Research

JAMA Oncology | Original Investigation

Association of Systemic Inflammation and Sarcopenia

With Survival in Nonmetastatic Colorectal Cancer
Results From the C SCANS Study
Elizabeth M. Cespedes Feliciano, ScD, MSc; Candyce H. Kroenke, ScD, MPH; Jeffrey A. Meyerhardt, MD, MPH;
Carla M. Prado, PhD; Patrick T. Bradshaw, PhD, MS; Marilyn L. Kwan, PhD; Jingjie Xiao, MSc; Stacey Alexeeff, PhD;
Douglas Corley, MD, PhD; Erin Weltzien; Adrienne L. Castillo, RD; Bette J. Caan, DrPH

Supplemental content
IMPORTANCE Systemic inflammation and sarcopenia are easily evaluated, predict mortality in
many cancers, and are potentially modifiable. The combination of inflammation and
sarcopenia may be able to identify patients with early-stage colorectal cancer (CRC) with poor
prognosis.

OBJECTIVE To examine associations of prediagnostic systemic inflammation with at-diagnosis

sarcopenia, and determine whether these factors interact to predict CRC survival, adjusting
for age, ethnicity, sex, body mass index, stage, and cancer site.

DESIGN, SETTING, AND PARTICIPANTS A prospective cohort of 2470 Kaiser Permanente

patients with stage I to III CRC diagnosed from 2006 through 2011.

EXPOSURES Our primary measure of inflammation was the neutrophil to lymphocyte ratio
(NLR). We averaged NLR in the 24 months before diagnosis (mean count = 3 measures; mean
time before diagnosis = 7 mo). The reference group was NLR of less than 3, indicating low or
no inflammation.

MAIN OUTCOMES AND MEASURES Using computed tomography scans, we calculated skeletal
muscle index (muscle area at the third lumbar vertebra divided by squared height). Sarcopenia
was defined as less than 52 cm2/m2 and less than 38 cm2/m2 for normal or overweight men
and women, respectively, and less than 54 cm2/m2 and less than 47 cm2/m2 for obese men
and women, respectively. The main outcome was death (overall or CRC related).

RESULTS Among 2470 patients, 1219 (49%) were female; mean (SD) age was 63 (12) years.
An NLR of 3 or greater and sarcopenia were common (1133 [46%] and 1078 [44%],
respectively). Over a median of 6 years of follow-up, we observed 656 deaths, 357 from CRC.
Increasing NLR was associated with sarcopenia in a dose-response manner (compared with
NLR < 3, odds ratio, 1.35; 95% CI, 1.10-1.67 for NLR 3 to <5; 1.47; 95% CI, 1.16-1.85 for NLR ⱖ 5;
P for trend < .001). An NLR of 3 or greater and sarcopenia independently predicted overall Author Affiliations: Division of
Research, Kaiser Permanente
(hazard ratio [HR], 1.64; 95% CI, 1.40-1.91 and HR, 1.28; 95% CI, 1.10-1.53, respectively) and Northern California, Oakland,
CRC-related death (HR, 1.71; 95% CI, 1.39-2.12 and HR, 1.42; 95% CI, 1.13-1.78, respectively). California (Cespedes Feliciano,
Patients with both sarcopenia and NLR of 3 or greater (vs neither) had double the risk of Kroenke, Kwan, Alexeeff, Corley,
Weltzien, Castillo, Caan); Department
death, overall (HR, 2.12; 95% CI, 1.70-2.65) and CRC related (HR, 2.43; 95% CI, 1.79-3.29).
of Medical Oncology, Dana-Farber
Cancer Institute, Harvard Medical
CONCLUSIONS AND RELEVANCE Prediagnosis inflammation was associated with at-diagnosis School, Boston, Massachusetts
sarcopenia. Sarcopenia combined with inflammation nearly doubled risk of death, suggesting (Meyerhardt); Department of
Agricultural, Food, and Nutritional
that these commonly collected biomarkers could enhance prognostication. A better Sciences, University of Alberta,
understanding of how the host inflammatory/immune response influences changes in Edmonton, Alberta, Canada (Prado,
skeletal muscle may open new therapeutic avenues to improve cancer outcomes. Xiao); Division of Epidemiology,
School of Public Health, University
of California–Berkeley (Bradshaw).
Corresponding Author: Elizabeth M.
Cespedes Feliciano, ScD, MSc, Division
of Research, Kaiser Permanente
Northern California, 2000 Broadway,
JAMA Oncol. doi:10.1001/jamaoncol.2017.2319 5th Floor, Oakland, CA 94612
Published online August 10, 2017. (elizabeth.m.cespedes@kp.org).

