuminemia (P=.002) at diagno-
sis was also associated with shorter ST on univariate
analysis, but hypercalcemia as assessed by total calcium
concentration was not (P=.584). Treatment type was
also positively associated with survival (P<.001), with
dogs receiving CHOP-based treatment having the
Obesity and Survival in Dogs with Cancer 1181
longest survival. The anatomic location of lymphoma
was not associated with ST on univariate analysis, but
demonstrated a strong trend with multicentric
lymphoma having the longest median survival [231 days
(73,747 days); P=.052]. On multivariate analysis, only
change in weight during treatment, anemia, immunophe-
notype, and stage remained significanta gain of more
than 10% of body weight during treatment was associated
with longer survival compared with dogs that maintained
weight or lost or gained <10% of initial body weight
(P<.001; Fig 2). Dogs with normal hematocrit and dogs
with stage 2 disease lived longer than dogs with anemia
(P=.007) or other stages (P=.001), respectively.
Dogs with T-cell lymphoma had shorter ST than dogs
with B-cell (P=.012). Significant interactions were
identified between stage and body weight change
(P<.001), immunophenotype (P<.001), and anemia
(P=.001).
OSA
Fifty-four dogs with OSA were included (Table 1).
The most common breeds represented were mixed
breeds (15/54, 27.8%), Rottweiler (8/54, 14.8%), Labra-
dor Retrievers (6/54, 11.1%), Golden Retrievers (5/54,
9.3%), and Doberman Pinscher (5/54, 9.3%). The BCS
distribution at diagnosis was as follows: 2.5 (1 dog),
3(1), 44.5 (8), 55.5(19), 66.5(19), 7 (3), 8 (2), and 9
(1). About half (23/44, 52.3%) of dogs lost weight
between diagnosis and death, after adjusting for
Table 1. Descriptive data of the populations of dogs with lymphoma and osteosarcoma as well as all dogs com-
bined. Data are presented as median (range).
Variable Lymphoma Osteosarcoma All Dogs
Number of dogs 270 54 324
Age (years) 7.6 (0.8 to 15.1) 8.7 (1.3 to 13.6) 7.8 (0.8 to 15.1)
Sex
Male Intact 17/270 (6.3%) 5/54 (9.3%) 22/324 (6.8%)
Male Neutered 140/270 (51.9%) 29/54 (53.7%) 169/324 (52.2%)
Female Intact 5/270 (1.9%) 0/54 (0%) 5/324 (1.5%)
Female Spayed 108/270 (40.0%) 20/54 (37.0%) 128/324 (39.5%)
Initial BCS 5/9 (1 to 9) 5.25 (3 to 9) 5 (1 to 9)
Initial BCS Category
Underweight 16/270 (5.9%) 2/54 (3.7%) 18/324 (5.5%)
Ideal weight 148/270 (54.8%) 27/54 (50.0%) 175/324 (54.0%)
Overweight 106/270 (39.3%) 25/54 (46.3%) 131/324 (40.4%)
Final BCS 5/9 (1 to 9) 5/9 (1 to 9) 5/9 (1 to 9)
Final BCS Category
Underweight 19/155 (12.3%) 1/25 (4.0%) 20/180 (11.1%)
Ideal weight 63/155 (40.6%) 15/25 (60%) 78/180 (43.3%)
Overweight 73/155 (47.1%) 9/25 (36%) 82/180 (46.6%)
Anemia 82/257 (31.9%) 10/47 (21.3%) 92/304 (30.3%)
Hypercalcemia 53/253 (20.9%) 4/44 (9.1%) 57/297 (19.2%)
Total calcium (mg/dL) 10.3 (6.0 to 21.0) 10.4 (9.0 to 12.0) 10.3 (6.0 to 21.0)
Hypoalbuminemia 51/254 (20.1%) 3/44 (6.8%) 54/298 (18.1%)
Albumin (mg/dL) 3.2 (1.1 to 4.6) 3.4 (2.2 to 4.1) 3.3 (1.1 to 4.6)
Weight change between diagnosis
and death (% change)
2.37 (30.9 to 37.9) 1.65 (27.5 to 26.6) 2.23 (30.9 to 37.9)
Lost >10% 50/236 (21.2%) 7/44 (15.9%) 57/280 (20.4%)
Lost 10% 80/236 (33.9%) 16/44 (36.4%) 96/280 (34.3%)
No change 14/236 (5.9%) 5/44 (11.4%) 19/280 (6.8%)
Gained 10% 53/236 (22.5%) 11/44 (25.0%) 64/280 (22.9%)
Gained >10% 39/236 (16.5%) 5/44 (11.4%) 44/280 (15.7%)
Alkaline phosphatase N/A 136 (19 to 767) N/A
KeyBCS =body condition score, underweight =<4/9, ideal weight =4to<6/9, and overweight =6/9.
