Chang, Yu-Ling MS, NP; Tsai, Yun-Fang PhD, RN; Wu, Yi-Cheng MD; Hsieh, Ming-Ju MD
Each year, esophageal cancer (EC) results in more than 460 000 new cases, accounting for approximately 375 000 deaths worldwide,1 because early detection strategies are rarely implemented, and EC is a virulent malignancy that causes an increasing number of deaths.2 In Taiwan, EC was the fifth leading cause of cancer death among men in 2010, and the standardized mortality ratio increased by more than 27.5% (34.7% in men) between 2000 and 2010.3 Although tobacco smoking and alcohol consumption are established major risk factors for esophageal squamous cell carcinoma (SCC) in Western populations, there is little information from prospective studies on the possible roles of tobacco, alcohol use, and diet as high-risk factors for EC in Eastern countries, suggesting additional unknown causal mechanisms.4
Surgery can offer a 30% chance of cure in early-stage EC5 and a 5-year overall survival rate of approximately 20% to 40%.6,7 However, surgery for EC is associated with a high risk of severe complications in approximately 40% of patients, carries a risk of in-hospital death of up to 10%, and has a detrimental impact on quality of life (QoL).8,9 Clearly, self-reported QoL information is important because it adds predictive value to the best available preoperative and postoperative prognosticators10 and because it supplements informed decision making before surgery.5,11
Esophageal resection can have serious negative effects on QoL, although after an initial postoperative decline, QoL often returns to baseline levels within 1 year after surgery.12 Previous reports have shown that most aspects of QoL significantly deteriorate within 1 month, and patients suffer severely from reduced QoL and various symptoms for 6 months after surgery.13,14 In these patients, characteristic surgical factors or surgical complications might influence QoL for 6 months after esophagectomy.8,15,16 These reports could provide prognostic information indicating acute problems in the 6-month postoperative period. Knowledge of risk factors for poor postoperative QoL may be relevant for clinical decision making8 and may help to fully inform patients of the possible consequences of major surgery, while contributing to the practitioner’s ability to detect and prioritize problems and treatment options in a busy clinical site.17,18 However, only very few studies have addressed the issue of short-term QoL and analyzed the exact impact factors after esophagectomy with cancer in Eastern countries. Past longitudinal studies show QoL recovery after surgery, but interpretation is difficult because of missing data and attrition. This current study explored and examined symptoms and QoL within 1 and 6 months after surgery for EC and identified factors predictive of QoL within 6 months after esophageal surgery in Taiwan.
Quality of life refers to the patient’s perspective about his/her ability to function and to derive satisfaction in that functioning. Self-reported, health-related QoL is a source of predictive value and appears to be the best available preoperative and postoperative prognosticator. The conceptual framework for this study was based on models of QoL published by Ferrell and Dow19 and on the postesophagectomy with cancer QoL literature. Four dimensions define QoL, including physical, psychological, social, and spiritual well-being. Symptoms are central to QoL in that they affect all dimensions of well-being.19 Based on postesophagectomy with cancer QoL literature, many factors that increase the risk of poor QoL were identified. These included sociodemographics, body weight status, activity performance, complications after surgery, and surgery-related factors that might diminish QoL.
Design and Setting
In this longitudinal, prospective study, structured questionnaires were used to collect data from patients in one-on-one interviews conducted at intervals of preoperative, 1 month, and 6 months after esophageal surgery. We used a convenience sampling approach to enroll participants, and the study took place at 2 medical centers in northern Taiwan. Data were collected from September 2008 through June 2011.
Participants and Procedures
All patients invited to participate had received a pathologically confirmed diagnosis of squamous cell cancer or adenocarcinoma of the esophagus or gastroesophageal junction and were about to undergo esophagectomy. Inclusion criteria were the following: (1) 18 years or older, (2) histological diagnosis of EC, (3) awareness of their diagnosis, (4) potentially surgically resectable (an evaluation, including computed tomographic scans of chest and abdomen and bone scan that were negative for metastasis disease), and (5) ability to communicate verbally or in writing. Before data were collected, the study was approved by the institutional review board of the study site, a medical center in northern Taiwan. The first author explained to patients the procedures and their right to withdraw from the study at any time with no effect on their postsurgical care. After patients signed the informed consent, they completed the before-surgery questionnaire. And they filled out the subsequent questionnaires when they visited the outpatient clinic or received telephone follow-ups at 1 and 6 months after surgery.
