- Email: [email protected]
UCLA Appropriateness Study
Defining Surgical Quality in Gastric Cancer: A RAND/UCLA Appropriateness Study Savtaj Brar, MD, MSc, Calvin Law, MD, MPH, Robin McLeod, MD, FACS, Lucy Helyer, MD, MSc, Carol Swallow, MD, PhD, FACS, Lawrence Paszat, MD, MSc, Rajini Seevaratnam, MSc, Roberta Cardoso, RN, PhD, Matthew Dixon, MD, Alyson Mahar, MSc, Laercio G Lourenco, MD, Lavanya Yohanathan, MD, Alina Bocicariu, MD, Tanios Bekaii-Saab, MD, Ian Chau, MD, Neal Church, MD, Daniel Coit, MD, FACS, Christopher H Crane, MD, Craig Earle, MD, MSc, Paul Mansfield, MD, FACS, Norman Marcon, MD, Thomas Miner, MD, FACS, Sung Hoon Noh, MD, Geoff Porter, MD, MSc, FACS, Mitchell C Posner, MD, FACS, Vivek Prachand, MD, FACS, Takeshi Sano, MD, PhD, Cornelis van de Velde, MD, PhD, FACS, Sandra Wong, MD, FACS, Natalie Coburn, MD, MPH, FACS 5-year survival rates of 40% to 60% in series from Asia, the 5-year survival for similarly staged patients in North America only approaches 30%.1 Differences in outcomes are postulated to be due, in part, to differences in genetics, the effects of stage migration, and treatment. Additionally, variation in the quality of surgical care can be an important contributor to differences in survival between patients.1 Differences in outcomes can also exist due to the complexity of decision making and the lack of conclusive evidence about optimal surgical management. Improved outcomes after gastrectomy have been associated with high-volume surgeons and might be due to technical proficiency and intraoperative decision-making processes.2 It is suggested that treatment in low-volume centers can have the effect of patients undergoing inappropriate surgical resections, with the low-volume surgeon choosing the less technically difficult operation due to less expertise and training.3 Interestingly, and probably not surprisingly, the standardization of surgical technique and training associated with the conduct of randomized controlled trials in The Netherlands has been credited with improving population-based outcomes for patients undergoing gastrectomy afterwards.4 This suggests considerable potential for quality improvement in surgery for GC. Unfortunately, many surgeons might not be aware of factors that can affect outcomes in patients undergoing curative resection for GC.5 Evaluations of processes of care are a component of quality-improvement efforts and can occur through establishment of quality indicators. The aim of this study was to establish appropriate and necessary processes of care for surgical management in GC patients. Although guidelines for the treatment of GC have been produced by various organizations, none address in detail the aspects of care related to surgery.
In 1881, Theodor Billroth performed the first successful resection for gastric adenocarcinoma (GC). More than a century later, surgical resection remains the only curative treatment for patients with gastric cancer. However, outcomes after surgical resection vary widely. Despite Disclosure Information: Nothing to disclose. Study funded by Canadian Cancer Society grant 019325. Dr Coburn (Career Scientist Award) and Dr Paszat have received funding through the Ontario Ministry of Health and Long-Term Care. Dr Law is supported by the Hanna Family Research Chair in Surgical Oncology. Presented in poster format at the Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology (GI-ASCO), San Francisco, CA, January 2012 and the Society of Surgical Oncology Annual Cancer Symposium, Orlando, FL, March 2012. Received October 19, 2012; Revised November 29, 2012; Accepted January 29, 2013. From the Departments of Surgery (Brar, Law, McLeod, Swallow, Coburn) and Medicine (Earle, Marcon), University of Toronto, Institute for Clinical Effectiveness Studies (Paszat, Earle, Coburn), Sunnybrook Research Institute (Seevaratnam, Cardoso, Dixon, Mahar, Bocicariu, Coburn), Toronto, Ontario, Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Helyer, Porter), Department of Surgery, University of Calgary, Calgary, Alberta (Church), Canada, Department of Surgery, Maimonides Medical Center, Brooklyn (Dixon), Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York (Coit), NY, Gastroenterology Surgery, Sao Paulo Federal University, Sao Paulo, Brazil (Lourenco), Department of Surgery, Brown University, Providence, RI (Yohanathan, Miner), Departments of Medicine and Pharmacology, The Ohio State University, Columbus, OH (Bekaii-Saab), Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, UK (Chau), Departments of Radiation Oncology (Crane) and Surgical Oncology (Mansfield), MD Anderson Cancer Center, Houston, TX, Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea (Noh), Department of Surgery, University of Chicago, Chicago, IL (Posner, Prachand), Department of Surgery, Cancer Institute Hospital, Tokyo, Japan (Sano), Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands (van de Velde), and Department of Surgery, University of Michigan Health System, Ann Arbor, MI (Wong). Correspondence address: Natalie Coburn, MD, MPH, FACS, Division of Surgical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Suite T2-60, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5. email: [email protected]
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
GC LN RAM RCT RY
¼ ¼ ¼ ¼ ¼
gastric adenocarcinoma lymph node RAND/UCLA Appropriateness Methodology randomized controlled trial Roux-en-Y
The RAND/UCLA Appropriateness Methodology (RAM) is a well-described methodology that has been developed to help determine appropriate care for patients in situations where strong, evidence-based guidelines are not possible. The RAM is a statistically validated methodology that incorporates expert consensus, and this methodology has been shown to produce appropriateness criteria that have face, construct, and predictive ability.6,7 Therefore, we organized an international expert panel to define appropriate and necessary processes of surgical care for GC. As GC is relatively rare in North America, international representation was sought to assemble a panel of experts withhigh levels of expertise and experience in a variety of clinical settings.
METHODS The RAM process is presented in Figure 1. In summary, the RAM involves performing a literature search to determine the evidence for processes of care; creating clinical scenarios for treatment options; assembling an expert panel to grade the appropriateness of treatments; and evaluating all appropriate processes for necessity. A detailed literature review was conducted to synthesize the latest evidence of a broad range of perioperative processes in GC. Electronic literature searches were conducted using Medline and Embase from January 1, 1998
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to December 31, 2010. Searches were performed for the following topics: endoscopy; radiology; multidisciplinary cancer care; peritoneal lavage; diagnostic laparoscopy; laparoscopic resection; lymph node (LN) dissection; neoadjuvant or adjuvant therapy for resectable GC; downstaging therapy for unresectable GC; palliative procedures; total or subtotal gastrectomy; gastrectomy with cholecystectomy; management of familial GC; institution volume; intraperitoneal chemotherapy; LN number; resection margin; multi-visceral resection; perforation; reconstruction; sentinel LN biopsy; surgeon volume and training; and post-treatment surveillance. Exclusion criteria included animal and/or ex vivo samples; did not provide short or long-term outcomes; involved mixed cancers; review articles; meta-analyses; abstracts; conference proceedings; editorials/letters; and case reports. More than 40,000 abstracts were reviewed with the subsequent inclusion of 691 articles in the literature review. Results from the literature review were used to inform both the development of clinical scenarios and scoring by the expert panel. Several systematic reviews were subsequently published based on the results of this literature review, outlining full details of the search process and results.8-20 Panelists were recruited through solicitation of nominations from the heads of surgical, medical, and radiation oncology units at all major cancer centers in North America, as well as corresponding authors of articles on clinical management of GC. From the applicants, a 16-member international, multidisciplinary panel of physicians with expertise in the care of GC was assembled, balancing practice type and geographic location. The expert panel was weighted to surgical representation, as the study was designed to focus on surgical process of care (Table 1).
1. Review and summary of the literature for processes of care
2. Expert panel members independently score scenarios for appropriateness
3. Data analyzed to guide expert panel discussion
4. Expert panel meeting to discuss areas of disagreement regarding processes of care in the scenarios
5. Re-scoring of scenarios for appropriateness and necessity
Figure 1. Overview flow chart of the modified RAND/UCLA Appropriateness Methodology used to develop the processes of care in gastric cancer.
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Table 1.
