M A G Elferink
email: m.elferink@ikno.nl

P Krijnen
email: p.krijnen@ikw.nl

M W J M Wouters

V E P P Lemmens
email: v.lemmens@ikz.nl

M L E A Jansen-Landheer

C J Van De Velde
email: c.j.h.van_de_velde@lumc.nl

J A Langendijk
email: j.a.langendijk@rt.umcg.nl

C A M Marijnen
email: c.a.m.marijnen@lumc.nl

S Siesling
email: s.siesling@ikno.nl

R A E M Tollenaar
email: r.a.e.m.tollenaar@lumc.nl

P O Box

Variation in treatment and outcome of patients with rectal cancer

Keywords: rectal cancer, guidelines, hospital characteristics, treatment, survival

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Worldwide, there is an increasing interest in variations in quality of cancer care. Many authors reported on differences in quality of care between hospitals analyzing the effects of differences in volume and specialization on patient outcome. [START_REF] Birkmeyer | Hospital volume and surgical mortality in the United States[END_REF][START_REF] Birkmeyer | Surgeon volume and operative mortality in the United States[END_REF][START_REF] Chowdhury | A systematic review of the impact of volume of surgery and specialization on patient outcome[END_REF] Only a few studies revealed differences regarding other aspects of the care process, such as compliance to (national) guidelines.

In the Netherlands, colorectal cancer is the second most common cause of cancer. In 2007, almost 12 000 patients were diagnosed with colorectal cancer of which approximately 3,300 included patients with rectal cancer. [START_REF]Comprehensive Cancer Centres[END_REF] In the same year, about 1,000 patients died of rectal cancer. [5] In the Netherlands, an improvement in survival of patients with rectal cancer has been demonstrated due to changes in treatment strategies, [START_REF] Den Dulk | Improved overall survival for patients with rectal cancer since 1990: the effects of TME surgery and pre-operative radiotherapy[END_REF][START_REF] Martijn | Improved survival of patients with rectal cancer since 1980: a population-based study[END_REF] including the wide clinical implementation of total mesorectal excision (TME) together with a shift from postoperative to preoperative radiotherapy.

According to the current Dutch treatment guidelines, preoperative radiotherapy is recommended for patients with clinical T2-T3 tumours, while in case of locally advanced tumours preoperative chemoradiation is preferred.[8] However, large interhospital variation in the use of radiotherapy was reported in a regional population-based study. [START_REF] Vulto | Population-based study of trends and variations in radiotherapy as part of primary treatment of cancer in the southern Netherlands between 1988 and 2006, with an emphasis on breast and rectal cancer[END_REF] Limited data exist on differences in treatment patterns of patients with rectal cancer and to what extent these differences could be explained by differences in hospital characteristics. Several studies revealed an association between high volume and better outcome after surgery for several cancers, such as cancer of the pancreas, esophagus and lung. [START_REF] Birkmeyer | Hospital volume and surgical mortality in the United States[END_REF][START_REF] Birkmeyer | Surgeon volume and operative mortality in the United States[END_REF][START_REF] Hannan | The influence of hospital and surgeon volume on inhospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer[END_REF][START_REF] Van Heek | Hospital volume and mortality after pancreatic resection: a systematic review and an evaluation of intervention in the Netherlands[END_REF][START_REF] Wouters | High-volume versus low-volume for esophageal resections for cancer: the essential role of case-mix adjustments based on clinical data[END_REF] However, the association between volume and outcome for rectal cancer surgery is not that clear: some reported lower postoperative mortality or better overall survival in patients who were operated in a high-volume hospital, while others did not find such relationship. [START_REF] Engel | Influence of hospital volume on local recurrence and survival in a population sample of rectal cancer patients[END_REF][START_REF] Simunovic | Hospital procedure volume and teaching status do not influence treatment and outcome measures of rectal cancer surgery in a large general population[END_REF][START_REF] Hodgson | Relation of hospital volume to colostomy rates and survival for patients with rectal cancer[END_REF][START_REF] Wibe | Effect of hospital caseload on long-term outcome after standardization of rectal cancer surgery at a national level[END_REF] Studies examining the relation between type of hospital and outcome also published contrasting results for rectal cancer. [START_REF] Simunovic | Hospital procedure volume and teaching status do not influence treatment and outcome measures of rectal cancer surgery in a large general population[END_REF][START_REF] Simons | Variations in treatment of rectal cancer: the influence of hospital type and caseload[END_REF][START_REF] Blomqvist | Survival after rectal cancer: differences between hospital catchment areas. A nationwide study in Sweden[END_REF][START_REF] Simunovic | Influence of hospital characteristics on operative death and survival of patients after major cancer surgery in Ontario[END_REF] The aim of this study was to describe variation in treatment patterns and outcome according to region and characteristics of individual hospitals among patients with rectal cancer in the Netherlands.

Methods

Netherlands Cancer Registry

In the Netherlands, all newly diagnosed malignancies are registered in the nationwide populationbased Netherlands Cancer Registry (NCR). The automated pathological archive (PALGA) and the Haematology Departments are the main sources of notification. The National Registry of Hospital Discharge Diagnosis is an additional source, which accounts for up to 8% of new cases. [START_REF] Visser | Incidence of cancer in the Netherlands[END_REF] Data are collected from the medical records by specially trained registrars and are coded according to a national manual. Information on patient characteristics, tumour characteristics, treatment, hospital of diagnosis, hospital of treatment and follow-up is recorded. For coding tumour site and morphology the International Classification of Diseases for Oncology (ICD-O) is used. [START_REF] Fritz | International Classification of Diseases for Oncology[END_REF] Cancers are staged according the TNM classification. [START_REF]TNM Atlas[END_REF] Quality of the data is high [START_REF] Schouten | Quality of cancer registry data: a comparison of data provided by clinicians with those of registration personnel[END_REF] and completeness is estimated to be at least 95%. [START_REF] Schouten | Completeness of cancer registration in Limburg, The Netherlands[END_REF] Patients All patients with invasive rectal carcinoma, diagnosed between 2001 and 2006 were selected from the NCR (N=16 039). Patients with diagnoses without histological confirmation, with diagnoses based only on autopsy findings, patients living abroad and patients with incomplete records were excluded from the analyses.

As we were mainly interested in the first choice of treatment, clinical stage was used, except for those cases where clinical stage was unknown. In these cases, the pathological stage was applied. In cases where clinical T-stage was unknown and in whom preoperative chemoradiation was applied, the tumour was assumed to be cT4, because according to the guidelines preoperative chemoradiation should, among others, be administered to patients with cT4-tumours.

Regions and hospitals

The Netherlands are divided in 9 regions, each served by a Comprehensive Cancer Centre (CCC).

Activities of CCCs are facilitation of consultancy services, development and implementation of guidelines, improving organisation of cancer care, coordinating palliative care and the cancer registry.

Each CCC serves an area covered by five to twenty hospitals. All hospitals are affiliated to one centre.

Within each CCC-region, treatment policies are discussed within multidisciplinary meetings which may lead to differences in oncologic care between the regions. Hospital characteristics, among others type of hospital, were retrieved from Prismant, an organisation which collects objective data about hospitals for e.g. quality of care assessment. [START_REF]Prismant[END_REF] Hospitals with several locations, but organized as one hospital in 2003 were considered as one hospital.

Patients of all 97 hospitals in the Netherlands were included in the analyses. Hospitals were categorized into general, teaching and university hospitals, based on data from Prismant for the period between 2003 and 2005. A teaching hospital was defined as a hospital which provides medical training to surgical residents and/or to residents of internal medicine. University hospitals were teaching hospitals affiliated to a medical university. The one specialized oncology centre in the Netherlands was also classified as university hospital.

For the analyses concerning treatment and overall survival, type of hospital was based on the hospital where the tumour was diagnosed reasoning that referral of patients for treatment in another hospital can be considered as a good standard of care. For the analyses on postoperative mortality, type of hospital was based on the hospital where the surgery was performed.

Hospital volume was based on the mean number of rectum and rectosigmoid resections for cancer per year. Since rectosigmoid tumours are frequently resected by the same surgical techniques as rectal tumours, we included the resections of rectosigmoid tumours to enlarge the hospital volume. Hospital volume was categorized into <25, 25-50 and >50 resections per year.

Statistical analyses

Treatment according to guidelines

Treatment was described as percentages per stage and age group (<75 years and ≥75 years). The influence of age at diagnosis, gender, year of diagnosis, depth of invasion, nodal involvement, type of hospital of diagnosis, hospital volume and CCC-region on the odds of receiving preoperative radiotherapy in patients with T2/T3-M0 was examined using logistic regression analysis. For this analysis, the period 2003-2006 was used, because preoperative radiotherapy was not introduced nationwide until 2003. One hospital was excluded from this analysis due to a deviating treatment policy. To compare the performance of the individual hospitals for this outcome measure, a funnel plot was made using 95% control limits calculated around the mean of the 20% best performing hospitals. [START_REF] Agresti | Approximate is better than "exact" for interval estimation of binomial proportions[END_REF][START_REF] Spiegelhalter | Funnel plots for comparing institutional performance[END_REF] In the funnel plot, each hospital was displayed as a scatter point presenting the hospital volume and type and the adjusted rate for proportion of patients receiving preoperative radiotherapy. The proportion was adjusted for gender, age at diagnosis, depth of invasion and nodal involvement in order to account for differences in case-mix between the hospitals.

