Jun 16, 2005 - Abstract. Knowledge of how factors related to esophageal cancer resection affect long-term quality of life after surgery is scarce, and no ...
World J. Surg. 29, 841–848 (2005) DOI: 10.1007/s00268-005-7887-9
Influence of Surgery-related Factors on Quality of Life after Esophageal or Cardia Cancer Resection Pernilla Viklund, R.N., Mats Lindblad, M.D, Ph.D., Jesper Lagergren, M.D., Ph.D. Department of Surgical Science, Karolinska University Hospital, Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden Published Online: June 16, 2005 Abstract. Knowledge of how factors related to esophageal cancer resection affect long-term quality of life after surgery is scarce, and no populationbased studies are available. Therefore, we conducted a Swedish nationwide, prospective, population-based study of how esophageal surgery–related factors influence quality of life 6 months postoperatively. The Swedish Esophageal and Cardia Cancer register (SECC-register) encompasses 174 hospital departments (97%). Microscopically radically operated patients responded to a validated written questionnaire assessing quality of life. The basic questionnaire (QLQ-C30) and the esophagusspecific module (OES-24) were developed by the European Organization for Research and Treatment of Cancer. The Mann-Whitney test, the Jonckheere-Terpstras test, and logistic regression were used in statistical analyses. Among 100 included patients, the occurrence of surgery-related complications was the main predictor of reduced global quality of life 6 months after surgery (p for trend = 0.03). This effect remained after adjustment for potential confounding variables. Except for anastomotic strictures, each of the predefined complications—i.e., anastomotic leakage, infections, cardiopulmonary complications, and operative technical complications—contributed to decreased quality-of-life scores. Other potentially relevant factors—e.g. degree of lymph node dissection, resection margins, operative blood loss or duration, and hospital type—did not significantly affect quality of life. In conclusion, any measures that can reduce the risk of major surgery–related complications can decrease the negative impact on quality of life after esophageal cancer surgery. More population-based studies are warranted, however.
The incidence of esophageal and cardia adenocarcinoma is increasing rapidly in large parts of the world [1], and the prognosis is poor [2]. Although the survival rates seem to have improved during the past decade, the 5-year survival is still only about 10% [3]. Esophagectomy is the only established curative treatment for these tumors [4]. A major problem with this extensive surgery is that it entails a considerable risk of severe and long-standing negative impact on quality of life [5, 6]. The operation can nonetheless offer cure with a reasonably good quality of life [7], and some studies support esophagectomy as a palliative strategy, even when the outcome is measured in terms of quality of life [8]. Although mortality is usually taken as the endpoint in studies examining surgical treatment with the Funding was provided by the Swedish Cancer Society and the National Board of Health and Welfare in Sweden. Correspondence to: Pernilla Viklund, R.N., e-mail: pernilla.viklund@ karolinska.se
intention to cure, quality of life is another important endpoint, particularly in oncological surgery [9]. Surgical factors that adversely affect the quality of life should be recognized and taken into consideration during the operation. Surgery-related factors that do not increase the chance of survival and that negatively affect the quality of life should be avoided whenever possible [10]. Moreover, knowledge of how the surgical procedure influences the quality of life is of obvious importance in any situation where esophageal resection can offer palliation only. The literature regarding how surgery-related factors influence the long-term quality of life after esophageal resection for cancer is sparse. A few hospital-based case series examining the influence of surgical radicality [11], type of reconstruction [12], site of the anastomosis [13], occurrence of anastomotic strictures [14], and use of neo-adjuvant therapy [15] have been published. Unfortunately, these studies suffer from a considerable risk of selection bias, and most of them evaluated small samples with limited statistical power. To our knowledge, no population-based study has previously been published regarding this issue. Therefore, we investigated how various factors related to esophageal resection surgery for cancer influenced different measures of quality of life and esophagus-specific symptoms in a nationwide population-based study in Sweden. Methods Design A prospective, population-based, and nationwide observational study was carried out in Sweden. Patients newly diagnosed with a histologically verified adenocarcinoma or squamous-cell carcinoma of the esophagus or adenocarcinoma of the gastric cardia that underwent macroscopically and microscopically radical tumor resection in Sweden from April 2, 2001, through January 2, 2003, were eligible for the study. The SECC-register The data were collected as part of a nationwide register of esophageal and cardia cancer in Sweden, the Swedish Esophageal and Cardia Cancer-register (SECC-register). This register is a continuation of a nationwide and all-encompassing Swedish net-