QUALITY OF LIFE
Assessment was made using a standard questionnaire with a cancer-specific core questionnaire, Quality of Life Questionnaire–Cancer (QLQ-C30; version 3.0) and an esophageal-specific module, QLQ-OES18. The QLQ-C30 contains 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), a global health/quality-of-life scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The QLQ-OES18 contains 4 symptom scales (dysphagia, eating disorders, reflux, and pain) and 6 single items (difficulty swallowing saliva, choking, dry mouth, taste disorder, cough, and speech-related issues). Each question has 4 possible responses (not at all, a little, quite a bit, very much) except for the global QoL scale, which has 7 response alternatives (from very poor to excellent). All QoL questionnaire responses were linearly transformed to scores 0 to 100 in accordance with the EORTC Scoring Manual.20 A high score for a functional scale represents a higher (“better”) level of functioning, whereas a high score for a symptom scale or item represents a higher (“worse”) level of symptoms. A visual analog scale was also used to assess current overall QoL, with higher scores representing better QoL (range, 0–100).
DEMOGRAPHICS AND CLINICAL CHARACTERISTICS DATA COLLECTION
Sociodemographic data, activity performance status, and body weight loss within 3 months were self-reported. Medical records were used to obtain data regarding the participant’s disease, treatment, surgery-related factors, and complications. These were prospectively recorded and validated though a review of medical records by the first author. Complications were grouped as follows: leakage, wound infection, pulmonary complication, vocal cord paralysis, and chylothorax. Stricture or leakage of the anastomosis site was defined by esophagogram. The definition of EC staging was based on the 2010 manual of the American Joint Committee on Cancer21 along with histology and circumferential margin as per pathology report.
SPSS version 17.0 (SPSS Inc, Chicago, Illinois) was used for data analysis. The sociodemographics, disease characteristics, and overall QoL data of the participants were summarized by descriptive statistics. Generalized estimating equation (GEE) models were used to investigate whether QoL scores improved and whether some factors impacted QoL over 3 points in time. Missing data are common in some longitudinal studies. The GEE method,22 which is a marginal approach, is especially useful while analyzing data with elements missing completely at random23 or repeated measurements in time to correlate longitudinal data. In the present study, GEE methods were used to predict the impact on QoL factors, 1 and 6 months after esophagectomy. P < .05 was considered statistically significant.
Of 105 patients interviewed before surgery, 103 consented to participate, all of whom underwent esophagectomy. Of the 103 patients, 4 were excluded from analysis because they were unable to self-report the questionnaire (they died in hospital during the first month). Among the final 99 patients included in the analysis, (96% of those eligible), 13 died within 2 to 6 months after surgery, and 86 survived over 6 months.
Sociodemographic and Surgery-Related Variables
All 99 participants are shown in Tables 1 and 2. There was, as expected, a male predominance (92.9%); the mean age was 55.5 years (range, 32-83 years). More than two-thirds were underweight with a body mass index (BMI) of less than 25 kg/m2 and had a habit of cigarette (87.9%) and alcohol (91.9%) use. In surgery-related data, the majority of the patients had SCC (92.2%) located in the lower and middle esophagus (30.3% and 41.4%) and with an R0 circumferential margin (72.2%). Almost half the patients underwent intrathoracic anastomosis (56.6%), and neoadjuvant therapy (concurrent chemoradiotherapy + surgery) (69.7%). Within 1 month, nearly 40% of the patients had at least 1 postoperative complication. The major causes were pulmonary complications (10.1%) and anastomosis stricture (13.1%).
Changes in Overall QoL and Esophageal-Specific Symptoms Over 3 Points in Time
Mean scores and SDs with 95% confidence intervals at 3 points in time of QLQ-C30 and QLQ-OES18 detailed data are presented in Table 3. These data were processed through descriptive statistics and GEE statistical analysis. In the QLQ-C30 score, after 1 month, categories where patients reported significant functional decline were physical (P < .001), role (P < .001), cognitive (P < .05), and global health (P < .05), which, after 6 months, although not recovering to baseline, gradually improved. Nonsignificant but persistent decline in social function was noted (Figure). On the symptoms scale report, after 1 month, categories significantly worse were fatigue (P < .001), pain (P < .001), dyspnea (P < .001), nausea and vomiting (P < .05), and insomnia (P < .05), whereas constipation was significantly better after 1 and 6 months (P < .05). The other symptoms after 6 months, although not recovering to baseline, had gradually improved. Financial difficulty was a persistent problem over 6 months (Figure). On the QLQ-OES18 scale, categories reported significantly worse after 1 month were eating problems (P < .05), reflux (P < .001), taste problems (P < .05), coughing (P < .001), and speech problems (P < .05). Better than baseline was esophageal pain (P < .05). Persistently worse after 6 months was reflux (P < .001) (Figure).
