G A Gooiker

W Van Gijn

P N Post

Cjh Van De Velde

Raem Tollenaar
email: r.a.e.m.tollenaar@lumc.nl

Mwjm Wouters

prof.dr R A E M Tollenaar

A systematic review and meta-analysis of the volume outcome relationship in the surgical treatment of breast cancer. Are breast cancer patients better of with a high volume provider?

Aims

To conduct a systematic review of the literature on the volume-outcome relationship for the surgical treatment of breast cancer with consideration of the methodological quality of the available evidence and to perform a meta-analysis on the studies of considered good quality.

Methods

A systematic search was done to identify all articles examining the effects of hospital or surgeon volume on clinical outcome of the surgical treatment of breast cancer. Reviews, opinion articles and surveys were excluded. All articles were critically appraised on methodological quality and risk of bias. After strict inclusion, meta-analysis assuming a random effects model was done to estimate the effect of higher hospital or surgeon volume on patient outcome.

Results

We found 12 studies of good methodological quality which could be included for meta-analysis.

The results showed a significant association between high volume providers and an improved survival. The association is the most robust for surgeon volume ( HR 0.80 (0.71-0.90) and RR 0.85 (0.80-0.90). In addition there is an effect of hospital volume on the in-hospital mortality, although the mortality was very low (0.1-0.2%). Results of meta-analysis were heterogeneous.

Sensitivity analysis showed a larger effect size for studies also adjusting for comorbidity for both studies on hospital and surgeon volume. The data were not suggestive for publication bias.

Conclusions

The results show that survival after breast cancer surgery is significantly associated with high volume providers.

Introduction

Should breast cancer treatment be centralized in high volume breast units or not? Since Sainsbury and Gillis showed better survival after breast cancer surgery with specialized high volume surgeons, this question dominates the debate on the quality of breast cancer care in many western countries. 1 2 Minimal volume standards are supported by many studies, that have shown differences in mortality and survival between high and low volume providers, especially with high risk, low volume procedures. [START_REF] Bilimoria | Directing surgical quality improvement initiatives: Comparison of perioperative mortality and long-term survival for cancer surgery[END_REF][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] Birkmeyer | Hospital volume and late survival after cancer surgery[END_REF][START_REF] Simunovic | Influence of hospital characteristics on operative death and survival of patients after major cancer surgery in Ontario[END_REF][START_REF] Urbach | Differences in operative mortality between high-and low-volume hospitals in Ontario for 5 major surgical procedures: estimating the number of lives potentially saved through regionalization[END_REF] These studies suggest that the superior outcomes are the result of more experience and better hospital based services with high volume providers. Centralization of cancer care in high volume centres is therefore expected to improve the outcome for many patients. This could not just apply to high risk, low volume procedures, but also to more common, low risk procedures, such as the surgical treatment of breast cancer.

Though the evidence on the volume outcome relationship of the treatment of cancer seems convincing, there is also solid criticism on the methodological quality of these studies. Most studies are based on administrative data instead of clinical data and do not allow for differences in case mix between low and high volume providers. 9 10 Moreover, a minimal volume standard cannot be identified. And though the association between procedural volume and clinical outcomes is subject of research of many studies over more than a decade, the strength of the evidence and the clinical importance remains unclear.

In the Netherlands, the Dutch Cancer Society formed a study group to investigate whether there is a potential benefit of centralization of the treatment of breast cancer in the Dutch hospitals.

As a part of the report the study group decided to review all available literature on the association of hospital and surgeon volume with postoperative mortality and survival for the surgical treatment of breast cancer with consideration of the methodological quality of the available evidence and to perform a meta-analysis on the studies of considered good quality.

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Method

Systematic Search Strategy

A specialised librarian and one of the investigators (GG) performed a systematic search to identify all relevant studies describing the association between hospital or surgeon volume and clinical outcomes. We conducted a search in the electronic databases Medline, Embase and the Cochrane Library, with a combination of MESH terms and text words. Table 1 shows the search terms used for Medline and Embase. Because the volume of procedures is not well indexed in the electronic databases, we formulated the search terms as sensitive as possible to ensure no publications were missed. In addition, reference lists of relevant articles were hand-searched to identify additional articles, which could have been missed in the search. We also used the "related articles" function in Pubmed. The last search was on Febrary 1 2010.

Study selection

Two reviewers (GG and WvG) independently screened titles and abstracts of all 63 retrieved articles. Studies were selected using the following inclusion criteria.

 The subject of the study is the surgical treatment of breast cancer.

 Hospital or surgeon volume is an independent variable.  The outcome parameter is postoperative mortality or survival.

 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 24 articles remained. These were obtained in full text and were further selected by the same two reviewers using the following exclusion criteria:  Multiple publications are based on the same database. In this case the study with the lowest quality is excluded. When studies have similar quality, the study with the shortest period or the least recent period is excluded.

 The study period is older than 20 years. Studies with a study period starting before 1988 are excluded, since surgical and clinical care has considerably changed.  There is no multivariate analysis done with adjustment for at least age and gender.

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 Volume is not defined as a distinct number or cut-off value (e.g. studies that defined volume as 'specialization' are excluded).

No language constraints were placed. We did not use abstracts or unpublished data. In the appendix is an overview of the excluded studies.

Any discrepancies regarding inclusion or exclusion of a study were solved by discussion or by a third author (PP, MW).

Assessment of study quality & Data-extraction

Two authors (GG, WvG) critically appraised each study on methodological quality and risk of bias. Data of the included studies were gathered in a data-extraction form, which was based on the STROBE criteria, to record study characteristics, methodological quality and the study results (www.strobe-statement.org). The form was recorded in Access (Microsoft Corporation tm, Redmond WA, USA).

From each study characteristics were collected regarding the tumour type, the type of surgery, the study period, the unit of analysis (hospital or surgeon), and the number of analysed patients, hospitals and surgeons and the country.

In addition we appraised the quality of the data source (administrative or clinical data), the study design (prospective or retrospective) and the degree of risk adjustment. We noted the casemix factors for which statistical adjustment was done. Casemix factors were categorized as age and gender; comorbidities, tumour characteristics; (neo-)adjuvant treatment or urgency of the operation. We also checked the inclusion criteria of the study to verify if there was a probability of selection bias.

Cut-off values for high and low volume used by the studies were noted per volume group, along with how these cut-off points were determined. It was not possible to categorize the volume groups of all studies in equal volume categories, since there was a high variation in cut-off values.

The study results were recorded separately for each unit (surgeon or hospital) and outcome parameter (30-day mortality, in-hospital mortality, postoperative mortality and 2 year or 5 year survival), the crude outcomes for each volume group were noted (when reported).

Subsequently, we noted for each volume group and outcome parameter the estimated effect

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size after adjustment, expressed as odds ratio's (OR), hazard ratio's (HR) or relative risks (RR) with confidence intervals (CI) and measures of significance.

Synthesis of the data

The reference category varied between studies. Therefore, we had to convert the effect sizes so that the lowest group was the reference in all studies. As a result, the OR of mortality or the HR of survival reflected the odds of mortality in the highest volume group compared to the odds of mortality in the lowest volume group. For each study, we only included one comparison. We chose to compare the results for the highest volume groups with the results of the lowest volume groups.

To determine a pooled estimated effect, we used the random effect model for the metaanalysis. The random effects model accounts for expected heterogeneity, which is more appropriate with pooling of observational studies. Data of the included studies were represented in a forest plot for each unit and outcome parameter, with the pooled effect size represented at the bottom.

Heterogeneity was quantified by the I 2 test. An I 2 > 50 was considered as notable heterogeneity. [START_REF] Higgins | Measuring inconsistency in meta-analyses[END_REF] We conducted a sensitivity analysis of meta-analyses including more than three studies to further explore heterogeneity and assess the impact of subgroups. A subgroup analysis was done for data source (administrative vs clinical), case mix adjustment (adjustment for comorbidity or severity) and study country.

Publication bias was assessed for meta-analyses with more than three studies with an Egger's regression intercept and shown in a funnelplot. [START_REF] Egger | Bias in meta-analysis detected by a simple, graphical test[END_REF] The meta-analysis was conducted with Comprehensive Meta Analysis, professional version 2.2 (©2006, Biostat inc. Englewood, USA).

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Results

Study characteristics

Our initial search retrieved 63 potentially relevant studies concerning the volume outcome relationship of the surgical treatment of breast cancer (figure 1). After the first screening we excluded 39 studies: 15 studies examining other outcome parameters; 10 studies in which hospital or surgeon volume is not the independent variable (but specialization, teaching status, or urban vs. rural hospital, as independent variable); and 14 studies contained no primary data (editorials, letters). After the first selection, 24 studies remained and were fully obtained for more detailed evaluation. A total of 12 studies were further excluded, because the study period was to old (5), because identical databases were used (4), because no risk adjustment was done (2) and volume was not an independent variable in multivariate analysis (1).