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work of hospital departments and clinicians involved in the diagnosis or treatment of patients with esophageal or cardia cancer. The network was initially developed for a populationbased case-control study concerning risk factors for esophageal and cardia cancer, and the organization of this network has been described in detail elsewhere [16]. We used this comprehensive organization for rapid identification of cases, with contact persons at 174 out of 179 (97%) relevant departments of general surgery, thoracic surgery, otorhinolaryngology, oncology, and pathology in Sweden. We also collaborated with all six Swedish regional tumor registries. This organization ensured that all patients throughout the country were identified shortly after their diagnosis was confirmed. At each participating department, a contact doctor was responsible for the local registration, which started on April 2, 2001. Details about the tumor (histological type, site, and stage), the surgical procedures, complications, and length of hospital stay were collected through our own manual review of each case record. The complications that were deemed to be of clinical relevance were defined by a group of leading Swedish esophageal surgeons prior to the inclusion phase of the study. These complications were grouped into anastomotic leakage (including necrosis of the substitute), infections (intra-abdominal or intrathoracic abscess, sepsis, or wound infection where intervention was needed), respiratory insufficiency (need for re-intubation or severe pneumonia), cardiac complications (myocardial infarction, or arrhythmia with need for intervention), technical complications (postoperative bleeding >2000 ml or need for reoperation, injury to the recurrent laryngeal nerve, or the thoracic duct first identified after surgery), anastomotic strictures, and others (intervention needed to treat embolus, deep venous thrombosis, rupture of the wound, intestinal obstruction, stroke, renal failure, or liver failure). The histological classification was based on the review of histopathology reports on surgical specimens from all patients included in the study. The classification of location of the adenocarcinomas was based on the Siewert definitions [17]. In our study, cardia cancer included adenocarcinoma Siewert type 2 and 3, whereas adenocarcinomas of Siewert type 1 were classified as esophageal. Information about tumor resection margins and number of removed lymph nodes was based on our continuous review of the histopathological records concerning the surgical specimens. This review also enabled us to define tumor stage, which was classified according to the definitions described by the Union Internationale Centre le Cancer [18]. Outcome Assessment The outcomes were different measures of quality of life, general symptoms, and esophagus-specific symptoms. The modules representing different aspects of quality of life were combined according to the validation analysis that has been described in detail elsewhere [19]. The evaluation of several measures of quality of life was based on a previously validated [20] written questionnaire, QLQ-C30, developed by the European Organization for Research and Treatment of Cancer (EORTC). The QLQ-C30 incorporates nine multi-item scales: one global qualityof-life scale; five functional scales addressing physical capacity, role functioning at work and during leisure time, cognitive function, emotional functioning, and social functioning; and three symptom scales regarding fatigue, pain, and nausea. Six singleitem symptom measures are also included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial problems). We
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also included another validated [19] EORTC questionnaire, OES24, that assesses symptoms specific to esophageal cancer. These symptoms include dysphagia, problems with swallowing, problems with eating, and indigestion. Based on results from previous studies addressing quality of life after esophageal resection [14, 15], we chose to assess the quality of life 6 months after surgery. Statistical Methods The mean scores regarding quality of life 6 months after surgery were analyzed. Scores were transformed into a 0–100 scale where a higher score represents a higher level of function (‘‘better’’) or a higher level of symptoms (‘‘worse’’). Hence, higher scores on the global quality-of-life scale and in the five functional scales mean better quality of life, whereas higher scores in all symptom evaluations mean worse problems. All exposure variables were categorized based on biological or distributional criteria. For each tested variable, we selected a reference category that was compared with the other categories within the exposure variable [20]. The MannWhitney test was used in the analyses comparing the outcome variables with the reference category within each variable. All tests were two-tailed with a 5% significance level. We conducted Jonckheere-Terpstras test for calculation of p values for trend in variables where a dose–response association was biologically plausible, and when the estimates from the Mann-Whitney test were statistically significant. The statistically significant findings were reanalyzed using a logistic regression model in which we adjusted for confounding by age (in three categories: < 60, 60–69, > 69 years), sex, and tumor stage (in four stages: 0–I, II, III, and IV). Ethical considerations Informed consent was obtained from each patient before inclusion in the study. The ethics committee at Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, approved the study. Results Participating Patients We registered 146 surgically treated patients with esophageal or cardia cancer during the study period. Of these patients, 37 died before the 6-month follow-up. Among those who died only four patients (3%) succumbed within 30 days after surgery. Another three patients did not return the questionnaire, and three others did not receive the questionnaire in time within the 6-month follow-up. During our review of the surgical specimens from the remaining 103 patients, three patients who were found to have microscopic signs of invasive cancer in the proximal resection margin were excluded from the study. Thereafter, 100 microscopically radically resected patients remained for final analysis. These patients were operated on at 26 different surgical departments. The age and sex distribution did not materially differ between the group of 46 patients that were not included in the analysis and the group of 100 patients that were further evaluated (data not shown). Distribution of Age, Sex, Tumor Type, and Surgery Some characteristics of the study participants are presented in Table 1. The majority of the patients were men (76%). This male
