- Email: [email protected]
The impact of age on nodal metastases and survival in gastric cancer
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The impact of age on nodal metastases and survival in gastric cancer A. Ahmad, MD,a,b,* H. Khan, MD,a,b G. Cholankeril, MD,a,b S.C. Katz, MD,a,b and P. Somasundar, MD, MPHa,b a b
Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island Boston University School of Medicine, Boston, Massachusetts
article info
abstract
Article history:
Background: In gastric adenocarcinoma, the disparity in lymph node involvement between
Received 2 January 2016
different age groups has not been thoroughly investigated. The objective of our study was
Received in revised form
to compare age-associated differences in adequate lymph node harvest and nodal
3 February 2016
involvement in gastric adenocarcinoma patients.
Accepted 26 February 2016
Methods: We analyzed data extracted from the Surveillance, Epidemiology and End Results
Available online xxx
database on 16,213 patients diagnosed with stage I-III gastric adenocarcinoma between 2004 and 2011. All patients underwent surgical resection. Statistical comparisons between
Keywords:
various age groups were done using the chi-square test and Cox regression.
Gastric cancer
Results: Among 16,213 gastrectomy patients, proportion of patients that had >15 lymph
Elderly
nodes examined decreases significantly with increasing age (P < 0.0001). When adequately
Lymph node metastases
staged, older patients had a significantly lower proportion of node-positive tumors
Survival
(P < 0.0001). Adequate nodal staging was also associated with improved 5-y disease-specific survival across all age groups. Conclusions: In gastric adenocarcinoma, older patients are less likely to be adequately staged. However, when adequately staged, they are less likely to have node-positive tumors. Adherence to national guidelines, regardless of age, is associated with improved survival outcomes and may alter multimodality management of gastric cancer in the elderly. ª 2016 Elsevier Inc. All rights reserved.
Introduction In the United States, the incidence of gastric cancer is declining but the mortality rate remains high.1 Overall 5-y survival rate for all stages combined is around 28%.1 Metastatic involvement of regional lymph nodes is one of the most important prognostic determinants of survival after resection of gastric cancer.2-5 National guidelines recommend pathologic assessment of at least 15 lymph nodes from a gastrectomy specimen for accurate staging.6 Improvement in
survival outcomes has been associated with adequate lymphadenectomy specifically in patients with node-positive disease.7-9 In gastric cancer, the sensitivity of diagnostic modalities used for preoperative assessment of nodal involvement is limited. Therefore, adequate surgical staging remains the cornerstone of management.8,9 Gastric cancer is a disease of the elderly with a median age of 69 y at diagnosis. In older patients, comorbidities and limited ability to tolerate systemic treatment may complicate decisions regarding adequate surgical resection. In the Dutch
* Corresponding author. Division of Surgical Oncology, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908. Tel.: þ1 347 553 3511; fax: þ1 401 456 6708. E-mail address: [email protected] (A. Ahmad). 0022-4804/$ e see front matter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2016.02.043
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Gastric Cancer Group Trial, age >70 years was independently associated with worse overall survival.3 However, optimal management should be tailored to individual physiological characteristics and properly selected elderly patients may benefit from aggressive treatment. As such, accurate identification of elderly patients at high risk for recurrence is of paramount importance. The objective of our study was to assess the frequency of adequate lymph node retrieval in resectable gastric cancer in the elderly and its impact on staging and survival when compared to younger patients.
Materials and methods Data for our study were extracted from November 2013 submission of the Surveillance Epidemiology and End Results (SEER) database on adult patients diagnosed with gastric adenocarcinoma between 2004 and 2011. The SEER database combines records of 18 cancer registries across the United States representing approximately 28% of the population. Cases were selected based on gastric anatomic site (International Classification of Disease-Oncology, third edition), adenocarcinoma histology (World Health Organization classification), and stage (AJCC seventh edition TNM classification). Patients with gastroesophageal junction tumors or those under the age of 20 years were excluded from the study. Similarly, patients with distant metastases (M1), those who underwent palliative intent gastrectomy or those with positive surgical margins (R1/R2) were excluded. Of the 20,425 patients diagnosed with stage I-III gastric adenocarcinoma, 13,165 underwent curative intent gastrectomy with negative margins (R0) and fulfilled the criteria for our study (Fig. 1). The study population was then subcategorized into the following age groups: 20-49 y, 50-64 y, 65-74 y, 75-84 y, and 85 y. Variables pertaining to the grade of tumor, number of lymph nodes examined (LNE) and the number with metastases were extracted from pathology reports. Neoadjuvant chemotherapy data were derived from a SEER flag for “yp” staging. In an attempt to maintain uniformity in data, nodal stage was re-defined according to the AJCC seventh edition TNM staging system (N1 ¼ 1-2 positive nodes; N2 ¼ 3-6 positive nodes; N3 7 positive nodes). Odds ratio (OR) was calculated for quantitative assessment of association between age, histopathology, LNE, and lymphatic metastases. Statistical comparison was tabulated using the Pearson chisquare test. The KaplaneMeier method was used to estimate survival in various groups. Overall survival (OS) was calculated by SEER using time from initial diagnosis till last contact, date of death or date of cutoff for database. For disease-specific survival (DSS), the event used was death from disease with all other events deemed censored. Univariate comparison between groups was performed using the log-rank test. Multivariate analysis was conducted to calculate hazard ratios using the Cox regression analysis. All statistical analyses report 95% confidence intervals and were performed using SPSS for windows (SPSS Inc, Chicago, IL). Significance of difference was assumed at P < 0.05.
Fig. 1 e Selection criteria flowchart.
Results Demographic and tumor characteristics of all patients are shown in Table 1. The male-to-female ratio was approximately 1.75:1 and remained constant throughout various age groups. Seventy percent of patients were >65 y of age. Tumor location was anatomically distributed among proximal (32%), body (8%), distal (31%), and whole stomach (28%). Most patients had T1/T2 tumors (72%). Sixty eight percent of patients aged 20-49 y had high grade tumors (grade III/IV), and this proportion decreased with increasing age. When compared to patients85 y.