Table 2 shows the characteristics of the remaining 12 studies. [START_REF] Allgood | Effects of specialisation on treatment and outcomes in screen-detected breast cancers in Wales: cohort study[END_REF][START_REF] Bailie | Survival after breast cancer treatment: the impact of provider volume[END_REF][START_REF] Chen | Does high surgeon and hospital surgical volume raise the five-year survival rate for breast cancer? A population-based study[END_REF][START_REF] Clayforth | Five-year survival from breast cancer in Western Australia over a decade[END_REF][START_REF] Gilligan | Relationship between number of breast cancer operations performed and 5-year survival after treatment for early-stage breast cancer[END_REF][START_REF] Guller | High hospital volume is associated with better outcomes for breast cancer surgery: analysis of 233,247 patients[END_REF][START_REF] Gutierrez | Are many community hospitals undertreating breast cancer?: lessons from 24,834 patients[END_REF][START_REF] Hebert-Croteau | Investigating the correlation between hospital of primary treatment and the survival of women with breast cancer[END_REF][START_REF] Nattinger | Exploring the surgeon volume-outcome relationship among women with breast cancer[END_REF][START_REF] Simunovic | Influence of hospital characteristics on operative death and survival of patients after major cancer surgery in Ontario[END_REF][START_REF] Skinner | Breast cancer: do specialists make a difference?[END_REF][START_REF] Mikeljevic | Surgeon workload and survival from breast cancer[END_REF] We included five studies with hospital volume as the independent factor, three studies with surgeon volume as the independent factor, and four studies with both hospital and surgeon volume as independent factors. Five studies were from the United States, one from Australia, two from Canada, three from the United Kingdom and one from Taiwan.

There was considerable variation between the included studies in the used cut-off values of the volume groups. For hospital volume, cut-off values of the highest volume strata varied between 40-195 procedures each year. The cut-off values of the lowest hospital volume strata varied between 10-86 procedures each year. As a result, it occurred that high volume in one study could be considered as low volume in another study and vice versa.

Methodological quality of the studies

All included studies had an observational design and 7/12 studies were based on clinical data, collected in cancer registries. The other five studies were based on administrative data.

The results of all included studies were adjusted for age and 7/12 were adjusted for comorbidity as well. The majority was adjusted for tumour stage and adjuvant treatment (11/12).

Study results

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Two studies were included concerning in-hospital mortality after breast cancer surgery. The mortality was low (0.1-0.2%), but was significantly lower in high volume hospitals.

Eight studies on hospital volume and survival were included of which seven studies showed a beneficial effect of a higher hospital volume on the survival.

All seven included studies concerning surgeon volume and survival, showed a better survival with high volume surgeons.

Pooled estimated effect size

Figure 2a shows the forest plot of the included studies regarding hospital volume and in-hospital mortality. The pooled estimated effect size was significant in favour of high volume providers in the analysis of postoperative mortality (OR 0.40 (CI 0.22-0.74). The results showed little heterogeneity (I 2 =12) Figure 2b shows the forest plots of the included studies on hospital volume and survival. The meta-analysis showed mixed results. The analysis of studies with Hazard Ratio's as effect size showed a significant pooled estimated effect size in favour of high volume hospitals (HR 0.84 (CI 0.76-0.93)). Though this result was heterogeneous (I 2 =76). The pooled estimated effect size of two studies with relative risks as effect size measure, was not significant (RR 0.90 (0.66-1.22)) and large heterogeneity was observed (I 2 =96).

Figure 2c shows the forest plots of the included studies regarding the effect of surgeon volume on survival. The meta-analysis showed a significant effect in favour of high volume. The pooled estimated effect size of studies with hazard ratio's was HR 0.82 (0.72-0.93) and with risk ratio's was RR 0.85 (0.80-0.91). The first analysis was statistically heterogenous ( I 2 =59) and the second analysis was statistically homogeneous (I 2 =0.0).

Sensitivity analysis

Table 3 shows the results of the sensitivity analysis of the 6 included studies on hospital volume and survival with hazard ratio's as effect size. Subgroup analysis of these studies showed a larger effect size for studies adjusting for differences in comorbidity(P=0.003). The pooled estimated effect of studies which were adjusted for comorbidity was HR 0.77 (CI 0.69-0.87, I 2 =46)

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Table 3 shows also the results of the sensitivity analysis of the 4 included studies on surgeon volume and survival with hazard ratio's as effect size. Subgroup analysis of these studies showed a larger effect size for studies adjusting for differences in comorbidity(P=0.003) .

Risk of publication bias

Figure 3 shows the qualitative analysis of publication bias of all studies regarding hospital volume and survival using HR's. Quantitative analysis with the Egger's regression intercept showed an intercept of -3.7 with a two-sided P value of 0.03.

Figure 3 shows also the qualitative analysis of publication bias of all studies regarding surgeon volume and survival using HR's. Quantitative analysis with the Egger's regression intercept showed an intercept of -1.6 with a two-sided P value of 0.41.

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Discussion

This is the first systematic review and meta-analysis examining the effect of surgeon and hospital volume on the outcomes of the surgical treatment of breast cancer, providing an overview of the current evidence. The present study shows that there is a strong significant association between high volume providers and improved survival in breast cancer treatment.

The association is most robust for surgeon volume [HR 0.80 (0.71-0.90) and RR 0.85 (0.80-0.91)].

In addition, there is an of hospital volume on in-hospital mortality, though one has to consider that postoperative mortality in breast cancer surgery is very low: 0.1-0.2% in the included studies.

The fact that no randomized studies on the volume outcome relationship for breast cancer treatment are available, hampers the interpretation of evidence provided in literature. All the studies included in our meta-analysis had an observational design and it was challenging to deal with the heterogeneity of the eligible studies. To reduce heterogeneity strict inclusion criteria were applied and only studies, which were at least risk-adjusted for age and gender, were included. All included studies using survival as an endpoint were adjusted for severity (tumour grade, stage and adjuvant treatment) as well. In addition, all studies with study periods older than 20 years were excluded, since breast cancer treatment has considerably changed in the last two decades. Studies defining volume as 'specialization' were also excluded since specialization was usually vaguely defined. Nevertheless, considerable heterogeneity remained.

The methodological quality of studies may have influenced the reported results. Therefore we performed a sensitivity analysis to examine the influence of study characteristics on heterogeneity. Sensitivity analysis showed a larger effect size with studies adjusted for comorbidity, with studies both on hospital volume and surgeon volume. The results were not sensitive to differences in any of the other variables.

Another issue was the considerable differences in cut-off values for volume categories between the included studies. High volume in one study was considered low volume in another and vice versa. This can have influenced our results. Therefore it was not feasible to identify a minimal required volume from the included studies.

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Acknowledging these limitations, the results of our meta-analysis provide evidence that quality of breast cancer surgery is superior with high volume providers. An explanatory theory for the volume-outcome relationship was already introduced by Luft et al in 1979. 25 26 He described two theories to explain the association: the practice makes perfect theory and the selective referral theory. Both theories can be relevant in our findings.

The practice makes perfect theory assumes that the more experienced a surgeon or a hospital is, the better the clinical outcomes. This seems a plausible explanation. A more experienced surgeon can for example have a higher percentage of radical excisions of the primary tumour, which improves recurrence-free survival. However, especially breast cancer treatment is a multidisciplinary process. Improved outcome can be also be obtained by more accurate imaging, adequate tumour biopsies, better decision making, (neo)adjuvant treatments and early detection of local recurrence and/or metastases. In short, the outcomes are the result of an adequate infrastructure in which adequate decisions are made and complex technical procedures are performed, all reflecting the high quality effort of an entire multidisciplinary team. This is further illustrated by Skinner et al, who showed that both hospital volume and surgeon volume contributed to a better survival. [START_REF] Skinner | Breast cancer: do specialists make a difference?[END_REF] The selective referral theory assumes that hospitals and surgeons with superior results attract more patients. This could also explain our findings. With increasing transparency of the quality of care provided by different hospitals, physicians can refer their patients to hospitals and surgeons with demonstrable good results. Patients are better informed and increasingly able to choose where they might receive optimal treatment. However, despite the numerous publications regarding the volume-outcome relationship, the mechanisms behind better clinical outcomes are not revealed yet. Several studies examined the association of provider volume with the use of different treatments or different interventions (breast conservative surgery, vs. breast ablative surgery). [START_REF] Sainsbury | Does it matter where you live? Treatment variation for breast cancer in Yorkshire. The Yorkshire Breast Cancer Group[END_REF][START_REF] Moritz | Variation in management of small invasive breast cancers detected on screening in the former South East Thames region: Observational study[END_REF][START_REF] Luther | Physician practice volume and alternative surgical treatment for breast cancer in Florida[END_REF][START_REF] Mckee | Provider case volume and outcome in the evaluation and treatment of patients with mammogram-detected breast carcinoma[END_REF][START_REF] Hiotis | Predictors of breast conservation therapy: size is not all that matters[END_REF] These studies showed a higher positive biopsy rate, more breast conservative surgery and a higher utilization of adjuvant therapy with high volume providers. This suggests that more accurate diagnosis, better resections and adequate use of radio-, chemo-and hormonal therapy may be the underlying reasons for improved outcomes in high volume centres. Unfortunately, studies investigating other outcome measures such as tumour recurrence, positive surgical margins or postoperative complications are lacking.

