- Email: [email protected]
Rates and Patterns of Recurrence after Curative Intent Resection for Gastric Cancer: A United States Multi-Institutional Analysis
Rates and Patterns of Recurrence after Curative Intent Resection for Gastric Cancer: A United States Multi-Institutional Analysis Gaya Spolverato, MD, Aslam Ejaz, MD, MPH, Yuhree Kim, MD, MPH, Malcolm H Squires, MD, George A Poultsides, MD, FACS, Ryan C Fields, MD, FACS, Carl Schmidt, MD, FACS, Sharon M Weber, MD, FACS, Konstantinos Votanopoulos, MD, FACS, Shishir K Maithel, MD, FACS, Timothy M Pawlik, MD, MPH, PhD, FACS Reports on recurrence and outcomes of US patients with gastric cancer are scarce. The aim of this study was to determine incidence and pattern of recurrence after curative intent surgery for gastric cancer. STUDY DESIGN: Using the multi-institutional US Gastric Cancer Collaborative database, we identified 817 patients undergoing curative intent resection for gastric cancer between 2000 and 2012. Patterns and rates of recurrence along with associated risk factors were identified using adjusted regression analysis. Recurrences were classified as locoregional, peritoneal, or hematogenous. RESULTS: Median patient age was 65.8 years (interquartile range [IQR] 56.4, 74.7); the majority of patients were male (n ¼ 462, 56.6%) and white (n ¼ 511, 62.5%). At the time of surgery, the majority of patients underwent a partial gastrectomy (n ¼ 481, 59.2%) with a complete R0 resection achieved in 91.6% (n ¼ 748) of patients. At the time of last follow-up, 244 (29.9%) of 817 patients developed a recurrence; 163 (66.8%) patients had recurrence at only a single site; the remaining 81 (33.2%) had multiple sites of initial recurrence. Among patients who recurred at a single site, recurrence was most common at a distant location and included hematogenous (n ¼ 57, 23.4%) or peritoneal (n ¼ 47, 19.3%) only metastasis. Tumors at the gastroesophageal junction (odds ratio [OR] 3.18, 95% CI 1.08 to 9.40; p ¼ 0.04) were associated with higher risk of locoregional recurrence, while the presence of multiple lesions (OR 10.82, 95% CI 3.56 to 32.85; p < 0.001) remained associated with an increased risk of distant hematogenous recurrence after adjusted analysis. Recurrence was associated with worse survival, with a median recurrence-free survival of 10.8 months (IQR 8.9, 12.8) among those who experienced a recurrence. CONCLUSIONS: Nearly one-third of patients experienced recurrence after gastric cancer surgery. The most common site of recurrence was distant. (J Am Coll Surg 2014;219:664e675. 2014 by the American College of Surgeons)
BACKGROUND:
Gastric adenocarcinoma is the fourth most common malignant tumor worldwide and the second most common cause of cancer-related deaths.1,2 There is a strong geographic variation in the incidence of gastric cancer, with higher rates seen in Asia, Eastern Europe, and South America, likely due to differences in diet, alcohol consumption, smoking patterns, and Helicobacter pylori infection.1 Despite the relative lower incidence of gastric cancer in the United States (US), there were still an estimated 21,600 new cases of gastric cancer resulting in nearly 11,000 deaths in 2012.3 The use of advanced
Disclosure Information: Nothing to disclose. Received January 26, 2014; Revised March 12, 2014; Accepted March 12, 2014. From the Departments of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD (Spolverato, Ejaz, Kim, Pawlik); Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (Squires, Maithel); Stanford University, Palo Alto, CA (Poultsides); Washington University, St Louis, MO (Fields); The Ohio State University, Columbus, OH (Schmidt); Division of Surgical Oncology, University of Wisconsin, Madison, WI (Weber); and Wake Forest University, Winston-Salem, NC (Votanopoulos). Correspondence address: Timothy M Pawlik, MD, MPH, PhD, FACS, Department of Surgery, Johns Hopkins Hospital, 600 N Wolfe St, Blalock 688, Baltimore, MD 21287. email: [email protected]
ª 2014 by the American College of Surgeons Published by Elsevier Inc.
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diagnostic techniques such as endoscopy, endoscopic ultrasound, and CT, has allowed for the earlier detection of gastric cancer among some patients.4 Many patients, however, still present with more advanced disease. Although improvements in surgical technique and perioperative care have led to better short-term outcomes,5 long-term prognosis of patients with gastric cancer remains guarded.6-8 Although chemotherapy and radiotherapy are often used in the adjuvant treatment of patients with gastric cancer, recurrence after curative intent resection is relatively common, occurring in 20% to 50% of patients.9-13 In fact, recurrence is one of the most important factors associated with death in patients with gastric cancer.10 Data on the incidence and factors associated with recurrence patterns after surgery for gastric cancer remain relatively scarce. In fact, most studies reporting on outcomes after surgical management of gastric cancer have focused largely on overall survival rather than recurrence.14-16 To date, previous studies that have examined recurrence after curative intent gastrectomy for gastric cancer have all been derived from the experience of single institutions. Perhaps more importantly, due to the relative rarity of gastric cancer in the US, previous data have almost exclusively been from centers in Asia,9,11,17,18 with 1 study from Turkey.13 Previous data on how tumor characteristics such as tumor size, grade, and nodal status may affect recurrence have not been validated in a US cohort.10,17,19,20 Because US patients with gastric cancer may have a different presentation, natural history, and prognosis than patients in Asia, information on rates and patterns of recurrence derived from a US cohort is critical. In this study, using a large multi-institutional cohort of patients, we sought to determine the rates of recurrence after curative intent surgery for gastric adenocarcinoma. Specifically, we examined the pattern of recurrence of patients who were managed with curative intent resection and identify factors predictive of overall recurrence as well as specific patterns of recurrence.
METHODS Patient demographic and clinical data Patients undergoing curative intent resection for gastric cancer between 2000 and 2012 at 1 of 7 major academic institutions participating in the US Gastric Cancer Collaborative (Johns Hopkins University, Emory University, Stanford University, Washington University, Wake Forest University, University of Wisconsin, The Ohio State University) were identified. Patients who underwent a palliative operation, had known metastatic disease preoperatively, or experienced perioperative mortality within 30 days of surgery were excluded from analysis. Only
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patients with a gastric adenocarcinoma were included in this study; patients with other gastric tumors (eg, carcinoid, gastrointestinal stromal tumor, etc) were not included. The Institutional Review Board of each institution approved the study. Standard patient demographic and clinicopathologic data were collected including age, sex, comorbidities, family history of gastric cancer, history of Helicobacter pylori infection, and history of alcohol abuse and smoking. Tumor characteristics were collected including tumor location, size, grade, depth of invasion, histology, lymph node status, presence of signet ring cells, and lymphovascular invasion and perineural invasion. Data regarding treatment details were also collected including type of resection and intestinal reconstruction, as well as the extent of lymphadenectomy (D1 vs D2). Proximal and distal resection margin status was recorded; margin status was classified as microscopically negative (R0), microscopically positive (R1), or macroscopically positive (R2). Information on the type and duration of chemotherapy and radiotherapy, if applicable, were also noted. Date of last follow-up, vital status, and recurrencerelated information were collected on all patients. Recurrence was defined as the presence of a biopsy-proven tumor showing adenocarcinoma cells or the presence of imaging highly suspicious of tumor recurrence. Information regarding the location and number of lesions, as well as the disease-free interval from the date of initial operation to the development of recurrent disease was recorded. For the cohort of patients who developed repeat recurrences, data on the pattern and time interval between subsequent recurrences were also noted. Recurrences were classified as locoregional (nodal or gastric), peritoneal, or hematogenous (eg, liver, lung, bone, etc).17 Statistical analysis Baseline characteristics of the study population were summarized according to the presence or absence of recurrence. Differences between the 2 groups were assessed by the chi-square test and 1-way analysis of variance (ANOVA), as appropriate. Data were correspondingly reported as numbers (percentage), means (standard deviations), or medians with interquartile ranges. Recurrence-free and overall survivals were estimated using the Kaplan-Meier method, and differences in survival were examined with the log-rank test. The association of relevant clinicopathologic variables with extent of recurrence was examined using logistic models. Patients who experienced only single-site recurrences (locoregional, hematogenous, or peritoneal only) were used in the logistic regression models to avoid possible interactions of factors. In examining time to recurrence,
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patients were analyzed as early (<12 month) vs late (12 months) recurrences.17 The most parsimonious model was created using a stepwise approach that included factors that were statically significant (eg, p < 0.05) on univariate analysis. All analyses were carried out with STATA version 12.0 (StataCorp), and a p value <0.05 was considered statistically significant.
RESULTS Clinicopathologic and treatment characteristics Using the US Gastric Cancer Collaborative database, 817 patients who underwent curative intent surgery between 2000 and 2012 for gastric cancer were identified. The median patient age was 65.8 years (interquartile range [IQR] 56.4, 74.7); the majority of patients were male (n ¼ 462, 56.6%) and non-Hispanic white (n ¼ 511, 62.5%) (Table 1). Only a small proportion of patients had a history of Helicobacter pylori infection (n ¼ 106, 13.0%) or a family history of gastric cancer (n ¼ 68, 8.3%). The most common location of the tumor was the antrum (n ¼ 301, 37.8%) or the body (n ¼ 292, 36.6%) of the stomach; the majority of lesions were found on the lesser curvature (n ¼ 275, 61.2%). The median size of the largest tumor was 4 cm (IQR 2.5, 6.5 cm). Most tumors were solitary (n ¼ 760, 95.8%) and penetrated the subserosa (n ¼ 263, 33%) or visceral peritoneum and adjacent structures (n ¼ 230, 28.8%). At the time of surgery, the majority of patients underwent a partial gastrectomy (n ¼ 481, 59.2%); the remaining 332 (40.8%) patients underwent a total gastrectomy. A complete R0 resection was achieved in 91.6% (n ¼ 748) of patients; the remaining 8.4% (n ¼ 69) of patients had at least 1 microscopically positive margin (R1). No patients had any evidence of macroscopic disease (R2) at the completion of surgery. Most patients underwent a D2 lymphadenectomy (n ¼ 484, 59.2%), while 293 patients (35.9%) underwent a D1 lymphadenectomy. The median number of lymph nodes harvested was 17 (IQR 11, 25); a majority of patients had lymph node metastasis (n ¼ 481, 58.9%). Most tumors were of the intestinal type (n ¼ 538, 65.9%), with the remaining lesions being of the diffuse (n ¼ 252, 30.8%) or mixed (n ¼ 27, 3.3%) sub-type. Signet ring cells were detected in 40.0% (n ¼ 327) of tumors, and evidence of lymphovascular and perineural invasion was found in 38.2% (n ¼ 312) and 22.9% (n ¼ 187) of tumors, respectively. According to the 7th edition American Joint Committee on Cancer (AJCC) staging system, most patients had stage III disease (n ¼ 356, 44.3%); the remaining patients had stage I (n ¼ 239, 29.8%) or stage II (n ¼ 208, 25.9%) disease.