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Table 1. Selected characteristics of the 100 patients treated with esophageal resection due to esophageal or gastric cardia cancer subdivided by type of tumor. Variable Sex (number) Male Female Age (years) Median Mean Range Type of hospital (number) University Other types Type of surgical technique (number) Transhiatal resection Transthoracic resection Type of surgery Esophageal resection Cardia resection Extended total gastrectomy Total gastrectomy and esophageal resection Adjuvant therapy (number) Surgery only Surgery + radio/chemotherapy Postoperative complications (number) 0 1–2 complications 3 or more complications
Esophageal adenocarcinoma
Esophageal squamous-cell carcinoma
Cardia adenocarcinoma
All diagnoses
27 (87%) 4 (13%)
14 (67%) 7 (33%)
35 (73%) 13 (27%)
76 (76%) 24 (24%)
70 67 41–77
62 62 50–76
65 64 34–84
65 64 34–84
19 (61%) 12 (39%)
15 (71%) 6 (29%)
20 (42%) 28 (58%)
54 (54%) 46 (46%)
1 (3%) 30 (97%)
0 (0%) 21 (100%)
20 (42%) 28 (58%)
21 (21%) 79 (79%)
30 (30%) 0 (0%) 0 (0%) 1 (1%)
22 (22%) 0 (0%) 0 (0%) 0 (0%)
14 (14%) 8 (8%) 14 (14%) 11 (11%)
66 (66%) 8 (8%) 14 (14%) 12 (12%)
26 (84%) 5 (16%)
16 (76%) 5 (24%)
42 (88%) 6 (12%)
84 (84%) 16 (16%)
20 (65%) 8 (26%) 3 (10%)
9 (43%) 12 (57%) 0 (0%)
27 (56%) 18 (38%) 3 (6%)
56 (56%) 38 (38%) 6 (6%)
predominance was particularly strong among patients with esophageal adenocarcinoma (87%). The overall median age at the time of surgery was 65 years. Patients with esophageal adenocarcinoma were on average older than those with one of the other two types of tumors, particularly esophageal squamous cell carcinoma. The majority (79%) of the tumors was adenocarcinomas. Most of patients with esophageal cancer (both histological types) were operated on at university hospitals, whereas cardia cancer was more commonly treated at other hospitals. The transhiatal approach was virtually confined to patients with cardia cancer, but also among these patients the transthoracic approach was more commonly chosen. A minority (16%) of the patients received adjuvant therapy. Almost every second operation (44%) led to at least one major complication. Complications were more common among patients with esophageal squamous cell carcinoma than among those with the other types of tumors (Table 1).
Table 2. Patient characteristics and global quality of life among 100 patients treated with esophageal resection due to esophageal or gastric cardia cancer. Variable Sex Males Females Age groups < 60 years 60–69 years > 69 years
Number
Mean score (SD*)
p Value
76 24
60 (22) 62 (24)
Reference 0.71
31 36 33
58 (24) 65 (19) 58 (24)
Reference 0.33 1.00
*Standard deviation.
The mean scores for global quality of life after surgery did not differ significantly between sexes or age groups (Table 2). Similarly, there were no statistically significant differences between sexes or age groups in any of the multi-item scales or single-item symptoms measuring the quality of life or the four esophagusspecific symptoms listed in the Methods section (data not shown).
of-life scores were worse among patients with tumors in the proximal esophagus than among patients with distal tumors, but the difference was not statistically significant. Patients with esophageal squamous cell carcinoma reported slightly better mean scores for global quality of life than patients with adenocarcinoma, but again no statistically significant difference was found (Table 3). Although patients with the early tumor stages (0 to I) reported better scores than patients with advanced (stage IV) disease, the limited number of patients with stage IV disease seemed to prevent the difference from reaching statistical significance (Table 3). No differences in mean scores were found between other tumor stages (0 to III). Tumor characteristics did not statistically significantly affect any of the other measures of quality of life or esophagus-specific symptoms (data not shown).
Influence of Tumor Characteristics on Quality of Life after Esophageal Resection
Influence of Surgery-related Factors on Quality of Life after Esophageal Resection
Most (85%) tumors were located in the distal part of the esophagus or in the gastric cardia (Table 3). The mean global quality-
The influence of differences in various surgery-related factors and scores regarding measures of quality of life is presented in Ta-
Influence of Sex and Age on Quality of Life after Esophageal Resection
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Table 3. Tumor characteristics and global quality of life among 100 patients treated with esophageal resection for esophageal or gastric cardia cancer. Variable Localization of the tumor Cardia Lower esophagus Middle or upper esophagus Type of tumor Cardia adenocarcinoma Esophageal adenocarcinoma Esophageal squamous-cell carcinoma Tumor stage Stage 0–1 Stage 2 Stage 3 Stage 4
Number
Mean score (SD*)
p Value
47 38 15
59 (22) 65 (21) 54 (27)
Reference 0.18 0.18
48 31 21
43 (22) 41 (22) 49 (23)
Reference 0.09 0.48
21 38 33 5
68 59 62 48
Reference 0.13 0.38 0.09
(18) (24) (23) (24)
*Standard deviation.