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 Research Original Investigation
I
dentifying which patients with early-stage cancer are at high
risk of adverse treatment outcomes and premature mortal-
ity is a clinical priority. Two novel prognostic indicators
receiving increasing attention across cancer types are sarco-
penia (low skeletal muscle mass)1 and an elevated neutrophil-
to-lymphocyte ratio (NLR, a measure of systemic inflam-
mation).2 Sarcopenia predicts poor surgical outcomes,3 treatment
toxic effects,4-6 and reduced survival.1,7 Routine diagnostic
imaging using computed tomography (CT) can be used to ac-
curately quantify muscle mass, revealing sarcopenia that might
otherwise go undetected. Similarly, pretreatment values
of NLR 2 and related blood biomarkers (eg, platelet-to-
lymphocyte ratio [PLR]8 and lymphocyte-to-monocyte ratio
[LMR]9) are commonly measured and predict treatment re-
sponse and survival. Whereas both sarcopenia and inflamma-
tion can be evaluated with existing clinical data and may be
modifiable, the relationship between these 2 factors and their
independent associations with survival are not well studied.
Recent trials treating cachexia with ω-3 fatty acid supple-
mentation and nonsteroidal anti-inflammatory drugs10,11 un-
derscore the importance of systemic inflammation as a driver
of muscle degradation in patients with late-stage disease.12,13
Proinflammatory cytokines and growth factors released as part
of the systemic inflammatory response to the tumor have pro-
found catabolic effects on host metabolism, which lead to
muscle breakdown.14 Low muscularity could contribute to lo-
cal inflammation in the muscle, leading to further breakdown
and driving systemic inflammation.15 In turn, this inflamma-
tory cycle could enhance tumor aggressiveness or reduce treat-
ment response, impairing the transition into survivorship.16,17
Whereas lower muscle mass also has deleterious conse-
quences for morbidity and/or mortality in patients with early-
stage disease,1,7 little research examines whether systemic in-
flammation predicts muscle mass in early-stage cancer.
To our knowledge, no prior study examines combined as-
sociations of the host systemic inflammatory response and sar-
copenia with colorectal cancer (CRC) survival. Not only are these
factors important as prognostic indicators, they are also poten-
tially modifiable. Colorectal cancer, a leading cause of cancer
death,18 is an ideal setting in which to evaluate this relation-
ship because of the availability of CT images and laboratory
blood biomarkers. Among 2470 patients with a diagnosis of
American Joint Committee on Cancer stage I to III CRC, we ex-
amined the association of prediagnostic NLR with at-
diagnosis sarcopenia. Subsequently, we assessed the indepen-
dent and combined associations of these risk factors with
survival. We also conducted sensitivity analyses to examine
whether associations were consistent across other inflamma-
tory biomarkers and subgroups defined by body mass index
(BMI, calculated as weight in kilograms divided by height in me-
ters squared), stage, age, and sex.
Methods
Study Population
The “C SCANS” (Colorectal Cancer: Sarcopenia, Cancer, and Near-
term Survival) cohort, described in detail elsewhere,7,19-21 in-
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Systemic Inflammation, Sarcopenia, and Survival in Colorectal Cancer
Key Points
Question Is systemic inflammation (manifest as elevated
neutrophil to lymphocyte ratio) associated with sarcopenia
(reduced skeletal muscle mass), and are these 2 risk factors
combined associated with survival after colorectal cancer (CRC)
diagnosis?
Findings In a cohort of 2470 patients with nonmetastatic CRC,
elevated neutrophil to lymphocyte ratio before diagnosis was
associated with at-diagnosis sarcopenia in a dose-response
manner; patients with both sarcopenia and neutrophil to
lymphocyte ratio of 3 or greater (vs neither) had double the risk of
death overall and from CRC.
Meaning Sarcopenia and inflammation predicted worse CRC
prognosis regardless of stage. Because these 2 biomarkers are
commonly collected and potentially modifiable, they have high
potential for clinical use in prognostication and possibly in guiding
intervention.
cluded 3276 Kaiser Permanente Northern California (KPNC)
health plan members who received a diagnosis of stage I to III
CRC between 2006 and 2011 who underwent surgical resection