J Am Coll Surg
A small subset of patients received neoadjuvant chemotherapy (n ¼ 168, 20.6%); even fewer received neoadjuvant radiotherapy (n ¼ 24, 2.9%). Nearly half of all patients received some form of adjuvant chemotherapy (n ¼ 417, 51%); almost one-third of patients (n ¼ 266, 32.6%) received adjuvant radiotherapy. Pattern of recurrence With a median follow-up of 28.9 months, 244 (29.9%) of 817 patients developed a recurrence. Among patients who experienced a recurrence, 163 (66.8%) recurred at only a single site. Among patients who recurred at a single site, recurrence was most common at a distant location and included hematogenous (n ¼ 57, 23.4%) or peritoneal (n ¼ 47, 19.3%) only metastasis (Fig. 1). Overall, 185 patients (75.8%) had some component of distant recurrence, and 59 (24.2%) patients developed only locoregional recurrent disease. The remaining 81 (33.2%) patients had multiple sites of recurrence; patients had hematogenous and peritoneal recurrence (n ¼ 7, 2.9%), hematogenous and locoregional recurrence (n ¼ 36, 14.8%), peritoneal and locoregional recurrence (n ¼ 25, 10.3%), or had evidence of hematogenous, peritoneal, and locoregional disease (n ¼ 13, 5.3%). The most common sites of distant recurrence included peritoneum (n ¼ 92), liver (n ¼ 52), lung (n ¼ 17), bone (n ¼ 4), and other sites (n ¼ 20). Overall, when considering patients with both single and multiple site recurrences, 133 (54.5%) and 113 (46.3%) patients had locoregional recurrence or hematogenous recurrence, respectively, as a component of failure; 92 (37.7%) patients had peritoneal metastasis. Factors associated with recurrence Several patient- and tumor-related factors were associated with “any site” recurrence including patient age, tumor sub-type and size, and lymph node status. Specifically, patients who experienced a recurrence were more likely to be younger (median age: no recurrence, 66.5 years vs recurrence, 63.7 years; OR 0.98, 95% CI 0.97 to 0.99; p ¼ 0.002) (Table 2). In addition, tumor size was associated with risk of recurrence because patients with larger gastric lesions were more at risk of recurrence (median tumor size: no recurrence, 3.7 cm vs recurrence, 4.8 cm; p < 0.001). Other tumor factors such as diffuse tumor type (referent, intestinal sub-type: OR 1.78, 95% CI 1.22 to 2.61), presence of signet ring features (OR 1.41, 95% CI 1.04 to 1.92), and evidence of lymphovascular (OR 1.93, 95% CI 1.40 to 2.66) or perineural invasion (OR 2.14, 95% CI 1.48 to 3.10) were each associated with a higher risk of any site recurrence (all p < 0.05). In addition, the presence of lymph node
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Table 1.
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Clinicopathologic Characteristics of Patients Who Underwent Curative Intent Surgery
Characteristic Age, y, median (IQR) Male sex, n (%) White race, n (%) Family history of gastric cancer, n (%) History of Helicobacter pylori, n (%) Alcohol abuse, n (%) Smoking, n (%) Operation type, n (%) Distal Subtotal Total Wedge resection R0 Margin, n (%) Tumor type, n (%) Diffuse Intestinal Mixed Tumor location, n (%) Antrum Body Cardia Fundus GE junction Curvature, n (%) Greater Lesser No. of lesions, n (%) Solitary lesion Multiple Size, cm, median (IQR) T stage, n (%) T1 T2 T3 T4 Lymph node metastasis, n (%) Lymph nodes harvested, median (IQR) AJCC stage, n (%) Stage I Stage II Stage III Tumor grade, n (%) Poor to moderate Moderate Moderate to well Signet ring, n (%) LVI, n (%) PNI, n (%) Neoadjuvant chemotherapy, n (%) Neoadjuvant radiotherapy, n (%) Adjuvant chemotherapy, n (%) Adjuvant radiotherapy, n (%) Death, n (%)
Total (n ¼ 817) 65.8 (56.4,74.7) 462 (56.6) 511 (62.5) 68 (8.3) 106 (13.0) 86 (10.5) 313 (38.3) 136 336 332 9 748
No recurrence (n ¼ 573) 66.5 (57.0,75.5) 331 (57.8) 360 (62.8) 46 (8.0) 78 (13.6) 52 (9.1) 222 (38.7)
(16.7) (41.3) (40.8) (1.2) (91.6)
94 253 217 7 530
(16.5) (44.3) (38.0) (1.2) (92.8)
Recurrence (n ¼ 244) 63.7 (54.3,72.1) 131 (53.7) 151 (61.9) 22 (9.0) 28 (11.5) 34 (13.9) 91 (37.3) 42 83 115 2 218
(17.4) (34.3) (47.5) (0.8) (90.5)
252 (30.8) 538 (65.9) 27 (3.3)
103 (26.8) 269 (69.9) 13 (3.3)
65 (40.4) 91 (56.5) 5 (3.1)
301 292 78 66 60
216 206 51 48 39
85 86 27 18 21
p Value 0.002 0.28 0.64 0.7 0.42 0.05 0.50 0.06
0.25 0.01
0.7 (37.8) (36.6) (9.8) (8.3) (7.5)
(38.7) (36.9) (9.1) (8.6) (6.7)
(35.6) (36.0) (11.3) (7.5) (9.6) 0.64
174 (38.8) 275 (61.2)
123 (38.1) 200 (61.9)
51 (40.5) 75 (59.5)
760 (95.8) 33 (4.2) 4.0 (2.5,6.5)
537 (96.8) 18 (3.2) 3.7 (2.0,6.4)
223 (93.6) 15 (6.4) 4.8 (3.2,7.0)
195 109 263 230 481 17
177 85 166 130 294 17
18 24 97 100 187 17
0.05
(24.5) (13.7) (33.0) (28.8) (58.9) (11, 25)
(31.7) (15.2) (29.8) (23.3) (51.3) (11, 25)
(7.5) (10.0) (40.6) (41.9) (76.6) (10, 24)
239 (29.8) 208 (25.9) 356 (44.3)
214 (38.2) 147 (26.2) 200 (35.6)
25 (10.3) 61 (25.2) 156 (64.5)
535 193 55 327 312 187 168 24 417 266 365
352 149 47 215 194 112 103 17 247 167 172
183 44 8 112 118 75 65 7 170 99 193
<0.001 <0.001
<0.001 0.67 <0.001
<0.001 (68.3) (24.7) (7.0) (40.0) (38.2) (22.9) (20.6) (2.9) (51.0) (32.6) (44.7)
GE, gastroesophageal; LVI, lymphovascular invasion; PNI, perineural invasion.
(64.2) (27.2) (8.6) (37.5) (33.9) (19.5) (18.0) (3.0) (43.1) (29.1) (30.3)
(77.9) (18.7) (3.4) (45.9) (48.4) (30.7) (26.6) (2.9) (69.7) (40.6) (79.1)
0.03 <0.001 <0.001 0.005 0.88 <0.001 0.01 <0.001
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metastasis similarly increased the risk of recurrence (OR 3.18, 95% CI 2.26 to 4.48; p < 0.001). In examining the pattern of recurrence, several factors were associated with specific patterns of recurrence. For example, on univariate analysis, gastric tumor location, extent of invasion, American Joint Committee on Cancer (AJCC) stage, lymph node metastasis, and extent of lymphadenectomy were associated with risk of locoregional recurrence (Table 3). Specifically, patients with a tumor at the gastroesophageal junction (referent, antrum: OR 2.57, 95% CI 1.05 to 6.26; p ¼ 0.04), increasing tumor depth (referent, T1: T2, OR 2.21, 95% CI 0.66 to 7.43; T3, OR 3.13, 95% CI 1.15 to 8.49; T4, OR 4.43, 95% CI 1.66 to 11.84; all p < 0.05), the presence of lymph node metastasis (OR 4.01, 95% CI 1.13 to 3.78; p ¼ 0.02), and D2 lymphadenectomy (OR 2.28, 95% CI 1.18 to 4.41; p ¼ 0.01) had an increased risk of locoregional recurrence. On multivariate analysis, tumor location at the gastroesophageal junction (OR 3.18, 95% CI 1.08 to 9.40; p ¼ 0.04) remained independently associated with higher risk of locoregional recurrence. On univariate analysis, peritoneal recurrence was associated with several factors including tumor histologic type, grade, extent of invasion, AJCC stage, perineural invasion, lymph node metastasis, and receipt of chemotherapy (all p < 0.05) (Table 4). Similarly, distant hematogenous recurrence was associated with the presence of multiple lesions,
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extent of tumor invasion, AJCC stage, lymph node metastasis, lymphovascular and perineural invasion, and receipt of adjuvant chemotherapy (all p < 0.05) (Table 5). After controlling for competing risk factors, the presence of multiple lesions (OR 10.82, 95% CI 3.56 to 32.85; p < 0.001) remained associated with an increased risk of distant hematogenous recurrence.
Timing of recurrence and long-term outcomes The median recurrence-free survival among all patients was 27.7 months (IQR 23.2, 35.5). Among patients who experienced a recurrence, the median recurrencefree survival was 10.8 months (IQR 8.9, 12.8) (Fig. 2). Median recurrence-free survival among patients with locoregional or peritoneal recurrence was 13.6 months (IQR 10.9, 18.9) and 8.5 months (IQR 7.3, 11.1), respectively, compared with 10.6 months (IQR 8.6, 13.3) for patients who had distant hematogenous disease as a component of their recurrence (p ¼ 0.19) (Fig. 3). For patients with distant hematogenous metastasis, the median time was 10.6 months for liver recurrence and 10.1 months for lung recurrence (p ¼ 0.5). Patients with early recurrence (<12 months) were more likely to have peritoneal or hematogenous recurrence compared with patients who had late recurrences, who were more likely to have a locoregional recurrence (p ¼ 0.002).
Figure 1. Overall pattern of recurrence.
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Table 2.
