Ann Surg Oncol (2014) 21:1138–1146 DOI 10.1245/s10434-013-3451-2

REVIEW ARTICLE – GASTROINTESTINAL ONCOLOGY

Outcome Quality Standards in Pancreatic Oncologic Surgery Luis Sabater, PhD1, Alvaro Garcı´a-Granero, MD1, Javier Escrig-Sos, PhD2, Maria del Carmen Go´mez-Mateo, MD3, Juan Sastre, PhD4, Antonio Ferra´ndez, PhD3, and Joaquı´n Ortega, PhD1 Department of Surgery, Hospital Clı´nico, University of Valencia, Valencia, Spain; 2Department of Surgery, Hospital General Universitario de Castello´n, Castello´n, Spain; 3Department of Pathology, Hospital Clı´nico University of Valencia, Valencia, Spain; 4Department of Physiology, University of Valencia, Valencia, Spain 1

ABSTRACT Purpose. To identify quality indicators and establish acceptable quality limits (AQLs) in pancreatic oncologic surgery using a formal statistical methodology. Methods. Indicators have been identified through systematic literature reviews and guidelines for pancreatic surgery. AQLs were determined for each indicator with confidence intervals of 99.8 and 95 % above and below the weighted average by sample size from the different series examined. Results. Several indicators have been identified with the following results as AQLs: resectability rate [59 %; morbidity, mortality, and pancreatic fistula rate in pancreaticoduodenectomy \55, \5, and \16 %, respectively; morbidity, mortality, and fistula rate in distal pancreatectomy \53, \4, and \31 %, respectively; number of lymph nodes retrieved [15; R1 resection \46 %; survival at 1, 3, and 5 years [54, [19, and [8 %, respectively. Conclusions. A series of different indicators for quality surgical care outcome in pancreatic cancer, as well as their

Previous Congress Presentations Partial and preliminary versions of this investigation have been presented at the II Symposium Grupo Espan˜ol Multidisciplinar en Ca´ncer Digestivo (GEMCAD) held in March 2009 in Valencia, Spain, and at the 110th Annual Congress of the Japan Surgical Society held in 2010 in Nagoya, Japan. Electronic supplementary material The online version of this article (doi:10.1245/s10434-013-3451-2) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 26 July 2013; Published Online: 6 January 2014 L. Sabater, PhD e-mail: [email protected]

limits, have been determined according to a standard methodology.

INTRODUCTION The investigation of quality surgical care is a multidimensional and complex challenge. The concept of quality may reflect different aspects of medical care, depending on the perspective under consideration such as: structure (sufficient personnel, resuscitation cart availability, working atmosphere, etc.), process (percentage of patients fulfilling antibiotic prophylaxis protocol, patients with informed consent, etc.), and direct clinical outcomes (morbidity, mortality, wound dehiscence, etc.) can be measured as a reflection of the quality of the medical care.1 Although all of these parameters are important and must be evaluated for an integrated and sustainable medical care system, some aspects are more relevant for each of the different professionals involved in the administration and management of the health care system. For the majority of clinicians and surgeons, quality means good clinical results and the effectiveness of their treatments or surgery. In the clinical setting, quality should be measured according to clinical indicators. In contrast with breast or colon and rectal cancer surgery, where several indicators of quality care and standards have been described, in pancreatic cancer surgery there is a lack of such indicators since most of the studies covering this area have mainly examined case volume and postoperative mortality.2–6 Given the complexity of pancreatic surgery, clinicians and surgeons need additional quality indicators (QIs) and their variability limits to reference what may be considered optimal or suboptimal. The aim of this investigation is to identify quality indicators of clinical relevance and to establish their

