Abstract
Standard time-to-surgery after neoadjuvant chemoradiotherapy for esophageal cancer has historically been 4–6 weeks. Observational studies have suggested improved oncological outcomes and health-related quality of life in patients after prolonged time-to-surgery. This study aimed to investigate whether prolonged time-to-surgery is associated with improved health-related quality of life compared to the standard interval. This study is a secondary endpoint analysis within the NeoRes II trial, in which patients with locally advanced resectable esophageal cancer were randomized to either standard time-to-surgery (4–6 weeks) or prolonged time-to-surgery (10–12 weeks). The primary endpoints have been reported previously. Health-related quality of life was assessed using the EORTC QLQ-C30 and QLQ-OG25 questionnaires at time of diagnosis, preoperatively, and at 6-months and 1–5 years postoperatively. A total of 249 patients were randomized of whom 192 were available for health-related quality of life analyses, with 97 (51%) assigned to standard time-to-surgery and 95 (49%) to prolonged time-to-surgery. The groups were well-matched regarding baseline characteristics. Preoperatively, within a week of the day of surgery, patients in the prolonged time-to-surgery group reported better global quality of life, improved physical functioning, and less fatigue, coughing, dysphagia, odynophagia, pain, discomfort, and weight loss compared to those in the standard time-to-surgery group. These benefits were observed at 6 months postoperatively, but not thereafter during follow-up, where no significant differences were observed. Although prolonged time-to-surgery was associated with better preoperative health-related quality of life, no such benefits were observed postoperatively. In addition, the results from the primary endpoint analysis suggested that longer time-to-surgery was associated with worse oncological outcomes. This, together with the results of the current sub-study, strongly supports that the standard time-to-surgery of 4–6 weeks should be recommended after neoadjuvant chemoradiotherapy for esophageal cancer.
Keywords: esophageal cancer, health-related quality of life, neoadjuvant chemoradiotherapy, time-to-surgery
INTRODUCTION
Timing of surgery after neoadjuvant treatment for patients with esophageal cancer has been a debated topic, largely due to absence of randomized data concerning ideal time-to-surgery (TTS), with only observational data, prone to selection bias, previously available. Since the 1960s, the standard TTS has been 4–6 weeks, initially based on a single-center study that concluded TTS of 6 weeks allowed patients to recover from neoadjuvant therapy while local inflammation subsides, and not leading to tumor progression.1 In the decades since, there has been substantial development in neoadjuvant therapy, and current treatment differs considerably from 60 years ago.
Current guidelines suggest different treatment strategies depending on esophageal cancer histological subtypes: For squamous cell carcinoma the recommendation is neoadjuvant chemoradiotherapy (nCRT) or definitive chemoradiotherapy (dCRT); For adenocarcinoma, the recommendation perioperative chemotherapy, or if not tolerated by the patient, nCRT.2
In recent years, the optimal TTS has been questioned. While some studies suggested an association between prolonged TTS and increased rate of R0 resection, improved survival, and health-related quality of life (HRQL), others indicated no survival benefit at all.3–6 The NeoRes II-trial evaluated complete histologic response as primary endpoint in patients with adenocarcinoma, which has been presented in detail. In conclusion, the study failed to show any significant differences in short-term outcomes concerning TTS regarding histologic response, postoperative morbidity, or for complications such as anastomotic leak, conduit necrosis, chyle leak, pneumonia, or respiratory failure.6 In addition, although not statistically significant, there was a trend toward worse overall survival in the prolonged TTS-group, with a statistically significant difference in the subgroup of patients with poor pathological response to nCRT.5,6
Before the NeoRes II data were published, there was a gradual shift in clinical practice toward increased TTS after neoadjuvant treatment. Data from the Swedish National Register for Esophageal and Gastric cancer show that between January 2006 and April 2017 approximately half the patients underwent surgery after 7 weeks or longer after completed neoadjuvant treatment.5 How a prolonged TTS, after preoperative neoadjuvant oncological treatment affects patients HRQL after esophagectomy, has still not previously been reported.
The aim of this study was to evaluate the impact of prolonged TTS of 10–12 weeks on pre- and postoperative HRQL compared to the standard TTS of 4–6 weeks after nCRT. The hypothesis is that a prolonged TTS will lead to improved recovery and HRQL pre- and postoperatively.