Nodal status Among all patients, only 43% of patients who underwent gastrectomy had appropriate nodal staging defined as 15 LNE on histopathologic analysis. Median number of lymph nodes examined for patients aged 20-49 y was 14; however, it
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261 Table 1 e Demographics and tumor characteristics. 262 <65 y, N (%) 263 20-49 y 50-64 y 264 265 Gender 266 Male 715 (69) 2024 (69) 267 Female 317 (31) 924 (31) 268 269 Tumor location 270 Proximal 393 (38) 1251 (41) 271 Body 67 (7) 208 (7) 272 Distal 284 (27) 769 (27) 273 274 Whole 290 (28) 718 (25) 275 T stage 276 T1 244 (24) 734 (25) 277 T2 451(44) 1377 (47) 278 T3 221 (21) 623 (21) 279 280 T4 116 (11) 214 (7) 281 Histologic grade 282 Grade I 51 (5) 153 (6) 283 Grade II 257 (27) 734 (26) 284 285 Grade III 632 (65) 1784 (65) 286 Grade IV 26 (3) 78 (3) 287 Lymph nodes examined 288 <15 467 (45) 1660 (57) 289 15 559 (55) 1269 (43) 290 291 N stage 292 N0 388 (38) 1192 (40) 293 N1 469 (45) 1159 (39) 294 N2 142 (14) 450 (16) 295 296 N3 27 (2) 128 (4) 297 Unknown but Nþ 6 (1) 19 (1) 298 299 300 301 declined with increasing age to a median of 8 in patients aged 302 85 y. When compared to the 20-49 y group, patients in each 303 older group were significantly less likely to have undergone an 304 adequate lymphadenectomy (Table 2). This deficiency was 305 most prominent in the patients aged 85 y (OR ¼ 0.49, 95% CI 306 ¼ 0.43-0.56, P < 0.001). 307 In the entire cohort, 7354 patients had lymph node me308 tastases (56%). This proportion was significantly higher in 309 younger patients (62%). Increasing age was associated with 310 decreased rate of lymphatic metastases (Table 3). 311 312 Because elderly patients were more likely to be under313 staged, we performed a subgroup analysis based on LNE status 314 315 316 317 Q4Q5 Table 2 e Adequate nodal staging (‡15 LNE). 318 Age groups (y) Odds ratio (OR) 95% CI P value 319 20-49 Reference d d 320 50-64 0.64 0.55-0.74 <0.001 321 322 65-74 0.75 0.64-0.88 <0.001 323 75-84 0.65 0.56-0.74 <0.001 324 85 0.49 0.43-0.56 <0.001 325
Q3
65 y, N (%) 65-74 y
75-84 y
85 y
813 (59)
2783 (67)
2185 (59)
559 (41)
1350 (33)
1495 (41)
435 (32)
1349 (33)
869 (24)
104 (8)
323 (8)
324 (9)
440 (32)
1282 (31)
1341 (36)
393 (28)
1179 (28)
1146 (31)
261 (19)
1147 (28)
1022 (28)
626 (46)
1882 (46)
1733 (47)
328 (24)
799 (20)
662 (18)
143 (11)
268 (6)
241 (7)
49 (4)
271 (7)
213 (6)
221 (17)
1198 (30)
1165 (33)
957 (75)
2372 (61)
2026 (58)
45 (4)
69 (2)
96 (3)
720 (53)
2321 (56)
2307 (63)
648 (47)
1794 (44)
1356 (37)
574 (42)
1903 (46)
1754 (48)
466 (34)
1489 (36)
1322 (36)
244 (18)
533 (13)
442 (12)
84 (6)
190 (5)
145 (3)
4 (<1)
18 (<1)
17 (1)
to reassess the association of age with lymphatic metastases. Sixty-four patients were excluded from this subgroup analysis due to the lack of specific data on the number of lymph nodes retrieved. The decrease in the rate of lymphatic metastases with increasing age persisted among the various age groups regardless of the nodal staging status (Table 3).
Survival analysis The median and 5-y OS for patients with stage I-III resected gastric adenocarcinoma was 53 mo and 45% for age group 2049 y, 52 mo and 44% for 50-64 y, 43 mo and 40% for 65-74 y, 28 mo and 29% for 75-84 y, 19 mo and 18% for patients aged 85 y (Fig. 2). Gastric cancer specific outcomes were analyzed by determining DSS. The 5-year DSS was 57% for age group 20-49 y, 64% for 50-64 y, 61% for 65-74 y, 51% for 75-84 y and 44% for patients 85 y (Fig. 3).
Survival analysis in node-negative patients To assess the impact of adequate nodal staging on survival, subgroup survival analyses were performed on patients who were node negative (N0) on final histopathologic analysis.
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391 Table 3 e Rate of lymphatic metastases. 392 Age groups (y) All patients Subgroup analysis 393 <15 lymph nodes examined 15 lymph nodes examined 394 395 OR (95% CI) P OR (95% CI) P OR (95% CI) P 396 397 20-49 Reference d Reference d Reference d 398 50-64 0.88 (0.77-1.03) 0.109 0.82 (0.62-0.92) 0.004 0.94 (0.70-1.12) 0.141 399 65-74 0.83 (0.71-0.98) 0.036 0.68 (0.57-0.83) <0.001 0.88 (0.63-0.95) 0.016 400 75-84 0.70 (0.61-0.81) <0.001 0.69 (0.61-0.89) <0.001 0.82 (0.65-0.97) 0.037 401 85 0.66 (0.57-0.76) <0.001 0.61 (0.55-0.87) <0.001 0.83 (0.62-0.98) 0.041 402 403 404 405 The 5-y OS in patients who were node negative decreased OS is age groups 20-49 y (32% versus 29%, P ¼ 0.02), 50-64 y (33% 406 with increasing age regardless of the LNE status (Figs. 4 and 5). versus 26%, P < 0.001), 65-74 y (27% versus 24%, P ¼ 0.006), and 407 To assess the impact of adequate nodal staging on 5-y OS, 75-84 y (18% versus 13%, P < 0.001) but worse 5-year OS in age 408 intragroup comparison was performed for each individual age group 85 y (8% versus 11%, P ¼ 0.08). 409 group with regard to their respective nodal staging status (<15 Age remained associated with a worse 5-y DSS in node410 versus 15 LNE). Examination of 15 lymph nodes was assopositive patients (Figs. 10 and 11). On comparison of each 411 ciated with improvement in 5-y OS is age groups 20-49 y (83% age group with respect to their nodal staging status, adequate 412 versus 67%, P < 0.001), 50-64 y (76% versus 63%, P < 0.001), 65-74 lymph node staging was associated with an improvement in 413 5-y DSS across all age groups (Fig. 10 versus Fig. 11). However, y (66% versus 54%, P < 0.001), 75-84 y (52% versus 43%, P < 0.001) 414 the difference was less pronounced: 20-49 y (43% versus 41%, and 85 y (39% versus 23%, P < 0.001). 