Postoperative mortality

Logistic regression analysis was used to investigate the odds of postoperative mortality by age at diagnosis, gender, type of resection, type of hospital of surgery, hospital volume and CCC-region.

Postoperative mortality was defined as death within 30 days after surgery. Patients with distant metastasis (M1) were excluded from this analysis. Postoperative mortality was determined for tumours diagnosed in 2005 and 2006, because date of surgery was not registered in the NCR before 2005.

Survival

Relative survival, an estimation of disease-specific survival, was calculated as the ratio of the observed rates in cancer patients to the expected rates in the general population using the Ederer method. [START_REF] Ederer | Instructions to IBM 650 Programmers in Processing Survival Computations[END_REF] Follow-up was calculated as the time from diagnosis to death or to 1 st January 2008.

Multivariate relative survival analyses were used to estimate relative excess risk (RER) of death by hospital type and volume. Only first tumours were included in the multivariate survival analyses.

STATA (version 10.0) was used for the analyses. A p-value below 0.05 was considered as statistically significant.

Results

In the Netherlands 16,039 patients with rectal carcinoma were diagnosed in the period from 2001 to 2006. During this period, the number of annual diagnoses increased from 2,325 in 2001 to 2,918 in 2006. Of these patients 59% were male and 30% were aged 75 years or older. In total, 59% had T2/T3-M0 tumours, 10% had T4-M0 tumours and 17% had tumours with distant metastases (M1).

More than 50% of the patients were diagnosed in a teaching hospital for surgery and 6% were diagnosed in a university hospital. Almost half of the patients (46%) were diagnosed in hospitals with 25-50 resections annually. The share of each CCC varied between 8 and 17% (Table 1).

Treatment by stage and age

Figure 1 shows treatment by stage and age group. Among patients with T1-M0 tumours, 34% of the patients younger than 75 years underwent polypectomy or Transanal Endoscopic Microsurgery (TEM), compared to 43% among patients of 75 years or older. Almost all other patients with T1-M0 tumours underwent a surgical resection with or without preoperative radiotherapy.

Most patients with T2/T3-M0 tumours underwent a resection, mainly combined with preoperative radiotherapy. Among the patients younger than 75 years, 70% underwent resection with preoperative radiotherapy compared to 57% among patients 75 years or older. Around 84% of the patients younger than 75 years with a T4-M0 tumour underwent a surgical resection, 37% in combination with preoperative radiotherapy and 40% in combination with neoadjuvant chemoradiation. Of the patients of 75 years or older with a T4-M0 tumour 57% underwent a surgical resection; including 31% in combination with preoperative radiotherapy and 11% in combination with neoadjuvant chemoradiation.

The proportion of patients younger than 75 years with a M1 tumour who underwent surgical resection of the primary tumour was 44%, compared to 31% for patients of 75 years or older. Around 16% of the younger patients with a M1 tumour and 42% of the older patients with a M1 tumour did not receive any treatment.

Preoperative radiotherapy and chemoradiation

Female patients were less likely to receive preoperative radiotherapy (Table 2). The odds ratio decreased with increasing age, down to 0.40 (95% CI 0.33-0.47) in patients aged 75 years and older compared to those younger than 60 years. Patients with a higher T-stage (T3) and with positive lymph nodes (N1) were more likely to receive preoperative radiotherapy. Patients diagnosed in a teaching hospital for surgery and in a university hospital had a lower odds of receiving preoperative radiotherapy compared to patients diagnosed in a general hospital (OR 0.84, 95% CI 0.72-0.99 and OR 0.70, 95% CI 0.52-0.93, respectively). Patient diagnosed in a hospital with more than 50 resections per year were more likely to receive preoperative radiotherapy (OR 1.39, 95% CI 1.09-1.76). There was variation between CCC-regions in the odds of receiving preoperative radiotherapy. In the funnel plot, the adjusted proportion of patients younger than 75 years who received preoperative radiotherapy is depicted for each hospital by hospital type and mean number of resections per year, showing a large variation between the individual hospitals (Figure 2). The proportion of patients who received preoperative radiotherapy ranged from 100% to less than 50%. 3).

Survival

Among all patients with rectal cancer as well as for most separate stages, no differences were found in overall survival between hospitals of different types and volumes. However, patients with a T1-M0 tumour diagnosed in hospitals with more than 50 resections per year had a lower risk of dying compared to patients diagnosed in hospitals with less than 25 resections per year (RER 0.11, 95% CI 0.02-0.78) (Table 4).

Discussion

In this nationwide population-based study, examining cancer registry data of 16,039 patients with rectal carcinoma diagnosed in the period 2001-2006 in the Netherlands, we revealed marked variation in treatment patterns and outcome. Even after correction for differences in case-mix, there were substantial differences between individual hospitals in the proportion of patients receiving preoperative radiotherapy. In addition, we found variation between CCC-regions in the proportion of patients receiving chemoradiation. Furthermore, hospital type and volume had effect on the odds of receiving preoperative radiotherapy. Hospital volume was also associated with postoperative mortality.

Preoperative radiotherapy

According to the Dutchl evidence-based guidelines for the treatment of rectal cancer, patients with T2-3 tumours without distant metastasis should receive 5x5 Gy radiotherapy preceding resection to reduce the risk of local recurrence. [START_REF]Guideline rectal cancer[END_REF] A French study, which combined the use of preoperative and postoperative radiotherapy, reported a higher odds of receiving radiotherapy in patients who were operated in university hospitals, suggesting a more rapid spread of improvements in emerging treatment strategies in university hospitals. [START_REF] Faivre-Finn | Changes in the practice of adjuvant radiotherapy in resectable rectal cancer within a French well-defined population[END_REF] A questionnaire completed by Korean surgeons also demonstrated a higher use of preoperative radiotherapy in university hospitals. [START_REF] Lee | A survey on the impact of operation volume on rectal cancer management[END_REF] However, our results showed patients diagnosed in a teaching hospital and in a university hospital were less likely to receive preoperative radiotherapy. Regretfully, our study was hampered by the lack of data on comorbidities of patients. Therefore, the differences between these groups of hospitals might actually be explained by selective referral of patients with more comorbidities and advanced cancer, who are likely to receive preoperative radiotherapy less often. [START_REF] Iversen | Influence of caseload and surgical speciality on outcome following surgery for colorectal cancer: a review of evidence. Part 1: short-term outcome[END_REF] A nationwide survey in Australia reported no relation between hospital volume and the percentage of patients receiving radiotherapy preoperatively, whereas our results show higher odds for patients diagnosed in a high-volume hospital. [START_REF] Mcgrath | Surgeon and hospital volume and the management of colorectal cancer patients in Australia[END_REF] A study with data from the California Cancer Registry reported patients diagnosed in the lowest-volume hospitals were less likely to receive adjuvant radiotherapy compared to the highest-volume hospitals. They suggested more accurate staging, closer affiliation with radiation facilities and a broader range of specialists and technologic resources in the high volume hospitals as explanations for this result. [START_REF] Rogers | Relation of surgeon and hospital volume to processes and outcomes of colorectal cancer surgery[END_REF] The explanation of a closer affiliation of high volume hospitals with radiation facilities does not apply to the situation in the Netherlands, because radiotherapy institutions and there regional networks are easily accessible in our country. On the other hand, there could be differences in local expertise between hospitals with and without radiotherapy facilities. Nevertheless, in our study a high volume proved no guarantee for a high percentage of patients receiving preoperative radiotherapy, as our funnel plot showed considerable variation between individual hospitals.

Chemoradiation

In 2004, several studies revealed improved local control with preoperative chemoradiation. [START_REF] Bosset | Chemotherapy with preoperative radiotherapy in rectal cancer[END_REF][START_REF] Gerard | Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203[END_REF] In the Netherlands, preoperative chemoradiation was recommended for T4 tumours and tumours with an expected positive CRM since the summer of 2005. Unfortunately, detailed information about the preoperative assessment of (circumferential) margins is not available in the NCR. Therefore, we could not include these tumours in our analyses concerning preoperative chemoradiation. Indeed, these tumours were included in the analyses of preoperative radiotherapy, because it is the minimum therapy they should receive.

This study demonstrated large differences in the pace and extent in which preoperative chemoradiation was introduced for patients with T4 rectal tumours in separate regions in the Netherlands, identifying slow and fast adaptors in the introduction of a relatively new treatment strategy among the hospitals within these CCC-regions. These differences could reflect different results of the debates in regionally organized multidisciplinary meetings (facilitated by the CCCs), which apparently can lead to differences in the adherence to national guidelines. To our knowledge no other research has been done on differences between hospitals in administering chemoradiation.

Preoperative mortality

The risk of death within 30 days after resection was most affected by age. Patients over 75 years of age had a substantially increased mortality risk. A study from the south of the Netherlands demonstrated a higher risk of developing treatment-related complications for older patients and patients with co-morbidity leading to a worse survival. [START_REF] Shahir | Elderly patients with rectal cancer have a higher risk of treatment-related complications and a poorer prognosis than younger patients: a population-based study[END_REF] Another Dutch study revealed that elderly patients have more complications leading to higher mortality. Furthermore, complications with a similar occurrence rate in younger as well as elderly patients were associated with a higher mortality in the elderly. [START_REF] Rutten | Controversies of total mesorectal excision for rectal cancer in elderly patients[END_REF] Unfortunately, no data about co-morbiditities, complications and performance status are available in the NCR.