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Expert Panel Membership
Name
Tanios Bekaii-Saab Ian Chau Neal Church Daniel Coit Christopher Crane Craig Earle Paul Mansfield Norman Marcon Thomas Miner Sung Hoon Noh Geoff Porter Mitchell Posner Vivek Prachand Takeshi Sano Cornelis Jan Hadde van de Velde Sandra Wong
Speciality
Country
Affiliation
Medical Oncology Medical Oncology Laparoscopic Surgery Surgical Oncology Radiation Oncology Medical Oncology Surgical Oncology Gastroenterologist Surgical Oncology Surgical Oncology Surgical Oncology Surgical Oncology Laparoscopic Surgery Surgical Oncology Surgical Oncology Surgical Oncology
United States England Canada United States United States Canada United States Canada United States Korea Canada United States United States Japan The Netherlands United States
The Ohio State University Royal Marsden Hospital University of Calgary Memorial Sloan-Kettering Cancer Center University of Texas MD Anderson Cancer Center University of Toronto University of Texas MD Anderson Cancer Center University of Toronto Brown University Yonsei University College of Medicine Dalhousie University University of Chicago University of Chicago Cancer Institute Hospital Leiden University Medical Centre University of Michigan Health System
Panelists were presented with 357 scenarios about the surgical management of GC. Definitions of key terms appear in Appendix 1 (online only). The scenarios were piloted initially with 3 surgical oncologists before being sent to the expert panel. Results of the literature review were first provided to each panelist. Next, the clinical scenarios were sent to the panelists in the spring of 2010. For each scenario, panelists were asked to score the appropriateness of the treatment in each scenario. Appropriateness is defined as “the expected health benefit of an intervention exceeding the expected negative consequences by a wide enough margin that the procedure is worth doing, regardless of cost.”21 Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate).7 Panelists returned the scoring for the scenarios and the data were analyzed for areas of agreement and disagreement. The panel then met in Toronto October 21e23, 2010 for a discussion of the scenarios and scoring. Discussion was focused on areas where there was disagreement. Some scenarios were rewritten for clarification based on discussions and recommendation from the expert panel. All scenarios were rescored for appropriateness by each panelist. In final analysis, a procedure was classified as “appropriate” if the median rating was 7 to 9, with agreement; “inappropriate” if the median rating was 1 to 3, with agreement; and “uncertain” if the median rating was 4 to 6, with agreement. Agreement was met when 4 panelists rated outside the 3-point region containing the median (ie, 1 to 3, 4 to 6, 7 to 9). Disagreement occurred when 4 panelists rated in each extreme 3point region (ie, 1 to 3, 7 to 9). Level of agreement
was indeterminate when it failed to satisfy either of these criteria. Any scenario where there was agreement that the statement was appropriate was subsequently scored for necessity in the same manner. Necessity is a more stringent criterion than appropriateness. If a procedure is necessary, the expected benefits outweigh the expected harms by such a margin that the service must be offered to the patient. In the final classification, each statement could be labeled as appropriate, necessary, inappropriate, indeterminate, uncertain, or disagreement. The study design was submitted to and approved by the Research Ethics Board of Sunnybrook Health Sciences Centre.
RESULTS The panelists scored 357 scenarios regarding the surgical management of GC. Agreement on appropriateness was reached in 109 of scenarios and disagreement in 10 scenarios, with the remaining scenarios scored as uncertain. Where agreement was made, 60 scenarios were appropriate (scores of 7 to 9), 1 was indeterminate (scores of 4 to 6), and 48 were inappropriate (scores of 1 to 3). In the scenarios that were appropriate, only 3% were deemed necessary. Type of resection For patients with curative GC of the proximal stomach, total gastrectomy was considered appropriate for all patients. For patients with distal GC, distal gastrectomy was considered appropriate and necessary for all patients. Although total gastrectomy scored very low for distal lesions, agreement was indeterminate (Table 2).
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Table 2.
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Type of Gastrectomy T1, N0
Proximal gastric cancer (M0) Proximal Disagreement gastrectomy (5.0) Total Appropriate gastrectomy (8.0)* Distal gastric cancer (M0) Distal Necessary gastrectomy (8.0)* Total Indeterminate gastrectomy (2.0)
Clinical T and N status T1e2, N2e3 T3e4, N0
T2, N0
T1e2, N1
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (3.5) Appropriate (8.0)*
Necessary (8.0)* Indeterminate (2.0)
Necessary (8.0)* Indeterminate (2.0)
Necessary (8.0)* Indeterminate (2.0)
T3e4, N1
T3e4, N2e3
Indeterminate (3.5) Appropriate (8.0)*
Indeterminate (3.5) Appropriate (8.0)*
Indeterminate (3.5) Appropriate (8.0)*
Necessary (8.0)* Indeterminate (2.0)
Necessary (8.0)* Indeterminate (2.0)
Necessary (8.0)* Indeterminate (2.5)
Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario.
Laparoscopic gastrectomy Open distal gastrectomy was considered appropriate for all patients with distal GC. Laparoscopic distal gastrectomy was appropriate for distal GC patients with T1-2 N0 disease only (Table 3). For patients with proximal GC, laparoscopic total gastrectomy was considered appropriate for patients with T1 N0 disease and indeterminate for patients with T2 N0 disease (Table 3). There was disagreement about the use of the laparoscopic approach in patients with GC more advanced than T2N0 (Table 3). Lymph nodes A D0 lymphadenectomy was inappropriate in all cases more advanced than T1N0 GC. For patients with T1 N0 disease, the appropriateness scores for performance of D1 or D2 lymphadenectomy were indeterminate (Table 4). In patients with more advanced cancers (>T1N0), appropriateness scores for D1 lymphadenectomy ranged from 4.0 for proximal GC and 4.5 to 6.0 for distal GC, with no agreement. However, D2 lymphadenectomy was considered appropriate in all patients with tumors >T1N0 (scores of 8.0). Necessity scores for D2 lymphadenectomy in these patients were high but indeterminate (6.0 to 8.0). The expert panel found that it was appropriate, but not necessary to assess 16 or more Table 3.
Proximal GC Distal GC
LNs in a curative resection. Sentinel LN biopsy was believed to be inappropriate (results not shown). Resection of other organs The expert panel believed that routine splenectomy for all patients undergoing gastrectomy was inappropriate (Table 5). On the question of whether a splenectomy should be performed if the LNs in the splenic hilum were enlarged, an appropriateness score of 7.0 was given, with indeterminate agreement. The expert panel disagreed on the appropriateness of omentectomy with gastric resections (range 4.5 to 6.5). The need for resection of the lesser sac peritoneum was also indeterminate. The panel believed it was inappropriate to perform routine cholecystectomy with gastrectomy, although in the presence of cholelithiasis, the appropriateness score for cholecystectomy was 7, with indeterminate agreement. Margins The expert panel believed that it was appropriate to perform intraoperative pathologic assessment with frozen sections of the proximal margin if the gross margin is <5 cm, or if the lesion is believed to be T3/T4 (Table 6). If the proximal margin was positive on intraoperative pathologic assessment for N0 and M0 patients, it
Laparoscopic Gastrectomy (M0) T1, N0
T2, N0
T1e2, N1
Appropriate (7.5)* Appropriate (7.5)*
Indeterminate (7.0) Appropriate (7.0)*
Disagreement (5.0) Disagreement (5.0)
Clinical T and N Status T1e2, N2e3 T3e4, N0
Disagreement (4.0) Disagreement (4.0)
Disagreement (4.0) Disagreement (4.0)
Results (in parentheses) shown as median appropriateness score or, when applicable, mean necessity score. *Agreement on appropriateness or necessity of scenario.
T3e4, N1
T3e4, N2e3
Disagreement (4.0) Disagreement (4.0)
Disagreement (4.0) Disagreement (4.0)
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Table 4.
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Extent of Lymphadenectomy (M0) Clinical T and N status T1e2, N2e3 T3e4, N0
T1, N0
T2, N0
T1e2, N1
Indeterminate (6.5) Indeterminate (6.5)
Disagreement (5.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Proximal tumor D1 Indeterminate (7.0) D2 Indeterminate (6.0)
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Distal tumor D1 D2
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T3e4, N1
T3e4, N2e3
Indeterminate (4.5) Appropriate (8.0)*
Indeterminate (4.5) Appropriate (8.0)*
Indeterminate (4.5) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario. D0, D0 lymphadenectomy; D1, D1 lymphadenectomy; D2, D2 lymphadenectomy.
was appropriate and necessary to perform a re-resection of the stomach and/or abdominal esophagus; and appropriate, but not necessary to perform a re-resection of the thoracic esophagus (Table 7). If the proximal margin was positive on intraoperative pathologic assessment, and Table 5. Scenario
Multiorgan Resection Appropriateness score
It is appropriate to perform a splenectomy In all gastric cancer resections Inappropriate (1.0)* All D2 lymph nodes dissections Inappropriate (1.5)* All total gastrectomy resections Inappropriate (1.0)* If enlarged LN in the hilum of the Indeterminate (7.0) spleen It is appropriate to perform a omentectomy In all curative gastric resections Disagreement (6.0) In all curative gastric resections Disagreement (6.5) performed open In all curative gastric resections Disagreement (4.5) performed laparoscopically It is appropriate to perform a lesser sac peritonectomy In all curative gastric resections Indeterminate (3.0) In all curative gastric resections Indeterminate (3.0) performed open In all curative gastric resections Indeterminate (3.0) performed laparoscopically It is appropriate to perform a cholecystectomy In all gastric resections Inappropriate (3.0)* In all distal gastrectomies Inappropriate (1.5)* In all total gastrectomies Indeterminate (2.0) All D2 LN dissections Indeterminate (2.5) Only if there are stones noted in the Indeterminate (7.0) gallbladder Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario. LN, lymph node.