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The results of the present meta-analysis provide an overview of the current evidence for the volume outcome relationship in breast cancer surgery and shows that there is a strong significant relationship between high volume providers and improved survival. This can be valuable information for professionals as well as policymakers. The findings support the assumption that centralization of breast cancer has the potential of improving the quality of care. In Europe there are already several developments on this part. Specialist breast units are a key component of the European guidelines on the organisation of breast cancer care. The European Society of Breast Cancer Specialists, EUSOMA, already introduced a concept of specialised breast units in 2000 and recently established a minimal volume standard of 150 new cases per year for hospitals and 50 procedures per year for surgeons. 32 33 The French National Institute of Cancer requires a minimum of 30 procedures per year for surgeons (www.ecancer.fr/en/les-soins/recommandations). And in the United Kingdom, concentration of breast cancer care in hands of specialist doctors was already recommended in the Calman-Hine report in 1995. [START_REF] Morris | The impact of the Calman-Hine report on the processes and outcomes of care for Yorkshire's breast cancer patients[END_REF] In Ireland, recently breast cancer treatment is centralized in 13 specialized breast units (www.europadonnaireland.ie).

However, the question remains if minimal volume standards for the surgical treatment of breast cancer actually improve the quality of care. Volume is a proxy for better quality, but remains a poor predictor of the quality of care in individual institutions. With the introduction of minimal volume standards there is a risk of selecting hospitals with inferior outcomes, lacking the facilities and expertise (future) referral centres need 35 36 . Therefore a minimal volume standard should not be the only criterion in the accreditation of breast cancer units.

In addition, several other disadvantages of minimal volume standards are mentioned in the debate. The increasing elderly population with often complex comorbid disease and decreased mobility, demands for care in the region. Care is preferably provided in a hospital where the patient has been or is treated for his/her comorbid diseases. Minimal volume standards do not take geographical spread into account and can cause logistic problems. 36 37 This is undesirable since breast cancer is one of the most common diseases in the developed world. Nevertheless, we can assume that to invest in infrastructure for optimal care and to maintain a certain level of expertise within the whole medical team, a certain amount of patients is needed.

Minimal volume standards alone thus seem an inadequate basis for centralization. Additional quality criteria should be formulated to direct centralization initiatives. For this purpose more

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research is needed to identify essential structural or organisational characteristics and high leverage care processes that lead to the better outcomes. This kind of research can have direct implications for quality improvement programs.

Conclusion

This meta-analysis shows that survival after breast cancer surgery is significantly better with high volume providers. This suggests that concentration of breast cancer treatment in a limited number of centres might be beneficial. However, solid evidence for a specific minimal volume standard can not be identified in literature. And since volume is a simplistic proxy for quality of care, additional criteria have to be identified to direct centralization initiatives.

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Figure 1

 1 Figure 1 Overview of the study selection process

Figure 2c

 2c Figure 2cFunnel plots of the included studies in meta-analysis on surgeon volume and survival with two effect sizes: Hazard Ratio's and relative risks.

Figure 3

 3 Figure3Qualitative analysis of risk of publication bias: funnel plot of studies included in metaanalysis on hospital volume and survival using hazard ratio's.

Figure 4

 4 Figure 4 Qualitative analysis of risk of publication bias: funnel plot of studies included in metaanalysis on surgeon volume and survival using hazard ratio's.

Figure

  Figure legend(s)

Table 1

 1 Search terms used in the search in the databases Medline and Embase 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 .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 Survival/ AND surgery/ OR exp cancer surgery/ OR surgeon.mp. OR exp Surgeon/ OR surgical procedures.mp.

	Medline (Pubmed)
	("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/

outcome

Table 1

 1 Search terms used in the search in the databases Medline and Embase 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 Survival/ AND surgery/ OR exp cancer surgery/ OR surgeon.mp. OR exp Surgeon/ OR surgical procedures.mp. or exp Surgical Technique/

	Table(s)
	Medline (Pubmed)
	("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)

Table 3

 3 Sensitivity analysis of the heterogeneity of 6 included studies of hospital volume and surgeon volume and survival with HR as effect size

	Factor	Subgroup	Nr	HR	CI	P-value
	Hospital
	volume
	Datasource	Administrative	3	0.78	0.69-0.89	< 0.001
		Clinical	3	0.91	0.83-1.00	0.064
						0.07
	Comorbidity	Not adjusted	2	0.94	0.88-0.99	0.04
		Adjusted	4	0.77	0.69-0.87	< 0.001
						0.003
	Surgeon
	volume
	Datasource	Administrative	1	0.77	0.69-0.85	< 0.001
		Clinical	3	0.85	0.74-0.99	0.033
						0.24
	Comorbidity	Not adjusted	2	0.90	0.84-0.96	0.002
		Adjusted	2	0.76	0.69-0.84	< 0.001
						0.007


MD Michel Wjm Wouters
email: m.wouters@nki.nl

PhD Sabine Siesling

MD, PhD Marlies L Jansen-Landheer

Marloes A G Elferink

MSc José Belderbos

MD Jan-Willem W Coebergh

MD, PhD Franz Mnh Schramel

Michel W J M Wouters

Variation in treatment and outcome in patients with Non-small cell lung cancer by region, hospital type and volume in the Netherlands

Keywords: Non-Small Cell Lung Cancer, variation, quality of care, hospital volume, resection rate, guideline adherence

Background: Care processes for patients with NSCLC can vary by provider, which may lead to unwanted variation in outcomes. Therefore, in modern health care an increased focus on guideline development and implementation is seen. It is expected that more guideline adherence leads to a higher number of patients receiving optimal treatment for their cancer which could improve overall survival.

Objective: The aim of this study was to evaluate variations in treatment patterns and outcomes of patients with NSCLC treated in different (types of) hospitals and regions in the Netherlands. Especially, variation in the percentage of patients receiving the optimal treatment for the stage of their disease, according to the Dutch national guideline of 2004, was analyzed.

Methods: All patients with a histological confirmed primary NSCLC diagnosed in the period 2001-2006 in all Dutch hospitals (N=97) were selected from the population-based Netherlands Cancer Registry. Hospitals were divided in groups based on their region (N=9), annual volume of NSCLC patients, teaching status and presence of radiotherapy facilities. Stage-specific differences in optimal treatment rates between (groups of) hospitals and regions were evaluated.

Results: In the study period 43,544 patients were diagnosed with NSCLC. The resection rates for stage I / II NSCLC patients increased during the study period, but resection rates varied by region and were higher in teaching hospitals for thoracic surgeons (OR 1.5; 95%CI 1.2 -1.9, p=0.001) and in hospitals with a diagnostic volume of more than 50/year (OR 1.3; 95%CI 1.1 -1.5, p=0.001). Also the use of chemoradiation in stage III patients increased, though marked differences between hospitals in the use of chemoradiation for stage III patients were revealed. Differences in optimal treatment rates between hospitals led to differences in survival.

Conclusion:

Treatment patterns and outcome of NSCLC patients in the Netherlands varied by region and the hospital their cancer was diagnosed in. Though resection rates were higher in hospitals training thoracic surgeons, variation between individual hospitals was much more distinct. Hospital characteristics like a high diagnostic volume, teaching status or availability of radiotherapy facilities proved no guarantee for optimal treatment rates.

WORDS

Introduction

In literature a plethora of studies describes hospital volume as an important predictor of surgical outcomes.

Most of these studies evaluate the inverse relationship between volume and adverse surgical outcomes, like postoperative complications and mortality [START_REF] Chowdhury | A Systematic Review of the Impact of Volume of Surgery and Specialization on Patient Outcome[END_REF]. Only few authors address the mechanisms which lead to these differences. Intermediate outcomes, like the percentage of patients receiving potentially curative treatment for their cancer, could explain differences in survival. Moreover, other hospital characteristics reflecting the setting in which care is delivered to cancer patients, could be equally important predictors of outcome as hospital volume.

The variation of care processes by caregiver is widely recognized and can sometimes lead to unwanted variation in patients outcomes. Therefore, in modern health care an increased focus on guideline development and implementation is seen. It is expected that more guideline adherence leads to a higher number of patients receiving optimal treatment for their cancer which could improve overall survival. Moreover, evaluating differences in guideline adherence between hospitals can reveal the reasons behind the differences in outcome and can identify best practices with better outcomes. Differences in guideline adherence have been described for patients with Non small cell lung cancer (NSCLC) in several countries [START_REF] Dransfield | Improving the Lung Cancer Resection Rate in the US Department of Veterans Affairs Health System[END_REF][START_REF] Laroche | Improving Surgical Resection Rate in Lung Cancer[END_REF][START_REF] Potosky | Population Variations in the Initial Treatment of Non-Small-Cell Lung Cancer[END_REF][START_REF] Walsh | Baseline Institutional Compliance With NCCN Guidelines: Non-Small-Cell Lung Cancer[END_REF]. In the Netherlands, lung cancer is the second common tumour in men and the third in women, with an incidence of 71 and 31 per 100,000 person years in 2007, respectively (European Standardized Rate) [START_REF]IKC-net[END_REF]. In 2007, 10,533 patients were diagnosed with lung cancer and in eighty percent it concerned NSCLC. Only 14% of patients diagnosed with NSCLC in the Netherlands survive 5 years.