METHODS
Study design
The details of this trial have been described in previous publications.5,6 Patients were randomized to two different exposures, either standard TTS (4–6 weeks) or prolonged TTS (10–12 weeks) following standard CROSS type nCRT. HRQL data was prospectively collected using the validated European Organization for Research and Treatment of Cancer (EORTC) questionnaires Core Quality of Life questionnaire (QLQ-C30) and Esophago-gastric quality of life questionnaire (QLQ-OG25) as patient reported outcomes at time of diagnosis, preoperatively after completed nCRT, postoperatively at 6 months, and at 1, 2, 3, 4, and 5 years after surgery. Patients were followed-up for up to 5 years after surgery, until death or end of follow-up. (Fig. 1).
Fig. 1.
CONSORT diagram for health-related quality-of-life assessment in the study.
Study cohort
Inclusion and exclusion criteria have previously been published.5,6 All patients who fulfilled the inclusion criteria at the time of diagnosis were invited to participate in the trial. Randomization was performed after completed nCRT.
Between February 2015 and March 2019, 249 patients were randomized at 10 participating European university hospitals (6 in Sweden, 3 in Norway, and 1 in Germany: Karolinska University Hospital, Sahlgrenska University Hospital, Akademiska University Hospital, Skåne University Hospital, Linköping University Hospital, Örebro University Hospital, Norrland’s University Hospital, Oslo University Hospital, St. Olavs Hospital, Trondheim University Hospital, University Hospital in Northern Norway, and University Hospital of Cologne).
Study questionnaires
EORTC-QLQ-C30 (version 3)
The EORTC QLQ-C30 consists of five functional scales (physical, role, emotional, cognitive, and social) and one global health/quality of life scale, three symptom scales (fatigue, nausea and vomiting, and pain) and six single items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulty). The EORTC QLQ-C30 has been validated for measuring quality of life in patients in oncological trials.7 In the questionnaire patients are asked about their level of activity, ability to go on short or long walks, their ability to perform activities of daily living, and measurements of different functions such as social, emotional, physical, and role functioning. They are also asked about pain, shortness of breath, sleep quality and insomnia, nausea, vomiting, constipation, anxiety, memory, and a global assessment of health and life-quality through different questions to assess their general HRQL.
EORTC-QLQ-OG-25
The questionnaire QLQ-OG25 measures disease specific metrics regarding the HRQL of patients with esophageal, gastric, or gastroesophageal junction cancer. The questionnaire evaluates symptoms such as dysphagia, eating restrictions, reflux, odynophagia, anxiety, and pain. QLQ-OG25 is recommended as a supplement to the QLQC30 questionnaire when assessing HRQL in patients with esophageal-, gastroesophageal junction-, or gastric cancer.8
Interpretation of questionnaires
The questions in the QLQ-C30 and QLQ-OG25 all have four response alternatives (1, not at all; 2, a little; 3, quite a bit; 4, very much), except for two questions in the C30 regarding overall health and QOL assessment, where there are seven response alternatives ranging from very poor to excellent. The answers is converted to a scoring system by calculating the average of each individual item that contribute to a scale, outputting a raw score. A linear transformation model is used on the raw score to calculate a final score ranging from 0 to 100. A higher score in the symptom scales indicates a higher symptom burden, while a higher score in the functioning scales indicates better functioning.9
Statistical analysis
Statistical analyses were performed using Stata® software version 16.0 (StataCorp, College Station, Texas, USA) and IBM SPSS statistics for Macintosh, version 29.0.2.0 (IBM Corp, Armonk, New York, USA). All analyses followed the intention-to-treat principle. Descriptive statistics were used to summarize baseline characteristics. Categorical data were presented as numbers and percentages, while numerical data were presented as means and mean differences (MDs). Data from the QLQ-C30 and QLQ-OG25 were linearly converted to a 0–100 scale according to the EORTC scoring manual.9 Analyses were conducted to compare the two treatment groups by calculating means and MDs using linear regression models with 95% confidence intervals. A MD of at least 10 points was defined as a clinically significant difference,10 and statistical significance was set at P < 0.05. A sensitivity analysis was performed to study the characteristics of patients who responded to the questionnaires to assess whether they differed over time between the groups.