and had an abdominal CT scan at diagnosis of sufficient image
quality to analyze. We further restricted the sample to those with
prediagnostic NLR values available from clinically acquired labo-
ratory data (n = 2470). Patients included and excluded due to
insufficient data were similar with respect to BMI, race/ethnicity,
sex, age, stage, and survival duration. The study was approved
by the KPNC Institutional Review Board. Informed consent was
waived due to the retrospective nature of the study.
Body Composition and BMI
We selected the height and weight obtained closest to the CT
scan measured by KPNC medical assistants and computed BMI,
categorized as less than 20, 20 to less than 25, 25 to less than
30, 30 to less than 35, or at least 35. “At-diagnosis” muscle mass
was assessed from a CT scan taken before chemotherapy or ra-
diation therapy (if received). On average, scans were 2 days be-
fore diagnosis (range, −2 to 4 months; 1951 [79%] presurgical).
A single, trained researcher at the University of Alberta (J.X.)
selected the third lumbar vertebra and analyzed the cross-
sectional area of muscle in centimeters squared according to pre-
defined tissue-specific Hounsfield units ranges using Slice-O-
Matic Software, version 5.0 (Tomovision).22 Single-slice muscle
area at the third lumbar vertebra is strongly correlated with
whole-body volume of muscle tissue23 and has been exten-
sively used in oncology settings.24,25 As in prior publications,7,26
we used optimal stratification to select BMI and sex-specific cut-
offs for skeletal muscle index (muscle area in centimeters
squared divided by squared height in meters squared) to de-
fine sarcopenia: for normal or overweight patients (BMI < 30),
these were less than 52 cm2/m2 for men and less than 38 cm2/m2
for women, while for obese patients (BMI ≥ 30), these were less
than 54 cm2/m2 for men and less than 47 cm2/m2 for women.
Markers of Systemic Inflammation
Our primary measure of systemic inflammation was NLR from
laboratory values obtained as part of routine blood tests (all
jamaoncology.com
 Systemic Inflammation, Sarcopenia, and Survival in Colorectal Cancer
measurements were prior to the diagnostic scan, surgery, or other
treatment). We averaged all available NLR measures in the 24
months prior to diagnosis (mean number of NLR measures was
3; mean interval before diagnosis was 7 months) and categorized
this average using standard cutoffs to define “normal” (<3),
“moderate” (3 to <5), and “high” (≥5) inflammation.2 Second-
ary biomarkers of inflammation (eTable 1 in the Supplement)
were available at the same time point; we averaged and catego-
rized available measures using clinically relevant cutoffs (PLR
of <150, 150 to <300, or ≥300 and LMR of <2, 2 to <3, 3 to <4, or
≥4 wherein higher PLR and lower LMR indicate more severe
inflammation).8,9 Serum albumin level, of particular interest as
a marker not only of nutritional status but also of systemic in-
flammation, was available for a subset of 716 participants, and
dichotomized at less than 3.5 g/dL (the cutoff for hypoalbumin-
emia; to convert to grams per liter, multiply by 10).14
Other Covariates and End Points
We reviewed the KPNC electronic medical record and Cancer
Registry for information on disease stage, tumor characteris-
tics, surgery, treatment (chemotherapy or radiation therapy),
and demographic (eg, age, race/ethnicity, and sex) and health
characteristics (Charlson comorbidity index). We obtained data
on overall and CRC-specific mortality from the KPNC mortal-
ity file, composed of data from the California Department of
Vital Statistics, US Social Security Administration, and KPNC
health care utilization data.
Statistical Analysis
In exploratory analyses, we tabulated descriptive statistics
(mean [SD] and percentages). Next, we conducted logistic re-
gression for categorical NLR (<3, 3-5, ≥5) as a predictor of sar-
copenia (yes or no), with the P value for a linear trend evalu-
ated by treating the median of each NLR category in
multivariable models as a continuous predictor. Using multi-
variable-adjusted linear regression, we evaluated differences
in muscle in centimeters squared by category of NLR and sec-
ondary biomarkers. Models were adjusted for race/ethnicity,
sex, cancer site, and at-diagnosis values of age, BMI category,
and cancer stage.
In analyses in which survival was the outcome, we cross-
