Lymph node evaluation and survival after curative-intent resection of duodenal adenocarcinoma: A matched cohort study

European Journal of Cancer 69 (2016) 135e141

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Original Research

Lymph node evaluation and survival after curative-intent resection of duodenal adenocarcinoma: A matched cohort study B.L. Ecker a, M.T. McMillan a, J. Datta a, D.T. Dempsey a, G.C. Karakousis a, D.L. Fraker a, J.A. Drebin a, R. Mamtani b, B.J. Giantonio b, R.E. Roses a,* a b

Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Received 13 March 2016; received in revised form 17 August 2016; accepted 25 September 2016

KEYWORDS Lymph node staging; Small bowel cancer; Cut-off point analysis; Adjuvant therapy; Chemotherapy; Propensity score

Abstract Background: Lymph node (LN) metastasis in patients with duodenal adenocarcinoma is associated with poor prognosis; however, the optimal extent of LN assessment and the interaction between LN assessment and adjuvant systemic therapy is poorly understood. Methods: Resected non-metastatic duodenal adenocarcinoma patients (n Z 1743) were identified in the National Cancer Database (1998e2011). Logistic regression analysis identified covariates associated with LN metastasis. The influence of increasing LN cut-off points on overall survival (OS) was analysed using the log-rank test and Cox proportional hazards modelling. Adjuvant chemotherapy (AC) and surgery alone cohorts were matched (1:1) by propensity scores based on the likelihood of nodal metastasis or survival hazard on Cox modelling. OS in the matched cohort was compared by KaplaneMeier estimates. Results: LN metastases were present in 865 (49.6%) patients. Increasing LN assessment was associated with an increased likelihood of nodal involvement (P Z 0.008). In node-negative patients, increasing LN assessment was associated with a decreased risk of death, with the largest actuarial survival differences observed for
15 LN (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.48e0.82, P Z 0.001). In the propensity score-matched cohort of nodenegative patients, AC was associated with non-significant improvements in 5-year actuarial (66.1% versus 58.7%, HR 0.79, 95% CI 0.53e1.18, P Z 0.249), and did not vary by adequacy of LN counts (<15 LNs: HR 0.79, 95% CI 0.51e1.24, P Z 0.305;
15 LNs: HR 0.90, 95% CI 0.35e2.30, P Z 0.900).

* Corresponding author: Hospital of the University of Pennsylvania, 3400 Spruce St., 4 Silverstein, Philadelphia, PA 19104, USA. Fax: þ1 215 662 7476. E-mail address: [email protected] (R.E. Roses). http://dx.doi.org/10.1016/j.ejca.2016.09.027 0959-8049/ª 2016 Elsevier Ltd. All rights reserved.

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Conclusions: The extent of LN identification has prognostic significance in resected nodenegative duodenal adenocarcinoma, but cannot be implicated in the selection of nodenegative patients for AC. ª 2016 Elsevier Ltd. All rights reserved.

