CP ONCO CA GASTRICO Implications

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Implications of Inadequate Lymph Node Staging in Resectable
Gastric Cancer
A Contemporary Analysis Using the National Cancer Data Base
Jashodeep Datta, MD1; Russell S. Lewis Jr, BA1; Ronac Mamtani, MD, MSCE2; Diana Stripp, MD3; Rachel R. Kelz, MD, MSCE1;
Jeffrey A. Drebin, MD, PhD1; Douglas L. Fraker, MD1; Giorgos C. Karakousis, MD1; and Robert E. Roses, MD1
BACKGROUND: National guidelines recommend examination of � 15 lymph nodes for adequate staging of resectable gastric adeno-
carcinoma (GA). The relevance of these guidelines, which were established before the increasing use of multimodality therapy, and
the impact of inadequate lymph node staging (LNS) in a contemporary cohort have not been extensively explored. METHODS: Stage
I-III GA patients who underwent gastrectomy from 1998 to 2011 were identified using the National Cancer Data Base. Trends in LNS
adequacy, predictors of inadequate LNS (< 15 LN examined) and the relationship between LNS and overall survival (OS) were ana-
lyzed. RESULTS: In 22,409 patients, compliance with LNS guidelines was poor (inadequate LNS in 61.2% of cases, median LN har-
vested in 11.0%). Subtotal/partial gastrectomy was the strongest predictor of inadequate LNS (OR52.01, P< .001). Survival analyses
included 9139 patients with minimum 5 years follow-up; median, 1-year, and 5-year survival was 35.6 months, 75.5%, and 39.7%,
respectively. LN positivity (HR5 1.90) and age >76 years (HR5 1.73) were the strongest predictors of worse OS (both P< .001). Inad-
equate LNS was independently associated with worse OS (HR5 1.33, P<.001). Median OS after inadequate compared to adequate
LNS was significantly worse (33.3 months versus 42.0 months, P< .001), regardless of AJCC clinical stage subgroup or tumor T classi-
fication (both P<.001). CONCLUSIONS: Adequate LNS is achieved in a minority of patients. Inadequate LNS was independently asso-
ciated with worse OS. Examination of � 15 LN is a reproducible prognosticator of gastric cancer outcomes in the United States and
should continue to serve as a benchmark for quality of care. Cancer 2014;120:2855-65. VC 2014 American Cancer Society.
KEYWORDS: gastric cancer, lymph node staging, survival, multimodality therapy, inadequate.
INTRODUCTION
In 2013, an estimated 21,600 new cases of gastric adenocarcinoma (GA) will be diagnosed in the United States. Despite a
3% per year decline in the mortality rate for GA over the last decade, 5-year survival in the United States remains 27.7%.1
In an attempt to explain inferior stage-stratified survival for GA in the United States compared with Japan, a “treatment
hypothesis” has been proposed: extended or D2 lymph node (LN) dissection long advocated by surgeons in Asia improves
overall survival (OS).2-4 Notably, 2 Western randomized clinical trials (RCTs) investigating the effect of D2 versus D1
lymphadenectomy on OS have failed to demonstrate a benefit with extended LN dissection.5,6 Recently, 15-year follow-
up from the Dutch trial suggested a disease-free survival benefit with D2 resection, although no improvement was
observed in OS compared with D1 resection (log-rank P5 .34).7
Despite lingering controversy regarding the impact of anatomically based LN dissection (D2) on survival inWestern
populations, efforts to standardize numerically based lymph node staging (LNS) practices across institutions in the United
States have been initiated.8,9 In 1997, the American Joint Commission on Cancer (AJCC) 5th edition guidelines recom-
mended examination of � 15 LN for adequate staging of resectable GA.10 Likewise, current National Comprehensive
Cancer Network (NCCN) guidelines advocate examination of � 15 LN.11 These recommendations have, in part, been
driven by: 1) studies showing the prognostic value of LN number regardless of anatomic location;12 and 2) mounting ret-
rospective evidence from US cancer registry studies suggesting that adequate LNS (ie, � 15 LN) is associated with
improved OS.3,9,12-14
Corresponding author: Robert E. Roses, MD, Department of Surgery, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia,
PA 19104; Fax: (215) 615-0555; robert.roses@uphs.upenn.edu
1Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; 2Division of Hematology/Oncology, University of
Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; 3Department of Radiation Oncology, University of Pennsylvania Perelman School of
Medicine, Philadelphia, Pennsylvania
DOI: 10.1002/cncr.28780, Received: January 27, 2014; Revised: March 20, 2014; Accepted: April 16, 2014, Published online May 22, 2014 in Wiley Online
Library (wileyonlinelibrary.com)
Cancer September 15, 2014 2855
Original Article
The surgical treatment of patients in these studies,
however, occurred before increasing implementation of
multimodality therapy in GA. Results from the Inter-
group 011615 and MAGIC16 trials, published in 2001
and 2006, respectively, established improved outcomes
associated with multimodality therapy compared with
surgery alone in GA. Consequently, use of perioperative
chemotherapy or adjuvant chemoradiotherapy (CRT) has
increased dramatically. Indeed, a recent National Cancer
Data Base (NCDB) study revealed that rates of neoadju-
vant or adjuvant systemic therapy receipt in GA increased
by 71% in the United States from 1998 to 2007.17 The
impact of LNS in a US cohort in whom multimodality
therapy was increasingly used, however, has not been
addressed in a randomized or retrospective fashion.