ble 4. The scores were similar among patients treated at university hospitals and other hospitals. No differences in global quality of life were found among patients operated with transhiatal or transthoracic approach. Similarly, a more radical lymph node dissection did not significantly affect the quality of life. Wider resection margins resulted in better mean scores for global quality of life, and, unadjusted, the differences reached statistically significant levels for physical and role functioning. After adjustment for confounding by age, sex, and tumor stage, however, the difference was no longer significant for physical functioning (p = 0.13). The choice of esophageal substitute, type of anastomosis, extent of bleeding during surgery, total operative time: none of these influenced the quality of life. Although the mean scores for quality of life were better among patients who did not receive adjuvant therapy than among those who did receive such therapy, the difference was not statistically significant. The occurrence of complications was a factor that statistically significantly reduced the mean scores of global quality of life, the physical functioning and the role functioning 6 months after surgery. There were significant dose–response relationships for all these outcomes (Table 4). These associations also remained statistically significant after adjustment for confounding variables, except for physical functioning (p = 0.10). The length of stay in the intensive care unit or the surgical ward was shown to have a negative influence on the physical, role, and social functioning. None of the surgery-related factors importantly influenced the symptoms listed in the Methods section and assessed in the QLQC30 questionnaire (data not shown). Influence of Specific Surgery-related Complications on Quality of Life after Esophageal Resection In Table 5, the specific groups of complications in relation to selected measures of quality of life are presented. The occurrence of reoperation, anastomotic leakage, infection, or respiratory insufficiency, each statistically significantly reduced both the physical functioning and the role functioning. The scores concerning the global quality of life were also decreased, but reaching statistical significance for infections only. The occurrence of cardiac complications also reduced the scores regarding quality of life, reaching statistical significance for global quality of life. Similarly, technical complications during surgery decreased the quality-of-life scores. The only predefined complication that did
not seem to affect the quality of life was the occurrence of anastomotic strictures. Influence of Surgery-related Factors on Esophagus-specific Symptoms after Esophageal Resection Some esophagus-specific symptoms reported 6 months after surgery are summarized in Table 6. Unadjusted, a shorter proximal resection margin indicated more problems with dysphagia than did wider margins, but this effect disappeared after adjustment for tumor stage (p = 0.63). When gastric tubes were used as the esophageal substitute, the scores suggested more problems with indigestion than when small bowel was used in an Roux-en-Y reconstruction (p = 0.04). Stapled anastomoses were associated with better scores regarding swallowing function than were handsewed anastomoses, but no statistically significant difference remained after adjustment for confounding by age, sex, and tumor stage (p = 0.54). A shorter time of stay in the intensive care unit gave worse scores with regard to dysphagia than a longer stay. Type of surgical approach, degree of lymph node dissection, bleeding volume during surgery, duration of surgery, and postoperative complications and number of days in the hospital did not significantly influence any of the esophagus-specific symptoms that were assessed. Discussion This study indicates that the occurrence of surgery-related complications is the main predictor of reduced quality of life 6 months after esophageal cancer resection. With the exception of anastomotic strictures, the major types of complications, i.e., anastomotic leakage, infections, cardiopulmonary complications, and technical complications, each contributed to a reduction in the scores of quality of life. Other potentially relevant surgery-related factors, e.g., a more radical surgical procedure with regard to lymph node dissection and proximal resection margins, the amount of blood lost during surgery or the length of the operation, or the type of hospital, did not affect the scores measuring quality of life. Similarly, no significant difference was found between types of anastomoses after multivariable adjustment. Some methodological issues deserve consideration. An advantage of our study is the nationwide and population-based design, which is in contrast to the previous literature within this
63 (25) 60 (22) p = 0.63 62 58 61 60 64 (19) 59 (22) p = 0.33 55 (27) p = 0.29
