CLINICAL AND ECONOMIC OUTCOMES FOR GASTRIC CANCER

PATIENTS TREATED WITH GASTRECTOMY AT CENTRES WITH

AND WITHOUT CANCER SURGERY CENTRE DESIGNATION IN

ONTARIO

by

Yunni Jeong

A thesis submitted in conformity with the requirements for the degree of Master of Science in Health Services Research

Institute of Health Policy, Management and Evaluation University of Toronto

© Copyright by Yunni Jeong 2019

ii

CLINICAL AND ECONOMIC OUTCOMES FOR GASTRIC CANCER PATIENTS

TREATED WITH GASTRECTOMY AT CENTRES WITH AND WITHOUT CANCER

SURGERY CENTRE DESIGNATION IN ONTARIO

Yunni Jeong

Master of Sciences in Health Services Research

Institute of Health Policy, Management and Evaluation University of Toronto

2019

Abstract

Gastric cancer places high clinical and economic burden on healthcare systems. This

study compares patient outcomes between centres with and without cancer surgery centre

designation (CSCD). Gastric cancer patients diagnosed 2002-2014, and treated with gastrectomy

were identified using Ontario’s linked administrative databases. Outcomes included 90-day

mortality, overall survival, and healthcare costs. Institutions with CSCD (n =1,436) were

associated with lower 90-day mortality (OR 0.70, 95% CI 0.52-0.94, p=0.02), and similar overall

survival (HR 0.94, 95% CI 0.85-1.04, p=0.24) as institutions without CSCD (n = 1,494). The

cost analysis included 1,143, and 1,256 patients treated at institutions with and without CSCD,

respectively. Adjusted mean monthly costs were $3,310 (95% CI $2,384-$4,595) for the CSCD

group, and $3,430 (95% CI $2,469-$4,765) for the non-CSCD group (p=0.36). Treatment at

institutions with CSCD may result in lower 90-day mortality, and similar overall survival, and

costs of care for gastric cancer patients.

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Co-Authorship

This thesis was the product of Yunni Jeong in collaboration with her supervisors Dr. Natalie G.

Coburn, Dr. Nicole Mittmann, Dr. Julie Hallet, and Dr. Alyson L. Mahar. Study design was

completed by Yunni Jeong, Dr. Coburn, Dr. Mittmann, Dr. Hallet, and Dr. Mahar. The algorithm

utilized to identify patients without metastatic disease was applied with guidance from Dr.

Alyson Mahar and Mr. Brandon Zagorski. Data linkage and macro application was performed by

Ms. Qing Li, Senior Research Analyst, Institute for Clinical Evaluative Sciences.

iv

Acknowledgments

First and foremost, I would like to thank my thesis supervisor Dr. Natalie Coburn, for her

mentorship, wisdom, and unwavering support.

Much gratitude to my Thesis Committee members for their patient time, effort, and knowledge:

Dr. Nicole Mittmann, Dr. Julie Hallet, and Dr. Alyson Mahar. This work would not have been

possible without you.

Last but not least, thank you to my family and friends for all their support and encouragement.

v

Table of Contents

Co-Authorship......................................................................................................................iii

Acknowledgments.................................................................................................................iv

Table of Contents...................................................................................................................v

List of Tables........................................................................................................................ix

List of Figures.......................................................................................................................xi

List of Appendices...............................................................................................................xii

Chapter 1...............................................................................................................................1

Introduction.....................................................................................................................11

1.1 Gastric Cancer Overview......................................................................................................1

1.1.1 Descriptive Epidemiology.......................................................................................................1

1.1.2 Risk Factors.............................................................................................................................3

1.1.3 Diagnosis and Workup............................................................................................................5

1.1.4 Staging....................................................................................................................................6

1.1.5 Treatment................................................................................................................................8

1.2 Gastric Cancer Outcomes....................................................................................................10

1.2.1 Short-term Mortality.............................................................................................................10

1.2.2 Long-term Survival...............................................................................................................10

1.2.3 Costs of Care.........................................................................................................................11

1.2.4 Factors Associated with Gastric Cancer Clinical and Economic Outcomes.........................13

1.3 Cancer Surgery Centre Designation....................................................................................16

1.3.1 Introduction to Cancer Surgery Centre Designation.............................................................16

1.3.2 Controversies with CSCD.....................................................................................................17

1.3.3 Cancer Surgery Centre Designation in Ontario, Canada.......................................................18

1.4 Ontario Healthcare System.................................................................................................19

1.5 Summary of Evidence and Rationale..................................................................................19

Chapter 2.............................................................................................................................21

Methods..........................................................................................................................212

vi

2.1 Study Objectives..................................................................................................................21

2.2 Hypotheses...........................................................................................................................21

2.3 Study Design........................................................................................................................21

2.4 Study Population.................................................................................................................22

2.4.1 Inclusion Criteria...................................................................................................................22

2.4.2 Exclusion Criteria..................................................................................................................23

2.4.3 Restrictions............................................................................................................................23

2.5 Study Perspective and Timeframe.......................................................................................23

2.5.1 90-dayMortalityandOverallSurvival...................................................................................23

2.5.2 CostsofCare.........................................................................................................................24

2.6 Study Setting........................................................................................................................25

2.7 Data Sources........................................................................................................................26

2.7.1 Ontario Cancer Registry........................................................................................................26

2.7.2 Canadian Institute for Health Information-Discharge Abstract Database and Same Day Surgery..............................................................................................................................................26

2.7.3 National Ambulatory Care Reporting System.......................................................................26

2.7.4 Home Care Database.............................................................................................................27

2.7.5 Ontario Health Insurance Plan..............................................................................................27

2.7.6 Registered Persons Database.................................................................................................27

2.7.7 Activity Level Reporting.......................................................................................................27

2.8 Study Variables...................................................................................................................27

2.8.1 PrimaryExposure..................................................................................................................29

2.8.2 Outcomes..............................................................................................................................31

2.8.3 Covariates..............................................................................................................................33

2.8.4 Confounders..........................................................................................................................38

2.9 Statistical Analysis...............................................................................................................39

2.9.1 Objective 1: CSCD and 90-Day Mortality............................................................................39

2.9.2 CSCD and Overall Survival..................................................................................................39

2.9.3 CSCD and Costs of Care.......................................................................................................40

2.10 Sensitivity and Subgroup Analyses....................................................................................41

2.10.1 Cohort Excluding 90-Day Decedent Patients......................................................................41

2.10.2 Cohort Restricted to Patients Treated with Distal Gastrectomy Only.................................41

2.10.3 Cohort Restricted to Patients with Complete Cost Data......................................................41

vii

2.10.4 Cohort Including Patients with Missing Institution Information.........................................41

2.10.5 Cohort Restricted to Non-Decedent Patients.......................................................................41

2.10.6 Cluster Analyses..................................................................................................................42

2.10.7 Missing Data.......................................................................................................................42

2.11 Ethical Considerations.......................................................................................................42

Chapter 3.............................................................................................................................44

Results............................................................................................................................443

3.1 Cohort Selection..................................................................................................................44

3.2 Cohort Description..............................................................................................................45

3.2.1 OverallStudyCohort.............................................................................................................45

3.2.2 CostStudyCohort.................................................................................................................47

3.3 Objective 1...........................................................................................................................49

3.4 Objective 2...........................................................................................................................52

3.5 Objective 3...........................................................................................................................56

3.6 Sensitivity and Subgroup Analyses......................................................................................60

3.6.1 Exclusion of 90-day Decedent Patients.................................................................................60

3.6.2 Cohort of Patients Who Underwent Distal Gastrectomy Only..............................................61

3.6.3 Complete Costs.....................................................................................................................62

3.6.4 Cohort of Missing Institution Information versus Non-Missing Institution Information......63

3.6.5 Cohort Restricted to Non-Decedent Patients.........................................................................64

3.6.6 Cluster Analyses....................................................................................................................64

Chapter 4.............................................................................................................................66

Discussion.......................................................................................................................664

4.1 Summary of Study Findings................................................................................................66

4.2 Summary of Study Cohorts.................................................................................................67

4.3 Centralization to Institutions with Cancer Surgery Centre Designation............................68

4.3.1 Objective1............................................................................................................................69