Although evidence supporting the AJCC/NCCN
recommendations for LNS adequacy is increasingly
acknowledged, surgical compliance with these guidelines
has been disturbingly poor to date, ranging from 18% in
an NCDB report from 20003 to 32% in a Surveillance,
Epidemiology, and End Results (SEER) analysis from
2005.8 These data suggest that surgical undertreatment of
GA continues to be a problem in the United States, and
underscore the need for further characterization of demo-
graphic and clinical factors predicting inadequate LNS.
We, therefore, sought to: 1) assess temporal trends in sur-
gical compliance with established AJCC/NCCN guide-
lines for LNS adequacy; 2) identify factors predicting
inadequate LNS; and 3) determine the impact of inad-
equate LNS on OS in the era of increasing multimodality
therapy use for GA, using a contemporary cohort from
the NCDB.
MATERIALS AND METHODS
Data Source
After approval by the institutional review board, data
from 1998 to 2011 were acquired from the esophagogas-
tric participant use file (PUF) of the NCDB, a collabora-
tive effort between the American College of Surgeons’
Commission on Cancer (CoC) and the American Cancer
Society. Established in 1989, the NCDB is a comprehen-
sive oncology surveillance program that captures approxi-
mately 70% of new cancer diagnoses from > 1500 CoC-
approved centers.18
Patient Selection
We identified patients aged � 18 years with invasive gas-
tric adenocarcinoma (defined by the International Classi-
fication of Disease–Oncology, 3rd revision19) and
potentially resectable disease (AJCC clinical stage I-III).
Patients were excluded if they had an indeterminate LN
harvest, did not undergo at least partial gastrectomy, or
underwent palliative resections (bleeding, obstruction,
perforation). Because of the previously described detri-
mental effect of neoadjuvant radiotherapy (RT) on LNS,
patients receiving preoperative RT were excluded from
analysis.9
Variables
LNS adequacy was defined according to criteria estab-
lished in the AJCC 5th/6th editions10 because a majority
of patients in this cohort received surgical treatment dur-
ing this period (ie, 1997-2010). Inadequate LNS was
defined as examination of < 15 LN, whereas adequate
LNS was defined as examination of � 15 LN. Demo-
graphic/preoperativeand clinical variables evaluated are
detailed in Table 1. A variable accounting for the timing
of multimodality therapy administration was created.
Patients were classified as surgery only (no chemotherapy/
RT), neoadjuvant chemotherapy only, or adjuvant ther-
apy (chemotherapy with or without RT). Because receipt
of surgery only or adjuvant therapy cannot be considered
predictive variables per se, a separate variable was created
classifying patients who received only neoadjuvant chem-
otherapy to assess its effect of LNS adequacy. OS was
defined as the interval between date of diagnosis and date
of death or last contact.
Statistical Analysis
Descriptive statistics were performed. Simple linear
regression was used to analyze trends in surgical compli-
ance with LNS guidelines from 1998-2011. Two metrics
were employed: 1) median number of LNs harvested per
case in a particular year, and 2) percentage of cases per
year with adequate LNS (% adequacy/year).
Univariate logistic regression was used to determine
relationships between demographic/clinical factors and
inadequate LNS. A multivariable logistic regression
model was developed to control for confounders using a
backward selection method. The threshold for variable re-
moval was P> .05. Odds ratios (OR) and 95% confi-
dence intervals (CI) were generated. Goodness-of-fit tests
were conducted to ensure model validity.