415 416 P ¼ 0.15), 50-64 y (52% versus 45%, P < 0.001), 65-74 y (45% versus Age was associated with a worse 5-y DSS whether patients 417 41%, P ¼ 0.002), 75-84 y (34% versus 29%, P < 0.001), and 85 y were adequately staged (Figs. 6 and 7). On a similar intragroup 418 (28% versus 22%, P < 0.001). comparison (Fig. 6 versus Fig. 7), 15 LNE was associated with a 419 significant improvement in 5-y DSS in patients in age groups 420 Multivariate analysis 20-49 y (92% versus 78%, P < 0.001), 50-64 y (86% versus 81%, 421 P ¼ 0.003), 65-74 y (85% versus 79%, P < 0.001), 75-84 y (77% 422 On multivariate analysis, after adjusting for confounding versus 70%, P < 0.001) and age 85 y (78% versus 57%, P < 0.001). 423 variables, the association of 15 LNE with prolonged 5-year 424 DSS was not found to be significant (P ¼ 0.288). Factors inde425 Survival analysis in node-positive patients pendently associated with survival were grade of tumor, age, 426 Survival analysis was also performed on patients with nodeand neoadjuvant therapy (Table 4). Specifically, age >75 y was 427 positive tumors. Predictably, patients with node-positive 428 associated with worse disease-specific survival outcomes. tumors had worse survival outcomes when compared to 429 node-negative tumors. 430 As seen with node-negative patients, increasing age was 431 associated with a decreased 5-y OS in node-positive patients Discussion 432 (Figs. 8 and 9). However, on comparing each individual age 433 group to their respective LNE status (<15 versus 15), examiGastric adenocarcinoma often presents with advanced age. In 434 435 nation of 15 lymph nodes was associated with improved 5-y elderly patients, declining physiological reserve and medical 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 Q9 Fig. 2 e Age stratified 5-y OS in all patients. (Color version Fig. 3 e Age stratified 5-y DSS in all patients. (Color version 455 of figure is available online.) of figure is available online.) 5.4.0 DTD YJSRE13681_proof 19 March 2016 7:41 am ce
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Fig. 4 e Five-year OS in node-negative patients with <15 LNE. (Color version of figure is available online.)
Fig. 6 e Five-year DSS in node-negative patients with <15 LNE. (Color version of figure is available online.)
comorbidities may limit tolerance of multimodality treatment plans. As such, adequate staging and risk stratification is essential to spare patients at low risk for recurrence from adjuvant therapy after surgery. The adherence to national oncologic guidelines in the elderly patients is an intricate issue especially when it comes to achieving “standard of care” goals for lymphadenectomies. Our study shows that the adequacy of lymphadenectomy (15 LNE) decreases with each increasing decade of age. It is not surprising to see that the median number of LNE for patients aged >85 y is 8, and the reason for this is likely multifactorial. Nienhueser et al.10 demonstrated that elderly patients were less likely to undergo extensive surgical resection for gastric cancer. It is plausible that the surgical decision pertaining to the extent of nodal dissection in the elderly population was affected by underlying comorbid issues.10 Age has been independently associated with lower lymph node yields in various tumors.11,12 Age-related immune changes, including decreased homeostatic proliferation of lymphocytes, may contribute to this association.13 Theoretically, altered lymphocyte physiology may play a role toward lower lymph node yields and worse survival outcomes in elderly gastric adenocarcinoma patients.
Wu et al.14 demonstrated lower lymph node yields after neoadjuvant treatment in gastric adenocarcinoma. In our study group, a significantly less proportion of elderly patients received neoadjuvant therapy. Despite this fact, lymph node yields and metastases were lower in the elderly as compared to younger age groups highlighting the possible role of other variables such as altered tumor biology in this disease. The definition of optimal lymphadenectomy for gastric adenocarcinoma has been thoroughly investigated in multiple trials and still remains contentious.3,4,7,15-17 However, national guidelines recommend analysis of at least 15 lymph nodes after curative intent gastrectomy for adequate staging.6 Bunt et al.18 emphasized that the combination of appropriate surgical technique and diligent pathologic examination of specimen determine the number of lymph nodes ultimately retrieved. With improved pathologic techniques such as comprehensive fat clearing, Candela et al.19 doubled their lymph node counts in gastrectomy specimens. Fifty-six percent of the entire cohort had lymph node metastases and is consistent with data reported in other studies.9,10 On subgroup analysis, the rate of lymph node metastases decreased from 62% in younger patients (20-49 y) to 53% in patients 75 y. As younger patients had a higher
Fig. 5 e Five-year OS in node-negative patients with ‡15 LNE. (Color version of figure is available online.)
Fig. 7 e Five-year DSS in node-negative patients with ‡15 LNE. (Color version of figure is available online.)
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Fig. 8 e Five-year OS in node-positive patients with <15 LNE. (Color version of figure is available online.)
Fig. 10 e Five-year DSS in node-positive patients with <15 LNE. (Color version of figure is available online.)
