ORIGINAL ARTICLE
Comparison of quality of life and worry of cancer recurrence between endoscopic and surgical treatment for early gastric cancer Jae Hyuk Choi, MD, PhD,1 Eun Soo Kim, MD, PhD,1 Yoo Jin Lee, MD,1 Kwang Bum Cho, MD, PhD,1 Kyung Sik Park, MD,1 Byoung Kuk Jang, MD, PhD,1 Woo Jin Chung, MD, PhD,1 Jae Seok Hwang, MD, PhD,1 Seung Wan Ryu, MD, PhD2 Daegu, South Korea
Background: The quality of life (QOL) of patients who survive early gastric cancer (EGC) is an area of increasing interest. Objective: To compare the QOL and degree of worry of cancer recurrence in EGC patients who underwent endoscopic submucosal dissection (ESD) or surgery. Design: Cross-sectional study. Settings: A tertiary referral center. Patients: A total of 565 patients with EGC who received ESD or surgery. Intervention: Questionnaires. Main Outcome Measurements: QOL was evaluated using the Short-form Health Survey and the European Organization for Research and Treatment of Cancer QOL questionnaires (QLQ-C30 and EORTC-QLQ-STO22). Mood disorders and the worry of cancer recurrence were estimated using the Hospital Anxiety and Depression Scale (HADS) and Worry of Cancer Scale, respectively. Results: Questionnaires were completed by 55.7% of the ESD (137/246) and 58.9% of the surgery (188/319) patients. The surgery group had more QOL-related symptomatic and functional problems, including fatigue (P Z .044), nausea/vomiting (P Z .032), appetite loss (P Z .023), diarrhea (P ! .001), pain (P Z .013), reflux symptoms (P Z .005), eating restrictions (P ! .001), anxiety (P Z .015), taste impairment (P Z .011), and poor body image (P ! .001). The ESD group had significantly higher worry of cancer recurrence scores after adjusting for covariates, especially when visiting their physicians. The HADS results did not differ between the groups. Limitations: Cross-sectional design. Conclusions: Endoscopic treatment for EGC provides a better QOL, but stomach preservation might provoke cancer recurrence worries. Endoscopists should address this issue for relieving a patient’s concern of cancer recurrence during follow-up period after ESD. (Clinical trial registration number: WHO ICTRP KCT0000791.) (Gastrointest Endosc 2015;-:1-9.)
In Asia, a region of high gastric cancer incidence, national health screening programs for gastric cancer have been successfully implemented in several countries,
including Korea.1,2 The overall survival rate among patients with gastric cancer has significantly improved because of early diagnosis and advancements in treatment
Abbreviations: EGC, early gastric cancer; EORTC, the European Organization for Research and Treatment of Cancer; ESD, endoscopic submucosal dissection; HADS, Hospital Anxiety and Depression Scale; QOL, quality of life; SF-36v2, Short-Form Health Survey; WOCS, Worry of Cancer Scale.
Received October 31, 2014. Accepted January 3, 2015. Current affiliations: Division of Gastroenterology and Hepatology, Department of Internal Medicine (1), Department of Surgery (2), Keimyung University School of Medicine, Daegu, South Korea.
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.
Reprint requests: Eun Soo Kim, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, 194 Dongsan-dong, Jung-gu, Daegu, South Korea, 700-712.
Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.01.019
If you would like to chat with an author of this article, you may contact Dr Eun Soo Kim at [email protected].
www.giejournal.org
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technologies.3 Given the high survival rate and increasing number of long-term survivors, physicians have begun to focus on improving the quality of life (QOL) of these patients.4-6 Early gastric cancer (EGC) is defined by the presence of cancerous cells confined to the mucosa or submucosa, regardless of lymph node metastasis.7,8 The 5-year overall survival rate of patients with EGC who undergo curative surgery exceeds 90%.9 Common postoperative adverse events include anastomosis site leakage/stenosis, bleeding, surgical wound infections, perforation, pancreatitis, and other functional problems.10-12 More than 50% of patients experience substantial deterioration in their QOL during the first 3 months after curative surgery, although QOL generally improves after 6 to 12 months.4,5,13 However, 20% to 35% of patients continue to experience unresolved functional and symptomatic problems that affect QOL.4,5,13 Endoscopic submucosal dissection (ESD) is considered an advanced and favorable technique for the treatment of properly selected patients with EGC because it preserves the entire stomach. The expanded indications for ESD are as follows: (1) differentiated mucosal cancer without evidence of ulceration, regardless of tumor size; (2) differentiated mucosal cancer % 3 cm in diameter, irrespective of ulceration; (3) differentiated shallow submucosal invasive cancer % 3 cm in diameter (SM1, %500 mm); and (4) undifferentiated mucosal cancer % 2 cm in diameter without ulceration.14 The reported 5-year disease-specific and overall survival rates after ESD for EGC are 100% and 96% to 97%, respectively.15,16 These rates are comparable with the outcome after curative surgery.9 The reported complete resection rates for ESD range from 87% to 91%, with lower adverse events rates compared with curative surgery (perforation, 1.2%-4.5%; bleeding, 1.8%-15.6%).15,17 Endoscopic treatment for EGC is assumed to confer a superior QOL relative to surgical treatment because endoscopy is a minimally invasive method, and the entire function of the stomach is preserved.4,7 However, patients with preserved stomachs after endoscopic treatment carry the risk of subsequent gastric cancer development.18 After endoscopic resection, up to 20% of patients have reported the development of metachronous gastric cancers.19,20 Lymph node metastasis after ESD has also been reported in EGC patients.21,22 Hence, ESD for EGC can potentially provoke the worry of cancer recurrence in patients. Although several studies have evaluated the QOL of gastric cancer patients after gastrectomy,4,6,8,13,23,24 a simultaneous evaluation of the QOL and worry of cancer recurrence after ESD or surgery for EGC has not been reported. The aim of this cross-sectional study was to compare the QOL, worry of cancer recurrence, and incidence of depression and anxiety in patients who underwent either ESD or surgery for EGC. 2 GASTROINTESTINAL ENDOSCOPY Volume
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METHODS Patients and clinical characteristics This cross-sectional study was conducted at Keimyung University Dongsan Hospital, a tertiary referral hospital in Daegu, Korea. The inclusion criteria were as follows: EGC treatment without concomitant lymph node metastasis between October 2010 and April 2013, no additional treatment (including chemotherapy or radiotherapy) after ESD or surgical treatment, no cancer recurrence, and survival up to the last follow-up visit. All records were reviewed for accuracy and completeness and validated by the senior investigator (E.S.K.). The specific criteria for the ESD group were as follows: en bloc resection with tumor-free vertical and lateral margins, differentiated adenocarcinoma, submucosal invasion % 500 mm from the muscularis mucosa, and absence of lymphovascular invasion upon histopathologic examination.25 The specific criterion for the surgical group was en bloc resection without any residual microscopic or macroscopic disease. Patients with advanced gastric cancer, defined as cancer invasion into or beyond the muscularis propria layer, and those with positive lymph nodes were excluded. Patients incapable of reading the questionnaires were also excluded. The study protocol was approved by the Institutional Review Board of Dongsan Hospital, and all patients signed a consent form before participating in this study. Demographic data (sex, age, monthly family income, employment status, housing, marital status, religion, education, smoking, and drinking) were collected from patients through self-reporting questionnaires. The Eastern Cooperative Oncology Group performance status of each patient was assessed during the survey. Clinical data (other primary cancers, comorbidities at the time of the survey, and histology of the resected specimens after ESD or surgical treatment) were retrieved from medical records. Clinical data regarding the type of surgery, resection, and reconstruction were collected for patients who underwent surgery.
QOL questionnaires We evaluated QOL using the validated Korean version of the Short-Form 36-item Health Survey, version 2 (SF-36v2).26,27 This generic questionnaire includes 36 questions that evaluate 8 discrete areas, including physical functioning, role limitations because of physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations resulting from emotional problems (role-emotional), and mental health.27 The disease-specific QOL was evaluated using the validated Korean version of the European Organization for Research and Treatment of Cancer 30-item core QOL questionnaire (EORTC-QLQ-C30).28,29 This cancer-specific questionnaire was designed as a multidimensional QOL www.giejournal.org
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assessment tool and includes a global health status and QOL score, 5 functional items (physical, role, emotional, cognitive, and social), 3 symptom dimensions (fatigue, nausea and vomiting, and pain), and 6 individual symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).28,29 The tumor-specific QOL was evaluated using the validated Korean version of the 22-item EORTC-QLQ gastric cancer module (EORTC-QLQ-STO22).29,30 This questionnaire was designed to specifically assess the QOL of patients with gastric cancer30,31 and includes 22 questions concerning a functional scale (body image), 5 symptom dimensions (dysphagia, pain, reflux symptoms, eating restrictions, and anxiety), and 3 individual symptom scales (dry mouth, taste, and hair loss). These questionnaires are reliable, validated, and widely used QOL examination tools. The initial scores of the SF-36v2, EORTC-QLQ-C30, and EORTC-QLQ-STO22 were transformed to scores ranging from 0 to 100. For the SF36v2 and the functional scales of the EORTC-QLQ-C30 and EORTC-QLQ-STO22, a higher score indicates a better QOL, with 100 being a perfect score. For the symptom scores, a lower score indicates a better QOL, with 0 being a perfect score indicating no reported symptoms.