The Kaplan-Meier method was used to estimate sur-
vival function.20 Univariate comparisons between groups
were performed by the log-rank test. Associations between
AJCC clinical stage subgroups (I-III) or pathologic T clas-
sification (T1-4) and OS were analyzed for LN cutoff
points of 15, 20, and 30 LN. The 10 LN cutoff was not
analyzed, because stage migration is most evident when
Original Article
2856 Cancer September 15, 2014
TABLE 1. Demographic and Clinical Characteristics of the Overall Cohort (n522,409), Relative Proportion of
Patients Undergoing Inadequate Lymph Node Staging (LNS), and Multivariate Logistic Regression Model
for Predictors of Inadequate LNS in Resectable Gastric Adenocarcinoma (n522,409)
Characteristic
No. in Overall
Cohort (%)
No. of Patients
With Inadequate LNS (%)
Odds Ratio
(95% CI) Pk
All patients 22,409 (100) 13,719 (61.2) – –
Demographic
Age quartiles, y
<56 4431 (19.8) 2418 (54.7) Ref NA
56-66 5701 (25.4) 3300 (57.9) 0.96 (0.85-1.08) .475
67-76 6687 (29.8) 4156 (62.2) 1.06 (0.95-1.19) .293
>76 5590 (25.0) 3845 (68.8) 1.36 (1.21-1.53) <.001
Sex
Male 13,847 (61.8) 8457 (61.1) – –
Female 8562 (38.2) 5262 (61.5)
Race
White 16,845 (75.2) 10,510 (62.4) Ref NA
Black 3140 (14.0) 1957 (62.3) 0.96 (0.86-1.07) .467
Asian 1569 (7.0) 766 (48.8) 0.61 (0.52-0.71) <.001
Other (American Indian, Pacific Islander, etc.) 855 (3.8) 486 (56.8) 0.86 (0.70-1.05) .142
Hispanic ethnicity
No 20,169 (90.0) 12,467 (61.8) Ref NA
Yes 2240 (10.0) 1252 (55.9) 0.82 (0.72-0.94) .003
Charlson Comorbidity Scorea
0 12,221 (68.5) 6851 (56.1) Ref NA
1 4149 (23.2) 2545 (61.3) 1.14 (1.04-1.24) .006
�2 1481 (8.3) 984 (66.4) 1.33 (1.16-1.53) <.001
Insurance typeb
Private 7847 (36.2) 4516 (57.6) – –
Medicare 11,727 (54.1) 7584 (64.7)
Medicaid 1252 (5.8) 673 (53.8)
Other (VA, Military, etc.) 177 (0.8) 98 (55.4)
Uninsured 657 (3.0) 392 (59.7)
Median incomec
�$46,000 8270 (39.3) 4908 (59.3) – –
<$46,000 12,800 (60.7) 7994 (62.5)
Facility location
Northeast 5801 (25.9) 3207 (55.3) Ref NA
West 4287 (19.1) 2455 (57.3) 1.15 (1.02-1.30) .02
Midwest 4887 (21.8) 3119 (63.8) 1.41 (1.26-1.57) <.001
South 7434 (33.2) 4938 (66.4) 1.62 (1.46-1.80) <.001
Urban/rurald
Metro 17,881 (85.3) 10,857 (60.7) – –
Urban 2719 (13.0) 1735 (63.8)
Rural 354 (1.7) 224 (63.3)
Facility type
Academic/research 9668 (43.1) 5067 (52.4) Ref NA
Community cancer center 2042 (9.1) 1446 (70.8) 1.92 (1.66-2.22) <.001
Comprehensive community cancer center 10,164 (45.4) 6780 (66.7) 1.65 (1.52-1.79) <.001
Other/nondesignated 535 (2.4) 426 (79.6) 3.61 (2.42-5.40) <.001
Clinical (Pathologic/Anatomic/Operative)
Primary tumor location
Distal 7073 (31.5) 4268 (61.8) – –
Proximal 7299 (32.6) 4371 (58.7)
Lesser/greater curvature/overlapping regions 8037 (35.9) 5062 (63.0)
Tumor sizee
<2 cm 4488 (23.2) 3054 (68.0) Ref NA
2-5 cm 8509 (44.0) 5211 (61.2) 0.79 (0.71-0.87) <.001
>5 cm 6327 (32.8) 3321 (52.5) 0.59 (0.53-0.66) <.001
Tumor gradef
Well/moderately differentiated 7985 (39.3) 5221 (65.4) Ref NA
Poorly/undifferentiated or anaplastic 12,355 (60.7) 6817 (55.2) 0.77 (0.71-0.84) <.001
Pathologic T classificationg
T 1/2 11,697 (58.1) 7492 (64.1) – –
T 3/4 8423 (41.9) 4482 (53.2)
Pathologic lymph node positivity
Negative 8924 (39.8) 5644 (63.2) j j
Lymph Node Staging Gastric Cancer/Datta et al
Cancer September 15, 2014 2857
< 10 LN are examined in resectable GA.13,21 Cox propor-
tional hazard regression served as a multivariate model
using a backward elimination method for all covariates.
The threshold for variable removal was P> .05. Hazard
ratios (HR) and 95% CI were generated. All tests were
2-sided. A P value of � 0.05 was considered statistically
significant. Analyses were performed with IBM SPSS ver-
sion 20.0 (SPSS Inc, Chicago, IL).
RESULTS
Descriptive Statistics and Multimodality Therapy
Use
The NCDB esophagogastric PUF included 206,928
patients with invasive GA treated from 1998 to 2011.
Structured queries allowed exclusion of patients with stage
IV (n5 53,203) or unknown stage (n5 103,685) disease,
indeterminate LN harvest (n5 749), those who did not
undergo at least partial gastrectomy (n5 22,210), and
underwent palliative resections (n5 114). Of the remain-
ing patients, those receiving preoperative RT (n5 4672)
were excluded, yielding a study cohort of 22,409 patients.