The higher risk of postoperative mortality in patients who underwent a low anterior resection, could reflect the high risk of anastomotic leakage after sphincter preserving surgery which is a major cause of postoperative death. [START_REF] Matthiessen | Population-based study of risk factors for postoperative death after anterior resection of the rectum[END_REF][START_REF] Rullier | Risk factors for anastomotic leakage after resection of rectal cancer[END_REF] Furthermore, we found a lower risk of postoperative mortality in patients operated in hospitals with 50 or more rectal cancer resections per year. This could be explained by the specialized and more experienced surgeons and by the technically more advanced equipment leading to a higher standard of perioperative care in these hospitals. [START_REF] Iversen | Influence of caseload and surgical speciality on outcome following surgery for colorectal cancer: a review of evidence. Part 1: short-term outcome[END_REF] Another explanation may be the lower rates of intraoperative and postoperative complications in high-volume hospitals. [START_REF] Marusch | Hospital caseload and the results achieved in patients with rectal cancer[END_REF] Survival

In our study, we found a positive association between a large hospital volume and survival only for patients with T1-M0 tumours. Furthermore, no differences between hospital types and volumes for relative survival were revealed. Notably, for patients with T2/3-M0 tumours, for whom preoperative radiotherapy depends on hospital characteristics, no effect of hospital type and volume on survival was found. This is in agreement with the long-term results of the TME-trial, which showed an effect of preoperative radiotherapy in addition to TME-surgery on the incidence of local recurrence but no effect on survival. [START_REF] Peeters | The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma[END_REF] Other studies have shown an association between hospital characteristics and survival. Two Scandinavian nationwide studies demonstrated an improved survival for university hospitals compared to local hospitals. [START_REF] Wibe | Effect of hospital caseload on long-term outcome after standardization of rectal cancer surgery at a national level[END_REF][START_REF] Blomqvist | Survival after rectal cancer: differences between hospital catchment areas. A nationwide study in Sweden[END_REF], whereas a Canadian study found no effect of teaching status of the hospital on overall survival. [START_REF] Simunovic | Hospital procedure volume and teaching status do not influence treatment and outcome measures of rectal cancer surgery in a large general population[END_REF] A nested cohort study from the US showed no significant relation between hospital volume and overall survival. [START_REF] Meyerhardt | Impact of hospital procedure volume on surgical operation and long-term outcomes in high-risk curatively resected rectal cancer: findings from the Intergroup 0114 Study[END_REF] Another American study demonstrated better survival rates among patients who underwent surgery at high-volume hospitals compared to patients treated in low-volume hospitals. [START_REF] Hodgson | Relation of hospital volume to colostomy rates and survival for patients with rectal cancer[END_REF] Measuring quality of care based on differences in characteristics of individual hospitals, like volume and teaching status, has some essential shortcomings. Our study demonstrated a large influence of local treatment patterns in individual hospitals. Beside differences in treatment between hospitals with different patient volumes, our results showed a large variation in providing preoperative radiotherapy within each volume category. This indicates a limitation of volume as a measure of quality of care:

individual, low-volume, hospitals could provide good care whereas high-volume hospitals could provide suboptimal care. [START_REF] Khuri | The case against volume as a measure of quality of surgical care[END_REF] Since 2005, the Netherlands has a nationwide guideline for the treatment of patients with rectal cancer. Differences in local practices between hospitals are expected to decrease due to general adaption of these guidelines, though without adequate monitoring of the actual compliance, the beneficial effects are unsure.

In conclusion, there is considerable variation in treatment and outcome of patients with rectal cancer in the Netherlands. Although this variation could be partly explained by differences in hospital type and volume, differences in local treatment patterns between individual hospitals seem to have a large influence. Further research is needed to identify factors causing this variation between individual hospitals, in which the identification of differences in casemix and patients preferences are essential.

By this, we could reveal the reasons behind differences in treatment patterns and outcome, potentially leading to more patients receiving optimal treatment for their rectal cancer.

CCC-region % Preoperative chemoradiation

Figure 3 ,

 3 Figure 3, showing the proportion of patients receiving preoperative chemoradiation aged <75 years with T4-M0 tumours according to year of diagnosis and CCC-region, demonstrates large variation in the administering of chemoradiation between CCC-regions.

Figure 1 :Figure 2 :

 12 Figure 1: Treatment by stage and age group at diagnosis

Table 1 :

 1 Description of study population (N=16 039)

	N	%

Table 2 :

 2 Odds ratio of receiving preoperative radiotherapy in patients with T2/T3-M0 in the period

	2003-2006
		OR	95% CI
	Gender
	Male	1.00	Reference
	Female	0.84*	0.74-0.96
	Age at diagnosis
	< 60 years	1.00	Reference
	60-74 years	0.84*	0.71-0.99
	≥ 75 years	0.40*	0.33-0.47
	Year of diagnosis
	2003	1.00	Reference
	2004	1.01	0.85-1.21
	2005	1.25*	1.04-1.50
	2006	1.06	0.89-1.27
	Depth of invasion
	cT2	1.00	Reference
	cT3	1.34*	1.18-1.52
	Nodal involvement
	cN0/X	1.00	Reference
	cN+	2.30*	1.78-2.97
	Hospital of diagnosis
	General hospital	1.00	Reference
	Teaching hospital for surgery	0.84*	0.72-0.99
	University hospital	0.70*	0.52-0.93
	Annual volume of hospital of diagnosis
	< 25 resections	1.00	Reference
	25-50 resections	0.93	0.78-1.10
	> 50 resections	1.39*	1.09-1.76
	Comprehensive Cancer Centre region
	1	1.00	Reference
	2	1.42*	1.10-1.82
	3	1.04	0.79-1.37
	4	0.70*	0.53-0.92
	5	1.04	0.80-1.35
	6	0.68*	0.54-0.85
	7	1.27	0.98-1.64
	8	0.70*	0.53-0.92
	9	0.60*	0.45-0.80
	* p<0.05

Table 3 :

 3 Odds ratio of death within 30 days after elective resection in patients without distant

	metastasis in the period 2005-2006
		OR	95% CI
	Gender
	Male	1.00	Reference
	Female	0.38*	0.25-0.59
	Age at diagnosis
	< 60 years	1.00	Reference
	60-74 years	4.39*	1.71-11.27
	≥ 75 years	21.32*	8.57-53.08
	Depth of invasion
	pT1	1.00	Reference
	pT2	0.68	0.35-1.31
	pT3	0.83	0.45-1.55
	pT4	0.83	0.28-2.49
	Nodal involvement
	pN0	1.00	Reference
	pN+	1.11	0.74-1.66
	Type of resection
	Low anterior resection	1.00	Reference
	Abdominoperineal resection	0.50*	0.33-0.76
	Other/unknown	0.74	0.37-1.47
	Hospital of surgery
	General hospital	1.00	Reference
	Teaching hospital for surgery	0.98	0.60-1.61
	University hospital	0.47	0.20-1.10
	Annual volume of hospital of surgery
	< 25 resections	1.00	Reference
	25-50 resections	0.70	0.44-1.14
	> 50 resections	0.40*	0.19-0.84
	Comprehensive Cancer Centre region
	1	1.00	Reference
	2	1.19	0.61-2.31
	3	2.25*	1.08-4.72
	4	1.11	0.47-2.66
	5	0.41	0.15-1.14
	6	0.87	0.41-1.83
	7	1.34	0.65-2.77
	8	3.20*	1.56-6.57
	9	0.84	0.31-2.25
	* p <0.05

Table 4 :

 4 Relative excess risks (RER) of dying for patients with rectal cancer diagnosed in the period 2001-2006, by clinical stage (multivariate relative survival Adjusted for gender, age at diagnosis, grade, year of diagnosis, clinical stage, surgery, chemotherapy, radiotherapy and CCC-region 2 Adjusted for gender, age at diagnosis, grade, year of diagnosis, clinical N stage, surgery, radiotherapy and CCC-region 3 Adjusted for gender, age at diagnosis, grade, year of diagnosis, clinical N stage, surgery, chemotherapy, radiotherapy and CCC-region 4 Adjusted for gender, age at diagnosis, grade, year of diagnosis, surgery, chemotherapy, radiotherapy and CCC-region

	analysis)
			Total 1		T1-M0 2	T2/T3-M0 2		T4-M0 3		M1 4
		RER	95% CI	RER	95% CI	RER	95% CI	RER	95% CI	RER	95% CI
	Hospital of diagnosis
	General hospital	1.00	Reference	1.00	Reference	1.00	Reference	1.00	Reference	1.00	Reference
	Teaching hospital for surgery	1.02	0.94-1.10	0.98	0.44-2.16	0.97	0.83-1.13	1.03	0.83-1.29	0.99	0.88-1.11
	University hospital	0.94	0.81-1.08	2.59	0.78-8.58	0.90	0.68-1.18	1.12	0.78-1.61	0.83	0.68-1.01
	Annual volume of hospital of diagnosis
	< 25 resections	1.00	Reference	1.00	Reference	1.00	Reference	1.00	Reference	1.00	Reference
	25-50 resections	0.95	0.88-1.04	0.53	0.20-1.41	0.98	0.83-1.14	1.10	0.88-1.39	0.90	0.80-1.02
	> 50 resections	1.02	0.91-1.14	0.11* 0.02-0.78	1.05	0.84-1.31	1.06	0.78-1.44	1.01	0.85-1.19

1 * p<0.05

1 235 7.7

Acknowledgements

The authors thank the registration teams of the Comprehensive Cancer Centres for the collection of data for the Netherlands Cancer Registry and the investigators of the Netherlands Cancer Registry involved in the analyses of quality of cancer care.