Fig 1. Kaplan-Meier survival curves comparing survival time
(days) for 270 dogs with lymphoma in different body condition
score categories at the time of diagnosisoverweight (n =106,
black dashed line); ideal weight (n =148; solid black line); and
underweight (n =16; gray dashed line), P=.017. Circles represent
censored cases.
1182 Romano et al
decreases in weight secondary to limb amputation when
appropriate, whereas 16/44 (36.4%) gained weight.
Thirty-six dogs (66.7%) had a primary tumor in a
forelimb versus 18/54 (33.3%) with a tumor in a hin-
dlimb. Metastasis was identified at the time of diagnosis
in 4/47 (8.5%) that had staging performed, but it was
not associated with ST (P=.802) or PFI (P=.474).
Progression-Free Interval. The median PFI for dogs
with OSA was 150 days (201,173 days). Weight change
between diagnosis and death was associated with
increased PFI on multivariate analysis with dogs gain-
ing more than 10% of body weight living longer than
those gaining <10% or losing <10% (both P<.001).
There was no significant association detected among
BCS category or any other variables and PFI on uni-
variate or multivariate analysis.
Survival Time. No dogs were confirmed alive at the
time of analysis. Nine dogs (16.7%) were lost to follow-
up and were censored by the last known date that they
were alive. Of the dogs confirmed to be deceased, 2 died,
40 were euthanized, and the cause of death was unknown
in 3. Median ST for dogs with OSA was 192.5 days (20
1,271 days) and there was no association with BCS cate-
gory (P=.474). On univariate survival analysis, anemia
(P=.005), hypoalbuminemia (P=.002), and change in
body weight after diagnosis (P=.003) were associated
with ST. Only weight change remained significant on
multivariate analysis with dogs gaining more than 10%
of body weight living longer than those gaining <10% or
losing <10% (both P<.001).
Discussion
Contrary to one of our hypotheses, obesity was not
associated with shorter ST or PFI among dogs with
LSA and OSA. For dogs with LSA, there was also no
difference among the groups for MTR or whether the
dogs achieved clinical remission within 6 weeks of start-
ing treatment among BCS categories. This is in contrast
to studies that have shown increased tumor aggressive-
ness
2
along with a higher risk of death caused by can-
cer
1,7,20
and shorter survival times
21
in overweight
humans.
There are several possible reasons why a detrimental
association between overweight or obese body condition
and outcomes was not observed in this study. The first
is that the majority of dogs in the overweight group for
both cancers had BCS between 6 and 7 (“overweight”)
rather than 8 or 9 (“obese”). It might be that being
overweight is not as harmful as being obese. If that is
true, then the relative lack of dogs of BCS 89 versus
67 could have obscured a survival difference between
the normal weight and obese dogs. Another possibility
is that the effects of obesity might differ with different
types of cancer. Indeed, while it is well accepted that
obesity increases the risk of development of many types
of cancers in people,
5
thus far it has only been clearly
reported to increase cancer-related mortality in colorec-
tal cancer and postmenopausal breast cancer.
3,6
Canine
LSA is most similar to non-Hodgkin’s lymphoma in
humans and the literature is rather inconsistent on the
association between obesity and this type of cancer:
studies indicating longer, shorter, or no change in ST
among overweight or obese people have each been
reported.