Median age was 68 (interquartile range [IQR]
58-76) years, and a majority of patients were male
(61.8%) and white (75.2%). Facility type and location
with the highest case volume were comprehensive com-
munity cancer centers (45.4%) and southern region
(33.2%), respectively. Primary tumor location was simi-
larly distributed between distal (31.5%), proximal
(32.6%), and lesser/greater curvatures or overlapping
regions (35.9%). A majority of tumors were > 2 cm
(76.8%) and had poorly/undifferentiated histology
(60.7%). Subtotal gastrectomy was the most commonly
performed operation (54.1%), and microscopically nega-
tive margins (R0) were achieved in 83.3% of cases. Almost
half of patients (49.7%) underwent surgery alone, 14.3%
received neoadjuvant chemotherapy alone followed by
surgery, and 36.0% received surgery plus adjuvant therapy
(Table 1). Of the 12,755 (81.2%) patients eligible for ad-
juvant therapy according to Intergroup 0116 trial criteria
TABLE 1. Continued
Characteristic
No. in Overall
Cohort (%)
No. of Patients
With Inadequate LNS (%)
Odds Ratio
(95% CI) Pk
Positive 10,333 (46.1) 4931 (47.7)
No nodes examined/unknown 3152 (14.1) 3144 (99.7)
AJCC clinical stage
Stage I 11,338 (50.6) 7679 (67.7) Ref NA
Stage II 5697 (25.4) 3256 (57.2) 0.90 (0.82-0.99) .025
Stage III 5374 (24.0) 2784 (51.8) 0.76 (0.68-0.84) <.001
Type of gastrectomy
Near total/total 2793 (12.5) 1260 (45.1) Ref NA
Subtotal/partial 12,131 (54.1) 8335 (68.7) 2.01 (1.78-2.26) <.001
Combined with partial esophageal resection 5287 (23.6) 3014 (57.0) 1.35 (1.19-1.54) <.001
Multivisceral/en bloc 2198 (9.8) 1110 (50.5) 1.19 (1.01-1.40) .034
Resection margin 18,677 (83.3) 11,408 (61.1) – –
R0 1468 (6.6) 838 (57.1)
R1 144 (0.6) 94 (65.3)
R2 2120 (9.5) 1379 (65.0)
Indeterminate
Multimodality therapy
Timing of multimodality therapyh
No chemo6RT (surgery only) 7806 (49.7) 5032 (64.5) j j
Neoadjuvant chemo only 2247 (14.3) 893 (39.7)
Adjuvant chemo/RT/both 5650 (36.0) 3013 (53.3)
Receipt of neoadjuvantchemotherapyi
None 13,456 (85.8) 8045 (59.8) Ref NA
Neoadjuvant chemotherapy 2247 (14.3) 893 (39.7) 0.57 (0.50-0.65) <.001
Abbreviations: AJCC, American Joint Commission on Cancer; CI, confidence interval; NA, not applicable; Ref, reference; RT, radiotherapy; VA, Veteran Affairs.
a Charlson Comorbidity Score data was missing in 4558 patients
b Insurance type data was missing in 749 patients
cMedian income data was missing in 1339 patients
dUrban/Rural data was missing in 1455 patients
e Tumor size information was missing in 3085 patients
f Tumor grade information was missing in 2069 patients
g Pathologic T classification data was missing in 2289 patients
hMultimodality therapy data was missing in 6706 patients
i Separate variable created to assess if neoadjuvant chemo alone was a prognostic factor in LNS (see Materials and Methods).
j These variables not included in multivariate logistic regression because this data is obtained postoperatively, and is not a predictive variable per se
k Bold values indicate statistical significance.
Original Article
2858 Cancer September 15, 2014
(ie, AJCC stage IB or T1N1/T2N0 and higher),15 5524
(43.3%) received any adjuvant therapy. Of these, 2910
(52.7%) patients underwent inadequate LNS. By com-
parison, 4009 (55.4%) patients with stage IB disease or
higher who did not receive adjuvant therapy underwent
inadequate LNS (P5 0.001).
Trends in Surgical Compliance With LNS
Guidelines
The median number of LN examined for the cohort was
11 (IQR 4-19), with 3134 (14.0%) patients having zero
LN examined. Overall, 13,719 patients (61.2%) patients
underwent inadequate LNS by AJCC/NCCN criteria. The
6 to 10 LN count category comprised the highest patient
frequency (4069, 18.1%, Fig. 1). Median number of LN
examined per case increased from 8 (IQR 2-14) to 12
(IQR 3-20) between 1998 and 2011 (P< .0001), with the
highest median LN count (14; IQR 7-22) observed in
2009. Likewise, the proportion of patients undergoing
adequate LNS from 1998 to 2011 increased by 18.5%,
from 23.7% to 42.3% adequacy/year (P< .0001), with the
highest LNS adequacy compliance rate (47.8%) observed
in 2009 (Fig. 2). As such, 57.7% of patients underwent
inadequate LNS in the United States as of 2011.