Ethical approval
The study was approved by the Research Ethics Committees in Sweden (Regionala etikprövningsnämnden in Stockholm, approval numbers: 2014/748-31, 2015/1271-32, 2016/626-32), Norway (REK Sør-Øst 2014/1938) and the Institutional Review Board of the University of Cologne, Cologne, Germany (IRB approval number: 17-012). The study was registered in ClinicalTrials.gov (NCT02415101).
RESULTS
A total of 249 patients were included and randomized in the NeoRes II trial. Of these, 125 patients were randomized to standard TTS, and 124 patients to prolonged TTS. Out of the included 249 patients, 192 (77%) patients answered one or more HRQL questionnaires and were included in this study. Among these, 97 (51%) patients were in the standard TTS group, and 95 (49%) in the prolonged TTS group. Mean age was similar, 65 years in the standard TTS group versus 63 years in the prolonged TTS group, and a majority of patients (83% vs. 86%, standard TTS vs. prolonged TTS) were male. There were some minor differences between the groups regarding comorbidities: cardiovascular (36% vs. 25.3%), pulmonary (10.3% vs. 6.3%), and diabetes (11.3% vs. 14.7%). Tumor stage was similar between the groups both at clinical and pathological evaluation. Mean time to surgery from completed nCRT in the standard TTS group was 39 days (range: 26–75), and in the prolonged TTS group 74 days (range: 34–109) (Table 1).
Table 1.
Baseline characteristics of all patients who answered one or more HRQL questionnaire
| Number (percent) | Standard TTS | Prolonged TTS |
|---|---|---|
| Total | 97 (50.6) | 95 (49.4) |
| Age, mean (range) | 65 (34–78) | 63 (42–78) |
| Sex | ||
| Male | 80 (82.5) | 82 (86.3) |
| Female | 16 (16.5) | 12 (12.6) |
| Missing | 1 (1.0) | 1 (1.1) |
| Comorbidity | ||
| Diabetes | 11 (11.3) | 14 (14.7) |
| Cardiovascular | 36 (37.1) | 24 (25.3) |
| Pulmonary | 10 (10.3) | 6 (6.3) |
| Smoking | 30 (30.9) | 32 (33.7) |
| Alcohol | 3 (3.1) | 4 (4.2) |
| Histology | ||
| Adenocarcinoma | 77 (79.4) | 73 (76.8) |
| Squamous cell carcinoma | 19 (19.6) | 21 (22.1) |
| Missing | 1 (1.0) | 1 (1.1) |
| Tumor stage | ||
| 1 | 1 (1.0) | 0 (0) |
| 2 | 22 (22.7) | 26 (27.4) |
| 3 | 60 (61.9) | 56 (58.9) |
| 4 | 13 (13.4) | 12 (12.6) |
| Missing | 1 (1.0) | 1 (1.1) |
| Nodal stage | ||
| 0 | 45 (46.4) | 34 (35.8) |
| 1 | 37 (38.1) | 42 (44.2) |
| 2 | 11 (11.3) | 14 (14.7) |
| 3 | 3 (3.1) | 4 (4.2) |
| Missing | 1 (1.0) | 1 (1.1) |
| Time to surgery, mean (range) | 39 (26–75) | 74 (34–109) |
HRQL—Health-related quality of life, TTS—time-to-surgery.
HRQL assessment
At time of diagnosis, the patient-reported outcomes (PRO) were completed by 47/97 (48%) of patients in the standard TTS group, and 44/95 (46%) of the patients in the prolonged TTS group. In the standard TTS group, 93/97 (96%) patients underwent surgery and 57/93 (61%) reported preoperative PRO. In the prolonged TTS group, 90/95 (95%) patients underwent surgery and 48/90 (53%) reported the preoperative PRO. The 6-month postoperative follow-up was completed by 71/88 (81%) in the standard TTS group, and 61/84 (73%) in the prolonged TTS group. The response rates over the long term follow-ups varied, as can be seen in the consort diagram (Fig. 1).
HRQL
Time of diagnosis
No clinically or statistically significant differences were seen between the two groups at time of diagnosis concerning HRQL. Most commonly occurring symptoms were dysphagia, problems with eating, odynophagia, and anxiety (Table 2).
Table 2.