proportion of high grade tumors and a significantly greater percentage of tumors located in proximal and whole stomach, both of which are independent predictors of metastatic potential, it could be speculated that the high rate of nodal metastases is a consequence of inherent aggressive tumor biology in younger patients.9 The exact impact of age on nodal metastases as observed in the entire cohort was likely confounded by the fact that a higher proportion of elderly patients were understaged secondary to the lower rate of adequate lymphadenectomy. When analysis was conducted on patients who were appropriately staged (15 LNE), age 65 y was still associated with lower rate of lymphatic metastases. On multivariate analysis, age remained independently associated with decreased incidence of lymphatic metastases. Although this may be secondary to differences in tumor biology, age-related changes in lymph node architecture could also render this compartment a less favorable metastatic niche for circulating gastric cancer cells in the elderly.20 Age by itself is associated with worse survival as previously highlighted by the Dutch Gastric Cancer Group Trial.7 The overall, disease-specific and median survival rates for all age groups were higher than previously recognized and is more in-
line with the data reported by Degiuli et al.21 The improvement in survival is likely secondary to advancements in multimodality care. In our study, the most favorable outcome was seen in the group aged 50-64 y. The 5-y DSS was significantly worse for patients aged 75 y with independent association. Adequate nodal staging (15 LNE) was associated with improved survival outcomes even as the age increases. This association was the strongest in patients who were considered node negative. This likely represents the effect of “stage migration” in patients who had <15 LNE. Skip lymphatic metastases are common in gastric adenocarcinoma, and the likelihood of being a false negative increases when <15 lymph nodes are retrieved.22 Multiple studies have emphasized the importance of stage migration and have established the cutoff point to be 15 lymph nodes for accurate staging.14,23-25 In a Dutch prospective randomized trial, the frequency of detected nodal metastases remained unaffected with median lymph node counts >16.26 The dilemma occurs once a patient is deemed node positive. The survival benefit of appropriate nodal staging as seen with node-negative patients was significantly less pronounced in patients who were deemed node positive. In our study, patients 85 y with node-positive tumors had no
Fig. 9 e Five-year OS in node-positive patients with ‡15 LNE. (Color version of figure is available online.)
Fig. 11 e Five-year DSS in node-positive patients with ‡15 LNE. (Color version of figure is available online.)
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781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845
Table 4 e Multivariate analysis of 5-y disease-specific survival. Hazard ratio (95% CI)
P value
Lymph nodes <15 lymph nodes examined
Reference
15 lymph nodes examined
0.93 (0.84-1.04)
d 0.288
Grade Well differentiated; grade I
Reference
d
Moderately differentiated; grade II
1.26 (1.15-2.12)
<0.001
Poorly differentiated; grade III
2.99 (2.42-3.66)
<0.001
Undifferentiated; anaplastic; grade IV
3.85 (2.86-4.88)
<0.001
20-49
Reference
d
50-64
0.87 (0.82-0.93)
<0.001
65-74
1.13 (0.94-1.22)
0.185
75-84
1.19 (1.02-1.42)
0.002
85
1.89 (1.63-2.01)
<0.001
Age (y)
7
have worse survival outcomes. The comprehensive understanding of age-related oncologic alterations in tumor biology along with the combination of appropriate staging can assist in the identification of elderly patients at low risk of relapse. The role of systemic therapy remains paramount in this disease. The results of our study highlight the issue of tailoring treatment to individual patients. Attempt should be made to exercise standard treatment options including systemic therapy and adequate surgical staging. We believe that absolute age should not be considered a limitation by itself. Our study attempts to underscore certain factors that may influence the decision-making process in providing optimal care to such patients.
Acknowledgment
Neoadjuvant therapy No
Reference
d
Yes
0.79 (0.62-0.96)
<0.001
Author contributions: A.A. was involved in project design, data management, statistical analysis and manuscript writing. H.K. assisted in data management and statistical analysis. G.C. performed data management. S.C.K. was involved in the study design and conception and manuscript writing. P.S. led project design, statistical analysis, manuscript writing, and final editing.
Disclosure improvement in 5-y OS with adequate nodal staging. On multivariate model, adequate nodal staging (15 LNE) was not independently associated with improved survival. The exact impact of stage migration versus improved regional disease control from adequate lymphadenectomy on survival cannot be separated based on our study design. Our data do however support the fact that adequate lymph node retrieval per national guidelines helps predict survival, and we believe that attempt should be made to achieve this goal which may allow appropriately individualized tailoring of multimodality care. Owing to the retrospective study design along with limitations of SEER database, the exact impact of adjuvant treatments could not be established. The low rate of neoadjuvant treatment seen in our group is likely secondary to the fact that most (72%) of the tumors were T1/T2, and neoadjuvant treatment guidelines as defined by the MAGIC trial27 were still in partial evolution. Neoadjuvant treatment however was still independently associated with disease-specific survival in our study, highlighting the significance of systemic therapy in the management of this disease. It is also possible that the survival outcomes are positively affected by early detection of these tumors. These findings illustrate the conundrum that surrounds the appropriate management of gastric adenocarcinoma in the elderly.
Conclusion In conclusion, elderly patients have lower rates of lymphatic metastases from gastric adenocarcinoma but continue to
The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
1. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Stomach Cancer. National Cancer Institute. Accessed: May 21, 2015. 2. Kodera Y, Yamamura Y, Shimizu Y, et al. The number of metastatic lymph nodes: a promising prognostic determinant for gastric carcinoma in the latest edition of the TNM classification. J Am Coll Surg. 1998;187:597e603. 3. Hartgrink HH, van de Velde CJ, Putter H, et al. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol. 2004;22:2069e2077. Epub 2004 Apr 13. 4. Siewert JR, Bottcher K, Stein HJ, et al. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg. 1998;228:449e461. 5. Kodera Y, Yamamura Y, Shimizu Y, et al. Metastatic gastric lymph node rate is a significant prognostic factor for resectable Stage IV stomach cancer. J Am Coll Surg. 1997;185:65e69. 6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 3.2015. Q6 7. Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomized nationwide Dutch D1D2 trial. Lancet Oncol. 2010;11:439e449. 8. Schwarz RE, Smith DD. Clinical impact of lymphadenectomy extent in resectable gastric cancer of advanced stage. Ann Surg Oncol. 2007;14:317e328. 9. Karpeh MS, Leon L, Klimstra D, et al. Lymph node staging in gastric cancer: is location more important than Number? an analysis of 1,038 patients. Ann Surg. 2000;232:362e371.
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10. Nienhueser H, Kunzmann R, Sisic L, et al. Surgery of gastric cancer and esophageal cancer: does age matter? J Surg Oncol. 2015;112:387e395. 11. Steele SR, Chen SL, Stojadinovic A, et al. The impact of age on quality measure adherence in colon cancer. J Am Coll Surg. 2011;213:95e105. 12. Thorn CC, Woodcock NP, Scott N, et al. What factors affect lymph node yield in surgery for rectal cancer? Colorectal Dis. 2004;6:356e361. 13. Malaguarnera L, Cristaldi E, Malaguarnera M. The role of immunity in elderly cancer. Crit Rev Oncol Hematol. 2010;74:40e60. 14. Wu ZM, Teng RY, Shen JG, et al. Reduced lymph node harvest after neoadjuvant chemotherapy in gastric cancer. J Int Med Res. 2011;39:2086e2095. 15. Bonenkamp JJ, Hermans J, Sasako M, et al. Extended lymphnode dissection for gastric cancer. Dutch Gastric Cancer Group. N Engl J Med. 1999;340:908e914. 16. Borie F, Plaisant N, Millat B, et al. Appropriate gastric resection with lymph node dissection for early gastric cancer. Ann Surg Oncol. 2004;11:512e517. 17. Bonenkamp JJ, Songun I, Hermans J, et al. Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet. 1995;345:745e748. 18. Bunt AM, Hermans J, Smit VT, et al. Surgical/pathologic-stage migration confounds comparisons of gastric cancer survival rates between Japan and Western countries. J Clin Oncol. 1995;13:19e25. 19. Candela FC, Urmacher C, Brennan MF. Comparison of the conventional method of lymph node staging with a
20.