Concern of cancer recurrence Concerns regarding cancer recurrence were determined using the validated Worry of Cancer Scale (WOCS) questionnaire.32,33 The following 4 subjective measures were used in the analysis: judged risk of cancer, worry of cancer when visiting a physician, more general worry of cancer over the previous months, and symptom level.32 The original WOCS scores were transformed to scores ranging from 0 to 10. The overall WOCS scores ranged from 0 to 40, with a higher score indicating a greater concern of cancer recurrence. We translated the original version of the WOCS questionnaire into a Korean version using forward–backward translation and an expert board review. First, 2 professional English translators who were also native Korean speakers translated the original version of the questionnaire into Korean. Next, 2 professional Korean translators who were also native English speakers and had no access to information about the questionnaire retranslated the Korean version of the WOCS questionnaire back into English. The translated Korean version of the questionnaire was then reviewed by an expert board (comprising J.H.C., E.S.K., K.B.C., and K.S.P.). This process was subsequently repeated.
Anxiety and depression Anxiety and depression were evaluated using the validated Korean version of the Hospital Anxiety and Depression Scale (HADS).34,35 This questionnaire was designed to assess the relative anxiety and depression symptom frequencies during the previous week using www.giejournal.org
Quality of life in patients with EGC
Early gastric cancer (T1N0M0) n=565
ESD n=246 (43.5%)
Reply n=137 (55.7%)
No reply n=77 (31.3%)
Surgery n=319 (56.5%)
Refuse n=32 (13.0%)
Reply n=188 (58.9%)
No reply n=77 (24.1%)
Refuse n=54 (16.9%)
Figure 1. Flowchart of patient selection in the study.
14 items (7 items related to anxiety and 7 items related to depression). Each item is scored on a 4-point Likert scale with maximum subscale scores of 21. A higher score indicates a greater probability of anxiety or depression. Scores of 8 to 10 indicate mild symptoms, whereas scores of 11 to 15 and 16 or higher indicate moderate and severe symptoms, respectively.34
Proceedings The questionnaires were mailed to the patients’ residences along with stamped return envelopes. If the questionnaire was not returned within 2 weeks, we contacted the patient via telephone to confirm receipt of the questionnaire and remind the patient to complete the questionnaire. This study has been registered at the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP KCT0000791).
Data analysis Statistical analyses were performed using SPSS software (version 17.0; SPSS Inc, Chicago, Ill). P ! .05 was considered statistically significant. The unadjusted associations between categorical outcome variables were compared using the Fisher exact test and the c2 test. We assessed differences between the scores for continuous variables using the Student t test. Variables that differed significantly between the ESD and surgery groups were used as covariates in additional analyses. Age and sex have been previously established as significant factors and therefore were used as covariates.36 Multivariate linear regression was used to compare the generic (SF-36) and functional disease-specific and tumor-specific QOL scores (EORTC-QLQ-C30 and EORTCQLQ-STO22) between the ESD and surgery groups. A multivariate logistic regression was used to compare the disease-specific and tumor-specific QOL symptom scales (EORTC-QLQ-C30 and EORTC-QLQ-STO22) between the ESD and surgery groups. The data were transformed into Volume
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TABLE 1. Demographics information of the patients
Age, mean (SD), y Sex, male (%) Monthly family income, mean (SD), US dollars
TABLE 1. Continued
ESD (n [ 137)
Surgery (n [ 188)
P value*
67.2 (9.9)
61.4 (11.5)
!.001y
103 (75.2)
126 (67.0)
.111
1602 (2488)
1738 (2720)
.645 y
Employment status, n (%)
.081
Employed
54 (39.4)
91 (48.4)
Unemployed
18 (13.1)
29 (15.4)
Retired
14 (10.2)
23 (12.2)
Housework
51 (37.2)
45 (23.9)
Housing, n (%)
.625
Metropolitan
71 (51.8)
100 (53.5)
Urban
34 (24.8)
52 (27.7)
Rural
32 (23.4)
36 (19.1)
Marital status, n (%)
.412
Married
111 (81.0)
144 (76.6)
Bereaved
18 (13.1)
23 (12.2)
Divorced
4 (2.9)
12 (6.4)
Unmarried
4 (2.9)
9 (4.8)
Buddhist
52 (38.0)
80 (42.6)
Non-Catholic Christians
24 (17.5)
28 (14.9)
Catholics
14 (10.2)
13 (6.9)
None
41 (29.9)
63 (33.5)
Others
6 (4.4)
4 (2.1)
Less than high school
69 (50.4)
76 (40.4)
High school or more
68 (49.6)
112 (59.6)
Religion, n (%)
P value*
7 (5.1)
14 (7.4)
.397
Comorbidity, n (%)
.047
0
44 (32.1)
80 (42.6)
1
46 (33.6)
59 (31.4)
2
24 (17.5)
36 (19.1)
3
16 (11.7)
7 (3.7)
4
6 (4.4)
6 (3.2)
R5
1 (.7)
0 (0)
Significant values with P ! .05 are shown in bold. ESD, Endoscopic submucosal dissection; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group. *c2, Fisher exact test. yStudent t test.
dichotomous data (no evident symptoms versus present symptoms). The analyses were adjusted for covariates. The multivariate linear regression model was built to compare the mean scores of the worry of cancer recurrence and anxiety and depression after adjusting for covariates.
RESULTS
.075
Smoking, n (%)
.545 7 (5.1)
6 (3.2)
Smoker
16 (11.7)
18 (9.6)
Nonsmoker
114 (83.2)
164 (87.2)
5 (3.6)
5 (2.7)
Drinking, n (%) Heavy drinkers
Surgery (n [ 188)
.490
Education, n (%)
Heavy smoker
Other primary cancer, n (%)
ESD (n [ 137)
.484
Drinker
24 (17.5)
25 (13.3)
Nondrinkers
108 (78.8)
158 (84.0)
0
73 (53.3)
91 (48.4)
1
49 (35.8)
83 (44.1)
2
5 (3.6)
6 (3.2)
3
9 (6.6)
8 (4.3)
4
1 (.7)
0 (0)
ECOG, n (%)
.383
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A total of 565 eligible patients underwent ESD or surgery for EGC between October 2010 and April 2013 (246 ESD and 319 surgery patients). We were able to contact 411 patients (169 ESD and 242 surgery patients) by telephone. Six patients (3 ESD and 3 surgery patients) died, and 80 patients (29 ESD and 51 surgery patients) did not wish to participate. The remaining 325 patients (137 ESD and 188 surgery patients) completed the questionnaire and were included in this study. The average total response rate for the questionnaire was 57.5% (ESD group, 55.7% [137/246]; surgery group, 58.9% [188/319]). The patient selection flowchart is shown in Figure 1. The ESD and surgery groups were comparable with regard to demographic information, Eastern Cooperative Oncology Group performance status at the time of the survey, and clinical data. However, patients in the ESD group were older (P ! .001) and had more comorbidities (P Z .047) than did those in the surgery group. In addition to sex, age and comorbidity were used as covariates. A histologic analysis of the resected specimens showed that a T1bN0M0 classification was the poorest histologic finding in both the ESD and surgery groups. The followup duration between the ESD and surgery groups did not significantly differ (mean duration, 19.9 months vs 20.6 months; P Z .546). The demographic information and clinical characteristics are shown in Tables 1 and 2, respectively. www.giejournal.org
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TABLE 2. Clinical characteristics of the patients ESD (n [ 137)
Surgery (n [ 188)
P value
Surgical treatment Type of surgery, n (%)
NA
Open surgery
79 (40.0)
Laparoscopy-assisted surgery
101 (53.7)
Robot-assisted surgery Type of surgical resection, n (%)
Worry of cancer recurrence As previously described, the surgery group reported significantly more symptoms than did the ESD group on the QOL questionnaire. The questions regarding symptoms listed in the WOCS (fatigue, weakness, nausea and vomiting, pain, appetite disturbance, fever, and dyspnea) were very similar to those on the EORTC-QLQ-C30; therefore, we decided to add the EORTC-QLQ-C30 symptom scales as a covariate along with age, sex, and comorbidity in the multivariate analysis. Therefore, the mean overall WOCS scores were compared after adjusting for these covariates. As shown by the overall WOCS scores, the ESD group reported a significantly greater fear of cancer recurrence than did the surgery group (P Z .032). In particular, the significant difference between the groups was related to fear when patients visited their doctors (P Z .018). The WOCS results are shown in Table 5.