Health-related quality of life at time of diagnosis comparing standard and prolonged time-to-surgery
| Standard TTS | Prolonged TTS | Mean difference | ||
|---|---|---|---|---|
| Mean score | Mean score | MD (95% CI) | P-value | |
| QLQ-C30 | ||||
| Global QoL | 66 | 68 | 2 (−6, 10) | 0.644 |
| Functional status | ||||
| Physical functioning | 87 | 92 | 5 (−1, 9) | 0.099 |
| Role functioning | 82 | 81 | −1 (−1, 9) | 0.782 |
| Emotional functioning | 76 | 74 | −2 (−9, 5) | 0.590 |
| Cognitive functioning | 91 | 86 | −5 (−11, 2) | 0.159 |
| Social functioning | 83 | 78 | −5 (−14, 4) | 0.282 |
| Symptom scales | ||||
| Fatigue | 23 | 28 | 5 (−4, 13) | 0.310 |
| Nausea/Vomiting | 15 | 10 | −5 (−13, 2) | 0.122 |
| Pain | 22 | 19 | −3 (−12, 6) | 0.532 |
| Dyspnea | 18 | 18 | 0 (−8, 9) | 0.896 |
| Insomnia | 25 | 25 | 0 (−10, 10) | 0.951 |
| Appetite loss | 25 | 24 | −1 (−13, 10) | 0.802 |
| Constipation | 14 | 14 | 0 (−10, 10) | 0.968 |
| Diarrhea | 16 | 9 | −7 (−15, 1) | 0.098 |
| Financial difficulty | 6 | 5 | −1 (−7, 6) | 0.870 |
| Body image | 92 | 86 | −6 (−15, 2) | 0.160 |
| QLQ-OG25 | ||||
| Symptom scales | ||||
| Dysphagia | 27 | 25 | −2 (−11, 8) | 0.789 |
| Problems with eating | 34 | 38 | 4 (−7, 15) | 0.483 |
| Reflux | 12 | 9 | −3 (−10, 4) | 0.395 |
| Odynophagia | 30 | 34 | 4 (−6, 16) | 0.413 |
| Pain and discomfort | 23 | 22 | −1 (−11, 9) | 0.833 |
| Anxiety | 59 | 58 | −1 (−12, 9) | 0.783 |
| Eating with others | 24 | 19 | −5 (−17, 7) | 0.434 |
| Dry mouth | 16 | 16 | 0 (−10, 9) | 0.912 |
| Trouble with taste | 9 | 15 | 6 (−3, 15) | 0.167 |
| Trouble swallowing saliva | 8 | 12 | 4 (−5, 12) | 0.379 |
| Choked when swallowing | 18 | 20 | 2 (−10, 13) | 0.765 |
| Trouble with coughing | 29 | 24 | −5 (−14, 3) | 0.229 |
| Trouble talking scale | 4 | 2 | −2 (−6, 1) | 0.177 |
| Weight loss scale | 18 | 18 | 0 (−10, 11) | 0.956 |
| Hair loss scale | 17 | 27 | 10 (−46, 66) | 0.685 |
HRQL—health-related quality of life, QLQ-C30—Core Quality of Life questionnaire, QLQ-OG25—Esophago-gastric quality of life questionnaire, TTS—time-to-surgery.
Preoperative after completed nCRT
After nCRT, shortly before surgery, patients in the prolonged TTS group reported better Global QoL (MD = 13, P < 0.001), and better Physical functioning (MD = 8, P = 0.002), although the latter was not clinically significant.
Patients in the prolonged TTS group reported both clinically and statistically less symptoms regarding fatigue (MD = 14, P < 0.001), pain (MD = 12 P = 0.008), dyspnea (MD = 12, P = 0.008), appetite loss (MD = 17, P = 0.001), problems with eating (MD = 14, P = 0.003), odynophagia (MD = 11, P = 0.025), pain and discomfort (MD = 14, P < 0.001), trouble with taste (MD = 11, P = 0.028), and weight loss (MD = 18, P < 0.001) (Table 3).
Table 3.