Impact Factors on QoL
ASSOCIATION BETWEEN PATIENT AND SURGERY-RELATED FACTORS AND GENERAL QOL
Body mass index, body weight loss within 3 months, activity performance status, and anastomosis site showed no significant association with function and symptom aspect of QoL 1 and 6 months after surgery (Table 4). Young or middle-aged patients (<60) had significantly lower social function by 7.86 (P < .05), and those with financial problems were lower by 10.04 (P < .05) compared with older patients. Male patients with adenocarcinoma histology and non–EC junction tumor location had significant financial problems. Patients who had experienced complications scored significantly lower in global health by 8.15 (P < .05), in physical by 10.22 (P < .05), in role by 9.74 (P < .05), and in fatigue by 8.58 (P < .05) as compared with those without complications. An advanced tumor stage (R2) indicated a significantly lower physical function by 10.24 (P < .05) than a curable stage (R0). Patients with middle tumor location and adjuvant therapy scored statistically significantly lower on role, social function, fatigue, and appetite loss when compared with other tumor locations and patients who did not receive adjuvant therapy. Also, patients with tumor location at the EC junction showed better symptoms than did others. Patients with a tumor at lower-middle location scored significantly lower on global health by 13.91 (P < .05) and fatigue by 26.42 (P < .5), insomnia by 32.97 (P < .05), appetite loss by 34.21 (P < .001), and financial difficulty by 26.39 (P < .05), compared with those with the tumor location at the EC junction. Patients with SCC histology scored better on insomnia by 27.29 (P < .05) and on appetite loss by 36.61 (P < .001) than did those diagnosed with adenocarcinoma.
ASSOCIATIONS AMONG PATIENT AND SURGERY-RELATED FACTORS AND ESOPHAGEAL-SPECIFIC SYMPTOMS
No associations between any factors (age, gender, body weight loss, and anastomosis site) and esophageal-specific aspects of QoL were found (Table 5). Patients with complications had significantly worse dysphagia by 9.59 (P < .05), eating difficulties by 10.49 (P < .05), reflux by 7.12 (P < .5), and coughing by 9.9 (P < .5) than did patients with no complications. Overweight (BMI ≥25 kg/m2) patients had a significant taste problem by 12.52 (P < .05) compared with those with BMI less than 25 kg/m2. Patients with tumor location at the EC junction and a poor score for activity performance had significant dysphagia. An advanced tumor stage (R2) indicated significantly greater eating difficulties by 10.25 (P < .05) and coughing by 11.18 (P < .05) than a curable tumor stage. Patients who received adjuvant therapy scored worse for reflux by 7.19 (P < .05), taste problems by 10.93 (P < .05), and dry mouth by 9.71 (P < .05) than did those who had surgery only. Patients with tumor location in the middle region or above, including the cervical region, had worse taste problems than did those whose tumor was located at the EC junction, whereas those with middle tumor location had worse dry mouth compared with those with EC junction tumor location.
In this report, cigarette smoking, alcohol consumption, and betel-quid chewing were found to be the most likely causes of esophageal SCC, similar to the findings of another study in southern Taiwan and Asian countries.24 Alcohol induces the activity of P450, leading to extensive metabolization of safrole to 1′-hydroxysafrole, and may increase cancer risk,25 particularly when combined with the habit of betel-quid chewing and smoking.24 This result indicates encouraging high-risk patients to be screened regularly by panendoscopy, because EC is asymptomatic in the early stages. In describing the longitudinal QoL after esophagectomy for cancer, we report that the scores for overall function and global QoL decline below baseline within 1 month after surgery and gradually improve but do not recover 6 months after surgery. Among the symptoms, dysphagia and esophageal pain are replaced by other symptoms such as fatigue, dry mouth, taste problems, eating difficulties, and reflux, similar to what has been found in prior studies.15–17,25–27 Based on these results, fatigue may be explained by the long recovery time required after the intensive surgical reconstruction. High scores for taste problems and eating difficulties may be due to dry mouth and reflux and may indicate the need for a change in the distribution and sizes of meals. However, we found that constipation is significantly improved, and there was also less diarrhea, in contrast to the findings of prior studies.15–17 These results indicate that minimal division of the vagal nerve during surgery and adequate fluid support after surgery are important. In the present study, all patients received early feeding via jejunostomy (esophageal substitutes with a stomach) and adequate nutritional support (para-parenteral nutrition) at least 2 weeks after surgery.