if the patient was N1 and M, there was agreement that it was appropriate to perform a re-resection of the stomach, abdominal, and/or thoracic esophagus. If the patient had N2 to 3 and M0 disease, there was agreement that it was appropriate to perform a re-resection of the stomach and/ or abdominal esophagus, but not the thoracic esophagus. There was no clear recommendation for re-resection if it meant performing a pancreaticoduodenectomy, with indeterminate scores for patients with N0 (appropriateness score 7.0) and N1 disease (appropriateness score 6.0) and agreement of uncertainty with N2 to 3 disease (appropriateness score 5.0). For margin status assessed on the final pathology report, with results available on postoperative day 7, there were no clear recommendations on performing reresection if the proximal, distal, or radial margins were Table 6. Margin Assessment Scenario
Appropriateness score
It is appropriate to perform intraoperative pathologic assessment (frozen sections) of the proximal margin For all gastric resections Indeterminate (7.0) If the gross margin is <5 cm Appropriate (7.0)* If the gross margin is <3 cm Appropriate (8.0)* If the lesion is believed to be T1 or T2 Indeterminate (7.0) If the lesion is believed to be T3 or T4 Appropriate (7.0)* It is appropriate to perform intraoperative pathologic assessment (frozen sections) of the distal margin For all gastric resections Indeterminate (5.0) If the gross margin is <5 cm Indeterminate (7.0) If the gross margin is <3 cm Indeterminate (7.5) If the lesion is believed to be T1 or T2 Indeterminate (5.0) If the lesion is believed to be T3 or T4 Indeterminate (6.0) Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario.
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Table 7. Scenario
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Intraoperative Positive Margins Appropriateness score
If resection is performed and the proximal margin on intra-operative frozen section is positive, it is appropriate to re-resect the patient to negative margins If re-resection would only include the Necessary (7.5)* stomach and the patient is N0 If re-resection would necessitate Necessary (7.0)* abdominal esophagus resection and the patient is N0 If re-resection would necessitate Appropriate (7.0)* thoracic esophagus resection and the patient is N0 If re-resection would only include the Appropriate (9.0)* stomach and the patient is N1 If re-resection would necessitate Appropriate (9.0)* abdominal esophagus resection and the patient is N1 If re-resection would necessitate Appropriate (7.0)* thoracic esophagus resection and the patient is N1 If re-resection would only include the Appropriate (8.0)* stomach and the patient is N2 or N3 If re-resection would necessitate Appropriate (8.0)* abdominal esophagus resection and the patient is N2 or N3 If re-resection would necessitate Indeterminate (7.0) thoracic esophagus resection and the patient is N2 or N3 If resection is performed and the distal or radial margin on intraoperative frozen section is positive, it is appropriate to re-resect the patient to negative margins If re-resection would require Indeterminate (7.0) pancreaticoduodenectomy and the patient is N0 If re-resection would require Indeterminate (6.0) pancreaticoduodenectomy and the patient is N1 If re-resection would Uncertain (5.0)* pancreaticoduodenectomy and the patient is N2 or N3 Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario.
positive, as all scenarios given were scored as indeterminate (Appendix 2, online only). Type of reconstruction With respect to reconstruction after resection, the expert panel believed it was appropriate but not necessary to reconstruct a subtotal gastrectomy via Roux-en-y (RY) gastrojejunostomy (Table 8). Other reconstruction options included Billroth I, which trended toward inappropriate, and Billroth II gastrojejunostomy, which
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scored indeterminate. Reconstruction after a total gastrectomy via an esophagojejunostomy, with or without a J pouch, was believed to be appropriate. Nutrition and drainage Scenarios about nutrition and postoperative drainage were included (Appendix 3, online only). The expert panel believed that it was appropriate that a feeding jejunostomy should be selectively placed for patients undergoing gastric resection (appropriateness score 7.5). For other scenarios about feeding jejunostomy, none reached agreement with appropriateness scores in the 4.0 to 5.5 range. No agreement was reached about preoperative total parenteral nutrition, postoperative nasoenteric tube drainage, or use of contrast studies to rule out anastomotic leak.
DISCUSSION Improving quality of surgical care was addressed by assembling an international, multidisciplinary expert panel using RAM to define the processes of care that are appropriate and necessary for patients with GC undergoing surgical resection. Although previous guidelines on GC have been developed,21-26 none used RAM in their development. The RAM allows for anonymous scoring, outlines differing levels of agreement between experts, and distinguishes between care that is suggested and that which is required. This distinction gives the user a sense of the nuance and uncertainty that surrounds the treatment of GC patients, especially in the processes of surgical care. Second, this article differs from the existing guidelines by its focus on processes of care specific to surgical resection and inclusion of Table 8. Reconstruction Options Scenario
Appropriateness score
It is appropriate to reconstruct a subtotal gastrectomy via a Roux-en-Y gastrojejunostomy It is appropriate to reconstruct a subtotal gastrectomy via a Billroth I gastroduodenostomy It is appropriate to reconstruct a subtotal gastrectomy via a Billroth II gastrojejunostomy It is appropriate to reconstruct a total gastrectomy via an esophagojejunostomy (with no pouch) It is appropriate to reconstruct a total gastrectomy via an esophagojejunostomy (with a J pouch)
Appropriate (8.0)*
Disagreement (4.0)
Indeterminate (6.5)
Appropriate (8.0)*
Appropriate (7.0)*
Results (in parentheses) shown as median appropriateness score or, when applicable, as (mean necessity score). *Agreement on appropriateness or necessity of scenario.
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important technical aspects that might otherwise be neglected. Finally, we sought diverse, international, multidisciplinary representation for the expert panel. Importantly, the expert panel reached agreement on appropriateness scores in only a minority of processes of care about surgical treatment of GC patients, and only 3% were considered necessary for surgical resection in patients with GC. This underscores the diversity in opinion and the lack of standard of care in the surgical treatment of GC. Type of resection Complete removal of the cancer without residual microscopic or macroscopic disease is an accepted primary tenet of oncologic surgery. The expert panel agreed that the type of operation performed to achieve these goals depended on both location and stage of the tumor. For patients with distal GC, a distal gastrectomy was the recommended resection. This recommendation is based on data from 2 large multicenter randomized controlled trials (RCTs) conducted in Europe, which concluded that total gastrectomy did not confer a survival benefit over subtotal gastrectomy for patients with GC in the distal half of the stomach.27,28 In addition, these RCTs showed that the patients who underwent subtotal gastrectomy had improved nutritional status and quality of life, comparatively.27 Patients with proximal GC are recommended to undergo a total gastrectomy. Alternatives to total gastrectomy in these patients include a proximal gastrectomy or proximal gastrectomy with jejunal interposition pouch reconstruction, which in one RCT was associated with reduced post-gastrectomy syndrome symptoms and improved nutritional status.29 Laparoscopic gastrectomy Laparoscopic gastrectomy was deemed appropriate only for patients with early GC. Importantly, in patients whose GC is predicted to be staged greater than T1 to 2 N0, there was significant disagreement, denoting a wide range of scores on the appropriateness of laparoscopic techniques in GC surgery. Several randomized and nonrandomized studies have examined laparoscopic gastrectomy and multiple meta-analyses have been performed.30-33 Laparoscopic resection for GC compares favorably with an open approach with respect to short-term results, with benefits of reduced blood loss, less postoperative pain, and earlier discharge from hospital.31,32,34 However, these trials have all been in the early GC patient population and longterm oncologic outcomes are lacking.35 Long-term results from a large, multicenter study in Korea are pending.32
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Lymphadenectomy The extent of lymphadenectomy is controversial in North America, with the most common resection consisting of resection of the stomach and immediate surrounding LN (D1). Nonrandomized series from Asia, Europe, and North America have reported improved survival for a more extensive lymphadenectomy36-39; although 2 RCTs failed to show a 5-year survival benefit for the D2 lymphadenectomy.40,41 The lack of a significant survival benefit and the higher complication rate in the RCTs might be due to low-volume surgeons performing the dissections; inadequate training; and resection of the tail of the pancreas and spleen, which are no longer recommended as standard during D2 lymphadenectomy.40-43 More recently, results from the 15-year follow-up data from one of the RCTs have reported improved diseasespecific survival for patients who were randomized to D2 lymphadenectomy.44 Updated guidelines published in the United States, United Kingdom, and Europe support a D2 lymphadenectomy.23,24,26 According to the UK guidelines, LN dissection should be tailored to the age and performance status of the patient, as well as the location and stage of the primary cancer.26 Similarly, our expert panel concluded that a D2 lymphadenectomy is preferred for curative-intent resection in advanced, nonmetastatic GC; and in patients with early GC or substantial comorbidities, a D1 lymphadenectomy is more appropriate. These findings are in keeping with recommendations from the Japanese Gastric Cancer Association.25 The necessity of these statements was deemed indeterminate, arguably due to the wide variety of clinical situations and lack of conclusive evidence. In addition, given the high operative morbidity and mortality found in the RCTs, several authors have suggested that D2 lymphadenectomy should be performed by surgeons trained in this technique and with adequate surgical volume.26,42,45,46 Although there is debate about the type of lymphadenectomy, there is agreement about the number of LNs required to adequately stage the patient. The panel believed that it was appropriate and necessary to assess at least 16 LNs for adequate staging of curative-resected GC, in accordance with American Joint Commission on Cancer/ Union for International Cancer Control TNM staging recommendations.47 Despite the long-standing recognition of the need for assessment of a minimum number of LNs for staging, studies show that in the United States, the minimum assessment is rarely performed, with considerable regional variation in the rate of adequate assessment.48-50 Importantly, in some population studies there appears to be a survival benefit for patients who had adequate LN assessment.49 It is unclear whether this benefit is conferred