1. Introduction Small bowel cancer is a rare malignancy of the gastrointestinal tract; there are an estimated 9410 new cases and 1260 deaths from small bowel cancer annually in the United States (US) [1]. Small bowel adenocarcinoma accounts for approximately 3140 of new cases annually, and is most commonly located in the duodenum [2]. The primary treatment strategy of duodenal adenocarcinoma remains surgical resection, which includes removal of the tumour and regional draining lymph nodes (LNs). Pathologic evaluation for regional LN involvement has implications for both prognosis [2,3] and treatment [4,5]. The minimum necessary extent of LN examination required for accurate staging in duodenal adenocarcinoma is poorly defined. There is some evidence that increasing LN evaluation is associated with improved patient survival [3,6]. Improved outcomes with more extensive LN examination, particularly for those patients without known nodal metastasis, suggest that stage migration might contribute to such findings [6]. Prognostication according to the total number of LNs assessed has been observed in several gastrointestinal malignancies, and LN ‘bench marks’ have been proposed to ensure optimal pathologic staging [7e9]; moreover, patients with American Joint Committee on Cancer (AJCC) stage II colorectal cancer and suboptimal LN staging (i.e. <12 nodes examined) are considered ‘high risk’ and candidates for adjuvant chemotherapy (AC) [10,11]. Given the paucity of data for the treatment of small bowel adenocarcinoma, current National Comprehensive Cancer Network guidelines endorse utilisation of systemic chemotherapy according to guidelines for colon cancer [11]. The present study aims to determine: (1) factors associated with nodal metastasis in duodenal adenocarcinoma; (2) prognostically relevant LN cut-off points associated with survival variations in resected patients; and (3) whether patients undergoing suboptimal LN assessment benefit from adjuvant systemic therapy. A matched cohort study using propensity score methodology was used to minimise the treatment bias associated with the administration of AC. 2. Methods 2.1. Data source After institutional review board’s approval, data from 1998 to 2012 were acquired from the small bowel

participant use file of the National Cancer Database (NCDB), a collaborative effort between the American Cancer Society and American College of Surgeons’ Commission on Cancer (CoC). Established in 1989, the NCDB is a comprehensive oncology surveillance program that captures approximately 70% of all new cancer diagnoses in the US from more than 1500 CoCapproved centres [12]. 2.2. Patient selection Patients with invasive duodenal adenocarcinoma (defined by ICD-O-3 topography codes C17.0 [13]) undergoing curative-intent resection for AJCC pathologic stage IeIII disease between 1998 and 2011 were identified. Patients with tumours of the ampulla of Vater, pancreas or distal common bile duct were excluded. Patients were excluded if they had an indeterminate LN harvest, received neoadjuvant chemotherapy, received radiotherapy at any time, underwent palliative therapy or died within 90 d from the time of surgery. Patients diagnosed in 2012 were excluded to ensure at least 1 year of follow-up for all patients. 2.3. Variables The demographic/clinical NCDB variables used in this study have been defined previously [14e18]. Our primary outcome, overall survival (OS), was defined as the interval between date of diagnosis and date of death or last contact. LN counts in surgical specimens were categorised as follows: 1e5, 6e10, 11e15, 16e20 and >20. AC was defined by receipt of either single-agent or multi-agent chemotherapy without a documented history of neoadjuvant or perioperative treatment. ‘Salvage’ chemotherapy, defined by initiation of chemotherapy later than 6 months postoperatively, was excluded. 2.4. Statistical analysis Descriptive statistics are presented as frequencies for categorical variables and median (interquartile range [IQR]) for continuous variables. Pearson’s c2 or Fisher’s exact tests and Wilcoxon rank-sum test were used to analyse categorical and continuous variables, respectively. Logistic regression analysis identified covariates associated with LN metastasis in the overall cohort. OS was analysed for patients without known nodal

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involvement using Cox proportional hazards modelling with backward stepwise selection (P  0.05 for entry; P > 0.10 for removal). A cut-off point survival analysis was performed to determine the LN count that generated the most statistically significant actuarial survival difference between resulting groups. The magnitude of the survival difference between varying LN cut-off points (1e4 versus
5, 1e9 versus
10, 1e14 versus
15 and 1e19 versus
20) was determined using the log-rank test chi-square statistic [9,19]. Cox proportional hazards regression, using a backward elimination method, served as a multivariable model for evaluating increasing LN cut-off points, accounting for all variables previously identified to be associated with either risk of nodal metastasis or survival hazard on Cox modelling (i.e. age, median income, facility type, T-stage classification, histologic grade and margin status). To evaluate the role of AC in patients who did not achieve the LN benchmark identified by cut-off point analysis, OS was compared between subjects receiving either surgery alone (SA) or AC using propensity scores. Propensity score-matched analysis was performed accounting for all factors significantly associated with either risk of nodal metastasis or survival hazard on Cox modelling [20]. Individual scores were calculated through logistic regression modelling based on the following six covariates: age, median income, facility type, T-stage classification, histologic grade and margin status. Subjects receiving either SA or AC were matched 1:1 on these propensity scores using the ‘greedy’ nearest neighbour matching algorithm without replacement [21]. A calliper size of 0.1  log [standard deviation of the propensity score] was used to minimise treatment bias [22]. Standardised differences were estimated before and after matching to evaluate the balance of covariates; small absolute values (<0.1) indicate balance between treatment groups. Following propensity score matching, OS between SA and AC patients was examined by KaplaneMeier estimates for previously identified LN cut-off points [23]. P-values 0.05 were considered statistically significant; all tests were two-sided. Analyses were carried out using SPSS v22.0 (IBM Corp., Armonk, NY).