Predictors of Inadequate LNS
Excluding sex, all demographic and clinical variables eval-
uated were associated with inadequate LNS on univariate
analysis (all P< .01; data not shown). After adjusting for
potential confounders, age> 76 years, comorbidity, treat-
ment at nonacademic facilities outside the Northeast, tu-
mor size< 2 cm, lower grade tumors, lower AJCC clinical
stage, and resection type other than total gastrectomy
were independent predictors of inadequate LNS (all
P< .05; Table 1). Undergoing subtotal/partial gastrec-
tomy was the strongest predictor of inadequate LNS
(OR 2.01, 95% CI 1.78-2.26, P< .001). In addition,
compared with academic/research institutions, the odds
of undergoing inadequate LNS was almost 2 times
(OR 1.92, 95% CI 1.66-2.22; P< .001) higher at Com-
munity Cancer centers. Asian race (P< .001), Hispanic
ethnicity (P5 .003), and receipt of neoadjuvant chemo-
therapy alone (P< .001) conferred a decreased risk for
inadequate LNS.
Multivariable Survival Model
Survival analyses included 9139 patients between 1998
and 2006, with a minimum follow-up of 5 years.18 Both
AJCC clinical stage and pathologic T classification and
LN positivity were included as covariates in the Cox pro-
portional hazard model (Table 2). After adjusting for
potential confounders, inadequate LNS conferred an
increased risk of death (HR 1.33, 95% CI 1.24-1.43,
P< .001). Other predictors of worse OS were advanced
age, Medicare/Medicaid insurance, income < $46,000,
treatment at nonacademic facilities, proximal tumor loca-
tion, tumor size > 2 cm, poorly/undifferentiated histol-
ogy, pathologic T classification 3/4 and LN positivity,
AJCC clinical stage III, R1 resection (all P< .05). LN
positivity (HR 1.90, 95% CI 1.75-2.06, P< .001), age
> 76 years (HR 1.73, 95% CI 1.53-1.97, P< .001), and
Figure 1. Absolute and relative frequency of patients within
lymph node (LN) examination categories for the overall
cohort (n522,409). [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
Figure 2. Trends in surgical compliance with established guide-
lines for lymph node staging (LNS) adequacy, assessed by me-
dian number of lymph nodes (LN) harvested per case in a
particular year, and percentage of cases per year with
adequate LNS (% adequacy/year). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
Lymph Node Staging Gastric Cancer/Datta et al
Cancer September 15, 2014 2859
TABLE 2. Final Cox Proportional Hazards Model for Overall Survival in the Patient Cohort With Minimum
5-Year Follow-Up (n59139)
Variable Hazard Ratio (95% CI) Pa
No. of patients5 9139
Age quartiles, y
<56 Ref NA
56-66 1.11 (0.99-1.24) .067
67-76 1.25 (1.11-1.42) <.001
>76 1.73 (1.53-1.97) <.001
Sex
Male Ref NA
Female 0.89 (0.83-0.96) .001
Race
White Ref NA
Black 1.05 (0.94-1.16) .408
Asian 0.71 (0.62-0.82) <.001
Other (American Indian, Pacific Islander, etc.) 0.94 (0.77-1.14) .51
Hispanic ethnicity
No Ref NA
Yes 0.79 (0.69-0.89) <.001
Insurance type
Uninsured Ref NA
Private Insurance 1.08 (0.84-1.40) .533
Medicare 1.58 (1.19-2.11) .002
Medicaid 1.30 (1.00-1.68) .047
Other (VA, Military, etc.) 1.19 (0.71-2.02) .511
Median income
�$46,000 Ref NA
<$46,000 1.08 (1.01-1.16) .018
Facility type/volume
Academic/research Ref NA
Community cancer center 1.17 (1.04-1.31) .008
Comprehensive community cancer center 1.14 (1.06-1.22) <.001
Other/undesignated 1.24 (1.01-1.52) .038
Primary tumor location
Distal Ref NA
Proximal 1.09 (1.00-1.19) .044
Lesser/greater curvature/overlapping regions 0.95 (0.88-1.03) .229
Tumor size
<2 cm Ref NA
2-5 cm 1.22 (1.11-1.34) <.001
>5 cm 1.24 (1.11-1.37) <.001
Tumor grade
Well/moderately differentiated Ref NA
Poorly/undifferentiated or anaplastic 1.13 (1.05-1.21) <.001
Pathologic T classification
T 1/2 Ref NA
T 3/4 1.61 (1.49-1.75) <.001
Pathologic lymph node positivity
Negative Ref NA
Positive 1.90 (1.75-2.06) <.001
Lymph node staging (LNS) adequacy
Adequate LNS (�15 LN) Ref NA
Inadequate LNS (<15 LN) 1.33 (1.24-1.43) <.001
AJCC clinical stage
Stage I Ref NA
Stage II 1.02 (0.93-1.11) .663
Stage III 1.16 (1.05-1.28) .003
Tumor margins
R0 Ref NA
R1 1.67 (1.49-1.87) <.001
R2 1.27 (0.89-1.79) .182
Indeterminate 1.46 (1.31-1.63) <.001
Timing of multimodality therapy
No chemo6RT (surgery only) Ref NA
Neoadjuvant chemo only 0.66 (0.46-0.94) .02
Adjuvant chemo/RT/both 0.65 (0.56-0.75) <.001
Abbreviations: AJCC, American Joint Commission on Cancer; CI, confidence interval; NA, not applicable; Ref, reference; RT, radiotherapy; VA, Veteran Affairs.
a Bold values indicate statistical significance
R1 resection (HR 1.67, 95% CI 1.49-1.87, P< .001)
were the strongest predictors of worse OS.