4.3.2 Objective2............................................................................................................................71

4.3.3 Objective3............................................................................................................................72

4.4 Study Limitations and Strengths.........................................................................................74

4.5 Implications.........................................................................................................................77

viii

4.6 Future Directions.................................................................................................................79

References or Bibliography.................................................................................................81

Appendices...........................................................................................................................89

ix

List of Tables

Table 1. Sources and definitions of patient and disease characteristics

Table 2. Cancer Care Ontario Institutions with CSCD, by type

Table 3. Definitions of type of gastrectomy performed

Table 4. Patient and disease characteristics of gastric cancer patients who underwent gastrectomy

in Ontario (n=2,930)

Table 5. Patient and disease characteristics of gastric cancer patients diagnosed between June 1,

2002 and March 31, 2013 who underwent gastrectomy in Ontario (n=2,399)

Table 6. Univariable and multivariable analyses of 90-day mortality for patients who underwent

gastrectomy (n=2,930)

Table 7. Median survival in days and results of Log-Rank tests comparing survival curves of

categories of variables

Table 8. Cox Proportional Hazards Analysis of overall survival in patients who underwent

gastrectomy in Ontario (n=2,930)

Table 9. Linear regression of log-transformed monthly costs for patients who underwent

gastrectomy in Ontario (n=2,399)

Table 10. Cox proportional hazards analyses of overall survival in patients treated with

gastrectomy, excluding patients who died within ninety days of surgery (n=2,718)

Table 11. Linear regression of log-transformed monthly costs of care for patients who underwent

gastrectomy, excluding patients who died within ninety days of surgery (n=2,216)

Table 12. Frequency of 90-day mortality by type of gastrectomy for centres with and without

CSCD

Table 13. Logistic Regression of 90-day mortality in patients who underwent distal gastrectomy

without multivisceral resection or preoperative therapy

x

Table 14. Cox Proportional Hazards Regression of overall survival in patients treated with distal

gastrectomy without multivisceral resection or preoperative therapy

Table 15. Linear regression of log-transformed monthly costs of care for patients who underwent

distal gastrectomy without multivisceral resection or preoperative therapy (n=1,183)

Table 16. Linear regression with monthly costs of care for patients who underwent gastrectomy

diagnosed between 2006 and 2013 (n=1,506)

Table 17. Logistic Regression of 90-day mortality in patients with and without missing

institution information (n=3,103)

Table 18. Linear regression of log-transformed monthly costs of care for patients with and

without missing institution information

Table 19. Linear regression of log-transformed monthly costs of care for non-decedent patients

(n=851)

xi

List of Figures

Figure 1. Outline of study timeframe for analyses of 90-day mortality and overall survival in

patients treated with gastrectomy in Ontario

Figure 2. Outline of study timeframe for cost analysis of patients treated with gastrectomy in

Ontario

Figure 3. Conceptual model depicting the relationship of patient, disease, and healthcare system

characteristics with outcomes

Figure 4. Cohort selection process for analyses of 90-day mortality and overall survival

Figure 5. Cohort selection process for cost analysis

Figure 6. Survival curves for patients who underwent gastrectomy, stratified by CSCD

Figure 7. Distribution of cost per person per 30 days alive

Figure 8. Distribution of log-transformed cost per patient per month

Figure 9. Proportions of patient-level mean total costs by contributing cost parameters for

patients treated at institutions with CSCD

Figure 10. Proportions of patient-level mean total costs by contributing cost parameters for

patients treated at institutions without CSCD

Figure 11. Distribution of inpatient costs

Figure 12. Median survival by institution, with institutions ordered by descending volume

Figure 13. Median costs per institution, with institutions ordered by descending volume

Figure 14. Survival curves for patients who underwent gastrectomy with exclusion of 90-day

decedents, stratified by cancer surgery centre designation

xii

List of Appendices

Supplemental Table 1. ICD-10 codes defining gastric cancer

Supplementary Table 2. ICD-O-3 codes defining adenocarcinoma

Supplementary Table 3. Test for multicollinearity of independent variables included in the

models

Supplementary Table 4. Patient and disease characteristics of gastric cancer patient cohort

restricted to patients who lived beyond 90 days following gastrectomy (n=2,718)

Supplementary Table 5. Patient and disease characteristics of gastric cancer patient cohort

restricted to patients treated with distal gastrectomy only (n=1,346)

Supplementary Table 6. Patient and disease characteristics of gastric cancer patient patients

diagnosed between June 1, 2006 and March 31, 2013 (n=1,506)

Supplementary Table 7. Patient and disease characteristics of gastric cancer patients with and

without missing institution information (n=3,103)

Supplementary Table 8. Patient and disease characteristics of non-decedent gastric cancer

patients June 1, 2002 and March 31, 2013 (n=851)

1

Chapter 1

Introduction 11.1 Gastric Cancer Overview

Gastric cancer is the fifth most common cancer and third leading cause of cancer-related

mortality in the world (1). In 1975, gastric cancer was the most common neoplasm in the world.

Since that time, the global incidence of gastric cancer has been on the decline with increased

food refrigeration, decreasing prevalence of Helicobacter pylori (H. pylori), and reduced tobacco

consumption (1, 2). Advances in diagnostics and therapy for gastric cancer have occurred, and

processes of care that improve gastric cancer outcomes have been identified (3-5). Despite these

developments, and the decreasing incidence, gastric cancer remains both clinically and

economically burdensome to healthcare systems (6, 7).

Gastric adenocarcinoma is the most common histopathologic subtype of gastric cancer.

Other cancers arise much less frequently in the stomach, including gastrointestinal stromal

tumours and other sarcomas, lymphomas, and neuroendocrine tumours (8). Henceforth, gastric

cancer will be used synonymously with gastric adenocarcinoma.

1.1.1 Descriptive Epidemiology

Gastric cancer incidence has significant geographic variability (1). Regions such as

Eastern Asia, Central and Eastern Europe, and South America have a high incidence of gastric

cancer with age-standardized incidence rates of 35.4 per 100,000 for males and 13.8 for females,

20.3 per 100,000 for males and 8.9 per 100,000 for females, and 14.2 per 100,000 for males and

7.0 per 100,000 for females, respectively. Conversely, regions such as Northern Europe, Western

Europe, Africa, and North America have a low incidence of gastric cancer with age-standardized

incidence rates of 7.4 per 100,000 for males and 3.7 per 100,000 for females, 8.8 per 100,000 for

males and 4.3 per 100,000 for females, 4.5 per 100,000 for males and 3.2 per 100,000 for

females, and 5.5 per 100,000 for males and 2.8 per 100,000 for females, respectively (3, 8).

World cancer data from 2012 estimated more than 70% of new cases occur in developing

countries, with an age-standardized incidence of 17.4 per 100,000 for males and 7.5 per 100,000

for females (1).

2

Gastric cancer mortality also varies significantly throughout the world. Overall, an

estimated 723,000 deaths due to gastric cancer occur annually throughout the world, making it

the fifth most common cause for cancer-related death (1). Similar to incidence, deaths

attributable to gastric cancer occur more frequently in males (age-standardized mortality rate of

12.8 per 100,000 in 2012) than in females (age-standardized mortality rate of 5.7 per 100,000 in

2012), and shows variability between countries (1).

In Canada, incidence rates are significantly less than the global incidence rates. In 2017,

the estimated age-standardized incidence rates for males was 11.8 per 100,000 for males and 5.9

per 100,000 for females (9). In the same year, an estimated 2,100 deaths occurred in Canada due

to gastric cancer—age-standardized mortality rates were 6.9 per 100,000 in males and 3.6 per

100,000 deaths in females (9). Ontario, the largest province in Canada, has age-standardized

incidence rates slightly higher than the national equivalent at 12.0 per 100,000 for males and 6.5

per 100,000 for females, and age-standardized mortality rates of 6.7 per 100,000 for males and

3.6 per 100,000 for females (9).

Although a higher incidence of the gastric cancer exists in Asian countries such as Japan

and Korea, the survival rate has improved over time. However, the same improvement in stage-

matched survival has not been observed in low-incidence regions such as North America (3, 4).