15,20,2224
Another possibility to explain the
lack of association noted in this study is that the effect
might be relatively modest and might require a much
larger study population to see a difference among BCS
categories. Most of the human studies that have demon-
strated inverse relationships between body mass index
and ST have included considerably higher numbers of
cases than did this study.
A similar effect was not seen in dogs with OSA likely
because of small numbers of dogs with OSA and the
different disease course seen with this cancer compared
with LSA. One study reported shorter ST in overweight
children with OSA,
25
but this study has been con-
tested.
26,27
Overall, there is not nearly as much litera-
ture investigating obesity and OSA in people as there is
for many other types of cancer, so there is not much
consensus. In addition, as OSA typically affects human
children, whereas it is most common in older dogs, the
mechanisms and associations might differ, and it might
be harder to translate findings in humans to those in
dogs.
As we hypothesized, median ST was significantly
shorter for dogs with LSA categorized as underweight
compared to ST for the ideal and overweight groups in
the univariate analysis, as occurs in humans with
LSA,
16,23
urothelial carcinoma,
28
esophageal cancer,
29
and gastric cancer,
30
and cats with various types of can-
cers.
17
Similar results were not seen for OSA, but there
were very few underweight dogs with OSA included in
this study. It has been reported that people with OSA
who lost more than 4.5 kg (10 pounds) of body weight
had a poorer prognosis, but it remains unclear what
percentage of body weight loss this represented, whether
the patients were at a normal weight at the time of
Fig 2. Kaplan-Meier survival curves comparing survival time
(days) for 236 dogs with lymphoma that lost <10% body weight
(n =80; dashed gray line), lost >10% body weight (n =50; solid
gray line), maintained weight (n =14, dotted black line), gained
<10% of body weight (n =53; dashed black line), or gained >10%
body weight (n =39; solid black line), P=.003. Circles represent
censored cases.
Obesity and Survival in Dogs with Cancer 1183
diagnosis or whether the weight of an amputated limb
was taken into account;
31
therefore, it is hard to draw
conclusions on the associations between being under-
weight and survival in people with OSA.
For dogs with either LSA or OSA, gaining 10% or
more body weight during the course of treatment was
associated with longer ST than those that gained less
than 10%, maintained, or lost weight. A similar situa-
tion has been reported in dogs with heart disease,
where dogs that gained weight had longer survival
compared to those that lost or maintained weight.
32
This might be a secondary, rather than a primary
effect (ie, dogs that live longer have a longer duration
of time to gain weight), but weight loss (and particu-
larly muscle loss) can have a primary role in survival
as well. Shorter ST in underweight dogs might be a
reflection of more severe disease, loss of lean body
mass, or chronic malnutrition, all of which can com-
promise host defenses and alter treatment protocols.
Dog owners might also be more likely to opt for
euthanasia for dogs that lose weight compared to dogs
that maintain or gain weight during treatment, which
can confound survival time. While it is likely that
weight loss during treatment reflects a poorer response
to treatment, more aggressive disease, or the contribu-
tion of comorbid conditions, suboptimal calorie and
nutrient intake also can play a role, making careful
attention to nutrition important. This strategy can be
achieved by a nutritional assessment at every visit,
which includes assessment of body weight, BCS,
muscle condition score, and diet history.
33,34
In addi-
tion, making specific nutritional recommendations
and adjusting these recommendations based on patient
response can play a role in maintaining optimal nutri-
tional status in dogs with cancer.
Other factors associated with shorter survival for
dogs with LSA included anemia and T-cell LSA. These
data agree with previous studies and suggest that hema-
tocrit at time of diagnosis might be a useful prognostic
indicator.
