Data were obtained from the nationwide Netherlands Cancer Registry (NCR), which routinely collects information on all newly diagnosed cancer cases in the Netherlands since 1989. Quality and completeness of the data are high7. In the NCR, topography and morphology are coded
according to the International Classification of Diseases for Oncology (ICD-O). Information about the performed surgical procedure was sub- tracted from the NCR on the basis of topography codes in combination with surgery specific codes. Tumor staging is documented according to the International Union Against Cancer (UICC) TNM classification in use in the year of diagnosis. Follow-up information on vital status was obtained through linkage with the Municipal Personal Records Database. Follow-up information was complete for all patients until February 2016. The NCR Review Board approved this study.
Patients
All patients with a primary adenocarcinoma or squamous cell carcinoma of the stomach (C16.1-16.9) who underwent surgical resection in the Netherlands between 2005 and 2014 were included in this study. Patients with a tumor of the gastro-esophageal junction (GEJ) or cardia (C16.0), and tumors with other/unknown histology were excluded. Patients with
in situ carcinoma or distant metastases, on the basis of the clinical TNM stage were excluded. Patients who underwent surgery abroad were also excluded from the analyses. The NCR does not collect information regard- ing patients’ comorbidities.
Hospital volume
Annual hospital volumes were calculated for three types of cancer resec- tions: the number of resections for primary gastric cancer (C16.1-16.9), the number of resections for primary esophageal cancer (C15.1-C15.9), including tumors of the gastro esophageal junction and cardia (C16.0)) and the number of resections for primary pancreatic cancer (C25.1-C25.9). The annual composite hospital volume was defined as the sum of these three upper GI cancer resections, stratified in tertiles (<15 resections per year, 15-39 resections per year, ≥40 resections per year).
Statistical analysis
Differences between patient, tumor and treatment characteristics for the composite hospital volume categories were described using frequency tables. Categorical variables were compared using chi-square tests. Sta- tistical significance was set at a threshold of 0.05, with p values calculated by two-sided tests. A univariable analysis was performed to determine the correlation between the composite hospital volume and lymph node yield, and between the composite hospital volume and 30-day mortality. A minimum of 15 lymph nodes in the resected specimen was chosen as a cut off value based on both national and international guidelines8,9. The
composite hospital volume effect for 30-day mortality was also analyzed using a multivariable logistic regression model, adjusted for sex, age, socio economic status (SES) and tumor stage. The pathological TNM stage was used for patients who did not receive preoperative treatment. For all other patients, the clinical TNM stage was used. Overall survival (OS) was calculated from the day of surgery until death. Differences in sur-
vival estimates for the three composite hospital volume categories were tested, both univariable using a log rank test, and multivariable with a Cox proportional hazards model, adjusted for sex, age, SES and tumor stage. Statistical analyses were performed in PASW Statistics version 22 (SPSS inc., Chicago, Il, USA).
0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 55% 60% 65% 70% 2005 (n=518) (n=526) 2006 (n=477) 2007 (n=509) 2008 (n=465) 2009 (n=475) 2010 (n=467) 2011 (n=446) 2012 (n=464) 2013 (n=490) 2014
% of gastric cancer resections
year
hospital performing ≥ 20 gastric cancer resections / year
hospital performing ≥ 20 oesophageal cancer resections (incl. cardia) / year
hospital performing ≥ 20 pancreatic cancer resections / year
ASN increases annual volume standard for both esophageal and pancreatic cancer surgery:
≥ 20 resections / hospital.
ASN increases annual volume standard for gastric cancer surgery:
≥ 20 resections / hospital.
ASN introduces an annual volume standard for gastric
cancer surgery: ≥ 10 resections per hospital.
Healthcare Inspectorate introduces volume standard for esophageal cancer surgery:
≥ 10 resections hospital.
Figure 1. Percentage of gastric cancer resections in the Netherlands performed in centers where at least 20 gastric can- cer resections, esophageal cancer resections or pancreatic cancer resections are performed annually.
RESuLTS Patients
Between 2005 and 2014 a total of 4,837 patients underwent a gastric cancer resection in the Netherlands. Differences in patient, tumor and treatment characteristics between the three composite hospital volume groups are displayed in Table 1. Patients with gastric cancer who under- went a resection in a hospital with a high annual composite volume were significantly younger and had a more favorable tumor stage. Perioperative treatment was administered more often in this group of patients and a higher percentage of patients underwent surgery in a university hospital.
