Abstract
Aims:
The role of resection remains debated in cases of metastatic gastric carcinoma (mGC). Some mGCs are technically resectable. At the population level, the real-world application of resection for mGC remains largely unclear in most Western countries. This large, population-based international investigation aimed to reveal the resection patterns and trends for mGC and the treatment-associated factors in Europe and the US.
Methods:
Data on cases with microscopically-confirmed primary invasive stomach carcinoma with distant metastasis were obtained from the nationwide cancer registries of the Netherlands, Belgium, Norway, Sweden, Estonia, and Slovenia and the US Surveillance, Epidemiology, and End Results-18 database. We calculated age-standardized rates of primary cancer-directed resection and assessed resection trends using linear regression. We investigated associations of treatment with patient and cancer factors using multivariable-adjusted log-binomial regression.
Results:
Among 133,321 patients with gastric cancer, overall, 40,215 cases with mGC diagnosed between 2003–2017 were investigated. Age-standardized resection rates significantly declined over time in the US, Belgium, Sweden, and Norway (by 5–14%). Resection rates greatly differed from 5% to 16% in 2013–2014. Cases with older ages, cardia tumors, or tumors involving adjacent structures were significantly less often operated across most countries. Sex was not significantly associated with resection. Across countries the association patterns and strengths differed largely. With multivariable adjustment, resection rates decreased significantly in all countries except Slovenia and Estonia (prevalence ratio per year = 0.90–0.98), and the decreasing trends were consistently observed in various stratifications by age and location.
Conclusion:
In Europe and the US, resection patterns and trends largely varied across countries for mGCs, which were mostly less often resected in the early 21st century. Various resection-associated factors were shown, with greatly varying association patterns and strengths. Our report could aid to identify discrepancies in clinical practice and highlight the great need for further clarifying the role of resection in mGCs to enhance standardization of care.
Keywords: great variations, large international population-based investigation, metastatic gastric carcinoma, patterns and trends, treatment
Introduction
With over 1,000,000 new cases and about 800,000 associated mortalities estimated in 2018, gastric carcinoma (GC) is the fifth most often diagnosed malignancy and the third leading cause of malignancy-associated mortality globally. 1 Because of its insidious nature, a significant proportion of patients with GC have distant metastasis at initial diagnosis. 2 GC with distant metastasis is typically not amenable to curative surgical resection and is usually managed with chemotherapy with/without radiotherapy.2–4 The prognosis of patients with metastatic GC (mGC) is very poor, with median survival ranging from about 4 months when managed with best supportive care only, to around 1 year when treated with palliative combination chemotherapy.5–8
The role of resection is still obscure among cases with mGC. 9 Some mGCs are technically resectable; palliative interventions used to relieve major symptoms may contribute to prolongation of life. Some studies10–15 suggest that selected patients with mGC and with good performance status may benefit from resection by experienced hands in expert centers, while relevant prospective and/or randomized evidence remains lacking.
With obscure effectiveness, some surgeons operate on patients with mGC, possibly because of identification of metastatic disease only during or after operation or for palliative purposes. However, the real-world patterns and trends of such management at the population level remain greatly unclear in most Western countries.
In our large, population-based international investigation, the use of primary cancer-directed resection for mGC in Europe and the United States (US) in the early 21st century was revealed, and the treatment-associated factors were explored.
Methods
Data
Selection of eligible European nationwide population-based cancer registries after extensive retrieval and contact and reasons for exclusion have been detailed previously. 16 We included patient-level data of cases with GC from the nationwide cancer registries of the Netherlands, Belgium, Norway, Sweden, Estonia, and Slovenia, and the Surveillance, Epidemiology, and End Results (SEER)-18 Program of the US for analysis (Supplemental Table S1). The characteristics of the participating European registries have been previously detailed;16,17generally the quality of the data was high. Being an authoritative source for the US cancer statistics, the SEER database collects information from population-based cancer registries in the US. 18
Tumor morphology and topography were in line with the International Classification of Diseases for Oncology, third edition (ICD-O-3). Cases with invasive primary carcinomas of the stomach (ICD-O-3 code, C16) confirmed microscopically during 2003 through 2017 were eligible. We included both cardia and non-cardia cancers. A detailed analysis of resection rates for non-metastatic GC has been reported elsewhere. 16 Here, we only analyzed cases with distant metastasis. Patients with non-stomach malignancies invading the stomach, or neoplasms originating from the germ-cell, neuroendocrine, or mesenchymal tissues were ineligible (Supplemental Table S2). We also excluded individuals diagnosed on the basis of autopsy or death certificate only.
Information on patient (age, sex, and diagnosis year), tumor (histology, differentiation, location, and stage), management (gastrectomy, chemotherapy, and radiation therapy), and follow-up (survival status and time) which was (re)coded according to a uniform standardized data-collection sheet was retrieved. Chemotherapy and/or radiotherapy were recorded with low sensitivity in the US and Estonia registry data. Neoadjuvant and adjuvant treatment could be hardly differentiated in the Norway and Estonia registry data, and adjuvant therapy was not recorded in the dataset from Sweden. Certain metastatic sites (bone, brain, liver, and lung) were only recorded in the registries from the US and the Netherlands.
We investigated primary cancer-directed resection and defined it as surgical excision of the primary cancer regardless of the type, radicality, and extent of gastrectomy and regional lymph node excision, of the concurrence of distant metastasectomy, and of the technique, approach, method, and procedure of surgery. We derived local cancer invasion and lymph node involvement from the tumor-node-metastasis (TNM) staging by the Union for International Cancer Control/American Joint Committee on Cancer; we re-categorized them into subgroups that were consistent across the studied periods during which the sixth or seventh edition of staging had been in effect.
Ethics statement
The Ethics Committee affiliated to the Medical Faculty Heidelberg approved our observational, registry-based, and population-based investigation (S-064/2016). The secondary data presented are all anonymous without any risk of identification, with no individual case data shown.
Analyses
We analyzed data and presented results separately for each registry without pooling. We stratified age into four categories (<60, 60–69, 70–79, and ⩾80 year-old). We computed age-standardized resection rates with the use of the distribution of age of the cases from the US, with the greatest number of analyzed cases, as the standard. We used linear regression to evaluate the time trends of the standardized rates and graphically illustrated the rates over 2-calendar-year time. We showed graphically the patient age- and cancer location-stratified rates in 2010 and later.