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27.
comprehensive fat-clearing method for gastric adenocarcinoma. Cancer. 1990;66:1828e1832. Luscieti P, Hubschmid TH, Cottier H, et al. Human lymph node morphology as a function of age and site. J Clin Pathol. 1980;33:454e461. Degiuli M, Sasako M, Ponti A, et al. Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer. Br J Surg. 2014;101:23e31. Smith DD, Schwarz RR, Schwarz RE. Impact of total lymph node count on staging and survival after gastrectomy for gastric cancer: data from a large US-population database. J Clin Oncol. 2005;23:7114e7124. Aurello P, D’Angelo F, Rossi S, et al. Classification of lymph node metastases from gastric cancer: comparison between Nsite and N-number systems. Our experience and review of the literature. Am Surg. 2007;73:359e366. Ichikawa D, Kurioka H, Ueshima Y, et al. Prognostic value of lymph node staging in gastric cancer. Hepatogastroenterology. 2003;50:301e304. Volpe CM, Koo J, Miloro SM, et al. The effect of extended lymphadenectomy on survival in patients with gastric adenocarcinoma. J Am Coll Surg. 1995;181:56e64. Bunt AM, Hermans J, van de Velde CJ, et al. Lymph node retrieval in a randomized trial on western-type versus Japanese-type surgery in gastric cancer. J Clin Oncol. 1996;14:2289e2294. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11e20.
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Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
The impact of age on nodal metastases and survival in gastric cancer A. Ahmad, MD,a,b,* H. Khan, MD,a,b G. Cholankeril, MD,a,b S.C. Katz, MD,a,b and P. Somasundar, MD, MPHa,b a b
Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island Boston University School of Medicine, Boston, Massachusetts
article info
abstract
Article history:
Background: In gastric adenocarcinoma, the disparity in lymph node involvement between
Received 2 January 2016
different age groups has not been thoroughly investigated. The objective of our study was
Received in revised form
to compare age-associated differences in adequate lymph node harvest and nodal
3 February 2016
involvement in gastric adenocarcinoma patients.
Accepted 26 February 2016
Methods: We analyzed data extracted from the Surveillance, Epidemiology and End Results
Available online xxx
database on 16,213 patients diagnosed with stage I-III gastric adenocarcinoma between 2004 and 2011. All patients underwent surgical resection. Statistical comparisons between
Keywords:
various age groups were done using the chi-square test and Cox regression.
Gastric cancer
Results: Among 16,213 gastrectomy patients, proportion of patients that had >15 lymph
Elderly
nodes examined decreases significantly with increasing age (P < 0.0001). When adequately
Lymph node metastases
staged, older patients had a significantly lower proportion of node-positive tumors
Survival
(P < 0.0001). Adequate nodal staging was also associated with improved 5-y disease-specific survival across all age groups. Conclusions: In gastric adenocarcinoma, older patients are less likely to be adequately staged. However, when adequately staged, they are less likely to have node-positive tumors. Adherence to national guidelines, regardless of age, is associated with improved survival outcomes and may alter multimodality management of gastric cancer in the elderly. ª 2016 Elsevier Inc. All rights reserved.
Introduction In the United States, the incidence of gastric cancer is declining but the mortality rate remains high.1 Overall 5-y survival rate for all stages combined is around 28%.1 Metastatic involvement of regional lymph nodes is one of the most important prognostic determinants of survival after resection of gastric cancer.2-5 National guidelines recommend pathologic assessment of at least 15 lymph nodes from a gastrectomy specimen for accurate staging.6 Improvement in
survival outcomes has been associated with adequate lymphadenectomy specifically in patients with node-positive disease.7-9 In gastric cancer, the sensitivity of diagnostic modalities used for preoperative assessment of nodal involvement is limited. Therefore, adequate surgical staging remains the cornerstone of management.8,9 Gastric cancer is a disease of the elderly with a median age of 69 y at diagnosis. In older patients, comorbidities and limited ability to tolerate systemic treatment may complicate decisions regarding adequate surgical resection. In the Dutch
* Corresponding author. Division of Surgical Oncology, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908. Tel.: þ1 347 553 3511; fax: þ1 401 456 6708. E-mail address: [email protected] (A. Ahmad). 0022-4804/$ e see front matter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2016.02.043
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Gastric Cancer Group Trial, age >70 years was independently associated with worse overall survival.3 However, optimal management should be tailored to individual physiological characteristics and properly selected elderly patients may benefit from aggressive treatment. As such, accurate identification of elderly patients at high risk for recurrence is of paramount importance. The objective of our study was to assess the frequency of adequate lymph node retrieval in resectable gastric cancer in the elderly and its impact on staging and survival when compared to younger patients.