Outcome Quality Standards in Pancreatic Oncologic Surgery

acceptable quality limits (AQLs) in pancreatic cancer surgery according to a formal methodology. MATERIALS AND METHODS Search Strategy Our research included two parts: first, to identify the relevant clinical QIs. For this purpose, a comprehensive search of practice guidelines, consensus conferences, and reviews of pancreatic oncologic surgery published in English was performed in MEDLINE/PubMed, Embase, and the Cochrane Library. Second, once a series of QIs was selected from the aforementioned literature, a new search was performed for each QIs in combination with the Medical Subject Heading (MeSH) keywords pancreas, pancreatic, periampullary, surgery, cancer, and oncology. Only papers published from January 2000 to December 2010 were included in this part of the investigation. Additional relevant studies were also selected from the references obtained through the search. For inclusion in the analysis, each evaluated QIs had to be clearly mentioned in the text or be easily calculated from the data presented in the study. When studies included series with oncologic and nononcologic cases, a careful selection of the results of the oncologic cases was performed; when such a selection was not possible, the paper was not included. When several studies were reported by the same institution, the one with the highest number of cases was selected. Selection of QIs and Series Indicators were selected according to clinical relevance (factors that clearly affect the prognosis or the postoperative course) and frequency of appearance in the different studies to ensure a sufficient amount of data for evaluation. Each QIs was investigated individually, which is why there is a different number of studies and cases for each one, depending on the information available for each item in particular. Publications were only included in our study if they presented a minimum number of cases for each item. Series reporting national or collected databases with thousands of patients were excluded because these studies are not a clear reflection of the results of any given team or institution. Data Collection and Determination of Standards Standards for each QIs were determined by Statistical Process Control (SPC) techniques. P-charts (categorical data) and X-charts (continuous data) were performed to graphically represent the weighted average according to sample size as a quality standard. The studies are sorted in the charts according to the number of cases included in each series from a smaller to a larger volume of patients. According to Spiegelhalter

1139

et al.7,8 two limits, represented by 99.8 % confidence intervals (±3 standard deviation [SD]) and 95 % confidence intervals (± 2 SD), respectively, were calculated from the weighted average to establish variability limits. Any result outside these limits significantly deviates from the weighted average (p \ 0.002 and p \ 0.05, respectively), and is considered out of control according to the SPC terminology. In our study, the AQLs for each QI were defined as being within the limits of the 99.8 % interval, which would point toward a favorable outcome. When a result was within the AQLs it was considered to be within the standards. RESULTS Quality Indicators (QIs) The QIs selected for the pancreatic oncologic surgery were9–16 resectability rate, morbidity, mortality, pancreatic fistula, number of resected lymph nodes, margin invasion (R1), and survival. These indicators had to be calculated independently for pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) because some of the QIs such as morbidity, mortality, and pancreatic leakage are related to the specific surgical procedure. Resectability Rate The resectability rate was evaluated in 27 series17–43 that included more than 25 patients each for a total of 2,740 patients (Supplemental Table S1). Weighted average resectability was 76 %, and the quality limit was [59 % (Fig. 1). Pancreaticoduodenectomy The results of QIs for morbidity, pancreatic fistula rate, and mortality were calculated in 22 series2,44–64 with more than 100 patients in each (Table 1) for a total of 6,336 patients, 6,802 patients, and 6,812 patients, respectively. Weighted average morbidity, pancreatic fistula, and mortality were 45, 10, and 2 %, respectively. The quality limits were\55,\16, and \5 %, respectively. These results are shown in Supplemental Fig. 1a–c. Regarding the pancreatic fistula rate, there is a wide variation depending on the definition used. Among the 22 studies used to calculate quality limits in pancreatic fistula, 12 different definitions were identified. Most of them can be organized within three main groups: the International Study Group for Pancreatic Fistula (ISGPF) definition, a definition based on 30 ml of pancreatic juice per day and a third group based on a volume of 50 ml day-1. The pancreatic fistula rates, according to these definitions,

1140 FIG. 1 Resectability rate (Pchart). Each dot represents a study included in Supplemental Table S1. Green color is within 95 % confidence intervals; yellow color is between 95 % and 99.8 % confidence interval; and grey color is outside the 99.8 % limit