Unfortunately, these survival figures have not improved in the last decades [START_REF]IKC-net[END_REF]. While the incidence of NSCLC in men is decreasing since the early eighties, it has been rising in women until 1999. Fortunately, recent reports predict the end of this lung cancer epidemic in women, meaning an overall decrease in lung cancer patients in the near future [START_REF] He | The Beginning of the End of the Lung Cancer Epidemic in Dutch Women?[END_REF].

In 2004 the first Dutch National Guideline on NSCLC was introduced (www.oncoline.nl). The main reasons for development of this evidence-based guideline were the introduction of PET-scanning in staging NSCLC, induction chemotherapy in locally advanced NSCLC, and concurrent chemoradiation in stage III NSCLC.

According to this guideline surgical resection is the preferred treatment in patients with stage I or II NSCLC,

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who are fit to undergo surgery. Under the guidelines valid in our study period, surgery is also the treatment of choice in patients with limited stage III disease (T1-3N1). Patients with more advanced stage III NSCLC (cT4 and/or cN2 or cN3) should be treated with a combination of radiation therapy and chemotherapy (chemoradiation), if their performance score is sufficient (WHO-score 0-1). Chemoradiation is given in a concurrent regimen or sequentially. In general, stage III patients with malignant pleural effusions or tumour volumes too extensive for radiation treatment are no candidates for this combined modality therapy and are treated like stage IV patients with a platinum based chemotherapy regimen and / or best supportive care.

The aim of this study was to evaluate variations in treatment patterns and outcomes of patients with NSCLC treated in different (types of) hospitals and regions in the Netherlands. Especially, variation in the percentage of patients receiving optimal treatment for the stage of their disease, according to the Dutch national guidelines, was analyzed. 10) 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%.( 12)

Patients and Methods

Netherlands

Patients

All patients with a histological confirmed primary NSCLC diagnosed in the period 2001-2006 were selected from the NCR. Excluded from analysis were clinical diagnosis (no pathology), autopsy findings, sarcomas, lymphomas, neuro-endocrine and carcinoid tumours. Moreover, patients living abroad and cases with an incomplete registration status in the NCR (<1%) were excluded from analyses. Stage grouping was done according to TNM classification, 6th edition.

Hospitals and regions

Patients treated in all 97 hospitals in the Netherlands were included in this analysis. Hospitals were divided in groups based on their teaching status, availability of radiotherapy facilities, annual amount of NSCLC diagnoses (hospital volume) and their region. For the analyses concerning treatment, type of hospital was based on the hospital where the tumour was diagnosed reasoning that referral of patients is good care as

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well. For the analyses on postoperative mortality and survival, type of hospital was based on the hospital where the resection was performed. Hospitals were categorized in three groups: non-teaching, teaching and academic. A teaching hospital was defined as a hospital which provides medical training to residents. A distinction was made between a teaching hospital for chest physicians and thoracic/lung surgeons. In the group of teaching hospitals for thoracic/lung surgeons all academic hospitals were included in the teaching hospital group. Academic hospitals are teaching hospitals affiliated with a university. The one specialized oncology centre in the Netherlands was also classified as an academic hospital as well.

Radiotherapy is an essential part of the treatment of patients with stage III NSCLC. In the Netherlands there are 24 hospitals with radiotherapy facilities and 73 hospitals without a radiotherapy department. These hospitals are affiliated with a radiotherapy department on a different location. All radiotherapy departments treat patients with NSCLC. Hospitals were categorized as having radiotherapy facilities in the same location or not.

Hospital volume stands for the mean number of NSCLC diagnoses per year or for the mean number of lung resections per year. Hospital volume was categorized in 3 groups: less than 50, 50-100 and more than 100 diagnoses per year. In the period 2005-2006, 88% of the patients were operated in the hospital were the tumour was diagnosed.

In addition, hospitals were categorized according to their Comprehensive Cancer Centre region (9 groups). These Comprehensive Cancer Centres (CCCs) are non-hospital organizations that facilitate provision of consultancy services, implementation of national guidelines, coordinate organisation of cancer care, palliative care and host the cancer registry. Each CCC serves a region that includes five to twenty hospitals. Hospitals are affiliated to one CCC.

Stage grouping

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Since clinical stage determines treatment policies for NSCLC, the cTNM was used in the analysis concerning the treatment policies. For the analysis concerning the outcome after resection the pathological stage (pTNM) was applied. During the study period PET-scanning was introduced gradually as an addition to traditional clinical staging in NSCLC patients. Effectiveness and stage migration effects of PET-scanning were reported in a Dutch randomized study [START_REF] Van | Effectiveness of Positron Emission Tomography in the Preoperative Assessment of Patients With Suspected Non-Small-Cell Lung Cancer: the PLUS Multicentre Randomised Trial[END_REF]. A report on cost-effectiveness and availability of PET-scanning showed an unequal distribution across the Netherlands in 2005-06 of mobile units aimed especially for staging of localised lung cancer [START_REF] Doelmatigheidsonderzoek | PET gepast gebruik(t)[END_REF].

Treatment

Treatment was categorized by resection (pneumonectomy, lobectomy or segmentectomy), radiation therapy, chemotherapy or combined modality treatment (chemoradiation). Chemoradiation was defined as radiation therapy combined with chemotherapy given concurrent or sequentially. Treatment was described as percentages per clinical stage and age group (<75 years and ≥75 years).

The optimal treatment ratio was defined as the percentage of patients receiving optimal treatment by stage of the disease according to the Dutch guideline of 2004 [START_REF]Kwaliteitsinstituut voor de gezondheidszorg CBO. Richtlijn Niet-kleincellig longcarcinoom: stadiering en behandeling[END_REF]: resection for stage I and II patients, chemoradiation (possibly followed by resection) for stage III patients and chemotherapy for stage IV patients. Resection ratios of stage IIIa patients, usually part of combined modality therapy was investigated separately.

Statistical analyses

Logistic regression analysis was performed to examine the influence of age at diagnosis (<60, 60-74, 75+), gender, tumour size and invasion (cT), type of hospital of diagnosis (academic, teaching, general), radiotherapy facilities (same versus different location), hospital volume (<50, 50-100, >100), CCC-region and year of diagnosis on the odds of receiving optimal treatment per stage as described above.

Performance of the individual hospitals for these optimal treatment rates was exhibited in funnel plots using 95% control limits calculated around the mean.( 16) Each hospital was displayed as a scatter point presenting the rates of optimal treatment, i.e. resection for patients with stage I and II disease (adjusted for age, gender Follow-up was calculated as the time from diagnosis to death or to 1 st January 2008. Cox proportional hazard modelling was used to investigate the relation between resection and survival in patients with stage I and II disease, adjusted for age at diagnosis, gender, T-stage and year of diagnosis. Furthermore, this analysis was used to determine the relation between the resection rate of hospitals and overall survival. The hospitals were split into 3 groups based on their resection rate in the funnel plot: higher than the 95% control limit, within the 95% control limits or below the 95% control limit. STATA (version 10.0) was used and a p-value of 0.05 was considered as being significant.

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Results

In the period 2001-2006, 43,544 patients (69% male) were diagnosed with primary NSCLC (table 1) . During the study period the annual number of new NSCLC diagnoses increased from 6,774 patients in 2001 to 7,853 in 2006 (16%). The rise in incidence was much higher in women than in men, 45 and 5% respectively and occurred largely at middle age, contrasting the situation in males. Twenty-five percent of NSCLC patients were older than 75 years at the time of diagnosis. During the study period there has been a minor shift from clinical stage I and II disease to the more advanced stages, especially stage IV (Figure 1a). Table 2 shows the distribution of patients between the different types of hospitals and their CCC region. The majority of the patients with NSCLC were diagnosed in general hospitals without training status for chest physicians (68%) or thoracic surgeons (84%). Only 18% of the patients were diagnosed in a centre with radiotherapy facilities and 9% in an academic centre. About 54% of the patients were diagnosed in 32 hospitals with an annual diagnostic volume of more than 100 cases with NSCLC.

Treatment Primary surgery i.c. resection of the tumour through pneumonectomy, lobectomy or segmentectomy, was performed in 23% of all NSCLC patients, being 60% for patients with clinical stage I or II (Figure 1b). The others received radiotherapy, either with or without chemotherapy. A substantial number of patients received no oncological therapy at all, being 25% in stage I and II patients older than 75 years. In only 43% of these elderly the tumour was resected. This percentage increased only slightly during the study period. In the younger patient group (<75 years), a resection was performed in 79% of the patients.