The associations of treatment with patient and cancer features adjusting for diagnosis year, age group, sex, cancer histology, location, and adjacent structure invasion were investigated by computing the multivariable log-binomial regression models. We calculated the log-binomial maximal likelihood prevalence ratios (PRs). 19 We further performed analyses stratified by patient age, tumor histology, and location. We used the SAS software (version 9.4; Cary, NC, the US) for data analyses. A two-sided p-value of <0.05 indicated statistical significance.
Results
Features of overall cases with mGC
From a total of 133,321 registered patients with GC, we investigated 40,215 cases with metastatic cancer (Supplemental Table S1 and Table 1). The majority of the patients were males (59–68% across countries). The mean age was 65–70 years, with 41–55% of the patients aged ⩾70 years. Most often, the malignancies originated from the cardia (37–60%; 14% in Estonia) and were poorly-differentiated or undifferentiated (66–77%). 12–39% of the mGCs also invaded adjacent structures. Only a small proportion of the malignancies did not involve lymph nodes (5–24%; 44% in the US). It should be noted 9% (Sweden) to 21% (Belgium) of the patients with mGC underwent gastrectomy. In countries where data on non-surgical management were recorded with good sensitivity, chemotherapy was given to between 25% (Slovenia) and 62% (Belgium) of cases, and radiation therapy was less frequently used (7–10%).
Table 1.
Demographic and clinical features of total and resected patients with gastric carcinoma with distant metastasis. a
| Variable | Category | The US |
The Netherlands |
Belgium |
Sweden |
Norway |
Slovenia |
Estonia |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Resected | Total | Resected | Total | Resected | Total | Resected | Total | Resected | Total | Resected | Total | Resected | ||
| n | 23280 | 3232 (14) | 7112 | 1201 (17) | 2805 | 598 (21) | 2783 | 254 (9) | 1779 | 222 (12) | 1655 | 323 (20) | 801 | 119 (15) | |
| Sex | Male | 14864 (64) | 1914 (59) | 4637 (65) | 750 (62) | 1894 (68) | 385 (64) | 1711 (61) | 144 (57) | 1083 (61) | 121 (55) | 1057 (64) | 200 (62) | 471 (59) | 68 (57) |
| Age at diagnosis | Year; as continuous | 65 ± 14 | 64 ± 14 | 68 ± 12 | 67 ± 12 | 69 ± 13 | 67 ± 13 | 70 ± 12 | 68 ± 11 | 69 ± 13 | 68 ± 14 | 67 ± 12 | 64 ± 12 | 68 ± 13 | 65 ± 14 |
| Age group | <60 years | 8071 (35) | 1211 (37) | 1574 (22) | 283 (24) | 648 (23) | 176 (29) | 483 (17) | 54 (21) | 398 (22) | 58 (26) | 424 (26) | 110 (34) | 199 (25) | 37 (31) |
| 60–69 years | 5763 (25) | 795 (25) | 1948 (27) | 338 (28) | 690 (25) | 138 (23) | 752 (27) | 74 (29) | 415 (23) | 47 (21) | 424 (26) | 91 (28) | 213 (27) | 33 (28) | |
| 70–79 years | 5585 (24) | 764 (24) | 2345 (33) | 399 (33) | 879 (31) | 179 (30) | 902 (32) | 85 (33) | 517 (29) | 65 (29) | 561 (34) | 100 (31) | 260 (32) | 35 (29) | |
| ⩾80 years | 3861 (17) | 462 (14) | 1245 (18) | 181 (15) | 588 (21) | 105 (18) | 646 (23) | 41 (16) | 449 (25) | 52 (23) | 246 (15) | 22 (7) | 129 (16) | 14 (12) | |
| Tumor location b | Gastric cardia | 7145 (50) | 518 (27) | 2143 (47) | 266 (34) | 889 (60) | 175 (54) | 856 (44) | 52 (25) | 465 (46) | 30 (22) | 240 (37) | 29 (19) | 70 (14) | 5 (6) |
| Gastric fundus/body | 3165 (22) | 395 (21) | 1116 (24) | 194 (25) | 289 (19) | 52 (16) | 629 (32) | 57 (28) | 257 (25) | 37 (27) | 171 (26) | 54 (36) | 296 (61) | 41 (53) | |
| Gastric antrum/pylorus | 3950 (28) | 981 (52) | 1352 (29) | 329 (42) | 315 (21) | 99 (30) | 458 (24) | 98 (47) | 289 (29) | 70 (51) | 236 (36) | 66 (44) | 123 (25) | 31 (40) | |
| Other | 9020 (39) | 1338 (41) | 2501 (35) | 412 (34) | 1312 (47) | 272 (46) | 840 (30) | 47 (19) | 768 (43) | 85 (38) | 1008 (61) | 174 (54) | 312 (39) | 42 (35) | |
| Histology | Adenocarcinoma | 16181 (70) | 2160 (67) | 5445 (77) | 890 (74) | 2226 (79) | 443 (74) | NA | NA | 1454 (82) | 177 (80) | 1393 (84) | 289 (89) | 425 (53) | 69 (58) |
| Signet ring cell carcinoma | 5129 (22) | 860 (27) | 1221 (17) | 248 (21) | 414 (15) | 120 (20) | NA | NA | 174 (10) | 28 (13) | 101 (6) | 19 (6) | 249 (31) | 36 (30) | |
| Other c | 1970 (8) | 212 (7) | 446 (6) | 63 (5) | 165 (6) | 35 (6) | NA | NA | 151 (8) | 17 (8) | 161 (10) | 15 (5) | 127 (16) | 14 (12) | |
| Differentiation d | Well | 374 (2) | 46 (2) | 65 (2) | 14 (2) | 173 (7) | 24 (5) | – | 5 (4) | 30 (3) | 2 (1) | 48 (5) | 11 (4) | 27 (5) | 4 (4) |
| Intermediate | 4021 (22) | 552 (19) | 847 (22) | 167 (21) | 635 (27) | 123 (23) | – | 21 (17) | 248 (21) | 43 (24) | 214 (23) | 55 (20) | 154 (26) | 26 (26) | |
| Poor/undifferentiated | 13715 (76) | 2383 (80) | 3010 (77) | 603 (77) | 1532 (66) | 390 (73) | – | 95 (79) | 904 (76) | 132 (75) | 681 (72) | 209 (76) | 411 (69) | 70 (70) | |
| Local invasion e | Lamina propria/submucosa | 3875 (28) | 182 (6) | 111 (3) | 19 (2) | 90 (5) | 14 (2) | 48 (2) | 10 (4) | – | 4 (3) | 20 (2) | 5 (2) | 3 (1) | 1 (1) |