classified NLR of 3 or greater and sarcopenia in 4 categories (in-
flammation only, sarcopenia only, both, or neither [reference])
and calculated Kaplan-Meier curves. Next, we examined NLR
of 3 or greater and sarcopenia as independent (mutually ad-
justed) predictors of survival in multivariable-adjusted Cox pro-
portional hazards models. Models were adjusted for race/
ethnicity, sex, cancer site, and at-diagnosis values of age, BMI
category, and cancer stage. We further adjusted for treatment
(chemotherapy and/or radiation therapy) and Charlson comor-
bidity index. Participants were observed from diagnosis until
death from any cause, death from CRC, or the end of follow-up
(December 31, 2015). For overall mortality, individuals alive at
the end of follow-up were censored at that time. For CRC mor-
tality, individuals who died of other causes during follow-up
were censored at that time. Evaluations for the presence of mul-
tiplicative interaction between NLR of 3 or greater and sarco-
penia used the likelihood ratio test (LRT).
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Original Investigation Research
Finally, given the existing literature suggesting associa-
tions of BMI category, sex, age, and stage at diagnosis with CRC
survival, we evaluated the main associations of each variable
with survival, as well as possible interactions of these vari-
ables with NLR and/or sarcopenia using stratified analyses and
LRTs.
Two-sided P < .05 was considered significant. We used Sta-
tistical Analysis Software, version 9.3 (SAS, Inc) for all statis-
tical analyses.
Results
Table 1 presents the characteristics of 2470 patients with non-
metastatic CRC by category of prediagnostic NLR. Patients with
a higher NLR in the 24 months prior to diagnosis had less fa-
vorable values for all other markers of systemic inflamma-
tion: higher PLR, lower LMR, and lower serum albumin level.
Patients with greater systemic inflammation prior to diagno-
sis were older, more likely to be female, to be non-Hispanic
white, to have colon (vs rectal) cancer, and to have stage II or
III (vs I) cancer. A majority were overweight (864 [35%]) or
obese (786 [32%]). The prevalence of sarcopenia and prediag-
nosis NLR of 3 or greater were 46% (n = 1133) and 44%
(n = 1078), respectively.
A higher prediagnostic NLR was associated in a dose-
response manner with the odds of sarcopenia independent of
race/ethnicity, cancer site, age, stage, and BMI: compared with
patients with NLR of less than 3, the odds ratios (ORs) for sar-
copenia were 1.35 (95% CI, 1.10-1.67) for NLR of 3 to less than
5 and 1.47 (95% CI, 1.16-1.85) for NLR of 5 or greater (P for trend
across categories, <.001). Results were consistent across other
markers of systemic inflammation, with higher PLR, lower
LMR, and hypoalbuminemia all associated with higher odds
of sarcopenia (eTable 1 in the Supplement), and, in continu-
ous analyses, with lower skeletal muscle index (eTable 2 in the
Supplement). Furthermore, the association of elevated NLR
with increased odds of sarcopenia was consistent across stage,
age, and sex (no evidence of interaction) (eTable 3 in the
Supplement).
As observed in the Kaplan-Meier curves (Figure), patients
with NLR of 3 or greater and sarcopenia had the worst sur-
vival, whereas patients with NLR of less than 3 and no sarco-
penia survived the longest (log-rank P < .001) (Figure). eFig-
ure 1 in the Supplement shows the multivariable-adjusted results
for overall survival in each category defined by the presence (or
absence) of NLR of 3 or greater and/or sarcopenia. These risks
are overlaid on the distribution of the categories according to
age at diagnosis, illustrating that although sarcopenia and in-
flammation were more common in older patients, both condi-
tions occurred across age groups and were associated with sur-
vival: for example, 200 (16%) of patients younger than 65 years
at diagnosis had both sarcopenia and inflammation. Survival
probabilities for NLR of 3 or greater and sarcopenia are shown
separately in eFigures 2 and 3 in the Supplement, respectively.
In multivariable analyses, the interaction of sarcopenia with
NLR was nonsignificant. Thus, we report the independent (mu-
tually adjusted) associations of each risk factor with overall and
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 Research Original Investigation Systemic Inflammation, Sarcopenia, and Survival in Colorectal Cancer