Stage I and II

Logistic regression confirmed this role of age in the chance of a resection; in stage I and II patients older than 75 years the OR of a resection is 0.09 (95%CI 0.08 -0.11, p=0.000). Also, the size of the tumour, expressed in T stage, was important. Nevertheless, the chance of resection did not only depend on patient-and tumourcharacteristics. Patients with clinical stage I or II disease more often had a resection of their tumour in

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10 hospitals with a teaching status for thoracic surgeons (OR 1.5; 95%CI 1.2 -1.9, p=0.001) and in hospitals with a diagnostic volume of more than 50 NSCLC patients a year (OR 1.3; 95%CI 1.1 -1.5, p=0.001). Marked differences in resection rates appeared between groups of hospitals and regionally. The chance of a resection for stage I or II NSCLC ranged from an OR of 2.0 in one region (95%CI; 1.6 -2.4, p=0.000) to 0.77 in another (95%CI 0.63 -0.91; p=0.004). Figure 2 Higher age and advanced tumour size were the most important factors to abandon chemoradiation (Table 3).The odds of receiving chemoradiation were lower when a patient was diagnosed in an academic centre. Chemoradiation rates were not higher in high volume hospitals (>100 diagnoses a year) or in hospitals with radiotherapy facilities, except for hospitals training thoracic or lung surgeons (OR 1.6, CI 1.3-1.9). Also, regional differences in the use of chemoradiation were revealed, but they seemed larger between individual

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11 hospitals, independent of their region, volume of NSCLC patients, teaching status or radiotherapy facilities (Figure 3). Patients younger than 75 years diagnosed with stage IIIa in an academic hospital (26%), teaching hospital (26%) or in radiotherapy centre (22%) had a resection of their tumour more often than patients in non teaching (15%) or hospitals without radiation facilities (16%). Resection rates in stage IIIa declined slightly during the study period (not significant), while combined treatment of stage IIIa disease with chemoradiation increased, from 24% in 2001 to 43% in 2006 (p=0.001). A multivariate analysis revealed marked regional differences in the percentage of patients having surgery for their stage IIIa NSCLC, varying between 9 and 25%.

Stage IV

The percentage of patients with stage IV NSCLC at primary diagnosis gradually increased during the study period from 38% in 2001 to 44% in 2006. The use of chemotherapy in the primary treatment of stage IV patients younger than 75 years also increased in this period, from 31% to 50% (p=0.001), but approximately 40% of stage IV patients received no active treatment. Hospital differences in the palliative use of chemotherapy in stage IV NSCLC were not a part of the current study.

Survival

Patients who underwent a resection for stage I or II disease had a significantly higher survival than patients without a resection (Figure 4). Adjusted for age, gender, T-stage and year of diagnosis, overall survival of stage I and II patients was significantly higher in hospitals with a higher resection rate and significantly lower in hospitals whose resection rate was lower than the group of hospitals within the 95% control limits of the funnel plot of figure 2 (HR 0.88, 95%CI 0.83-0.93 and HR 1.15, 95% CI 1.07-1.24, respectively). Though, no differences were found in overall survival for patients who underwent resection in the hospitals with high and with low resection ratios.

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Discussion

The introduction of a national evidence-based guideline in 2002, appears to have had several effects on staging and patterns of care for NSCLC patients in our country. Especially the routine use of PET-scanning in the work-up of patients for curative therapy led to an increased number of patients with stage IV at diagnosis.

In addition, recommendations on the use of chemoradiation for stage III patients led to an increased utilization of radiotherapy combined with chemotherapy, concurrent or sequentially. Nevertheless this study reveals marked variation in treatment patterns and outcome of patients with NSCLC in our country. Not only are these differences influenced by patient or tumour characteristics, also the hospital of diagnosis seems to affect the treatment given. On the level of the individual hospital resection rates in stage I / II patients varied between 54 and 97 percent. The administration of potentially curative chemoradiation in stage III patients varied from less than 10 to more than 40 percent. These differences were only sporadically explained by structural differences between hospitals, like their teaching status or the availability of radiotherapy facilities. Nevertheless, the variation in optimal treatment rates identified in this study could mean that there's room for further improvement in the treatment of NSCLC patients in our country, possibly leading to actual survival benefits.

Inequality in the treatment of NSCLC has been addressed in many publications. Several patient factors are associated with lower odds of undergoing a potentially curative treatment for lung cancer. Higher age is the most important factor, but in studies from the United States as well as Europe gender, comorbidity, race, socio-economic status, region or country of origin have also proven to be predictive [START_REF] Cerfolio | Women With Pathologic Stage I, II, and III Non-Small Cell Lung Cancer Have Better Survival Than Men[END_REF][START_REF] Damhuis | Resection Rates and Postoperative Mortality in 7,899 Patients With Lung Cancer[END_REF][START_REF] Esnaola | Underuse of Surgical Resection for Localized, Non-Small Cell Lung Cancer Among Whites and African Americans in South Carolina[END_REF][START_REF] Jack | Geographical Inequalities in Lung Cancer Management and Survival in South East England: Evidence of Variation in Access to Oncology Services[END_REF][START_REF] Jazieh | Disparities in Surgical Resection of Early-Stage Non-Small Cell Lung Cancer[END_REF][START_REF] Lathan | The Effect of Race on Invasive Staging and Surgery in Non-Small-Cell Lung Cancer[END_REF]. These inequalities are not only due to decreased access to care, but also differences in physicians' treatment choices and differences in guideline implementation and adherence are believed to be of influence. Whereas active treatment of NSCLC patients appeared to be strongly associated with better survival, studies from Yorkshire and the Southeast of England [START_REF]Kwaliteitsinstituut voor de gezondheidszorg CBO. Richtlijn Niet-kleincellig longcarcinoom: stadiering en behandeling[END_REF][START_REF] Agresti | Approximate Is Better Than "Exact" for Interval Estimation of Binomial Proportions[END_REF]) demonstrated wide regional variations in the use of active treatments like surgery and radiotherapy (23;24). In one of these studies the use of any active treatment in NSCLC patients, independent of stage, ranged from 15% in one area to 42% in another. Despite corrections for case-mix the reasons behind this variation stayed unclear, but if the first hospital visited was a radiotherapy centre, patients were more likely to receive any active treatment.

M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 13

In the present study, we analyzed the treatment compliance according to the Dutch evidence-based guidelines, not only at the regional level, but also on the level of the individual hospital. For early stage NSCLC (stage I and II) surgical resection by (bi)lobectomy or pneumonectomy is treatment of choice and for advanced stage NSCLC (stage III) a combined treatment with radiotherapy and chemotherapy (sequentially or concurrent) is the advised treatment.

After adequate staging, the best chances for survival in early stage NSCLC are obtained by surgical resection.

Despite, our study showed marked differences in resection rates between individual hospitals and regions.

Patients who were diagnosed in a (specialized) centre, with a training status for thoracic surgery, seem to have higher chances for resection. These results confirm the findings of a regional study from the Netherlands showing that patients diagnosed with stage I or II disease at specialized centres or higher volume hospitals are more likely to receive surgical therapy. These differences were seen in all age groups and led to a better survival of patients diagnosed in specialized centres than those that initially went to a community hospital [START_REF] Li | The Influence of Provider Characteristics on Resection Rates and Survival in Patients With Localized Non-Small Cell Lung Cancer[END_REF].

Our study confirms these observations, but we cannot exclude that selective referral of patients with a good performance status has taken place before their NSCLC was diagnosed. Moreover, variation was most prominent on the individual hospital level, with resection rates for early stage NSCLC varying between 55 and 100%. Also among teaching hospitals and specialized centres a wide range of variation was exhibited, between 64 and 89% and 75 and 93% respectively. Considering the results of our study, the choice for a teaching hospital or specialized hospital does not guarantee better care and guideline compliance.

In literature many reports have shown that resection rates and surgical outcome of patients with early stage NSCLC can be improved by treatment in experienced and specialized multidisciplinary teams (2;3;26;27). The combination of heightened awareness, more adequate staging, improved surgical skill and postoperative care might lead to better outcome. In this context, the inverse relationship between procedural volume and mortality has been studied extensively (24;28). In our study half of the resections for early stage NSCLC were performed in low volume hospitals with an annual volume less than 20. Mortality hardly differed between lowand high volume hospitals, but ranged from 1% in the younger (< 60 years) to 8% in the oldest group (> 75 years). Opposite to our findings in high volume hospitals, a lower mortality rate was found in the specialized centres (1%). This is remarkable, considering the higher resection rates we found in elderly patients diagnosed with stage I and II NSCLC in the same centres. Patient selection for operative treatment as well as

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ACCEPTED MANUSCRIPT 14 peri-operative management of the older patient could thus be better in specialized centres. Future 'in depth' studies could reveal the aspects of these care processes (best practices) that lead to these better outcomes and can be used to improve the care for older NSCLC patients in the whole field.

In contrast with the plethora of studies investigating the differences in surgical outcome, only a few studies have investigated institutional differences for non-surgical treatments. In stage III patients with a favourable performance status, a potentially curative treatment by a combination of radio-and chemotherapy is recommended. In our study the use of this chemoradiation increased for stage IIIa as well as for stage IIIb patients. Nevertheless, our study showed a wide variation in the use of chemoradiation between regions and individual hospitals (figure 3), without a clear explanation based on their (infra)structural characteristics. For example, the use of chemoradiation was not different between hospitals with or without radiotherapy facilities.