| Muscularis propria/subserosa | 3797 (28) | 1073 (35) | 1805 (53) | 409 (49) | 641 (36) | 192 (33) | 797 (38) | 86 (35) | – | 39 (34) | 163 (20) | 69 (23) | 260 (47) | 44 (42) | |
| Serosa | 1773 (13) | 1023 (33) | 586 (17) | 265 (32) | 742 (42) | 284 (49) | 418 (20) | 102 (42) | – | 72 (63) | 377 (45) | 169 (57) | 228 (41) | 48 (46) | |
| Adjacent structures | 4256 (31) | 788 (26) | 878 (26) | 147 (18) | 291 (17) | 95 (16) | 819 (39) | 46 (19) | – | 270 (33) | 54 (18) | 67 (12) | 11 (11) | ||
| Positive lymph node f | 0 | 7743 (44) | 554 (18) | 1002 (18) | 160 (15) | 268 (15) | 62 (11) | 504 (24) | 49 (20) | – | 16 (16) | – | 19 (7) | 18 (5) | 5 (5) |
| 1–6 | 8308 (47) | 1288 (42) | 4150 (76) | 700 (67) | 1067 (58) | 252 (44) | 1127 (54) | 107 (43) | – | 50 (51) | – | 75 (26) | 233 (71) | 44 (48) | |
| ⩾7 | 1630 (9) | 1237 (40) | 287 (5) | 187 (18) | 519 (28) | 262 (46) | 470 (22) | 95 (38) | – | 33 (33) | – | 193 (67) | 77 (23) | 42 (46) | |
| Harvested node no. | \ | 13 ± 13 | \ | 9 ± 17 | \ | NA | \ | 19 ± 17 | \ | NA | \ | NA | \ | NA | |
| Resection type g | Partial/subtotal gastrectomy | \ | 1914 (59) | \ | 847 (71) | \ | NA | \ | 91 (62) | \ | NA | \ | NA | \ | NA |
| Total/near-total gastrectomy | \ | 755 (23) | \ | 299 (25) | \ | NA | \ | 47 (32) | \ | NA | \ | NA | \ | NA | |
| Other | \ | 563 (17) | \ | 55 (5) | \ | NA | \ | 9 (6) | \ | NA | \ | NA | \ | NA | |
| Neoadjuvant CHT h | Yes | \ | NA | \ | 225 (19) | \ | 172 (29) | \ | 62 (24) | \ | NA | \ | 27 (8) | \ | NA |
| Neoadjuvant RT h | Yes | \ | 148 (5) | \ | 17 (1) | \ | 32 (5) | \ | 6 (2) | \ | NA | \ | 7 (2) | \ | NA |
| Total/adjuvant CHT h | Yes | 12501 (54) | 1724 (53) | 2732 (38) | 338 (28) | 1745 (62) | 284 (48) | NA | NA | 522 (29) | 58 (26) | 408 (25) | 120 (37) | 254 (32) | 36 (30) |
| Total/adjuvant RT h | Yes | 3714 (16) | 380 (12) | 519 (7) | 62 (5) | 279 (10) | 54 (9) | NA | NA | 140 (8) | 10 (5) | 114 (7) | 34 (11) | 19 (2) | 5 (4) |
| Variable | Category | The US |
The Netherlands |
Belgium |
Sweden |
Norway |
Slovenia |
Estonia |
|||||||
| Total | Resected | Total | Resected | Total | Resected | Total | Resected | Total | Resected | Total | Resected | Total | Resected | ||
| Bone metastasis i | Yes | 1557 (14) | 54 (4) | 457 (7) | 46 (4) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Brain metastasis j | Yes | 241 (2) | 15 (1) | 34 (1) | 3 (<1) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Liver metastasis k | Yes | 5150 (44) | 365 (29) | 2810 (41) | 355 (31) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Lung metastasis l | Yes | 1787 (16) | 78 (6) | 672 (10) | 70 (6) | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
Categorical data are shown as count [percentage (%)], and numeric data as mean ± standard deviation. Records are complete otherwise specified below.
The percentages of gastric cardia, fundus/body, and antrum/pylorus cancers are the proportions compared to the total tumor cases of the three locations; ‘other’ includes lesser curvature, greater curvature, and overlapping lesion of stomach and stomach (NOS), and its proportion is relative to the whole cases.
Cystic/mucinous/serous (excluding signet ring cell), squamous cell, ductal/lobular, complex, unspecified, and epithelial (NOS) neoplasms.
Unknown differentiation: total patients: the US, 5170 (22%); the Netherlands, 3190 (45%); Belgium, 465 (17%); Sweden, 2614 (94%); Norway, 597 (34%); Slovenia, 712 (43%); Estonia, 209 (26%); resected patients: the US, 251 (8%); the Netherlands, 417 (35%); Belgium, 61 (10%); Sweden, 133 (52%); Norway, 45 (20%); Slovenia, 48 (15%); Estonia, 19 (16%).
Unknown tumor local invasion: total patients: the US, 9579 (41%); the Netherlands, 3732 (53%); Belgium, 1041 (37%); Sweden, 701 (25%); Norway, 1162 (65%); Slovenia, 825 (50%); Estonia, 243 (30%); resected patients: the US, 166 (5%); the Netherlands, 361 (30%); Belgium, 13 (2%); Sweden, 903 (4%); Norway, 107 (48%); Slovenia, 26 (8%); Estonia, 15 (13%). Invasion of serosa and adjacent structures could not be differentiated from each other in Norway or Slovenia.
Unknown positive lymph node: total patients: the US, 5599 (24%); the Netherlands, 1673 (24%); Belgium, 951 (34%); Sweden, 682 (25%); Norway, 1263 (71%); Slovenia, 1037 (63%); Estonia, 473 (59%); resected patients: the US, 153 (5%); the Netherlands, 154 (13%); Belgium, 22 (4%); Sweden, 3 (1%); Norway, 123 (55%); Slovenia, 36 (11%); Estonia, 28 (24%).
Gastrectomy (NOS) or local resection. Available in Sweden since 2010.
Non-surgical therapies in the US and Estonia had low sensitivity, and the counterpart category of “Yes” was “No/unknown”. In Norway and Estonia, neoadjuvant and adjuvant therapies could not be distinguished from each other. Total CHT/RT is for total patients, and (neo)adjuvant CHT/RT for resected patients.
Unknown bone metastasis: total patients: the US, 651 (5%); the Netherlands, 251 (4%); resected patients: the US, 63 (5%); the Netherlands, 53 (4%). Information in the US was only available since 2010 (n = 12091).