21 79 55 43 37 51 14 43 16
60 (23) 62 (23) p = 0.88 58 (23) p = 0.70 60 (23) 62 (24) p = 0.79 57 (21) p = 0.58 61 (23) 57 (22) p = 0.52 65 (21) 54 (23) p = 0.03* 51 (24) p = 0.18 p for trend = 0.03*
18 31 44 35 40 25 84 16 56 38 6 51 28 13 47 34 15
Days at intensive care unit 0–3 days (reference) 4–7 days >7 days
Day at surgical ward after surgery < 14 days (reference) 14–21 days > 21 days
*Statistically significant difference
59 (24) 62 (21) p = 0.51
48 48
65 (21) 56 (22) p = 0.12 58 (22) p = 0.38
63 (20) 64 (20) p = 0.73 47 (28) p = 0.09
61 (22) 59 (22) p = 0.64 58 (38) p = 0.74
73 23 3
(24) (21) p = 0.31 (20) (24) p = 0.98
61 (24) 59 (21) p = 0.78
Global Score (SD)
54 46
Patients (number)
Esophageal substitute Stomach (reference) Small bowel (Roux-en-Y reconstruction) Colon Type of anastomosis Hand sutured (reference) Stapled Operative bleeding 1000 ml Operative time < 5 hours (reference) 5–7 hours >7 hours Adjuvant therapy Surgery only (reference) Surgery and radio-or chemotherapy Postoperative complications None (reference) 1–2 complications 3 or more complications
Type of hospital University (reference) Other types Type of surgical technique Transhiatal resection (reference) Transthoracic resection Level of lymph node dissection Non 2-field dissection (reference) 2-field dissection < 10 lymph nodes (reference) > 10 lymph nodes Proximal resection margin >49 mm (reference) 11–49 mm 0–10 mm
Variable
(22) (20) p = 0.23 (21) (20) p = 0.48
83 (20) 74 (21) p = 0.02* 68 (17) p = 0.007* p for trend = 0.01*
80 (20) 78 (19) p = 0.39 65 (24) p = 0.02* p for tend = 0.01*
82 (19) 73 (22) p = 0.04* 62 (24) p = 0.04* p for trend = 0.03*
78 (22) 74 (17) p = 0.28
77 (23) 78 (19) p = 0.88 77 (23) p = 0.67
77 (19) 78 (24) p = 0.67 75 (21) p = 0.71
75 (22) 80 (21) p = 0.21
77 (21) 77 (22) p = 0.97 82 (20) p = 0.73
87 (15) 78 (22) p = 0.26 68 (23) p = 0.02* p for trend = 0.03*
79 75 79 77
80 (23) 77 (21) p = 0.27
77 (21) 78 (21) p = 0.86
Physical score (SD)
(34) (34) p = 0.55 (30) (35) p = 0.26
71 (32) 65 (33) p = 0.40 42 (31) p = 0.005* p for trend = 0.28
68 (31) 63 (33) p = 0.43 49 (32) p = 0.05* p for trend = 0.28
74 (30) 54 (35) p = 0.01* 33 (18) p = 0.003* p for trend p = 0.004*
65 (33) 55 (35) p = 0.24
69 (35) 60 (33) p = 0.21 63 (34) p = 0.30
66 (33) 64 (36) p = 0.96 63 (35) p = 0.84
60 (34) 66 (33) p = 0.38
64 (34) 62 (36) p = 0.86 72 (35) p = 0.72
76 (20) 67 (34) p = 0.65 47 (40) p = 0.04* p for trend = 0.08
66 62 69 60
65 (35) 64 (34) p = 0.82
62 (35) 66 (32) p = 0.65
Role score (SD)
(21) (21) p = 0.48 (20) (22) p = 0.97
82 (22) 82 (20) p = 0.76 80 (21) p = 0.64
85 (19) 77 (20) p = 0.08 83 (23) p = 0.99
79 (22) 85 (20) p = 0.15 81 (22) p = 0.89
82 (22) 77 (18) p = 0.14
80 (22) 83 (22) p = 0.55 82 (20) p = 0.83
84 (19) 75 (27) p = 0.39 84 (18) p = 0.88
70 (20) 82 (22) p = 0.55
83 (20) 75 (27) p = 0.23 89 (10) p = 0.83
76 (22) 85 (20) p = 0.11 78 (26) p = 0.70
82 80 82 82
76 (28) 83 (19) p = 0.54
80 (22) 83 (20) p = 0.62
Cognitive score (SD)
Measures of quality of life in mean scores (score) with standard deviations (SD) and p values (p)
(27) (30) p = 0.15 (27) (29) p = 0.19
77 (28) 69 (28) p = 0.12 54 (26) p = 0.004* p for trend = 0.08
71 (29) 72 (28) p = 0.82 72 (20) p = 0.78
72 (30) 69 (29) p = 0.45 69 (7) p = 0.46
72 (28) 63 (30) p = 0.19
70 (28) 69 (29) p = 0.97 75 (28) p = 0.46
69 (31) 65 (28) p = 0.60 74 (27) p = 0.53
68 (26) 72 (30) p = 0.30
71 (28) 72 (27) p = 0.91 67 (58) p = 0.75
73 (25) 74 (25) p = 0.88 65 (35) p = 0.67
75 66 76 68
69 (31) 71 (28) p = 0.83
69 (30) 73 (26) p = 0.55
Social score (SD)
Table 4. Surgery-related factors and variables representing global, physical, role, cognitive and social measures of quality of life among 100 patients treated with esophageal resection due to esophageal or gastric cardia cancer. Viklund et al.: Surgery and Quality of Life 845
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Table 5. Surgery-related factors and variables representing global, physical and role measures of quality of life among 100 patients treated with esophageal resection due to esophageal or gastric cardia cancer. Measures of quality life in mean scores (score) with standard deviations (SD) and p-values (p) Variable
Patients (number)
Global score (SD)
Physical score (SD)
Role core (SD)
No complication (reference) Re-operation Anastomotic leakage Infections Respiratory insufficiency Cardiac complications Technical complications Anastomotic strictures
56 9 8 9 14 10 7 4
65 56 53 48 51 49 61 60
82 63 65 62 68 71 73 87
74 37 38 43 48 53 50 71
(21) (26) (16) (23) (26) (22) (22) (30)
p p p p p p p
= = = = = = =
0.42 0.10 0.05* 0.08 0.04* 0.67 0.90
(19) (23) (19) (25) (22) (25) (19) (22)
p p p p p p p
= = = = = = =
0.014* 0.024* 0.024* 0.03* 0.13 0.16 0.51
(30) (31) (32) (32) (31) (29) (36) (39)
p p p p p p p
= = = = = = =
0.002* 0.008* 0.01* 0.007* 0.05 0.08 1.00
*Statistically significant difference.