High mortality rates are also observed in Central and Eastern Europe as well Central and South

America (1). In low-incidence countries such as the United States and Canada, presentation with

advanced disease, and high recurrence rates of 40-65% have been described as contributing

factors to the poor prognosis of patients with gastric cancer (3). Theories to explain the

differences in the incidence and outcomes for gastric cancer patients in the East versus the West

include biologic (tumour location, tumour type), patient comorbidities, and treatment differences

(10).

Although the incidence of gastric cancer in Canada and Ontario is low, the high mortality

of Canadian patients diagnosed with gastric cancer behooves investigation into factors affecting

outcomes for these patients.

3

1.1.2 Risk Factors

A wide range of risk factors for gastric cancer have been described, including ethnicity,

infectious, dietary, environmental, medical, and hereditary factors.

The remarkable differences in incidence and mortality of gastric cancer in Asia and

Western countries suggest an ethnic, or environmental origin as a possible risk factor for the

development of gastric cancer (3). In particular, individuals of Korean, Vietnamese, Japanese,

Native American, and Hawaiian descent have been identified as a high risk group; Latino,

Chinese, and black individuals as an intermediate risk group; and Filipino and white individuals

as a low risk group for gastric cancer development (3). Interestingly, the first generation of

individuals who migrate from high-incidence to low-incidence regions retain the risk rate of their

native country, while subsequent generations acquire the risk rate of their new environment,

suggesting an environmental etiology over an ethnic etiology (3, 11).

A very significant factor in the etiology of gastric cancer is H. pylori. In 1994, the

International Agency for Research on Cancer declared the gram-negative microaerophilic

spirochete as a human carcinogen for its role in gastric cancer carcinogenesis (12). The pattern of

H. pylori infection affects outcomes; patients with antrum-predominant gastritis have increased

acid production, predisposition to duodenal ulcer formation, and decreased risk of gastric cancer

formation, while chronic corpus-predominant gastritis is associated with lower acid secretion,

multifocal atrophic gastritis, and increased risk of intestinal type gastric cancer formation (12,

13). H. pylori virulence factors such as cytotoxin-associated gene (Cag)A, CagL, vacuolating

cytotoxin A (VacA), outer inflammatory protein A (OipA), and H. pylori peptidoglycan, as well

as the inflammatory response to, the oxidative stress from, and the E-cadherin gene induction by

H. pylori infection have been described in gastric tumorigenesis (12, 13). Factors such as diet

and lifestyle behaviours may also play a role in the gastric cancer pathogenesis mediated by H.

pylori infection. A synergistic effect on the development of gastric cancer is observed with a

high-salt diet in combination with H. pylori infection and smoking in the context of H. pylori

infection may also enhance gastric cancer formation. On the other hand, concurrent helminth

infection and antioxidant intake with H. pylori infection may have a protective effect against

H.pylori-mediated gastric cancer (13). H. pylori eradication through a prophylactic regimen has

4

been shown effective for the prevention of metachronous lesions in early stage gastric cancer

(14).

The etiology of gastric cancer also includes dietary factors. High consumption of salt

including cured or salt-preserved meat and fish, as well as pickled vegetables, high starch, and

low protein have been associated with increased gastric cancer risk (15, 16). Gastric

carcinogenesis is thought to occur through enhanced N-nitroso compounds formed by the

nitrosation of amides or amines in the stomach by nitrites, but is inhibited by Vitamin C in

gastric juice (15). High fruit and vegetable intake, therefore, has been described as protective

against gastric cancer formation (15, 16).

The environment in which a person lives is also described as playing a potential role in

gastric cancer development. Environmental risk factors for gastric cancer include lack of

refrigeration of food, occupation hazards such as mining, farming, refining, and fishing, as well

as rubber, timber, and asbestos processing. Lifestyle factors have also been shown to be

associated with gastric carcinogenesis. Alcohol, by acting as a gastric irritant, and smoking, by

decreasing prostaglandins important to maintain gastric mucosal integrity are involved in gastric

cancer development (16).

Other medical diagnoses are also associated with increased risk of developing gastric

cancer. Pernicious anemia is a condition characterized by achlorhydria, which leads to the

destruction of chief and parietal cells in an autoimmune reaction. Gastric mucosa then becomes

atrophic, leading to antral and intestinal metaplasia (17). Rare inherited disorders such as Li-

Fraumeni syndrome (tumour suppressor gene p53 mutation), Peutz-Jeghers syndrome, hereditary

diffuse gastric cancer (E-cadherin or CDH1 mutation), or hereditary nonpolyposis colorectal

cancer or Lynch syndrome (microsatellite instability) have also been linked to gastric cancer (17,

18). While familial adenomatous polyposis is associated with benign fundic gland polyps, a new

autosomal dominant gastric polyposis syndrome called gastric adenocarcinoma and proximal

polyposis of the stomach (GAPPS), characterized by fundic gland polyposis of the gastric body

and fundus, has been reported as progressing to dysplasia and intestinal type gastric

adenocarcinoma (17, 19).

Modifiable risk factors of gastric cancer necessitate investigation to identify targets for

the potential prevention of gastric cancer development. Furthermore, factors strongly correlated

5

with the development of gastric cancer warrant investigation to identify those at risk for

development of gastric cancer, facilitate early diagnosis, and may improve outcomes for those

diagnosed with gastric cancer.

1.1.3 Diagnosis and Workup

To guide diagnostic workup, a comprehensive history should be taken to elicit potential

symptoms of gastric cancer, including dyspepsia, dysphagia, involuntary weight loss, vomiting,

early satiety, and bleeding (8). Patients should also be screened for a family history of gastric

cancer (20). Physical examination should be conducted with a focus on detection of features

suggestive of advanced disease, including palpable abdominal masses, ascites, hepatomegaly,

left supraclavicular lymphadenopathy (Virchow’s node), left axillary lymphadenopathy (Irish’s

node), periumbilical lymphadenopathy (Sister Mary-Joseph’s node), or cachexia (3). Bloodwork,

including a complete blood count to assess for iron deficiency anemia, and comprehensive

chemistry profile to assess renal and liver function, should also be performed (8, 20). Diagnosis

of gastric cancer should be made by biopsy from endoscopic examination, or from a metastatic

disease site. Biopsies with adequate tissue should be taken to collect 6-8 specimens.

In high-incidence countries such as Korea and Japan, systematic screening programs exist

to facilitate gastric cancer detection at earlier stages (21, 22). Early gastric cancers also have a

favourable prognosis, further supporting screening programs (22). In addition to increased

diagnosis of gastric cancer at earlier stage, screening has afforded other benefits of early gastric

cancer detection, such as more minimally invasive therapeutic treatments such as endoscopic

mucosal resection and endoscopic submucosal resection (23). These interventions have also

resulted in increased long-term outcomes and quality of life for patients with early gastric cancer

(23). In high incidence regions such as China, Japan, and Korea, screening programs have been

found to be cost-effective (24).

In Canada, screening is not considered cost-effective given the low incidence of gastric

cancer in the country, as population-level screening for rare diseases is costly (25). A lack of

population-based screening programs and the nonspecific symptomatology of gastric cancer thus

lead to presentation with the disease at advanced stages, and contribute to the poor prognosis of

gastric cancer patients in these low-incidence regions (8, 21). The insidious onset and lack of

early detection perpetuated by an absence of systematic screening further contributes to high

6

mortality for patients diagnosed with gastric cancer in Canada, and poses questions regarding the

processes of care that affect outcomes for these patients.