Unknown brain metastasis: total patients: the US, 701 (6%); the Netherlands, 251 (4%); resected patients: the US, 60 (5%); the Netherlands, 53 (4%). Information in the US was only available since 2010 (n = 12091).
Unknown liver metastasis: total patients: the US, 512 (4%); the Netherlands, 251 (4%); resected patients: the US, 44 (3%); the Netherlands, 53 (4%). Information in the US was only available since 2010 (n = 12091).
Unknown lung metastasis: total patients: the US, 736 (6%); the Netherlands, 251 (4%); resected patients: the US, 52 (4%); the Netherlands, 53 (4%). Information in the US was only available since 2010 (n = 12091).
\, resection-specific variables not applicable for total patients; –, not shown due to >60% missing values; CHT, chemotherapy; NA, not available; NOS, not otherwise specified; RT, radiotherapy.
Based on the information available on distant metastasis sites in the US and the Netherlands, the liver was the most frequent metastasis site (43% and 41%), followed by lung (15% and 10%) and bone (13% and 7%).
Characteristics of patients with resected mGC
Compared with overall patients with mGC, those with resected cancer were on average 1–3 years younger. Resected tumors were much less often located at the cardia (6–54%) and invaded adjacent structures less frequently (11–26%). Partial/subtotal gastrectomy was the most frequent primary cancer-directed resection (59–71%). On average, 9–19 lymph nodes were retrieved. In registries with data on non-operational treatment of high quality, neoadjuvant chemotherapy was used for from 8% (Slovenia) to 29% of cases (Belgium); however, neoadjuvant radiation therapy was scarcely used (1–5%). Adjuvant chemotherapy was applied from 26% (Norway) to 48% of cases (Belgium); however, adjuvant radiation therapy was much less often used (5–11%).
Trends of resection
We observed significantly decreasing trends of resection across all registries except those from the Netherlands (Ptrend = 0.132), Estonia (Ptrend = 0.329), and Slovenia (Ptrend = 0.139; Figure 1). We identified the most dramatic decline in Norway (from 2003–2004 to 2013–2014: from 19% to 5%; Ptrend < 0.001), and the least pronounced decline in Sweden (from 2005–2006 to 2013–2014: from 14% to 9%; Ptrend = 0.004). We saw moderate declines in the US (from 2003–2004 to 2013–2014: 19% to 10%; Ptrend < 0.001) and Belgium (from 2003–2004 to 2013–2014: 24% to 16%; Ptrend = 0.001).
Figure 1.
Age-standardized rates of resection for gastric carcinoma with synchronous distant metastasis.
Recent rates of resection by patient age and cancer location
We restricted cases to those who were diagnosed in 2010 and later, a more recent time period during which information was available from the registries of all the countries, to analyze rates of resection by patient age and cancer location (Figure 2). In most countries, rates of resection decreased with older ages, and were dramatically lower among cases aged 80 years or older [4% (Norway) to 17% (Belgium)] compared to in the others [<60 years: from 8% (Norway) to 25% (Slovenia); 60–69 years: from 8% (Norway and Sweden) to 18% (Slovenia); 70–79 years: from 7% (Norway) to 20% (Slovenia)], with great international variations observed. Rates of resection were mostly lower in tumors of the cardia [3% (Norway) to 17% (Belgium)] compared to those of the fundus/body [from 7% (Sweden) to 34% (Slovenia)] or of the antrum/pylorus [from 13% (Norway) to 30% (Belgium)].
Figure 2.
Rates of resection for gastric carcinoma with synchronous distant metastasis stratified by patient age and tumor location, 2010 or later.
Variables associated with resection
The log-binomial regression modeling with multivariable adjustment was used to further explore the treatment-associated factors in each country (Table 2). The findings further supported the decreasing rates of resection across most countries [PR = 0.90 (Norway) to 0.98 per year (the Netherlands), except Slovenia and Estonia].
Table 2.
Association of demographic and clinical features with resection for gastric carcinoma with distant metastasis using multivariable-adjusted log-binomial regression.
| Variable | Category | The US |
The Netherlands |
Belgium |
Sweden |
Norway |
Slovenia |
Estonia |
|---|---|---|---|---|---|---|---|---|
| PR (95% CI) a | PR (95% CI) a | PR (95% CI) a | PR (95% CI) a | PR (95% CI) a | PR (95% CI) a | PR (95% CI) a | ||
| Year of diagnosis | Per 1 year | 0.93 (0.92–0.94) | 0.98 (0.96–1.00) | 0.94 (0.92–0.97) | 0.96 (0.92–1.00) | 0.90 (0.86–0.93) | 0.98 (0.95–1.01) | 1.03 (0.94–1.13) |
| Sex | Female versus male | 1.06 (0.99–1.13) | 1.05 (0.94–1.17) | 1.10 (0.95–1.28) | 1.14 (0.90–1.44) | 1.17 (0.92–1.49) | 1.15 (0.94–1.40) | 1.13 (0.81–1.58) |
| Age group | 60–69 years | 0.97 (0.90–1.06) | 0.97 (0.84–1.12) | 0.77 (0.63–0.93) | 0.87 (0.63–1.20) | 0.76 (0.53–1.07) | 0.93 (0.65–1.05) | 0.80 (0.52–1.23) |
| <60 years as reference | 70–79 years | 0.91 (0.84–0.99) | 0.92 (0.80–1.06) | 0.78 (0.65–0.94) | 0.76 (0.56–1.04) | 0.70 (0.50–0.96) | 0.66 (0.52–0.83) | 0.74 (0.48–1.13) |
| ⩾80 years | 0.78 (0.70–0.86) | 0.78 (0.66–0.92) | 0.68 (0.54–0.84) | 0.49 (0.33–0.72) | 0.62 (0.44–0.87) | 0.33 (0.21–0.50) | 0.53 (0.30–0.95) | |
| Tumor location | Gastric fundus/body | 1.65 (1.46–1.87) | 1.40 (1.18–1.66) | 0.94 (0.71–1.25) | 1.50 (1.04–2.17) | 2.15 (1.36–3.39) | 2.56 (1.71–3.84) | 2.02 (0.83–4.94) |
| Gastric cardia as reference | Gastric antrum/pylorus | 3.25 (2.94–3.59) | 1.95 (1.68–2.27) | 1.57 (1.27–1.94) | 3.57 (2.59–4.93) | 3.72 (2.47–5.60) | 2.46 (1.65–3.65) | 3.63 (1.48–8.94) |
| Other b | 1.95 (1.76–2.15) | 1.31 (1.13–1.51) | 1.00 (0.84–1.20) | 0.93 (0.63–1.37) | 1.68 (1.12–2.51) | 1.45 (1.01–2.10) | 1.95 (0.80–4.79) | |
| Tumor histology | SRC versus non-SRC | 1.09 (1.02–1.18) | 1.13 (1.00–1.29) | 1.35 (1.14–1.61) | – | 0.98 (0.68–1.39) | 0.78 (0.52–1.18) | 0.89 (0.61–1.29) |
| Adjacent structure invasion | Yes versus no | 0.65 (0.61–0.70) | 0.49 (0.42–0.57) | 0.86 (0.72–1.04) | 0.34 (0.23–0.49) | \ | 0.42 (0.32–0.54) | 0.80 (0.45–1.42) |
Prevalence ratios and 95% confidence intervals for resection versus non-resection were calculated using multivariable-adjusted log-binomial regression models adjusting for year of diagnosis, sex, age group, tumor location, and histology. For the association with adjacent structure invasion, this factor was additionally added into the main model. Previous cancer was available and also adjusted for in the US, the Netherlands, and Belgium. All models converged. PRs shown in bold are statistically significant.