3. Results

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received palliative therapy (n Z 33), radiation therapy (n Z 799) or neoadjuvant or salvage chemotherapy (n Z 243), had an indeterminate LN harvest (n Z 70), or had a non-duodenal tumour location (jejunum: n Z 995; ileum: n Z 827; overlapping/unknown: n Z 756) yielded a study cohort of 1743 patients. Median age was 67 (IQR 56e75) years, 53.6% of patients were men and 81.2% of patients were white. At the time of surgical resection, 14.1% had stage I disease, 36.3% stage II disease and 49.6% stage III disease. The rate of nodal metastasis increased with higher T-classification; 17.3% of T1 lesions were associated with LN metastases, as compared with 27.4% of T2 lesions, 51.3% of T3 lesions and 60.6% of T4 lesions (P < 0.001). Factors associated with nodal metastasis during univariate testing (i.e. increasing T-stage classification, increasing tumour size, poorly differentiated histology and increasing LN count) were entered into a multivariable model. Available demographic variables (i.e. age, gender, race, Hispanic ethnicity, insurance status, median income, population density) and facility characteristics (i.e. geographic region, academic affiliation of treating hospital) were not associated with the rate of detected nodal metastasis. T-stage classification, poorly differentiated histology and increasing LN count were independently associated with increased odds of nodal metastasis (Table 1). 3.2. Survival impact of extent of lymph node examination in the unmatched cohort The influence of the extent of LN examination on OS between 1998 and 2011 was examined in the cohort of patients without known nodal involvement (n Z 878) using Cox proportional hazards modelling. Clinical and pathologic variables significantly associated with OS (age, median income, facility type, T-stage classification, LN count, resection margin status) were entered into a multivariable cox regression. Gender, race, Hispanic ethnicity, insurance status, population density, geographic region, tumour grade and receipt of AC were not associated with OS. After adjusting for potential confounders, increasing LN identification conferred a decreased risk of death (Ref: 1e5 LN; 6e10 LN: hazard ratio [HR] 0.87, 95% CI 0.67e1.13, P Z 0.299; 11e15 LN: HR 0.83, 95% CI 0.62e1.12, P Z 0.225; 16e20 LN: 0.58, 95% CI 0.40e0.86, P Z 0.006;
21 LN: HR 0.64, 95% CI 0.42e0.97, P Z 0.036) (Table 2).

3.1. Risk of lymph node metastasis 3.3. Cut-off point analysis There were 17,373 patients with invasive small bowel adenocarcinoma identified in the NCDB participant use file. Serial exclusion of patients who did not undergo curative-intent surgical resection (n Z 7240), had metastatic disease or unknown pathologic staging (n Z 2986), were diagnosed in the year 2012 (n Z 600), died within 90 d from the time of surgery (n Z 521),

A cut-off point analysis was conducted to determine the LN cut-off associated with the largest actuarial survival difference between resulting groups for patients without known nodal disease (Table 3). For each incremental increase in number of LNs identified, both a c2 statistic and multivariable HR were calculated. The most

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Table 1 Relative proportion of patients with nodal metastasis, and multivariable logistic regression model for predictors of nodal metastasis in resected duodenal adenocarcinoma (n Z 1743).