Table 1. Patient, tumor, treatment and hospital characteristics Patients with gastric cancer (n=4837)
Annual composite hospital volume (procedures / year) <15 15-39 ≥40 p value n % n % n % Total 1643 100% 1762 100% 1432 100% Sex male 1003 61.0% 1080 61.3% 896 62.6% 0.851 female 640 39.0% 682 38.7% 536 37.4% Age (years) <65 430 26.2% 556 31.6% 511 35.7% <0.001 65-74 531 32.3% 570 32.3% 477 33.3% ≥75 682 41.5% 636 36.1% 444 31.0% mean age 70 69 67
Socio economic status
low 500 30.4% 565 32.1% 497 34.7% 0.009
medium 684 41.6% 699 39.7% 506 35.3%
Table 1. (continued) Patients with gastric cancer (n=4837) Annual composite hospital volume (procedures / year) <15 15-39 ≥40 p value n % n % n % TNM stage group 0-I 595 36.3% 633 35.9% 619 43.3% <0.001 II 356 21.7% 443 25.1% 354 24.7% III 353 21.5% 312 17.7% 215 15.0% IV 155 9.4% 176 10.0% 163 11.4% Unknown 184 11.2% 198 11.2% 81 5.7% Preoperative therapy none 1324 80.6% 1399 79.4% 995 69.5% <0.001 chemotherapy 223 13.6% 271 15.4% 340 23.7% other 96 5.8% 92 5.2% 97 6.8% Postoperative therapy none 1186 72.2% 1200 68.1% 693 48.4% <0.001 chemotherapy 454 27.6% 555 31.5% 717 50.1% other 3 0.2% 7 0.4% 22 1.5% Type of surgery partial gastrectomy 1088 66.2% 1118 63.5% 762 53.2% <0.001 total gastrectomy 483 29.4% 511 29.0% 582 40.6%
gastrectomy and additional resection 65 4.0% 109 6.2% 78 5.4%
other 7 0.4% 24 1.4% 10 0.7% Year of surgery 2005-2006 434 26.4% 542 30.8% 68 4.7% <0.001 2007-2008 452 27.5% 404 22.9% 130 9.1% 2009-2010 360 21.9% 360 20.4% 220 15.4% 2011-2012 279 17.0% 251 14.2% 383 26.7% 2013-2014 118 7.2% 205 11.6% 631 44.1% Hospital type general hospital 1255 76.4% 467 26.5% 130 9.1% <0.001 teaching hospital 381 23.2% 1154 65.5% 652 45.5% university hospital 7 0.4% 141 8.0% 650 45.4%
Table 1. (continued) Patients with gastric cancer (n=4837) Annual composite hospital volume (procedures / year)
<15 15-39 ≥40
p value
n % n % n %
Annual volume upper GI cancer resections (median)
gastric cancer resections 6 10 14
esophageal cancer resections (incl. cardia) 0 8 28
primary pancreatic cancer resections 0 4 23
* Tumor Node Metastasis system (6th edition)
0 50 100 150 200 250 300 350 400 450 500 550 600 2005 (n=518) 2006 (n=526) 2007 (n=477) 2008 (n=509) 2009 (n=465) 2010 (n=475) 2011 (n=467) 2012 (n=446) 2013 (n=464) 2014 (n=490)
Number of gastric caner resections
year
< 15 upper GI cancer resections / year 15 - 39 upper GI cancer resections / year ≥ 40 upper GI cancer resections / year
Figure 2. Number of gastric cancer resections per composite hospital volume category for upper gastrointestinal (GI) cancer resections.
Hospital volume
From 2005 to 2014 the percentage of patients who underwent gastric cancer surgery in a hospital with an annual volume of at least 20 gastric cancer resec- tions, 20 esophageal cancer resections or 20 pancreatic cancer resections per year increased (Figure 1). As a result, the proportion of gastric cancer resec- tions performed in hospitals with an annual composite volume of ≥ 40 upper GI cancer resections also increased during this period from 5.8 per cent (30 procedures) in 2005 to 80 per cent (394 procedures) in 2014 (Figure 2).
Follow-up (years) P<0.05* 5 2 1 0 3 4
Annual composite hospital volume
< 15 upper GI resections / year 15 - 39 upper GI resections / year
40 upper GI resections / year
0 90 Cumulative survival (%) 30 10 20 70 60 50 40 80 100
Figure 3. Association between annual composite hospital volume and overall survival for patients who underwent a resection for gastric cancer. *p<0.05 compared to the reference category (<15 upper GI cancer resections per year).