Lesser curvature, greater curvature, and overlapping lesion of stomach, and stomach (not otherwise specified).
–, not available; \, not estimable; CI, confidence interval; PR, prevalence ratio; SRC, signet ring cell carcinoma.
We did not observe any significant associations of resection with patient sex. Older patients mostly underwent less often resection [versus <60 years, PR70–79 years = 0.66 (Slovenia) to 0.91 (the US); PR⩾80 years = 0.33 (Slovenia) to 0.78 (the US and the Netherlands)]. Compared to cardia tumors, gastric fundus/body [PR = 1.40 (the Netherlands) to 2.56 (Slovenia)] and pylorus/antrum tumors [PR = 1.57 (Belgium) to 3.72 (Norway)] were more often resected across most countries. Resection was more frequently performed for signet ring cell cancers (SRCs) in the US (PR = 1.09) and Belgium (PR = 1.35). Patients with invasion of adjacent structure mostly underwent less often resection [PR = 0.34 (Sweden) to 0.65 (the US)].
Stratified analyses of the temporal resection trends
We further analyzed the association between resection and diagnosis year stratified by patient age, tumor histology, and location (Table 3). While the patterns and strengths of association across the various strata were mostly similar to the overall findings, we observed stronger decreasing trends for cardia tumors compared with non-cardia tumors in the US.
Table 3.
Association of year of diagnosis (as continuous) with resection for gastric carcinoma with distant metastasis using multivariable-adjusted log-binomial regression.
| Variable | The US | The Netherlands | Belgium | Sweden | Norway | Slovenia | Estonia |
|---|---|---|---|---|---|---|---|
| <70 years | |||||||
| Resected/total no. | 2006/13834 | 621/3522 | 314/1338 | 128/1235 | 105/813 | 201/848 | 70/412 |
| PR per 1 year (95% CI) a | 0.93 (0.92–0.94) | 0.99 (0.96–1.02) | 0.92 (0.89–0.96) | 0.93 (0.88–0.98) | 0.88 (0.84–0.93) | 0.97 (0.93–1.00) | 1.05 (0.93–1.18) |
| ⩾70 years | |||||||
| Resected/total no. | 1226/9446 | 580/3590 | 284/1467 | 126/1548 | 117/966 | 122/807 | 49/389 |
| PR per 1 year (95% CI) a | 0.93 (0.91–0.94) | 0.97 (0.94–0.99) | 0.97 (0.93–1.00) | 0.99 (0.93–1.04) | 0.91 (0.86–0.96) | 0.99 (0.94–1.04) | 1.03 (0.89–1.18) |
| Cardia | |||||||
| Resected/total no. | 518/7145 | 266/2143 | 175/889 | 52/856 | 30/465 | 29/240 | 5/70 |
| PR per 1 year (95% CI) a | 0.90 (0.88–0.92) | 0.99 (0.95–1.03) | 0.94 (0.90–0.99) | 0.89 (0.81–0.97) | / | / | / |
| Non-cardia | |||||||
| Resected/total no. | 1376/7115 | 523/2468 | 151/604 | 155/1087 | 107/546 | 120/407 | 72/419 |
| PR per 1 year (95% CI) a | 0.94 (0.93–0.96) | 0.96 (0.94–0.99) | 0.97 (0.93–1.02) | 1.00 (0.95–1.05) | 0.90 (0.85–0.95) | 0.98 (0.94–1.03) | 1.05 (0.93–1.18) |
| Signet ring cell carcinoma | |||||||
| Resected/total no. | 860/5129 | 248/1221 | 120/414 | – | 28/174 | 19/101 | 36/249 |
| PR per 1 year (95% CI) a | 0.92 (0.90–0.93) | 1.00 (0.96–1.04) | 0.92 (0.87–0.96) | – | / | / | / |
Prevalence ratios and 95% confidence intervals for association of year of diagnosis (as continuous) with resection versus non-resection were calculated using multivariable-adjusted log-binomial regression models adjusting for sex, age group, tumor location, and histology. Previous cancer was available and also adjusted for in the US, the Netherlands, and Belgium. All models converged. Results were not shown for countries with <40 resected and/or <80 total cases. PRs shown in bold are statistically significant.
–, not available; /, not shown due to small case number (<40 resected and/or <80 total cases); CI, confidence interval; PR, prevalence ratio.
Discussion
To the best of our knowledge, our report is a population-based international investigation of the largest scale on the patient and cancer features, resection patterns and trends, and factors associated with resection for mGCs in Europe and the US. Great variations across countries were revealed. Rates of resection mostly decreased for mGCs. We consistently observed decreasing trends across various stratifications. We further identified various patient and cancer factors associated with management.
In general, upfront excision of the primary malignancy is not routinely recommended for cases with mGC,2,20 while resection could be considered for colorectal cancer with limited manageable metastasis, with possible survival benefits.21,22 Although advances in surgery and perioperative care have contributed to fewer mortalities and morbidities, the role of resection is still debated among cases with technically resectable mGC.9,23 Reports on trends of resection for mGCs in European countries have been rare. Some patients with mGC underwent primary cancer-directed gastrectomy, albeit with declining trends seen across most countries in our study. The decreasing trends remained after controlling for multiple patient and cancer features, and were mostly consistent across various stratifications by age, histology, and location. We further showed that the decreasing degree varied largely across countries, and that resection rates decreased on average by as much as 10% per year in Norway compared with 2% per year in the Netherlands. The temporal trends in Slovenia and Estonia were insignificant and could possibly be explained by the paucity of the cases. Greatly discrepant rates of resection in 2013–2014 (5–16%) resulted from the largely varying temporal trends.