8 (4.3) NA
Total gastrectomy
29 (15.4)
Subtotal gastrectomy
159 (84.6)
Type of reconstruction, n (%)
NA
Roux-en-Y
29 (15.4)
Billroth-I
121 (64.4)
Billroth-II
38 (20.2)
Post-treatment data Histology of the resected specimen,* n (%) Adenocarcinoma T1aN0M0
131 (95.6)
87 (46.3)
Adenocarcinoma T1bN0M0 (SM1)
6 (4.4)
29 (15.4)
Adenocarcinoma T1bN0M0 (SM2)
0 (0)
33 (17.6)
Adenocarcinoma T1bN0M0 (SM3)
0 (0)
39 (20.7)
19.9 (9.8)
20.6 (9.5)
Length of follow-up after treatment,
Anxiety and depression Based on the HADS results, no statistically significant differences in anxiety and depression were observed between the ESD and surgery groups (Table 6).
DISCUSSION .546y
mean (SD), mo ESD, Endoscopic submucosal dissection; NA, not applicable; SD, standard deviation. *American Joint Committee on Cancer 7th edition. yStudent t-test.
Comparison of the QOL scores of the ESD and surgery groups Generic QOL. According to the SF-36v2 results, the ESD and surgery groups did not significantly differ regarding the mean generic QOL scores. The SF-36v2 results are shown in Table 3. Disease-specific QOL. The ESD and surgery groups did not significantly differ in terms of the mean EORTCQLQ-C30 functional scores (Table 3). However, the surgery group had significantly higher rates of fatigue (D Z 2.4, P Z .044), nausea and vomiting (D Z 1.7, P Z .032), appetite loss (D Z 1.8, P Z .023), and diarrhea (D Z 3.5, P ! .001) relative to the ESD group (Table 4). Tumor-specific QOL. According to the EORTC-QLQSTO22 functional scale results, patients in the surgery group were more likely to have a poor body image (P ! .001) than those in the ESD group (Table 3). In addition, www.giejournal.org
the surgery group reported significantly higher rates of pain (D Z 1.9, P Z .013), reflux symptoms (D Z 2.0, P Z .005), eating restrictions (D Z 5.0, P ! .001), anxiety (D Z 2.6, P Z .015), and taste impairments (D Z 2.1, P Z .011) compared with the ESD group (Table 4).
Technologic developments in endoscopic therapy have enabled ESD to become a standard alternative to surgery for the treatment of EGC.15 Although it is generally presumed that the QOL of patients who have undergone ESD is superior to that of patients who have undergone surgery, the effects of ESD on the QOL, worry of cancer recurrence, and mood disorders, such as anxiety and depression, of these patients have not been elucidated. The current study revealed that endoscopic treatment with stomach preservation provided a superior QOL compared with surgical treatment, as demonstrated by a more positive body image and fewer reports of symptoms on the disease-specific and tumor-specific QOL questionnaires. In contrast, patients treated via endoscopy had a greater degree of concern regarding cancer recurrence than did those treated surgically. There was no difference in the incidence of anxiety and depression between the groups. To the best of our knowledge, this study is the first to examine and compare the QOL, worry of cancer recurrence, and anxiety and depression in EGC patients treated with either ESD or surgery. The relatively low QOL, which included a poorer body image and increased symptom prevalence, in the surgery Volume
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TABLE 3. QOL SF-36 and functional scales of the EORTC-QLQ-C30 and the EORTC-QLQ-STO22 (multivariate analysis) ESD (n [ 137) mean (SD)
Surgery (n [ 188) mean (SD)
Mean difference (ESD-surgery)
P value
Physical functioning
75.0 (27.9)
81.2 (21.0)
6.2
.534
Role-physical
63.8 (31.9)
65.3 (26.7)
1.5
.364
Bodily pain
73.8 (25.6)
76.0 (21.9)
2.1
.835
General health
52.1 (18.2)
50.6 (17.5)
þ1.4
.131
Vitality
61.5 (21.1)
62.0 (20.2)
–.6
.818
Social functioning
77.6 (22.7)
76.1 (20.6)
þ1.5
.268
Role-emotional
67.2 (28.6)
66.1 (24.3)
þ1.1
.107
Mental health
62.8 (19.8)
62.3 (19.1)
þ.5
.649
Global health status
61.3 (21.9)
64.9 (22.7)
3.6
.542
Physical functioning
73.4 (22.6)
76.8 (17.3)
3.4
.985
Role functioning
75.3 (25.0)
79.1 (20.2)
3.8
.601
SF-36
EORTC-QLQ-C30 functional scales
Emotional functioning
76.7 (18.9)
75.1 (18.5)
þ1.6
.624
Cognitive functioning
77.2 (18.5)
78.1 (16.7)
–.9
.967
Social functioning
79.3 (24.0)
78.7 (20.4)
þ.6
.214
78.8 (25.5)
62.6 (31.8)
þ16.2
!.001
EORTC-QLQSTO22 functional scales Body image
The multivariate analysis controls for age, sex, and comorbidity. Significant values with P ! .05 are shown in bold. QOL, Quality of life; SF-36, 36-item short-form survey; EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire; EORTC-QLQ-STO22, European Organization for Research and Treatment of Cancer gastric cancer module 22-item core quality of life questionnaire; ESD, endoscopic submucosal dissection; SD, standard deviation.
group relative to the ESD group was expected because of the anatomic alterations resulting from surgical resection. Indeed, many patients with gastric cancer experience significant impairments in their QOL after curative surgery.4,5 Although most symptoms resolve over time, 20% to 35% of patients continuously have refractory functional and symptomatic problems related to their QOL.5,13 Interestingly, we found that patients who underwent ESD reported a significantly greater degree of worry about cancer recurrence, especially when they visited the doctor’s office. This result corroborates an earlier study of Barrett’s esophagus in which patients who underwent endoscopic treatment were reported to exhibit greater concerns regarding recurrence than were those treated surgically.33 However, the number of patients in the previous study was small (81 in total), and the pathologic features of those patients were heterogeneous (inflammation, low-grade dysplasia, high-grade dysplasia, and cancer). These limitations were not a factor in our current study. Although the exact causes of the increased worry of recurrence among patients who underwent ESD relative to those treated surgically remain unclear, we propose several hypotheses. First, meticulously scheduled endoscopic surveillance after ESD may evoke worry of cancer recurrence in patients. Intensive surveillance is recommended during the first year after ESD, and annual surveillance is recommended for at least 5 years after 6 GASTROINTESTINAL ENDOSCOPY Volume
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ESD, because 14% of patients with EGC develop multiple synchronous or metachronous cancers after ESD.18 In our hospital, we endoscopically monitored patients 3 months after ESD, every 6 months for 1 year, and then annually for 5 years. Meanwhile, there is no consensus regarding the follow-up strategy after surgical treatment; therefore, individual surgeons determine the follow-up strategy for their patients.37 Second, preservation of the whole stomach after ESD may cause patients to worry that the cancer will recur at the same site. In this context, we hypothesize that patients treated via surgery were more likely to believe that all potential sites of recurrence had been removed, resulting in a greater sense of security relative to that experienced by patients who underwent ESD. Although the fear assessed by the WOCS is considered to be psychologically similar to anxiety, we did not observe a difference between the groups on the HADS questionnaire. This result supports previous findings.33 The discordance between the WOCS and HADS might be explained by the fact that the WOCS specifically estimates the worry of cancer recurrence, whereas the HADS measures general anxiety. Our results provide important information about the QOL, worry of cancer recurrence, and anxiety and depression after treatment for EGC. These data can be used in daily clinical practice, given the accelerated paradigm shift from surgery to endoscopic resection for the management www.giejournal.org
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TABLE 4. Symptoms scales of the EORTC-QLQ-C30 and the EORTC-QLQ-STO22 (logistic regression) Symptoms (%) ESD (n[137)
Surgery (n[188)
Odds ratio (surgery vs ESD)
95% CI
P value
EORTC-QLQ-C30 symptom scales Fatigue
88.3
94.7
2.416
1.024-5.701
.044
Nausea and vomiting
35.8
48.9
1.678
1.046-2.690
.032
Pain
56.2
51.1
.942
.587-1.510
.803
Dyspnea
46.0
42.0
.887
.557-1.412
.613
Insomnia
51.8
42.6
.756
.477-1.200
.236
Appetite loss
39.4
48.9
1.750
1.081-2.832
.023
Constipation
46.7
47.3
1.221
.766-1.946
.401
Diarrhea
42.3
74.5
3.538
2.175-5.756
!.001
Financial difficulties
56.2
60.1
1.450
.902-2.329
.125
67.9
72.9
1.439
.863-2.401
.163
EORTC-QLQ-STO22 symptom scales Dysphagia Pain
65.7
79.3
1.935
1.146-3.265
.013
Reflux symptoms
49.6
65.4
1.981
1.235-3.177
.005
Eating restrictions
71.5
92.6
4.958
2.506-9.811
!.001
Anxiety
85.4
93.1
2.645
1.212-5.773
.015
Dry mouth
56.2
58.5
1.341
.829-2.170
.232
Taste
21.2
32.4
2.052
1.177-3.578
.011
Hair loss
42.3
45.7
1.246
.785-1.979
.351
The logistic regression analysis controls for age, sex, and comorbidity. Significant values with P ! .05 are shown in bold. EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire; EORTC-QLQ-STO22, European Organization for Research and Treatment of Cancer gastric cancer module 22-item core quality of life questionnaire; ESD, endoscopic submucosal dissection; CI, confidence interval.