field of research, where only hospital-based case series have been published so far. The risk of selection bias is reduced by a population-based design. Remaining sources of selection bias in our study are non-participation in the registration and mortality before the 6-month follow-up. During the 21-month study period, the number of 146 resected patients seems low. The frequency of resected patients is approaching only 25% in Sweden, however, and during the initial phase of the registration, the registration frequency was limited, which explains the rather small number of included resected patients. This non-participation was not likely to affect the validity of the study severely, however, because non-registration was mainly due to the workup of the registration process throughout Sweden. Most of the patients who died within the 6-month follow-up period had not been microscopically radically resected, and they were therefore not eligible for our follow-up. Furthermore, no difference with regard to sociodemographic variables was found between participants and non-participants in our study. Moreover, because the short-term mortality rate after esophageal surgery is relatively low, the extent of such selection bias should be limited. Finally, any such bias is shared by all previous studies addressing the quality of life after esophageal cancer resection. Another advantage of our study was that all the exposure data were collected prospectively, i.e., before the endpoint was assessed. Prospective collection of exposure data circumvents the risk of information bias. Although the sample size of our study was larger than that of most previous studies, our study had limited power to identify weak differences in the mean scores of quality of life. Another source of chance error is the multiple testing made with numerous variables; this might introduce spurious associations. The biologically plausible hypotheses, all of which were formulated before the start of the study should limit such chance effects, however. Associations that were not included in the hypotheses were not considered. The lack of spurious chance findings in our study is supported by the fact that we only identified one positive association, i.e., between complications and risk of poor quality of life. Moreover, the dose–response relationship, with regard to number of complications also indicates that this finding reflects a true association. We selected one time window for the assessment of quality of life, i.e., 6 months after the surgery. This choice was based on results from previous reports that the quality of life is generally back to stable baseline (preoperative) values about 6 months after esophageal surgery, indicating that acute problems after surgery
had subsided [14, 15]. Moreover, previous studies have found that tumor recurrence is the single strongest negative factor for the quality of life [14]. It was important to avoid the influence of recurrences, as the aim of the study was evaluate surgery-related factors. Our time window, relatively soon after surgery, would make interference from recurrent disease unlikely. To further avoid influence of tumor recurrences, we only included patients who were radically operated based on both macroscopic and microscopic examinations. The number of studies addressing the influence of surgeryrelated factors on the quality of life after esophageal cancer surgery is small. A previous finding of worse scores among women than among men after esophagectomy [5] was not confirmed by our results. Because there is no obvious biological mechanism that would support the previous finding, and because our data contradict a sex difference, the earlier finding may perhaps be attributed to chance. Our results concerning the lack of influence of the extensiveness of surgery and the type of reconstruction on measures of quality of life are in line with previous data [11, 12]. The occurrence of anastomotic strictures has been found to interact with the global quality of life in a previous study [14]. However, this particular complication was not among those that affected the outcome in our study. Therefore, data are contradictory, but the influence of anastomotic strictures on global quality of life is probably