Observational studies10–15 showed that palliative excision of primary tumor might enhance survival and quality of life within a selected subgroup of cases with mGC especially in expert centers. A meta-analysis 10 of about 20 randomized studies showed that cyto-reductive operation for mGC with peritoneal carcinomatosis was associated with enhanced survival outcomes up to 3 years, although not at 5 years. It should be noted, that, for patients with limited metastatic disease, no evidence supporting survival benefits associated with reduction gastrectomy, which aims at improving survival by reducing cancer volume, was observed in the randomized REGATTA study established in Asian patients.24,25 However, in the German phase II AIO-FLOT3 trial, 26 cases with limited distant metastasis who received neoadjuvant chemotherapy and proceeded to resection had favorable survival outcomes. Another important study 27 evaluated cytoreductive surgery for selected patients with mGC treated with systemic chemotherapy by analyzing about 30,000 chemotherapy-treated patients from the National Cancer Database (NCDB) and applying the nearest-neighbor 1:1 propensity score-matching method; after matching, patients undergoing cytoreductive surgery comprising gastrectomy and metastasectomy had longer overall survival than those receiving no surgery [median: 16 versus 9 months; hazard ratio for surgery versus no surgery: 0.56, 95% confidence interval (CI) = 0.49–0.63]. The findings suggest that in addition to systemic chemotherapy, cytoreductive surgery may be associated with an overall survival benefit for a selected group of patients with mGC, which warrants further prospective investigation. Before further evidence is obtained, gastrectomy should only be regarded to be experimental for cases with mGC or for palliation purposes among tumors with stomach outlet obstruction.
Recent advancement in chemotherapy has contributed to great regression of tumor in some patients with initially inoperable mGC and might render them resectable after a good response.3,4 While the pre-surgical management may improve resectability through down-staging cancer, it may as well allow abundant time for further development of more advanced tumors or even distant metastases.
The decreasing rates of resection may suggest the increasingly stricter criteria of selecting candidates for resection, which potentially leads to more favorable outcomes for patients undergoing gastrectomy. Recent advancement in diagnostics has made the identification of cases with metastatic cancer more efficient and therefore they less frequently received aggressive management.28,29 Improvements in imaging, increase in use of diagnostic laparoscopy and of peritoneal washings may account for some of the trends, and more patients who were previously thought to have locoregional disease are now considered to have metastatic disease and may not be considered for surgical treatment.
Compared with cases with non-metastatic cancer, 16 those with mGC were younger and more often had cardia and poorly-differentiated or undifferentiated cancers, which more frequently involved adjacent structures and/or lymph nodes. The associations of resection with patient and cancer factors in mGCs were similar to those in non-metastatic diseases. 16 Older ages (especially ⩾70 years) and cardia cancers (especially when compared with antrum/pylorus cancers) were found to be significantly associated with less frequent resection. Before starting management for older individuals who are more often frailer and who have more frequent comorbidities and anticipated post-treatment morbidities or mortalities, generally it would be helpful to perform geriatric evaluation taking the overall conditions and expected lifespan into account. Distal cancers may be more frequently associated with obstructive symptoms which could not be easily managed by less aggressive measures like feeding tube, rendering them more frequent candidates for resection. Furthermore, proximal cancers could be more surgically challenging especially concerning anastomosis after resection. 30 Tumors with adjacent structures invasion were mostly less frequently resected, possibly because of the difficulty of surgery. Patients with SRCs, a quickly increasing patient group with inferior survival outcomes, have been revealed as inherently less sensitive to chemotherapy.31–33 Metastatic SRCs were more frequently operated in certain countries, and the disparities across countries might be influenced by variations in SRC classification. The discrepant strengths and patterns of the correlations of treatment with patient and cancer features across countries underline the greatly differing clinical practice and the necessity for further clarification of the definitive role of resection in mGCs.
This difference in clinical practice could be explained in part by a lack of a uniform definition for cases with limited (oligo)metastatic cancer who are potentially suitable candidates for surgery. This lack of consensus is addressed by the OligoMetastatic Esophagogastric Cancer (OMEC) project, a multidisciplinary project endorsed by ESMO, IGCA, EORTC, ESTRO, ESSO, and ESDE which will establish a European multidisciplinary consensus statement for esophagogastric cancer with limited (oligo)metastasis (www.OMECproject.eu).
Our observational study has some limitations. National registry-based studies are particularly prone to unavoidable selection bias due to the retrospective nature. Among patients with mGCs, those with better performance status might be more likely to receive gastric resection. In our observational, population-based study of multiple nationwide European cancer registries and the US SEER-18 database, information on the Eastern Cooperative Oncology Group (ECOG) performance status or number of comorbidities for mGC was not available or had large proportions of missing values which prohibited a meaningful analysis in most registries, and was hence not included in the multivariable analyses; however, performance status and comorbidities might be important confounders that might impact the multivariable findings. The potential subtle differences in patients’ demographics between countries might in part account for the varying resection trends. Being aware of this, we first showed the resection rates standardized by age, and further the multivariable-adjusted associations of year of diagnosis with resection. The relatively small proportion of cardia cancers in Estonia might be a factor impacting the overall trend of resection. Accordingly, we further looked into the multivariable-adjusted trends as revealed by the associations of year of diagnosis with resection, overall (Table 2) and in subgroups stratified by factors including tumor location (Table 3), and after adjustment for multiple variables including tumor location, resection trends remained similar both overall and in stratified analyses. Various studies on resection of the primary tumor and isolated metastases in mGC including the GYMSSA trial34,35 evaluating gastrectomy plus metastasectomy followed by chemotherapy in oligometastatic GC highlight the importance to distinguish patients with different metastatic burdens especially between those with multiple non-resectable metastases and those with potentially resectable oligometastatic GC. In our population-based study only data on metastasis to bone, brain, liver, or lung were available in the US (since 2010) and the Netherlands (Table 1), and more specific information on metastatic burden (single resectable distant metastasis, oligometastatic disease, or multiple metastases) or number of metastases could not be derived from the current available information also considering that there might be distant metastases to other sites the information on which was not available. We focused on the application of resection; information on the use of modern systemic (including targeted) therapies, expensive palliative endoscopic treatment (stents), and diagnostic/staging laparoscopy, which is interesting to further investigate, was not available or had low sensitivity making this information not suitable for such pattern and trend association analyses across countries.