1.1.4 Staging

Worldwide, the most commonly used system for staging is that which is maintained by

the Union for International Cancer Control (UICC) and the American Joint Committee on

Cancer (AJCC). This system classifies the anatomic extent of cancer by description of primary

tumour (T), status of regional lymph nodes (N), and presence or absence of distant metastases

(M) in the TNM classification (26). Accurate clinical staging is important in the guidance of

clinical decision-making and appropriate administration of treatment. Preoperative evaluation

has also been described as a specific process of care for gastric cancer that influences the

outcome of health following the care received by a patient (4)

Appropriate clinical investigations need to be conducted to obtain accurate disease

staging. Endoscopic examination is important for establishing the location of the gastric tumour

(20). Cross-sectional imaging with a CT scan of the chest, abdomen, and pelvis, is the

preoperative staging investigation recommended by many gastric cancer guidelines, including

those from the National Comprehensive Cancer Network (NCCN), the European Society for

Medical Oncology (ESMO), and Cancer Care Ontario’s Program in Evidence-Based Care

(PEBC) (8, 20, 27). The accuracy, sensitivity, and specificity of CT varies from 60-100%, 60-

100%, and 92-100%, respectively, so adjunct investigations may be employed to compensate for

deficiencies in CT performance, including endoscopic ultrasound (EUS), positron emission

tomography (PET) scan, magnetic resonance imaging (MRI), and diagnostic laparoscopy (27,

28). These alternative investigations have specific indications, however, and should only be

utilized if the results of the adjunct investigations will change the management plan (29).

EUS may be employed in patients with planned curative-intent treatment with suspicion

for local invasion or involvement of regional lymph nodes, and, if technically feasible and safe,

combined with fine-needle aspiration to further inform stage and subsequent management (29).

A systematic review and meta-analysis of the utility of EUS for preoperative staging for gastric

cancer by Cardoso et al. reported EUS may be most useful for advanced cancers with a pooled

accuracy of 85% for T3 staging and 69% for T4 staging (30). From the same study, the pooled

7

accuracy, sensitivity, and specificity of EUS for N staging was 64%, 74%, and 80%, respectively

(30).

PET scan may be helpful in the detection of anatomically small or occult foci of

metastastic disease (8, 31). For N staging in particular, PET has been reported to have low

sensitivity (40%) but high specificity (98%). However, PET has poor spatial resolution, and

limited utility in the context of mucinous carcinoma, signet ring cell carcinoma, and poorly

differentiated adenocarcinomas as these diseases are less PET avid (31). Thus, PET is not

routinely recommended for gastric cancer staging (5).

MRI scans may be useful to aid in further characterization of liver lesions (29). MRI has

also been reported to have improved performance accuracy over CT with an overall accuracy of

83% for T staging. MRI scans, however, are limited by motion artifacts from respiration,

prolonged examination times, high costs, and a lack of a standardized gastric protocol. MRI

scans, like PET scans are therefore also not recommended to be routinely performed unless

finding of metastatic disease will change the treatment plan (29).

Diagnostic laparoscopy is recommended for patients under consideration for neoadjuvant

therapy prior to initiation of chemotherapy (8, 20, 29). Additionally, patients with clinical

suspicion of T3 or T4 disease and patients at higher risk for metastatic disease—those with

poorly differentiated tumours and those with higher nodal disease burden should undergo

diagnostic laparoscopy prior to initiation of therapy (29). Cytologic examination of ascitic fluid

or instillation of 200 mL of normal saline for peritoneal washings at the time of diagnostic

laparoscopy may be used to increase the informative yield (27). The aim of diagnostic

laparoscopy should be to increase staging accuracy beyond that of the CT scan to potentially

avoid the morbidity of a laparotomy without curative intent in these patients (29, 32). In a

systematic review of the accuracy and indications for diagnostic laparoscopy prior to curative-

intent gastric cancer resection by Leake et al., diagnostic laparoscopy was particularly useful in

the detection of metastatic disease, especially peritoneal carcinomatosis, with accuracy of

detecting overall metastatic disease reported between 90-100% (27). Diagnostic laparoscopy has

also been reported to change the management plan in up to 60% of cases (27).

Substantial evidence outlines the appropriate staging of patients with gastric cancer and

how accurate staging guides treatment for these patients. However, in a population-based study

8

exploring the processes of care for patients with gastric cancer in Ontario, the underuse of both

preoperative radiology and endoscopy was found (4). Furthermore, relevant information,

including tumour size and pathologic markers were not consistently recorded in pathology or

operative reports (33). This variation in the application of guidelines that affect the management

of and outcomes for patients with gastric cancer warrants further investigation.

1.1.5 Treatment

Many treatment options exist for gastric cancer patients depending on stage and treatment

intent, including therapeutic endoscopy, surgery, chemotherapy, radiotherapy, targeted therapies,

or any combination of these. Before initiation of treatment, all patients with a confirmed

diagnosis of gastric cancer and completed appropriate workup should be discussed at a

multidisciplinary tumour board (MTB) meeting (29). MTB meetings are regularly occurring,

formal meetings whereby networks of cancer care specialists prospectively review individual

patients with cancer, discuss the diagnosis, and formulate management plans in an evidence-

based approach to improve diagnostic accuracy, clinical practice guideline adherence, and

clinical outcomes (34). The care of patients with gastric cancer should also be delivered by a

multidisciplinary team, which may include surgeons, medical oncologists, radiation oncologists,

radiologists, pathologists, gastroenterologists, nurses, social workers, palliative care specialists,

and dietitians (5).

1.1.5.1 Surgery

Surgical resection is the cornerstone of curative therapy for gastric cancer. Surgical

interventions for gastric cancer include local resection, segmental gastrectomy, proximal

gastrectomy, pylorus-preserving gastrectomy, distal gastrectomy, and total gastrectomy (35).

Non-resectional surgical options include bypass surgery, gastrostomy, and jejunostomy.

Selection of gastrectomy is dependent on tumour location, and stage. For clinically node positive

tumours, or T2 to T4a tumours, the standard oncologic surgical procedures are total or distal

gastrectomy (35). Distal tumours may be treated with distal gastrectomy if a satisfactory

proximal margin can be obtained. Total gastrectomy should be considered for proximal tumours,

or tumours along the greater curvature with involvement of 4sb lymph nodes along the left

gastroepiploic artery (35). T1a lesions with no positive nodes should be considered for removal

by endoscopic methods (5).

9

Beyond the appropriate type of surgery performed, quality oncologic surgery for gastric

cancer should focus on complete removal of the cancer, or R0 resection, and adequate lymph

node dissection (5, 35). To assist with achievement of R0 resection, intraoperative assessment of

margin status through frozen section is an important consideration (5). For curative-intent

resection in patients with advanced, non-metastatic gastric cancer, more aggressive (D2)

lymphadenectomy is the preferred method of lymph node dissection, and for patients with early

gastric cancer, or patients with significant comorbidities, a less aggressive (D1)

lymphadenectomy is the preferred method of lymph node dissection (5). Furthermore, a

minimum of 16 lymph nodes need to be assessed for patients treated with curative-intent

resection for gastric cancer for improved accuracy of staging and improved survival (5).

1.1.5.2 Adjuvant Therapy

All gastric cancer patients with curatively resectable tumours should be considered for

neoadjuvant and/or adjuvant therapy (36). The two most common regimens were the

postoperative 5-fluorouracil (5-FU)-based chemoradiotherapy (Macdonald) approach or

perioperative epirubicin/cisplatin/5-FU (ECF)-based chemotherapy (Cunningham/Medical

Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC)) approach (37, 38). If

contraindications to either the Macdonald or MAGIC approaches exist, adjuvant chemotherapy is

considered a reasonable alternative (36). A recent multicenter randomized phase 3 trial

comparing perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin

(FLOT) versus ECF or epirubicin/cisplatin/capecitabine (Xeloda) (ECX) revealed improved 30-

and 90-day mortality rates, progression-free survival, and overall survival with FLOT compared

to ECF/ECX (39). Within the study period of this project, the standard treatments were

perioperative chemotherapy (MAGIC), or postoperative chemoradiotherapy, as FLOT was not

introduced as standard therapy until after the end of the study period, in 2017.

Despite guidelines on the surgical and non-surgical treatments recommended for

curative-intent resectable gastric cancer tumours, variation in management exists. A population-

based study in Ontario investigated variation in practice patterns within the universal, publicly

funded healthcare system for the treatment of patients with early stage, resectable gastric cancer

and found significant variation in the types of surgical and non-surgical treatments provided (33).

The rare incidence of potentially curative gastric cancer in combination with variability in the

10

care provided to patients with curable gastric cancer raises interesting questions regarding the

optimal organization of care for patients, with consideration of providers and healthcare systems.