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by removing more LN, or by having surgery within a system that performs appropriate staging, and therefore, perhaps, other parts of patient care more carefully.51 Margin assessment Patients whose tumor is incompletely removed by surgery have markedly worse survival, including those who have microscopic tumor on pathologic examination of the resection margins.52,53 Although these effects can be confounded by factors associated with aggressive biology, including nodal involvement, depth of invasion, and histologic subtype, there does appear to be an independent association with worse survival in patients with positive margins.54,55 The accuracy of intraoperative frozen-section analysis in the assessment of margin status for GC is reported to be 97%.56 Therefore, to achieve R0 margins, the expert panel agreed that intraoperative assessment of proximal margin status by frozen section was appropriate for T3 to 4 GC undergoing curativeintent resection with gross margins <5 cm. The issue of re-resection to negative margins is complex and should be individualized, depending on patient and tumor factors. Overall, re-resection was believed by the panel to be most beneficial in patients with early-stage disease. The appropriateness scores in these scenarios decreased as surgical complexity and nodal status increased. These scores reflected the findings that microscopic positive margins were less likely to adversely impact survival in patients with more advanced cancer, where the risk of distant metastatic disease was higher.53 A retrospective study of a single-center database showed a survival benefit only in patients with <5 nodes involved.53 Importantly, re-resection of patients with positive margins on frozen section with N0 disease was believed to be necessary when involving stomach and/or abdominal esophagus, representing 2 of the few processes of care scored necessary in this study. Re-resection was recognized to be a difficult decision, as additional resection does not always ensure negative margins. A Japanese study showed persistently involved margins in 25% of patients who underwent re-resection.57 In addition, resection to achieve negative margins can be difficult due to the location of the margin, or extension of tumor into adjacent organs, necessitating a multivisceral resection to achieve R0 status. Interestingly, the appropriateness scores for re-resection of the proximal margins were higher than distal margins, perhaps reflecting the need to convert to a pancreaticoduodenectomy for distal margin involvement, with an associated increase in operative morbidity.18 As an alternative to re-resection, some authors have suggested that patients with positive margins can be followed closely for recurrence.58,59
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Reconstruction Surgical reconstruction after gastrectomy was considered by the expert panel. An RY esophagojejunostomy is the most commonly used reconstruction after a total gastrectomy. An alternative strategy is RY with pouch reconstruction, which, in a recent study, showed no difference in operative complications, but a slight improvement in quality of life at 2 years.60 For subtotal gastrectomy, RY gastrojejunostomy is commonly performed, although other alternatives exist, such as Billroth I and Billroth II gastrojejunostomy, with or without a Braun enteroenterostomy. Numerous studies with short-term and long-term outcomes after different reconstruction options post gastrectomy have been published.61-65 Agreement of appropriateness was reached by the expert panel for RY reconstruction for subtotal gastrectomy, as well as an esophagojejunostomy with or without pouch for total gastrectomy, with indeterminate necessity for each scenario. Appropriateness scores for the Billroth I and II reconstructions did not reach agreement. Limitations There are several limitations to this study. Although an extensive and rigorous review of the literature was provided to the panel, the majority of the data were gathered from retrospective studies. During the RAM process, in scenarios where little or poor-quality evidence exists, the opinion of the experts often becomes more influential.66 In addition, a potential drawback might be the preponderance of surgical experts, and especially surgical oncologists, among the membership of the panel, which can affect the outcomes of the RAM. However, although previous studies have shown the importance of multidisciplinary representation, similar panel results tend to occur regardless of exact composition.7 The composition of the expert panel was purposely international, although this might have contributed to difficulties in obtaining agreement on appropriateness and necessity due to regional variations in experience. Finally, many of the members of the expert panel were from tertiary academic centers, which can limit the understanding of the challenges facing physicians in hospitals with fewer resources and lower case volumes. As a high percentage of care occurs in community hospitals, attempts were made to introduce this perspective during the discussions.
CONCLUSIONS A multidisciplinary, international expert panel using the RAM has identified processes of care that are appropriate and necessary for the surgical management of patients with curative GC. Most patients with curative GC should
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undergo resection with D2 lymphadenectomy assessing at least 16 LNs. Laparoscopic gastrectomy for early-stage GC is supported, and considerable disagreement exists for more advanced cancers. Frozen-section analysis and subsequent consideration of re-resection to ensure negative margins is appropriate if the gross margin is <5 cm, or the lesion is T3 to T4. The findings from the expert panel can be used to assess the quality of surgical care. Author Contributions Study conception and design: Law, McLeod, Helyer, Swallow, Paszat, Coburn Acquisition of data: Brar, Law, McLeod, Helyer, Swallow, Paszat, Seevaratnam, Cardoso, Dixon, Mahar, Lourenco, Yohanathan, Bocicariu, Bekaii-Saab, Chau, Church, Coit, Crane, Earle, Mansfield, Marcon, Miner, Noh, Porter, Posner, Prachand, Sano, van de Velde, Wong, Coburn Analysis and interpretation of data: Brar, Law, McLeod, Helyer, Swallow, Paszat, Seevaratnam, Cardoso, Dixon, Mahar, Lourenco, Yohanathan, Bocicariu, Bekaii-Saab, Chau, Church, Coit, Crane, Earle, Mansfield, Marcon, Miner, Noh, Porter, Posner, Prachand, Sano, van de Velde, Wong, Coburn Drafting of manuscript: Brar, Law, McLeod, Helyer, Swallow, Paszat, Seevaratnam, Cardoso, Dixon, Mahar, Lourenco, Yohanathan, Bocicariu, Bekaii-Saab, Chau, Church, Coit, Crane, Earle, Mansfield, Marcon, Miner, Noh, Porter, Posner, Prachand, Sano, van de Velde, Wong, Coburn Critical revision: Brar, Law, McLeod, Helyer, Swallow, Paszat, Seevaratnam, Cardoso, Dixon, Mahar, Lourenco, Yohanathan, Bocicariu, Bekaii-Saab, Chau, Church, Coit, Crane, Earle, Mansfield, Marcon, Miner, Noh, Porter, Posner, Prachand, Sano, van de Velde, Wong, Coburn Acknowledgment: Ian Chau would like to acknowledge National Health Service funding to the National Institute for Health Research’s Biomedical Research Center.
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5. 6. 7. 8. 9. 10. 11.
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Appendix 1. Definition of key terms for RAND/UCLA Appropriateness Methodology scenarios R0 refers to complete resection of all micro- and macroscopic disease. R1 refers to residual microscopic disease. R2 refers to residual macroscopic disease. Minor symptoms will be considered to be anemia, dysphagia, and/or dysphagia. Major symptoms will be considered to be bleeding requiring transfusion and/or obstruction. D0 is an incomplete lymph node assessment. D1 lymphadenectomy is removal of the N1 grouping of lymph nodes. D2 lymphadenectomy is removal of the N1 and N2 grouping of lymph nodes.
Appendix 2. Postoperative positive margins Scenario
Appropriateness score
If resection is performed and the final proximal margin is positive it is appropriate to immediately re-resect the patient to negative margins If re-resection would only include the stomach and the patient is N0 Indeterminate (7.0) Even if re-resection would necessitate abdominal esophagus resection and the patient is N0 Indeterminate (6.5) Even if re-resection would necessitate thoracic esophagus resection and the patient is N0 Indeterminate (5.5) If re-resection would only include the stomach and the patient is N1 Indeterminate (6.5) Even if re-resection would necessitate abdominal esophagus resection and the patient is N1 Indeterminate (6.0) Even if re-resection would necessitate thoracic esophagus resection and the patient is N1 Indeterminate (5.0) If re-resection would only include the stomach and the patient is N2 or N3 Indeterminate (5.0) Even if re-resection would necessitate abdominal esophagus resection and the patient is N2 or N3 Indeterminate (5.0) Even if re-resection would necessitate thoracic esophagus resection and the patient is N2 or N3 Indeterminate (4.0) If resection is performed and the final distal or radial margin is positive it is appropriate to immediately re-resect the patient to negative margins: Even if re-resection would require pancreaticoduodenectomy and the patient is N0 Indeterminate (5.0) Even if re-resection would require pancreaticoduodenectomy and the patient is N1 Indeterminate (5.0) Even if re-resection would require pancreaticoduodenectomy and the patient is N2 or N3 Indeterminate (2.5) If a resection is performed and the final proximal margin is positive it is appropriate to have the Appropriateness score patient undergo chemoradiation to the area of the positive margin For all patients Indeterminate (7.0) Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score.