T-stage classification

T1e2 T3 T4 Well/moderately differentiated Poorly/undifferentiated or anaplastic Unknown 1e5 6e10 11e15 16e20
21

Grade

LN total

No. in overall cohort (%)

No. of patients with Nþ disease (%)

Odds ratio (95% CI)

P-value

334 (19.2) 760 (43.6) 648 (37.2) 1071 (61.4) 603 (34.6) 69 (4.0) 408 (23.4) 463 (26.6) 391 (22.4) 241 (13.8) 240 (13.8)

81 (9.4) 390 (45.1) 393 (45.4) 478 (55.3) 357 (41.3) 30 (3.5) 154 (17.8) 214 (24.7) 209 (24.2) 136 (15.7) 152 (17.6)

Ref 3.02 4.13 Ref 1.61 1.18 Ref 1.50 1.91 2.06 2.59

<0.001 <0.001 <0.001 <0.001 <0.001 0.576 0.008 <0.001 <0.001 <0.001 <0.001

(2.20e4.14) (2.98e5.72) (1.29e2.00) (0.67e2.07) (1.11e2.02) (1.41e2.60) (1.45e2.92) (1.82e3.71)

CI, confidence interval; LN, lymph node.

Table 2 Multivariable cox proportional hazards modelling for overall survival in patients without known nodal metastases (n Z 878). HRa 95% CI >75 68e75 67 Median <$48,000 income
$48,000 Facility Non-academic/research type Academic/research T-stage T4 classification T3 T1e2 Resection Margin positive margin (R1eR2) Margin negative (R0) Lymph node 1e5 total 6e10 11e15 16e20
21 Age

P-value

Ref 0.78 0.45 Ref 0.76 Ref 0.77 Ref 0.66 0.53 Ref

e 0.61e1.01 0.35e0.58 e 0.61e0.93 e 0.63e0.95 e 0.52e0.83 0.40e0.70 e

<0.001 0.064 <0.001 e 0.008 e 0.013 <0.001 0.001 <0.001 e

0.47

0.28e0.78 0.004

Ref 0.87 0.83 0.58 0.64

e 0.67e1.13 0.62e1.12 0.40e0.86 0.42e0.97

0.040 0.299 0.225 0.006 0.036

CI, confidence interval; HR, hazard ratio. a HRs indicate relative hazard for death and were adjusted for all variables included.

pronounced survival difference was observed at the 15 LN cut-off point (c2 16.68, P < 0.001; HR 0.63, 95% confidence interval [CI] 0.48e0.82, P Z 0.001). Survival

Table 3 Cut-off point analysis to determine the most statistically significant survival difference among patients without known nodal metastases by varying LN harvest levels (n Z 878). 1e4 versus
5 1e9 versus
10 1e14 versus
15 1e19 versus
20

X2

P-value

HR

16.17 9.33 16.68 6.56

<0.001 0.002 <0.001 0.010

0.78 0.78 0.63 0.69

P-value (0.62e0.99) (0.64e0.97) (0.48e0.82) (0.48e0.99)

0.037 0.023 0.001 0.047

Bold values indicate the LN cut-off point associated with the largest survival difference between resultant groups. LN, lymph node; HR, hazard ratio.