1.2 Gastric Cancer Outcomes

Many important outcomes exist for patients with gastric cancer. This study focuses on

short-term mortality (Section 1.2.1), long-term survival (Section 1.2.2), and costs of care

(Section 1.2.3).

1.2.1 Short-term Mortality

The short-term mortality following gastrectomy for patients diagnosed with gastric

cancer ranges from 0.6 to 5.2% (33, 40-42). In the United Kingdom, where centralization of

esophagogastric cancer surgery has occurred, the National Oesophago-Gastric Cancer Audit,

evaluating the care delivered by all English hospitals performing esophagogastric cancer surgery

was interrogated for patients treated with curative surgery between April 1, 2011 and March 31,

2013. From these data, the overall 30-day mortality was found to be 2.3%, and the overall 90-day

mortality to be 4.4% (40). From the nationally maintained American College of Surgeons

National Surgical Quality Improvement Program (ACS-NSQIP) database, patients treated with

gastrectomy between 2011 and 2013 for both benign and malignant pathologies were found to

have a 30-day mortality rate of 5.2% (41). In a population-based cohort study of resected, non-

metastatic gastric cancer patients diagnosed between April 1, 2005 and March 31, 2008 treated in

the province of Ontario, the in-hospital mortality was 5.1% (33).

1.2.2 Long-term Survival

Despite the variety of treatment options available to patients with gastric cancer, in low-

incidence countries, the overall prognosis following diagnosis with the disease is poor (8).

Survival varies across disease stage and geography. High-incident Asian countries have reported

improved survival compared to low-incident North American countries. In Japan, five-year

survival has been described as ranging from 90.2% in Stage I disease, 75.2% in Stage IIA

disease, 59.3% in Stage IIB disease, 43.4% in Stage III disease, to 14.1% in Stage IV disease

(26). Five-year survival in the United States from the National Cancer Database (NCDB) have

been described as ranging from 56.7% for Stage I disease, 47.3% in Stage IIA disease, 33.1% in

Stage IIB disease, 25.9% in Stage III disease, to 5% in Stage IV disease (26). In non-metastatic,

11

resected gastric cancer patients in Ontario, five-year overall survival was 71% for patients with

Stage I disease, 51% for patients with Stage II disease, and 27% for patients with Stage III

disease (33).

Disease-level, patient-level, provider-level, and healthcare system-level factors are

implicated in the determination of outcome for patients with cancer (43). Even within a

universal, publicly-funded healthcare system, variation in practice patterns, and outcomes has

been described (33). Identifying modifiable factors in gastric cancer care is fundamental to

optimizing outcomes for patients with gastric cancer.

1.2.3 Costs of Care

1.2.3.1 Introduction to Health Economics

Health economics is the study of efficiency and effectiveness of health procedures,

services, or programs, as well as the optimization of available resource allocation within the

healthcare sector (44). The study of health economics includes the monetary valuation of direct

or indirect resource utilization related to medical procedures, services, or programs in a given

timeframe, from an assumed evaluation viewpoint or perspective (e.g. patient, institution,

healthcare system, societal) (44). The field of health economics encompasses the identification,

measurement, and valuation of costs and consequences through economic evaluation—the

comparative analysis of both costs and consequences of alternative courses of action (44). Within

a climate of escalating demands on a healthcare system with increasingly scarce resources, health

economics and economic evaluation have been sought for the provision of evidence-based

frameworks to assist in healthcare decision-making (45). Information regarding the economic

impact of medical programs, services, or programs may also be valuable for forecasting

healthcare system use, planning of resource allocation, and budgeting at the political (macro)

level (45).

At the level of the physician or patient, however, the role of health economics and

economic evaluation is controversial. While economic evaluation helps to identify alternatives

that are good value for money from a population standpoint, physicians are tasked with

providing optimal patient-centred care at an individual level. What may benefit one patient may

not align with the best interests of society as a whole, or with the remainder of patients seeking

12

care once resources have been committed to the first patient (45). An understanding of health

economics and economic evaluation, then, may help in overall decision-making by viewing

every decision made by a clinician for a patient as an opportunity cost in terms of what cannot be

provided for another patient. Furthermore, training in health economics would facilitate

appropriate and efficient health resource allocation within the current constraints of the

healthcare system, particularly as clinicians expand their roles beyond healthcare provision to

join decision-making bodies and committees involved in health policy creation (45).

1.2.3.2 Gastric Cancer Costs

Gastric cancer care is expensive and gastric cancer healthcare costs are generally higher

than that of other cancers (46). The costs of treating gastric cancer increase as the disease

progresses, with the highest costs of care associated with the treatment of patients with

metastatic gastric cancer (46). Similar to that of incidence and mortality, the economic burden

associated with gastric cancer care also varies across geographic regions with annual costs

ranging from 27 million in Iran to 8.5 billion United States (US) dollars in Japan (46). The

estimated annual cost of gastric cancer and gastroesophageal cancer care in 2017 for Europe

(France, Germany, Italy, Spain, United Kingdom), Asia (Iran, Japan, China), North America

(United States and Canada), and Australia was 20.6 billion US dollars (46).

In a Canadian study estimating the mean net costs for the 21 most prevalent cancers,

gastric cancer was identified as the third most expensive cancer to treat (7). Models predicting

the costs of gastric cancer have identified primary treatment strategy as the explanatory variable

accounting for the greatest amount of variance within the models, and surgery described as the

most expensive treatment strategy (47). Of the highest costs of care, inpatient hospital days are

the highest contributor to costs in the healthcare system (47, 48). Despite evidence suggesting the

high economic burden of gastric cancer care, particularly related to surgical care, health

economic literature providing detailed costing of gastric cancer phases of care or information on

selecting cost-effective gastric cancer treatment at the level of the population, or individual

patient, is sparse (49). Investigating the clinical and economic outcomes of gastric cancer care

collectively is essential to identifying potential areas for sustainable improvement in the care of

patients with gastric cancer.

13

1.2.4 Factors Associated with Gastric Cancer Clinical and Economic Outcomes

Various predictors of cancer outcomes have been identified. Factors associated with

cancer outcomes have previously been classified as tumour-related, host-related, and

environment-related in acknowledgement of the factors beyond the tumour itself that affect the

clinical outcomes of patients (43). The factors associated with cancer outcomes relevant to this

study include patient characteristics (age, sex, comorbidities, rurality, socioeconomic status),

disease characteristics (tumour location, burden of disease), and healthcare system characteristics

such as processes of care (50-54).

Age

Older age of gastric cancer patients has been reported to be independently associated with

mortality, worse overall survival and early recurrence (41, 50-52). Conversely, patients with

younger age experienced more aggressive disease and poorer outcomes compared to older

patients diagnosed with breast, as well as colorectal cancer (55, 56). Similarly, patients

diagnosed with gastric cancer at a young age had a higher incidence of advanced disease

compared to that of the general patient population (57)

Sex

Gastric cancer incidence and mortality is much higher in male patients than female

patients worldwide (1). Male sex has also been independently associated with worse overall

survival in gastric cancer (50). Furthermore, the absolute lifetime costs of gastric cancer care in

Ontario was higher for male patients than for females, but the third most expensive cancer to

treat for both sexes (7).

Comorbidity

In a joint report from the American Cancer Society, Centers for Disease Control and

Prevention, the National Cancer Institute, and the North American Association of Central Cancer

Registries, level of comorbidity was described as an important influence on the probability of

death for patients diagnosed with lung, colorectal, breast, or prostate cancer (58). Increased

comorbidity burden has also been associated with decreased participation in screening,

prolonged length of stay, and increased readmission in patients with breast, cervical, and

14

colorectal cancer (58, 59). Independent association between comorbidity and overall survival for

gastric cancer patients has also been reported with the presence of preoperative comorbidity

conferring a higher risk of death compared to those without preoperative comorbidity (60).

Rurality of Residence

Rurality presents a challenge in cancer care as patients living in rural areas may face

transportation barriers, financial issues, limited access to clinical trials, and reduced availability

of cancer treatments and providers (61). Overall, the impact of rurality on screening rates,

receipt of recommended treatment and follow-up, and cancer outcomes is unclear. (61).