Conflict of interest

None declared.


W Van Gijn

G A Gooiker

M W J M Wouters

P N Post

R A E M Tollenaar

MD Cornelis J H Van De Velde
email: c.j.h.van_de_velde@lumc.nl

Volume and outcome in colorectal cancer surgery

M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT

Abstract Aims

There is a growing consensus to concentrate high-risk surgical procedures to highvolume surgeons in high-volume hospitals. However, there is fierce debate about centralizing more common malignancies such as colorectal cancer. The objective of this review is to conduct a meta-analysis using the best evidence available on the volume-outcome relationship for colorectal cancer treatment.

Methods

A systematic search was performed to identify all relevant articles studying the relation between hospital and/or surgeon volume and clinical outcomes for colorectal cancer. Using strict inclusion criteria, 23 articles were selected concerning colon cancer, rectal cancer or both diseases together as 'colorectal cancer'. Pooled estimated effect sizes were calculated using the casemix adjusted outcomes of the highest volume group opposed to the lowest volume group.

Results

High volume hospitals have a significantly lower postoperative mortality in half of the pooled results. Non significant results show a trend in favour of high volume hospitals. All results showed a significantly better long term survival in high volume hospitals. High volume surgeons have a lower postoperative mortality, although evidence is sparse. All analyses showed a significantly better long term survival in favour of high volume surgeons.

Conclusions

The results show a clear and consistent relation between high volume providers and improved long term survival. This applies to both high volume hospitals and high volume surgeons. Most results show a relation between high volume providers and a reduced postoperative mortality, but evidence is less convincing.

In the ideal world, extensive population based audit registrations with casemix adjusted feedback should make rigid minimal volume standards obsolete. Until then, using volume criteria for hospitals and surgeons treating colorectal cancer can improve mortality and especially long term survival.

Introduction

Since the relation between surgical volume and mortality was first described in the late seventies, many publications have reconfirmed a positive volume-outcome relationship, especially for highrisk surgical procedures such as esophagectomies or pancreatectomies [START_REF] Luft | Should Operations Be Regionalized? The Empirical Relation Between Surgical Volume and Mortality[END_REF][START_REF] Chowdhury | A Systematic Review of the Impact of Volume of Surgery and Specialization on Patient Outcome[END_REF][START_REF] Birkmeyer | Hospital Volume and Surgical Mortality in the United States[END_REF] . All striving for the best possible care, there is an ongoing and sometimes fierce debate between doctors, politicians and patients about centralizing surgical care to high volume centres. This led to a growing consensus to concentrate high-risk, relatively low incidence surgical procedures in high-volume hospitals [START_REF] Birkmeyer | Volume Standards for High-Risk Surgical Procedures: Potential Benefits of the Leapfrog Initiative[END_REF] .

However, the expertise for diagnosis and treatment of common types of cancer should preferably be widespread and easily accessible for all patients. After lung-and breast cancer, colorectal cancer is the third most common malignancy worldwide, with 1.15 million new cases every year 5 .

Referring all colorectal cancer patients to a limited number of high volume centres will inevitably decrease accessibility for patients and their family. Not only for the operation, but also for (neo)adjuvant treatment and many years of follow-up.

Because several studies on this topic do not correct adequately for casemix variation or have other methodological flaws, results can easily be misinterpreted. Fundamental decisions such as centralisation of colorectal cancer care should be made relying on the best available evidence.

The objective of this review is to contribute to the debate by conducting a meta-analysis using the best available evidence about the volume-outcome relationship for colorectal cancer treatment.

Methods

Systematic Search Strategy

A specialised librarian performed a systematic search in Medline and Embase to identify all relevant studies describing the association between hospital or surgeon volume and clinical outcomes. Because volume is not well indexed, a combination of MESH terms and free text words was used (table 1). In addition, reference lists of relevant articles were hand-searched to identify additional articles and the "related articles" function in Pubmed was used. The last search was performed on February 1 st 2010.

Study selection

The first two authors of this article independently screened titles and abstracts of all retrieved articles, using the following inclusion criteria:

-The subject of the study is the surgical treatment of colon cancer, rectal cancer or both.

-Hospital and/or surgeon volume is an independent variable.

-The outcome parameter is postoperative mortality and/or survival.

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-The study does not describe a single hospital or surgeon.

-The study uses primary data (e.g. editorials, systematic reviews, are excluded).

After the first selection, articles were assessed in full text and further selected using the following criteria:

-If multiple publications are based on the same database, the study with the highest methodological quality was selected. In case of similar quality, the publication with the most recent study period was selected.

-Due to considerable changes in clinical and surgical practise, data older than 20 years was considered obsolete. Because the first selection for this review took place in 2008, studies older than 1988 were excluded.

-Multivariate analysis had to be corrected for at least age and gender.

-Volume had to be defined as a distinct number or cut-off value. Studies that defined volume as 'specialization' were excluded.

Assessment of study quality & Data-extraction

Each study in the final selection was critically appraised following the STROBE criteria (www.strobe-statement.org) for study characteristics and methodological quality. For each volume group, crude and adjusted outcomes were recorded for postoperative mortality and survival.

Parameters for adjusted outcomes were expressed as odds ratio's (OR), hazard ratio's (HR) or relative risks (RR) with confidence intervals (CI) and P-values. All items were scored in an Access 2003 database (Microsoft Corporation tm, Redmond WA, USA).

Statistical analysis

Data were analysed using Comprehensive Meta Analysis professional, version 2.2 (Biostat inc. Englewood, USA). Pooled estimated effect sizes were calculated using the adjusted outcomes of the highest volume group opposed to the lowest volume group (reference). In case the highest volume group was used as reference, results were re-calculated (1/effect size) to fit the statistical model. The random effect model was used to account for expected heterogeneity when pooling observational studies. Heterogeneity was quantified using the I 2 test. An I 2 > 50 was considered as notable heterogeneous. In case of heterogeneity, the impact of subgroups was explored with subgroup analyses for data source (administrative vs clinical), casemix adjustment (adjustment for comorbidity or severity) and country. For all pooled analyses involving three or more studies, publication bias was explored using an Egger's regression test.

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Results

After combining the electronic library results and removing duplicates, 74 potentially relevant studies remained. Using the above described selection rounds, 23 studies were selected for the meta-analyses: 10 concerning colon cancer (table 2), 7 concerning rectal cancer (table 3) and 7 that analysed both diseases together as 'colorectal cancer' (table 4).

Colon Cancer

The following risk adjusted outcomes could be extracted from the 10 colon cancer studies:

A. the effect of hospital volume on postoperative mortality (n=6)

Five outcomes were expressed in Odds ratio's, with a pooled estimated effect of 0.88, 95% confidence interval 0.71-1.09, I 2 =87.1. Subgroup analysis showed that omitting correction for comorbidity was a significant factor of heterogeneity, (p=0.004). When the analysis was repeated without the single study that did not correct for comorbidity [engel], the pooled estimated effect turned significant in favour of high volume hospitals: OR 0.82, 95% CI 0.68-0.99, p=0.039.

One outcome was expressed in a Hazard ratio of 0.813, 95% confidence interval 0.734-0.90. See figure 1a.

B. the effect of hospital volume on long term survival (n=4)

All four outcomes were expressed in Hazard ratio's, with a pooled estimated effect of 0.916, 95% confidence interval 0.872-0.962, I 2 =45.7. See figure 1b.

C. the effect of surgeon volume on postoperative mortality (n=1)

One Odds ratio was available: 0.820, 95% confidence interval 0.675-0.997. See figure 1c.

D. the effect of surgeon volume on survival (n=1)

One Hazard ratio was available: 0.657, 95% confidence interval 0.532-0.811. See figure 1d.

Rectal Cancer

The following risk adjusted outcomes could be extracted from the 7 rectal cancer studies:

A. the effect of hospital volume on postoperative mortality (n=5)

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Four outcomes were expressed in Odds ratio's, with a pooled estimated effect of 0.744, 95% confidence interval 0.496-1.116, I 2 =76.7. One outcome was expressed in a Hazard ratio of 0.752, 95% confidence interval 0.621-0.910. See figure 2a.

B. the effect of hospital volume on survival (n=5)

All five outcomes were expressed in Hazard ratio's, with a pooled estimated effect of 0.838, 95% confidence interval 0.805-0.873, I 2 =0.0. See figure 2b.

'Colorectal Cancer'

The following risk adjusted outcomes could be extracted from the 7 studies that analysed colonand rectal cancer as one group:

A. the effect of hospital volume on postoperative mortality (n=2)

One Odds ratio was available: 0.781, 95% confidence interval 0.617-0.989 and one Risk ratio was available: 1.11, 95% confidence interval 0.886-1.393. See figure 3a.