Notably, receipt of neoadjuvant chemotherapy
alone (HR5 0.66, 95% CI5 0.46-0.94, P5 0.02) or
any adjuvant therapy (HR5 0.65, 95% CI5 0.56-0.75,
P< .001) was associated with improved OS in this model.
Female sex (P5 0.001), Asian race (P< .001), and His-
panic ethnicity (P< .001) were also predictive of
improved OS. Charlson score, facility location, urban/ru-
ral setting, and gastrectomy type did not retain signifi-
cance after adjusting for confounders.
Univariate Survival Analysis Based on LNS
Adequacy
At a median follow-up of 88 months (IQR 67-117
months), median OS for eligible patients was 35.6
months; 1- and 5-year actuarial survival rates were 75.5%
and 39.7%, respectively. Univariate survival results for
the overall cohort and AJCCclinical stage subgroups
based on LNS adequacy (< 15 or� 15 LN) are illustrated
in Figure 3. Median OS of patients receiving inadequate
LNS were significantly worse than those receiving
adequate LNS (33.3 months versus 42.0 months;
P< .001). The association between inadequate LNS and
poorer OS was significant in every AJCC clinical stage
subgroup (stage I: 61.7 months [inadequate] versus 86.2
months [adequate]; stage II: 25.5 months versus 42.7
months; stage III: 15.5 months versus 23.1 months; all
P< .001). When varying LN cutoff points (ie, � 20 or
� 30 LN) were examined, OS increased with increasing
LN counts in the overall cohort and all AJCC stage sub-
groups (Table 3).
Similar OS patterns with increasing LN counts were
observed across tumor T classifications (Table 3). Median
OS of patients with T classification 1 through 4 tumors
undergoing inadequate LNS was significantly worse com-
pared to those undergoing adequate LNS (all P< .01;
Fig. 4).
Cutpoint Survival and Stage Migration Analyses
A cutpoint analysis was performed to determine the LN
count that generated the most statistically significant actua-
rial survival difference between resulting groups. The mag-
nitude of the survival difference between varying LN
Figure 3. Impact of inadequate lymph node staging (LNS) on overall survival in resectable gastric adenocarcinoma, stratified by
AJCC clinical stage. Overall survival was significantly worse in patients with inadequate LNS (< 15 lymph nodes examined),
regardless of clinical stage: (A) overall cohort; (B) stage I; (C) stage II; (D) stage III. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
Lymph Node Staging Gastric Cancer/Datta et al
Cancer September 15, 2014 2861
cutpoints (� 14 versus � 15, � 19 versus � 20, etc.) was
determined using the log-rank test chi-square statistic.13, 14
For all AJCC clinical stage subgroups, the greatest survival
difference at every LN cutpoint was identified at the < 15
(inadequate) versus � 15 (adequate) LN level (Table 4).
The most pronounced survival difference between
adequately and inadequately staged groups was observed in
AJCC clinical stage II patients (chi-square 46.35,
P< .001). This survival disparity can be appreciated
graphically in Figure 3C. Survival differences remained sig-
nificant for� 20 and� 30 LN cutpoints as well, always in
favor of higher LN counts.
The effect of stage migration was tested as previously
described.13 Linear regression showed a proportional
increase in TNM stage (dependent variable) with increas-
ing numbers of LN examined or positive LN detected
(independent variables; both P< .001). Moreover, as
the number of negative LN examined (total LN
minus positive LN) increased, TNM stage decreased
(P< .001).
DISCUSSION
The adoption of numerically rather than anatomically
based LNS and recommendation of a LN examination
threshold (ie,� 15 LN) in GA by the AJCC/NCCNwere
intended to simplify staging and standardize surgery in
the United States.22 Our results reaffirm the relevance of
these guidelines in a contemporary cohort and indicate
that inadequate LNS is an independent predictor of worse
OS, regardless of AJCC clinical stage subgroup or tumor
T classification. Moreover, examination of � 15 LN
resulted in the greatest survival differences in every AJCC
stage subgroup, supporting the current LN examination
threshold as a “minimum target” in GA resections.