of select EGC cases. This study also provides quantitative measures of patient self-reported outcomes that physicians and patients can recognize and integrate into the decisionmaking process. In agreement with previous studies, patients experienced deterioration in their QOL after surgical treatment for EGC.4,5 Therefore, physicians should routinely assess this deterioration in QOL by using quantitative measures to detect early changes and subsequently support suitable interventions for symptom management. For patients who undergo ESD, physicians must assess the worry of cancer recurrence and reassure patients that although stomach preservation increases the risk of developing multiple cancers from the remnant stomach portion, nearly all recurrent lesions found during scheduled endoscopic surveillance are treatable.18 This study features several strengths that merit attention. We used rigorous criteria to select patients with EGC and created 2 groups according to the treatment modality. The 2 groups were as homogenous as possible. In addition, 565 patients with EGC who had been successfully treated with ESD or surgery were analyzed and thus made the present study among the largest to date. The questionnaires used in this study have been widely used, standardized, and well validated. This history provides confidence www.giejournal.org
TABLE 5. Worry of Cancer Scale (WOCS) scores (multivariate analysis) ESD Surgery (n [ 137) (n [ 188) Mean difference P mean (SD) mean (SD) (ESD-surgery) value* Judged risk of cancer
4.0 (2.3)
3.5 (2.4)
þ.5
.079
Worry about cancer at doctor’s office
1.8 (1.9)
1.3 (1.8)
þ.5
.018
Worry about cancer over past month
2.9 (2.0)
2.7 (2.1)
þ.2
.360
Symptom levely
2.0 (1.6)
2.4 (1.9)
–.4
.205
Total WOCS scorey
10.7 (6.0)
9.9 (6.3)
þ.8
.032
Significant values with P ! .05 are shown in bold. SD, Standard deviation; ESD, endoscopic submucosal dissection. *The multivariate analysis controls for age, sex, and comorbidity. yThe multivariate analysis controls for age, sex, comorbidity, and the symptom scores of disease-specific QOL (EORTC-QLQ-C30).
that the results of this study are representative and generalizable to other institutions with comparable patients. In addition to QOL, we are the first group to assess patients’ Volume
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TABLE 6. Hospital Anxiety and Depression Scale (HADS) scores (multivariate analysis) ESD Surgery Mean (n [ 137) (n [ 188) difference mean (SD) mean (SD) (ESD-surgery) P value Anxiety score
2.1 (1.7)
2.3 (1.8)
–.2
.497
Depression score
2.6 (1.9)
2.8 (2.0)
–.3
.078
The multivariate analysis controls for age, sex, and comorbidity. ESD, Endoscopic submucosal dissection; SD, standard deviation.
worry of cancer recurrence and the incidence of anxiety and depression after ESD or surgical treatment for EGC. Although this study provides valuable insight into the global well-being of EGC patients, it includes several limitations. Because of the cross-sectional study design, randomization for ESD and surgical treatment was impossible. Selection bias was therefore inevitable because of the different indications for ESD and surgical treatments for EGC. For instance, the ESD group was older and had more comorbidities, whereas the surgery group was more likely to have T1b lesions. In addition, the cross-sectional study design may have limited the determination of long-term outcomes. Given these limitations, the validity of our findings should be confirmed in a prospective, randomized, controlled, and longitudinal study. In conclusion, the findings of our cross-sectional study indicate that stomach preservation after endoscopic treatment for EGC provides a better QOL; however, this preservation may also induce the worry of cancer recurrence. In addition to the clinical efficacy of EGC treatments, patient self-reported outcomes, including QOL and worry of cancer recurrence, must be evaluated. Endoscopists should address this issue for relieving patient’s concern of cancer recurrence during follow-up period after ESD.
REFERENCES 1. Fock KM, Talley N, Moayyedi P, et al. Asia-Pacific consensus guidelines on gastric cancer prevention. J Gastroenterol Hepatol 2008;23:351-65. 2. Mihaljevic AL, Friess H, Schuhmacher C. Clinical trials in gastric cancer and the future. J Surg Oncol 2013;107:289-97. 3. Roukos DH. Current advances and changes in treatment strategy may improve survival and quality of life in patients with potentially curable gastric cancer. Ann Surg Oncol 1999;6:46-56. 4. Karanicolas PJ, Graham D, Gonen M, et al. Quality of life after gastrectomy for adenocarcinoma: a prospective cohort study. Ann Surg 2013;257:1039-46. 5. Kim AR, Cho J, Hsu YJ, et al. Changes of quality of life in gastric cancer patients after curative resection: a longitudinal cohort study in Korea. Ann Surg 2012;256:1008-13. 6. Bae JM, Kim S, Kim YW, et al. Health-related quality of life among disease-free stomach cancer survivors in Korea. Qual Life Res 2006;15:1587-96. 7. Carter KJ, Schaffer HA, Ritchie WP Jr. Early gastric cancer. Ann Surg 1984;199:604-9. 8. Everett SM, Axon AT. Early gastric cancer in Europe. Gut 1997;41: 142-50.
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9. Kunisaki C, Akiyama H, Nomura M, et al. Significance of long-term follow-up of early gastric cancer. Ann Surg Oncol 2006;13:363-9. 10. Vural S, Civil O, Kement M, et al. Risk factors for early postoperative morbidity and mortality in patients underwent radical surgery for gastric carcinoma: a single center experience. Int J Surg 2013;11:1103-9. 11. Bonenkamp JJ, Songun I, Hermans J, et al. Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet 1995;345:745-8. 12. Cuschieri A, Fayers P, Fielding J, et al. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial. The Surgical Cooperative Group. Lancet 1996;347:995-9. 13. Avery K, Hughes R, McNair A, et al. Health-related quality of life and survival in the 2 years after surgery for gastric cancer. Eur J Surg Oncol 2010;36:148-54. 14. Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at 2 large centers. Gastric Cancer 2000;3:219-25. 15. Isomoto H, Shikuwa S, Yamaguchi N, et al. Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study. Gut 2009;58:331-6. 16. Goto O, Fujishiro M, Kodashima S, et al. Outcomes of endoscopic submucosal dissection for early gastric cancer with special reference to validation for curability criteria. Endoscopy 2009;41:118-22. 17. Chung IK, Lee JH, Lee SH, et al. Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study. Gastrointest Endosc 2009;69: 1228-35. 18. Kato M, Nishida T, Yamamoto K, et al. Scheduled endoscopic surveillance controls secondary cancer after curative endoscopic resection for early gastric cancer: a multicentre retrospective cohort study by Osaka University ESD study group. Gut 2013;62:1425-32. 19. Nakajima T, Oda I, Gotoda T, et al. Metachronous gastric cancers after endoscopic resection: how effective is annual endoscopic surveillance? Gastric Cancer 2006;9:93-8. 20. Nasu J, Doi T, Endo H, et al. Characteristics of metachronous multiple early gastric cancers after endoscopic mucosal resection. Endoscopy 2005;37:990-3. 21. Ahn JY, Jung HY, Choi KD, et al. Endoscopic and oncologic outcomes after endoscopic resection for early gastric cancer: 1370 cases of absolute and extended indications. Gastrointest Endosc 2011;74:485-93. 22. Kang HJ, Kim DH, Jeon TY, et al. Lymph node metastasis from intestinal-type early gastric cancer: experience in a single institution and reassessment of the extended criteria for endoscopic submucosal dissection. Gastrointest Endosc 2010;72:508-15. 23. Nakamura M, Hosoya Y, Yano M, et al. Extent of gastric resection impacts patient quality of life: the Dysfunction After Upper Gastrointestinal Surgery for Cancer (DAUGS32) scoring system. Ann Surg Oncol 2011;18:314-20. 24. Huang CC, Lien HH, Wang PC, et al. Quality of life in disease-free gastric adenocarcinoma survivors: impacts of clinical stages and reconstructive surgical procedures. Dig Surg 2007;24:59-65. 25. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010, version 3. Gastric Cancer 2011;14:113-23. 26. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36). II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31: 247-63. 27. Hawthorne G, Osborne RH, Taylor A, et al. The SF36 Version 2: critical analyses of population weights, scoring algorithms and population norms. Qual Life Res 2007;16:661-73. 28. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76. 29. Yun YH, Park YS, Lee ES, et al. Validation of the Korean version of the EORTC QLQ-C30. Qual Life Res 2004;13:863-8.