B. the effect of hospital volume on survival (n=4)

All four outcomes were expressed in Hazard ratio's, with a pooled estimated effect of 0.912, 95% confidence interval 0.861-0.967, I 2 =37.7. See figure 3b.

C. the effect of surgeon volume on postoperative mortality (n=2)

Both outcomes were expressed in Odds ratio's, with a pooled estimated effect of: 0.665, 95% confidence interval 0.528-0.836. See figure 3c.

D. the effect of surgeon volume on survival (n=4)

All four outcomes were expressed in Hazard ratio's, with a pooled estimated effect of 0.869, 95% confidence interval 0.823-0.919, I 2 =0.0. See figure 3d.

Interpretation

With this meta-analysis, an attempt is made to pool all available studies with a predefined statistical and methodological quality. With a final selection of 23 articles originating from many databases and several countries, it is inevitable to find a variety in endpoints, volume group cut-off

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values and statistical effect measurements. Therefore, the results of this meta-analysis have to be interpreted with care.

Hospital volume

In table 5, the effects of high hospital volume on postoperative mortality and long term survival are summarized. The effects on postoperative mortality vary. Half of the results are significant in favour of high volume hospitals, evenly distributed over colon, rectal and colorectal cancer. Twothirds of the non significant results show a trend in favour of high volume hospitals.

The effects on long term survival are more uniform. All pooled effects are homogeneous and show significant survival benefits for patients treated in high volume hospitals.

The median cut-off point of high volume hospitals is ≥ 126 annual procedures for colon cancer, ≥ 24 for rectal cancer and ≥ 55 for the combined 'colorectal' group.

None of the Egger's regression tests were significant for publication bias.

Surgeon volume

In table 6, the effects of high surgeon volume on postoperative mortality and long term survival are summarized. Except for long term survival after colorectal cancer, evidence is sparse and non existent for rectal cancer. Nevertheless, both effects for postoperative mortality are significant in favour of high volume surgeons.

Again, effects on long term survival are more convincing. Both effects show strongly significant long term survival benefits for patients treated by high volume surgeons.

The median cut-off point of high volume surgeons is ≥ 4 annual procedures for colon cancer and ≥ 17 for the combined 'colorectal' group.

None of the Egger's regression tests were significant for publication bias.

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Discussion

There is a clear and consistent relationship between high volume providers and an improved long term survival. This counts for both high volume hospitals and high volume surgeons. For the relation between volume and postoperative mortality, evidence is less convincing. Nonetheless, with one non significant exception, all results point at a lower mortality in high volume settings.

Besides the 'practice makes perfect' theory, it is likely that volume is an indirect indicator for other important quality characteristics of health care providers. Certainly, the teamwork between the different consultants (gastro-enterology, surgery, radiology, radiotherapy, pathology) plays an important role. The existence of a good multidisciplinary infrastructure in which every patient is discussed in multidisciplinary meetings for an individual treatment regimen, seems an important factor for good outcomes [START_REF] Fleissig | Multidisciplinary Teams in Cancer Care: Are They Effective in the UK?[END_REF] . Quality of surgical wards and intensive care units are likely to be an important factor influencing outcome. While measuring these factors is difficult, hospital and surgeon volume are relatively easy to register.

Given the fact that high volume hospitals and surgeons perform better than their low volume equivalents, a logical reaction would be to define minimal volume standards for surgeons and hospitals. Unfortunately, it is not easy to define such standards based on the available evidence.

The selected studies in this meta-analysis demonstrate a wide range of high and low volume definitions. Despite the definitions summarized in table 5, few surgeons will qualify themselves as 'high-volume surgeons' when they perform only 4 colon resections annually. On the other hand, median cut-off points calculated form several studies give better indications. For instance, the high volume hospital definitions of ≥ 126 for colon cancer and ≥ 24 for rectal cancer seem more realistic.

One could state that effect sizes around 0.9 in favour of high volume providers are not worth the negative consequences that come with centralization. On the other hand, with the high incidence of colorectal cancer, small improvements can save many lives. Besides, some expensive and widely adopted chemotherapy regimes have about the same effects.

Unfortunately, underperforming high volume providers do exist, as there are low volume providers with excellent outcomes. Rigid minimal volume standards leave underperforming high volume centres untouched and undeservedly close well performing low volume centres. Surgical audit with active feedback to health care providers might be a better instrument to improve quality of care.

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Health care providers should ideally be provided with reliable and casemix adjusted feedback on their treatments. A comprehensive nationwide surgical audit provides insight in delivered quality of care, identifies and spreads best practice. Scandinavian experiences show how this can lead to spectacular improvements at very low costs 29;30 .

In the ideal world, extensive population based audit registrations with casemix adjusted feedback should make rigid minimal volume standards obsolete. Until then, using volume criteria for hospitals and surgeons treating colorectal cancer can improve mortality and especially long term survival.

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Figure 1a .

 1a Figure 1a. The effect of hospital volume on postoperative mortality for colon cancer treatment

Table 1 :

 1 Terms used for the systematic search in the databases Medline and Embase ("hospital volume" OR "surgeon volume" OR "surgical volume" OR workload OR caseload OR "procedure volume" OR "procedural volume") AND (surgical complications OR "Postoperative Complications"[Mesh] OR mortality OR (("Survival Rate"[Mesh] OR "Survival"[Mesh]) OR "Disease-Free Survival"[Mesh]) OR "Mortality"[Mesh] OR "Neoplasm Recurrence, Local"[Mesh] OR "Recurrence"[Mesh] OR treatment outcome[Mesh] OR "treatment outcome") AND ("Surgical Procedures, Operative"[Mesh] OR surgery OR surgical OR surgeon) Embase hospital volume.mp. OR surgeon volume.mp. OR workload.mp. OR Workload/ OR caseload.mp. OR procedure volume.mp. AND surgical complications.mp. OR postoperative complications.mp. OR exp Postoperative Complication/ OR Mortality/ OR mortality.mp. OR exp Survival Rate/ OR exp Survival/ OR survival.mp. OR exp Cancer Recurrence/ OR neoplasm recurrence.mp. OR treatment outcome.mp. OR exp Treatment Outcome/ OR surgical mortality.mp. OR exp Surgical Mortality/ OR exp recurrent disease/ or exp tumor recurrence/ OR exp cancer survival/ OR disease free survival.mp. or exp Disease Free OR exp cancer surgery/ OR surgeon.mp. OR exp Surgeon/ OR surgical procedures.mp. or exp Surgical Technique/

	Medline (Pubmed)

Table 2 :

 2 selected publications colon cancer


W Van Gijn

C J H Van De Velde

A Dziki

P Mroczkowski

H Ortiz

D Pavalkis

G Romano

V Valentini

A Wibe

Improving quality of cancer care through surgical

Quality of healthcare is a hot topic and this is especially true for cancer care. New surgical techniques and effective neoadjuvant treatment regimens have significantly improved colorectal cancer outcome. Nevertheless, there seem to be substantial differences in quality of care between European countries, hospitals and doctors. To reduce hospital variation, most initiatives aim on selective referral, encouraging patients to seek care in high-volume hospitals, where cancer care is concentrated to site-specialist multidisciplinary teams. As an alternative to volume-based referral, hospitals and surgeons can also improve their results by learning from their own outcome statistics and those from colleagues treating a similar patient group.

European national audit registries in surgical oncology have led to improvements with a greater impact on survival than any of the adjuvant therapies currently under study.

Moreover, they offer the possibility to perform research on patient groups that are usually excluded from clinical trials.

Nevertheless, between European countries remain differences in outcome and treatment schedules that cannot be easily explained. The European CanCer Organisation (ECCO) has recognised these importances's and created the 'European Registration of Cancer Care' (EURECCA) framework to develop a European colorectal audit structure. EURECCA will advance future treatment improvements and spread these to all European cancer patients. It provides opportunities to treat elderly and comorbid patients evidence based while it offers an unique insight in social-economical healthcare matters such as the consequences of commercialisation, treatment availability and screening initiatives. As such, ECCO has established the basis for a strong, multidisciplinary audit structure with the commitment to improve cancer care for every European cancer patient.

Introduction

Quality of healthcare is a hot topic and this is especially true for cancer care. Several ranking lists for doctors and hospitals can be found on the internet and in the popular press around the world. Unfortunately, many of those lists do not meet the requirements needed for a fair judgement on healthcare providers and can therefore give misleading results. Nevertheless, the search for quality is plausible since there seem to be substantial differences in quality of care between countries, hospitals and doctors. In Europe, 5 year relative survival for colorectal cancer varies between 32% and 64% [START_REF] Sant | EUROCARE-4. Survival of Cancer Patients Diagnosed in 1995-1999. Results and Commentary[END_REF] . In most western health care systems, efforts are made to reduce hospital variation. Most initiatives focus on selective referral, encouraging patients to seek care in high-volume hospitals, where cancer care is concentrated to site-specialist multidisciplinary teams. Such a strategy of treating a larger proportion of patients in specialized centres, can evidently improve outcomes for complex surgical procedures, like esophagectomies and pancreatectomies [START_REF] Birkmeyer | Volume Standards for High-Risk Surgical Procedures: Potential Benefits of the Leapfrog Initiative[END_REF] . Elsewhere in this EJSO supplement, a relationship between hospital or surgical volume and patient outcomes is demonstrated for breast and colorectal cancer. However, the expertise for diagnosis and treatment of common types of cancer should be preferably widespread and easily accessible for all patients. Besides, one must keep in mind that there will always be low volume providers that perform very well as there are high volume providers with unacceptable outcomes. As an alternative to volume-based referral, hospitals and surgeons can also improve their results by learning from their own outcome statistics and those from colleagues treating a similar patient group. Quality assurance in surgical oncology is relative new compared to other medical fields such as chemotherapy and radiotherapy. For a long time, surgery was thought to have too much unexpected variation to be feasible for standardization and quality control.