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Univariate/Multivariate Analysis of Risk Factors Associated with Any-Site Recurrence
Risk factor
Age Size Diffuse and mixed type AJCC stage I II III T stage I II III IV Grade Well to moderate Moderate to poor No. of positive LN LN positive LN metastasis ratio LVI PNI Signet ring cell
OR
Univariate analysis 95% CI
p Value
OR
Multivariate analysis 95% CI
p Value
0.98 1.08 1.78
0.97e0.99 1.03e1.13 1.22e2.61
0.002 <0.001 0.003
0.99 0.99 0.94
0.97e1.01 0.92e1.06 0.52e1.69
0.54 0.81 0.84
Ref 3.55 6.68
2.13e5.92 4.20e10.62
<0.001 <0.001
Ref 3.06 6.65
0.68e13.77 0.97e45.41
0.15 0.05
Ref 2.78 5.75 7.56
1.43e5.39 3.33e9.92 4.36e13.12
0.003 <0.001 <0.001
Ref 1.28 1.54 1.63
0.33e4.89 0.32e7.34 0.32e8.38
0.72 0.59 0.56
Ref 1.96 1.05 3.18 6.74 1.93 2.14 1.41
1.38e2.79 1.03e1.07 2.26e4.48 4.00e11.37 1.40e2.66 1.48e3.10 1.04e1.92
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.03
Ref 1.09 0.97 0.84 3.63 0.69 1.10 1.22
0.58e2.05 0.92e1.01 0.34e2.04 0.97e13.61 0.38e1.27 0.61e2.00 0.68e2.20
0.80 0.14 0.69 0.06 0.23 0.75 0.51
AJCC, American Joint Committee on Cancer; LN, lymph node; LVI, lymphovascular invasion; OR, odds ratio; PNI, perineural invasion.
Overall median survival was 38 months (IQR 33.4, 45.0) with 1-year, 3-year, and 5-year survival rates of 77.9%, 50.9%, and 39.3%, respectively. Median survival after recurrence was 5.0 months (locoregional recurrence, 9.1 months vs peritoneal recurrence, 2.7 months vs hematogenous recurrence, 4.8 months; p ¼ 0.01) (Fig. 4). Median survival times after early recurrence was 4.5 months vs 5.7 months among patients with a late recurrence (p ¼ 0.16). Patients experiencing a distant hematogenous recurrence tended to have a worse long-term prognosis (1-, 3-, and 5-year survivals: 75.3%, 19.3%, and 4.7%, respectively) compared with patients who had peritoneal recurrence (1-, 3-, and 5-year survivals: 61.0%, 19.9%, and 9.9%, respectively) or locoregional recurrence (1-, 3-, and 5-year survivals: 68.8%, 34.3%, and 14.7%, respectively) (p ¼ 0.13) (Fig. 4).
DISCUSSION For patients with gastric cancer, resection of the primary lesion with an appropriate lymphadenectomy is the cornerstone of curative intent therapy. Most studies that have reported on curative intent surgery for gastric cancer have focused largely on overall survival.14-16 Data on recurrence and patterns of recurrence after resection of gastric cancer have been more infrequent, and these studies have typically
examined small, single-institution cohorts.10,17,19,20 Furthermore, these past series have largely come from outside of the US.10,13 Given that previous studies have suggested geographic variations in the genetics, phenotypes, and natural history of gastric cancer,10,17,19,20 data specifically derived from a US cohort may be particularly important and relevant to inform clinical decision-making in the US. Data on recurrence are important not only as a surrogate of prognosis, but also as a means to inform clinicians about where they should focus their attention during postoperative surveillance. This study is important because it defines the incidence and pattern of recurrence after curative intent surgery for gastric cancer in a large, multiinstitutional US cohort of patients. Among patients who recurred with a single initial site of disease (n ¼ 163), the pattern of recurrence was distributed relatively equally among distant hematogenous (n ¼ 57), peritoneal (n ¼ 47), and locoregional (n ¼ 59) sites. In contrast, a subset of patients (n ¼ 81) initially recurred at multiple sites, and all patients had distant disease as a component of their failure. The median time to recurrence was about 2 years and, of note, median survival after recurrence was extremely short (5.0 months). There are generally 3 main patterns of recurrence after curative intent resection of gastric cancer: locoregional,
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Table 3.
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Univariate/Multivariate Analysis of Risk Factors Associated with Locoregional Recurrence
Risk factor
Size Tumor location Antrum Body Cardia Fundus GE junction Lesser curvature Diffuse and mixed type AJCC stage I II III T stage I II III IV Tumor grade Well to moderate Moderate to poor No. of positive LN N stage LN metastasis ratio LVI PNI Operation type Wedge resection Distal Subtotal Total R1 margin Neoadjuvant chemotherapy Neoadjuvant radiotherapy Adjuvant chemotherapy Adjuvant radiotherapy D2 lymphadenectomy
OR
Univariate analysis 95% CI
p Value
OR
Multivariate analysis 95% CI
p Value
1.06
0.99e1.14
0.10
NA
e
e
Ref 1.16 1.65 1.37 2.57 1.10 0.71
0.59e2.28 0.66e4.12 0.49e3.85 1.05e6.26 0.51e2.37 0.36e1.41
0.66 0.29 0.55 0.04 0.81 0.32
1.25 2.27 1.21 2.66 NA NA
0.58e2.67 0.81e6.41 0.37e3.96 0.97e7.24 e e
0.57 0.12 0.76 0.06 e e
Ref 2.08 3.25
0.86e5.07 1.48e7.12
0.11 0.003
1.93 1.81
0.30e12.18 0.18e18.11
0.49 0.62
Ref 2.21 3.13 4.43
0.66e7.43 1.15e8.49 1.66e11.84
0.20 0.03 0.003
0.92 0.96 1.34 NA
0.18e4.75 0.16e5.68 0.21e8.56 e
0.92 0.96 0.76 e
Ref 1.22 1.04 2.06 4.01 1.18 0.90
0.66e2.26 1e1.07 1.13e3.78 1.79e9.01 0.67e2.09 0.35e1.83
0.52 0.03 0.02 0.001 0.57 0.60
0.97 1.07 5.54 NA NA NA
0.92e1.03 0.36e3.17 1.21e25.42 e e e
0.40 0.90 0.03 e e e
Ref 0.57 0.51 0.74 1.68 1.62 1.04 3.00 1.32 2.28
0.06e5.05 0.06e4.25 0.09e6.11 0.73e3.87 0.90e2.93 0.24e4.59 2.08e4.35 0.76e2.31 1.18e4.41
0.61 0.53 0.78 0.22 0.11 0.95 <0.001 0.33 0.01
NA NA NA 0.91 NA 2.41
e e e 0.45e1.84 e 0.93e5.14
e e e 0.80 e 0.05
AJCC, American Joint Committee on Cancer; GE, gastroesophageal; LN, lymph nodes; LVI, lymphovascular invasion; OR, odds ratio; PNI, perineural invasion.
peritoneal, and distant.10,11,17 Previous data have demonstrated heterogeneity in the distribution of patients with different patterns of recurrence.21-26 The differences in the reported recurrence patterns are undoubtedly multifactorial and may relate to variations in tumor biology, operative technique, and use of perioperative adjuvant therapies. Interestingly, geographic differences in patterns of recurrence have also been noted. Specifically, several studies
from the East have noted a lower incidence of locoregional recurrences. For example, in 2 separate studies from Japan, peritoneal dissemination was noted to be the main pattern of recurrence after curative gastrectomy.27 Similarly Wu and colleagues11 reported that most recurrences (n ¼ 213; 86.9%) were distant, 110 recurrences (44.9%) were local, and 78 recurrences (49.8%) were both local and distant. Among the distant metastases, Wu and associates noted
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Table 4.
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Univariate/Multivariate Analysis of Risk Factors Associated with Distant Peritoneal Recurrence
Risk factor
Size Tumor location Antrum Body Cardia Fundus GE junction Lesser curvature Diffuse and mixed type AJCC stage I II III T stage I II III IV Grade Well to moderate Moderate to poor No. of positive LN LN positive LN metastasis ratio LVI PNI Operation type Wedge resection Distal Subtotal Total R1 margin Neoadjuvant chemotherapy Neoadjuvant radiotherapy Adjuvant chemotherapy Adjuvant radiotherapy D2 lymphadenectomy
OR
Univariate analysis 95% CI
1.09
1.03e1.16
Ref 1.31 0.92 0.71 1.23 1.29 5.76
0.75e2.28 0.36e2.33 0.24e2.12 0.48e3.13 0.65e2.59 2.95e11.24
Ref 7.66 8.29
p Value
0.006
OR
Multivariate analysis 95% CI
p Value
1.06 NA
0.97e1.17 e
0.21 e
0.34 0.86 0.54 0.67 0.47 <0.001
NA 2.38
e 0.98e5.77
e 0.06
2.61e22.47 2.94e23.38
<0.001 <0.001
Ref 4.74 4.89
0.19e117.87 0.11e208.45
0.34 0.41
Ref 4.39 8.87 9.6
1.11e17.3 2.67e29.40 2.88e31.98
0.04 <0.001 <0.001
Ref 1.06 1.46 1.41
0.05e22.05 0.06e36.52 0.05e37.22
0.97 0.82 0.84
Ref 4.00 1.02 2.03 1.98 1.39 2.64
1.89e8.49 0.98e1.05 1.18e3.49 0.90e4.33 0.84e2.31 1.49e4.69
<0.001 0.33 0.01 0.09 0.20 0.001
Ref 1.37 NA 0.55 NA NA 1.23 NA
0.41e4.59 e 0.13e2.36 e e 0.51e3.00 e
0.61 e 0.42 e e 0.65 e
Ref 0.61 0.60 NA 1.81 1.80 0.48 2.62 1.27 1.20
0.30e1.27 0.35e1.02 e 0.85e3.84 1.06e3.07 0.06e3.64 1.50e4.57 0.77e2.10 0.71e2.03
0.19 0.06 e 0.12 0.03 0.48 0.001 0.34 0.49
1.47 NA 2.59 NA NA
0.57e3.79 e 0.79e8.47 e e
0.42 e 0.11 e e
AJCC, American Joint Committee on Cancer; GE, gastroesophageal; LN, lymph nodes; LVI, lymphovascular invasion; OR, odds ratio; PNI, perineural invasion.
that the most common site of distant recurrence was the peritoneum (53.5%), while 43.3% of patients had hematogenous metastases.11 In contrast, an Italian series reported by Roviello and coworkers28 noted locoregional disease to be the most common pattern of recurrence. Although a report from the Memorial Sloan-Kettering group in the US similarly noted a relatively high incidence of locoregional recurrence, the incidence of peritoneal and distant
recurrence was comparably high.29 In this study, we noted that nearly 3 of every 4 patients who experienced a recurrence had a distant site as part of their pattern of recurrence (Fig. 1). Among patients who had only an initial solitary site of recurrence (63.8%) as well as those with multiple site of recurrence (100.0%), distant metastases were common. Collectively, these data suggest that underlying tumor biology leading to distant recurrenceerather than local
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Table 5.