With the data available in the NCR, we can only suggest that differences in experience with the complex radiotherapy techniques and the nontrivial toxicity encountered in patients undergoing these treatments, is causing hospital variation in the use of chemoradiation.

Our study has several limitations. First, only a limited set of (infra)structural characteristics of hospitals was available. For example, during the study period PET-scanning was introduced gradually for the staging of NSCLC in the Netherlands from 2000 on [START_REF] Doelmatigheidsonderzoek | PET gepast gebruik(t)[END_REF]. Improved clinical staging in hospitals using PET-scans could have influenced outcome for different stages of the disease. The addition of PET to conventional workup can improve staging and prevents unnecessary surgery in one out of five patients with suspected non-small-cell lung cancer [START_REF] Van | Effectiveness of Positron Emission Tomography in the Preoperative Assessment of Patients With Suspected Non-Small-Cell Lung Cancer: the PLUS Multicentre Randomised Trial[END_REF]. Though, in our study only a minor shift from early to advanced stages NSCLC was detected (Figure 1a), the differential introduction of PET-scanning in the Netherlands can be a confounding factor for the survival analyses performed. Furthermore, data on comorbidities and performance status of patients diagnosed with NSCLC were not available in the NCR. Lung cancer is predominantly a disease of the elderly. Physician treatment decisions can be guided by a patients' age and general medical condition, in all stages of the disease (29;30). On the other hand, in the Dutch setting there are no indications that patient groups of individual hospitals are truly different. Nevertheless, remarkable variation in resection rates (stage I-II) and the use of combined modality M A N U S C R I P T A C C E P T E D treatment (stage III) was shown. These differences are relevant, because they led to differences in survival, as was shown for stage I-II patients diagnosed in groups of hospitals with low-and high resection rates.

In conclusion, treatment patterns and outcome of NSCLC patients vary by region and the hospital their cancer is diagnosed in. Though, resection rates are higher in hospitals training thoracic surgeons, variation between individual hospitals is much more distinct. Hospital characteristics like a high diagnostic volume, teaching status or availability of radiotherapy facilities proved no guarantee for optimal treatment compliance.

Therefore, initiatives to improve quality of care for NSCLC patients should focus on actual differences in treatment patterns and outcome between hospitals, instead of using hospital characteristics as proxies for high quality of care. In addition, 'in depth' prospective documentation studies or medical audits could reveal high leverage processes of care that lead to the better outcomes. This information creates the opportunity to optimize treatment of NSCLC patients and move the medical field forward. WORDS:

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  Cancer Registry In the Netherlands, all newly diagnosed malignancies are registered in the nationwide population-based 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.(8) 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.(9) Cancers are staged according the TNM classification.(

8 and

 8 tumour size) and chemoradiation for those with stage III disease (adjusted for age, gender, tumour size and nodal involvement). Furthermore, logistic regression analysis was used to investigate the influence of age at diagnosis (<60, 60-74, 75+), gender, tumour size and invasion (cT), type of hospital of surgery (academic, teaching, general), hospital volume of resections (<10, 10-19, 20-29 and ≥30/year) and CCC-region on the odds of postoperative mortality, defined as death within 30 days after resection. Patients with stage IV disease were excluded from this analysis. Postoperative mortality was determined for patients diagnosed in 2005 and 2006 only.

  shows differences in resection rates between individual hospitals from 75 to 93% for hospitals with accredited training of thoracic surgeons and from 54 to 97% for hospitals without training facilities. The postoperative mortality rates after a resection for NSCLC were based on data from 2005 and 2006. Within 30 days after the resection 111 of 3206 patients died (3.3%), being 7.5% for patients older than 75 years. Tumour size (pT) and operative procedure also proved important factors. Patients operated in the 63 hospitals with less than 20 resections a year exhibited a similar postoperative mortality rate as in a higher volume hospital with 20 or more NSCLC resections annually (34 hospitals). Patients with stage I or II NSCLC operated in the academic centres had a significantly lower postoperative mortality (1.3%, p=0.012). Logistic regression showed that this reduced risk of dying postoperatively in academic centres is only borderline significant (OR 0.25; 95%CI 0.06 -0.93, p=0.038). Stage III During the study period 13,744 patients were diagnosed with stage III NSCLC, 4,938 stage IIIa and 8,806 stage IIIb patients. In the whole group of stage III patients 24% received combined modality treatment (figure 1b), 30% of the younger patients (<75 years, n=10,069) and 9% of the older patients (>75 years, n=3,675). The percentage of patients receiving chemoradiation went from 18% in 2001 to 29% in 2006 (p<0.001).

25 Figure 1a : 26 Figure 2 : 27 Figure 3 :

 251a262273 Figure 1a: Stage migration in patients diagnosed with Non Small Cell Lung Cancer during the study period 2001-2006

Figure 4 :

 4 Figure 4: Survival of stage I and II NSCLC patients with or without surgical resection.

Table 1 :

 1 Patient and tumour characteristics of patients diagnosed with Non Small Cell Lung Cancer in the

	Netherlands 2001-2006
		N	%
	Total
	Patients	43 544	100%
	Age (years)
	< 60	11 357	26%
	60-74	21 403	49%
	≥ 75	10 784	25%
	Gender
	male	30 172	69%
	female	13 372	31%
	Year of diagnosis
	2001	6 774	16%
	2002	6 954	16%
	2003	7 108	16%
	2004	7 395	17%
	2005	7 460	17%
	2006	7 853	18%
	Histology
	adenocarcinoma	14 454	33%
	squamous cell carcinoma	14 310	33%
	large cell carcinoma	14 332	33%
	other histology	448	1%
	Clinical stage
	In situ	78	0%
	stage I	9 544	22%
	stage II	1 930	4%
	stage III	13 715	32%
	stage IV	17 231	40%
	unknown	1 046	2%
	Pathological stage (in case of surgery)
	In situ	13	0%
	stage I	5 681	13%
	stage II	2 002	5%
	stage III	1 749	4%
	stage IV	389	1%
	unknown	56	0%

Table 2 :

 2 Number of Non Small Cell Lung Cancer patients per hospital volume category, teaching status, radiotherapy facility and region 2001-2006.

	N	%

Table 3 :

 3 Multivariate analysis for the odds of resection for stage I and II NSCLC in the Netherlands during

	2001-2006
		OR	95% CI	p-value
	Age (years)
	< 60	ref
	60-74	0.40	0.35-0.46	< 0.001
	≥ 75	0.09	0.08-0.11	< 0.001
	Gender
	male	ref
	female	1.00	0.90-1.12	0.896
	Year of diagnosis
	2001	ref
	2002	1,20	1,01-1,39	0.030
	2003	1,53	1,31-1,78	< 0.001
	2004	1,53	1,32-1,78	< 0.001
	2005	2,04	1,75-2,37	< 0.001
	2006	1,99	1,71-2,31	< 0.001
	T-stage
	T 1	ref
	T 2	0.48	0.43-0.54	< 0.001
	T 3	0.21	0.18-0.25	< 0.001
	Hospital volume
	<50	ref
	50-100	1.40	1.17-1.68	< 0.001
	>100	1.69	1.40-2.04	< 0.001
	Teaching status (chest physician)
	non-teaching hospitals	ref
	teaching hospitals	0.91	0.80-1.05	0.212
	academic hospitals	1.02	0.74-1.42	0.741
	Teaching status (lung-/ thoracic surgery)
	phn-tysician) non-teaching hospitals	ref
	teaching hospitals (incl. academic hospitals)	1.58	1.28-1.94	<0.001
	Radiotherapy facilities
	no	ref
	yes	0.92	0.77-1.05	0.304
	Region
	I	0.94	0.82-1.12	0.452
	II	1.52	1.23-1.76	< 0.001
	III	0.82	0.69-1.01	0.045

Table 4 :

 4 Multivariate analysis for the odds of receiving combined modality therapy for stage III NSCLC

	OR	95% CI	p-value

Acknowledgements

The authors would like to thank the working group Output of the NCR for providing data from the cancer registry and all the members of the Quality of Cancer Care working party of the Dutch Cancer Society for financing.

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B L Van Leeuwen

S Rostoft Kristjansson

R A Audisio

Should specialized oncogeriatric surgeons operate older unfit cancer patients?

Introduction

Increasing age is one of the strongest risk factors for cancer development [START_REF] Depinho | The age of cancer[END_REF] . Life expectancy is continuingly increasing, and in many countries it advances by several hours per day [START_REF] Kirkwood | A systematic look at an old problem[END_REF] . Thus, the number of older adults with cancer is likely to increase over the coming years. Surgical treatment has a pivotal role in offering long-term survival for cancer patients with solid tumors. Furthermore, when cure cannot be achieved, surgery can palliate symptoms and improve quality of life. Cancer registry data from the Netherlands and Norway have shown that surgical management of lung, prostate, and rectal cancer steadily decline with increasing age [START_REF] Janssen-Heijnen | Prognostic impact of increasing age and co-morbidity in cancer patients: A population-based approach[END_REF][START_REF] Endreseth | Rectal cancer treatment of the elderly[END_REF] . For lung cancer, this trend prevails even when correcting for co-morbidity 5 . Conversely, the resection rate for colon cancer remains high even in advanced age.