limited. Some preliminary results support the hypothesis that neo-adjuvant treatment might decrease the quality of life after esophageal surgery [15], and although we found no statistically significant difference, the mean scores were generally worse among oncologically treated patients also in our study. Taken together, these results suggest that adjuvant therapy might decrease the quality of life. However, selection bias and the choice of different time windows for the assessment of the quality of life might at least partially explain the few contradictions between the available studies. The occurrence of major surgery-related complications importantly reduces quality of life even 6 months after surgery. The significant findings with regard to the length of stay at intensive care units and surgical wards should only mirror the relation between complications and quality of life. Even though our results do not show that the size of the hospital has any impact on quality of life 6 month after surgery, it has previously been proven that complications after esophageal resection can be reduced if the operations are done in high-volume hospitals [21, 22]. It is relevant to note that several potentially important factors
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Table 6. Surgery-related factors and variables representing esophagus-specific symptoms among 100 patients treated with esophageal resection due to esophageal or gastric cardia cancer. Measures of esophageal-specific symptom in mean scores (score) with standard devations (SD) and p-values (p) Patients (number)
Dysphagia score (SD)
Swallowing score (SD)
Eating score (SD)
Indigestion score (SD)
54 46
20 (22) 21 (22) p = 0.93
21 (22) 13 (17) p = 0.06
36 (27) 35 (24) p = 0.97
26 (30) 25 (30) p = 0.77
21 79
21 (17) 20 (23) p = 0.60
16 (21) 18 (20) p = 0.50
39 (27) 35 (25) p = 0.53
27 (35) 25 (29) p = 0.98
55 43 37 51
20 21 20 20
17 19 14 19
34 38 34 36
26 24 23 27
14 43 16
10 (11) 20 (22) p = 0.15 33 (30) p = 0.02*
14 (27) 19 (20) p = 0.23 14 (20) p = 0.68 p for trend = 0.02*
32 (20) 35 (29) p = 0.97 41 (15) p = 0.25
25 (28) 26 (33) p = 0.85 28 (28) p = 0.84
73 23 3
19 (22) 27 (20) p = 0.06 19 (17) p = 0.85
19 (21) 13 (19) p = 0.15 17 (0) p = 0.81
37 (27) 33 (23) p = 0.70 33 (8) p = 1.00
29 (30) 17 (30) p = 0.04* 6 (10) p = 0.17
48 48
22 (23) 19 (20) p = 0.54
23 (24) 13 (15) p = 0.02*
37 (27) 34 (25) p = 0.66
21 (27) 27 (29) p = 0.26
18 31 44
18 (19) 24 (26) p = 0.55 20 (21) p = 0.76
20 (24) 16 (18) p = 0.84 16 (16) p = 0.89
40 (30) 38 (23) p = 0.98 34 (25) p = 0.58
35 (38) 23 (24) p = 0.36 25 (31) p = 0.38
35 40 25
20 (18) 25 (25) p = 0.61 14 (20) p = 0.10
17 (21) 16 (19) p = 0.94 19 (22) p = 0.54
39 (28) 38 (23) p = 0.95 27 (23) p = 0.09
29 (32) 23 (27) p = 0.49 25 (31) p = 0.69
84 16
21 (22) 19 (20) p = 0.90
17 (20) 21 (21) p = 0.38
34 (25) 46 (27) p = 0.12
24 (29) 33 (34) p = 0.34
56 38 6
21 (21) 21 (23) p = 0.77 11 (14) p = 0.28
15 (22) 21 (18) p = 0.02* 19 (19) p = 0.36 p for trend = 0.02*
37 (25) 36 (27) p = 0.81 29 (22) p = 0.61
23 (31) 29 (29) p = 0.21 25 (29) p = 0.84
Days at intensive care unit 0–3 days (reference) 4–7 days >7 days
51 28 13
22 (22) 22 (22) p = 0.83 9 (13) p = 0.04* p for trend = 0.84
19 (23) 17 (17) p = 0.93 13 (15) p = 0.51
36 (24) 44 (28) p = 0.26 24 (23) p = 0.10
24 (30) 32 (31) p = 0.25 22 (30) p = 0.67
Days at surgical ward after surgery < 14 days (reference) 14–21 days > 21 days
47 34 15
19 (23) 20 (20) p = 0.62 20 (21) p = 0.90
14 (21) 19 (20) p = 0.15 22 (20) p = 0.05
30 (25) 40 (25) p = 0.09 43 (28) p = 0.12
26 (31) 20 (23) p = 0.53 38 (35) p = 0.20
Variable Type of hospital University (reference) Other types Type of surgical technique Transhiatal resection (reference) Transthoracic resection Level of lymph node dissection Non 2-field dissection (reference) 2-field dissection < 10 lymph nodes (reference) >10 lymph nodes Proximal resection margin >49 mm (reference) 11–49 mm 0–10 mm Esophageal substitute Stomach (reference) Small bowel (Roux-en-Y reconstruction) Colon Type of anastomosis Hand sutured (reference) Stapled Operative bleeding 1000 ml Operation time < 5 hours (reference) 5–7 hours > 7 hours Adjuvant therapy Surgery only (reference) Surgery and radio- or chemotherapy Postoperative complications None (reference) 1–2 complications 3 or more complications