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Univariate/Multivariate Analysis of Risk Factors Associated with Distant Hematogenous Recurrence
Risk factor
Size Multiple lesions Location Antrum Body Cardia Fundus GE junction Lesser curvature Diffuse and mixed type AJCC stage I II III T stage I II III IV Grade Well to moderate Moderate to poor No. of positive LN LN positive LN metastasis ratio LVI PNI Operation type Wedge resection Distal Subtotal Total R1 margin Neoadjuvant chemotherapy Neoadjuvant radiotherapy Adjuvant chemotherapy Adjuvant radiotherapy D2 lymphadenectomy
OR
Univariate analysis 95% CI
Multivariate analysis 95% CI
p Value
OR
NA 10.82 NA
e 3.56e32.85 e
p Value
e <0.001 e
1.03 3.77
0.98e1.09 1.80e7.90
0.24 <0.001
Ref 0.84 1.31 0.95 1.06 0.67 1.06
0.52e1.36 0.68e2.55 0.44e2.05 0.49e2.31 0.38e1.17 0.63e1.79
0.48 0.86 0.89 0.89 0.16 0.83
NA NA
e e
e e
Ref 2.16 4.72
1.07e4.38 2.55e8.72
0.03 <0.001
Ref 1.23 1.74
0.19e8.06 0.19e16.07
0.83 0.63
Ref 2.08 3.82 4.63
0.85e5.06 1.87e7.79 2.27e9.44
0.11 <0.001 <0.001
Ref 2.42 4.64 4.43
0.37e15.72 0.58e36.77 0.53e37.07
0.35 0.15 0.17
Ref 1.35 1.04 3.43 6.02 2.32 2.05
0.86e2.12 1.02e1.07 2.09e5.65 3.23e1.24 1.50e3.60 1.26e3.34
0.20 <0.001 <0.001 <0.001 <0.001 0.004
Ref NA 0.98 1.18 2.51 1.25 1.27 NA
e 0.93e1.03 0.43e3.22 0.67e9.45 0.67e2.35 0.68e2.36 e
e 0.42 0.75 0.17 0.48 0.45 e
Ref 1.63 1.05 1.39 0.75 1.18 1.19 2.64 1.44 0.77
0.19e3.66 0.13e8.63 0.17e1.32 0.33e1.69 0.73e1.90 0.40e3.56 1.68e4.15 0.96e2.18 0.51e1.17
0.65 0.96 0.76 0.49 0.49 0.75 <0.001 0.08 0.23
NA NA 1.54 NA NA
e e 0.81e2.92 e e
e e 0.19 e e
AJCC, American Joint Committee on Cancer; GE, gastroesophageal; LN, lymph nodes; LVI, lymphovascular invasion; OR, odds ratio; PNI, perineural invasion.
issueseis the preeminent concern among patients with gastric cancer after curative intent surgery. Several factors were associated with the overall risk of recurrence. Specifically, in this study, factors associated with an increased risk of any-site recurrence included both patient (age), as well as tumor-specific factors (tumor burden, type, size, grade, extent of invasion, lymph node involvement, lymphovascular and perineural invasion)
(Table 2). Several investigators had previously reported that recurrence after curative intent surgery was influenced by factors such as tumor size, lymph node metastasis, perineural invasion, and tumor location.10,17,18,29 In fact, some authors have noted that certain factors were associated with different recurrence patterns.18,29 For example, D’Angelica and colleagues29 and Yoo and associates18 noted that proximal tumor location was associated with a higher risk of
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Figure 2. Incidence of recurrence over time.
locoregional recurrence. Interestingly, data from our large multi-institutional cohort similarly noted that patients with tumors anatomically located proximally at the gastroesophageal junction had nearly a 3-fold increased risk of locoregional recurrence. The reason for the increased risk of locoregional recurrence among patients with gastroesophageal junction tumors is unclear, but it may relate to issues with adequacy of treatment, increased difficulty achieving a “wide” negative margin and argue for more aggressive locoregional therapy. Perhaps not surprising, factors associated with distant recurrence were more related to underlying characteristics of tumor biology: tumor histologic type, grade, extent of invasion, perineural invasion, lymph node metastasis, etc. Few studies have provided data regarding the time to recurrence and the frequencies of recurrence patterns relative to time of recurrence.11,17 We noted that overall recurrence-free survival was 27.7 months when examining the entire cohort. Of note, however, was the finding that
Figure 3. Cumulative recurrence rate in patients with locoregional, peritoneal, and hematogenous distant recurrence.
the median time to recurrence among patients who did experience a recurrence was very short, at less than 1 year (10.8 months). Wu and colleagues11 reported a similarly short recurrence-free survival of 16.7 months among patients with recurrence. In looking at the risk of recurrence over time, the overwhelming majority of recurrences occurred within the first 3 years after surgery, with a subsequent plateauing of the risk thereafter (Fig. 3). Although Papachristou and Fortner30 reported that the risk of recurrence did not decrease over time, other investigators have noted that the risk of recurrence indeed does level off after 2 to 3 years.18,31 We also noted that the timing of recurrence was different based on the pattern of recurrence because patients with early recurrence (<12 months) were more likely to have peritoneal or hematogenous recurrence compared with patients who had late recurrences, who were more likely to have a locoregional recurrence (p ¼ 0.002). These findings are consistent with those reported by Eom and associates,17 who similarly reported that hematogenous metastasis was the most common type of recurrence in the early group compared with locoregional in the late recurrence group. Another interesting finding in our study was how quickly patients died after their disease recurred. Of note, median survival after recurrence was only 5.0 months. Patients with locoregional recurrence did have a longer survival after recurrence (9.1 months) compared with patients who had hematogenous distant (4.8 months) or peritoneal (2.7 months) disease. Of note, whether the recurrence occurred either “early” or “late” did not seem to affect prognosis after recurrence (4.5 months vs 5.7 months; p ¼ 0.16). This study has several limitations. As with all retrospective studies, there was undoubtedly some selection bias, as well as confounding by indication. For example, the finding that adjuvant chemotherapy was a risk factor for distant recurrence was likely a reflection of the fact that
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and pattern of recurrence after curative intent surgery, as well as provide evidence to tailor postoperative surveillance programs. Data on specific patterns of recurrence and the timing of recurrence can inform both the interval and perhaps the type, of surveillance imaging. The finding that 50% of recurrences occurred with the first 2 years strongly suggests that the most intensive followup should occur during this time period. Furthermore, the finding that 75.8% of patients had some component of distal recurrence suggests that imaging that incorporates all possible sites (eg, liver, lung, etc) is important.
Figure 4. Kaplan-Meier curve for overall survival in patients with locoregional, peritoneal, and hematogenous distant recurrence.
patients with more aggressive disease biology were more likely to receive this treatment. Rather, as other prospective studies have noted, chemotherapy is likely to decrease the risk of tumor recurrence among gastric cancer patients.14,32-34 The goal of this study was not to assess the efficacy of surgical techniques or adjuvant therapies, which is notoriously difficult to do in retrospective series. Rather, we sought to define the pattern of recurrence after curative intent gastric surgery. We noted that one-third of patients recurred, yet 5-year actuarial survival was estimated at 39.3%. The reason for this finding was probably multifactorial and may be related to incomplete patient follow-up (eg, the patient has not made it to 5 years yet) as well as “competing” causes of death. Although the multi-institutional nature of the study was a strength, it undoubtedly led to heterogeneity in the surgical approach and selection bias, especially when it came to the extent of lymphadenectomy. For example, the finding that D2 lymphadenectomy was associated with a higher risk of local recurrence was probably secondary to selection bias (ie, those patients with more extensive nodal disease underwent a more extensive lymph node dissection).
CONCLUSIONS In conclusion, nearly one-third of patients who undergo curative intent surgery for gastric cancer experienced a recurrence. Recurrence at a distant site was the most common site of recurrence among patients with either solitary or multiple site recurrence. Locoregional recurrence was also fairly common, but this pattern of recurrence tends to occur later as compared with distant recurrence, which more commonly presents within the first 12 months after surgery. Data from this study can hopefully inform providers and patients with regard to the risk of recurrence
Author Contributions Study conception and design: Spolverato, Ejaz, Kim, Pawlik Acquisition of data: Spolverato, Ejaz, Kim, Squires, Poultsides, Fields, Schmidt, Weber, Votanopoulos, Maithel, Pawlik Analysis and interpretation of data: Spolverato, Ejaz, Kim, Pawlik Drafting of manuscript: Spolverato, Pawlik Critical revision: Spolverato, Ejaz, Kim, Pawlik Acknowledgment: We would like to thank Linda X Jin, Alexandra W Acher, Neil Saunders, Clifford S Cho, Mark Bloomston, David J Worhunsky, Douglas Swords, and all the participants of the US Gastric Cancer Collaborative. REFERENCES 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69e90. 2. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006;12:354e362. 3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11e30. 4. Hirota WK, Zuckerman MJ, Adler DG, et al. ASGE guideline: the role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. Gastrointest Endosc 2006;63: 570e580. 5. Akoh JA, Macintyre IM. Improving survival in gastric cancer: review of 5-year survival rates in English language publications from 1970. Br J Surg 1992;79:293e299. 6. Arkenau HT. Gastric cancer in the era of molecularly targeted agents: current drug development strategies. J Cancer Res Clin Oncol 2009;135:855e866. 7. Wang J, Yu JC, Kang WM, Ma ZQ. Treatment strategy for early gastric cancer. Surg Oncol 2012;21:119e123. 8. Park do J, Han SU, Hyung WJ, et al. Long-term outcomes after laparoscopy-assisted gastrectomy for advanced gastric cancer: a large-scale multicenter retrospective study. Surg Endosc 2012;26:1548e1553. 9. Lee SE, Ryu KW, Nam BH, et al. Prognostic significance of intraoperatively estimated surgical stage in curatively resected gastric cancer patients. J Am Coll Surg 2009;209:461e467.
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10. Deng J, Liang H, Wang D, et al. Investigation of the recurrence patterns of gastric cancer following a curative resection. Surg Today 2011;41:210e215. 11. Wu CW, Lo SS, Shen KH, et al. Incidence and factors associated with recurrence patterns after intended curative surgery for gastric cancer. World J Surg 2003;27:153e158. 12. Huang KH, Chen JH, Wu CW, et al. Factors affecting recurrence in node-negative advanced gastric cancer. J Gastroenterol Hepatol 2009;24:1522e1526. 13. Sakar B, Karagol H, Gumus M, et al. Timing of death from tumor recurrence after curative gastrectomy for gastric cancer. Am J Clin Oncol 2004;27:205e209. 14. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11e20. 15. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29: 1715e1721. 16. Bringeland EA, Wasmuth HH, Johnsen G, et al. Outcomes among patients treated for gastric adenocarcinoma during the last decade. J Surg Oncol 2013;107:752e757. 17. Eom BW, Yoon H, Ryu KW, et al. Predictors of timing and patterns of recurrence after curative resection for gastric cancer. Dig Surg 2010;27:481e486. 18. Yoo CH, Noh SH, Shin DW, et al. Recurrence following curative resection for gastric carcinoma. Br J Surg 2000;87: 236e242. 19. Li JH, Zhang SW, Liu J, et al. Review of clinical investigation on recurrence of gastric cancer following curative resection. Chin Med J (Engl) 2012;125:1479e1495. 20. Li F, Zhang R, Liang H, et al. The pattern and risk factors of recurrence of proximal gastric cancer after curative resection. J Surg Oncol 2013;107:130e135. 21. Arnaoutakis DJ, Mavros MN, Shen F, et al. Recurrence patterns and prognostic factors in patients with hepatocellular carcinoma in noncirrhotic liver: a multi-institutional analysis. Ann Surg Oncol 2014;21:147e154. 22. Assumpcao L, Choti MA, Gleisner AL, et al. Patterns of recurrence following liver resection for colorectal metastases: effect
23.