Despite studies from individual institutions report-
ing admirable rates of LNS adequacy (range, 54%-
73%),12,23 evidence from US cancer registries has demon-
strated lower rates of adequate LNS in the United States
overall.3,8,9 A SEER database study comparing pre- and
post-1997 LNS trends showed an increase in adequate
LNS from 27% pre-1997 to 33.1% between 1998 and
2002,9 suggesting that formalization of LNS guidelines
might ultimately improve LNS performance. Our assess-
ment of a post-1997 cohort, however, reveals that surgical
compliance with LNS guidelines continues to be poor:
61.2% of patients underwent examination of < 15 LN
during the study period. Despite an initial rise in LNS
compliance, a worsening trend in 2 performance metrics
TABLE 3. Overall Survival of Study Cohort (Minimum 5-Year Follow-Up) Stratified by AJCC Clinical Stage
Subgroups and Tumor T Classifications Given Varying Lymph Node Examination Cutoff Levels (15, 20, and
30)
15 LN Cutoff 20 LN Cutoff 30 LN Cutoff
N
Median
Overall
Survival
(months) Log-Rank Pa n
Median
Overall Sur-
vival
(months) Log-Rank Pa n
Median
Overall
Survival
(months) Log-Rank Pa
Overall Cohort <LN cutoff 6285 33.3 7500 33.6 8,608 34.8
�LN cutoff 2854 42.0 <.001 1639 47.9 <.001 531 63.6 <.001
Stratified by AJCC clinical stage
Stage I <LN cutoff 3387 61.7 3869 62.8 4,325 64.8
�LN cutoff 1146 86.2 <.001 664 89.2 <.001 208 91.1 .001
Stage II <LN cutoff 1455 25.5 1769 27.5 2,043 29.3
�LN cutoff 727 42.7 <.001 413 47.0 <.001 139 73.6 <.001
Stage III <LN cutoff 1443 15.5 1862 16.0 2,240 16.9
�LN cutoff 981 23.1 <.001 562 25.8 <.001 184 30.5 <.001
Stratified by tumor T classification
T1 <LN cutoff 1435 91.2 1626 95.6 1,800 100.5
�LN cutoff 455 118.2 <.001 264 118.2 <.001 90 134.0 .05
T2 <LN cutoff 1876 35.5 2274 37.9 2,648 39.7
�LN cutoff 963 60.7 <.001 565 68.9 <.001 191 78.1 <.001
T3 <LN cutoff 1711 17.2 2193 17.9 2,636 18.8
�LN cutoff 1112 24.9 <.001 630 27.2 <.001 187 31.4 <.001
T4 <LN cutoff 260 11.6 317 11.6 362 11.9
�LN cutoff 132 13.9 .006 75 16.9 .027 30 18.9 0.397
Abbreviations: AJCC, American Joint Commission on Cancer; LN, lymph node.
a Bold values indicate statistical significance.
Original Article
2862 Cancer September 15, 2014
(% adequacy/year and LNs harvested/case/year) was
observed between 2009 and 2011.
Several demographic and clinical factors affected the
odds of inadequate LNS. Subtotal/partial gastrectomy
was the strongest predictor of inadequate LNS, an associa-
tion that has been observed in other population-based
reports.9,24 This may reflect a tendency toward “lower
impact” operations that prioritize gastric remnant volume
over oncologic principle in distal tumors. In addition,
inadequate LNS occurred less frequently at academic/
research institutions in the Northeast, affirming previ-
ously identified regional variations in LNS adequacy.8,9
Importantly, more than half of the patients even in these
“higher-performing” centers underwent inadequate LNS
(52.4% in academic centers, 55.3% in Northeastern cen-
ters), suggesting considerable room for improvement.
Figure 4. Impact of inadequate lymph node staging (LNS) on overall survival is shown in gastric adenocarcinoma, stratified by
pathologic T classification. Overall survival was significantly worse in patients with inadequate LNS (< 15 lymph nodes examined),
regardless of pathologic T classification: (A) T1; (B) T2; (C) T3; (D) T4. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
TABLE 4. Cutpoint Analysis to Determine the Most Statistically Significant Survival Difference Among AJCC
Clinical Stage Subgroups by Varying LN Harvest Levels
LN Cutpoint Level
Stage I Stage II Stage III
v2 Pa v2 Pa v2 Pa
�14 vs. �15 25.23b <.001 46.35b <.001 43.05b <.001
�19 vs. �20 24.35 <.001 27.68 <.001 38.34 <.001
�29 vs. �30 10.16 <.001 14.67 <.001 27.98 <.001
�39 vs. �40 6.99 .008 1.99 .158 9.43 .002
Abbreviations: AJCC, American Joint Commission on Cancer; LN, lymph node.
a Bold values indicate statistical significance
b Indicates the LN cutpoint level with the largest chi-square log-rank statistic, ie, the greatest detectable survival differences between groups.
Lymph Node Staging Gastric Cancer/Datta et al
Cancer September 15, 2014 2863
Receipt of neoadjuvant RT has been associated with
a higher likelihoodof inadequate LNS,9 which may be
related to the challenges associated with post-RT surgical
dissection and pathologic assessment of specimens.25 The
effect of neoadjuvant chemotherapy alone on LN counts,
however, is not well characterized. After excluding
patients receiving preoperative RT, receipt of neoadjuvant
chemotherapy decreased the odds of inadequate LNS sig-
nificantly, with 60.3% of patients undergoing examina-
tion of � 15 LN. The etiology underlying this novel
observation warrants further exploration given prior data
indicating that neoadjuvant chemotherapy may be associ-
ated with inadequate LNS.26
Five-year survival in our cohort undergoing
curative-intent gastrectomy was 39.7%, a rate that is con-
sistent (ie, 28%-35%) with other reports of Western
cohorts.3 In our survival model, inadequate LNS was in-
dependently associated with worse OS, regardless of
AJCC clinical stage or tumor T classification. This associ-
ation has most often been attributed to stage migration,
which is particularly pronounced in stage II and III
GA.22,27 Our linear regression analysis does point to stage
migration as the dominant contributor to improved OS.