Table 1. Characteristics by Level of Systemic Inflammation Prior to Diagnosis in 2470 Patients

With Nonmetastatic Colorectal Cancer (CRC)

NLR Prior to CRC Diagnosis

<3 3 to <5 ≥5
a
Characteristic (n = 1337) (n = 646) (n = 487)
NLR, median (IQR) 2.0 (1.6-2.4) 3.8 (3.4-4.3) 6.9 (5.8-9.9)
Other inflammatory markers, median (IQR)
Platelet to lymphocyte ratio 129 (103-166) 185 (150-236) 273 (205-370)
Lymphocyte to monocyte ratio 3.6 (3.0-4.6) 2.5 (2.0-3.1) 1.8 (1.3-2.4)
Albumin level, g/dLb 4.2 (3.8-4.4) 3.9 (3.5-4.2) 3.7 (3.1-4.2)
Time from NLR to scan, mean (SD), mo −6 (6) −5 (6) −5 (6)
Age at diagnosis, mean (SD), y 62 (11) 63 (12) 65 (12)
Charlson comorbidity score, mean (SD) 0.8 (1.3) 1.0 (1.6) 1.4 (1.8)
Body mass index, mean (SD) 28 (6) 28 (6) 28 (7)
Race/ethnicity, No. (%)
Non-Hispanic white 842 (63) 433 (67) 346 (71)
Black 120 (9) 45 (7) 24 (5)
Hispanic 160 (12) 84 (13) 34 (7)
Asian/Pacific islander 214 (16) 84 (13) 78 (16)
Other 13 (1) 6 (1) 5 (1)
Sex, No. (%)
Female 615 (46) 336 (52) 268 (55)
Male 722 (54) 310 (48) 219 (45) Abbreviations: IQR, interquartile
Cancer stage, No. (%) range; NLR, neutrophil to lymphocyte
ratio.
I 428 (32) 155 (24) 107 (22)
SI conversion factor: To convert
II 388 (29) 233 (36) 185 (38) albumin to grams per liter, multiply
III 508 (38) 258 (40) 200 (41) by 10.
a
Cancer site, No. (%) Percentages may not total 100
because of rounding.
Colon 936 (70) 491 (76) 394 (81)
b
Albumin level was only available on
Rectum 401 (30) 155 (24) 93 (19)
a subset of 716 patients.

Figure. Kaplan-Meier Survivorship Function According to Neutrophil to Lymphocyte Ratio

and Sarcopenia Status in 2470 Patients With Nonmetastatic Colorectal Cancer

1.0

0.9
Overall Survival Probability

0.8
NLR <3; no sarcopenia

0.7
NLR <3; sarcopenia

NLR ≥3; no sarcopenia

0.6

NLR ≥3; sarcopenia

0.5
0 1 2 3 4 5 6 7 8 9 10
Time Since Diagnosis, y
No. at risk
NLR <3; no sarcopenia 819 789 743 516 225 20
NLR <3; sarcopenia 560 481 435 282 118 14
NLR ≥3; no sarcopenia 517 511 456 321 149 15
NLR ≥3; sarcopenia 561 478 412 277 137 13 NLR indicates neutrophil to
lymphocyte ratio.

CRC-specific survival (Table 2) in the form of hazard ratios (HRs).
Neutrophil-to-lymphocyte ratio of 3 or greater and sarcopenia
independently predicted overall survival (HR, 1.64; 95% CI, 1.40-
1.91 and HR, 1.28; 95% CI, 1.10-1.53, respectively), as well as CRC-
specific survival (HR, 1.71; 95% CI, 1.39-2.12 and HR, 1.42; 95%
CI, 1.13-1.78, respectively). Under the model of independent
effects (Table 2), a patient with both sarcopenia and NLR of 3
or greater was estimated to have much worse overall (HR, 2.12;
95% CI, 1.70-2.65) and CRC-specific survival (HR, 2.43; 95% CI,
1.79-3.29) than a patient with neither risk factor.