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25. 26. 27. 28. 29. 30. 31.
32. 33.
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of primary rectal tumor site. Arch Surg 2008;143:743e749; discussion 749e750. de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg 2009;250:440e448. Pawlik TM, Zorzi D, Abdalla EK, et al. Hepatic resection for metastatic melanoma: distinct patterns of recurrence and prognosis for ocular versus cutaneous disease. Ann Surg Oncol 2006;13:712e720. Peng PD, Hyder O, Mavros MN, et al. Management and recurrence patterns of desmoids tumors: a multi-institutional analysis of 211 patients. Ann Surg Oncol 2012;19:4036e4042. Sadahiro S, Suzuki T, Ishikawa K, et al. Recurrence patterns after curative resection of colorectal cancer in patients followed for a minimum of ten years. Hepatogastroenterology 2003;50:1362e1366. Maehara Y, Hasuda S, Koga T, et al. Postoperative outcome and sites of recurrence in patients following curative resection of gastric cancer. Br J Surg 2000;87:353e357. Roviello F, Marrelli D, de Manzoni G, et al. Prospective study of peritoneal recurrence after curative surgery for gastric cancer. Br J Surg 2003;90:1113e1119. D’Angelica M, Gonen M, Brennan MF, et al. Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann Surg 2004;240:808e816. Papachristou DN, Fortner JG. Local recurrence of gastric adenocarcinomas after gastrectomy. J Surg Oncol 1981;18:47e53. Koga S, Takebayashi M, Kaibara N, et al. Pathological characteristics of gastric cancer that develop hematogenous recurrence, with special reference to the site of recurrence. J Surg Oncol 1987;36:239e242. Weber SM, Karpeh MS. Randomized clinical trials in gastric cancer. Surg Oncol Clin North Am 2002;11:111e131. ix. Mari E, Floriani I, Tinazzi A, et al. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol 2000;11:837e843. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810e1820.
BACKGROUND:
Gastric adenocarcinoma is the fourth most common malignant tumor worldwide and the second most common cause of cancer-related deaths.1,2 There is a strong geographic variation in the incidence of gastric cancer, with higher rates seen in Asia, Eastern Europe, and South America, likely due to differences in diet, alcohol consumption, smoking patterns, and Helicobacter pylori infection.1 Despite the relative lower incidence of gastric cancer in the United States (US), there were still an estimated 21,600 new cases of gastric cancer resulting in nearly 11,000 deaths in 2012.3 The use of advanced
Disclosure Information: Nothing to disclose. Received January 26, 2014; Revised March 12, 2014; Accepted March 12, 2014. From the Departments of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD (Spolverato, Ejaz, Kim, Pawlik); Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (Squires, Maithel); Stanford University, Palo Alto, CA (Poultsides); Washington University, St Louis, MO (Fields); The Ohio State University, Columbus, OH (Schmidt); Division of Surgical Oncology, University of Wisconsin, Madison, WI (Weber); and Wake Forest University, Winston-Salem, NC (Votanopoulos). Correspondence address: Timothy M Pawlik, MD, MPH, PhD, FACS, Department of Surgery, Johns Hopkins Hospital, 600 N Wolfe St, Blalock 688, Baltimore, MD 21287. email: [email protected]
ª 2014 by the American College of Surgeons Published by Elsevier Inc.
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diagnostic techniques such as endoscopy, endoscopic ultrasound, and CT, has allowed for the earlier detection of gastric cancer among some patients.4 Many patients, however, still present with more advanced disease. Although improvements in surgical technique and perioperative care have led to better short-term outcomes,5 long-term prognosis of patients with gastric cancer remains guarded.6-8 Although chemotherapy and radiotherapy are often used in the adjuvant treatment of patients with gastric cancer, recurrence after curative intent resection is relatively common, occurring in 20% to 50% of patients.9-13 In fact, recurrence is one of the most important factors associated with death in patients with gastric cancer.10 Data on the incidence and factors associated with recurrence patterns after surgery for gastric cancer remain relatively scarce. In fact, most studies reporting on outcomes after surgical management of gastric cancer have focused largely on overall survival rather than recurrence.14-16 To date, previous studies that have examined recurrence after curative intent gastrectomy for gastric cancer have all been derived from the experience of single institutions. Perhaps more importantly, due to the relative rarity of gastric cancer in the US, previous data have almost exclusively been from centers in Asia,9,11,17,18 with 1 study from Turkey.13 Previous data on how tumor characteristics such as tumor size, grade, and nodal status may affect recurrence have not been validated in a US cohort.10,17,19,20 Because US patients with gastric cancer may have a different presentation, natural history, and prognosis than patients in Asia, information on rates and patterns of recurrence derived from a US cohort is critical. In this study, using a large multi-institutional cohort of patients, we sought to determine the rates of recurrence after curative intent surgery for gastric adenocarcinoma. Specifically, we examined the pattern of recurrence of patients who were managed with curative intent resection and identify factors predictive of overall recurrence as well as specific patterns of recurrence.
METHODS Patient demographic and clinical data Patients undergoing curative intent resection for gastric cancer between 2000 and 2012 at 1 of 7 major academic institutions participating in the US Gastric Cancer Collaborative (Johns Hopkins University, Emory University, Stanford University, Washington University, Wake Forest University, University of Wisconsin, The Ohio State University) were identified. Patients who underwent a palliative operation, had known metastatic disease preoperatively, or experienced perioperative mortality within 30 days of surgery were excluded from analysis. Only
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patients with a gastric adenocarcinoma were included in this study; patients with other gastric tumors (eg, carcinoid, gastrointestinal stromal tumor, etc) were not included. The Institutional Review Board of each institution approved the study. Standard patient demographic and clinicopathologic data were collected including age, sex, comorbidities, family history of gastric cancer, history of Helicobacter pylori infection, and history of alcohol abuse and smoking. Tumor characteristics were collected including tumor location, size, grade, depth of invasion, histology, lymph node status, presence of signet ring cells, and lymphovascular invasion and perineural invasion. Data regarding treatment details were also collected including type of resection and intestinal reconstruction, as well as the extent of lymphadenectomy (D1 vs D2). Proximal and distal resection margin status was recorded; margin status was classified as microscopically negative (R0), microscopically positive (R1), or macroscopically positive (R2). Information on the type and duration of chemotherapy and radiotherapy, if applicable, were also noted. Date of last follow-up, vital status, and recurrencerelated information were collected on all patients. Recurrence was defined as the presence of a biopsy-proven tumor showing adenocarcinoma cells or the presence of imaging highly suspicious of tumor recurrence. Information regarding the location and number of lesions, as well as the disease-free interval from the date of initial operation to the development of recurrent disease was recorded. For the cohort of patients who developed repeat recurrences, data on the pattern and time interval between subsequent recurrences were also noted. Recurrences were classified as locoregional (nodal or gastric), peritoneal, or hematogenous (eg, liver, lung, bone, etc).17 Statistical analysis Baseline characteristics of the study population were summarized according to the presence or absence of recurrence. Differences between the 2 groups were assessed by the chi-square test and 1-way analysis of variance (ANOVA), as appropriate. Data were correspondingly reported as numbers (percentage), means (standard deviations), or medians with interquartile ranges. Recurrence-free and overall survivals were estimated using the Kaplan-Meier method, and differences in survival were examined with the log-rank test. The association of relevant clinicopathologic variables with extent of recurrence was examined using logistic models. Patients who experienced only single-site recurrences (locoregional, hematogenous, or peritoneal only) were used in the logistic regression models to avoid possible interactions of factors. In examining time to recurrence,
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patients were analyzed as early (<12 month) vs late (12 months) recurrences.17 The most parsimonious model was created using a stepwise approach that included factors that were statically significant (eg, p < 0.05) on univariate analysis. All analyses were carried out with STATA version 12.0 (StataCorp), and a p value <0.05 was considered statistically significant.
RESULTS Clinicopathologic and treatment characteristics Using the US Gastric Cancer Collaborative database, 817 patients who underwent curative intent surgery between 2000 and 2012 for gastric cancer were identified. The median patient age was 65.8 years (interquartile range [IQR] 56.4, 74.7); the majority of patients were male (n ¼ 462, 56.6%) and non-Hispanic white (n ¼ 511, 62.5%) (Table 1). Only a small proportion of patients had a history of Helicobacter pylori infection (n ¼ 106, 13.0%) or a family history of gastric cancer (n ¼ 68, 8.3%). The most common location of the tumor was the antrum (n ¼ 301, 37.8%) or the body (n ¼ 292, 36.6%) of the stomach; the majority of lesions were found on the lesser curvature (n ¼ 275, 61.2%). The median size of the largest tumor was 4 cm (IQR 2.5, 6.5 cm). Most tumors were solitary (n ¼ 760, 95.8%) and penetrated the subserosa (n ¼ 263, 33%) or visceral peritoneum and adjacent structures (n ¼ 230, 28.8%). At the time of surgery, the majority of patients underwent a partial gastrectomy (n ¼ 481, 59.2%); the remaining 332 (40.8%) patients underwent a total gastrectomy. A complete R0 resection was achieved in 91.6% (n ¼ 748) of patients; the remaining 8.4% (n ¼ 69) of patients had at least 1 microscopically positive margin (R1). No patients had any evidence of macroscopic disease (R2) at the completion of surgery. Most patients underwent a D2 lymphadenectomy (n ¼ 484, 59.2%), while 293 patients (35.9%) underwent a D1 lymphadenectomy. The median number of lymph nodes harvested was 17 (IQR 11, 25); a majority of patients had lymph node metastasis (n ¼ 481, 58.9%). Most tumors were of the intestinal type (n ¼ 538, 65.9%), with the remaining lesions being of the diffuse (n ¼ 252, 30.8%) or mixed (n ¼ 27, 3.3%) sub-type. Signet ring cells were detected in 40.0% (n ¼ 327) of tumors, and evidence of lymphovascular and perineural invasion was found in 38.2% (n ¼ 312) and 22.9% (n ¼ 187) of tumors, respectively. According to the 7th edition American Joint Committee on Cancer (AJCC) staging system, most patients had stage III disease (n ¼ 356, 44.3%); the remaining patients had stage I (n ¼ 239, 29.8%) or stage II (n ¼ 208, 25.9%) disease.