However, the perception of surgery is steadily shifting from being a non definable craftsmanship to a transparent and well defined skill. Training, specialisation, knowledge, teamwork and continuous quality improvement are considered mandatory for surgeons in the 21 st century [START_REF] Mcculloch | Surgical Professionalism in the 21st Century[END_REF] . Surgical audit is a quality instrument that collects detailed clinical data from different health care providers, which can be adjusted for baseline risk and subsequently fed back to individual hospitals or surgeons. In this way, 'best practices' can be identified, communicated and broadly adopted. After casemix adjustments, a fair judgement can be made on the quality of cancer

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treatments. Hospitals and surgeons can be faced with their own results compared to those of colleagues treating the same patient category. Another important advantage is the fact that audit registries include the entire patient population which makes it possible to perform research on patient groups that are usually excluded from clinical trials (e.g. elderly, high comorbidity).

European surgical audits for colorectal cancer

In the last two decades, several surgical audits have been established in Europe. Most audits were initially set up for rectal cancer, because of poor outcome together with a remarkable variation between hospitals and between individual surgeons [START_REF] Gatta | Survival of Colorectal Cancer Patients in Europe During the Period 1978-1989[END_REF] . In that time, several European studies had shown that improvements in outcome were possible when rectal cancer surgery was refined with the total mesorectal excision (TME) technique [START_REF] Heald | The Mesorectum in Rectal Cancer Surgery-the Clue to Pelvic Recurrence[END_REF][START_REF] Heald | Recurrence and Survival After Total Mesorectal Excision for Rectal Cancer[END_REF][START_REF] Macfarlane | Mesorectal Excision for Rectal Cancer[END_REF] . Implementation of this new surgical technique and reduction of the variation in outcome between hospitals and surgeons, were the main reasons to initiate audit registries for the surgical treatment of rectal cancer. Later, most rectal cancer audits were broadened with colon cancer. Between 1993 and 2009, eight surgical (colo)rectal audits were founded in Europe (table 1).

In 1993 the Norwegian Rectal Cancer Project was founded, including more than 99% of patients operated for rectal cancer. After four years the results of this audit were remarkable: the proportion of TME surgery rose from 78 to 92% and the local recurrence rate dropped from 28 to 7% 8 . Moreover, the audit showed to be very cost effective with every saved life being less then €700,- [START_REF] Wibe | Nationwide quality Assurance of rectal cancer treatment[END_REF] . Currently, the audit's name is changed to The Norwegian Colorectal Cancer Project because colon cancer is also being registered.

The Swedish Rectal Cancer Registry was set up in 1995 and includes over 97% of all Swedish rectal cancer patients [START_REF] Pahlman | The Swedish Rectal Cancer Registry[END_REF] . Postoperative mortality dropped under 2.5% and the local recurrence rate dropped under 10%. Survival improved dramatically: patients with rectal cancer had an even better 5-year survival rate than those with colon cancer [START_REF] Birgisson | Improved Survival in Cancer of the Colon and Rectum in Sweden[END_REF] . This is remarkable because in the same period important improvements in chemotherapy for patients with colonic cancer had been achieved. Rectal cancer

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patients did not benefit from these changes as adjuvant treatment after rectal cancer surgery is still considered experimental in many European countries. The fact that survival of rectal cancer patients was superior to those of colon cancer patients shows the considerable impact of structural surgical training and feedback. Nowadays, colon cancer is also part of the audit, which is renamed to The Swedish Colorectal Cancer Registry.

The Danish Colorectal Cancer Database also led to satisfying results. Since 1994, 93% of all colorectal cancer patients were included. After 5 years of auditing, 5-year survival increased from 42% to 63% for women and from 37% to 55% for men [START_REF] Harling | Survival of Rectal Cancer Patients in Denmark During 1994-99[END_REF] .

More recently, other European countries followed in the Scandinavian footsteps by

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In 2009, the Dutch society of surgical oncology, the Dutch society of gastrointestinal surgery and the Dutch colorectal cancer group started the Dutch Surgical Colorectal Audit (DSCA). Within a year all hospitals in the Netherlands agreed to take part in the audit and more than 10,000 patients were included in early 2010. Recently, the DSCA published its first annual report covering 2009 18 . Obviously, in a first report no statements can be made about the quality enhancing effect of the audit. However, important findings were discovered such as the percentage non-elective colon cancer operations. 21% of all operations were acute or urgent, with a mortality rate up to 14%. Striking is the fact that 26% of the patients that underwent acute or urgent surgery, had visited a surgical outpatient clinic before their situation became urgent.

Given the fact that for colon cancer, mortality after elective surgery is only 2.9% compared to 14.3% after acute surgery, it seems obvious that many lives can be saved when these 'unnecessary acute' patients are reduced.

Considering the magnitude of improvements induced by the audit projects described above, the costs are futile in comparison to several adjuvant therapies. Most importantly, the benefit for individual patients of most adjuvant therapies is several orders of magnitude smaller than that of the major improvements achieved by the audits. Although all national audits achieved excellent results, differences remain between European countries that cannot be easily explained. On review of the results, there are differences in mortality, complications, recurrence and survival. Moreover, there are substantial differences in (neo)adjuvant treatment regimens. While in Sweden and the Netherlands most rectal cancer patients receive preoperative radiotherapy, in Norway a minority of patients receive radiotherapy (4% between 1993 and 1997 [START_REF] Wibe | Nationwide quality Assurance of rectal cancer treatment[END_REF] .

European Registration of Cancer

Nevertheless, local recurrence rates in Norway equal the rates in Sweden and the Netherlands 8 .

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Despite the numerous national projects, international initiatives are limited. To generate the best care for colorectal cancer in the whole of Europe and to meet political and public demands for transparency, a deep and broad insight in treatment outcomes is needed union wide. A European audit registration will provide transparency, benchmarking and feedback across nation's borders. This can rapidly lead to treatment improvements and a decrease in variation in the quality of care around the continent.

Urged by these arguments, the European CanCer Organisation (ECCO) initiated an international, multidisciplinary, outcome-based quality improvement program: European Registration of Cancer Care (EURECCA). The goal is to create a multidisciplinary European registration structure for patient, tumour and treatment characteristics linked to outcome registration (morbidity, mortality, loco-regional control, and survival). The registration will be used for benchmarking and internal feedback among participants and enhance further improvements in quality and efficiency of cancer care. All eight audit registries described in this article have given their full commitment to participate in the EURECCA framework.

Considering the multi-disciplinary aspect of cancer treatment, collaboration between the European cancer organizations is pivotal for the success of EURECCA. Key partners in realizing the vision are the European CanCer Organisation, the European Society of Surgical Oncology, the European Society for Therapeutic Radiology and Oncologists, the European Organisation of Research and Treatment of Cancer and the national audit structures.

The EURECCA project has a strong clinical research component complemented by the provision of practical tools for care providers all aiming at the optimization of the delivery of surgery, radiotherapy and chemotherapy in colorectal cancer. Among the main scopes of the research is the definition of the "core quality treatment standards" which, by way of recommendations, will be systematically disseminated in order to optimize current treatment patterns and offer patients the maximum quality treatment locally available with strategies to limit undesirable effects. The main objectives of the project are:

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-To perform research on the currently available population-based registries of patients with colorectal cancer in order to identify communalities and differences of surgery, radiotherapy and chemotherapy modalities of treatment in the European regions covered by these registries.

-Research to derive treatment outcomes from population-based registries in order to optimize current treatment approaches by defining "core quality treatment strategies" as well as treatment recommendations.

-To integrate "core treatment quality strategies" in clinical practice data collection, develop validation methods and facilitate outcome monitoring with feedback.

-To optimize the level of knowledge and experience in the treatment of colorectal cancer through professional education and dissemination programs.

Conclusion and future perspectives

National audit registries in surgical oncology have led to improvements with a greater impact on survival than any of the adjuvant therapies currently under study. Moreover, they offer the possibility to perform research on patient groups that are usually excluded from clinical trials such as elderly. The ECCO has recognised these importances's and created the EURECCA framework to develop a European colorectal audit structure. EURECCA will advance future treatment improvements and spread these to every cancer patient in Europe. It provides opportunities to treat elderly and comorbid patients evidence based while it offers an unique insight in social-economical healthcare matters such as the consequences of commercialisation, treatment availability and screening initiatives. Although EURECCA definitely contributes to transparency in healthcare, there is emphatically no intention to create an environment which is dominated by a 'naming, shaming and blaming culture'. Therefore, individual surgeon or hospital data will only be accessible for the concerning health care providers, compared with an international case-mix adjusted mean outcome. While to a large extent, the EURECCA framework is still under Momentarily, final preparations are made for pooled analyses on the effects of neoadjuvant radiotherapy on long term outcomes. Simultaneously, datasets are being harmonized to facilitate future analyses with respect to national privacy legislations.

