http://www.kankerregistratie.nl 1 2 4 2 4 3 5 6 7 9 10 11 12 13 14 Few studies, if any, have attempted to relate esophageal cancer patient survival to surgeon expertise or hospital volume. To remedy this, in this study, we assessed the effect of surgeon-related expertise and hospital volume on the relative survival of operated esophageal cancer patients. We compared data from university, teaching nonuniversity, and nonteaching hospitals. PATIENTS AND METHODS Patients All patients diagnosed with a primary invasive esophageal cancer in the region of the Comprehensive Cancer Centre North-Netherlands (CCCN) between January 1994 and January 2002 were eligible for entry onto the study. Patients with a history of cancer other than nonmelanoma skin cancer were excluded. The patients were selected through the population-based Regional Cancer Registry of the CCCN, which covers the northern part of the Netherlands, a mainly rural area with a population of approximately 2.1 million. The area is served by 17 community hospitals, 3 of which are teaching hospitals and 1 of which is a university hospital; the hospitals include four radiotherapy departments and seven pathology laboratories. Data Collection by the Regional Cancer Registry 15 16 In the Netherlands, the population registries of the municipality contain information on the vital status of their inhabitants. Vital status was established either through information derived from the patient’s medical records or through linkage of cancer registry data with information from the population registries of the municipality within the registry areas or through linkage with the national death registry of the Central Bureau of Genealogy. The regional cancer registry of the CCCN checked vital status by active record linkage with municipal population registries in 2002–2003 and 2005 and with the national death registry of the Central Bureau of Genealogy in 2004. Guidelines for Staging and Treatment By establishing multidisciplinary teams and cancer networks, the CCCN strives to improve the quality of cancer care. Within the CCCN area tumor working groups, comprising delegated specialists representing all regional hospitals, that have been developing and revising guidelines on diagnosis and treatment. The regional guidelines for esophageal cancer were based on the international TNM classification according to the International Union Against Cancer in use at that time. Statistics and Definitions of Variables 2 http://www.statline.cbs.nl 17 18 Variables included in the final model were age (<50, 50–59, 60–69, >70), stage based on collapsed TNM data (stage 1,2a, 2b, 3/4, unknown), hospital volume (<20 patients operated, ≥20 patients operated), frequency of referral (high referral [>33.3%], low referral [≤33.3%]), and time since diagnosis (1-year intervals). The pathological stage was used whenever possible; in the absence of information about the pathological stage, the clinical stage was used. RESULTS TABLE 1. Characteristics of operated and nonoperated patients with esophageal cancer diagnosed 1994–2002 Characteristic Total Operated Nonoperated P N % n % n % Sex .465 Male 796 69.1 152 71.4 644 68.6  Female 353 30.9 61 28.6 292 31.2  Histology <.001 Squamous cell carcinoma 415 36.1 62 29.1 353 37.7  Adenocarcinoma 592 51.6 140 65.7 453 48.4  Other 141 12.3 11 5.2 130 13.9  Tumor location <.001 Upper thoracic 82 7.1 3 1.4 79 8.4  Middle thoracic 210 18.3 36 16.9 174 18.6  Lower thoracic 770 67.0 169 79.3 601 64.2  Overlapping and unspecified 87 7.6 5 2.3 82 8.8  Age at diagnosis (y) <.001 <50 86 7.5 24 11.3 62 6.6  50–59 221 19.2 67 31.5 154 16.5  60–69 319 27.8 80 37.6 239 25.5  70+ 523 45.5 42 19.7 481 51.4  Stage <.001 1 52 4.5 32 15.0 20 2.1  2A 174 15.1 65 30.5 109 11.7  2B 69 6.0 26 12.2 43 4.6  3 207 18.0 74 34.7 133 14.2  4 316 27.5 8 3.8 308 32.9  Unknown 331 28.8 8 3.8 323 34.5  