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A small subset of patients received neoadjuvant chemotherapy (n ¼ 168, 20.6%); even fewer received neoadjuvant radiotherapy (n ¼ 24, 2.9%). Nearly half of all patients received some form of adjuvant chemotherapy (n ¼ 417, 51%); almost one-third of patients (n ¼ 266, 32.6%) received adjuvant radiotherapy. Pattern of recurrence With a median follow-up of 28.9 months, 244 (29.9%) of 817 patients developed a recurrence. Among patients who experienced a recurrence, 163 (66.8%) recurred at only a single site. Among patients who recurred at a single site, recurrence was most common at a distant location and included hematogenous (n ¼ 57, 23.4%) or peritoneal (n ¼ 47, 19.3%) only metastasis (Fig. 1). Overall, 185 patients (75.8%) had some component of distant recurrence, and 59 (24.2%) patients developed only locoregional recurrent disease. The remaining 81 (33.2%) patients had multiple sites of recurrence; patients had hematogenous and peritoneal recurrence (n ¼ 7, 2.9%), hematogenous and locoregional recurrence (n ¼ 36, 14.8%), peritoneal and locoregional recurrence (n ¼ 25, 10.3%), or had evidence of hematogenous, peritoneal, and locoregional disease (n ¼ 13, 5.3%). The most common sites of distant recurrence included peritoneum (n ¼ 92), liver (n ¼ 52), lung (n ¼ 17), bone (n ¼ 4), and other sites (n ¼ 20). Overall, when considering patients with both single and multiple site recurrences, 133 (54.5%) and 113 (46.3%) patients had locoregional recurrence or hematogenous recurrence, respectively, as a component of failure; 92 (37.7%) patients had peritoneal metastasis. Factors associated with recurrence Several patient- and tumor-related factors were associated with “any site” recurrence including patient age, tumor sub-type and size, and lymph node status. Specifically, patients who experienced a recurrence were more likely to be younger (median age: no recurrence, 66.5 years vs recurrence, 63.7 years; OR 0.98, 95% CI 0.97 to 0.99; p ¼ 0.002) (Table 2). In addition, tumor size was associated with risk of recurrence because patients with larger gastric lesions were more at risk of recurrence (median tumor size: no recurrence, 3.7 cm vs recurrence, 4.8 cm; p < 0.001). Other tumor factors such as diffuse tumor type (referent, intestinal sub-type: OR 1.78, 95% CI 1.22 to 2.61), presence of signet ring features (OR 1.41, 95% CI 1.04 to 1.92), and evidence of lymphovascular (OR 1.93, 95% CI 1.40 to 2.66) or perineural invasion (OR 2.14, 95% CI 1.48 to 3.10) were each associated with a higher risk of any site recurrence (all p < 0.05). In addition, the presence of lymph node
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Table 1.
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Clinicopathologic Characteristics of Patients Who Underwent Curative Intent Surgery
Characteristic Age, y, median (IQR) Male sex, n (%) White race, n (%) Family history of gastric cancer, n (%) History of Helicobacter pylori, n (%) Alcohol abuse, n (%) Smoking, n (%) Operation type, n (%) Distal Subtotal Total Wedge resection R0 Margin, n (%) Tumor type, n (%) Diffuse Intestinal Mixed Tumor location, n (%) Antrum Body Cardia Fundus GE junction Curvature, n (%) Greater Lesser No. of lesions, n (%) Solitary lesion Multiple Size, cm, median (IQR) T stage, n (%) T1 T2 T3 T4 Lymph node metastasis, n (%) Lymph nodes harvested, median (IQR) AJCC stage, n (%) Stage I Stage II Stage III Tumor grade, n (%) Poor to moderate Moderate Moderate to well Signet ring, n (%) LVI, n (%) PNI, n (%) Neoadjuvant chemotherapy, n (%) Neoadjuvant radiotherapy, n (%) Adjuvant chemotherapy, n (%) Adjuvant radiotherapy, n (%) Death, n (%)
Total (n ¼ 817) 65.8 (56.4,74.7) 462 (56.6) 511 (62.5) 68 (8.3) 106 (13.0) 86 (10.5) 313 (38.3) 136 336 332 9 748
No recurrence (n ¼ 573) 66.5 (57.0,75.5) 331 (57.8) 360 (62.8) 46 (8.0) 78 (13.6) 52 (9.1) 222 (38.7)
(16.7) (41.3) (40.8) (1.2) (91.6)
94 253 217 7 530
(16.5) (44.3) (38.0) (1.2) (92.8)
Recurrence (n ¼ 244) 63.7 (54.3,72.1) 131 (53.7) 151 (61.9) 22 (9.0) 28 (11.5) 34 (13.9) 91 (37.3) 42 83 115 2 218
(17.4) (34.3) (47.5) (0.8) (90.5)
252 (30.8) 538 (65.9) 27 (3.3)
103 (26.8) 269 (69.9) 13 (3.3)
65 (40.4) 91 (56.5) 5 (3.1)
301 292 78 66 60
216 206 51 48 39
85 86 27 18 21
p Value 0.002 0.28 0.64 0.7 0.42 0.05 0.50 0.06
0.25 0.01
0.7 (37.8) (36.6) (9.8) (8.3) (7.5)
(38.7) (36.9) (9.1) (8.6) (6.7)
(35.6) (36.0) (11.3) (7.5) (9.6) 0.64
174 (38.8) 275 (61.2)
123 (38.1) 200 (61.9)
51 (40.5) 75 (59.5)
760 (95.8) 33 (4.2) 4.0 (2.5,6.5)
537 (96.8) 18 (3.2) 3.7 (2.0,6.4)
223 (93.6) 15 (6.4) 4.8 (3.2,7.0)
195 109 263 230 481 17
177 85 166 130 294 17
18 24 97 100 187 17
0.05
(24.5) (13.7) (33.0) (28.8) (58.9) (11, 25)
(31.7) (15.2) (29.8) (23.3) (51.3) (11, 25)
(7.5) (10.0) (40.6) (41.9) (76.6) (10, 24)
239 (29.8) 208 (25.9) 356 (44.3)
214 (38.2) 147 (26.2) 200 (35.6)
25 (10.3) 61 (25.2) 156 (64.5)
535 193 55 327 312 187 168 24 417 266 365
352 149 47 215 194 112 103 17 247 167 172
183 44 8 112 118 75 65 7 170 99 193
<0.001 <0.001
<0.001 0.67 <0.001
<0.001 (68.3) (24.7) (7.0) (40.0) (38.2) (22.9) (20.6) (2.9) (51.0) (32.6) (44.7)
GE, gastroesophageal; LVI, lymphovascular invasion; PNI, perineural invasion.
(64.2) (27.2) (8.6) (37.5) (33.9) (19.5) (18.0) (3.0) (43.1) (29.1) (30.3)
(77.9) (18.7) (3.4) (45.9) (48.4) (30.7) (26.6) (2.9) (69.7) (40.6) (79.1)
0.03 <0.001 <0.001 0.005 0.88 <0.001 0.01 <0.001
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metastasis similarly increased the risk of recurrence (OR 3.18, 95% CI 2.26 to 4.48; p < 0.001). In examining the pattern of recurrence, several factors were associated with specific patterns of recurrence. For example, on univariate analysis, gastric tumor location, extent of invasion, American Joint Committee on Cancer (AJCC) stage, lymph node metastasis, and extent of lymphadenectomy were associated with risk of locoregional recurrence (Table 3). Specifically, patients with a tumor at the gastroesophageal junction (referent, antrum: OR 2.57, 95% CI 1.05 to 6.26; p ¼ 0.04), increasing tumor depth (referent, T1: T2, OR 2.21, 95% CI 0.66 to 7.43; T3, OR 3.13, 95% CI 1.15 to 8.49; T4, OR 4.43, 95% CI 1.66 to 11.84; all p < 0.05), the presence of lymph node metastasis (OR 4.01, 95% CI 1.13 to 3.78; p ¼ 0.02), and D2 lymphadenectomy (OR 2.28, 95% CI 1.18 to 4.41; p ¼ 0.01) had an increased risk of locoregional recurrence. On multivariate analysis, tumor location at the gastroesophageal junction (OR 3.18, 95% CI 1.08 to 9.40; p ¼ 0.04) remained independently associated with higher risk of locoregional recurrence. On univariate analysis, peritoneal recurrence was associated with several factors including tumor histologic type, grade, extent of invasion, AJCC stage, perineural invasion, lymph node metastasis, and receipt of chemotherapy (all p < 0.05) (Table 4). Similarly, distant hematogenous recurrence was associated with the presence of multiple lesions,
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extent of tumor invasion, AJCC stage, lymph node metastasis, lymphovascular and perineural invasion, and receipt of adjuvant chemotherapy (all p < 0.05) (Table 5). After controlling for competing risk factors, the presence of multiple lesions (OR 10.82, 95% CI 3.56 to 32.85; p < 0.001) remained associated with an increased risk of distant hematogenous recurrence.
Timing of recurrence and long-term outcomes The median recurrence-free survival among all patients was 27.7 months (IQR 23.2, 35.5). Among patients who experienced a recurrence, the median recurrencefree survival was 10.8 months (IQR 8.9, 12.8) (Fig. 2). Median recurrence-free survival among patients with locoregional or peritoneal recurrence was 13.6 months (IQR 10.9, 18.9) and 8.5 months (IQR 7.3, 11.1), respectively, compared with 10.6 months (IQR 8.6, 13.3) for patients who had distant hematogenous disease as a component of their recurrence (p ¼ 0.19) (Fig. 3). For patients with distant hematogenous metastasis, the median time was 10.6 months for liver recurrence and 10.1 months for lung recurrence (p ¼ 0.5). Patients with early recurrence (<12 months) were more likely to have peritoneal or hematogenous recurrence compared with patients who had late recurrences, who were more likely to have a locoregional recurrence (p ¼ 0.002).
Figure 1. Overall pattern of recurrence.
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Table 2.
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Univariate/Multivariate Analysis of Risk Factors Associated with Any-Site Recurrence
Risk factor
Age Size Diffuse and mixed type AJCC stage I II III T stage I II III IV Grade Well to moderate Moderate to poor No. of positive LN LN positive LN metastasis ratio LVI PNI Signet ring cell
OR
Univariate analysis 95% CI
p Value
OR
Multivariate analysis 95% CI
p Value
0.98 1.08 1.78
0.97e0.99 1.03e1.13 1.22e2.61
0.002 <0.001 0.003
0.99 0.99 0.94
0.97e1.01 0.92e1.06 0.52e1.69
0.54 0.81 0.84
Ref 3.55 6.68
2.13e5.92 4.20e10.62
<0.001 <0.001
Ref 3.06 6.65
0.68e13.77 0.97e45.41
0.15 0.05
Ref 2.78 5.75 7.56
1.43e5.39 3.33e9.92 4.36e13.12
0.003 <0.001 <0.001
Ref 1.28 1.54 1.63
0.33e4.89 0.32e7.34 0.32e8.38
0.72 0.59 0.56
Ref 1.96 1.05 3.18 6.74 1.93 2.14 1.41
1.38e2.79 1.03e1.07 2.26e4.48 4.00e11.37 1.40e2.66 1.48e3.10 1.04e1.92
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.03
Ref 1.09 0.97 0.84 3.63 0.69 1.10 1.22
0.58e2.05 0.92e1.01 0.34e2.04 0.97e13.61 0.38e1.27 0.61e2.00 0.68e2.20
0.80 0.14 0.69 0.06 0.23 0.75 0.51
AJCC, American Joint Committee on Cancer; LN, lymph node; LVI, lymphovascular invasion; OR, odds ratio; PNI, perineural invasion.