Registration quality may vary. Some variables (e.g., differentiation) were not incorporated into models considering the relatively large proportions of unknown data. Data were not pooled, given the possible heterogeneity; they were separately analyzed, shown, and interpreted for each individual registry. In some countries certain variables were not registered. Information on metastatic site was only available in the registries of the US (since 2010) and the Netherlands. Nevertheless, regardless of metastatic site, GCs with distant metastasis were recognized as unresectable disease across guidelines.9,29,36 Notably, in Estonia, the proportion of cardia tumor was relatively low (14%), and SRC was commonly reported (31%). While this might indicate the varying disease patterns in different parts of Europe, possible discrepancies in registry and clinical practices may as well have some roles, highlighting the significance of further standardization. The study periods were not completely the same. Nonetheless, the time period 2003/2004–2013/2014 were mostly covered, and diagnosis year was included in all the multivariable-adjusted modelling. In addition, our study was limited to Europe and the US, and the findings might not be generalizable to the other countries, particularly those in East Asia in which the GC incidence rate is higher.
Of note, the greatest number of mGCs ever studied, consistently coded variables across multiple population-based nationwide cancer registries, strict quality control, careful selection of cases, and valid standardized statistics enable our work to present informative and important findings concerning care for mGC. Our report may aid to identify discrepancies in clinical practices and offer new pivotal references for making effective strategies for management of GC at the population level, which has possible pivotal relevance for guiding appropriate resource allocation and healthcare policymaking in Europe and the US.
Conclusions
In Europe and the US patterns and trends of resection largely varied across countries for mGCs, which mostly underwent less often primary cancer-directed resection in the early 21st century. Various variables were identified to be associated with resection, with greatly varying patterns and strengths of associations across countries. Our findings highlight the great need for further clarifying the role of resection in mGCs to enhance standardization of care.
Supplemental Material
Supplemental material, sj-pdf-1-tam-10.1177_17588359211027837 for Largely varying patterns and trends of primary cancer-directed resection for gastric carcinoma with synchronous distant metastasis in Europe and the US: a population-based study calling for further standardization of care by Lei Huang, Lina Jansen, Rob H.A. Verhoeven, Jelle P. Ruurda, Liesbet Van Eycken, Harlinde De Schutter, Jan Johansson, Mats Lindblad, Tom B. Johannesen, Vesna Zadnik, Tina Žagar, Margit Mägi, Sjoerd M. Lagarde, Esther Bastiaannet, Cornelis J.H. van de Velde, Petra Schrotz-King and Hermann Brenner in Therapeutic Advances in Medical Oncology
Acknowledgments
We are very grateful to the European Registration of Cancer Care (EURECCA) group for their great support and to the staff in Surveillance, Epidemiology, and End Results Program (SEER), Netherlands Cancer Registry (NCR), Belgian Cancer Registry (BCR), Swedish Cancer Registry (SCR), Cancer Registry of Norway (CRN), Cancer Registry of Slovenia (CRS), and Estonian Cancer Registry (ECR) for their kind work in data collection and delivery.
Footnotes
Authors’ contributions: Conception or design: Huang L, Jansen L, Brenner H.
Acquisition, analysis, or interpretation of data: Huang L, Jansen L, Verhoeven R, Ruurda J, Van Eycken L, De Schutter H, Johasson J, Lindblad M, Johannesen T, Zadnik V, Zagar T, Mägi M, Bastiaannet E, Lagarde S, van de Velde C, Schrotz-King P, Brenner H.
Drafting of the manuscript: Huang L.
Critical revision of the manuscript for important intellectual content: Jansen L, Verhoeven R, Ruurda J, Van Eycken L, De Schutter H, Johasson J, Lindblad M, Johannesen T, Zadnik V, Zagar T, Mägi M, Bastiaannet E, Lagarde S, van de Velde C, Schrotz-King P, Brenner H.
Statistical analysis: Huang L.
Administrative, technical, or material support: van de Velde C, Brenner H.
All authors have given final approval of the manuscript for submission and publication.
Conflict of interest statement: The authors declare that there is no conflict of interest.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by the German Cancer Aid (Deutsche Krebshilfe, #111365). The funder had no involvement in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Ethics approval and consent to participate: This study was approved by the Ethics Committee of the Medical Faculty Heidelberg. Consent was waived considering the anonymous, observational, population-based, and registry-based nature. No individual patient data were reported.
Consent for publication: Not applicable.
ORCID iD: Lei Huang 
https://orcid.org/0000-0002-4225-9200
Availability of data and materials: The data that support the findings of this study are available from each participating registry, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.
Supplemental material: Supplemental material for this article is available online.
Contributor Information
Lei Huang, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany; Dr. Lei Huang is the lead contact for this work.
Lina Jansen, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Rob H.A. Verhoeven, Department of Research, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands Department of Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands.
Jelle P. Ruurda, Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
Liesbet Van Eycken, Belgian Cancer Registry (BCR), Brussels, Belgium.
Harlinde De Schutter, Belgian Cancer Registry (BCR), Brussels, Belgium.
Jan Johansson, Department of Esophageal and Gastric Surgery, Lund University Hospital, Lund, Sweden.
Mats Lindblad, Department of Clinical Science, Intervention, and Technology (CLINTEC), Division of Surgery, Karolinska University Hospital, Stockholm, Sweden.
Tom B. Johannesen, Registry Department, The Cancer Registry of Norway (CRN), Oslo, Norway
Vesna Zadnik, Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Tina Žagar, Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Margit Mägi, Estonian Cancer Registry, National Institute for Health Development, Tallinn, Estonia.
Sjoerd M. Lagarde, Department of Surgery, Erasmus MC-University Medical Centre Rotterdam, Rotterdam, The Netherlands
Esther Bastiaannet, Department of Surgical Oncology, Leiden University Medical Center, The Netherlands.