(22) (22) p = 0.76 (24) (20) p = 0.70
(22) (18) p = 0.27 (17) (23) p = 0.61
(25) (26) p = 0.49 (24) (26) p = 0.86
(31) (26) p = 0.95 (27) (32) p = 0.54
*Statistically significant difference
during surgery did not negatively affect the quality of life. It is particularly interesting that a more extensive lymph node dissection or longer operative time did not interfere with quality of life. University hospitals were compared with other hospitals without any clear difference in results, but a larger sample size is needed to more definitely address the influence of hospital volume on the quality of life. In conclusion, our prospective, population-based study indicates that the best way to avoid adding negative impact on the global quality of life 6 months after esophageal cancer surgery is to reduce surgery-related complications. This may be possible
through concentration of this type of surgery to true high-volume units. Other surgery-related factors seem to play little or no role with regard to aspects of quality of life or esophageal-specific symptoms. More population-based and larger studies are needed to confirm these results, however. Acknowledgments We are grateful to Eja Fridsta for invaluable help with the fieldwork of the Swedish Esophageal and Cardia Cancer register (SECC-register). We sincerely appreciate the collaboration with
848
all contact doctors that participate in the SECC-register: Erik Aasberg, Gunnar Adell, Stig-Olof Almgren, Christer Andersson, Bengt Anesten, Ebbe Ankeraa, Lena Appelgren, John Blomberg, Bernt Boeryd, Poul Boiesen, Mogens Bove, Mats Broberg, Pawel Burian, Bjo ¨rn Ba¨ckstrand, Tora Campbell-Chiru, Ulf Carlsson, ˚ ke Dahlqvist, Jan Dalenba¨ck, Stefan Dedorson, Jan Dolata, A Thomas Edekling, Kent Edin, Tom Ekstrand, Annika Elmhorn Rosenborg, Lars-Krister Enander, Mats Eriksson, Thomas Eriksson, Bo Erlandsson, Ivan Farago, Elisabeth Flashar Lindahl, Petra Flygare, Ulla Friberg, Signe Friesland, Ashok Gadre´, Ulf Gerdes, Per Gullstrand, Olle Gunder, Gustav Gustavsson, Mehmet Go ¨zen, Andrea Halasz, Marianne Hall Angera˚s, Ann Hammarlund, Jo ¨rgen Hansen, Poul Erik Hansen, Mats Hedberg, Lennart Hedenborg, Antti Heikkila¨, Per Herlin, Leif HoffmannLaursen, Erik Holm, Fredrik Holmner, Hans-Olof Ha˚kansson, Hans Ho ¨gstro ¨m, Leif Ingvarsson, Peter Jilcke, Bengt Johansson, Karl-Erik Johansson, Leif Johansson, Sven Johansson, Erik Johnsson, Go ¨ran Karlsson, Mats Karlsson, Staffan Kinman, Gerhard Kjelle´n, Wieslava Kranze, Hans Krook, Richard Kuylenstierna, Anders Kyleba¨ck, Peter Lannes, Sven Larsson, Gustav Levin, Pontus Lidberg, Bengt Liedman, Ha˚kan Liljehohn, Ramon Lillo-Gil, Daniel Lindahl, Gert Lindell, Christer Lindholm, Johan Lindholm, Christina Lindstro ¨m, Gunilla Ljung, Anders Lundberg, Kjell Lundberg, Lars Lundell, Britta Lo ¨den, Ulf Lo ¨nn, Ester Lo ¨rinc, Shabaz Majid, Janusz Matusik, Kai Mele´n, Lennart Mellblom, Hans Modig, Eva Munck-Wikland, Torbjo ¨rn Myrna¨s, Ewa Ma˚rtensson, Torben Navne, Anders Nihlberg, Erik Nilsson, Mats Nilsson, Roland Nilsson, Torgny Norde´n, Tomas Norlander, Johan Nyman, Ingmar Na¨slund, Bengt Ohlander, Bo Ojen, Sante Olling, Bengt Olsson, Ha˚kan Olsson, Mikael Olsson, Rickard Palmkvist, Fredrik Petersson, Johan Ramstro ¨m, Gunnar Rimba¨ck, Pehr Rissler, Staffan Rosendahl, Claes Rudberg, Valter Ryd, Thure Ra˚dmark, Bjo ¨rn Sandmark, Charles Silseth, Svante Sjo ¨stedt, Stefan Spinnell, Roger Stenling, Dag Stockeld, Edith Sto ¨ckel, Magnus Sundblad, Erik Svartholm, Conny Svensson, JanOlov Svensson, Robert Szepesvari, Claes So ¨derlund, Claes The¨ rnberg, Tibor Tot, Torbjo ander, Stefan Thelin, Maria Thore´n O ¨rn Tuveson, Maciej Tytor, So ¨ren Vallgren, Svend Vang Petersen, Anders Victorin, Torkel Wahlin, Kjell Wallin, Bruno Walther, ˚ ke O ¨ sth, and Go ¨ stberg Olle Wihlborg, Bo J Wilhelmsson, A ¨rel O Reference 1. Bollschweiler E, Wolfgarten E, Gutschow C, et al. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer 2001;92:549–555 2. Berrino FCR, Esteve J, Gatta G, et al. Survival of Cancer Patients in Europe: The Eurocare-2 Study. IARC Scientific Publications, Vol. 151; International Agency for Research on Cancer, 1999
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