Materials and methods Data for our study were extracted from November 2013 submission of the Surveillance Epidemiology and End Results (SEER) database on adult patients diagnosed with gastric adenocarcinoma between 2004 and 2011. The SEER database combines records of 18 cancer registries across the United States representing approximately 28% of the population. Cases were selected based on gastric anatomic site (International Classification of Disease-Oncology, third edition), adenocarcinoma histology (World Health Organization classification), and stage (AJCC seventh edition TNM classification). Patients with gastroesophageal junction tumors or those under the age of 20 years were excluded from the study. Similarly, patients with distant metastases (M1), those who underwent palliative intent gastrectomy or those with positive surgical margins (R1/R2) were excluded. Of the 20,425 patients diagnosed with stage I-III gastric adenocarcinoma, 13,165 underwent curative intent gastrectomy with negative margins (R0) and fulfilled the criteria for our study (Fig. 1). The study population was then subcategorized into the following age groups: 20-49 y, 50-64 y, 65-74 y, 75-84 y, and 85 y. Variables pertaining to the grade of tumor, number of lymph nodes examined (LNE) and the number with metastases were extracted from pathology reports. Neoadjuvant chemotherapy data were derived from a SEER flag for “yp” staging. In an attempt to maintain uniformity in data, nodal stage was re-defined according to the AJCC seventh edition TNM staging system (N1 ¼ 1-2 positive nodes; N2 ¼ 3-6 positive nodes; N3 7 positive nodes). Odds ratio (OR) was calculated for quantitative assessment of association between age, histopathology, LNE, and lymphatic metastases. Statistical comparison was tabulated using the Pearson chisquare test. The KaplaneMeier method was used to estimate survival in various groups. Overall survival (OS) was calculated by SEER using time from initial diagnosis till last contact, date of death or date of cutoff for database. For disease-specific survival (DSS), the event used was death from disease with all other events deemed censored. Univariate comparison between groups was performed using the log-rank test. Multivariate analysis was conducted to calculate hazard ratios using the Cox regression analysis. All statistical analyses report 95% confidence intervals and were performed using SPSS for windows (SPSS Inc, Chicago, IL). Significance of difference was assumed at P < 0.05.
Fig. 1 e Selection criteria flowchart.
Results Demographic and tumor characteristics of all patients are shown in Table 1. The male-to-female ratio was approximately 1.75:1 and remained constant throughout various age groups. Seventy percent of patients were >65 y of age. Tumor location was anatomically distributed among proximal (32%), body (8%), distal (31%), and whole stomach (28%). Most patients had T1/T2 tumors (72%). Sixty eight percent of patients aged 20-49 y had high grade tumors (grade III/IV), and this proportion decreased with increasing age. When compared to patients
Nodal status Among all patients, only 43% of patients who underwent gastrectomy had appropriate nodal staging defined as 15 LNE on histopathologic analysis. Median number of lymph nodes examined for patients aged 20-49 y was 14; however, it
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261 Table 1 e Demographics and tumor characteristics. 262 <65 y, N (%) 263 20-49 y 50-64 y 264 265 Gender 266 Male 715 (69) 2024 (69) 267 Female 317 (31) 924 (31) 268 269 Tumor location 270 Proximal 393 (38) 1251 (41) 271 Body 67 (7) 208 (7) 272 Distal 284 (27) 769 (27) 273 274 Whole 290 (28) 718 (25) 275 T stage 276 T1 244 (24) 734 (25) 277 T2 451(44) 1377 (47) 278 T3 221 (21) 623 (21) 279 280 T4 116 (11) 214 (7) 281 Histologic grade 282 Grade I 51 (5) 153 (6) 283 Grade II 257 (27) 734 (26) 284 285 Grade III 632 (65) 1784 (65) 286 Grade IV 26 (3) 78 (3) 287 Lymph nodes examined 288 <15 467 (45) 1660 (57) 289 15 559 (55) 1269 (43) 290 291 N stage 292 N0 388 (38) 1192 (40) 293 N1 469 (45) 1159 (39) 294 N2 142 (14) 450 (16) 295 296 N3 27 (2) 128 (4) 297 Unknown but Nþ 6 (1) 19 (1) 298 299 300 301 declined with increasing age to a median of 8 in patients aged 302 85 y. When compared to the 20-49 y group, patients in each 303 older group were significantly less likely to have undergone an 304 adequate lymphadenectomy (Table 2). This deficiency was 305 most prominent in the patients aged 85 y (OR ¼ 0.49, 95% CI 306 ¼ 0.43-0.56, P < 0.001). 307 In the entire cohort, 7354 patients had lymph node me308 tastases (56%). This proportion was significantly higher in 309 younger patients (62%). Increasing age was associated with 310 decreased rate of lymphatic metastases (Table 3). 311 312 Because elderly patients were more likely to be under313 staged, we performed a subgroup analysis based on LNE status 314 315 316 317 Q4Q5 Table 2 e Adequate nodal staging (‡15 LNE). 318 Age groups (y) Odds ratio (OR) 95% CI P value 319 20-49 Reference d d 320 50-64 0.64 0.55-0.74 <0.001 321 322 65-74 0.75 0.64-0.88 <0.001 323 75-84 0.65 0.56-0.74 <0.001 324 85 0.49 0.43-0.56 <0.001 325
Q3
65 y, N (%) 65-74 y
75-84 y
85 y
813 (59)
2783 (67)
2185 (59)
559 (41)
1350 (33)
1495 (41)
435 (32)
1349 (33)
869 (24)
104 (8)
323 (8)
324 (9)
440 (32)
1282 (31)
1341 (36)
393 (28)
1179 (28)
1146 (31)
261 (19)
1147 (28)
1022 (28)
626 (46)
1882 (46)
1733 (47)
328 (24)
799 (20)
662 (18)
143 (11)
268 (6)
241 (7)
49 (4)
271 (7)
213 (6)
221 (17)
1198 (30)
1165 (33)
957 (75)
2372 (61)
2026 (58)
45 (4)
69 (2)
96 (3)
720 (53)
2321 (56)
2307 (63)
648 (47)
1794 (44)
1356 (37)
574 (42)
1903 (46)
1754 (48)
466 (34)
1489 (36)
1322 (36)
244 (18)
533 (13)
442 (12)
84 (6)
190 (5)
145 (3)
4 (<1)
18 (<1)
17 (1)
to reassess the association of age with lymphatic metastases. Sixty-four patients were excluded from this subgroup analysis due to the lack of specific data on the number of lymph nodes retrieved. The decrease in the rate of lymphatic metastases with increasing age persisted among the various age groups regardless of the nodal staging status (Table 3).
Survival analysis The median and 5-y OS for patients with stage I-III resected gastric adenocarcinoma was 53 mo and 45% for age group 2049 y, 52 mo and 44% for 50-64 y, 43 mo and 40% for 65-74 y, 28 mo and 29% for 75-84 y, 19 mo and 18% for patients aged 85 y (Fig. 2). Gastric cancer specific outcomes were analyzed by determining DSS. The 5-year DSS was 57% for age group 20-49 y, 64% for 50-64 y, 61% for 65-74 y, 51% for 75-84 y and 44% for patients 85 y (Fig. 3).