Composite hospital volume-outcome relations
Results from the univariable analyses on the relation between the composite hospital volume and lymph node yield, 30-day mortality, and overall survival are shown in Table 2 and Figure 3. A high composite hospital volume was significantly associated with a higher lymph node yield, lower 30-day mortality and better overall survival for patients who underwent a gastric cancer resection. Table 3 shows results of the multi- variable analyses. For both 30-day mortality and overall survival statistical significance was lost after adjusting for sex, age, SES and tumor stage, though there was still a trend for better 30-day results in hospitals with a high composite volume. A sub group analysis including only patients in the highest age category (≥75 years) showed a significant association between composite hospital volume and 30-day mortality (Table 4).
Table 2. Composite hospital volume- outcome relations for gastric cancer resections between 2005 - 2014 (univariable analysis)
Patients with gastric cancer (n=4837) Annual composite hospital volume (procedures / year)
<15 15-39 ≥40
p*
n % n % n %
Total 1643 100% 1762 100% 1432 100%
Lymph node yield
< 15 1094 66.6% 1054 59.8% 587 41.0% <0.001 ≥15 495 30.1% 634 36.0% 834 58.2% Unknown 54 3.3% 74 4.2% 11 0.8% 30-day mortality no 1522 92.6% 1654 93.9% 1363 95.2% 0.014 yes 121 7.4% 108 6.1% 69 4.8%
DISCuSSION
During the study period, the number of patients with gastric cancer who underwent a resection in a hospital with an annual volume of at least 20 gastric cancer resections increased substantially. At the same time, there
Table 3. Composite hospital volume- outcome relations for gastric cancer resections between 2005 - 2014 (multivariable analysis)
30-day mortality overall survival
OR 95% CI HR 95% CI
Annual composite hospital volume (procedures / year)
< 15 1.00 1.00 15-39 0.91 0.69-1.20 0.94 0.87-1.02 ≥ 40 0.77 0.56-1.05 0.98 0.89-1.08 Sex male 1.00 1.00 female 0.84 0.65-1.08 0.97 0.90-1.05 Age <65 1.00 1.00 65-74 0.29 0.18-0.45 0.82 0.74-0.91 ≥75 1.93 1.48-2.52 1.43 1.30-1.57 SES low 1.00 1.00 medium 0.84 0.63-1.12 1.03 0.94-1.13 high 1.05 0.78-1.41 1.02 0.93-1.13 TNM stage group* I 1.00 1.00 II 0.83 0.58-1.20 1.97 1.75-2.22 III 1.58 1.14-2.19 3.22 2.86-3.63 IV 2.01 1.37-2.95 5.02 4.32-5.82 unknown 1.96 1.34-2.86 1.57 1.40-1.77
was an increase in the percentage of patients with gastric cancer who underwent a resection in hospitals with an annual volume of 20 or more other upper GI cancer resections, i.e., esophageal (including GEJ tumors) and pancreatic cancer resections. Parallel with this process of centraliza- tion towards upper GI cancer centers, there was a trend for increased overall survival, lower 30-day mortality and a higher lymph node yield for patients who underwent a gastric cancer resection.
Table 4. Composite hospital volume- outcome relations for gastric cancer resections between 2005 - 2014 in elderly patients (≥75 years) only (multivariable analysis)
30-day mortality overall survival
OR 95% CI HR 95% CI
Annual composite hospital volume (procedures / year)
< 15 1.00 1.00 15-39 0.91 0.65-1.29 0.91 0.80-1.02 ≥ 40 0.61 0.40-0.94 0.99 0.86-1.15 Sex male 1.00 1.00 female 0.73 0.53-1.02 0.91 0.81-1.01 SES low 1.00 1.00 medium 0.84 0.58-1.21 1.05 0.92-1.20 high 1.02 0.69-1.51 1.05 0.91-1.21 TNM stage group* I 1.00 1.00 II 0.58 0.35-0.95 1.94 1.66-2.26 III 1.23 0.82-1.86 3.35 2.87-3.91 IV 1.91 1.17-3.14 4.75 3.90-5.79 unknown 1.37 0.85-2.23 1.53 1.26-1.86
Quality assurance is acknowledged as a crucial factor in the oncologi- cal surgical care process10. Therefore it is essential to identify adequate
predictors for good quality of care. The understanding that centralization of major cancer surgery results in better outcomes is based on an implicit association between the hospital volume of a specific surgical procedure and outcomes for this specific procedure (“operation-specific hospital volume”). Hospital volume is considered to act as a proxy measure for various process and provider characteristics like benefits of a qualified multidisciplinary team, facilitated acces to sophisticated tumor imaging methods, availability of skilled surgeons and better postoperative care fa- cilities1,11-15. For example, radiologist experience and CT scan quality play
an important role in the detection of distant metastasis in esophageal and gastric cardia cancer16. Also, intensive care units with a dedicated board
certified staff are associated with lower mortality for some procedures17,18.