Under elective conditions, there is a marked variability in the prevalence of postoperative complications according to cancer site and type of operation. In one study of cancer surgery in patients aged 70 years and older, 30-50% developed post-operative complications, and half of them were major, potentially lifethreatening ones [START_REF] Audisio | Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study[END_REF] . The emergency setting is associated with an excessively high mortality and morbidity rate, even more pronounced in elderly patients [START_REF] Turrentine | Surgical risk factors, morbidity, and mortality in elderly patients[END_REF][START_REF] Hamel | Surgical outcomes for patients aged 80 and older: morbidity and mortality from major noncardiac surgery[END_REF][START_REF] Leung | Relative importance of preoperative health status versus intraoperative factors in predicting postoperative adverse outcomes in geriatric surgical patients[END_REF] .

For surgeons deciding upon treatment in older adults with a solid tumor, a number of challenges have to be faced. Firstly, there is little evidence from the medical literature regarding this group of patients because they are often excluded from clinical trials due to advanced age and/or severe co-morbidity [START_REF] Hutchins | Underrepresentation of patients 65 years of age or older in cancer-treatment trials[END_REF] . Secondly, the elderly population is characterized by a marked variability in the rate of aging, and chronological age does not accurately reflect remaining life expectancy and treatment tolerance. Patients of the same age may be frail, with severe co-morbidity and functional impairment, or fit, with no co-morbidities and a high physical activity level. Thirdly, the training of oncologists and surgeons is mainly focused on choosing the best therapy for physically fit younger patients. Geriatricians, who are experienced in dealing with elderly patients, have limited knowledge about oncology and surgery.

Over the recent years, orthogeriatric units for hip fracture patients and acute care of the elderly units have been proven beneficial for frail elderly [START_REF] Adunsky | A comparative study of rehabilitation outcomes of elderly hip fracture patients: the advantage of a comprehensive orthogeriatric approach[END_REF][START_REF] Saltvedt | Reduced mortality in treating acutely sick, frail older patients in a geriatric evaluation and management unit. A prospective randomized trial[END_REF][START_REF] Adunsky | Five-year experience with the 'Sheba' model of comprehensive orthogeriatric care for elderly hip fracture patients[END_REF] . These units have been organized in a geriatric-based setting, demonstrating lower in-hospital mortality rates. Such units are seeking to provide all surgical, medical, and rehabilitation needs of the complex frail elderly patients in one single unit in the hospital. It is possible that a similar approach would benefit frail cancer patients.

DECISION-MAKING IN ELDERLY PATIENTS

Almost all age-related changes lead to reduced function and physiological decline, and chronological age is an important predictor of morbidity. However, due to the variability in the rate of functional deterioration, an individualized assessment of elderly patients in order to establish their biological age is necessary. An important first step in the decision-making process is to determine remaining life expectancy, which will depend on chronological age, co-morbidity, and functional status. Knowing the distribution of remaining life expectancy at different ages is useful. It has been calculated from US statistics that among women who have reached 80 years, 25% will live more than 13 years, approximately 50% will live for at least nine years (median), while 25% will live shorter than five years [START_REF] Walter | Cancer screening in elderly patients: a framework for individualized decision making[END_REF] . The most important determinants are functional status (does the patient need daily assistance?) and number and severity of comorbidities.

The next step would be to evaluate whether the cancer represents a threat to the patient's health or function within her remaining lifetime. The term competing risks describes how a number of diseases may compete to threaten the patient's life [START_REF] Welch | Estimating Treatment Benefits for the Elderly: The Effect of Competing Risks[END_REF] . It must also be considered whether the cancer and complications from the cancer represents a threat to functional status and quality of life. The risk of having surgery must be weighted against the risk of not having surgery. It is well documented that both caregivers and health professionals under-estimate the older adult's willingness to undergo treatment [START_REF] Hamel | Age-related differences in care preferences, treatment decisions, and clinical outcomes of seriously ill hospitalized adults: lessons from SUPPORT[END_REF] . Furthermore, older adults in general want to know about their diagnosis and prognosis. In a study published in 2001, 88% of patients over the age of 65 wanted as much information as possible about their cancer disease [START_REF] Ajaj | Should elderly patients be told they have cancer? Questionnaire survey of older people[END_REF] . However, among patients who required assistance in their activities of daily living, 28% did not want to know details about their cancer diagnosis.

In summary, the decision-making process requires that the surgeon has sufficient knowledge about remaining life expectancy of the patient, the anticipated natural progress of the cancer disease, and the risks of surgery for the individual patient. Furthermore, in order to tailor pre-operative counseling, the surgeon needs to know if the patient has cognitive dysfunction, and he or she should be sensitive to the patient's preferences regarding information about the disease and prognosis.

PRE-OPERATIVE ASSESSMENT OF ELDERLY CANCER PATIENTS

The lack of evidence and the variability within the elderly population put the usefulness of established preoperative assessment tools, such as the American Society of Anesthesiologists Physical Status Classification System (ASA classification) into question. Recent evidence from cohorts of elderly colorectal cancer patients indicate that the majority of electively operated patients are classified as ASA II or ASA III, and that the ASA classification is not sufficiently sensitive to predict differences in operative risk between those two groups [START_REF] Kristjansson | Comprehensive geriatric assessment can predict complications in elderly patients after elective surgery for colorectal cancer: a prospective observational cohort study[END_REF][START_REF] Sjo | Short term outcome after emergency and elective surgery for colon cancer[END_REF] . In geriatric medicine, elderly patients are systematically assessed across areas where they frequently present with problems: functional status, co-morbidity, nutritional status, emotional status, polypharmacy, cognitive function, and social support. This comprehensive geriatric assessment (CGA) allows for an estimate of the patient's remaining life expectancy, functional reserves, and treatment tolerance. Furthermore, CGA may uncover previously unknown medical problems, in addition to providing information with importance to adherence to treatment protocol and improving discharge planning. In the Preoperative Assessment of Cancer in the Elderly (PACE) study, elements from CGA were found to predict post-operative complications [START_REF]Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help A SIOG surgical task force prospective study[END_REF] . A recent study including a cohort of 178 elderly colorectal cancer patients with a median age of 80 years also found that CGA, but not increasing age, predicted surgical morbidity [START_REF] Kristjansson | Comprehensive geriatric assessment can predict complications in elderly patients after elective surgery for colorectal cancer: a prospective observational cohort study[END_REF] .

The main drawback of CGA is that it is a time-consuming assessment. A number of shorter screening tools are being tested. The aim is to identify frail elderly patients who will benefit from a full CGA. Frailty describes an elderly patient who is at heightened vulnerability to adverse health status change because of a multisystem reduction in reserve capacity [START_REF] Martin | Frailty: different tools for different purposes?[END_REF] . How to identify frailty, however, remains controversial. A frail patient is likely to have several issues that will be identified through CGA, such as cognitive dysfunction, malnutrition and functional limitations, issues that increase the surgical risk. In some cases, these risks may be addressed and decreased. As an example, pre-operative cognitive dysfunction increases the risk of post-operative delirium. It has been shown that a multicomponent intervention, including early mobilization, early interventions for volume depletion, and communication methods (eyeglasses and hearing aids) may prevent delirium [START_REF] Inouye | A Multicomponent Intervention to Prevent Delirium in Hospitalized Older Patients[END_REF] .