Patient-reported outcome measurements preoperatively comparing standard and prolonged time-to-surgery
| Standard TTS | Prolonged TTS | Standard vs. Prolonged | ||
|---|---|---|---|---|
| Mean score | Mean score | MD (95% CI) | P-value | |
| QLQ-C30 | ||||
| Global QoL | 61 | 74 | 13 (6, 20) | <0.001 |
| Functional status | ||||
| Physical functioning | 80 | 88 | 8 (3, 14) | 0.002 |
| Role functioning | 67 | 76 | 9 (0, 19) | 0.041 |
| Emotional functioning | 75 | 80 | 5 (−2, 12) | 0.159 |
| Cognitive functioning | 88 | 90 | 2 (−3, 8) | 0.406 |
| Social functioning | 73 | 78 | 5 (−3, 14) | 0.212 |
| Symptom scales | ||||
| Fatigue | 39 | 25 | −14 (−21, 6) | <0.001 |
| Nausea/Vomiting | 15 | 9 | −6 (−12, 1) | 0.072 |
| Pain | 25 | 13 | −12 (−20, −3) | 0.008 |
| Dyspnea | 31 | 19 | −12 (−20, −4) | 0.005 |
| Insomnia | 29 | 21 | −8 (−18, 0) | 0.052 |
| Appetite loss | 32 | 15 | −17 (−27, −7) | 0.001 |
| Constipation | 20 | 16 | −4 (−13, 5) | 0.382 |
| Diarrhea | 14 | 9 | −5 (−12, 2) | 0.198 |
| Financial difficulty | 13 | 6 | −7 (−13, 1) | 0.099 |
| Body image | 79 | 85 | 6 (−2, 15) | 0.129 |
| QLQ-OG25 | ||||
| Symptom scales | ||||
| Dysphagia | 19 | 10 | −9 (−17, −2) | 0.009 |
| Problems with eating | 34 | 20 | −14 (−23, −5) | 0.003 |
| Reflux | 14 | 9 | −5 (−11, 1) | 0.123 |
| Odynophagia | 25 | 14 | −11 (−20, −1) | 0.025 |
| Pain and discomfort | 26 | 12 | −14 (−22, −7) | <0.001 |
| Anxiety | 55 | 53 | −2 (−12, 7) | 0.595 |
| Eating with others | 17 | 11 | −6 (−15, 4) | 0.229 |
| Dry mouth | 22 | 17 | −5 (−14, 4) | 0.253 |
| Trouble with taste | 26 | 15 | −11 (−21, −1) | 0.028 |
| Trouble swallowing saliva | 12 | 5 | −7 (−14, −2) | 0.010 |
| Choked when swallowing | 12 | 11 | −1 (−9, 5) | 0.624 |
| Trouble with coughing | 30 | 21 | −9 (−16, −1) | 0.027 |
| Trouble talking scale | 4 | 3 | −1 (−6, 3) | 0.539 |
| Weight loss scale | 30 | 12 | −18 (−27, −9) | <0.001 |
| Hair loss scale | 28 | 16 | −12 (−29, 4) | 0.148 |
Bold numbers are used to signify a statistically significant p-value >0.05. HRQL—health-related quality of life, QLQ-C30—Core Quality of Life questionnaire, QLQ-OG25—Esophago-gastric quality of life questionnaire, TTS—time-to-surgery.
Postoperative follow-ups
At the 6-month follow-up after surgery, patients in the prolonged TTS group reported clinically and statistically less symptoms regarding insomnia (MD = 11, P = 0.024), constipation (MD = 10, P = 0.029), problems with eating (MD = 10, P = 0.023). During subsequent years following surgery there was no clinically relevant differences at all postoperative PRO measurements (Tables 4 and 5).
Table 4.