However, survival rates of gastric cancer patients in rural versus urban China have been found to

be significantly different, and improvement in survival observed with regional economic

development (62). Improved survival of gastric cancer patients living in urban versus rural areas

has also been reported in Russia (63).

Socioeconomic Status

Socioeconomic status impacts cancer incidence and prognosis (64). High socioeconomic

status has been associated with higher risk for patients diagnosed with breast cancer and

malignant melanoma, whereas low socioeconomic status is associated with adverse prognosis in

lung, prostate, and ovarian cancers (64). Specific to gastric cancer patients, high individual

socioeconomic status is associated with a lower risk of mortality (65, 66).

Tumour Location

Tumour location has been associated with differences in overall survival with distal

tumours associated with the highest 5-year survival rate, of 50.7%, followed by corpus or fundus

tumours at 28.6%, and lastly, tumours in the proximal stomach, with a 5-year survival rate of

21.4% (p

15

Tumour Burden

Increased tumour burden necessitating resection of adjacent organs has also been

identified as independently associated with overall survival, and an increased risk of death

compared to no resection of adjacent organs is described (50).

Processes of Care

Processes of care involve specific steps leading to a particular outcome metric, and have

become a target for quality improvement in healthcare delivery (68, 69). Processes, with

structures and outcomes, also comprise the Donabedian model of healthcare quality

conceptualization to understand potential sources of perioperative variation, and to outline

modifiable sources of risk for surgical quality optimization (69). Processes of care have been

emphasized as excess variation in care has been identified as a potential source of medical errors,

and standardization of care delivery processes as a solution for improved healthcare outcomes

and quality (69). In the treatment of patients with breast and colorectal cancer, processes of care,

including timing of diagnosis, sequence of treatment, and appropriateness of treatment have been

identified as targets for care quality improvement (68, 70).

Gastric cancer outcomes are also influenced by processes of care such as preoperative

evaluation, resection criteria, operative techniques, referral patterns, and administration of

adjuncts to surgical treatment (4). While the relationship between genetics, surgical techniques,

and stage migration and worse survival particular to Western gastric cancer patients has been

broadly studied, studies examining the processes of care for gastric cancer are sparse (4). In a

study describing the processes of gastric cancer care associated with improved survival in a

population of gastric cancer patients diagnosed in Ontario between April 1, 2000 and March 31,

2005, age, surgical type, and resection in an institution with higher volumes was found to be

associated with survival (4). Furthermore, an international RAND/UCLA Expert Panel created

tenets for optimal gastric cancer management, including processes of gastric cancer surgical care

such as the performance of gastric cancer surgery by a surgeon experienced in gastric cancer

management with an annual volume of greater than 6 cases per year, and at a centre with

sufficient support to prevent or manage complications of gastric cancer surgery with an

institutional volume of greater than 15 gastric cancer resections per year (5). In the Netherlands,

16

where gastric cancer care has been centralized, processes of care, including centralization, and

clinical audits were identified as potential methods of gastric cancer outcome improvement (71).

1.3 Cancer Surgery Centre Designation

1.3.1 Introduction to Cancer Surgery Centre Designation

Regionalization of surgical healthcare delivery, establishment of surgical centres of

excellence, or cancer surgery centre designation (CSCD), has been described as a specific

process of care that improves patient outcomes, including morbidity and mortality (72, 73).

Through concentration of expertise and relevant resources centred on a specific area of medicine,

care is anticipated to be delivered in a comprehensive and interdisciplinary fashion to afford the

best possible outcomes to patients (74). High procedure volumes, greater access to

multidisciplinary consultation and tumour boards, computerized physician order entry, high

nursing-to-patient ratios, earlier adoption of newer, beneficial therapies, increased use of

standard treatment protocols and clinical pathways, and less practice variation are proposed as

reasons for improved outcomes to patients receiving treatment at these specialized centres (72,

75).

Minimum operative volume standards have been the hallmark of regionalization or

establishment of designated specialty surgery centres (76). Higher volumes of select procedures

are suggested to enhance proficiency in surgeons and team-based familiarity in the healthcare

system, and in turn, improve patient outcomes (77, 78). Another theory to explain the volume-

outcome relationship is the tendency of patients to be referred to institutions already seen to

provide high quality care, thereby increasing the case volume of the institution (78). A third

hypothesis to describe the causal model of the volume-outcome relationship is the concept of an

ecosystem, in which system characteristics of institutions, such as technology, staffing, and

expertise in other surgical procedures may equip institutions to optimize the healthcare provided

to patients and effect improved healthcare outcomes (78).

Specific to surgical oncology patients, higher numbers of specialist staff and higher

procedural volume have been associated with reduced perioperative mortality rates (79-82). In

particular, volume-outcome relationships exhibiting high volumes resulting in improved

outcomes are strong for rare, high-risk surgical conditions, such as pancreatic cancer, and weaker

17

for common conditions, such as bariatric surgery for obesity (75). Rare and complex diseases,

through disparate and dispersed treatment, have been found to have variation in treatment that

may affect outcomes (33). To improve care and outcomes to these patients of low-incident

disease, regionalization to specialty centres has been proposed and implemented (83). For

example, in the Netherlands, Lemmens et al. described increased resection rates, reduced

postoperative mortality, and improved survival in the post-centralization period compared to the

pre-centralization period for pancreatic cancer surgery (84). As well, Wouters et al. described

reduced postoperative morbidity, shorter length of stay, and improved mortality following

centralization compared to pre-centralization for patients undergoing esophagectomy (84, 85).

The costs of care at specialized centres have also been evaluated. Higher costs of care

have been attributed to centres designated as teaching hospitals (86). The higher care costs may

be owing to more complex case mixes, the location of these teaching institutions in urban areas,

where labour and overhead costs are higher, costs associated with the provision of graduate

medical education, and the use of more sophisticated forms of technology (86). However, a study

evaluating hospital volume and clinical as well as economic outcomes following complex

gastrointestinal surgical procedures suggested an inverse relationship between hospital volume

and in-hospital death and lower costs associated with high-volume centres (87). A similar study

aiming to investigate the effect of regionalization and cost specific to

pancreaticoduodenectomies revealed high-volume regional centres were associated with lower

total hospital charges (88). However, while the costs specific to particular procedures may

decrease as the procedural volume increases, the overall costs will increase at tertiary centres for

the delivery of high-cost specialty care (88).

1.3.2 Perspectives Regarding CSCD

Movements towards volume-based surgical performance, however, have been met with

controversy. Examples include advocacy for volume-based referral by Leapfrog Group, a

consortium of large corporations and public agencies involved in purchasing healthcare, and the

“Take the Volume Pledge” by Dartmouth-Hitchcock Medical Center, Johns Hopkins Hospital

and Health System, and the University of Michigan Health System, asking healthcare systems to

join in restricting the performance of specific surgical procedures to hospitals and surgeons with

minimum volume standards (76, 89). This approach to restricting surgical care to high-volume

18

hospitals aimed to have the performance of complex elective surgery conducted by providers and

hospitals performing the highest numbers of the complex elective surgeries. However, the

question of performance of complex surgery in small and rural hospitals has not been answered,

and low-volume surgeons were offended by their portrayal as hobbyists fueled by pride and

professional autonomy to continue performing complex and rare procedures irrespective of

clinical and economic consequences (89). Furthermore, patient preferences for local care,

financial incentives for smaller hospitals to retain surgical cases, and lack of access to high-

volume centres in some regions are barriers to regionalization (76). Increased travel demands,

and lack of support from nearby family and friends, are other possible disadvantages of

centralization that could lead to decreased access to care (90).

1.3.3 Cancer Surgery Centre Designation in Ontario, Canada

In Ontario, CSCD has been assigned to hospitals meeting safety and quality standards for

the delivery of specific procedures or particular types of care, including hepato-pancreatic

biliary, thoracic, head and neck, and gynecological cancers (91). The establishment of CSCD

mandates the fulfillment of surgeon and hospital criteria (e.g. knowledge, training, minimum

number of surgeons) as well as physical (e.g. operating room, diagnostic modalities), system

(e.g. multidisciplinary cancer conferences, regional cancer program participation) and human

(e.g. surgeon, radiology, pathology) resources with guidelines for quality assurance measures to

be met (91).