It may not, however, entirely explain the improved sur-
vival seen with increasing nodal harvest in early disease
states. For instance, in patients with T1 tumors, OS
improved from 118.2 months when� 15 LN were exam-
ined to 134.0 months when � 30 LN were examined. In
such cases, the frequency of occult nodal involvement
should be relatively low when � 16 LNs are examined,
suggesting other explanations. Though difficult to sub-
stantiate, this might reflect a therapeutic benefit of
extended lymphadenectomy, as has been suggested in pre-
vious studies.7,13,14
Alternatively, persistence of the association between
inadequate LNS and worse OS despite adjusting for clini-
cal stage and pathologic T classification/LN positivity in
the Cox model may reflect a contribution of unaccounted
for factors that influence such an interaction. For instance,
inadequate LN retrieval may occur disproportionately in
patients with greater comorbid illness or inferior perform-
ance status. To this end, the inability to incorporate
patient comorbidity into our final survival model because
of frequently incomplete Charlson score data precluded
examination of its effect on OS. In addition, a clustering
of factors that are difficult to dissect apart in a study of
this nature (eg, quality of surgical care, quality of patho-
logic assessment of specimens, and timeliness of adjuvant
therapy) may also influence outcomes. In this context,
LNS may represent a surrogate for overall quality of
care.9,13,14 Specifically, inadequate LNS may reflect
unfavorable practice patterns that ultimately translate into
worse outcomes. Supporting this notion is the observation
that among patients eligible for adjuvant CRT based on
inclusion criteria for Intergroup 0116 (ie, AJCC stage IB
and higher15), a significantly higher rate of inadequate
LNS was seen in patients who did not receive adjuvant
therapy compared to those who did. Indeed, a similar
phenomenon has been described in colon cancer where
superior comprehensive cancer care might explain the
relationship between adequate LNS and improved OS.28
Study periods in the previous analyses investigating
associations between LNS and OS in GA predated the
increasing use of multimodality therapy,9,13,14 which was
heralded by outcomes from the Intergroup 0116 trial in
2001.15 As such, the interaction between increasing mul-
timodality therapy use17 and the survival impact of inad-
equate LNS has not been addressed in a US cohort. This
interaction is relevant because critics of the Intergroup
trial have suggested that in improving survival, adjuvant
CRT may have merely compensated for surgical under-
treatment29; only 10% of patients underwent D2 resec-
tion, whereas 54% underwent D0 resection.15 Similarly,
only 40% of all resections in the MAGIC trial, which
indicated a benefit of perioperative chemotherapy,
included a D2 dissection.16 In our analysis, both adjuvant
therapy (P< .001) and neoadjuvant chemotherapy alone
(P5 0.02) were independently associated with improved
OS. Notably, the association between inadequate LNS
and worse OS persisted despite including both adjuvant
therapy and neoadjuvant chemotherapy in the final Cox
model. This observation should be interpreted with cau-
tion; our Cox model included 5 years of treatment data in
the post-Intergroup 0116 trial era (ie, 2001-2006), and
also included patients treated before this era (ie, 1998-
2001). Given this, and the fact that a moderate propor-
tion of patients in the Cox model did not have complete
multimodality therapy data available, our study cannot
definitively characterize the relation between LNS and
multimodality therapy use.
Other limitations warrant emphasis; most impor-
tantly, this study is subject to the limitations of retrospec-
tive database analyses, which include missing data and
coding inconsistencies. Second, due to temporal variation
in the types of facilities contributing data to the NCDB
(ie, proportion of academic versus community hospitals),
our trends analysis of LNS compliance may not accurately
reflect national LNS patterns. Third, details regarding
technique of anatomically-based nodal dissection
(D1 versus D2) or surgical approach (open versus
Original Article
2864 Cancer September 15, 2014
laparoscopic) are not available in the NCDB, limiting our
understanding of their contribution to the study findings.
Fourth, details about specific chemotherapy regimens
used were not available and the impact of multimodality
therapy may be under or overestimated. Lastly, lack of
disease-specific mortality or recurrence data precluded
adjustment for age-related mortality or assessment of dis-
ease specific survival, respectively. Notwithstanding, OS
has been shown to be an appropriate endpoint in GA anal-
ysis given the high rate of disease-related mortality.9
In summary, a majority of patients undergoing
curative-intent gastrectomy in the US received inadequate
LNS. In a contemporary cohort, inadequate LNS was
associated with worse OS regardless of AJCC stage sub-
group or tumor T classification. OS improved incremen-
tally with higher LN counts, undoubtedly reflecting the
contribution of stage migration. A therapeutic benefit of
regional lymphadenectomy or influence of other unac-
counted for factors are not excluded. Regardless of the
underlying mechanism, the survival impact of inadequate
LNS suggests that examination of�15 LN should be con-
sidered a benchmark for quality of care because it appears
to be a reproducible prognosticator of gastric cancer out-
comes in the United States.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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