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 Systemic Inflammation, Sarcopenia, and Survival in Colorectal Cancer Original Investigation Research

Table 2. Neutrophil to Lymphocyte Ratio (NLR), Sarcopenia, Table 3. Neutrophil to Lymphocyte Ratio (NLR), Sarcopenia,
and Colorectal Cancer (CRC) Survival in 2470 Patients and Colorectal Cancer (CRC) Survival Stratified by Body Mass Index,
With Nonmetastatic CRCa Stage, Age, and Sex (n = 2470)a

HR (95% CI)b HR (95% CI)b

Independent, Mutually Overall Survival CRC Survival Stratification Variable Overall Survival CRC Survival
Adjusted Associations (674 Events) (357 Events)
BMI
Sarcopenia
<20 1.63 (0.48-5.59) 4.02 (0.60-27.06)
Yes 1.28 (1.10-1.53) 1.42 (1.13-1.78)
20 to <25 2.53 (1.66-3.87) 3.24 (1.81-5.81)
No [1 Reference] [1 Reference]
25 to <30 1.81 (1.22-2.70) 2.01 (1.14-3.53)
NLR
30 to <35 2.30 (1.38-3.82) 2.07 (1.08-4.04)
≥3 1.64 (1.40-1.91) 1.71 (1.39-2.12)
≥35 2.95 (1.58-5.54) 2.78 (1.13-6.85)
<3 [1 Reference] [1 Reference]
Cancer stage
NLR ≥ 3 and sarcopenia
I 1.81 (1.07-3.09) 4.21 (1.45-12.23)
Both 2.12 (1.70-2.65) 2.43 (1.79-3.29)
II 1.54 (1.02-2.31) 1.79 (0.96-3.33)
Neither [1 Reference] [1 Reference]
III 2.79 (2.05-3.81) 2.56 (1.77-3.73)
Abbreviations: HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio. Age at diagnosis, y
a
Cox proportional hazards models adjust for race/ethnicity (black, Hispanic, <65 1.65 (1.15-2.37) 1.70 (1.09-2.68)
Asian/Pacific islander, other, or non-Hispanic white), cancer site (colon or
rectum), and at-diagnosis values of age (years), body mass index category (<20, ≥65 2.32 (1.75-3.08) 3.15 (2.05 4.84)
20 to <25, 25 to <30, 30 to <35, or ⱖ35; calculated as weight in kilograms Sex
divided by height in meters squared), sex (male or female), and stage (I, II, or III). Male 2.05 (1.49-2.83) 2.16 (1.39-3.35)
b
All HR estimates are from the same model in which sarcopenia and NLR of 3 or
Female 2.30 (1.67-3.17) 2.71 (1.74-4.23)
greater are mutually adjusted, assuming independent effects.
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided
by height in meters squared); HR, hazard ratio.
As in previous studies, older age, later stage, and BMI of a
Cox proportional hazards models adjust for race/ethnicity (black, Hispanic,
greater than 35 were associated with lower overall survival (data Asian/Pacific islander, other, or non-Hispanic white), cancer site (colon or
not shown).19 However, there was no statistical evidence that rectum), and at-diagnosis values of age (years), BMI category (<20, 20 to <25,
25 to <30, 30 to <35, or ⱖ35), sex (male or female), and stage (I, II, or III),
BMI, stage, age, or sex modified the associations of NLR of 3 or unless stratified by those variables.
greater or sarcopenia with overall or CRC survival. Indeed, even b
All HRs compare patients with NLR of 3 or greater and sarcopenia vs patients
stage I (HR, 1.81; 95% CI, 1.07-3.09) and younger patients (<65 with NLR less than 3 and no sarcopenia. All HR estimates are from the same
years, HR, 1.65; 95% CI, 1.15-2.37) with NLR of 3 or greater and model in which sarcopenia and NLR of 3 or greater are mutually adjusted,
assuming independent effects.
sarcopenia had nearly 2-fold increased risk of death from any
cause compared with patients of similar age and stage but with
neither condition (Table 3). cancers,1-5,8,9,14 most studies addressed them individually and
In sensitivity analyses, further adjustment for cancer treat- in patients with metastatic disease. Our study newly sug-
ment and Charlson comorbidity index did not alter the HRs; gests that similar processes occur in nonmetastatic CRC: el-
these variables were excluded from models. evated NLR in the months prior to diagnosis and other aber-
rations in inflammatory markers were present in nearly half
of patients, were associated with sarcopenia, and were pre-
dictive of survival. Furthermore, we observed similar results
Discussion regardless of stage at diagnosis, suggesting that muscle break-
To our knowledge, this is the largest study to examine the re- down is not solely an artifact of increasing stage of disease;
lationship of markers of systemic inflammation to muscle mass some of the same mechanisms implicated in cancer cachexia
in CRC, and the only one to examine independent and com- may be operating earlier on in the cancer trajectory and lead-
bined associations with survival. In our cohort of 2470 pa- ing to relatively lower muscle mass long before the extreme
tients with stage I to III CRC, we found that greater NLR in the muscle loss that is the hallmark of cachexia. Our findings that
months prior to diagnosis was associated with sarcopenia at di- measures of inflammation were associated with sarcopenia and
agnosis. In addition, we found that the co-occurrence of high that the co-occurrence of inflammation and sarcopenia were
NLR and sarcopenia was associated with double the mortality associated with a high mortality risk are consistent with the
risk among patients with nonmetastatic CRC. Whereas both NLR limited prior literature on this topic. For example, a cross-
and sarcopenia increase with age and stage, they identify high- sectional study of 763 patients with stage I to IV CRC found that
risk subgroups of patients across the spectrum of age and stage. preoperative NLR and serum albumin levels were associated
Measures of inflammation and sarcopenia are easily obtain- with compromised muscle mass.29,30 With respect to sur-
able in the clinical setting and are each independently, and in vival, 1 prior study conducted in 117 men with small-cell lung
combination, powerful prognostic indicators in patients with cancer compared patients classified according to the co-
nonmetastatic cancer. occurrence of NLR and sarcopenia31; consistent with our re-
Although sarcopenia27 and systemic inflammation28 have sults, overall and progression-free survival were worse in the
previously been associated with prognosis in CRC and other group with both sarcopenia and elevated NLR.