In Canada, regionalization of both esophageal and pancreas surgery based solely on

hospital volumes has not had a clear relationship to postoperative outcomes. An investigation of

the effect of hospital volume on in-hospital mortality for patients undergoing esophagectomy in

Canada revealed no significant reduction in in-hospital mortality with increasing hospital

volume, suggesting hospital volumes alone did not explain the improved outcomes observed at

higher-volume institutions (92). Another study investigating the volume-outcome hypothesis in

patients undergoing pancreas surgery in Ontario and Quebec revealed improved operative

mortality in Ontario, but not in Quebec, despite similar increases in annual pancreas surgery

volume over the study period. The results of this study do not support the volume-outcome

hypothesis, suggesting more complexity to the relationship between volume and outcome than

simply increased surgeon experience or selective referral to providers perceived to have better

19

outcomes resulting in improved outcomes (93). These studies suggested regionalization may lead

to better outcomes through mechanisms other than increased volume, including optimization of

the use of limited resources, increased clinical trial accrual, or regional quality improvement

program facilitation (93).

Although pancreatic and esophageal cancers have similar morbidity and mortality to that

of gastric cancer with similarly challenging resections necessary to effect cure, no

regionalization of gastric cancer has been established in North America, including Canada.

1.4 Ontario Healthcare System

Healthcare in Canada is provided through a publicly funded system with a mandate to

maintain and improve the health of Canadians. The Canada Health Act governs this mandate

through its five pillars of public administration, comprehensiveness, universality, portability, and

accessibility (94). The provincial and territorial health systems, supported by the federal

government, have the responsibility and accountability for the organization, management,

delivery, quality, safety, and performance for acute, chronic, long-term, and palliative, end-of-

life needs of their respective residents (94). The provincial and territorial governments in turn

distribute the provision and planning of health services to regional governance structures such as

health authorities and local health integration networks (94).

In Ontario, the Ministry of Health and Long-Term Care is tasked with medically

necessary healthcare provision to Ontario residents through the Ontario Health Insurance Plan

(95). The Ontario government has a principal cancer advisor in Cancer Care Ontario. Through

accountability, data, planning, and performance, Cancer Care Ontario works towards cancer

prevention and cancer care delivery (91).

1.5 Summary of Evidence and Rationale

In North America, gastric cancer care places a relatively substantial clinical and

economic burden on the healthcare system (7, 8, 33). Curative-intent gastrectomy with

corresponding lymph node dissection is the cornerstone of gastric cancer therapy, but is

technically challenging and complex, and is associated with considerable morbidity, mortality,

and cost (33, 47). While diseases with similar levels of surgical care complexity, including

esophageal and pancreatic cancer, have had care regionalized to institutions with CSCD, the

20

same has not been implemented for gastric cancer surgical care. Gastric cancer care has also

been delivered with significantly variability in care patterns (33). Currently established

specialized centres, however, through standardized processes of care, concentration of relevant

expertise and resources, and increased access to newer, beneficial therapies, may effect improved

outcomes on similar non-regionalized procedures (72, 74).

Despite evidence suggesting gastric cancer care is very expensive, a paucity of literature

exists regarding the economic burden of gastric cancer care (7, 49). While regionalization of care

has been suggested in the literature as a method of improving outcomes to patients, it may result

in increased costs to the healthcare system for an already costly disease (88).

This thesis therefore compares the clinical and economic outcomes of curatively resected

gastric cancer patients between those treated at institutions with and without CSCD with a view

to evaluate whether CSCD is an organizational system that can result in improved short-term

mortality and overall survival, and at how much more cost to the healthcare system compared to

institutions without CSCD.

21

Chapter 2

Methods 22.1 Study Objectives

In a population-based, retrospective cohort study of resected, non-metastatic gastric cancer

patients in Ontario, the study objectives were to

1. Compare 90-day mortality between patients who underwent gastrectomy at an institution

with CSCD and patients who underwent gastrectomy at an institution without CSCD.

2. Compare overall survival between patients who underwent gastrectomy at an institution

with CSCD and patients who underwent gastrectomy at an institution without CSCD.

3. Compare costs of care between patients who underwent gastrectomy at an institution with

CSCD and patients who underwent gastrectomy at an institution without CSCD.

2.2 Hypotheses

The hypotheses of this thesis include:

1. 90-day mortality is lower for patients treated with gastrectomy at institutions with CSCD

compared to patients treated with gastrectomy at institutions without CSCD.

2. Overall survival is improved for patients treated with gastrectomy at institutions with

CSCD compared with patients treated with gastrectomy without CSCD.

3. Costs of care are higher for patients treated with gastrectomy at institutions with CSCD

compared to patients treated with gastrectomy at institutions without CSCD.

2.3 Study Design

This study followed a population-based, observational, retrospective cohort study design.

The design was chosen to describe the clinical (90-day mortality and overall survival) and

economic (costs of care) outcomes of patients diagnosed with gastric cancer in Ontario and to

22

compare the outcomes of patients who underwent gastrectomy at centres with cancer surgery

centre designation (CSCD) to patients who underwent gastrectomy at centres without CSCD.

2.4 Study Population

This study included a target population of individuals diagnosed and treated with curative-

intent gastrectomy for gastric adenocarcinoma in Ontario. Patients with a diagnosis of gastric

adenocarcinoma in the Ontario Cancer Registry (OCR) between January 1, 2002 and December

31, 2014 were included.

2.4.1 Inclusion Criteria

Patients aged 18 years or greater with a valid Ontario Health Insurance Plan (OHIP) number,

a valid Institute for Clinical Evaluative Sciences (ICES) key number (IKN) traceable in the

Registered Persons Database (RPDB), a confirmed gastric adenocarcinoma diagnosis within the

study period identified using the International Classification of Diseases-10 (ICD-10) codes

(C16.x) (Supplemental Table 1), an ICD for Oncology-3 (ICD-O-3) histology code for

adenocarcinoma (Supplemental Table 2), treated with a gastrectomy within a year of the date of

diagnosis, and those with non-metastatic disease were included.

Complete and accurate stage data for gastric cancer was not available in the Ontario Cancer

Registry. Metastatic disease was therefore identified using the algorithm with the highest

accuracy (73%) and specificity (82%) from a series of algorithms created using administrative

healthcare data captured in the peri-diagnostic period for identification of metastatic gastric

cancer in the absence of population-based stage data, and validated using American Joint

Committee of Cancer (AJCC) 7th Edition TNM stage data from patient hospital charts (96). Data

from one or more hospitalization, emergency department visits, or outpatient physician visits

were collected from the Canadian Institute of Health Information-Discharge Abstract Database

and the Same Day Surgery Database, the National Ambulatory Care Reporting System, and the

OHIP database at ICES were collected, and identified metastatic disease from a conservative list

of ICD diagnosis codes in the six months before or after diagnosis (96). Patient hospital chart

information was collected in a province-wide chart review including data from operative,

endoscopy, radiology, and pathology reports, and were the reference standard for validation of

the algorithms (96).

23

2.4.2 Exclusion Criteria

Patients were deemed ineligible for inclusion and excluded from this study if they died

before the date of diagnosis, if their date of last contact was missing or before the date of

diagnosis, were missing an institution number associated with a gastrectomy, had a tumour

location in the esophagus (ICD-10 codes C15.x), had previous or multiple primary cancers, or

had metastatic disease.

2.4.3 Restrictions

The cost analysis was limited to those patients diagnosed before March 31, 2013, as they did

not have the opportunity to accrue costs for the entirety of the time horizon selected.

2.5 Study Perspective and Timeframe

2.5.1 90-day Mortality and Overall Survival

The study timeframe for the analyses of 90-day mortality and overall survival are outlined in

Figure 1. For the comparison of 90-day mortality between patients treated at centres with and

without CSCD, the index event date was the date of surgery. For the comparison of overall

survival between patients treated at centres with and without CSCD, the index event date was the

date of diagnosis.