3538
There are some limitations to this study. Body con-
dition score, our main variable of interest, is subjec-
tive
39
and we had to rely on BCS performed by
numerous clinicians across and within cases. It has
been the authors’ experience that clinicians tend to
underestimate BCS, so it is possible that some over-
weight animals were included in the ideal weight
group, but less likely that the reverse occurred. Coat
length and thickness can also complicate estimation of
BCS as the authors appreciate that thick-coated dogs
might feel like they have more “fat padding” over their
ribs than thin-coated dogs. Another potential limita-
tion is that the BCS within a month of the time of
diagnosis was used to categorize cases into under-
weight, ideal weight, and overweight; however, this
value might not be the most accurate marker of a
dog’s nutritional status at the time that the cancer first
developed. For example, a history of anorexia or
weight loss prior to diagnosis could result in a BCS at
the time of diagnosis that was not reflective of the
typical BCS of the animal prior to the development of
cancer. In addition, BCS measurements were not
always available on the exact day of diagnosissome
of the BCS measurements were recorded after the diag-
nosis, others before, and some on the day of diagnosis
(although all within 1 month of diagnosis). It has been
suggested that the timing of body mass index measure-
ment (ie, prediagnosis versus at the time of diagnosis)
in humans might alter interpretation of associations
among various body mass index categories and cancer
prognosis.
40
Moreover, body condition scoring is an
estimate of body fat, but changes in BCS do not
correlate with loss of muscle until the very lowest
scores (1 and 2/9).
39
In humans, cachexia, or muscle
loss because of systemic illness, regardless of overall
body weight and BMI, has been associated with poorer
survival.
41
Although several different subjective muscle
condition scoring systems for dogs have been pro-
posed, these systems have not been well validated and
adoption by individual clinicians is quite variable.
12,34
We were thus unable to assess muscle condition reli-
ably from the medical records of dogs in this study.
Unlike in studies of rodents and humans, dogs with
cancer can be euthanized as a result of owner’s finan-
cial constraints, progressive disease, treatment failure,
or treatment adverse effects, and including euthanasia
as a cause of death could confound true assessment of
ST. Nearly all of the dogs in this study were eutha-
nized versus dying from their cancer directly. Finally,
animals presented to our teaching hospital might not
reflect the general population of dogs with LSA and
OSA.
The number of LSA dogs with clinical substage b
was higher in this study than has been reported in
previous studies.
35,38
The retrospective nature of this
study made it difficult to assess severity of the systemic
signs, so clinical substage was frequently assigned
based on systemic signs reported in the record (such as
decreased appetite, lethargy, weight loss, vomiting, or
diarrhea). It is possible that some of these animals
might have been categorized as substage a if evaluated
prospectively. The PFI and ST for both LSA and
OSA reported here are shorter than those documented
in other clinical studies. This is likely as a result of the
inclusion of dogs that received palliative care rather
than just regular standard-of-care treatment in this
investigation.
In conclusion, our data do not indicate that over-
weightedness/obesity as defined as a BCS 6/9 at diag-
nosis adversely affects progression or survival in dogs
with LSA or OSA. However, weight gain during treat-
ment was associated with increased survival for both
OSA and LSA, whereas anemia, T-cell phenotype, and
higher stage in dogs with LSA were associated with
shorter ST. A large, prospective casecontrol study
would enable more definitive conclusions to be drawn
about these relationships. We are aware of one such
study in golden Retrievers that is ongoing
c
which will
provide additional data that could help elucidate these
complex issues in dogs.
1184 Romano et al
Footnotes
a
Systat, Cranes Software International, Ltd. San Jose, California
b
SPSS, IBM Corporation, Armonk, New York
c
Morris Animal Foundation Golden Retriever Lifetime Study
http://caninelifetimehealth.org
Acknowledgments
The authors acknowledge the Tufts Harrington
Oncology program for providing cases and assistance
with study design.
Grant Support: This project was funded by the Merial
Veterinary Scholars program. The project described was
also supported in part by the National Center for
Advancing Translational Sciences, National Institutes
of Health, Award Number UL1TR000073, and the U.S.
Department of Agriculture, under agreement No. 58-
1950-7-707. The content is solely the responsibility of
the authors and does not necessarily represent the offi-
cial views of the NIH, or do any opinions, findings,
conclusion, or recommendations expressed in this publi-
cation necessarily reflect the view of the U.S. Dept. of
Agriculture.
Conflict of Interest Declaration: Authors declare no
conflict of interest.
Off-label Antimicrobial Declaration: Authors declare
no off-label use of antimicrobials.