L. Sabater et al.

Proportion resections 1.0

Upper 99.8% limit 92% 0.9

Upper 95% limit 88%

0.8

Average 76%

0.7

Lower 95% limit 65% Lower 99.8% limit 59%

0.6

0.5

20

30

40

50

60

70

80

100

90

Number of cases

are as follows: the ISGPF group had a weighted average of 21 % and a quality limit\31 %; the volume C30 ml group had a weighted average of 8 % and a quality limit \13 %; and the volume C50 ml group had a weighted average of 10 % and a quality limit \16 %. DistalPancreatectomy (DP) Eleven series45,65–74 with more than 100 patients in each were used for evaluating morbidity, pancreatic fistula rate, and mortality (Table 2). Morbidity was calculated for a total of 2,651 patients, pancreatic fistula rate for 3,333 patients, and mortality for 2,871 cases. Weighted average morbidity, pancreatic fistula, and mortality for DP were 42, 23, and 1 % respectively, and the quality limits were \53, \31, and \4 %, respectively. The results of QIs for DP are shown in Supplemental Fig. 2a–c. Lymph Nodes The average number of lymph nodes evaluated in the selected series is shown in Supplemental Table S2 and Fig. 2a. Fourteen series49,75–87 with more than 70 patients in each were included, for a total of 3,093 patients. In these series, the weighted average was 19 resected lymph nodes and the quality limit [15. Margin Status Margin involvement (R1) was investigated in 16 series47,52,77,80,84,88–98 with more than 90 patients in each, for a total of 5,645 patients. The average percentage of patients with affected resection margin is shown in Fig. 2b and in the corresponding series of Supplemental Table S3. The weighted average for R1 resection was 36 % and the quality limit \46 %.

TABLE 1 Pancreaticoduodenectomy Author

Year

No Patients

Morbidity (%)

Fistula (%)

Mortality (%)

Bu¨chler

2000

331

38.4

2.1

2.1

Gouma

2000

300

47.5

7.5

1

Balcom

2001

489

37

11

1

Richter

2003

194

29.9

3.6

3

Schmidt

2004

202

43

9

3.9

Munoz-Bongrand

2004

242

–

13

–

Farnell Bassi

2005 2005

132 151

82 34

10.1 14.5

1.2 0.5

Kazanjian

2005

437

47.1

12.6

1.1

Winter

2006

1423

38

5

2

De Oliveira

2006

633

58.5

9

0.3

Aranha

2006

235

43

13.6

0.9

Carrere

2006

133

60

17.3

5

Grobmyer

2007

204

47

12

1

Pratt

2007

176

40.3

30

1.7

Schell

2008

369

61

9

4

Schnelldorfer

2008

357

39

–

1.4

Veillete

2008

581

–

12.9

1.9

Nikfarjam

2009

105

60

16

–

Haddad

2009

121

46

30

4.2

Mukherjee

2009

140

37.1

8.6

6.4

Busquets

2010

204

45

10

7

Morbidity, fistula rate and mortality

Survival Survival rates for 1, 3, and 5 years are shown in Table 3 and Supplemental Fig. 3a–c. Nineteen series46,47,52,78,89–91,97,99–109 with more than 100 patients in each have been included in this part of the study for a total of 5,752 patients. A summary of the

Outcome Quality Standards in Pancreatic Oncologic Surgery TABLE 2 Distal pancreatectomy Author

Year

No Patients

Morbidity (%)

Fistula (%)

Mortality (%)