Timely recognition and successful management of complications after high-risk cancer surgery might be better in high-volume hospitals19.
Furthermore, large hospital variation was found for the proportion of patients with esphageal cancer that underwent surgery in a center of referral, suggesting all patients should be discussed within a regional mul- tidisciplinary expert panel to define the best treatment options20. These
findings underline the importance of the entire multidisciplinary team for high-quality care of patients who undergo complex surgical procedures such as gastric cancer resections.
Following from the above, it would be reasonable to expect that hospitals performing a particular complex surgical procedure, may benefit from the in-hospital experience with related procedures which involve the same multidisciplinary team and depend on the same hospital facilities. This can be of added value for the quality of care delivered for a related surgi- cal procedure. In other words, skills and expertise derived from one surgi- cal care process may be transferred to other surgical procedures. Such a
relation between overall hospital volume of related surgical procedures (‘composite hospital volume’) and outcomes for gastric cancer resections, has never been investigated before.
In 2004, a study was published investigating the specificity of hospital- volume outcome assciations concluding that volume-outcome asso- ciations are not specific to volume and outcome of the same procedure but rather on the experience with high risk surgery in general in that hospital21. A similar study for surgeon volume was published in 2011
suggesting a positive association between composite surgeon volume and outcomes of open AAA repair22. The present study also suggests a
beneficial association between a high composite volume of complex up- per GI cancer resections (34 or more resections per year) and outcomes for patients undergoing a gastric cancer resection. This confirms that besides surgical volume other factors, e.g. hospital facilities, or timely recognition of complications determine outcome, since the surgeon who performs gastric and esophageal cancer resections is not necessarlily also perform- ing pancreatectomies.
For this study, a clinical database was used with highly reliable data covering a ten-year period of gastric cancer surgery in the Netherlands (4837 patients). Results of this study show that patients who seek care at low-volume (general) hospitals are older compared to patients seeking care at high-volume (university) hospitals. Similar findings have been described for pancreatic cancer surgery in the Netherlands 23. Elderly
patients seem less likely to take an active role in the treatment decision- making process 24. Additionally, one may speculate that elderly patients
prefer treatment in a nearby hospital out of convenience e.g. because of shorter travel distances or because they already receive treatment in the specific hospital for other medical conditions. Also, referral patterns may differ by age at the level of general practitioners (before the first hospital
visit) low-volume (general) hospitals. A sub analysis including all patients in the highest age category (≥75 years) showed a significant association between composite hospital volume and 30-day mortality. Therefore, centralization of gastric cancer surgery should not only stimulate referral of younger patients to high-volume hospitals as elderly patients might specifically benefit from this.
This study also has its limitations. Outcomes were adjusted for patient and tumor characteristics, increasing the reliability of the results. Because the NCR does not collect information on comorbidity, SES was used as a proxy for overall health status, including comorbidity. However, results of this study show no association between SES and the outcome of interest. Sec- ondly, since composite hospital volume is a relatively new concept, not yet used in clinical practice, cutt of points for different volume categories were defined using tertiles. This way, cutt offs were made as objective as possible. When dividing volume categories based on quartiles or quin- tiles, no differences in outcomes were observed (data not shown). Finally, the composite hospital volume also includes the number of gastic cancer resections. To ensure the results could not solely be ascribed to a higher annual volume of gastric cancer resections, the same analyses were per- formed excluding the number of gastric cancer resections. No relevant changes in the results were found (data not shown).
The results of this study suggest that composite hospital volume may be a valid proxy for the quality of surgical care for patients with gastric cancer. In practice, this might lead to the introduction of composite hospital vol- ume standards replacing procedure-specific hospital volume standards. Special attention needs to be payed to elderly patients, as centralization of gastric cancer surgery should not only stimulate referral of younger patients to hospitals with higher volumes. Finally, centralization towards
Upper GI cancer centers might also benefit patients with GEJ tumors since the choice of surgical strategy for this group of patients is controversial. In the Netherlands, an increasing number of gastric cancer resections is performed in hospitals that are high volume centers for esophageal cancer resections and pancreatic cancer resections. Experience with these complex upper GI cancer resections may be associated with better post- operative outcomes following gastric cancer resections. Referral of elderly patients to high volume centers might further improve gastric cancer care in the Netherlands.
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