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1186 Romano et al
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Among patients undergoing resection for gastric cancer, the impact of body mass index (BMI) on outcomes is not well understood. We sought to define the impact of non-normal BMI on short- and long-term outcomes after gastric cancer resection. We identified 775 patients who underwent gastrectomy for adenocarcinoma between 2000 and 2012 from the multi-institutional US Gastric Cancer Collaborative. Clinicopathologic characteristics, operative details, and oncologic outcomes were collected, and patients were stratified according to BMI. Most patients in the cohort were classified as having normal BMI (n = 338, 43.6%), followed by overweight (n = 229, 29.6%), obese (n = 153, 19.7%), and underweight (n = 55, 7.1%). After stratifying by BMI, there were no significant differences in the incidence of postoperative blood transfusions, perioperative morbidity, postoperative infectious complications, length of stay, perioperative 30-d in-hospital death, or readmission across groups (all P > 0.05). BMI did not impact overall or recurrence-free survival after stratifying by stage (all P > 0.05). However, underweight patients with low preoperative albumin levels had worse overall survival (OS) compared with that of patients of normal BMI. BMI did not impact perioperative morbidity, recurrence-free, or OS in patients undergoing gastric resection for adenocarcinoma. Underweight patients with BMI <18.5 kg/m(2) and low preoperative albumin levels, however, had a significantly decreased OS after gastrectomy for cancer. These high-risk patients should have their nutritional status optimized both before and after gastrectomy in an attempt to modify this risk factor and, in turn, achieve better outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.
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There is no consensus about the impact of a high BMI on postoperative morbidity and survival after esophagectomy. The aim of this study was to determine the influence of a high BMI on postoperative complications and survival in a large cohort of esophageal cancer patients. From January 2006 to December 2012, 1,342 consecutive esophageal cancer patients who underwent esophagectomy were included in this study. Patients were divided into three groups: 950 patients were classified as normal BMI (BMI 18.5-24.9 kg/m(2)), 279 were classified as high BMI (BMI ≥ 25 kg/m(2)), and 113 as low BMI (BMI < 18.5 kg/m(2)). Multivariate logistic regression models were used to identify confounding factors associated with postoperative complications. The impact of BMI on overall survival (OS) was estimated by the Kaplan-Meier method and Cox proportional hazard models. The predominance of pathological type was esophageal squamous cell carcinoma (n = 1,280, 95.4 %). Overall morbidity, mortality, and hospital stay did not differ among groups. The incidence of pneumonia was higher in patients with high BMI compared with those with normal BMI (14.7 vs. 9.9 %, P = 0.025). However, chylothorax was less frequent in high-BMI group (0.4 % in high-BMI group, 3.1 % in normal group, and 3.5 % in low group, P = 0.011). Logistic regression analysis revealed high BMI was independently associated with decreased incidence of chylothorax [HR 0.86; 95 % confidence interval 0.76-0.97]. Overweight and obese patients had significantly better overall survival than underweight patients (median OS 55.6 vs. 32.5 months, P = 0.013), while the pathological stage was significantly higher in underweight patients (P = 0.001). In multivariate analysis, T status, N status, differentiation grade, and tumor length were identified as independent prognostic factors. A high BMI is not associated with increased overall morbidity following esophagectomy; moreover, it is associated with decreased incidence of chylothorax. The better overall survival in patients with high BMI compared with those with low BMI might be due to a relatively low pathological stage. A high BMI should therefore not be a relative contraindication for esophagectomy.
Article
Aim: To clarify how body mass index (BMI) affects the risk of death from upper urinary tract urothelial carcinoma (UUTUC) we investigated the impact of BMI on UUTUC using a Japanese multicenter database. Patients and methods: Between January 1995 and December 2010, 1,329 patients with upper urinary tract tumors were treated in 13 institutions in Japan. From this group, a cohort of 1,014 patients treated with radical nephroureterectomy was retrospectively reviewed. BMI was categorized into the following three groups: BMI <22.5, BMI 22.5 to <25 and BMI ≥ 25. The association between each group and cancer-specific survival (CSS) was analyzed using Cox proportional hazards regression models. Results: The median BMI was 22.4 kg/m(2) (interquartile range, 20.5-24.8). Out of all patients, 213 (21%) died of UUTUC. Hazard ratios of the BMI ≥ 25 and the BMI <22.5 group were 1.76 and 1.66, respectively. Conclusion: Both higher and lower BMI affect the prognosis of UUTUC treated with radical nephroureterectomy.