Reflux and problems with eating were worse, just as in prior studies.16 The development of reflux after esophagectomy is directly related to new anatomic and functional configuration of the upper gastrointestinal tract after surgery.28 Up to 80% of presenting patient symptoms were related to acid or biliopancreatic reflux and rapid satiety, with postprandial discomfort at 10% to 50% after esophagectomy.29 Symptoms are worse in the prone position and may be associated with episodes of inhalation, recurrent pneumonia, and nighttime cough, compromising sleep.27 This finding suggests educating patients to avoid the prone position after eating and in particular to avoid the full prone position (180 degrees) at night, with dietary advice to eat small meals. The additional beneficial effect of proton pump inhibitors for this situation has recently been demonstrated.29,30 From the function scales, an important finding of this study is that if scores for insomnia are worse than those for other symptoms and the social role score, the global health score decreases more than does any other function. The result may support the idea that cancer patients exhibit abnormalities in circadian rhythm function,31 which suggests that circadian rhythm alterations and social function are related in complex ways: social cues help to reset the biological clock, whereas disruptions in circadian and sleep cycle patterns tend to affect social interactions.10
Among impact factors, our study findings also indicate that anastomosis site (intrathoracic or cervical) has no relevant influence on patients’ QoL within 6 months, as also shown by prior studies32; similarly, loss of body weight and low BMI had no effect after surgery.33 However, the presence of surgical complications, neodjuvant therapy, tumor location away from the EC junction, and advanced cancer have considerable and deleterious effects on many aspects of QoL in the early postoperative phase, as was similarly found in prior studies.8,15,32,33 The discovery of greater financial difficulties and poorer social function in younger patients can probably be explained by the fact that they are of working age. Postoperative complications can negatively impact QoL with worse dysphagia, eating difficulties, reflux, and coughing, as noted in many studies.16
Decreased scores for role and social function and worse fatigue among those who received neoadjuvant treatment suggest that the prolonged treatment period induces loss of social and role function. Patients with neoadjuvant treatment experienced appetite loss, taste problems, and dry mouth more strongly than did those who received only surgery, because those are adverse effects of concurrent chemoradiotherapy.
One surprising result of the present study was that lower BMI or body weight loss before surgery did not impact QoL after surgery, which is presumably related to the intensive nutritional support given as soon as possible after the surgery. Nutritional support given as early as possible via jejunostomy tube may be needed to reduce symptoms, thereby maintaining or improving QoL.
Strengths and Limitations of Study
Strengths of the study include its design; high participation rate, which reduces the risk of selection bias; its use of validated QoL questionnaires; and the high quality of clinical data regarding risk factors. Notable limitations include the relatively small sample size, but the clinically relevant changes in scores detected between baseline and 2 follow-up points in time appear to have the power to demonstrate statistical significance. Thus, future multicenter studies are needed to obtain more samples in order to help identify more clinical and surgical factors. Another limitation was the 6-month time window, which may not be sufficient to include recurrent tumors that greatly influence factors for QoL. This is because the rate of recurrence is low within 6 months.
Implications for Practice
This study provides valuable information about QoL and specific symptoms after esophagectomy. The results indicate that cigarette smoking, alcohol consumption, and betel-quid chewing are the most likely causes of esophageal SCC and that the scores for overall function and global QoL decline below baseline within 1 month after surgery and gradually improve but do not recover 6 months after surgery. Among the symptoms, dysphagia and esophageal pain are replaced by other symptoms such as fatigue, dry mouth, taste problems, eating difficulties, and reflux.
First, in view of this, because EC is asymptomatic in the early stages, more education is needed to increase knowledge about EC to high-risk patients that encourages them to be screened regularly by panendoscopy. Second, our study results illustrate the need for knowledge of the risk factors for poor postoperative QoL, in order for patients to be fully informed of possible consequences after surgery. Presurgery patient education should include a brief review of possible symptoms and treatment after surgery and knowledge that it is normal that some symptoms appear and continue for many months after surgery and that continued support and reassurance are necessary. Patients need to learn to limit caloric intake during postoperative recovery time and to eat smaller, more frequent meals, and to avoid the prone position after eating. Reflux must be prevented and managed by proton pump inhibitors. Preparing patients for the possibility of postoperative endoscopy with dilation for anastomosis stricture may help to reduce their fear of recurrence. Finally, healthcare providers need to detect and prioritize problems and treatment options in a busy clinical site. Nutritional support given as early as possible via gastrotomy tube may be needed to reduce symptoms, thereby maintaining or improving QoL. Providing continuity of care and offering support in managing physical symptoms to advanced cancer patients and those with complications are important during the acute stage.
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