Appendix 3. Nutrition and drainage Scenario
Appropriateness score
A feeding jejunostomy should be placed for patients undergoing gastric resection A feeding jejunostomy should be placed for patients undergoing a total gastrectomy A feeding jejunostomy should be placed for patients undergoing gastric resection who are expected to undergo postoperative chemotherapy or chemoradiation A feeding jejunostomy should be placed selectively for patients undergoing gastric resection Preoperative total parenteral nutrition or tube feeds should be considered in malnourished patients A decompressive nasoenteric tube should be placed after a subtotal gastrectomy A decompressive nasoenteric tube should be placed after a total gastrectomy A contrast study should be obtained to rule-out leak prior to starting oral feeds
Indeterminate (4.0) Disagreement (5.5) Disagreement (4.0)
Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario.
Appropriate (7.5)* Indeterminate (7.0) Indeterminate (6.5) Indeterminate (6.0) Disagreement (5.0)
In 1881, Theodor Billroth performed the first successful resection for gastric adenocarcinoma (GC). More than a century later, surgical resection remains the only curative treatment for patients with gastric cancer. However, outcomes after surgical resection vary widely. Despite Disclosure Information: Nothing to disclose. Study funded by Canadian Cancer Society grant 019325. Dr Coburn (Career Scientist Award) and Dr Paszat have received funding through the Ontario Ministry of Health and Long-Term Care. Dr Law is supported by the Hanna Family Research Chair in Surgical Oncology. Presented in poster format at the Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology (GI-ASCO), San Francisco, CA, January 2012 and the Society of Surgical Oncology Annual Cancer Symposium, Orlando, FL, March 2012. Received October 19, 2012; Revised November 29, 2012; Accepted January 29, 2013. From the Departments of Surgery (Brar, Law, McLeod, Swallow, Coburn) and Medicine (Earle, Marcon), University of Toronto, Institute for Clinical Effectiveness Studies (Paszat, Earle, Coburn), Sunnybrook Research Institute (Seevaratnam, Cardoso, Dixon, Mahar, Bocicariu, Coburn), Toronto, Ontario, Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Helyer, Porter), Department of Surgery, University of Calgary, Calgary, Alberta (Church), Canada, Department of Surgery, Maimonides Medical Center, Brooklyn (Dixon), Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York (Coit), NY, Gastroenterology Surgery, Sao Paulo Federal University, Sao Paulo, Brazil (Lourenco), Department of Surgery, Brown University, Providence, RI (Yohanathan, Miner), Departments of Medicine and Pharmacology, The Ohio State University, Columbus, OH (Bekaii-Saab), Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, UK (Chau), Departments of Radiation Oncology (Crane) and Surgical Oncology (Mansfield), MD Anderson Cancer Center, Houston, TX, Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea (Noh), Department of Surgery, University of Chicago, Chicago, IL (Posner, Prachand), Department of Surgery, Cancer Institute Hospital, Tokyo, Japan (Sano), Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands (van de Velde), and Department of Surgery, University of Michigan Health System, Ann Arbor, MI (Wong). Correspondence address: Natalie Coburn, MD, MPH, FACS, Division of Surgical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Suite T2-60, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5. email: [email protected]
ª 2013 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
GC LN RAM RCT RY
¼ ¼ ¼ ¼ ¼
gastric adenocarcinoma lymph node RAND/UCLA Appropriateness Methodology randomized controlled trial Roux-en-Y
The RAND/UCLA Appropriateness Methodology (RAM) is a well-described methodology that has been developed to help determine appropriate care for patients in situations where strong, evidence-based guidelines are not possible. The RAM is a statistically validated methodology that incorporates expert consensus, and this methodology has been shown to produce appropriateness criteria that have face, construct, and predictive ability.6,7 Therefore, we organized an international expert panel to define appropriate and necessary processes of surgical care for GC. As GC is relatively rare in North America, international representation was sought to assemble a panel of experts withhigh levels of expertise and experience in a variety of clinical settings.
METHODS The RAM process is presented in Figure 1. In summary, the RAM involves performing a literature search to determine the evidence for processes of care; creating clinical scenarios for treatment options; assembling an expert panel to grade the appropriateness of treatments; and evaluating all appropriate processes for necessity. A detailed literature review was conducted to synthesize the latest evidence of a broad range of perioperative processes in GC. Electronic literature searches were conducted using Medline and Embase from January 1, 1998
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to December 31, 2010. Searches were performed for the following topics: endoscopy; radiology; multidisciplinary cancer care; peritoneal lavage; diagnostic laparoscopy; laparoscopic resection; lymph node (LN) dissection; neoadjuvant or adjuvant therapy for resectable GC; downstaging therapy for unresectable GC; palliative procedures; total or subtotal gastrectomy; gastrectomy with cholecystectomy; management of familial GC; institution volume; intraperitoneal chemotherapy; LN number; resection margin; multi-visceral resection; perforation; reconstruction; sentinel LN biopsy; surgeon volume and training; and post-treatment surveillance. Exclusion criteria included animal and/or ex vivo samples; did not provide short or long-term outcomes; involved mixed cancers; review articles; meta-analyses; abstracts; conference proceedings; editorials/letters; and case reports. More than 40,000 abstracts were reviewed with the subsequent inclusion of 691 articles in the literature review. Results from the literature review were used to inform both the development of clinical scenarios and scoring by the expert panel. Several systematic reviews were subsequently published based on the results of this literature review, outlining full details of the search process and results.8-20 Panelists were recruited through solicitation of nominations from the heads of surgical, medical, and radiation oncology units at all major cancer centers in North America, as well as corresponding authors of articles on clinical management of GC. From the applicants, a 16-member international, multidisciplinary panel of physicians with expertise in the care of GC was assembled, balancing practice type and geographic location. The expert panel was weighted to surgical representation, as the study was designed to focus on surgical process of care (Table 1).
1. Review and summary of the literature for processes of care
2. Expert panel members independently score scenarios for appropriateness
3. Data analyzed to guide expert panel discussion
4. Expert panel meeting to discuss areas of disagreement regarding processes of care in the scenarios
5. Re-scoring of scenarios for appropriateness and necessity
Figure 1. Overview flow chart of the modified RAND/UCLA Appropriateness Methodology used to develop the processes of care in gastric cancer.
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Table 1.
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Expert Panel Membership
Name
Tanios Bekaii-Saab Ian Chau Neal Church Daniel Coit Christopher Crane Craig Earle Paul Mansfield Norman Marcon Thomas Miner Sung Hoon Noh Geoff Porter Mitchell Posner Vivek Prachand Takeshi Sano Cornelis Jan Hadde van de Velde Sandra Wong
Speciality
Country
Affiliation
Medical Oncology Medical Oncology Laparoscopic Surgery Surgical Oncology Radiation Oncology Medical Oncology Surgical Oncology Gastroenterologist Surgical Oncology Surgical Oncology Surgical Oncology Surgical Oncology Laparoscopic Surgery Surgical Oncology Surgical Oncology Surgical Oncology
United States England Canada United States United States Canada United States Canada United States Korea Canada United States United States Japan The Netherlands United States
The Ohio State University Royal Marsden Hospital University of Calgary Memorial Sloan-Kettering Cancer Center University of Texas MD Anderson Cancer Center University of Toronto University of Texas MD Anderson Cancer Center University of Toronto Brown University Yonsei University College of Medicine Dalhousie University University of Chicago University of Chicago Cancer Institute Hospital Leiden University Medical Centre University of Michigan Health System
Panelists were presented with 357 scenarios about the surgical management of GC. Definitions of key terms appear in Appendix 1 (online only). The scenarios were piloted initially with 3 surgical oncologists before being sent to the expert panel. Results of the literature review were first provided to each panelist. Next, the clinical scenarios were sent to the panelists in the spring of 2010. For each scenario, panelists were asked to score the appropriateness of the treatment in each scenario. Appropriateness is defined as “the expected health benefit of an intervention exceeding the expected negative consequences by a wide enough margin that the procedure is worth doing, regardless of cost.”21 Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate).7 Panelists returned the scoring for the scenarios and the data were analyzed for areas of agreement and disagreement. The panel then met in Toronto October 21e23, 2010 for a discussion of the scenarios and scoring. Discussion was focused on areas where there was disagreement. Some scenarios were rewritten for clarification based on discussions and recommendation from the expert panel. All scenarios were rescored for appropriateness by each panelist. In final analysis, a procedure was classified as “appropriate” if the median rating was 7 to 9, with agreement; “inappropriate” if the median rating was 1 to 3, with agreement; and “uncertain” if the median rating was 4 to 6, with agreement. Agreement was met when 4 panelists rated outside the 3-point region containing the median (ie, 1 to 3, 4 to 6, 7 to 9). Disagreement occurred when 4 panelists rated in each extreme 3point region (ie, 1 to 3, 7 to 9). Level of agreement
was indeterminate when it failed to satisfy either of these criteria. Any scenario where there was agreement that the statement was appropriate was subsequently scored for necessity in the same manner. Necessity is a more stringent criterion than appropriateness. If a procedure is necessary, the expected benefits outweigh the expected harms by such a margin that the service must be offered to the patient. In the final classification, each statement could be labeled as appropriate, necessary, inappropriate, indeterminate, uncertain, or disagreement. The study design was submitted to and approved by the Research Ethics Board of Sunnybrook Health Sciences Centre.