POST-OPERATIVE OUTCOMES

When discussing elderly patients and outcomes after surgery the emphasis has usually been on short term outcomes and survival. [START_REF] Refaie | Major cancer surgery in the elderly: results from the American College of Surgeons National Surgical Quality Improvement Program[END_REF][START_REF] Massarweh | Impact of advancing age on abdominal surgical outcomes[END_REF] This is not without reason; surviving surgery used to be an accomplishment in itself. However, in past decades anesthesiological techniques and peri-operative care have evolved to such an extent that early post-operative death is rare, even in the elderly population. Reports on outcomes after (major) surgical interventions in the elderly population have been positive, emphasising that in the fit elderly patient there is no limit to which surgical interventions can be performed, and outcomes are comparable to that in younger generations. [START_REF] Gardner | Ovarian cancer cytoreductive surgery in the elderly[END_REF][START_REF] Berry | Risk factors for morbidity after lobectomy for lung cancer in elderly patients[END_REF] Several major problems remain when interpreting these seemingly positive results. Firstly, there is the problem of patient selection. As discussed above there is no uniform definition of fit or frail, and even less uniform are the screening tools used to identify whether the patient is in one category or the other. Secondly, there certainly is more to life after surgery than survival. This holds true for every age category, but especially for the elderly as the remaining lifespan is less than in the younger age category. Preserving functional independence is key in maintaining quality of life in elderly, yet this outcome is rarely included in surgical publications. Lawrence and colleagues showed that of patients 60 years old or more, a substantial group experienced protracted disability at 6 months after major abdominal operations. Several components of physical and mental functioning did not return to preoperative levels. [START_REF] Lawrence | Functional independence after major abdominal surgery in the elderly[END_REF] One interesting example of post-operative functional decline is post-operative cognitive dysfunction (POCD). This phenomenon may affect several aspects of cognitive functioning such as memory and concentration and occurs in patients of all ages. In contrast to what is generally believed, knowledge of the incidence and impact of POCD on quality of life is limited. [START_REF] Culley | General anesthetic-induced neurotoxicity: an emerging problem for the young and old?[END_REF] There is neither a uniform definition of POCD in the literature, nor are there standardised diagnostic criteria. Although there are a few studies describing its incidence in an elderly surgical population, it has been studied more extensively in a younger population and in younger patients undergoing open heart surgery requiring cardio-pulmonary bypass. [START_REF] Rasmussen | Postoperative cognitive dysfunction: Incidence and prevention[END_REF][START_REF] Stroobant | Neuropsychological functioning 3-5 years after coronary artery bypass grafting: does the pump make a difference?[END_REF] The causes of POCD are postulated to be multifactorial, but there is increasing evidence that the inflammatory response caused by the surgical procedure plays a role. [START_REF] Van Den Kommer | Homocysteine and inflammation: Predictors of cognitive decline in older persons?[END_REF][START_REF] Exel | Interaction of atherosclerosis and inflammation in elderly subjects with poor cognitive function[END_REF] A relation between POCD and the development of Alzheimer's disease has been suggested, but so far solid evidence is lacking. [START_REF] Hu | Inflammation: A bridge between postoperative cognitive dysfunction and Alzheimer's disease[END_REF] The older brain has a reduced potential for recovery compared to the younger brain, and it is therefore to be expected that postoperative cognitive decline in the elderly patient will have greater implications in terms of loss of independent functioning and quality of life. Part of our elderly population are only just able to function independently pre-operatively, any functional loss post-operatively will go hand in hand with increased consumption of care and increased costs. A factor closely related with POCD is post-operative delirium. This acute cognitive complication is seldom reported in the surgical literature.

There is a wide range of estimates of postoperative delirium, depending on type of surgical procedure. It is estimated to occur in 13-33% of patients undergoing elective abdominal aneurysm surgery [START_REF] Ansaloni | Risk factors and incidence of postoperative delirium in elderly patients after elective and emergency surgery[END_REF][START_REF] Benoit | Risk factors and prevalence of perioperative cognitive dysfunction in abdominal aneurysm patients[END_REF] and up to 60 % of patients undergoing hip surgery. [START_REF] Marcantonio | The association of intraoperative factors with the development of postoperative delirium[END_REF] Frail elderly are at increased risk of delirium with an incidence of up to 60%. [START_REF] Francis | A prospective study of delirium in hospitalized elderly[END_REF] Although all elderly patients may be at some risk for the development of delirium, it is possible to identify patients at highest risk preoperatively and focus interventions on this group. [START_REF] Beliveau | Perioperative care for the elderly patient[END_REF] .This is especially interesting as postoperative delirium is predictive of the development of long term POCD.

Long term survival is seldom reported when discussing outcome after major surgical procedures in elderly patients. Rutten et al. showed that especially in the older patient categories (≥ 75 years), the occurrence of complications after rectal surgery is associated with a higher post-operative mortality even at 6 months post-operatively. They go as far as to recommend non-surgical treatment for the frail elderly patient with rectal cancer. [START_REF] Rutten | Controversies of total mesorectal excision for rectal cancer in elderly patients[END_REF] Similarly, Legner showed that postoperative complications after abdominopelvic surgery increase the rate of discharge to an institutional care facility for elderly patients. [START_REF] Legner | The significance of discharge to skilled care after abdominopelvic surgery in older adults[END_REF] Both 30-day and 1year mortality were increased in this patient category to 4.3% and 22.2%, respectively, compared to patients discharged to their home. These potential risks of a surgical intervention require more investigation, and surgeons treating patients in the older age categories should be aware of them.

ALTERNATIVES TO SURGERY

Technically, there is no difference between operating a solid tumor in an octogenarian or a 30-year old patient. If anything, the loss of firmness of tissue can make resections easier. The response to the intervention, however, may be very different, depending on the age and frailty category the patient belongs to.

In view of the above the old adagium "first do no harm" seems perfectly applicable to the elderly surgical population. Limiting the harm by limiting the surgical intervention, whilst maintaining oncological principles (ie still aiming at a radical resection of the tumor), seems a logical choice to make when faced with doubt about what treatment to choose. And this is exactly where the heart of the problem is. How do we decide what patient to operate on and what patient to decline a possibly life saving procedure? It has been reported that declining guideline breast surgery (including lymph node evaluation) to elderly women (even the octogenarians) substantially decreases breast cancer survival. [START_REF] Owusu | Effect of undertreatment on the disparity in age-related breast cancer-specific survival among older women[END_REF][START_REF] Bouchardy | J Undertreatment strongly decreases prognosis of breast cancer in elderly women[END_REF] As mentioned above regarding the treatment of rectal cancer in frail elderly patients, the mortality that can be related to the surgical procedure is sometimes too high to justify surgery. An interesting alternative to surgery in this respect is the treatment of patients with rectal tumors with chemoradiation only. [START_REF] Habr-Gama | Non-operative management of rectal cancer after neoadjuvant chemoradiation[END_REF] Part of the patients treated in this way may not show any evidence of tumor recurrence, even after several years of follow-up.

In parallel to this approach, it has been shown that the wait and see approach for the surveillance of renal masses prevents overtreatment especially in the older and frail patient category. [START_REF] Volpe | The role of surveillance in the management of small renal masses[END_REF] The surgical removal of renal cell carcinomas < 4cm does not lead to a decrease in mortality, a fact that warrants consideration, especially in the frail elderly patient with decreased life expectancy.

Limiting the surgical resection to part of the affected organ may also be a good alternative in the treatment of some tumors. Transanal endoscopic microsurgery for T1 and T2 rectal tumors is a far less invasive procedure than rectal resection in elderly frail patients. [START_REF] Baatrup | Transanal endoscopic microsurgery in 143 consecutive patients with rectal adenocarcinoma: results from a Danish multicenter study[END_REF] For intraabdominal tumors in general, the laparoscopic approach seems to be associated with better immune and inflammatory responses and earlier post-operative recovery. Although the evidence is scarce, this minimally invasive surgical approach may especially benefit the elderly patient. [START_REF] Tei | Postoperative complications in elderly patients with colorectal cancer: comparison of open and laparoscopic surgical procedures[END_REF] Limited lung resections such as wedge resections for stage Ia lung cancer (tumors < or = 2cm), instead of a formal lobectomy have recently been shown not to decrease cancer specific survival whilst causing less postoperative complications. [START_REF] Wisnivesky | Limited resection for the treatment of patients with stage IA lung cancer[END_REF] Again, this is an interesting alternative, especially for the frail elderly patient.

Self expanding metal stents appear to be a safe alternative to emergency surgery for obstructive colorectal cancer. [START_REF] Sebastian | Pooled analysis of the efficacy and safety of self expanding metal stenting in malignant colorectal obstruction[END_REF] They may be used as a bridge to surgery to avoid emergency surgery, as emergency surgery has a high mortality and morbidity. Stents may also be a suitable alternative in the palliative setting.

ROOM FOR IMPROVEMENT

It is striking that the basic surgical curriculum offers little education in geriatric care. [START_REF] Webb | Geriatrics for surgeons: infusing life into an aging subject[END_REF] In our opinion there is room for improvement, not only concerning the training of doctors, but the training of nurses as well. Educating medical staff in the recognition of specific geriatric syndromes, such as delirium, and communication with hearing impaired elderly or patients with cognitive dysfunction is only the beginning of optimising peri-operative care. [START_REF] Cicerchia | Geriatric syndromes in peri-operative elderly cancer patients[END_REF] Furthermore, medical staff dealing with elderly patients need to be educated about managing co-morbidity and polypharmacy, and the importance of functional assessments for treatment planning. It is up to geriatricians and surgeons combined to change the omnipresent image that geriatric medicine is dull and stuffy. On the contrary, geriatric medicine is vibrant, complicated, and full of opportunities. We need to convince our hospital boards and governments that developing better education and care pathways for our frail elderly patients will require time and money. Many clinically relevant questions remain, leaving open a vast field of basic and general research.

Even with appealing alternatives, (major) surgical procedures will still be performed in unfit elderly patients in the future, and at an increasing rate. The question remains whether the decision making process and peri-operative care should be performed by specialized surgeons. Taking all of the above into account, from estimating frailty, to choosing the optimal treatment and optimising peri-operative care, it is evident that we need to improve the knowledge regarding taking care of elderly patients among surgeons. start training our surgeons how to take care of elderly patients. The elderly form such an essential part of the surgical population that it seems inappropriate to limit this training to specialized surgeons. However for the treatment of the frail subpopulation of elderly, educating dedicated surgeons may be justifiable.

The authors have no conflict of interest to report. This paper was not funded through external sources.