Article
Objectives: The aim of this study is to determine the impact of obesity on surgical and oncologic outcomes after primary debulking surgery (PDS) in advanced epithelial ovarian cancer (EOC). Methods: Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/2/2003 and 12/30/2011 were included. Patient characteristics, intraoperative and postoperative outcomes, recurrence and status were abstracted. Complications were graded according to the 4-point Accordion classification. For analyses, patients were divided into three groups according to body mass index (BMI): group 1-BMI <25.0 kg/m(2); group 2-BMI 25.0-39.9 kg/m(2); and group 3-BMI ≥40.0 kg/m(2). Results: Of the 620 patients included in the study, 36.6%, 56.9%, and 6.5% were in weight groups 1, 2, and 3, respectively. Weight group 3 was an independent predictor of severe complications after adjusting for confounders (adjusted odds ratio (95% CI): 2.93 (1.38, 6.20) for group 3 vs. group 2). Weight group was not associated with differences in residual disease (p=0.80). The 90-day mortality rates were 11.9%, 6.7%, and 15.7%, respectively, in weight group 1, 2, and 3 (p=0.049 unadjusted, p=0.01 adjusted). There was no difference in OS (p=0.52) or PFS (p=0.23) between weight groups. Conclusions: BMI ≥40.0 kg/m(2) is an independent predictor of severe 30-day postoperative morbidity and 90-day mortality after PDS for EOC-information useful in preoperative counseling. BMI does not appear to impact long-term oncologic outcomes including residual disease at PDS, although we had limited power at the extremes of BMI. BMI may be an important factor to consider in risk-adjustment models and reimbursement strategies.
Article
Purpose Previous studies that assessed the relationship between obesity, overweight, and survival in colorectal cancer (CRC) have provided conflicting results. Therefore, we quantitatively summarized existing evidence to estimate the association between obesity/overweight and overall survival (OS) in CRC patients and explored potentially important sources of variability. Methods Eligible studies were identified via PubMed and EMBASE searches. The summary hazard ratio (sHR) was estimated using a fixed-effects or random-effects model according to the heterogeneity between the studies. Meta-regression and subgroup analyses were performed to explore potential sources of heterogeneity. Results A total of 29 eligible studies, with 51,303 CRC patients, were finally included. The overall analysis showed worse OS among obese patients [sHR 1.10, 95 % confidence intervals (CI) 1.06–1.15], but not among overweight patients (sHR 0.92, 95 % CI 0.86–1.00), than in normal-weight patients. Considerable heterogeneity was observed across studies, which was primarily attributed to the timing of body mass index (BMI) assessment (meta-regression p
Article
Purpose Obesity increases mortality for several malignancies, but for non-Hodgkin lymphoma (NHL), the association between body mass index (BMI) and survival is unclear. We examined the association of pre-diagnostic BMI with overall and NHL-specific survival in the multiethnic cohort (MEC) study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Caucasians. Methods MEC participants free of NHL at cohort entry and diagnosed with NHL during follow-up were included in the analyses (n = 1,331). BMI was based on self-reported weight and height at cohort entry and after 6.1 years of cohort entry. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95 % confidence intervals (CI) with BMI as time-varying exposure in relation to all-cause and NHL-specific mortality while adjusting for known confounders. Results The mean age at NHL diagnosis was 70.5 (range 45–89) years. After a mean follow-up of 4.3 ± 3.5 years, 667 deaths including 450 NHL-specific deaths occurred. In multivariable models, obese patients (BMI ≥30.0 kg/m2) had higher all-cause (HR 1.46, 95 % CI 1.13–1.87) and NHL-specific (HR 1.77, 95 % CI 1.30–2.41) mortality compared with patients with high-normal BMI (22.5–24.9 kg/m2). For overweight patients (BMI = 25.0–29.9 kg/m2), the respective HRs were 1.21 (95 % CI 0.99–1.49) and 1.36 (95 % CI 1.06–1.75). Cases with low-normal BMI (