24

Figure 1. Outline of study timeframe for analyses of 90-day mortality and overall survival

in patients treated with gastrectomy in Ontario

2.5.2 Costs of Care

The study perspective for the analysis of costs of care was the perspective of the Ministry of

Health and Long-Term Care (MOHLTC), or the healthcare system payer. The costing

perspective chosen for an economic evaluation should be directly related to the decision

problem, and the costs and outcomes included in the analysis defined by the selected costing

perspective for inclusion in the study (97). The healthcare system payer perspective is often

chosen as it accounts for direct medical costs for their relevance to health policy planners and

healthcare system decision-makers (98). Within a publicly funded healthcare system such as that

of Canada, relevant sources of costs include drugs, medical procedures, equipment, facilities,

overhead, healthcare provider fees, hospital services, investigations, rehabilitation, and

community-based services such as home care (97).

For economic evaluations, the study perspective and time horizon need to be relevant to the

research question and appropriate for the outcomes of an economic study (44, 97). The median

survival of gastric cancer patients in Ontario who have undergone gastrectomy for non-

metastatic disease is 32 months (IQR 25-38) (33). The reported median time to recurrence for

gastric cancer patients in the United States who have undergone curative-intent gastrectomy is 28

months (IQR 23-36). Therefore, a time horizon of 38 months—2 months prior to date of

Look-back Window for

Comorbidity Data Collection :

2 years

Observation Window:

January 1, 2002-June 30, 2015

Index Event Date

Accrual Window: January 1,

2002-December 31, 2014

Max Follow-up Date: March 31,

2017

25

diagnosis and up to 3 years following date of diagnosis was chosen to accommodate costs related

to diagnostic workup, treatment, and end-of-life care (49, 99). The outline of the study timeframe

for the cost analysis is outlined in Figure 2.

Figure 2. Outline of study timeframe for cost analysis of patients treated with gastrectomy

in Ontario

2.6 Study Setting

This research took place at the ICES Central research facility. Conduct of the study at this

facility uses the housed administrative databases facilitated the study of all patients with a

confirmed diagnosis of gastric cancer in Ontario within the study period.

The data holdings at ICES uniquely positions researchers with the advantages of a

repository of all routinely collected, publicly funded healthcare administrative data within a

single-payer universal healthcare system. Furthermore, a population-based cohort study could be

conducted with a large sample size, and the provision of statistical power. This type of study will

realistically reflect the outcomes of a heterogeneous group of patients as they are treated across

multiple institutions, with variation, and with minimal loss to follow-up, whereas controlled

clinical trials reflect the outcomes of a homogeneous group of patients as they are treated using

strict guidelines and protocols. Moreover, the low incidence of gastric cancer in Canada renders

randomized controlled trials unfeasible.

Look-back Window for

Comorbidity Data Collection

2 years

Observation Window:

Index Date to (Index Date + 1095 days)

Index Event Date

Accrual Window: January

1, 2002-March 31, 2013

Max Follow-up Date: March

31, 2016

26

2.7 Data Sources

Administrative healthcare databases are held at ICES and linked by individual patients’

IKNs. The following databases were accessed for this project.

2.7.1 Ontario Cancer Registry

The Ontario Cancer Registry database is updated annually and is a source of information on

the burden of cancer in the province (91). This database was utilized to derive the study cohort

through identification of patients with gastric cancer registered within the database and their

respective diagnosis dates. Although stage capture rates for breast, prostate, colorectal, lung and

cervical cancer are greater than 90%, the stage capture rate for all cases of cancer diagnosed is

57% (100).

2.7.2 Canadian Institute for Health Information-Discharge Abstract Database and Same Day Surgery

Data from the Canadian Institute for Health Information (CIHI)-Discharge Abstract Database

(DAD) and Same Day Surgery (SDS) database are updated on an annual basis. They are a source

of national patient- and facility-level data on all acute, chronic, rehabilitation, and same day

surgery facilities in Canada (101). Data from CIHI-DAD & SDS were utilized to identify

patients who underwent gastrectomy, the institutions at which they underwent gastrectomy, and

the costs associated with inpatient hospital care. The Johns Hopkins Resource Utilization Band

for each patient to provide a metric for comorbidity was also derived using this database.

2.7.3 National Ambulatory Care Reporting System

The National Ambulatory Care Reporting System (NACRS) is a database that is updated

annually and is a source for patient and facility-level information on emergency department

visits, day surgery, dialysis, and outpatient clinic visits including cancer visits (101). NACRS

was used in the derivation of comorbidity measures and in the algorithm to identify patients with

metastatic disease and to derive costs for dialysis, emergency department visits, and cancer

visits.

27

2.7.4 Home Care Database

The Home Care Database (HCD) is updated on a yearly basis and is a source of community-

based in-home services provided to Ontario residents (101). The services provided are

coordinated by Community Care Access Centres and include services such as personal support

work, nursing, and social work. The HCD was used to identify costs associated with home care

provision.

2.7.5 Ontario Health Insurance Plan

The Ontario Health Insurance Plan (OHIP) Claims Database is a updated bi-monthly and

is a source of claims submitted by healthcare providers able to claim under OHIP (physicians

both in and out of province, and laboratories) for remuneration from the MOHLTC (101).

Information derived from the OHIP Claim Database included identification of patients who

underwent gastrectomy, and the institution at which patients underwent gastrectomy,

chemotherapy use, radiotherapy use, and costs associated with physician billings.

2.7.6 Registered Persons Database

The Registered Persons Database (RPDB) files are updated bi-monthly and are a source of

patient-level demographic data. The database is coordinated by the Ontario MOHLTC and

includes basic demographic information about all recipients of an Ontario health card number, as

well as geographic, contact, and death information from other ICES data holdings (101). The

RPDB was used to derive patient demographic information, the Local Health Integration

Network of residence, rurality of residence, death date, date of last contact with the healthcare

system, and aggregate-level data on socioeconomic status.

2.7.7 Activity Level Reporting

The cancer Activity Level Reporting (ALR) database is updated annually and is a source of

provincial patient-level data on radiotherapy and systemic therapy services (91). The ALR

database was used to derive information regarding patient receipt of radiotherapy.

2.8 Study Variables

The following sections describe all variables used to describe the curatively resected gastric

cancer population, including the primary exposure, covariates, and outcomes. Patient and disease

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variables to describe the cohort and to compare patients treated at centres with and without

CSCD were identified a priori using literature, and based on clinical relevance. Variables were

limited to those available within the administrative healthcare data holdings at ICES. Variables

with their respective sources and definitions are outlined in Table 1.

Table 1. Sources and definitions of patient and disease characteristics

Variable Type Source Definition

Patient Characteristic

Age Categorical RPDB 74 years

Sex Categorical RPDB Female/Male

Johns Hopkins Resource Utilization Band

Categorical CIHI-DAD 0 or 1/2/3/4/5

Rurality of Residence

Categorical RPDB Rural/Urban

Income Quintile Categorical RPDB Lowest/2/3/4/Highest

Disease Characteristic

Type of Gastrectomy Categorical CIHI-DAD, OHIP

Distal/Proximal/Total/Unknown

Multivisceral Resection

Categorical CIHI-DAD, OHIP

Yes/No

Healthcare System Characteristics

CSCD Categorical CIHI-DAD, OHIP

Yes/No

Preoperative Chemotherapy

Categorical OHIP Yes/No

Preoperative Radiotherapy

Categorical OHIP, ALR Yes/No

Length of Stay Continuous CIHI-DAD Number of Days in Hospital

RPDB=Registered Persons Database; CIHI-DAD=Canadian Institute for Health

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Information-Discharge Abstract Database; OHIP=Ontario Health Insurance Plan; ALR=Activity Level Reporting

2.8.1 Primary Exposure

The primary exposure of interest was gastrectomy at an institution with Cancer Surgery

Centre Designation (CSCD). CSCD was defined according to current status of CSCD as outlined

by Cancer Care Ontario (91). These institutions are hospitals that have received designation for

meeting specified safety and quality standards for hepato-pancreatic biliary (HPB), thoracic,

head and neck, and gynecological cancers. All types of CSCD were included as the required

standards include surgeon criteria such as subspecialty training, and hospital criteria such as

specialty-specific diagnostic and therapeutic resources, and volume, in addition to benchmarks

for quality assurance such as a ta