RESULTS The panelists scored 357 scenarios regarding the surgical management of GC. Agreement on appropriateness was reached in 109 of scenarios and disagreement in 10 scenarios, with the remaining scenarios scored as uncertain. Where agreement was made, 60 scenarios were appropriate (scores of 7 to 9), 1 was indeterminate (scores of 4 to 6), and 48 were inappropriate (scores of 1 to 3). In the scenarios that were appropriate, only 3% were deemed necessary. Type of resection For patients with curative GC of the proximal stomach, total gastrectomy was considered appropriate for all patients. For patients with distal GC, distal gastrectomy was considered appropriate and necessary for all patients. Although total gastrectomy scored very low for distal lesions, agreement was indeterminate (Table 2).
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Table 2.
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Type of Gastrectomy T1, N0
Proximal gastric cancer (M0) Proximal Disagreement gastrectomy (5.0) Total Appropriate gastrectomy (8.0)* Distal gastric cancer (M0) Distal Necessary gastrectomy (8.0)* Total Indeterminate gastrectomy (2.0)
Clinical T and N status T1e2, N2e3 T3e4, N0
T2, N0
T1e2, N1
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (3.5) Appropriate (8.0)*
Necessary (8.0)* Indeterminate (2.0)
Necessary (8.0)* Indeterminate (2.0)
Necessary (8.0)* Indeterminate (2.0)
T3e4, N1
T3e4, N2e3
Indeterminate (3.5) Appropriate (8.0)*
Indeterminate (3.5) Appropriate (8.0)*
Indeterminate (3.5) Appropriate (8.0)*
Necessary (8.0)* Indeterminate (2.0)
Necessary (8.0)* Indeterminate (2.0)
Necessary (8.0)* Indeterminate (2.5)
Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario.
Laparoscopic gastrectomy Open distal gastrectomy was considered appropriate for all patients with distal GC. Laparoscopic distal gastrectomy was appropriate for distal GC patients with T1-2 N0 disease only (Table 3). For patients with proximal GC, laparoscopic total gastrectomy was considered appropriate for patients with T1 N0 disease and indeterminate for patients with T2 N0 disease (Table 3). There was disagreement about the use of the laparoscopic approach in patients with GC more advanced than T2N0 (Table 3). Lymph nodes A D0 lymphadenectomy was inappropriate in all cases more advanced than T1N0 GC. For patients with T1 N0 disease, the appropriateness scores for performance of D1 or D2 lymphadenectomy were indeterminate (Table 4). In patients with more advanced cancers (>T1N0), appropriateness scores for D1 lymphadenectomy ranged from 4.0 for proximal GC and 4.5 to 6.0 for distal GC, with no agreement. However, D2 lymphadenectomy was considered appropriate in all patients with tumors >T1N0 (scores of 8.0). Necessity scores for D2 lymphadenectomy in these patients were high but indeterminate (6.0 to 8.0). The expert panel found that it was appropriate, but not necessary to assess 16 or more Table 3.
Proximal GC Distal GC
LNs in a curative resection. Sentinel LN biopsy was believed to be inappropriate (results not shown). Resection of other organs The expert panel believed that routine splenectomy for all patients undergoing gastrectomy was inappropriate (Table 5). On the question of whether a splenectomy should be performed if the LNs in the splenic hilum were enlarged, an appropriateness score of 7.0 was given, with indeterminate agreement. The expert panel disagreed on the appropriateness of omentectomy with gastric resections (range 4.5 to 6.5). The need for resection of the lesser sac peritoneum was also indeterminate. The panel believed it was inappropriate to perform routine cholecystectomy with gastrectomy, although in the presence of cholelithiasis, the appropriateness score for cholecystectomy was 7, with indeterminate agreement. Margins The expert panel believed that it was appropriate to perform intraoperative pathologic assessment with frozen sections of the proximal margin if the gross margin is <5 cm, or if the lesion is believed to be T3/T4 (Table 6). If the proximal margin was positive on intraoperative pathologic assessment for N0 and M0 patients, it
Laparoscopic Gastrectomy (M0) T1, N0
T2, N0
T1e2, N1
Appropriate (7.5)* Appropriate (7.5)*
Indeterminate (7.0) Appropriate (7.0)*
Disagreement (5.0) Disagreement (5.0)
Clinical T and N Status T1e2, N2e3 T3e4, N0
Disagreement (4.0) Disagreement (4.0)
Disagreement (4.0) Disagreement (4.0)
Results (in parentheses) shown as median appropriateness score or, when applicable, mean necessity score. *Agreement on appropriateness or necessity of scenario.
T3e4, N1
T3e4, N2e3
Disagreement (4.0) Disagreement (4.0)
Disagreement (4.0) Disagreement (4.0)
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Table 4.
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Extent of Lymphadenectomy (M0) Clinical T and N status T1e2, N2e3 T3e4, N0
T1, N0
T2, N0
T1e2, N1
Indeterminate (6.5) Indeterminate (6.5)
Disagreement (5.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Proximal tumor D1 Indeterminate (7.0) D2 Indeterminate (6.0)
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Distal tumor D1 D2
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T3e4, N1
T3e4, N2e3
Indeterminate (4.5) Appropriate (8.0)*
Indeterminate (4.5) Appropriate (8.0)*
Indeterminate (4.5) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Indeterminate (4.0) Appropriate (8.0)*
Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario. D0, D0 lymphadenectomy; D1, D1 lymphadenectomy; D2, D2 lymphadenectomy.
was appropriate and necessary to perform a re-resection of the stomach and/or abdominal esophagus; and appropriate, but not necessary to perform a re-resection of the thoracic esophagus (Table 7). If the proximal margin was positive on intraoperative pathologic assessment, and Table 5. Scenario
Multiorgan Resection Appropriateness score
It is appropriate to perform a splenectomy In all gastric cancer resections Inappropriate (1.0)* All D2 lymph nodes dissections Inappropriate (1.5)* All total gastrectomy resections Inappropriate (1.0)* If enlarged LN in the hilum of the Indeterminate (7.0) spleen It is appropriate to perform a omentectomy In all curative gastric resections Disagreement (6.0) In all curative gastric resections Disagreement (6.5) performed open In all curative gastric resections Disagreement (4.5) performed laparoscopically It is appropriate to perform a lesser sac peritonectomy In all curative gastric resections Indeterminate (3.0) In all curative gastric resections Indeterminate (3.0) performed open In all curative gastric resections Indeterminate (3.0) performed laparoscopically It is appropriate to perform a cholecystectomy In all gastric resections Inappropriate (3.0)* In all distal gastrectomies Inappropriate (1.5)* In all total gastrectomies Indeterminate (2.0) All D2 LN dissections Indeterminate (2.5) Only if there are stones noted in the Indeterminate (7.0) gallbladder Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario. LN, lymph node.
if the patient was N1 and M, there was agreement that it was appropriate to perform a re-resection of the stomach, abdominal, and/or thoracic esophagus. If the patient had N2 to 3 and M0 disease, there was agreement that it was appropriate to perform a re-resection of the stomach and/ or abdominal esophagus, but not the thoracic esophagus. There was no clear recommendation for re-resection if it meant performing a pancreaticoduodenectomy, with indeterminate scores for patients with N0 (appropriateness score 7.0) and N1 disease (appropriateness score 6.0) and agreement of uncertainty with N2 to 3 disease (appropriateness score 5.0). For margin status assessed on the final pathology report, with results available on postoperative day 7, there were no clear recommendations on performing reresection if the proximal, distal, or radial margins were Table 6. Margin Assessment Scenario
Appropriateness score
It is appropriate to perform intraoperative pathologic assessment (frozen sections) of the proximal margin For all gastric resections Indeterminate (7.0) If the gross margin is <5 cm Appropriate (7.0)* If the gross margin is <3 cm Appropriate (8.0)* If the lesion is believed to be T1 or T2 Indeterminate (7.0) If the lesion is believed to be T3 or T4 Appropriate (7.0)* It is appropriate to perform intraoperative pathologic assessment (frozen sections) of the distal margin For all gastric resections Indeterminate (5.0) If the gross margin is <5 cm Indeterminate (7.0) If the gross margin is <3 cm Indeterminate (7.5) If the lesion is believed to be T1 or T2 Indeterminate (5.0) If the lesion is believed to be T3 or T4 Indeterminate (6.0) Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario.