Balcom

2001

190

37

14

0.1

Bilimoria

2003

126

53

19,8

3.2

Balzano

2005

123

48

34

0

Pannegeon

2006

175

42

23

0

Sierzega

2007

132

57

13,6

4.5

Kleeff

2007

302

35

11,6

2

Ferrone Goh

2008 2008

462 232

– 47

29 31

– 3

Kooby

2008

667

50

29

0.1

Vin

2008

220

–

13

2

Nathan

2009

704

33

21

1

Morbidity, fistula rate and mortality

weighted average for the different quality indicators and AQLs is shown in Supplemental Table S4. DISCUSSION A QI is a parameter used to measure the quality of medical assistance and provides information on aspects that can be improved. To evaluate the quality of a service or process, it is necessary to establish comparisons with some sort of guide or reference. This reference is what we define as a standard. Ideally, quality should be measured for populations with a common health care system and similar social customs (i.e., those in which different surgical teams have similar access to resources). Moreover, any risk-adjusted evaluation of the parameters involved in measuring the quality should be taken into account for comparisons. In the absence of these ideal conditions, it is necessary to find the standards in the data available in the literature, even if this means comparing systems as different as those in Japan, Europe, or the USA. This will at least offer a global perspective of what standards should be considered. Although several studies have demonstrated the importance of hospital volume and mortality, and they have made important contributions to our understanding of the quality of surgical care, these parameters are not enough.110–112 In 2009, Bilimoria et al.113 published an assessment of pancreatic cancer care based on formally developed quality indicators. In this relevant paper, 43 QIs, including structural factors, clinical care process, treatment appropriateness, efficiency and outcomes, are described; however, quality limits are established for only five items: number 26 (time from diagnosis to surgery or first treatment \2 months), number 29 (risk-adjusted perioperative mortality \5 %), number 31 (C12 cases performed per year),

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number 38 (C10 regional lymph nodes resected), and number 42 (operative time \ 10 h). There are important methodological differences between the study by Bilimoria et al.113 and ours. The most relevant difference is that the former study identifies QIs for a variety of factors based on the estimations of a panel of pancreatic cancer experts, and by using the data obtained from the National Cancer Data Base (2004–2005) in the USA. Nevertheless, the study establishes quality limits for only five items. Our study identifies outcome QIs and establishes AQLs for all the items according to worldwide data and uses a different statistical methodology. Because the two studies cover different aspects of quality health care and methodology, they can be considered complementary. An investigation such as ours necessarily presents several drawbacks when selecting QIs and series. Regarding QIs, there may be other indicators (e.g., operative time, blood transfusion, length of hospital stay, and costs). However, our selection is based on the most frequently published data available to have a relevant volume of series and cases for analysis. We used literature published in English between the years 2000 and 2010 for the selection of the series; the first decade of this century has seen a worldwide development and progress in this highly complex surgery. Albeit the inconveniences, we believe that our results offer both a general view of what the clinical indicators should be, as well as establishing AQLs that can be considered standard. In our review, standards and AQLs have been obtained using weighted average and confidence intervals of 99.8 and 95 %. With this method, the probability of a given observation being outside such limits is very low if the evaluated procedure is under control (i.e., \0.002 and \0.05, respectively). In SPC terminology, such limits establish alarm (99.8 %) or alert (95 %) areas. When a result is either above or below the alarm zone it may be considered either unfavorable or outstanding, depending on the nature of the evaluated variable. For example, regarding resectability, a result below the alarm zone should be considered a bad outcome; in morbidity, however, when a result is below the alarm zone, it is considered to be an excellent result. Some results of the series included in our investigation, such as pancreatic fistula in PD, show great variability, with figures between 30 and \5 %. This variability can be explained by the different definitions used in the studies. Among the 22 series used to establish the AQLs in pancreatic fistula, there were 12 different definitions. In 36 % of the studies, the definition was based on a volume C30 ml of amylase rich fluid after the 5th, 7th, or 10th postoperative day. In 22 % of the studies, the volume of amylase rich fluid had to be C50 ml after the same postoperative days or 1 day

1142 FIG. 2 a Lymphadenectomy (X-Chart). Each dot represents a study included in Supplemental Table S2. Green color is within 95 % confidence intervals; yellow color is between 95 % and 99.8 % confidence interval; and grey color is outside the 99.8 % limit. b R1 margin status (P-chart). Each dot represents a study included in Supplemental Table S3. Green color is within 95 % confidence intervals; yellow color is between 95 % and 99.8 % confidence interval; and grey color is outside the 99.8 % limit