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Choi et al 30. Blazeby JM, Conroy T, Bottomley A, et al. Clinical and psychometric validation of a questionnaire module, the EORTC QLQ-STO 22, to assess quality of life in patients with gastric cancer. Eur J Cancer 2004;40:2260-8. 31. Vickery CW, Blazeby JM, Conroy T, et al. Development of an EORTC disease-specific quality of life module for use in patients with gastric cancer. Eur J Cancer 2001;37:966-71. 32. Easterling DV, Leventhal H. Contribution of concrete cognition to emotion: neutral symptoms as elicitors of worry about cancer. J Appl Psychol 1989;74:787-96. 33. Rosmolen WD, Boer KR, de Leeuw RJ, et al. Quality of life and fear of cancer recurrence after endoscopic and surgical treatment
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34. 35.
36.
37.
for early neoplasia in Barrett’s esophagus. Endoscopy 2010;42: 525-31. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361-70. Herrmann C. International experiences with the Hospital Anxiety and Depression Scaleda review of validation data and clinical results. J Psychosom Res 1997;42:17-41. Wan GJ, Counte MA, Cella DF, et al. An analysis of the impact of demographic, clinical, and social factors on health-related quality of life. Value Health 1999;2:308-18. Allum WH, Blazeby JM, Griffin SM, et al. Guidelines for the management of oesophageal and gastric cancer. Gut 2011;60:1449-72.
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Comparison of quality of life and worry of cancer recurrence between endoscopic and surgical treatment for early gastric cancer Jae Hyuk Choi, MD, PhD,1 Eun Soo Kim, MD, PhD,1 Yoo Jin Lee, MD,1 Kwang Bum Cho, MD, PhD,1 Kyung Sik Park, MD,1 Byoung Kuk Jang, MD, PhD,1 Woo Jin Chung, MD, PhD,1 Jae Seok Hwang, MD, PhD,1 Seung Wan Ryu, MD, PhD2 Daegu, South Korea
Background: The quality of life (QOL) of patients who survive early gastric cancer (EGC) is an area of increasing interest. Objective: To compare the QOL and degree of worry of cancer recurrence in EGC patients who underwent endoscopic submucosal dissection (ESD) or surgery. Design: Cross-sectional study. Settings: A tertiary referral center. Patients: A total of 565 patients with EGC who received ESD or surgery. Intervention: Questionnaires. Main Outcome Measurements: QOL was evaluated using the Short-form Health Survey and the European Organization for Research and Treatment of Cancer QOL questionnaires (QLQ-C30 and EORTC-QLQ-STO22). Mood disorders and the worry of cancer recurrence were estimated using the Hospital Anxiety and Depression Scale (HADS) and Worry of Cancer Scale, respectively. Results: Questionnaires were completed by 55.7% of the ESD (137/246) and 58.9% of the surgery (188/319) patients. The surgery group had more QOL-related symptomatic and functional problems, including fatigue (P Z .044), nausea/vomiting (P Z .032), appetite loss (P Z .023), diarrhea (P ! .001), pain (P Z .013), reflux symptoms (P Z .005), eating restrictions (P ! .001), anxiety (P Z .015), taste impairment (P Z .011), and poor body image (P ! .001). The ESD group had significantly higher worry of cancer recurrence scores after adjusting for covariates, especially when visiting their physicians. The HADS results did not differ between the groups. Limitations: Cross-sectional design. Conclusions: Endoscopic treatment for EGC provides a better QOL, but stomach preservation might provoke cancer recurrence worries. Endoscopists should address this issue for relieving a patient’s concern of cancer recurrence during follow-up period after ESD. (Clinical trial registration number: WHO ICTRP KCT0000791.) (Gastrointest Endosc 2015;-:1-9.)
In Asia, a region of high gastric cancer incidence, national health screening programs for gastric cancer have been successfully implemented in several countries,
including Korea.1,2 The overall survival rate among patients with gastric cancer has significantly improved because of early diagnosis and advancements in treatment
Abbreviations: EGC, early gastric cancer; EORTC, the European Organization for Research and Treatment of Cancer; ESD, endoscopic submucosal dissection; HADS, Hospital Anxiety and Depression Scale; QOL, quality of life; SF-36v2, Short-Form Health Survey; WOCS, Worry of Cancer Scale.
Received October 31, 2014. Accepted January 3, 2015. Current affiliations: Division of Gastroenterology and Hepatology, Department of Internal Medicine (1), Department of Surgery (2), Keimyung University School of Medicine, Daegu, South Korea.
DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.
Reprint requests: Eun Soo Kim, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, 194 Dongsan-dong, Jung-gu, Daegu, South Korea, 700-712.
Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.01.019
If you would like to chat with an author of this article, you may contact Dr Eun Soo Kim at [email protected].
www.giejournal.org
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technologies.3 Given the high survival rate and increasing number of long-term survivors, physicians have begun to focus on improving the quality of life (QOL) of these patients.4-6 Early gastric cancer (EGC) is defined by the presence of cancerous cells confined to the mucosa or submucosa, regardless of lymph node metastasis.7,8 The 5-year overall survival rate of patients with EGC who undergo curative surgery exceeds 90%.9 Common postoperative adverse events include anastomosis site leakage/stenosis, bleeding, surgical wound infections, perforation, pancreatitis, and other functional problems.10-12 More than 50% of patients experience substantial deterioration in their QOL during the first 3 months after curative surgery, although QOL generally improves after 6 to 12 months.4,5,13 However, 20% to 35% of patients continue to experience unresolved functional and symptomatic problems that affect QOL.4,5,13 Endoscopic submucosal dissection (ESD) is considered an advanced and favorable technique for the treatment of properly selected patients with EGC because it preserves the entire stomach. The expanded indications for ESD are as follows: (1) differentiated mucosal cancer without evidence of ulceration, regardless of tumor size; (2) differentiated mucosal cancer % 3 cm in diameter, irrespective of ulceration; (3) differentiated shallow submucosal invasive cancer % 3 cm in diameter (SM1, %500 mm); and (4) undifferentiated mucosal cancer % 2 cm in diameter without ulceration.14 The reported 5-year disease-specific and overall survival rates after ESD for EGC are 100% and 96% to 97%, respectively.15,16 These rates are comparable with the outcome after curative surgery.9 The reported complete resection rates for ESD range from 87% to 91%, with lower adverse events rates compared with curative surgery (perforation, 1.2%-4.5%; bleeding, 1.8%-15.6%).15,17 Endoscopic treatment for EGC is assumed to confer a superior QOL relative to surgical treatment because endoscopy is a minimally invasive method, and the entire function of the stomach is preserved.4,7 However, patients with preserved stomachs after endoscopic treatment carry the risk of subsequent gastric cancer development.18 After endoscopic resection, up to 20% of patients have reported the development of metachronous gastric cancers.19,20 Lymph node metastasis after ESD has also been reported in EGC patients.21,22 Hence, ESD for EGC can potentially provoke the worry of cancer recurrence in patients. Although several studies have evaluated the QOL of gastric cancer patients after gastrectomy,4,6,8,13,23,24 a simultaneous evaluation of the QOL and worry of cancer recurrence after ESD or surgery for EGC has not been reported. The aim of this cross-sectional study was to compare the QOL, worry of cancer recurrence, and incidence of depression and anxiety in patients who underwent either ESD or surgery for EGC. 2 GASTROINTESTINAL ENDOSCOPY Volume
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METHODS Patients and clinical characteristics This cross-sectional study was conducted at Keimyung University Dongsan Hospital, a tertiary referral hospital in Daegu, Korea. The inclusion criteria were as follows: EGC treatment without concomitant lymph node metastasis between October 2010 and April 2013, no additional treatment (including chemotherapy or radiotherapy) after ESD or surgical treatment, no cancer recurrence, and survival up to the last follow-up visit. All records were reviewed for accuracy and completeness and validated by the senior investigator (E.S.K.). The specific criteria for the ESD group were as follows: en bloc resection with tumor-free vertical and lateral margins, differentiated adenocarcinoma, submucosal invasion % 500 mm from the muscularis mucosa, and absence of lymphovascular invasion upon histopathologic examination.25 The specific criterion for the surgical group was en bloc resection without any residual microscopic or macroscopic disease. Patients with advanced gastric cancer, defined as cancer invasion into or beyond the muscularis propria layer, and those with positive lymph nodes were excluded. Patients incapable of reading the questionnaires were also excluded. The study protocol was approved by the Institutional Review Board of Dongsan Hospital, and all patients signed a consent form before participating in this study. Demographic data (sex, age, monthly family income, employment status, housing, marital status, religion, education, smoking, and drinking) were collected from patients through self-reporting questionnaires. The Eastern Cooperative Oncology Group performance status of each patient was assessed during the survey. Clinical data (other primary cancers, comorbidities at the time of the survey, and histology of the resected specimens after ESD or surgical treatment) were retrieved from medical records. Clinical data regarding the type of surgery, resection, and reconstruction were collected for patients who underwent surgery.