Survival analysis in node-negative patients To assess the impact of adequate nodal staging on survival, subgroup survival analyses were performed on patients who were node negative (N0) on final histopathologic analysis.
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391 Table 3 e Rate of lymphatic metastases. 392 Age groups (y) All patients Subgroup analysis 393 <15 lymph nodes examined 15 lymph nodes examined 394 395 OR (95% CI) P OR (95% CI) P OR (95% CI) P 396 397 20-49 Reference d Reference d Reference d 398 50-64 0.88 (0.77-1.03) 0.109 0.82 (0.62-0.92) 0.004 0.94 (0.70-1.12) 0.141 399 65-74 0.83 (0.71-0.98) 0.036 0.68 (0.57-0.83) <0.001 0.88 (0.63-0.95) 0.016 400 75-84 0.70 (0.61-0.81) <0.001 0.69 (0.61-0.89) <0.001 0.82 (0.65-0.97) 0.037 401 85 0.66 (0.57-0.76) <0.001 0.61 (0.55-0.87) <0.001 0.83 (0.62-0.98) 0.041 402 403 404 405 The 5-y OS in patients who were node negative decreased OS is age groups 20-49 y (32% versus 29%, P ¼ 0.02), 50-64 y (33% 406 with increasing age regardless of the LNE status (Figs. 4 and 5). versus 26%, P < 0.001), 65-74 y (27% versus 24%, P ¼ 0.006), and 407 To assess the impact of adequate nodal staging on 5-y OS, 75-84 y (18% versus 13%, P < 0.001) but worse 5-year OS in age 408 intragroup comparison was performed for each individual age group 85 y (8% versus 11%, P ¼ 0.08). 409 group with regard to their respective nodal staging status (<15 Age remained associated with a worse 5-y DSS in node410 versus 15 LNE). Examination of 15 lymph nodes was assopositive patients (Figs. 10 and 11). On comparison of each 411 ciated with improvement in 5-y OS is age groups 20-49 y (83% age group with respect to their nodal staging status, adequate 412 versus 67%, P < 0.001), 50-64 y (76% versus 63%, P < 0.001), 65-74 lymph node staging was associated with an improvement in 413 5-y DSS across all age groups (Fig. 10 versus Fig. 11). However, y (66% versus 54%, P < 0.001), 75-84 y (52% versus 43%, P < 0.001) 414 the difference was less pronounced: 20-49 y (43% versus 41%, and 85 y (39% versus 23%, P < 0.001). 415 416 P ¼ 0.15), 50-64 y (52% versus 45%, P < 0.001), 65-74 y (45% versus Age was associated with a worse 5-y DSS whether patients 417 41%, P ¼ 0.002), 75-84 y (34% versus 29%, P < 0.001), and 85 y were adequately staged (Figs. 6 and 7). On a similar intragroup 418 (28% versus 22%, P < 0.001). comparison (Fig. 6 versus Fig. 7), 15 LNE was associated with a 419 significant improvement in 5-y DSS in patients in age groups 420 Multivariate analysis 20-49 y (92% versus 78%, P < 0.001), 50-64 y (86% versus 81%, 421 P ¼ 0.003), 65-74 y (85% versus 79%, P < 0.001), 75-84 y (77% 422 On multivariate analysis, after adjusting for confounding versus 70%, P < 0.001) and age 85 y (78% versus 57%, P < 0.001). 423 variables, the association of 15 LNE with prolonged 5-year 424 DSS was not found to be significant (P ¼ 0.288). Factors inde425 Survival analysis in node-positive patients pendently associated with survival were grade of tumor, age, 426 Survival analysis was also performed on patients with nodeand neoadjuvant therapy (Table 4). Specifically, age >75 y was 427 positive tumors. Predictably, patients with node-positive 428 associated with worse disease-specific survival outcomes. tumors had worse survival outcomes when compared to 429 node-negative tumors. 430 As seen with node-negative patients, increasing age was 431 associated with a decreased 5-y OS in node-positive patients Discussion 432 (Figs. 8 and 9). However, on comparing each individual age 433 group to their respective LNE status (<15 versus 15), examiGastric adenocarcinoma often presents with advanced age. In 434 435 nation of 15 lymph nodes was associated with improved 5-y elderly patients, declining physiological reserve and medical 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 Q9 Fig. 2 e Age stratified 5-y OS in all patients. (Color version Fig. 3 e Age stratified 5-y DSS in all patients. (Color version 455 of figure is available online.) of figure is available online.) 5.4.0 DTD YJSRE13681_proof 19 March 2016 7:41 am ce
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5
Fig. 4 e Five-year OS in node-negative patients with <15 LNE. (Color version of figure is available online.)
Fig. 6 e Five-year DSS in node-negative patients with <15 LNE. (Color version of figure is available online.)
comorbidities may limit tolerance of multimodality treatment plans. As such, adequate staging and risk stratification is essential to spare patients at low risk for recurrence from adjuvant therapy after surgery. The adherence to national oncologic guidelines in the elderly patients is an intricate issue especially when it comes to achieving “standard of care” goals for lymphadenectomies. Our study shows that the adequacy of lymphadenectomy (15 LNE) decreases with each increasing decade of age. It is not surprising to see that the median number of LNE for patients aged >85 y is 8, and the reason for this is likely multifactorial. Nienhueser et al.10 demonstrated that elderly patients were less likely to undergo extensive surgical resection for gastric cancer. It is plausible that the surgical decision pertaining to the extent of nodal dissection in the elderly population was affected by underlying comorbid issues.10 Age has been independently associated with lower lymph node yields in various tumors.11,12 Age-related immune changes, including decreased homeostatic proliferation of lymphocytes, may contribute to this association.13 Theoretically, altered lymphocyte physiology may play a role toward lower lymph node yields and worse survival outcomes in elderly gastric adenocarcinoma patients.