L. Sabater et al.

(a) Mean lymph nodes 30

25

Upper 99.8% limit 23% Upper 95% limit 21% Mean 19 Lower 95% limit 17%

20

Lower 99.8% limit 15%

15

10

50

150

250

350

450

550

650

750

850

950

1050

Number of cases

(b) Proportion R1 resections 0.9 0.8 0.7 0.6

Upper 99.8% limit 46% Upper 95% limit 42% Average 36% Lower 95% limit 29% Lower 99.8% limit 26%

0.5 0.4 0.3 0.2 0.1 0

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

Number of cases

after eating. Only four series (18 %) used the definition of the International Study Group for Pancreatic Fistula (ISGPF). Other definitions required a radiological demonstration of fistula by fistulography or imaging studies. When the standards of pancreatic fistula rate are analyzed according to the aforementioned definitions, the quality limits are as follows: \31 % for the ISGPF criteria; \13 % for the volume C30 ml criteria; \16 % for the volume C50 ml criteria. These results show that the use of the ISGPF definition doubles the fistula rate in comparison with the other definitions. This stresses the need for using international definitions such as the ISGPF for pancreatic fistula114 and the Clavien-Dindo115 classification of surgical complications. The variability observed in margin status may reflect the fact that until recently there was no clearly established protocol for a standardized management of the surgical specimens. In fact, our results show that the acceptable limit in R1 resection was \46 %, whereas recent studies from well recognized surgical groups have evidenced that when the surgical

specimens are analyzed according to a standard protocol, then the rate of R1 resection is 70 %.116 Regarding the histopathologic analysis of the surgical specimen, an interesting item is the number of lymph nodes retrieved. We have found that the examination of a minimum of 15 lymph nodes is an acceptable limit. This result is within the range of different studies that have investigated this topic as a potential quality measure or for determining the minimum number of lymph nodes required to appropriately stage periampullary tumors.117 This parameter is essential for establishing the accurate stage of the patients, and it is dependent on both the surgeon and the pathologist. Taken together, the margin status and the number of lymph nodes are parameters reflecting the quality of the pathological examination, and therefore an additional quality indicator should be the standardized examination of the surgical specimen. Survival at 1, 3, and 5 years has also been included as an outcome QI, resulting in an average survival rate of 63, 28,

Outcome Quality Standards in Pancreatic Oncologic Surgery

1143

TABLE 3 Survival Author

Year

No patients (%)

1-year (%)

3-year (%)

5-year (%)

Wenger

2000

158

–

–

11.8

Kedra

2001

212

–

–

15.2

Ahmad

2001

116

60

23

19

Richter

2003

194

–

–

25.4

Kuhlmann

2004

160

64

–

8

Cleary

2004

123

–

–

14.6

Wagner Berger

2004 2004

211 128

67.1 –

23.4 –

19.8 9.3

Schmidt

2004

202

55

15

–

Kure

2005

182

–

–

6.6

Winter

2006

1423

65

37

18

Han

2006

123

–

–

12

Howard

2006

226

49

14

4

Ferrone

2008

618

–

–

12

Katz

2009

329

–

–

27

Boggi

2009

307

59

20

11.5

You

2009

219

–

24

14

Fatima

2010

617

69.8

–

17.4

Fabregat

2010

204

60

21

13

and 16 %, respectively. It is interesting that the results of survival-based studies between the years 2000 and 2010 do not differ greatly from the figures presented in the study by Garcea et al.118 which was based on all the series published from 1980 to 2008, including 154 papers and 25,930 patients, reporting a survival of 63, 22, and 12 % at 1, 3, and 5 years, respectively. In summary, we have identified a series of clinical outcome indicators in oncologic pancreatic surgery and AQLs according to data available in the medical literature. This study is clinically relevant because it offers different surgical groups involved in pancreatic cancer surgery an opportunity to monitor and compare their results. In addition, by identifying potential areas for improvement, pancreatic cancer patients will benefit from better surgical and clinical care. ACKNOWLEDGMENT The authors would like to thank Ms. Landy Menzies and Mr. Mervin Eyler for their language assistance in revising the English of this manuscript. DISCLOSURE All the authors declare no commercial interest, no financial interest, and no material support related to this investigation.

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