Overall median survival was 38 months (IQR 33.4, 45.0) with 1-year, 3-year, and 5-year survival rates of 77.9%, 50.9%, and 39.3%, respectively. Median survival after recurrence was 5.0 months (locoregional recurrence, 9.1 months vs peritoneal recurrence, 2.7 months vs hematogenous recurrence, 4.8 months; p ¼ 0.01) (Fig. 4). Median survival times after early recurrence was 4.5 months vs 5.7 months among patients with a late recurrence (p ¼ 0.16). Patients experiencing a distant hematogenous recurrence tended to have a worse long-term prognosis (1-, 3-, and 5-year survivals: 75.3%, 19.3%, and 4.7%, respectively) compared with patients who had peritoneal recurrence (1-, 3-, and 5-year survivals: 61.0%, 19.9%, and 9.9%, respectively) or locoregional recurrence (1-, 3-, and 5-year survivals: 68.8%, 34.3%, and 14.7%, respectively) (p ¼ 0.13) (Fig. 4).
DISCUSSION For patients with gastric cancer, resection of the primary lesion with an appropriate lymphadenectomy is the cornerstone of curative intent therapy. Most studies that have reported on curative intent surgery for gastric cancer have focused largely on overall survival.14-16 Data on recurrence and patterns of recurrence after resection of gastric cancer have been more infrequent, and these studies have typically
examined small, single-institution cohorts.10,17,19,20 Furthermore, these past series have largely come from outside of the US.10,13 Given that previous studies have suggested geographic variations in the genetics, phenotypes, and natural history of gastric cancer,10,17,19,20 data specifically derived from a US cohort may be particularly important and relevant to inform clinical decision-making in the US. Data on recurrence are important not only as a surrogate of prognosis, but also as a means to inform clinicians about where they should focus their attention during postoperative surveillance. This study is important because it defines the incidence and pattern of recurrence after curative intent surgery for gastric cancer in a large, multiinstitutional US cohort of patients. Among patients who recurred with a single initial site of disease (n ¼ 163), the pattern of recurrence was distributed relatively equally among distant hematogenous (n ¼ 57), peritoneal (n ¼ 47), and locoregional (n ¼ 59) sites. In contrast, a subset of patients (n ¼ 81) initially recurred at multiple sites, and all patients had distant disease as a component of their failure. The median time to recurrence was about 2 years and, of note, median survival after recurrence was extremely short (5.0 months). There are generally 3 main patterns of recurrence after curative intent resection of gastric cancer: locoregional,
670
Table 3.
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Univariate/Multivariate Analysis of Risk Factors Associated with Locoregional Recurrence
Risk factor
Size Tumor location Antrum Body Cardia Fundus GE junction Lesser curvature Diffuse and mixed type AJCC stage I II III T stage I II III IV Tumor grade Well to moderate Moderate to poor No. of positive LN N stage LN metastasis ratio LVI PNI Operation type Wedge resection Distal Subtotal Total R1 margin Neoadjuvant chemotherapy Neoadjuvant radiotherapy Adjuvant chemotherapy Adjuvant radiotherapy D2 lymphadenectomy
OR
Univariate analysis 95% CI
p Value
OR
Multivariate analysis 95% CI
p Value
1.06
0.99e1.14
0.10
NA
e
e
Ref 1.16 1.65 1.37 2.57 1.10 0.71
0.59e2.28 0.66e4.12 0.49e3.85 1.05e6.26 0.51e2.37 0.36e1.41
0.66 0.29 0.55 0.04 0.81 0.32
1.25 2.27 1.21 2.66 NA NA
0.58e2.67 0.81e6.41 0.37e3.96 0.97e7.24 e e
0.57 0.12 0.76 0.06 e e
Ref 2.08 3.25
0.86e5.07 1.48e7.12
0.11 0.003
1.93 1.81
0.30e12.18 0.18e18.11
0.49 0.62
Ref 2.21 3.13 4.43
0.66e7.43 1.15e8.49 1.66e11.84
0.20 0.03 0.003
0.92 0.96 1.34 NA
0.18e4.75 0.16e5.68 0.21e8.56 e
0.92 0.96 0.76 e
Ref 1.22 1.04 2.06 4.01 1.18 0.90
0.66e2.26 1e1.07 1.13e3.78 1.79e9.01 0.67e2.09 0.35e1.83
0.52 0.03 0.02 0.001 0.57 0.60
0.97 1.07 5.54 NA NA NA
0.92e1.03 0.36e3.17 1.21e25.42 e e e
0.40 0.90 0.03 e e e
Ref 0.57 0.51 0.74 1.68 1.62 1.04 3.00 1.32 2.28
0.06e5.05 0.06e4.25 0.09e6.11 0.73e3.87 0.90e2.93 0.24e4.59 2.08e4.35 0.76e2.31 1.18e4.41
0.61 0.53 0.78 0.22 0.11 0.95 <0.001 0.33 0.01
NA NA NA 0.91 NA 2.41
e e e 0.45e1.84 e 0.93e5.14
e e e 0.80 e 0.05
AJCC, American Joint Committee on Cancer; GE, gastroesophageal; LN, lymph nodes; LVI, lymphovascular invasion; OR, odds ratio; PNI, perineural invasion.
peritoneal, and distant.10,11,17 Previous data have demonstrated heterogeneity in the distribution of patients with different patterns of recurrence.21-26 The differences in the reported recurrence patterns are undoubtedly multifactorial and may relate to variations in tumor biology, operative technique, and use of perioperative adjuvant therapies. Interestingly, geographic differences in patterns of recurrence have also been noted. Specifically, several studies
from the East have noted a lower incidence of locoregional recurrences. For example, in 2 separate studies from Japan, peritoneal dissemination was noted to be the main pattern of recurrence after curative gastrectomy.27 Similarly Wu and colleagues11 reported that most recurrences (n ¼ 213; 86.9%) were distant, 110 recurrences (44.9%) were local, and 78 recurrences (49.8%) were both local and distant. Among the distant metastases, Wu and associates noted
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Table 4.
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Univariate/Multivariate Analysis of Risk Factors Associated with Distant Peritoneal Recurrence
Risk factor
Size Tumor location Antrum Body Cardia Fundus GE junction Lesser curvature Diffuse and mixed type AJCC stage I II III T stage I II III IV Grade Well to moderate Moderate to poor No. of positive LN LN positive LN metastasis ratio LVI PNI Operation type Wedge resection Distal Subtotal Total R1 margin Neoadjuvant chemotherapy Neoadjuvant radiotherapy Adjuvant chemotherapy Adjuvant radiotherapy D2 lymphadenectomy
OR
Univariate analysis 95% CI
1.09
1.03e1.16
Ref 1.31 0.92 0.71 1.23 1.29 5.76
0.75e2.28 0.36e2.33 0.24e2.12 0.48e3.13 0.65e2.59 2.95e11.24
Ref 7.66 8.29
p Value
0.006
OR
Multivariate analysis 95% CI
p Value
1.06 NA
0.97e1.17 e
0.21 e
0.34 0.86 0.54 0.67 0.47 <0.001
NA 2.38
e 0.98e5.77
e 0.06
2.61e22.47 2.94e23.38
<0.001 <0.001
Ref 4.74 4.89
0.19e117.87 0.11e208.45
0.34 0.41
Ref 4.39 8.87 9.6
1.11e17.3 2.67e29.40 2.88e31.98
0.04 <0.001 <0.001
Ref 1.06 1.46 1.41
0.05e22.05 0.06e36.52 0.05e37.22
0.97 0.82 0.84
Ref 4.00 1.02 2.03 1.98 1.39 2.64
1.89e8.49 0.98e1.05 1.18e3.49 0.90e4.33 0.84e2.31 1.49e4.69
<0.001 0.33 0.01 0.09 0.20 0.001
Ref 1.37 NA 0.55 NA NA 1.23 NA
0.41e4.59 e 0.13e2.36 e e 0.51e3.00 e
0.61 e 0.42 e e 0.65 e
Ref 0.61 0.60 NA 1.81 1.80 0.48 2.62 1.27 1.20
0.30e1.27 0.35e1.02 e 0.85e3.84 1.06e3.07 0.06e3.64 1.50e4.57 0.77e2.10 0.71e2.03
0.19 0.06 e 0.12 0.03 0.48 0.001 0.34 0.49
1.47 NA 2.59 NA NA
0.57e3.79 e 0.79e8.47 e e
0.42 e 0.11 e e
AJCC, American Joint Committee on Cancer; GE, gastroesophageal; LN, lymph nodes; LVI, lymphovascular invasion; OR, odds ratio; PNI, perineural invasion.
that the most common site of distant recurrence was the peritoneum (53.5%), while 43.3% of patients had hematogenous metastases.11 In contrast, an Italian series reported by Roviello and coworkers28 noted locoregional disease to be the most common pattern of recurrence. Although a report from the Memorial Sloan-Kettering group in the US similarly noted a relatively high incidence of locoregional recurrence, the incidence of peritoneal and distant
recurrence was comparably high.29 In this study, we noted that nearly 3 of every 4 patients who experienced a recurrence had a distant site as part of their pattern of recurrence (Fig. 1). Among patients who had only an initial solitary site of recurrence (63.8%) as well as those with multiple site of recurrence (100.0%), distant metastases were common. Collectively, these data suggest that underlying tumor biology leading to distant recurrenceerather than local
672
Table 5.