Total 1149 100.0 213 100.0 935 100.0  1 P P 1 P P P P 2 TABLE 2. Referral pattern for esophageal cancer surgery per hospital in the North-Netherlands, 1994–2002 Hospital Operated in hospital of diagnosis, n (%) Referred for surgery, n (%) Total (n) High-referral nonteaching hospitals  20 (20.8) 76 (79.2) 96 Hospital A – 2 (100.0) 2 Hospital B – 3 (100.0) 3 Hospital C – 3 (100.0) 3 Hospital D – 9 (100.0) 9 Hospital E 2 (11.8) 15 (88.2) 17 Hospital F 1 (14.3) 6 (85.7) 7 Hospital G 3 (18.8) 13 (81.3) 16 Hospital H 3(25.0) 9 (75.0) 12 Hospital I 3 (30.0) 7 (70.0) 10 Hospital J 1 (33.3) 2 (66.7) 3 Hospital K 1 (33.3) 2 (66.7) 3 Hospital L 6 (54.5) 5 (45.5) 11 Low-referral nonteaching hospitals  38 (95.0) 2 (5.0) 40 Hospital M 27 (93.1) 2 (6.9) 29 Hospital N 11 (100.0) – 11 High-referral teaching, nonuniversity hospitals 7 (36.8) 12 (63.2) 19 Hospital O 7 (36.8) 12 (63.2) 19 Low-referral teaching, nonuniversity hospitals 43 (87.8) 6 (12.2) 49 Hospital P 24 (82.8) 5 (17.2) 29 Hospital Q 19 (95.0) 1 (5.0) 20 Low-referral university hospital 9 (100.0) – 9 Hospital R 9 (100.0) – 9  117 (54.9) 96 (45.1) 213 3 P P P TABLE 3. Characteristics for operated esophageal cancer patients diagnosed 1994–2002, according to hospital of surgery Characteristic Total Teaching, nonuniversity University Nonteaching P N % n % n % n % Stage Stage 1 32 15.5 12 20.0 14 14.7 6 10.3 a Stage 2A 65 26.8 18 38.3 23 25.3 24 31.0  Stage 2B 26 12.2 8 13.3 12 12.6 6 10.3  Stage 3 + 4 82 38.5 16 26.7 39 41.1 27 46.6  Unknown 8 7.0 1 1.7 6 6.3 1 1.7  Age at diagnosis (y) <50 24 11.3 8 13.3 13 13.7 3 5.2 .230 50–59 67 31.5 16 26.7 36 37.9 15 25.9  60–69 80 37.6 25 41.7 30 31.6 25 43.1  70+ 42 19.7 11 18.3 16 16.8 15 25.9  Histology Squamous cell carcinoma 62 29.1 21 35.0 27 28.4 14 24.1 .606 Adenocarcinoma 140 65.7 35 58.3 63 66.3 42 72.4  Other 11 5.2 4 6.7 5 5.3 2 3.4  Tumor location Upper and middle thoracic 39 18.3 13 21.7 17 17.9 9 15.5 .130 Lower thoracic 169 79.3 47 78.3 73 76.8 49 84.5  Not stated 5 2.3 – – 5 5.3 – –  Total 213 100.0 60 100.0 95 100.0 58 100.0  a 1 4 P FIG. 1. Cumulative relative survival of patients operated for esophageal cancer diagnosed during 1994–2002 according to hospital type.  TABLE 4. Overall and relative 5-year survival and estimated excess risk (RER) of death with 95% confidence intervals (95% CI) for operated esophageal cancer patients diagnosed 1994–2002 Characteristic N OS (5 y) RS (5 y) OD (5 y) Univariate Multivariate 95% CI P ED (5 y) a 95% CI a Stage <.0001 Stage 1  32 87.5% 99.1% 4 3.1 .06 .01–.32 .05 .01–.22  Stage 2A 65 46.1% 52.4% 33 3.9 .44 .27–.70 .39 .24–.63  Stage 2B 26 21.8% 24.7% 19 1.1 .75 .43–1.29 .72 .40–1.27  Stage 3+4 (reference) 82 14.2% 14.5% 65 1.6 1.00  1.00   Unknown 8 16.7% 18.0% 6 .2 .99 .41–2.35 1.62 .65–4.01  Hospital type .0126 Nonteaching (reference) 58 24.9% 27.3% 40 2.3 1.00  1.00   Teaching nonuniversity 60 29.7% 32.6% 39 1.9 .89 .55–1.42 1.32 .79–2.22  University 95 44.3% 49.2% 48 5.6 .48 .30–.77 .57 .29–1.12  Age (y) .0467 <50 (reference) 24 47.6% 48.6% 11 .2 1.00  1.00   50–59 67 32.1% 33.6% 42 1.2 1.73 .87–3.44 1.51 .74–3.04  60–69 80 30.9% 35.1% 52 3.5 2.12 1.07–4.18 2.36 1.18–4.70  70+ 42 41.9% 54.5% 22 4.9 1.42 .64–3.14 2.05 .94–4.46  Hospital volume .1125 <20 patients operated 38 19.0% 22.3% 27 1.3 1.00  1.00   ≥20 patients operated 175 37.8% 41.7% 100 8.5 .53 .33–.83 .62 .34–1.12  Referral rate  .8080 High (>33.3%) 115 35.4% 39.2% 66 5.2 1.00  1.00   Low (≤ 33.3%)  98 34.1% 37.8% 61 4.6 1.16 .79–1.69 .94 .57–1.54  OS, overall survival; RS, relative survival; OD, observed deaths; ED, expected deaths. a 4 P 5 TABLE 5. Adjuvant therapies for patients operated for esophageal cancer diagnosed 1994–2002, according to hospital of treatment Treatment Nonteaching Teaching, nonuniversity University Total n % n % N % N % Surgery 57 98.3 58 96.7 79 83.2 194 91.1 Surgery + radiotherapy 1 1.7 – – 