Wu et al.14 demonstrated lower lymph node yields after neoadjuvant treatment in gastric adenocarcinoma. In our study group, a significantly less proportion of elderly patients received neoadjuvant therapy. Despite this fact, lymph node yields and metastases were lower in the elderly as compared to younger age groups highlighting the possible role of other variables such as altered tumor biology in this disease. The definition of optimal lymphadenectomy for gastric adenocarcinoma has been thoroughly investigated in multiple trials and still remains contentious.3,4,7,15-17 However, national guidelines recommend analysis of at least 15 lymph nodes after curative intent gastrectomy for adequate staging.6 Bunt et al.18 emphasized that the combination of appropriate surgical technique and diligent pathologic examination of specimen determine the number of lymph nodes ultimately retrieved. With improved pathologic techniques such as comprehensive fat clearing, Candela et al.19 doubled their lymph node counts in gastrectomy specimens. Fifty-six percent of the entire cohort had lymph node metastases and is consistent with data reported in other studies.9,10 On subgroup analysis, the rate of lymph node metastases decreased from 62% in younger patients (20-49 y) to 53% in patients 75 y. As younger patients had a higher
Fig. 5 e Five-year OS in node-negative patients with ‡15 LNE. (Color version of figure is available online.)
Fig. 7 e Five-year DSS in node-negative patients with ‡15 LNE. (Color version of figure is available online.)
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6
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j o u r n a l o f s u r g i c a l r e s e a r c h - 2 0 1 6 ( - ) 1 e8
Fig. 8 e Five-year OS in node-positive patients with <15 LNE. (Color version of figure is available online.)
Fig. 10 e Five-year DSS in node-positive patients with <15 LNE. (Color version of figure is available online.)
proportion of high grade tumors and a significantly greater percentage of tumors located in proximal and whole stomach, both of which are independent predictors of metastatic potential, it could be speculated that the high rate of nodal metastases is a consequence of inherent aggressive tumor biology in younger patients.9 The exact impact of age on nodal metastases as observed in the entire cohort was likely confounded by the fact that a higher proportion of elderly patients were understaged secondary to the lower rate of adequate lymphadenectomy. When analysis was conducted on patients who were appropriately staged (15 LNE), age 65 y was still associated with lower rate of lymphatic metastases. On multivariate analysis, age remained independently associated with decreased incidence of lymphatic metastases. Although this may be secondary to differences in tumor biology, age-related changes in lymph node architecture could also render this compartment a less favorable metastatic niche for circulating gastric cancer cells in the elderly.20 Age by itself is associated with worse survival as previously highlighted by the Dutch Gastric Cancer Group Trial.7 The overall, disease-specific and median survival rates for all age groups were higher than previously recognized and is more in-
line with the data reported by Degiuli et al.21 The improvement in survival is likely secondary to advancements in multimodality care. In our study, the most favorable outcome was seen in the group aged 50-64 y. The 5-y DSS was significantly worse for patients aged 75 y with independent association. Adequate nodal staging (15 LNE) was associated with improved survival outcomes even as the age increases. This association was the strongest in patients who were considered node negative. This likely represents the effect of “stage migration” in patients who had <15 LNE. Skip lymphatic metastases are common in gastric adenocarcinoma, and the likelihood of being a false negative increases when <15 lymph nodes are retrieved.22 Multiple studies have emphasized the importance of stage migration and have established the cutoff point to be 15 lymph nodes for accurate staging.14,23-25 In a Dutch prospective randomized trial, the frequency of detected nodal metastases remained unaffected with median lymph node counts >16.26 The dilemma occurs once a patient is deemed node positive. The survival benefit of appropriate nodal staging as seen with node-negative patients was significantly less pronounced in patients who were deemed node positive. In our study, patients 85 y with node-positive tumors had no
Fig. 9 e Five-year OS in node-positive patients with ‡15 LNE. (Color version of figure is available online.)
Fig. 11 e Five-year DSS in node-positive patients with ‡15 LNE. (Color version of figure is available online.)
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716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780
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781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845
Table 4 e Multivariate analysis of 5-y disease-specific survival. Hazard ratio (95% CI)
P value
Lymph nodes <15 lymph nodes examined
Reference
15 lymph nodes examined
0.93 (0.84-1.04)
d 0.288
Grade Well differentiated; grade I
Reference
d
Moderately differentiated; grade II
1.26 (1.15-2.12)
<0.001
Poorly differentiated; grade III
2.99 (2.42-3.66)
<0.001
Undifferentiated; anaplastic; grade IV
3.85 (2.86-4.88)
<0.001
20-49
Reference
d
50-64
0.87 (0.82-0.93)
<0.001
65-74
1.13 (0.94-1.22)
0.185
75-84
1.19 (1.02-1.42)
0.002
85
1.89 (1.63-2.01)
<0.001
Age (y)
7
have worse survival outcomes. The comprehensive understanding of age-related oncologic alterations in tumor biology along with the combination of appropriate staging can assist in the identification of elderly patients at low risk of relapse. The role of systemic therapy remains paramount in this disease. The results of our study highlight the issue of tailoring treatment to individual patients. Attempt should be made to exercise standard treatment options including systemic therapy and adequate surgical staging. We believe that absolute age should not be considered a limitation by itself. Our study attempts to underscore certain factors that may influence the decision-making process in providing optimal care to such patients.
Acknowledgment
Neoadjuvant therapy No
Reference
d
Yes
0.79 (0.62-0.96)
<0.001
Author contributions: A.A. was involved in project design, data management, statistical analysis and manuscript writing. H.K. assisted in data management and statistical analysis. G.C. performed data management. S.C.K. was involved in the study design and conception and manuscript writing. P.S. led project design, statistical analysis, manuscript writing, and final editing.
Disclosure improvement in 5-y OS with adequate nodal staging. On multivariate model, adequate nodal staging (15 LNE) was not independently associated with improved survival. The exact impact of stage migration versus improved regional disease control from adequate lymphadenectomy on survival cannot be separated based on our study design. Our data do however support the fact that adequate lymph node retrieval per national guidelines helps predict survival, and we believe that attempt should be made to achieve this goal which may allow appropriately individualized tailoring of multimodality care. Owing to the retrospective study design along with limitations of SEER database, the exact impact of adjuvant treatments could not be established. The low rate of neoadjuvant treatment seen in our group is likely secondary to the fact that most (72%) of the tumors were T1/T2, and neoadjuvant treatment guidelines as defined by the MAGIC trial27 were still in partial evolution. Neoadjuvant treatment however was still independently associated with disease-specific survival in our study, highlighting the significance of systemic therapy in the management of this disease. It is also possible that the survival outcomes are positively affected by early detection of these tumors. These findings illustrate the conundrum that surrounds the appropriate management of gastric adenocarcinoma in the elderly.
Conclusion In conclusion, elderly patients have lower rates of lymphatic metastases from gastric adenocarcinoma but continue to
The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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