QOL questionnaires We evaluated QOL using the validated Korean version of the Short-Form 36-item Health Survey, version 2 (SF-36v2).26,27 This generic questionnaire includes 36 questions that evaluate 8 discrete areas, including physical functioning, role limitations because of physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations resulting from emotional problems (role-emotional), and mental health.27 The disease-specific QOL was evaluated using the validated Korean version of the European Organization for Research and Treatment of Cancer 30-item core QOL questionnaire (EORTC-QLQ-C30).28,29 This cancer-specific questionnaire was designed as a multidimensional QOL www.giejournal.org
Choi et al
assessment tool and includes a global health status and QOL score, 5 functional items (physical, role, emotional, cognitive, and social), 3 symptom dimensions (fatigue, nausea and vomiting, and pain), and 6 individual symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).28,29 The tumor-specific QOL was evaluated using the validated Korean version of the 22-item EORTC-QLQ gastric cancer module (EORTC-QLQ-STO22).29,30 This questionnaire was designed to specifically assess the QOL of patients with gastric cancer30,31 and includes 22 questions concerning a functional scale (body image), 5 symptom dimensions (dysphagia, pain, reflux symptoms, eating restrictions, and anxiety), and 3 individual symptom scales (dry mouth, taste, and hair loss). These questionnaires are reliable, validated, and widely used QOL examination tools. The initial scores of the SF-36v2, EORTC-QLQ-C30, and EORTC-QLQ-STO22 were transformed to scores ranging from 0 to 100. For the SF36v2 and the functional scales of the EORTC-QLQ-C30 and EORTC-QLQ-STO22, a higher score indicates a better QOL, with 100 being a perfect score. For the symptom scores, a lower score indicates a better QOL, with 0 being a perfect score indicating no reported symptoms.
Concern of cancer recurrence Concerns regarding cancer recurrence were determined using the validated Worry of Cancer Scale (WOCS) questionnaire.32,33 The following 4 subjective measures were used in the analysis: judged risk of cancer, worry of cancer when visiting a physician, more general worry of cancer over the previous months, and symptom level.32 The original WOCS scores were transformed to scores ranging from 0 to 10. The overall WOCS scores ranged from 0 to 40, with a higher score indicating a greater concern of cancer recurrence. We translated the original version of the WOCS questionnaire into a Korean version using forward–backward translation and an expert board review. First, 2 professional English translators who were also native Korean speakers translated the original version of the questionnaire into Korean. Next, 2 professional Korean translators who were also native English speakers and had no access to information about the questionnaire retranslated the Korean version of the WOCS questionnaire back into English. The translated Korean version of the questionnaire was then reviewed by an expert board (comprising J.H.C., E.S.K., K.B.C., and K.S.P.). This process was subsequently repeated.
Anxiety and depression Anxiety and depression were evaluated using the validated Korean version of the Hospital Anxiety and Depression Scale (HADS).34,35 This questionnaire was designed to assess the relative anxiety and depression symptom frequencies during the previous week using www.giejournal.org
Quality of life in patients with EGC
Early gastric cancer (T1N0M0) n=565
ESD n=246 (43.5%)
Reply n=137 (55.7%)
No reply n=77 (31.3%)
Surgery n=319 (56.5%)
Refuse n=32 (13.0%)
Reply n=188 (58.9%)
No reply n=77 (24.1%)
Refuse n=54 (16.9%)
Figure 1. Flowchart of patient selection in the study.
14 items (7 items related to anxiety and 7 items related to depression). Each item is scored on a 4-point Likert scale with maximum subscale scores of 21. A higher score indicates a greater probability of anxiety or depression. Scores of 8 to 10 indicate mild symptoms, whereas scores of 11 to 15 and 16 or higher indicate moderate and severe symptoms, respectively.34
Proceedings The questionnaires were mailed to the patients’ residences along with stamped return envelopes. If the questionnaire was not returned within 2 weeks, we contacted the patient via telephone to confirm receipt of the questionnaire and remind the patient to complete the questionnaire. This study has been registered at the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP KCT0000791).
Data analysis Statistical analyses were performed using SPSS software (version 17.0; SPSS Inc, Chicago, Ill). P ! .05 was considered statistically significant. The unadjusted associations between categorical outcome variables were compared using the Fisher exact test and the c2 test. We assessed differences between the scores for continuous variables using the Student t test. Variables that differed significantly between the ESD and surgery groups were used as covariates in additional analyses. Age and sex have been previously established as significant factors and therefore were used as covariates.36 Multivariate linear regression was used to compare the generic (SF-36) and functional disease-specific and tumor-specific QOL scores (EORTC-QLQ-C30 and EORTCQLQ-STO22) between the ESD and surgery groups. A multivariate logistic regression was used to compare the disease-specific and tumor-specific QOL symptom scales (EORTC-QLQ-C30 and EORTC-QLQ-STO22) between the ESD and surgery groups. The data were transformed into Volume
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TABLE 1. Demographics information of the patients
Age, mean (SD), y Sex, male (%) Monthly family income, mean (SD), US dollars
TABLE 1. Continued
ESD (n [ 137)
Surgery (n [ 188)
P value*
67.2 (9.9)
61.4 (11.5)
!.001y
103 (75.2)
126 (67.0)
.111
1602 (2488)
1738 (2720)
.645 y
Employment status, n (%)
.081
Employed
54 (39.4)
91 (48.4)
Unemployed
18 (13.1)
29 (15.4)
Retired
14 (10.2)
23 (12.2)
Housework
51 (37.2)
45 (23.9)
Housing, n (%)
.625
Metropolitan
71 (51.8)
100 (53.5)
Urban
34 (24.8)
52 (27.7)
Rural
32 (23.4)
36 (19.1)
Marital status, n (%)
.412
Married
111 (81.0)
144 (76.6)
Bereaved
18 (13.1)
23 (12.2)
Divorced
4 (2.9)
12 (6.4)
Unmarried
4 (2.9)
9 (4.8)
Buddhist
52 (38.0)
80 (42.6)
Non-Catholic Christians
24 (17.5)
28 (14.9)
Catholics
14 (10.2)
13 (6.9)
None
41 (29.9)
63 (33.5)
Others
6 (4.4)
4 (2.1)
Less than high school
69 (50.4)
76 (40.4)
High school or more
68 (49.6)
112 (59.6)
Religion, n (%)
P value*
7 (5.1)
14 (7.4)
.397
Comorbidity, n (%)
.047
0
44 (32.1)
80 (42.6)
1
46 (33.6)
59 (31.4)
2
24 (17.5)
36 (19.1)
3
16 (11.7)
7 (3.7)
4
6 (4.4)
6 (3.2)
R5
1 (.7)
0 (0)
Significant values with P ! .05 are shown in bold. ESD, Endoscopic submucosal dissection; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group. *c2, Fisher exact test. yStudent t test.
dichotomous data (no evident symptoms versus present symptoms). The analyses were adjusted for covariates. The multivariate linear regression model was built to compare the mean scores of the worry of cancer recurrence and anxiety and depression after adjusting for covariates.