differences remained significant for
20 LN, in favour of higher LN counts. 3.4. Propensity score matching to evaluate the role of adjuvant chemotherapy in patients with ‘inadequate’ LN staging ‘Inadequate’ LN staging was subsequently defined by LN counts less than the benchmark defined by the cutoff point analysis (i.e. <15 LN). To minimise treatment bias, patients were matched based upon the likelihood of either nodal metastasis or factors associated with survival hazard in the unmatched cohort. In the unmatched sample, AC was infrequently used (n Z 129; 14.7%). The resulting propensity score-matched cohort matched the 129 AC patients with 127 SA patients, for a total cohort size of 256 patients. Previously observed differences between cohorts with respect to age, median income, facility type, T-classification, histologic grade and margin-positive resection were successfully balanced after matching (Table 4). As such, standardised differences between covariates were less than 0.1, indicating balance between treatment groups. At a median follow-up of 71.9 (IQR 35.5e109.3) months, median OS of the propensity-matched cohort with duodenal adenocarcinoma was 95.8 (IQR 31.1 e not reached) months. There was a statistically non-significant difference in a 5-year actuarial survival between AC (66.1%) and SA (58.7%) cohorts (HR 0.79, 95% CI 0.53e1.18, P Z 0.249). When stratified by adequacy of LN staging, there was no survival advantage associated with AC in those with <15 LNs identified (HR 0.79, 95% CI 0.51e1.24, P Z 0.305) or
15 LNs identified (HR 0.90, 95% CI 0.35e2.30, P Z 0.900; Fig. 1). 4. Discussion The present cohort study identifies (1) clinicopathologic features associated with increased risk of LN

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Table 4 Demographic and clinicopathologic variables of the propensity score-matched cohort, and univariate comparison between patients receiving adjuvant chemotherapy or surgery alone (n Z 256). Age

Median income Facility type T-stage classification

Grade

Resection margin

67 68e75 >75 <$48,000
$48,000 Non-academic/research Academic/research T1e2 T3 T4 Well/moderately differentiated Poorly/undifferentiated or anaplastic Unknown Margin negative (R0) Margin positive (R1eR2) Unknown

Surgery alone (%)

Adjuvant chemotherapy (%)

P-value

87 (68.5) 28 (22.0) 12 (9.4) 56 (44.1) 68 (53.5) 62 (48.8) 65 (51.2) 17 (13.4) 57 (44.9) 53 (41.7) 85 (66.9) 41 (32.3) 1 (0.8) 117 (92.1) 7 (5.5) 2 (2.4)

85 (65.9) 29 (22.5) 15 (11.6) 55 (42.6) 68 (52.7) 66 (51.2) 63 (48.8) 15 (11.6) 57 (44.2) 57 (44.2) 85 (65.9) 42 (32.6) 1 (1.6) 114 (88.4) 8 (6.2) 7 (5.4)

0.836

0.609 0.708 0.880

0.848

0.430

Fig. 1. Comparative effect of adjuvant chemotherapy versus surgery alone on overall survival in the propensity-matched cohorts with resected duodenal adenocarcinoma without known nodal metastases, stratified by adequacy of LN staging (adequate:
15 LN; inadequate: <15 LN). CI, confidence interval; HR, hazard ratio; LN, lymph node.

metastasis following curative-intent resection of duodenal adenocarcinoma and (2) LN benchmarks associated with improvements in patient survival. Increasing LN assessment is associated with improved survival in putative node-negative patients. A propensity score-matched analysis e used to control more comprehensively for the biases inherent in selection of adjuvant therapy e failed to identify a significant survival benefit of AC, even in cases of inadequately staged patients. Given the paucity of data specific to small bowel adenocarcinoma, indications for AC have primarily been extrapolated from colon cancer where chemotherapy is associated with improved long-term survival for node-positive disease [24,25]. Identification of nodal metastases depends on appropriate surgical resection of regional LNs and detailed pathologic evaluation. Compared with colon cancer, small bowel cancers more

often present in the emergency setting, as a local complication of obstruction or bleeding [26,27], which may decrease the likelihood of timely recognition of the need for an oncologic resection. For a disease without established pathologic LN benchmarks, there may be heterogeneous national practices in the pathologic processing of surgical specimens. Together, these may, in part, explain the large proportion of patients in this series with five or less LNs identified. This study identifies tumour factors that are important determinants of LN involvement. Increasing depth of tumour invasion was the single strongest predictor of LN metastases, recapitulating data from colon cancer [28]. Increased nodal involvement was also associated with higher nodal yields, likely a result of more complete sampling, but perhaps reflecting improved recognition of pathologic LNs or tumoureimmune interactions in the draining mesentery [29].