Patient-reported outcome measurements 6 months postoperatively comparing standard and prolonged time-to-surgery
| Standard TTS | Prolonged TTS | Standard vs. Prolonged | ||
|---|---|---|---|---|
| Mean score | Mean score | MD (95% CI) | P-value | |
| QLQ-C30 | ||||
| Global QoL | 63 | 68 | 5 (−1, 12) | 0.121 |
| Functional status | ||||
| Physical functioning | 76 | 80 | 4 (−2, 10) | 0.221 |
| Role functioning | 63 | 70 | 7 (−3, 17) | 0.183 |
| Emotional functioning | 77 | 83 | 6 (−1, 13) | 0.093 |
| Cognitive functioning | 84 | 86 | 2 (−5, 9) | 0.551 |
| Social functioning | 68 | 74 | 6 (−3, 15) | 0.186 |
| Symptom scales | ||||
| Fatigue | 39 | 32 | −7 (−14, 0) | 0.058 |
| Nausea/Vomiting | 18 | 14 | −4 (−19, 2) | 0.209 |
| Pain | 29 | 20 | −9 (−17, 0) | 0.042 |
| Dyspnea | 35 | 32 | −3 (−12, 7) | 0.552 |
| Insomnia | 29 | 18 | −11 (−20, −1) | 0.024 |
| Appetite loss | 31 | 22 | −9 (−19, 2) | 0.102 |
| Constipation | 22 | 12 | −10 (−19, −1) | 0.029 |
| Diarrhea | 24 | 19 | −5 (−15, 5) | 0.269 |
| Financial difficulty | 14 | 11 | −3 (−10, 5) | 0.530 |
| Body image | 77 | 83 | 6 (−3, 16) | 0.172 |
| QLQ-OG25 | ||||
| Symptom scales | ||||
| Dysphagia | 18 | 13 | −5 (−12, 1) | 0.109 |
| Problems with eating | 40 | 30 | −10 (−18, −1) | 0.023 |
| Reflux | 21 | 17 | −4 (−11, 3) | 0.259 |
| Odynophagia | 18 | 16 | −2 (−9, 3) | 0.431 |
| Pain and discomfort | 27 | 28 | 1 (−8, 9) | 0.864 |
| Anxiety | 48 | 39 | −9 (−18, 2) | 0.110 |
| Eating with others | 17 | 12 | −5 (−13, 4) | 0.290 |
| Dry mouth | 28 | 18 | −10 (−20, −1) | 0.030 |
| Trouble with taste | 25 | 18 | −7 (−17, 2) | 0.136 |
| Trouble swallowing saliva | 10 | 6 | −4 (−9, 3) | 0.306 |
| Choked when swallowing | 17 | 14 | −3 (−10, 6) | 0.581 |
| Trouble with coughing | 42 | 33 | −9 (−18, 0) | 0.039 |
| Trouble talking scale | 7 | 7 | 0 (−6, 5) | 0.923 |
| Weight loss scale | 40 | 28 | −12 (−24, −1) | 0.032 |
| Hair loss scale | 23 | 9 | −14 (−37, 9) | 0.234 |
Bold numbers are used to signify a statistically significant p-value >0.05. HRQL—health-related quality of life, QLQ-C30—Core Quality of Life questionnaire, QLQ-OG25—Esophago-gastric quality of life questionnaire, TTS—time-to-surgery.
Table 5.
Patient-reported outcome measurements 5 years postoperatively comparing standard and prolonged time-to-surgery
| Standard TTS | Prolonged TTS | Standard vs. Prolonged | ||
|---|---|---|---|---|
| Mean score | Mean score | MD (95% CI) | P-value | |
| QLQ-C30 | ||||
| Global QoL | 72 | 78 | 6 (−5, 18) | 0.282 |
| Functional status | ||||
| Physical functioning | 82 | 88 | 5 (−4, 15) | 0.229 |
| Role functioning | 73 | 80 | 7 (−9, 24) | 0.391 |
| Emotional functioning | 85 | 88 | 3 (−8, 15) | 0.578 |
| Cognitive functioning | 87 | 86 | 0 (−10, 10) | 0.931 |
| Social functioning | 78 | 76 | −2 (−18, 14) | 0.815 |
| Symptom scales | ||||
| Fatigue | 28 | 30 | 2 (−12, 17) | 0.737 |
| Nausea/Vomiting | 13 | 13 | 0 (−13, 12) | 0.964 |
| Pain | 24 | 13 | −11 (−26, 4) | 0.145 |
| Dyspnea | 25 | 30 | 5 (−10, 20) | 0.504 |
| Insomnia | 20 | 12 | −8 (−23, 6) | 0.245 |
| Appetite loss | 17 | 16 | −1 (−18, 15) | 0.863 |
| Constipation | 19 | 10 | −9 (−23, 6) | 0.254 |
| Diarrhea | 24 | 13 | −11 (−26, 4) | 0.141 |
| Financial difficulty | 3 | 9 | 6 (−5, 17) | 0.267 |
| Body image | 85 | 90 | 5 (−10, 20) | 0.543 |