RESULTS
.075
Smoking, n (%)
.545 7 (5.1)
6 (3.2)
Smoker
16 (11.7)
18 (9.6)
Nonsmoker
114 (83.2)
164 (87.2)
5 (3.6)
5 (2.7)
Drinking, n (%) Heavy drinkers
Surgery (n [ 188)
.490
Education, n (%)
Heavy smoker
Other primary cancer, n (%)
ESD (n [ 137)
.484
Drinker
24 (17.5)
25 (13.3)
Nondrinkers
108 (78.8)
158 (84.0)
0
73 (53.3)
91 (48.4)
1
49 (35.8)
83 (44.1)
2
5 (3.6)
6 (3.2)
3
9 (6.6)
8 (4.3)
4
1 (.7)
0 (0)
ECOG, n (%)
.383
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A total of 565 eligible patients underwent ESD or surgery for EGC between October 2010 and April 2013 (246 ESD and 319 surgery patients). We were able to contact 411 patients (169 ESD and 242 surgery patients) by telephone. Six patients (3 ESD and 3 surgery patients) died, and 80 patients (29 ESD and 51 surgery patients) did not wish to participate. The remaining 325 patients (137 ESD and 188 surgery patients) completed the questionnaire and were included in this study. The average total response rate for the questionnaire was 57.5% (ESD group, 55.7% [137/246]; surgery group, 58.9% [188/319]). The patient selection flowchart is shown in Figure 1. The ESD and surgery groups were comparable with regard to demographic information, Eastern Cooperative Oncology Group performance status at the time of the survey, and clinical data. However, patients in the ESD group were older (P ! .001) and had more comorbidities (P Z .047) than did those in the surgery group. In addition to sex, age and comorbidity were used as covariates. A histologic analysis of the resected specimens showed that a T1bN0M0 classification was the poorest histologic finding in both the ESD and surgery groups. The followup duration between the ESD and surgery groups did not significantly differ (mean duration, 19.9 months vs 20.6 months; P Z .546). The demographic information and clinical characteristics are shown in Tables 1 and 2, respectively. www.giejournal.org
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Quality of life in patients with EGC
TABLE 2. Clinical characteristics of the patients ESD (n [ 137)
Surgery (n [ 188)
P value
Surgical treatment Type of surgery, n (%)
NA
Open surgery
79 (40.0)
Laparoscopy-assisted surgery
101 (53.7)
Robot-assisted surgery Type of surgical resection, n (%)
Worry of cancer recurrence As previously described, the surgery group reported significantly more symptoms than did the ESD group on the QOL questionnaire. The questions regarding symptoms listed in the WOCS (fatigue, weakness, nausea and vomiting, pain, appetite disturbance, fever, and dyspnea) were very similar to those on the EORTC-QLQ-C30; therefore, we decided to add the EORTC-QLQ-C30 symptom scales as a covariate along with age, sex, and comorbidity in the multivariate analysis. Therefore, the mean overall WOCS scores were compared after adjusting for these covariates. As shown by the overall WOCS scores, the ESD group reported a significantly greater fear of cancer recurrence than did the surgery group (P Z .032). In particular, the significant difference between the groups was related to fear when patients visited their doctors (P Z .018). The WOCS results are shown in Table 5.
8 (4.3) NA
Total gastrectomy
29 (15.4)
Subtotal gastrectomy
159 (84.6)
Type of reconstruction, n (%)
NA
Roux-en-Y
29 (15.4)
Billroth-I
121 (64.4)
Billroth-II
38 (20.2)
Post-treatment data Histology of the resected specimen,* n (%) Adenocarcinoma T1aN0M0
131 (95.6)
87 (46.3)
Adenocarcinoma T1bN0M0 (SM1)
6 (4.4)
29 (15.4)
Adenocarcinoma T1bN0M0 (SM2)
0 (0)
33 (17.6)
Adenocarcinoma T1bN0M0 (SM3)
0 (0)
39 (20.7)
19.9 (9.8)
20.6 (9.5)
Length of follow-up after treatment,
Anxiety and depression Based on the HADS results, no statistically significant differences in anxiety and depression were observed between the ESD and surgery groups (Table 6).
DISCUSSION .546y
mean (SD), mo ESD, Endoscopic submucosal dissection; NA, not applicable; SD, standard deviation. *American Joint Committee on Cancer 7th edition. yStudent t-test.
Comparison of the QOL scores of the ESD and surgery groups Generic QOL. According to the SF-36v2 results, the ESD and surgery groups did not significantly differ regarding the mean generic QOL scores. The SF-36v2 results are shown in Table 3. Disease-specific QOL. The ESD and surgery groups did not significantly differ in terms of the mean EORTCQLQ-C30 functional scores (Table 3). However, the surgery group had significantly higher rates of fatigue (D Z 2.4, P Z .044), nausea and vomiting (D Z 1.7, P Z .032), appetite loss (D Z 1.8, P Z .023), and diarrhea (D Z 3.5, P ! .001) relative to the ESD group (Table 4). Tumor-specific QOL. According to the EORTC-QLQSTO22 functional scale results, patients in the surgery group were more likely to have a poor body image (P ! .001) than those in the ESD group (Table 3). In addition, www.giejournal.org
the surgery group reported significantly higher rates of pain (D Z 1.9, P Z .013), reflux symptoms (D Z 2.0, P Z .005), eating restrictions (D Z 5.0, P ! .001), anxiety (D Z 2.6, P Z .015), and taste impairments (D Z 2.1, P Z .011) compared with the ESD group (Table 4).
Technologic developments in endoscopic therapy have enabled ESD to become a standard alternative to surgery for the treatment of EGC.15 Although it is generally presumed that the QOL of patients who have undergone ESD is superior to that of patients who have undergone surgery, the effects of ESD on the QOL, worry of cancer recurrence, and mood disorders, such as anxiety and depression, of these patients have not been elucidated. The current study revealed that endoscopic treatment with stomach preservation provided a superior QOL compared with surgical treatment, as demonstrated by a more positive body image and fewer reports of symptoms on the disease-specific and tumor-specific QOL questionnaires. In contrast, patients treated via endoscopy had a greater degree of concern regarding cancer recurrence than did those treated surgically. There was no difference in the incidence of anxiety and depression between the groups. To the best of our knowledge, this study is the first to examine and compare the QOL, worry of cancer recurrence, and anxiety and depression in EGC patients treated with either ESD or surgery. The relatively low QOL, which included a poorer body image and increased symptom prevalence, in the surgery Volume
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TABLE 3. QOL SF-36 and functional scales of the EORTC-QLQ-C30 and the EORTC-QLQ-STO22 (multivariate analysis) ESD (n [ 137) mean (SD)
Surgery (n [ 188) mean (SD)
Mean difference (ESD-surgery)
P value
Physical functioning
75.0 (27.9)
81.2 (21.0)
6.2
.534
Role-physical
63.8 (31.9)
65.3 (26.7)
1.5
.364
Bodily pain
73.8 (25.6)
76.0 (21.9)
2.1
.835
General health
52.1 (18.2)
50.6 (17.5)
þ1.4
.131
Vitality
61.5 (21.1)
62.0 (20.2)
–.6
.818
Social functioning
77.6 (22.7)
76.1 (20.6)
þ1.5
.268
Role-emotional
67.2 (28.6)
66.1 (24.3)
þ1.1
.107
Mental health
62.8 (19.8)
62.3 (19.1)
þ.5
.649
Global health status
61.3 (21.9)
64.9 (22.7)
3.6
.542
Physical functioning
73.4 (22.6)
76.8 (17.3)
3.4
.985
Role functioning
75.3 (25.0)
79.1 (20.2)
3.8
.601
SF-36
EORTC-QLQ-C30 functional scales
Emotional functioning
76.7 (18.9)
75.1 (18.5)
þ1.6
.624
Cognitive functioning
77.2 (18.5)
78.1 (16.7)
–.9
.967
Social functioning
79.3 (24.0)
78.7 (20.4)
þ.6
.214
78.8 (25.5)
62.6 (31.8)
þ16.2
!.001
EORTC-QLQSTO22 functional scales Body image
The multivariate analysis controls for age, sex, and comorbidity. Significant values with P ! .05 are shown in bold. QOL, Quality of life; SF-36, 36-item short-form survey; EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire; EORTC-QLQ-STO22, European Organization for Research and Treatment of Cancer gastric cancer module 22-item core quality of life questionnaire; ESD, endoscopic submucosal dissection; SD, standard deviation.