Early summarily results will be presented at the ESSO conference 'surgical outcome: can we do better' in September 2010 in Bordeaux. At this conference, a prenegotiated call of agreement will be signed by all participants. In 2011, a multidisciplinary consensus meeting will be organised in Perugia, Italy. The objective is to present extensive results at the 2013 ECCO-17 conference in Amsterdam. As such, ECCO has established the basis for a strong, multidisciplinary audit structure with the commitment to improve cancer care for every European cancer patient.

  setting up their own national (colo)rectal audit programs. In 2001, The Association of Coloproctology of Great Britain and Ireland (ACPGBI) started the National Bowel Cancer Audit Programme (NBOCAP). In 2008, 95% of trusts in England and Wales submitted data. Within 5 years, 30 day mortality dropped from 7% to 4.5% 13 . In 2000, the 'International Quality Assurance in Colorectal Carcinoma' was initiated in Magdeburg, Germany. Between 2000 and 2008, 372 hospitals from Germany and Poland included 57.429 patients. Since 2009, patients from Naples, Italy are included and Lithuania is scheduled to join 2010. The percentage of abdominoperineal excision was significantly reduced from 26.1% in 2000 to 21.3% in 2008 14 .In 2005, Belgian surgeons initiated the Project on Cancer of the Rectum (PROCARE)[START_REF] Penninckx | Survival of Rectal Cancer Patients in Belgium 1997-98 and the Potential Benefit of a National Project[END_REF] . After standardisation and implementation of guidelines, prospective registration started in 2006 on a voluntary basis. Until now, 50% of the Belgian hospitals participate and around 2500 patients are included[START_REF]Global results[END_REF] . Besides registering crude outcome data after rectal cancer treatment, extensive efforts and resources are used to train surgeons, pathologists and radiologists in the latest standards of rectal cancer treatment.In 2006 Spanish TME project was founded. This rectal cancer audit registration has a national coverage of 20%. So far, 3100 patients are included. First reports show a 30 day mortality of 3.1% and an anastomotic leakage rate of 8.2%[START_REF]Spanish TME project[END_REF] .

  Care [EURECCA]: an International, Multidisciplinary, Outcome-based Quality Improvement Project of the European CanCer Organisation.

  orientations are already made for future intercontinental comparisons.

All information about EURECCA can be found on the webpage:


Lone S Jensen

Henrik Nielsen

Peter Brøndum Mortensen

Hans K Pilegaard

Paaske Søren

Johnsen

ENFORCING CENTRALIZATION FOR GASTRIC CANCER IN DENMARK

Keywords: Surgery, Gastric cancer, Volume, Centralization, Clinical guidelines, Audits, Outcome

Background: Population-based data on the early postoperative outcome after surgery for gastric cancer are very sparse. We examined the development in the quality of surgery and early postoperative outcomes in Denmark following centralization of gastric cancer surgery and implementation of national clinical guidelines.

Methods: All patients in Denmark who underwent resection with curative intent for gastric cancer between 1th. July 2003 to 31th. December 2008 in one of five university hospitals were registered in a national database. Data on surgical quality and mortality was obtained from the database and compared with the results from the period before centralization (1999)(2000)(2001)(2002)(2003).

Results: A total of 416 patients underwent resection in the study period. The risk of anastomotic leakages for the whole period was 5.0% (95%CI; 3.2-7.7) compared to 6.1 % (95%CI; 4.3-8.6 ) before centralization, whereas the 30-days hospital mortality was 2.4 % (95%CI;1.2-4.4) compared to 8.2 % (95%CI;6.0-10.4) before centralization. In addition, the percentage of patients with at least 15 lymph node removed increased during the study period from 19 in 2003 to 76 in 2008.

Conclusions: Centralization of gastric cancer surgery in Denmark and implementation of national clinical guidelines monitored by a national database was associated with improvements in surgical quality and a substantially lower in-hospital mortality.

Introduction

Several reports [START_REF] Birkmeyer | Surgeon volume and operative mortality in The United States[END_REF][START_REF] Hannan | The influence of hospital and surgeon volume on in-hospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer[END_REF][START_REF] Meyer | The influence of case load and the extent of resection on the quality of treatment outcome in gastric cancer[END_REF][START_REF] Skipworth | The relationship between hospital volume and post-operative mortality rates for upper gastrointestinal cancer resections: Scotland 1982-2003[END_REF] have concluded that hospital volume is associated with in-hospital as well as long-term survival following major cancer surgery. Many of the studies have supported the hypothesis that treatment of complex oncologic diseases should be carried out by multidisciplinary teams in high-volume hospitals [START_REF] Meyer | The influence of case load and the extent of resection on the quality of treatment outcome in gastric cancer[END_REF][START_REF] Sasako | Role of surgery in multidisciplinary treatment for solid cancers[END_REF][START_REF] Bachmann | Cohort study in South and West England of the influence of specialization on the management and outcome of patients with oesophageal and gastric cancers[END_REF] thereby reducing in-hospital morbidity and mortality as well as improving long-term survival [START_REF] Meyer | The influence of case load and the extent of resection on the quality of treatment outcome in gastric cancer[END_REF][START_REF] Callahan | Influence of surgical subspecialty, training on in-hospital mortality for gastrectomy and colectomy patients[END_REF][START_REF] Brennan | Outcome-more than just operative mortality[END_REF]). However, up-to-date population-based data on operative mortality after gastric cancer resection are lacking [START_REF] Lepage | Eurocare working group. Operative mortality after gastric cancer resection and long-term survival differences across Europe[END_REF] In Denmark with approximately 5.5 million inhabitants gastric cancer surgery has previously been carried out in a total of 37 different departments with an overall in-hospital mortality of 8.2% [10]. However, both in 1996 and in 2001 The National Board of Health recommended [START_REF] Sundhedsstyrelsen | Specialeplanlaegning og lands-og landsdelsfunktioner i sygehusvaesenet[END_REF] reorganization, so that all major surgical procedures were carried out in fewer departments, and especially gastric cancer surgery was recommended to be restricted to five university departments only.

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Patients and Methods

The Danish National Health Service provides tax-supported health care to all Danish residents, including free access to general practitioners and hospitals.

We identified all the patients who had underwent resections with curative intent for gastric cancer between 1th. July 2003 to 31th. December 2008 at one of the five university hospitals in Denmark using the national database on gastric cancer. Data are reported prospectively to the database both when the diagnostic procedures have been completed, when a specific treatment has been finished and at follow up. From 2009, data on oncologic treatment have also been registered.

However, these data are not included in the present study.

All Danish citizens are assigned a unique 10-digit civil registration number, which is used in all Danish registries and therefore enables unambiguous, individual-level record linkage between the registries. Using the civil registration number we linked the data from the national database with data from the National Pathology Registry, the National Registry of Patients and the Danish Civil Registration System. The National Pathology Registry holds detailed data on all pathology specimens analysed in Denmark since 1997 [START_REF] Erichsen | Existing data sources for clinical epidemiology: the Danish national Pathology Registry and Data Bank[END_REF]. The National Registry of Patients contains data on all discharges from all non psychiatric hospitals in Denmark since 1977 [START_REF] Andersen | The Danish National hospital Register. A valuable source of data for modern health sciences[END_REF]. Data from the National Pathology Registry and the National Registry of Patients were used to ensure the completeness on the national gastric cancer database. The Danish Civil Registration System has maintained electronic records of changes in the vital status of all citizens since 1968 [START_REF] Pedersen | The Danish Civil Registration System. A cohort of eight million persons[END_REF]. Data from the Civil Registration System were used to determine survival following gastric cancer surgery.

According to the guidelines the standard surgical procedures are total gastrectomy or distal gastric resections (tumour-free margin of at least five cm to the proximal resection line).

Patients with carcinoma in the gastric cardia are excluded from this study when resection included a partial gastrectomy in combination with resection of a part of the esophagus. In accordance with the

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guidelines established by the Japanese Cancer Association [START_REF] Gastric | Japanese classification of gastric carcinoma; second English edition[END_REF] it is recommended, that a D2lymphadenectomy has to be considered, but without resection of the tail of pancreas and without removal of the spleen. However in accordance with other studies a minimum of 15 lymphnodes should be removed [START_REF] Volpe | Outcome of patients with proximal gastric cancer depends on extent of resection and number of resected lymph nodes[END_REF], and therefore this is one of several quality of care indicators which is monitored in the national database.

Other quality of care indicators include postoperative morbidity defined as anastomotic leakages, hospital mortality (defined as postoperative death within 30 days) and fiveyear survival after surgery.

Concerning the performance the database provides feed-back on a regular basis (every 3 months) to all of the clinical departments in order to enable local audits. Furthermore, a nationwide audit is held annually resulting in an annual report, presenting the national and department specific data together with comments, conclusions and recommendations from a multidisciplinary steering committee including gastric and thoracic surgeons, pathologists, oncologists, clinical epidemiologists and biostatisticians. The report is distributed to the departments, to all relevant scientific societies and to administrators and is also made publicly available by publication on the internet.

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Results

A total of 416 patients with gastric cancer underwent resection with curative intent during the study period (Table 1). The patients were treated at one of the five university departments from 2003 to Total gastrectomy was performed in 264 patients whereas 152 patients underwent subtotal gastrectomy or a distal gastric resection (Billroth-II-resection) (Table 1).