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For patients without nodal involvement, increasing LN assessment was associated with a significant improvement in survival, possibly due to more accurate pathologic staging; a threshold of 15 LN for duodenal tumours was associated with the largest actuarial difference in patient survival. Previous studies have suggested varying LN thresholds to avoid understaging [3,30,31], but inclusion of AJCC stage III patients in these analyses e who often have greater number of LNs identified e may have biased the results for those without known nodal metastases. In one singleinstitution study of 72 patients with resected duodenal adenocarcinoma, the prognostic significance of N-classification varied by total LN yield; improved survival was observed for putative node-negative patients only in cases where
15 LNs were identified and not when <15 LNs were identified, possibly supporting a stagemigration hypothesis [30]. Lastly, AC did not significantly improve survival in resected duodenal cancer patients regardless of extent of LN dissection. The use of AC for resected AJCC stage II colon cancer patients, even for those with poor prognostic clinicopathologic characteristics, remains controversial [32,33]. Although consensus guidelines recommend against routine administration of AC for stage II patients, its role in select high-risk patients e including those with inadequate lymphadenectomy e has been suggested [10]. In the propensity score-matched cohort, AC was associated with an approximately 7% absolute improvement in 5-year actuarial survival, which compares similarly to the degree of benefit observed for stage II colon cancer patients who receive AC [33]. The survival impact of AC did not vary by adequacy of LN counts. Unfortunately, given the rarity of this malignancy and the uncommon use of chemotherapy for node-negative patients, the propensity scorematched cohort may have been underpowered to detect a significant difference when performing a LN benchmark-stratified analysis. Several additional limitations warrant emphasis, specifically, those inherent to retrospective database analyses. As with all observational studies, miscoding and data omission are possible. Particular to this data set, the NCDB does not detail the specific chemotherapeutics and dosing schedules. Although speculative, it is likely that oxaliplatin-based regimens, with either infusional 5-fluorouracil or capecitabine, were the predominant therapies used, given the support for these regimens in the literature [5,34]. The NCDB also does not capture patient performance status or diseasespecific mortality; however, most of the patients in this study were less than 65 years of age and OS may closely parallel disease-specific survival for these young e and presumably otherwise healthy e patients. Notably, the NCDB does not included data on the extent of resection, which is particularly relevant in cases of duodenal tumours. Although pancreaticoduodenectomy may not

improve survival relative to segmental resection for appropriately selected surgical patients, there are likely differences in the LN yield between procedures [35]. Also noteworthy is the potential variability in pathologic evaluation and its unknown contribution to the results. Lastly, the results of any observational cohort study are subject to the immortal time bias, where those patients who die before initiation of therapy are categorised into the control arm which may exaggerate the apparent benefits seen in the treatment arm. By excluding patients who died within 90 d from surgery, we attempted to minimise this bias. Moreover, exclusion of patients who died within 90 d reduces selection bias as this subgroup likely suffered early mortality from postoperative complications unrelated to the cancer. In conclusion, extent of LN identification has prognostic significance in resected node-negative duodenal adenocarcinoma, supporting efforts to standardise LN assessment for this rare disease. Barring a larger study cohort, the current data suggest a non-significant benefit in survival associated with AC, which does not strongly vary by adequacy of LN staging. Nevertheless, given increasing support in the literature for adjuvant therapy in the setting of node-positive disease, these results underscore the importance of LN assessment in establishing prognosis and guiding subsequent therapy. Funding No funding to report for this submission. Conflict of interest statement None declared.

Acknowledgements The NCDB is a joint project of the CoC of the American College of Surgeons and the American Cancer Society. The CoC’s NCDB and the hospitals participating in the CoC NCDB are the source of the deidentified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.

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