| QLQ-OG25 | ||||
| Symptom scales | ||||
| Dysphagia | 12 | 11 | −1 (−13, 11) | 0.825 |
| Problems with eating | 26 | 23 | −2 (−18, 13) | 0.744 |
| Reflux | 20 | 27 | 7 (−9, 23) | 0.400 |
| Odynophagia | 13 | 12 | −1 (−14, 12) | 0.876 |
| Pain and discomfort | 25 | 17 | −9 (−26, 8) | 0.315 |
| Anxiety | 27 | 21 | −6 (−22, 9) | 0.421 |
| Eating with others | 17 | 13 | −4 (−22, 15) | 0.693 |
| Dry mouth | 20 | 10 | −10 (−25, 5) | 0.187 |
| Trouble with taste | 9 | 3 | −6 (−14, 1) | 0.090 |
| Trouble swallowing saliva | 3 | 1 | −1 (−6, 3) | 0.611 |
| Choked when swallowing | 11 | 12 | 1 (−10, 13) | 0.807 |
| Trouble with coughing | 23 | 27 | 5 (−8, 17) | 0.467 |
| Trouble talking scale | 3 | 6 | 3 (−4, 11) | 0.386 |
| Weight loss scale | 16 | 15 | −1 (−17, 16) | 0.918 |
| Hair loss scale | 20 | 33 | 13 (−42, 69) | 0.541 |
HRQL—health-related quality of life, QLQ-C30—Core Quality of Life questionnaire, QLQ-OG25—Esophago-gastric quality of life questionnaire, TTS—time-to-surgery.
Sensitivity analysis
To evaluate the robustness of our data and examine potential confounding concerning patients’ willingness to undertake the HRQL assessments, a sensitivity analysis was performed comparing the characteristics of the patients who answered the HRQL questionnaires with those that did not. This was performed at each specific time point with regards to sex, age, histologic subtype, TNM score, and Clavien–Dindo score. We found no statistically significant differences between patients who took part of the HRQL assessments, with those that did not.
DISCUSSION
The results of the current study suggest no long-term differences, except for 6 months postoperatively, regarding HRQL depending on TTS. In the time span between nCRT and surgery, there was a decline in HRQL in both groups, although less pronounced in patients with prolonged TTS, suggesting that longer recovery after nCRT may be beneficial concerning HRQL at the time of surgery. However, these advantages did not translate into better postoperative HRQL, as no differences in HRQL between the allocated TTS groups were detected in the postoperative measurements. Since data from the NeoRes II trial suggest worse oncological outcomes in patients with a prolonged TTS, this sub-study further supports adhering to the standard TTS practice after nCRT in the treatment of esophageal and gastroesophageal junction cancer.
Previous research on the effect of TTS on HRQL in patients with esophageal cancer is limited, but deterioration of HRQL after nCRT is a well-known problem. The negative impact of nCRT on HRQL align with what has been described by Noordman et al., reporting a decline in all HRQL-parameters during, and two weeks after nCRT, with physical functioning and odynophagia returning to baseline levels after eight and four weeks respectively.11 Similarly, Van Meerten et al. has described that nCRT causes considerable deterioration in most aspects of HRQL, with gradual improvements observed within 4–8 weeks following nCRT.12 Other studies have reported a similar tendency.13,14 This is in line with our finding of better HRQL observed in the prolonged compared to standard TTS group measured just before surgery, as patients had more time to recover from the side effects of nCRT in the prolonged TS group.