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Table 7. Scenario
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Intraoperative Positive Margins Appropriateness score
If resection is performed and the proximal margin on intra-operative frozen section is positive, it is appropriate to re-resect the patient to negative margins If re-resection would only include the Necessary (7.5)* stomach and the patient is N0 If re-resection would necessitate Necessary (7.0)* abdominal esophagus resection and the patient is N0 If re-resection would necessitate Appropriate (7.0)* thoracic esophagus resection and the patient is N0 If re-resection would only include the Appropriate (9.0)* stomach and the patient is N1 If re-resection would necessitate Appropriate (9.0)* abdominal esophagus resection and the patient is N1 If re-resection would necessitate Appropriate (7.0)* thoracic esophagus resection and the patient is N1 If re-resection would only include the Appropriate (8.0)* stomach and the patient is N2 or N3 If re-resection would necessitate Appropriate (8.0)* abdominal esophagus resection and the patient is N2 or N3 If re-resection would necessitate Indeterminate (7.0) thoracic esophagus resection and the patient is N2 or N3 If resection is performed and the distal or radial margin on intraoperative frozen section is positive, it is appropriate to re-resect the patient to negative margins If re-resection would require Indeterminate (7.0) pancreaticoduodenectomy and the patient is N0 If re-resection would require Indeterminate (6.0) pancreaticoduodenectomy and the patient is N1 If re-resection would Uncertain (5.0)* pancreaticoduodenectomy and the patient is N2 or N3 Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario.
positive, as all scenarios given were scored as indeterminate (Appendix 2, online only). Type of reconstruction With respect to reconstruction after resection, the expert panel believed it was appropriate but not necessary to reconstruct a subtotal gastrectomy via Roux-en-y (RY) gastrojejunostomy (Table 8). Other reconstruction options included Billroth I, which trended toward inappropriate, and Billroth II gastrojejunostomy, which
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scored indeterminate. Reconstruction after a total gastrectomy via an esophagojejunostomy, with or without a J pouch, was believed to be appropriate. Nutrition and drainage Scenarios about nutrition and postoperative drainage were included (Appendix 3, online only). The expert panel believed that it was appropriate that a feeding jejunostomy should be selectively placed for patients undergoing gastric resection (appropriateness score 7.5). For other scenarios about feeding jejunostomy, none reached agreement with appropriateness scores in the 4.0 to 5.5 range. No agreement was reached about preoperative total parenteral nutrition, postoperative nasoenteric tube drainage, or use of contrast studies to rule out anastomotic leak.
DISCUSSION Improving quality of surgical care was addressed by assembling an international, multidisciplinary expert panel using RAM to define the processes of care that are appropriate and necessary for patients with GC undergoing surgical resection. Although previous guidelines on GC have been developed,21-26 none used RAM in their development. The RAM allows for anonymous scoring, outlines differing levels of agreement between experts, and distinguishes between care that is suggested and that which is required. This distinction gives the user a sense of the nuance and uncertainty that surrounds the treatment of GC patients, especially in the processes of surgical care. Second, this article differs from the existing guidelines by its focus on processes of care specific to surgical resection and inclusion of Table 8. Reconstruction Options Scenario
Appropriateness score
It is appropriate to reconstruct a subtotal gastrectomy via a Roux-en-Y gastrojejunostomy It is appropriate to reconstruct a subtotal gastrectomy via a Billroth I gastroduodenostomy It is appropriate to reconstruct a subtotal gastrectomy via a Billroth II gastrojejunostomy It is appropriate to reconstruct a total gastrectomy via an esophagojejunostomy (with no pouch) It is appropriate to reconstruct a total gastrectomy via an esophagojejunostomy (with a J pouch)
Appropriate (8.0)*
Disagreement (4.0)
Indeterminate (6.5)
Appropriate (8.0)*
Appropriate (7.0)*
Results (in parentheses) shown as median appropriateness score or, when applicable, as (mean necessity score). *Agreement on appropriateness or necessity of scenario.
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important technical aspects that might otherwise be neglected. Finally, we sought diverse, international, multidisciplinary representation for the expert panel. Importantly, the expert panel reached agreement on appropriateness scores in only a minority of processes of care about surgical treatment of GC patients, and only 3% were considered necessary for surgical resection in patients with GC. This underscores the diversity in opinion and the lack of standard of care in the surgical treatment of GC. Type of resection Complete removal of the cancer without residual microscopic or macroscopic disease is an accepted primary tenet of oncologic surgery. The expert panel agreed that the type of operation performed to achieve these goals depended on both location and stage of the tumor. For patients with distal GC, a distal gastrectomy was the recommended resection. This recommendation is based on data from 2 large multicenter randomized controlled trials (RCTs) conducted in Europe, which concluded that total gastrectomy did not confer a survival benefit over subtotal gastrectomy for patients with GC in the distal half of the stomach.27,28 In addition, these RCTs showed that the patients who underwent subtotal gastrectomy had improved nutritional status and quality of life, comparatively.27 Patients with proximal GC are recommended to undergo a total gastrectomy. Alternatives to total gastrectomy in these patients include a proximal gastrectomy or proximal gastrectomy with jejunal interposition pouch reconstruction, which in one RCT was associated with reduced post-gastrectomy syndrome symptoms and improved nutritional status.29 Laparoscopic gastrectomy Laparoscopic gastrectomy was deemed appropriate only for patients with early GC. Importantly, in patients whose GC is predicted to be staged greater than T1 to 2 N0, there was significant disagreement, denoting a wide range of scores on the appropriateness of laparoscopic techniques in GC surgery. Several randomized and nonrandomized studies have examined laparoscopic gastrectomy and multiple meta-analyses have been performed.30-33 Laparoscopic resection for GC compares favorably with an open approach with respect to short-term results, with benefits of reduced blood loss, less postoperative pain, and earlier discharge from hospital.31,32,34 However, these trials have all been in the early GC patient population and longterm oncologic outcomes are lacking.35 Long-term results from a large, multicenter study in Korea are pending.32
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Lymphadenectomy The extent of lymphadenectomy is controversial in North America, with the most common resection consisting of resection of the stomach and immediate surrounding LN (D1). Nonrandomized series from Asia, Europe, and North America have reported improved survival for a more extensive lymphadenectomy36-39; although 2 RCTs failed to show a 5-year survival benefit for the D2 lymphadenectomy.40,41 The lack of a significant survival benefit and the higher complication rate in the RCTs might be due to low-volume surgeons performing the dissections; inadequate training; and resection of the tail of the pancreas and spleen, which are no longer recommended as standard during D2 lymphadenectomy.40-43 More recently, results from the 15-year follow-up data from one of the RCTs have reported improved diseasespecific survival for patients who were randomized to D2 lymphadenectomy.44 Updated guidelines published in the United States, United Kingdom, and Europe support a D2 lymphadenectomy.23,24,26 According to the UK guidelines, LN dissection should be tailored to the age and performance status of the patient, as well as the location and stage of the primary cancer.26 Similarly, our expert panel concluded that a D2 lymphadenectomy is preferred for curative-intent resection in advanced, nonmetastatic GC; and in patients with early GC or substantial comorbidities, a D1 lymphadenectomy is more appropriate. These findings are in keeping with recommendations from the Japanese Gastric Cancer Association.25 The necessity of these statements was deemed indeterminate, arguably due to the wide variety of clinical situations and lack of conclusive evidence. In addition, given the high operative morbidity and mortality found in the RCTs, several authors have suggested that D2 lymphadenectomy should be performed by surgeons trained in this technique and with adequate surgical volume.26,42,45,46 Although there is debate about the type of lymphadenectomy, there is agreement about the number of LNs required to adequately stage the patient. The panel believed that it was appropriate and necessary to assess at least 16 LNs for adequate staging of curative-resected GC, in accordance with American Joint Commission on Cancer/ Union for International Cancer Control TNM staging recommendations.47 Despite the long-standing recognition of the need for assessment of a minimum number of LNs for staging, studies show that in the United States, the minimum assessment is rarely performed, with considerable regional variation in the rate of adequate assessment.48-50 Importantly, in some population studies there appears to be a survival benefit for patients who had adequate LN assessment.49 It is unclear whether this benefit is conferred