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Univariate/Multivariate Analysis of Risk Factors Associated with Distant Hematogenous Recurrence
Risk factor
Size Multiple lesions Location Antrum Body Cardia Fundus GE junction Lesser curvature Diffuse and mixed type AJCC stage I II III T stage I II III IV Grade Well to moderate Moderate to poor No. of positive LN LN positive LN metastasis ratio LVI PNI Operation type Wedge resection Distal Subtotal Total R1 margin Neoadjuvant chemotherapy Neoadjuvant radiotherapy Adjuvant chemotherapy Adjuvant radiotherapy D2 lymphadenectomy
OR
Univariate analysis 95% CI
Multivariate analysis 95% CI
p Value
OR
NA 10.82 NA
e 3.56e32.85 e
p Value
e <0.001 e
1.03 3.77
0.98e1.09 1.80e7.90
0.24 <0.001
Ref 0.84 1.31 0.95 1.06 0.67 1.06
0.52e1.36 0.68e2.55 0.44e2.05 0.49e2.31 0.38e1.17 0.63e1.79
0.48 0.86 0.89 0.89 0.16 0.83
NA NA
e e
e e
Ref 2.16 4.72
1.07e4.38 2.55e8.72
0.03 <0.001
Ref 1.23 1.74
0.19e8.06 0.19e16.07
0.83 0.63
Ref 2.08 3.82 4.63
0.85e5.06 1.87e7.79 2.27e9.44
0.11 <0.001 <0.001
Ref 2.42 4.64 4.43
0.37e15.72 0.58e36.77 0.53e37.07
0.35 0.15 0.17
Ref 1.35 1.04 3.43 6.02 2.32 2.05
0.86e2.12 1.02e1.07 2.09e5.65 3.23e1.24 1.50e3.60 1.26e3.34
0.20 <0.001 <0.001 <0.001 <0.001 0.004
Ref NA 0.98 1.18 2.51 1.25 1.27 NA
e 0.93e1.03 0.43e3.22 0.67e9.45 0.67e2.35 0.68e2.36 e
e 0.42 0.75 0.17 0.48 0.45 e
Ref 1.63 1.05 1.39 0.75 1.18 1.19 2.64 1.44 0.77
0.19e3.66 0.13e8.63 0.17e1.32 0.33e1.69 0.73e1.90 0.40e3.56 1.68e4.15 0.96e2.18 0.51e1.17
0.65 0.96 0.76 0.49 0.49 0.75 <0.001 0.08 0.23
NA NA 1.54 NA NA
e e 0.81e2.92 e e
e e 0.19 e e
AJCC, American Joint Committee on Cancer; GE, gastroesophageal; LN, lymph nodes; LVI, lymphovascular invasion; OR, odds ratio; PNI, perineural invasion.
issueseis the preeminent concern among patients with gastric cancer after curative intent surgery. Several factors were associated with the overall risk of recurrence. Specifically, in this study, factors associated with an increased risk of any-site recurrence included both patient (age), as well as tumor-specific factors (tumor burden, type, size, grade, extent of invasion, lymph node involvement, lymphovascular and perineural invasion)
(Table 2). Several investigators had previously reported that recurrence after curative intent surgery was influenced by factors such as tumor size, lymph node metastasis, perineural invasion, and tumor location.10,17,18,29 In fact, some authors have noted that certain factors were associated with different recurrence patterns.18,29 For example, D’Angelica and colleagues29 and Yoo and associates18 noted that proximal tumor location was associated with a higher risk of
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Figure 2. Incidence of recurrence over time.
locoregional recurrence. Interestingly, data from our large multi-institutional cohort similarly noted that patients with tumors anatomically located proximally at the gastroesophageal junction had nearly a 3-fold increased risk of locoregional recurrence. The reason for the increased risk of locoregional recurrence among patients with gastroesophageal junction tumors is unclear, but it may relate to issues with adequacy of treatment, increased difficulty achieving a “wide” negative margin and argue for more aggressive locoregional therapy. Perhaps not surprising, factors associated with distant recurrence were more related to underlying characteristics of tumor biology: tumor histologic type, grade, extent of invasion, perineural invasion, lymph node metastasis, etc. Few studies have provided data regarding the time to recurrence and the frequencies of recurrence patterns relative to time of recurrence.11,17 We noted that overall recurrence-free survival was 27.7 months when examining the entire cohort. Of note, however, was the finding that
Figure 3. Cumulative recurrence rate in patients with locoregional, peritoneal, and hematogenous distant recurrence.
the median time to recurrence among patients who did experience a recurrence was very short, at less than 1 year (10.8 months). Wu and colleagues11 reported a similarly short recurrence-free survival of 16.7 months among patients with recurrence. In looking at the risk of recurrence over time, the overwhelming majority of recurrences occurred within the first 3 years after surgery, with a subsequent plateauing of the risk thereafter (Fig. 3). Although Papachristou and Fortner30 reported that the risk of recurrence did not decrease over time, other investigators have noted that the risk of recurrence indeed does level off after 2 to 3 years.18,31 We also noted that the timing of recurrence was different based on the pattern of recurrence because patients with early recurrence (<12 months) were more likely to have peritoneal or hematogenous recurrence compared with patients who had late recurrences, who were more likely to have a locoregional recurrence (p ¼ 0.002). These findings are consistent with those reported by Eom and associates,17 who similarly reported that hematogenous metastasis was the most common type of recurrence in the early group compared with locoregional in the late recurrence group. Another interesting finding in our study was how quickly patients died after their disease recurred. Of note, median survival after recurrence was only 5.0 months. Patients with locoregional recurrence did have a longer survival after recurrence (9.1 months) compared with patients who had hematogenous distant (4.8 months) or peritoneal (2.7 months) disease. Of note, whether the recurrence occurred either “early” or “late” did not seem to affect prognosis after recurrence (4.5 months vs 5.7 months; p ¼ 0.16). This study has several limitations. As with all retrospective studies, there was undoubtedly some selection bias, as well as confounding by indication. For example, the finding that adjuvant chemotherapy was a risk factor for distant recurrence was likely a reflection of the fact that
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and pattern of recurrence after curative intent surgery, as well as provide evidence to tailor postoperative surveillance programs. Data on specific patterns of recurrence and the timing of recurrence can inform both the interval and perhaps the type, of surveillance imaging. The finding that 50% of recurrences occurred with the first 2 years strongly suggests that the most intensive followup should occur during this time period. Furthermore, the finding that 75.8% of patients had some component of distal recurrence suggests that imaging that incorporates all possible sites (eg, liver, lung, etc) is important.
Figure 4. Kaplan-Meier curve for overall survival in patients with locoregional, peritoneal, and hematogenous distant recurrence.
patients with more aggressive disease biology were more likely to receive this treatment. Rather, as other prospective studies have noted, chemotherapy is likely to decrease the risk of tumor recurrence among gastric cancer patients.14,32-34 The goal of this study was not to assess the efficacy of surgical techniques or adjuvant therapies, which is notoriously difficult to do in retrospective series. Rather, we sought to define the pattern of recurrence after curative intent gastric surgery. We noted that one-third of patients recurred, yet 5-year actuarial survival was estimated at 39.3%. The reason for this finding was probably multifactorial and may be related to incomplete patient follow-up (eg, the patient has not made it to 5 years yet) as well as “competing” causes of death. Although the multi-institutional nature of the study was a strength, it undoubtedly led to heterogeneity in the surgical approach and selection bias, especially when it came to the extent of lymphadenectomy. For example, the finding that D2 lymphadenectomy was associated with a higher risk of local recurrence was probably secondary to selection bias (ie, those patients with more extensive nodal disease underwent a more extensive lymph node dissection).
CONCLUSIONS In conclusion, nearly one-third of patients who undergo curative intent surgery for gastric cancer experienced a recurrence. Recurrence at a distant site was the most common site of recurrence among patients with either solitary or multiple site recurrence. Locoregional recurrence was also fairly common, but this pattern of recurrence tends to occur later as compared with distant recurrence, which more commonly presents within the first 12 months after surgery. Data from this study can hopefully inform providers and patients with regard to the risk of recurrence
Author Contributions Study conception and design: Spolverato, Ejaz, Kim, Pawlik Acquisition of data: Spolverato, Ejaz, Kim, Squires, Poultsides, Fields, Schmidt, Weber, Votanopoulos, Maithel, Pawlik Analysis and interpretation of data: Spolverato, Ejaz, Kim, Pawlik Drafting of manuscript: Spolverato, Pawlik Critical revision: Spolverato, Ejaz, Kim, Pawlik Acknowledgment: We would like to thank Linda X Jin, Alexandra W Acher, Neil Saunders, Clifford S Cho, Mark Bloomston, David J Worhunsky, Douglas Swords, and all the participants of the US Gastric Cancer Collaborative. REFERENCES 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69e90. 2. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006;12:354e362. 3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11e30. 4. Hirota WK, Zuckerman MJ, Adler DG, et al. ASGE guideline: the role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. Gastrointest Endosc 2006;63: 570e580. 5. Akoh JA, Macintyre IM. Improving survival in gastric cancer: review of 5-year survival rates in English language publications from 1970. Br J Surg 1992;79:293e299. 6. Arkenau HT. Gastric cancer in the era of molecularly targeted agents: current drug development strategies. J Cancer Res Clin Oncol 2009;135:855e866. 7. Wang J, Yu JC, Kang WM, Ma ZQ. Treatment strategy for early gastric cancer. Surg Oncol 2012;21:119e123. 8. Park do J, Han SU, Hyung WJ, et al. Long-term outcomes after laparoscopy-assisted gastrectomy for advanced gastric cancer: a large-scale multicenter retrospective study. Surg Endosc 2012;26:1548e1553. 9. Lee SE, Ryu KW, Nam BH, et al. Prognostic significance of intraoperatively estimated surgical stage in curatively resected gastric cancer patients. J Am Coll Surg 2009;209:461e467.
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10. Deng J, Liang H, Wang D, et al. Investigation of the recurrence patterns of gastric cancer following a curative resection. Surg Today 2011;41:210e215. 11. Wu CW, Lo SS, Shen KH, et al. Incidence and factors associated with recurrence patterns after intended curative surgery for gastric cancer. World J Surg 2003;27:153e158. 12. Huang KH, Chen JH, Wu CW, et al. Factors affecting recurrence in node-negative advanced gastric cancer. J Gastroenterol Hepatol 2009;24:1522e1526. 13. Sakar B, Karagol H, Gumus M, et al. Timing of death from tumor recurrence after curative gastrectomy for gastric cancer. Am J Clin Oncol 2004;27:205e209. 14. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11e20. 15. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29: 1715e1721. 16. Bringeland EA, Wasmuth HH, Johnsen G, et al. Outcomes among patients treated for gastric adenocarcinoma during the last decade. J Surg Oncol 2013;107:752e757. 17. Eom BW, Yoon H, Ryu KW, et al. Predictors of timing and patterns of recurrence after curative resection for gastric cancer. Dig Surg 2010;27:481e486. 18. Yoo CH, Noh SH, Shin DW, et al. Recurrence following curative resection for gastric carcinoma. Br J Surg 2000;87: 236e242. 19. Li JH, Zhang SW, Liu J, et al. Review of clinical investigation on recurrence of gastric cancer following curative resection. Chin Med J (Engl) 2012;125:1479e1495. 20. Li F, Zhang R, Liang H, et al. The pattern and risk factors of recurrence of proximal gastric cancer after curative resection. J Surg Oncol 2013;107:130e135. 21. Arnaoutakis DJ, Mavros MN, Shen F, et al. Recurrence patterns and prognostic factors in patients with hepatocellular carcinoma in noncirrhotic liver: a multi-institutional analysis. Ann Surg Oncol 2014;21:147e154. 22. Assumpcao L, Choti MA, Gleisner AL, et al. Patterns of recurrence following liver resection for colorectal metastases: effect
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24.
25. 26. 27. 28. 29. 30. 31.
32. 33.
34.
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