Strengths of the study include the randomized controlled design with NeoRes II being the only RCT to date, comparing standard TTS to prolonged TTS after nCRT in patients with esophageal or gastroesophageal junction cancer. Long-term follow-up of 5 years allows for investigation of long-term complications, survival and HRQL after prolonged compared to standard TTS.6,15 The HRQL assessments, using the EORTC QLQ-C30 and QLQ-OG25 questionnaires, which are validated and considered highly reliable for reporting HRQL in patients with esophageal and gastro-esophageal junction cancer, presents another strength.8,16,17
The trial has some weaknesses that have been discussed in prior publications.6,15 Among those mentioned was that not all patients were operated on in accordance with the protocol. In eight patients (7%) surgery was delayed >7 weeks in the standard TTS group, mainly because not considered appropriately recovered after nCRT. But, since this represents only a small proportion of patients who were managed in accordance with how they would be treated in normal clinical settings, this was suggested to have a negligible impact on the external validity. Another weakness of the current study was the uneven distribution of the HRQL questionnaires among the participating centers, limiting the number of patients that were able to respond. The reported response rates did not include patients who had died, or were not contacted because of logistical capacities. As a result of this, the response rates were high as these patients were not included in the denominator. Sensitivity analysis did, however, fail to show any differences in patient characteristics between those who responded and those who did not. However, the analysis did not account for completion of nCRT, and therefore complications related to chemoradiotherapy were not assessed for, which could explain the improvement of HRQL in the prolonged TTS group. Finally, the open-label design presents another weakness as it introduces a potential risk of bias.
A weakness not unique to our study, nor to the studies by Noordman and Van Meerten, but indeed pervasive in the field of esophageal cancer, is the mix of cancer subtypes in the clinical studies. Since squamous cell carcinoma and adenocarcinoma differ significantly in etiology, demographics, treatment strategies, and prognosis, it is inappropriate to study them as a single disease entity. Patients with squamous cell carcinoma are also more frequently treated with radiotherapy, known to cause complications such as esophagitis, pneumonitis, and cardiac issues further linked to dysphagia, odynophagia, coughing problems, and dyspnea, all inflicting patients HRQL.18 The issue of combining different cancer subtypes introduces multiple sources of bias and increases the risk of drawing incorrect conclusions. This is, without question, a significant and persistent problem in the field of esophageal cancer research.
CONCLUSION
The results from this sub-study suggest that there were no significant long-term benefits with prolonged time to surgery in regard to HRQL. This, together with the results of primary endpoint analysis that demonstrated that longer TTS was associated with worse oncological outcomes suggests that the standard TTS of 4–6 weeks should be recommended after nCRT for esophageal cancer.
Financial support: None.
Potential competing interests: None.
Conflicts of interest: The authors declare that they have no conflict of interest.
Contributor Information
Anders Holmén, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, Södersjukhuset, Stockholm, Sweden.
Fahad Murad, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden.
Klara Nilsson, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Surgery, Danderyd Hospital, Stockholm, Sweden.
Ioannis Rouvelas, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden.
Mats Lindblad, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden.
Eva Szabo, Department of Surgery, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
Ingvar Halldestam, Department of Surgery, University Hospital of Linköping, Linköping, Sweden.
Ulrika Smedh, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
Bengt Wallner, Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.
Jan Johansson, Department of Surgery, Skåne University Hospital, Lund, Sweden.
Gjermund Johnsen, Department of Gastrointestinal Surgery, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway.
Eirik Kjus Aahlin, Department of GI and HPB Surgery, University Hospital of Northern Norway, Tromsø, Norway and Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.
Hans-Olaf Johannessen, Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway.
Gabriella Alexandersson von Döbeln, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Radiotherapy, Karolinska University Hospital, Stockholm, Sweden.
Geir Olav Hjortland, Department of Oncology, Oslo University Hospital, Oslo, Norway.
Naining Wang, Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
Ying Shang, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
David Borg, Department of Oncology, Skåne University Hospital, Lund, Sweden.
Alexander Quaas, Institute of Pathology, University of Cologne, Cologne, Germany.
Isabel Bartella, Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.
Christiane Bruns, Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.
Wolfgang Schröder, Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.
Magnus Nilsson, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden.
Fredrik Klevebro, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden.
Berit Sunde, Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden.
ABBREVIATIONS
CI, confidence interval; CROSS, chemoradiotherapy for esophageal cancer followed by surgery; CT, chemotherapy; dCRT, definitive chemoradiotherapy; ECOG, Eastern cooperative oncology group; EORTC, European Organization for Research and Treatment of Cancer; Gy, Gray; HRQL, health-related quality of life; MD, mean difference; nCRT, neoadjuvant chemoradiotherapy; nCT, neoadjuvant chemotherapy; pCT, perioperative chemotherapy; PRO, patient-reported outcomes; QLQ-C30, core quality of life questionnaire; QLQ-OG25, esophago-gastric quality of life questionnaire; RT, radiotherapy; TTS, time-to-surgery
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