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by removing more LN, or by having surgery within a system that performs appropriate staging, and therefore, perhaps, other parts of patient care more carefully.51 Margin assessment Patients whose tumor is incompletely removed by surgery have markedly worse survival, including those who have microscopic tumor on pathologic examination of the resection margins.52,53 Although these effects can be confounded by factors associated with aggressive biology, including nodal involvement, depth of invasion, and histologic subtype, there does appear to be an independent association with worse survival in patients with positive margins.54,55 The accuracy of intraoperative frozen-section analysis in the assessment of margin status for GC is reported to be 97%.56 Therefore, to achieve R0 margins, the expert panel agreed that intraoperative assessment of proximal margin status by frozen section was appropriate for T3 to 4 GC undergoing curativeintent resection with gross margins <5 cm. The issue of re-resection to negative margins is complex and should be individualized, depending on patient and tumor factors. Overall, re-resection was believed by the panel to be most beneficial in patients with early-stage disease. The appropriateness scores in these scenarios decreased as surgical complexity and nodal status increased. These scores reflected the findings that microscopic positive margins were less likely to adversely impact survival in patients with more advanced cancer, where the risk of distant metastatic disease was higher.53 A retrospective study of a single-center database showed a survival benefit only in patients with <5 nodes involved.53 Importantly, re-resection of patients with positive margins on frozen section with N0 disease was believed to be necessary when involving stomach and/or abdominal esophagus, representing 2 of the few processes of care scored necessary in this study. Re-resection was recognized to be a difficult decision, as additional resection does not always ensure negative margins. A Japanese study showed persistently involved margins in 25% of patients who underwent re-resection.57 In addition, resection to achieve negative margins can be difficult due to the location of the margin, or extension of tumor into adjacent organs, necessitating a multivisceral resection to achieve R0 status. Interestingly, the appropriateness scores for re-resection of the proximal margins were higher than distal margins, perhaps reflecting the need to convert to a pancreaticoduodenectomy for distal margin involvement, with an associated increase in operative morbidity.18 As an alternative to re-resection, some authors have suggested that patients with positive margins can be followed closely for recurrence.58,59
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Reconstruction Surgical reconstruction after gastrectomy was considered by the expert panel. An RY esophagojejunostomy is the most commonly used reconstruction after a total gastrectomy. An alternative strategy is RY with pouch reconstruction, which, in a recent study, showed no difference in operative complications, but a slight improvement in quality of life at 2 years.60 For subtotal gastrectomy, RY gastrojejunostomy is commonly performed, although other alternatives exist, such as Billroth I and Billroth II gastrojejunostomy, with or without a Braun enteroenterostomy. Numerous studies with short-term and long-term outcomes after different reconstruction options post gastrectomy have been published.61-65 Agreement of appropriateness was reached by the expert panel for RY reconstruction for subtotal gastrectomy, as well as an esophagojejunostomy with or without pouch for total gastrectomy, with indeterminate necessity for each scenario. Appropriateness scores for the Billroth I and II reconstructions did not reach agreement. Limitations There are several limitations to this study. Although an extensive and rigorous review of the literature was provided to the panel, the majority of the data were gathered from retrospective studies. During the RAM process, in scenarios where little or poor-quality evidence exists, the opinion of the experts often becomes more influential.66 In addition, a potential drawback might be the preponderance of surgical experts, and especially surgical oncologists, among the membership of the panel, which can affect the outcomes of the RAM. However, although previous studies have shown the importance of multidisciplinary representation, similar panel results tend to occur regardless of exact composition.7 The composition of the expert panel was purposely international, although this might have contributed to difficulties in obtaining agreement on appropriateness and necessity due to regional variations in experience. Finally, many of the members of the expert panel were from tertiary academic centers, which can limit the understanding of the challenges facing physicians in hospitals with fewer resources and lower case volumes. As a high percentage of care occurs in community hospitals, attempts were made to introduce this perspective during the discussions.
CONCLUSIONS A multidisciplinary, international expert panel using the RAM has identified processes of care that are appropriate and necessary for the surgical management of patients with curative GC. Most patients with curative GC should
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undergo resection with D2 lymphadenectomy assessing at least 16 LNs. Laparoscopic gastrectomy for early-stage GC is supported, and considerable disagreement exists for more advanced cancers. Frozen-section analysis and subsequent consideration of re-resection to ensure negative margins is appropriate if the gross margin is <5 cm, or the lesion is T3 to T4. The findings from the expert panel can be used to assess the quality of surgical care. Author Contributions Study conception and design: Law, McLeod, Helyer, Swallow, Paszat, Coburn Acquisition of data: Brar, Law, McLeod, Helyer, Swallow, Paszat, Seevaratnam, Cardoso, Dixon, Mahar, Lourenco, Yohanathan, Bocicariu, Bekaii-Saab, Chau, Church, Coit, Crane, Earle, Mansfield, Marcon, Miner, Noh, Porter, Posner, Prachand, Sano, van de Velde, Wong, Coburn Analysis and interpretation of data: Brar, Law, McLeod, Helyer, Swallow, Paszat, Seevaratnam, Cardoso, Dixon, Mahar, Lourenco, Yohanathan, Bocicariu, Bekaii-Saab, Chau, Church, Coit, Crane, Earle, Mansfield, Marcon, Miner, Noh, Porter, Posner, Prachand, Sano, van de Velde, Wong, Coburn Drafting of manuscript: Brar, Law, McLeod, Helyer, Swallow, Paszat, Seevaratnam, Cardoso, Dixon, Mahar, Lourenco, Yohanathan, Bocicariu, Bekaii-Saab, Chau, Church, Coit, Crane, Earle, Mansfield, Marcon, Miner, Noh, Porter, Posner, Prachand, Sano, van de Velde, Wong, Coburn Critical revision: Brar, Law, McLeod, Helyer, Swallow, Paszat, Seevaratnam, Cardoso, Dixon, Mahar, Lourenco, Yohanathan, Bocicariu, Bekaii-Saab, Chau, Church, Coit, Crane, Earle, Mansfield, Marcon, Miner, Noh, Porter, Posner, Prachand, Sano, van de Velde, Wong, Coburn Acknowledgment: Ian Chau would like to acknowledge National Health Service funding to the National Institute for Health Research’s Biomedical Research Center.
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5. 6. 7. 8. 9. 10. 11.
12.
13. 14.
15. 16.
17.
18. 19.
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Appendix 1. Definition of key terms for RAND/UCLA Appropriateness Methodology scenarios R0 refers to complete resection of all micro- and macroscopic disease. R1 refers to residual microscopic disease. R2 refers to residual macroscopic disease. Minor symptoms will be considered to be anemia, dysphagia, and/or dysphagia. Major symptoms will be considered to be bleeding requiring transfusion and/or obstruction. D0 is an incomplete lymph node assessment. D1 lymphadenectomy is removal of the N1 grouping of lymph nodes. D2 lymphadenectomy is removal of the N1 and N2 grouping of lymph nodes.
Appendix 2. Postoperative positive margins Scenario
Appropriateness score
If resection is performed and the final proximal margin is positive it is appropriate to immediately re-resect the patient to negative margins If re-resection would only include the stomach and the patient is N0 Indeterminate (7.0) Even if re-resection would necessitate abdominal esophagus resection and the patient is N0 Indeterminate (6.5) Even if re-resection would necessitate thoracic esophagus resection and the patient is N0 Indeterminate (5.5) If re-resection would only include the stomach and the patient is N1 Indeterminate (6.5) Even if re-resection would necessitate abdominal esophagus resection and the patient is N1 Indeterminate (6.0) Even if re-resection would necessitate thoracic esophagus resection and the patient is N1 Indeterminate (5.0) If re-resection would only include the stomach and the patient is N2 or N3 Indeterminate (5.0) Even if re-resection would necessitate abdominal esophagus resection and the patient is N2 or N3 Indeterminate (5.0) Even if re-resection would necessitate thoracic esophagus resection and the patient is N2 or N3 Indeterminate (4.0) If resection is performed and the final distal or radial margin is positive it is appropriate to immediately re-resect the patient to negative margins: Even if re-resection would require pancreaticoduodenectomy and the patient is N0 Indeterminate (5.0) Even if re-resection would require pancreaticoduodenectomy and the patient is N1 Indeterminate (5.0) Even if re-resection would require pancreaticoduodenectomy and the patient is N2 or N3 Indeterminate (2.5) If a resection is performed and the final proximal margin is positive it is appropriate to have the Appropriateness score patient undergo chemoradiation to the area of the positive margin For all patients Indeterminate (7.0) Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score.
Appendix 3. Nutrition and drainage Scenario
Appropriateness score
A feeding jejunostomy should be placed for patients undergoing gastric resection A feeding jejunostomy should be placed for patients undergoing a total gastrectomy A feeding jejunostomy should be placed for patients undergoing gastric resection who are expected to undergo postoperative chemotherapy or chemoradiation A feeding jejunostomy should be placed selectively for patients undergoing gastric resection Preoperative total parenteral nutrition or tube feeds should be considered in malnourished patients A decompressive nasoenteric tube should be placed after a subtotal gastrectomy A decompressive nasoenteric tube should be placed after a total gastrectomy A contrast study should be obtained to rule-out leak prior to starting oral feeds
Indeterminate (4.0) Disagreement (5.5) Disagreement (4.0)
Results (in parentheses) shown as median appropriateness score or, when applicable, as mean necessity score. *Agreement on appropriateness or necessity of scenario.
Appropriate (7.5)* Indeterminate (7.0) Indeterminate (6.5) Indeterminate (6.0) Disagreement (5.0)