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 Research Original Investigation
We hypothesize that inflammation both underlies and is
enhanced by muscle breakdown, part of a mutually reinforc-
ing cycle conducive to cancer progression. Markers of sys-
temic inflammation such as NLR are correlated with elevated
circulating concentrations of various cytokines in CRC,32 and
these are implicated in the activation of several catabolic path-
ways. For example, cytokines such as tumor necrosis factor and
interleukin 6 are produced by the tumor or surrounding cells
and promote protein degradation and decreased synthesis.33
Tumor necrosis factor inhibits skeletal myocyte differentia-
tion, promotes muscle atrophy,13,34 and contributes to insu-
lin resistance by impairing the insulin signaling pathway.35 In-
terleukin 6 can further reduce muscle protein synthesis.16
Increases in inflammatory cytokines can also lead to insulin
resistance and muscle wasting by activation of the ubiquitin-
proteasome proteolytic pathway,36 while muscle loss itself fur-
ther exacerbates insulin resistance.37,38 Low-grade, systemic
inflammation caused by the tumor (and exacerbated possi-
bly by obesity or insulin resistance) could drive local inflam-
mation in the muscle. This, in turn, contributes further to sys-
temic inflammation and muscle degradation (through both
increased proteolysis, manifesting in decreased muscle mass
[sarcopenia], and increased lipid deposition in skeletal muscle
[measured via CT muscle radiodensity]).15 Although outside
the scope of this analysis, excess fat may also play a role in this
vicious cycle: most of our patients were overweight or obese.
Intramuscular lipid levels, increased in obesity, can promote
lipotoxicity and insulin resistance, as well as enhancing se-
cretion of some proinflammatory myokines capable of both in-
ducing muscle dysfunction and exacerbating chronic, low-
grade systemic inflammation.15
Importantly, low BMI is not sufficient to identify low
muscle mass in an inflammatory and catabolic disease such
as CRC,7 particularly because obesity is common. Among the
patients with nonmetastatic disease in this study, fewer than
5% had a BMI of less than 20, yet 44% had sarcopenia and 46%
had a prediagnosis NLR of 3 or greater. These factors may help
identify patients with an elevated mortality risk where BMI
and/or weight change cannot.7,19-21 Using clinically acquired
CT images to aid in the early identification of sarcopenia could
facilitate therapeutic intervention to ensure a successful tran-
sition into survivorship. Treatments might include anti-
inflammatory drugs10,11 and/or resistance training, which is
proven to be safe and effective in maintaining and/or increas-
ing muscle mass and function in patients with cancer, im-
proves quality of life, and is associated with longer survival.39-42
This study cannot disentangle the web of bidirectional re-
lationships among inflammation, body composition, and can-
cer progression. Although there was a temporal order to our
data—patients who presented with sarcopenia at diagnosis had
elevated levels of NLR over the 24 months prior to diagno-
sis—we cannot determine whether this consistently inflamed
state precipitated sarcopenia or whether these are concur-
rent conditions. Cancer begins years before diagnosis, yet the
appearance of sarcopenia was evaluated once, for the first time,
at diagnosis; thus, we cannot determine how muscle mass
changes in relation to cancer initiation or the onset of inflam-
mation. Furthermore, whereas sarcopenia and elevated NLR
E6 JAMA Oncology Published online August 10, 2017 (Reprinted)
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Systemic Inflammation, Sarcopenia, and Survival in Colorectal Cancer
were independently associated with survival, we do not know
to what extent inflammation or sarcopenia are consequences
of a more aggressive tumor or a shared pathologic mecha-
nism vs conditions that enhance tumor growth.
We called the condition of low muscle “sarcopenia” in our