group relative to the ESD group was expected because of the anatomic alterations resulting from surgical resection. Indeed, many patients with gastric cancer experience significant impairments in their QOL after curative surgery.4,5 Although most symptoms resolve over time, 20% to 35% of patients continuously have refractory functional and symptomatic problems related to their QOL.5,13 Interestingly, we found that patients who underwent ESD reported a significantly greater degree of worry about cancer recurrence, especially when they visited the doctor’s office. This result corroborates an earlier study of Barrett’s esophagus in which patients who underwent endoscopic treatment were reported to exhibit greater concerns regarding recurrence than were those treated surgically.33 However, the number of patients in the previous study was small (81 in total), and the pathologic features of those patients were heterogeneous (inflammation, low-grade dysplasia, high-grade dysplasia, and cancer). These limitations were not a factor in our current study. Although the exact causes of the increased worry of recurrence among patients who underwent ESD relative to those treated surgically remain unclear, we propose several hypotheses. First, meticulously scheduled endoscopic surveillance after ESD may evoke worry of cancer recurrence in patients. Intensive surveillance is recommended during the first year after ESD, and annual surveillance is recommended for at least 5 years after 6 GASTROINTESTINAL ENDOSCOPY Volume
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ESD, because 14% of patients with EGC develop multiple synchronous or metachronous cancers after ESD.18 In our hospital, we endoscopically monitored patients 3 months after ESD, every 6 months for 1 year, and then annually for 5 years. Meanwhile, there is no consensus regarding the follow-up strategy after surgical treatment; therefore, individual surgeons determine the follow-up strategy for their patients.37 Second, preservation of the whole stomach after ESD may cause patients to worry that the cancer will recur at the same site. In this context, we hypothesize that patients treated via surgery were more likely to believe that all potential sites of recurrence had been removed, resulting in a greater sense of security relative to that experienced by patients who underwent ESD. Although the fear assessed by the WOCS is considered to be psychologically similar to anxiety, we did not observe a difference between the groups on the HADS questionnaire. This result supports previous findings.33 The discordance between the WOCS and HADS might be explained by the fact that the WOCS specifically estimates the worry of cancer recurrence, whereas the HADS measures general anxiety. Our results provide important information about the QOL, worry of cancer recurrence, and anxiety and depression after treatment for EGC. These data can be used in daily clinical practice, given the accelerated paradigm shift from surgery to endoscopic resection for the management www.giejournal.org
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Quality of life in patients with EGC
TABLE 4. Symptoms scales of the EORTC-QLQ-C30 and the EORTC-QLQ-STO22 (logistic regression) Symptoms (%) ESD (n[137)
Surgery (n[188)
Odds ratio (surgery vs ESD)
95% CI
P value
EORTC-QLQ-C30 symptom scales Fatigue
88.3
94.7
2.416
1.024-5.701
.044
Nausea and vomiting
35.8
48.9
1.678
1.046-2.690
.032
Pain
56.2
51.1
.942
.587-1.510
.803
Dyspnea
46.0
42.0
.887
.557-1.412
.613
Insomnia
51.8
42.6
.756
.477-1.200
.236
Appetite loss
39.4
48.9
1.750
1.081-2.832
.023
Constipation
46.7
47.3
1.221
.766-1.946
.401
Diarrhea
42.3
74.5
3.538
2.175-5.756
!.001
Financial difficulties
56.2
60.1
1.450
.902-2.329
.125
67.9
72.9
1.439
.863-2.401
.163
EORTC-QLQ-STO22 symptom scales Dysphagia Pain
65.7
79.3
1.935
1.146-3.265
.013
Reflux symptoms
49.6
65.4
1.981
1.235-3.177
.005
Eating restrictions
71.5
92.6
4.958
2.506-9.811
!.001
Anxiety
85.4
93.1
2.645
1.212-5.773
.015
Dry mouth
56.2
58.5
1.341
.829-2.170
.232
Taste
21.2
32.4
2.052
1.177-3.578
.011
Hair loss
42.3
45.7
1.246
.785-1.979
.351
The logistic regression analysis controls for age, sex, and comorbidity. Significant values with P ! .05 are shown in bold. EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire; EORTC-QLQ-STO22, European Organization for Research and Treatment of Cancer gastric cancer module 22-item core quality of life questionnaire; ESD, endoscopic submucosal dissection; CI, confidence interval.
of select EGC cases. This study also provides quantitative measures of patient self-reported outcomes that physicians and patients can recognize and integrate into the decisionmaking process. In agreement with previous studies, patients experienced deterioration in their QOL after surgical treatment for EGC.4,5 Therefore, physicians should routinely assess this deterioration in QOL by using quantitative measures to detect early changes and subsequently support suitable interventions for symptom management. For patients who undergo ESD, physicians must assess the worry of cancer recurrence and reassure patients that although stomach preservation increases the risk of developing multiple cancers from the remnant stomach portion, nearly all recurrent lesions found during scheduled endoscopic surveillance are treatable.18 This study features several strengths that merit attention. We used rigorous criteria to select patients with EGC and created 2 groups according to the treatment modality. The 2 groups were as homogenous as possible. In addition, 565 patients with EGC who had been successfully treated with ESD or surgery were analyzed and thus made the present study among the largest to date. The questionnaires used in this study have been widely used, standardized, and well validated. This history provides confidence www.giejournal.org
TABLE 5. Worry of Cancer Scale (WOCS) scores (multivariate analysis) ESD Surgery (n [ 137) (n [ 188) Mean difference P mean (SD) mean (SD) (ESD-surgery) value* Judged risk of cancer
4.0 (2.3)
3.5 (2.4)
þ.5
.079
Worry about cancer at doctor’s office
1.8 (1.9)
1.3 (1.8)
þ.5
.018
Worry about cancer over past month
2.9 (2.0)
2.7 (2.1)
þ.2
.360
Symptom levely
2.0 (1.6)
2.4 (1.9)
–.4
.205
Total WOCS scorey
10.7 (6.0)
9.9 (6.3)
þ.8
.032
Significant values with P ! .05 are shown in bold. SD, Standard deviation; ESD, endoscopic submucosal dissection. *The multivariate analysis controls for age, sex, and comorbidity. yThe multivariate analysis controls for age, sex, comorbidity, and the symptom scores of disease-specific QOL (EORTC-QLQ-C30).
that the results of this study are representative and generalizable to other institutions with comparable patients. In addition to QOL, we are the first group to assess patients’ Volume
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TABLE 6. Hospital Anxiety and Depression Scale (HADS) scores (multivariate analysis) ESD Surgery Mean (n [ 137) (n [ 188) difference mean (SD) mean (SD) (ESD-surgery) P value Anxiety score
2.1 (1.7)
2.3 (1.8)
–.2
.497
Depression score
2.6 (1.9)
2.8 (2.0)
–.3
.078
The multivariate analysis controls for age, sex, and comorbidity. ESD, Endoscopic submucosal dissection; SD, standard deviation.
worry of cancer recurrence and the incidence of anxiety and depression after ESD or surgical treatment for EGC. Although this study provides valuable insight into the global well-being of EGC patients, it includes several limitations. Because of the cross-sectional study design, randomization for ESD and surgical treatment was impossible. Selection bias was therefore inevitable because of the different indications for ESD and surgical treatments for EGC. For instance, the ESD group was older and had more comorbidities, whereas the surgery group was more likely to have T1b lesions. In addition, the cross-sectional study design may have limited the determination of long-term outcomes. Given these limitations, the validity of our findings should be confirmed in a prospective, randomized, controlled, and longitudinal study. In conclusion, the findings of our cross-sectional study indicate that stomach preservation after endoscopic treatment for EGC provides a better QOL; however, this preservation may also induce the worry of cancer recurrence. In addition to the clinical efficacy of EGC treatments, patient self-reported outcomes, including QOL and worry of cancer recurrence, must be evaluated. Endoscopists should address this issue for relieving patient’s concern of cancer recurrence during follow-up period after ESD.
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