5 5.3 6 2.8 Surgery + chemotherapy – – 2 3.3 11 11.6 13 6.1 Total 58 100.0 60 100.0 95 100.0 213 100.0 DISCUSSION 10 8 11 19 19 12 2 To minimize the eventual effect of any residual selection referral, the relative survival rate was adjusted for case mix, despite there being no statistically significant differences in the distribution of age, stage, and sex between the different types of hospital. One may suggest that patients who underwent esophagectomy in the university hospital were mostly referred for treatment, thus adding a delay before surgery. A consequence could be that these patients had thus a slightly longer preoperative survival time, estimated to be between 2 and 4 weeks in our study. This short delay could mean that prognostically worse patients scheduled for surgery eventually fall out of the surgery category through disease progression during the delay period. However, little is known in the literature about the effect of longer preoperative delays on surgical outcome or eligibility in esophageal cancer. Although patients with advanced disease may miss surgery through stage progression, patients who do end up having surgery also progress, meaning the university hospital operates on patients with more advanced disease. This should negatively influence the survival outcome and would not explain the better performance by the university hospital. Furthermore, even if we were very conservative and excluded all patients who died in the first 3 months of our study, the university hospital still performs far better than teaching nonuniversity and nonteaching hospitals. So although we cannot discount early mortality as a factor in survival, we think that it is unlikely that the difference in performance can be fully explained by this. We had no information about the operative procedure that had been performed. Treatment guidelines indicated a curative surgical approach for tumors encompassing ≤5 cm of the length of the esophagus, as based on ultrasonographic or radiological examination. Surgical resection could be attempted for tumors 5–8 cm in length. For this last group, neoadjuvant chemotherapy, which was provided in the university hospital after proof of locally advanced disease, could be attempted to improve resectability. For adenocarcinomas, a transthoracoabdominal approach with two-field lymphadenectomy was advised, combining a midline laparotomy and a right-sided thoracotomy. Alternatively a transhiatal blind esophagectomy could be performed with a cervical esophagogastrostomy. For distal adenocarcinomas without Barrett dysplasia, a left-sided thoracotomy with intrathoracic anastomosis was an alternative approach. 14 20 21 22 25 26 27 28 29 We found a tentative relationship between higher volume and a better relative survival. However, this issue still is a debatable problem in determining treatment guidelines. Therefore, we suggest that guidelines concerning specific referral of esophageal cancer patients should be based on hospital outcomes, preferably in experienced centers, rather than on annual numbers of procedures as long as the factor that is determining patient survival is still unknown. 7 30 9 14 31 P 32 7 9 9 33 In conclusion, we demonstrated that in our region, the relative survival for patients operated on for esophageal cancer is better in the university hospital compared with teaching nonuniversity and nonteaching hospitals, emphasizing the need for referral to centers focused on the treatment of esophageal cancer. The underlying parameter for the observed difference remains unclear. We suggest that centers at least periodically review the morbidity and mortality rates of esophageal resections to assess their outcome and the possibility of referral. Eligibility for centers focused on esophageal cancer treatment should therefore be based on patient outcomes rather than on patient numbers.