study because patients had nonmetastatic disease and did not
exhibit the degree of weight loss characteristic of cachexia.
However, we cannot truly distinguish whether patients (1) have
low muscle because of normal aging (sarcopenia) and sarco-
penia exacerbates their mortality risk once they have cancer,
(2) are precachexic, although early in the trajectory, or (3) both.
Inflammation underlies both sarcopenia and cachexia, but re-
cent reviews43 suggest that the pathogenesis of muscle loss in
normal aging differs from cancer cachexia, in which activa-
tion of the ubiquitin-proteasome system and nuclear fac-
tor–κB signaling result in rapid atrophy.44 Further research is
needed to elucidate the biological sequence of inflammation,
changes in body composition, and cancer progression.
Limitations
To our knowledge, this is the largest study to examine the re-
lationship between biomarkers of systemic inflammation and
sarcopenia in CRC, and the only study to examine whether NLR
and sarcopenia are independently associated with CRC sur-
vival. The use of clinically acquired CT scans makes our ap-
proach replicable at low cost in clinical practice. This link to
clinical practice also presents a limitation: markers of sys-
temic inflammation were obtained opportunistically through
routine laboratory test results available in the electronic medi-
cal record. C-reactive protein level was available for few pa-
tients (<10%) and was therefore not used. However, results
were largely consistent regardless of the metric of systemic in-
flammation examined, as well as across subgroups defined by
age, BMI, sex, and stage. As in any observational study, re-
sidual confounding is possible; for example, physical activity
is not well measured in the electronic medical record and pa-
tients with higher NLR may experience fatigue leading to in-
activity and therefore to compromised muscle mass. Further-
more, socioeconomic status, diet, and alcohol consumption
were not captured and could plausibly influence NLR, sarco-
penia, and cancer death.
Conclusions
Both sarcopenia and high NLR were independent prognostic
indicators in nonmetastatic CRC. If our findings are con-
firmed by additional studies, these 2 biomarkers are already
collected in routine care and thus have high potential for use
in clinical prognostication. We also found that the co-
occurrence of sarcopenia and inflammation at diagnosis iden-
tified patients with a more than 2-fold risk of mortality com-
pared with patients with neither condition; before this
information can be used to influence treatment decisions or
tailor interventions, future research must clarify whether
reducing systemic inflammation or increasing muscle mass
can enhance progression-free survival and through what
mechanisms.
jamaoncology.com
 Systemic Inflammation, Sarcopenia, and Survival in Colorectal Cancer
ARTICLE INFORMATION
Accepted for Publication: June 5, 2017.
Published Online: August 10, 2017.
doi:10.1001/jamaoncol.2017.2319
Author Contributions: Drs Cespedes Feliciano and
Caan had full access to all the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Cespedes Feliciano,
Prado, Kroenke, Alexeeff, Caan.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Cespedes Feliciano.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Cespedes Feliciano, Bradshaw,
Alexeeff, Weltzien.
Obtained funding: Prado, Caan.
Administrative, technical, or material support:
Cespedes Feliciano, Prado, Castillo.
Supervision: Cespedes Feliciano, Prado, Corley,
Caan.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by
grant R01 CA175011-01 from the National Cancer
Institute of the National Institutes of Health.
Role of the Funder/Sponsor: The funding source
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Previous Presentation: An earlier version of this
analysis was presented as a poster at the American
Association for Cancer Research Annual Meeting;
April 3, 2017; Washington, DC.
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