For the whole period the risk of anastomotic leakage was 5.0%, with 7.2 % for total gastrectomy and 1.3% for other resections (Tabel 1). The risk tended to decline during the study period. The 30-day hospital mortality was 2.4 % for the whole period with 2.7% for total gastrectomy and 2.0% for other resections. A comparison between the results obtained after centralization and the period just before centralization of gastric cancer surgery [10] is shown in Table 2. Significantly (p<0.01) more partial resections compared to total gastrectomy were performed during the period before

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centralization compared to after. Furthermore, the hospital mortality decreased from 8.2% before centralization to 2.4% after centralization (p<0.05).

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Discussion

This nationwide Danish study of patients undergoing operation for gastric cancer found that centralization of treatment to five (four) university departments together with implementation of national clinical guidelines and the establishment of a national database was followed by clear improvement in surgical quality and in-hospital mortality.

It was remarkable that even if the National Board of Health in agreement with the Danish Surgical Society already in 1996 and again in 2001 [START_REF] Sundhedsstyrelsen | Specialeplanlaegning og lands-og landsdelsfunktioner i sygehusvaesenet[END_REF] recommended that gastrectomies should be performed only at four to five dedicated university departments, this goal was not obtained before the preparation and implementation of national clinical guidelines and a national database for registration.

Already, during the first years after the surveillance of clinical practice and treatment outcome was introduced only few patients were operated outside the recommended departments, and hereafter gastric cancer surgery have been entirely restricted to the university departments as recommended.

In the earlier Danish study [10] it was demonstrated that operations for gastric cancer were performed at up to 37 departments in a five year period (1999 -2003) before centralization, resulting in a total hospital mortality of 8.2% with 8.5% for total gastrectomy and 7.9% for other resections. No clear trends were observed from 1999-2003 or between the 37 departments. However, only one department operated more than 20 cases/year [10]. Thus, the total number of operations at the department classified as "high-volume" before centralization was not comparable with high-volume centres outside Denmark reporting lower mortality [START_REF] Birkmeyer | Surgeon volume and operative mortality in The United States[END_REF][START_REF] Hannan | The influence of hospital and surgeon volume on in-hospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer[END_REF][START_REF] Callahan | Influence of surgical subspecialty, training on in-hospital mortality for gastrectomy and colectomy patients[END_REF]. Similar observations were made in a Dutch study [START_REF] Krijnen | Improved survival after resectable non-cardia gastric cancer in the Netherlands: The importance of surgical training and quality control[END_REF] reporting that all hospitals in one region performed only between 3

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and 13 resections for gastric cancer per year and therefore none of these could be classified as "high-volume" departments. Moreover, it was remarkable that before centralization the operative procedures for gastric cancer consisted of a significantly smaller number of total gastrectomies compared to the period after centralization. The great spread of operations, with few procedures per surgeon, probably resulted in less surgical training, which may explain the preference for a less technical demanding procedure. Also, the introduction of the national clinical guidelines as well as the regularly audits after centralization resulted in high priority and attention towards surgical quality.

Despite centralization, the overall decreasing incidence of gastric carcinoma will result in fewer cases per department over time. We identified a total of 416 operations during 5½ year study period, which corresponds to a maximum of 80 procedures per year calling for further centralization. However, the "cut-off-point" for the number of gastrectomies to be carried out resulting in improved short-term as well as long-term results cannot be defined exactly. Moreover it has to be taken into consideration that a parallel reduction in gastric resections for benign diseases during the study period also has a big impact on training as it is reducing any potential volume [START_REF] Munksgaard | Centralization on fewer surgeons -an example from gastric surgery[END_REF].

Other studies have argued that mortality decreased significantly at hospitals performing more than 63 gastrectomies per year [START_REF] Hannan | The influence of hospital and surgeon volume on in-hospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer[END_REF]. Furthermore, it has been reported that each increase of ten patients in a surgeon's annual caseload is associated with a 41% lower hospital mortality [START_REF] Bachmann | Cohort study in South and West England of the influence of specialization on the management and outcome of patients with oesophageal and gastric cancers[END_REF][START_REF] Portanova | Results of specialization in the surgical treatment of gastric cancer in Peru[END_REF].

In the present study the case-load per department actually declined a little every year.

However, the surgeons involved in surgery for gastric carcinoma are identical with the surgeons involved in surgery for carcinoma of the esophagus and gastro-esophageal junction. Due to the national clinical guidelines a close collaboration between gastric and thoracic surgeons has been implemented resulting in an increased case-load for similar operations. This might also explain why the short-term results in this study are quite comparable to the best results obtained at high-volume [START_REF] Birkmeyer | Surgeon volume and operative mortality in The United States[END_REF][START_REF] Hannan | The influence of hospital and surgeon volume on in-hospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer[END_REF][START_REF] Callahan | Influence of surgical subspecialty, training on in-hospital mortality for gastrectomy and colectomy patients[END_REF]. Besides, other factors may also have contributed to the decline in both morbidity (anastomotic leakages) and hospital mortality. In accordance with the reflections made by others this includes the establishment of specialist multidisciplinary teams improving patient selection, as well as great advances in anaesthetic and postoperative care [START_REF] Robertson | Ventilatory and intensive care requirements following oesophageal resection[END_REF] The extent of lymphadenectomy has throughout the process been monitored as an indicator for surgical quality and in accordance with the classification in the TNM-system we have used removal of a minimum of 15 lymph nodes as quality criteria. Moreover, this is also the minimum of dissected lymph nodes necessary for proper staging and prognosis [START_REF] Gastric | Japanese classification of gastric carcinoma; second English edition[END_REF][START_REF] Maruyama | Pancreas preserving total gastrectomy for proximal gastric cancer[END_REF]. The proportion of patients, who had at least 15 lymph nodes removed increased substantially during the study period. Moreover, the median number of nodes removed was 24 for total gastrectomy at the end of the study period indicating that the recommendations in the guidelines were successfully implemented. The discussion concerning D1 and D2-lymphadenectomy in relation to survival cannot be qualified here as the data required to answer this question were not available.

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The overall five year survival rate of 43% appears to be acceptable. No directly comparable data from Denmark exist from the period before centralization. However, for the period from 1978 to1989 the relative risk of death at 5 years was at least 30% higher in Denmark compared to the European average [START_REF] Faivre | Eurocare working group. Survival of patients with oesophageal and gastric cancers in Europe[END_REF]. A recent study report that substantial differences in survival after gastric cancer resection within Europe remain [START_REF] Lepage | Eurocare working group. Operative mortality after gastric cancer resection and long-term survival differences across Europe[END_REF]. However, the 5 year survival rate in Denmark of 43% is now quite comparable to the survival rate of other European countries which varies between 24 and 42% [START_REF] Lepage | Eurocare working group. Operative mortality after gastric cancer resection and long-term survival differences across Europe[END_REF].

In conclusion, the process of centralization of all gastric cancer surgery in Denmark to only a few dedicated centers has been combined with the implementation of upgraded national clinical guidelines as well as a national database with systematic and continuous audits and annual

Furthermore, in

  1999 the Danish Societies of General and Thoracic Surgery established a working group with the purpose of establishing national clinical guidelines for diagnosis and treatment of cancer in the upper gastrointestinal tract. The guidelines were introduced in 2002 and hereafter a national database was launched in 2003 with the primary aim of monitoring the implementation of the guidelines. The aim of the present study was to examine the development of the quality of surgery and early postoperative outcomes following the centralization of gastric cancer surgery in Denmark together with the implementation of national clinical guidelines.

  Data from the annual reports from 2003-2008 are used in the present study and are compared with data from the period before centralization and implementation of national clinical guidelines [10]. Results are given with confidence limits of 95%.

  2007. Two departments merged in 2007 and the treatment continued at four departments hereafter. Using data from the National Pathology Registry and the National Registry of Patients we identified four to six patients annually between 2003-2006, who were treated outside the university departments and not registered in the gastric cancer database. Since 2007 no patient has been operated outside the university departments.

  The number of patients who had at least 15 lymph nodes removed increased considerably during the study period as only 19% fulfilled the indicator requirements in 2003 whereas it was 76% in 2008 (Fig1). In 2008, the mean number of nodes removed was 24 (3-52) for total gastrectomy and 15 (1-41) for other resections.The 5-year survival for patients who had undergone treatment with curative intent was 43 % (95%CI; 36-50).

1

 1 reports. Following these initiatives, substantial improvements in surgical quality and patient outcomes have been observed. Development in percentage of operations where at least 15 lymph nodes are removed during gastric cancer surgery in Denmark 2003-2008 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT

  2) 0.0 (0.0-13.2) 0.0 (0.0-9.5) 0.0 (0.0-18.5) 0.0 (0.0-14.8)1.3 (0.2-4.7)

Figure 1 .

 1 Figure 1. Development in percentage of operations where at least 15 lymph nodes are removed during gastric cancer surgery in Denmark 2003-2008.

Table 1 .

 1 Gastric cancer surgery activity and outcomes in Denmark between 2003-2008

	2003*	2004	2005	2006	2007	2008	Total

Table 2 .

 2 Comparison of gastric cancer surgery in Denmark: 1999-2003 versus 2003-2008

	1999-2003	2003-2008

Funding

None

Conflicts of interest

The authors have no conflict of interest.

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