Cornelis J.H. van de Velde, Department of Surgical Oncology, Leiden University Medical Center, The Netherlands
Petra Schrotz-King, Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
Hermann Brenner, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, Baden-Württemberg 69120, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
References
- 1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394–424. [DOI] [PubMed] [Google Scholar]
- 2. Thrumurthy SG, Chaudry MA, Hochhauser D, et al. The diagnosis and management of gastric cancer. BMJ 2013; 347: f6367. [DOI] [PubMed] [Google Scholar]
- 3. Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010; 3: CD004064. [DOI] [PubMed] [Google Scholar]
- 4. Bouche O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study–FFCD 9803. J Clin Oncol 2004; 22: 4319–4328. [DOI] [PubMed] [Google Scholar]
- 5. Chau I, Norman AR, Cunningham D, et al. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer–pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004; 22:0 2395–2403. [DOI] [PubMed] [Google Scholar]
- 6. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. J Clin Oncol 2006; 24: 4991–4997. [DOI] [PubMed] [Google Scholar]
- 7. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008; 358: 36–46. [DOI] [PubMed] [Google Scholar]
- 8. Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2017; 8: CD004064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer 2017; 20: 1–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Coccolini F, Cotte E, Glehen O, et al. Intraperitoneal chemotherapy in advanced gastric cancer. Meta-analysis of randomized trials. Eur J Surg Oncol 2014; 40: 12–26. [DOI] [PubMed] [Google Scholar]
- 11. Zhang JZ, Lu HS, Huang CM, et al. Outcome of palliative total gastrectomy for stage IV proximal gastric cancer. Am J Surg 2011; 202: 91–96. [DOI] [PubMed] [Google Scholar]
- 12. Warschkow R, Baechtold M, Leung K, et al. Selective survival advantage associated with primary tumor resection for metastatic gastric cancer in a Western population. Gastric Cancer 2018; 21: 324–337. [DOI] [PubMed] [Google Scholar]
- 13. Yang LP, Wang ZX, He MM, et al. The survival benefit of palliative gastrectomy and/or metastasectomy in gastric cancer patients with synchronous metastasis: a population-based study using propensity score matching and coarsened exact matching. J Cancer 2019; 10: 602–610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Li Q, Zou J, Jia M, et al. Palliative gastrectomy and survival in patients with metastatic gastric cancer: a propensity score-matched analysis of a large population-based study. Clin Transl Gastroenterol 2019; 10: 1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. de Gara CJ, Hanson J, Hamilton S. A population-based study of tumor-node relationship, resection margins, and surgeon volume on gastric cancer survival. Am J Surg 2003; 186: 23–27. [DOI] [PubMed] [Google Scholar]
- 16. Huang L, Jansen L, Balavarca Y, et al. Decreasing resection rates for nonmetastatic gastric cancer in Europe and the United States. Clin Transl Med 2020; 10: e203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Huang L, Jansen L, Balavarca Y, et al. Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. Gut 2019; 68: 130–139. [DOI] [PubMed] [Google Scholar]
- 18. Surveillance, Epidemiology, and End Results (SEER) Program. Research Data (1973-2016), National Cancer Institute, DCCPS, Surveillance Research Program, https://seer.cancer.gov/ (2019, accessed 30 May 2018).
- 19. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol 2005; 162: 199–200. [DOI] [PubMed] [Google Scholar]
- 20. Muro K, Van Cutsem E, Narita Y, et al. Pan-Asian adapted ESMO clinical practice guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann Oncol 2019; 30: 19–33. [DOI] [PubMed] [Google Scholar]
- 21. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27: 1386–1422. [DOI] [PubMed] [Google Scholar]
- 22. Yoshino T, Arnold D, Taniguchi H, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol 2018; 29: 44–70. [DOI] [PubMed] [Google Scholar]
- 23. Mezhir JJ, Shah MA, Jacks LM, et al. Positive peritoneal cytology in patients with gastric cancer: natural history and outcome of 291 patients. Ann Surg Oncol 2010; 17: 3173–3180. [DOI] [PubMed] [Google Scholar]
- 24. Fujitani K, Yang HK, Mizusawa J, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol 2016; 17: 309–318. [DOI] [PubMed] [Google Scholar]
- 25. D’Ugo D, Cananzi FC, Persiani R, et al. REGATTA trial: a call for the USA and Europe. Lancet Oncol 2016; 17: 261–262. [DOI] [PubMed] [Google Scholar]
- 26. Al-Batran SE, Homann N, Pauligk C, et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 trial. JAMA Oncol 2017; 3: 1237–1244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Berger Y, Giurcanu M, Vining CC, et al. Cytoreductive surgery for selected patients whose metastatic gastric cancer was treated with systemic chemotherapy. Ann Surg Oncol. Epub ahead of print 8 January 2021. DOI: 10.1245/s10434-020-09475-6. [DOI] [PubMed] [Google Scholar]
- 28. Kwee RM, Kwee TC. Imaging in local staging of gastric cancer: a systematic review. J Clin Oncol 2007; 25: 2107–2116. [DOI] [PubMed] [Google Scholar]
- 29. Ajani JA, D’Amico TA, Almhanna K, et al. Gastric cancer, version 3.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2016; 14: 1286–1312. [DOI] [PubMed] [Google Scholar]
- 30. Sasako M, Sano T, Yamamoto S, et al. Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial. Lancet Oncol 2006; 7: 644–651. [DOI] [PubMed] [Google Scholar]
- 31. Messager M, Lefevre JH, Pichot-Delahaye V, et al. The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study. Ann Surg 2011; 254: 684–693; discussion 93. [DOI] [PubMed] [Google Scholar]
- 32. Heger U, Blank S, Wiecha C, et al. Is preoperative chemotherapy followed by surgery the appropriate treatment for signet ring cell containing adenocarcinomas of the esophagogastric junction and stomach? Ann Surg Oncol 2014; 21: 1739–1748. [DOI] [PubMed] [Google Scholar]
- 33. Charalampakis N, Nogueras Gonzalez GM, Elimova E, et al. The proportion of signet ring cell component in patients with localized gastric adenocarcinoma correlates with the degree of response to pre-operative chemoradiation. Oncology 2016; 90: 239–247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Rudloff U, Langan RC, Mullinax JE, et al. Impact of maximal cytoreductive surgery plus regional heated intraperitoneal chemotherapy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric origin: results of the GYMSSA trial. J Surg Oncol 2014; 110: 275–284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Kerkar SP, Kemp CD, Duffy A, et al. The GYMSSA trial: a prospective randomized trial comparing gastrectomy, metastasectomy plus systemic therapy versus systemic therapy alone. Trials 2009; 10: 121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Smyth EC, Verheij M, Allum W, et al. Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27: v38–v49. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material, sj-pdf-1-tam-10.1177_17588359211027837 for Largely varying patterns and trends of primary cancer-directed resection for gastric carcinoma with synchronous distant metastasis in Europe and the US: a population-based study calling for further standardization of care by Lei Huang, Lina Jansen, Rob H.A. Verhoeven, Jelle P. Ruurda, Liesbet Van Eycken, Harlinde De Schutter, Jan Johansson, Mats Lindblad, Tom B. Johannesen, Vesna Zadnik, Tina Žagar, Margit Mägi, Sjoerd M. Lagarde, Esther Bastiaannet, Cornelis J.H. van de Velde, Petra Schrotz-King and Hermann Brenner in Therapeutic Advances in Medical Oncology