Impact of neoadjuvant chemoradiotherapy on health-related quality of life in long-term survivors of esophageal or junctional cancer: results from the randomized CROSS trial

Impact of neoadjuvant chemoradiotherapy on health-related quality of life in long-term survivors... Abstract Background Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone. Patients and methods Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4-Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30). Results After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen’s d −0.37, P = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen’s d −0.56 and 0.51, respectively, both P < 0.001). Conclusions Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care. Trial registration number Netherlands Trial Register NTR487. esophageal cancer, neoadjuvant chemoradiotherapy, health-related quality of life Key Message In addition to the earlier described improvement in overall and disease-free survival and the absent impact on early recovery, this study indicates that neoadjuvant chemoradiotherapy plus surgery does not impact long-term HRQOL, compared with surgery alone. This supports the view that this multimodality treatment can be considered as a standard of care for patients with esophageal cancer. Introduction Esophageal cancer is characterized by frequent locoregional and distant recurrence. The 5-year overall survival rate rarely exceeds 40% after primary surgery. In order to improve locoregional control and overall survival, neoadjuvant chemo(radio)therapy has been investigated in many clinical trials [1]. The ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial compared a carboplatin and paclitaxel based neoadjuvant chemoradiotherapy (nCRT) regimen plus surgery with surgery alone. Eight centers in the Netherlands participated. After a minimum follow-up of 5 years, a clinically relevant and statistically significant benefit in overall- and progression-free survival rates was shown for the multimodality group. Treatment-related toxicity and postoperative complication rate were acceptable [2, 3]. Based on these results, nCRT followed by surgery according to the CROSS regimen is a standard care in many countries [4]. The increasing emphasis on patient-reported outcome measures and health-related quality of life (HRQOL) leads to a more prominent role of these measures as end points in clinical trials. Thus far, HRQOL has received limited attention in the field of esophageal cancer, but the wide introduction of nCRT and the associated increased survival emphasize the need for high-quality HRQOL data from these patients. It is known that esophagectomy has profound and lasting impact on patients’ HRQOL [5, 6]. The short-term HRQOL analysis of the CROSS trial (follow-up ≤1 year) showed that adding nCRT to surgery does not adversely impact postoperative HRQOL [6], which is in line with results from earlier retrospective studies [7–9]. However, follow-up of these studies did not exceed 24 months [6–9]. Importantly, side-effects of radiotherapy can develop years after treatment, with the lungs being the most radiosensitive organ in the chest [10]. Therefore, long-term HRQOL data from patients treated with nCRT plus surgery are desired. The aim of this sub-study of the CROSS trial was to compare HRQOL in long-term survivors (>6 years) who received nCRT plus surgery or surgery alone. Methods Details of this randomized trial have been reported previously [2, 3]. Briefly, patients with locally advanced (clinical stage T1N1M0 or T2-3N0-1M0, 6th edition of the Union for International Cancer Control TNM cancer staging) [11] esophageal or esophagogastric junctional squamous cell carcinoma or adenocarcinoma were eligible. Patients were randomized between nCRT plus surgery and surgery alone. The study protocol was approved by the ethical committees of the participating centers, and ethical approval for long-term HRQOL measurement was provided by the medical ethical committee of the Erasmus MC. All included patients provided written informed consent. Procedures Patients assigned to nCRT were treated with carboplatin (AUC 2 mg/ml/min) and paclitaxel (50 mg/m2 of body-surface area) for five weekly cycles. Concomitant radiation therapy was given in 23 fractions of 1.8 Gy (41.4 Gy total). Patients assigned to surgery alone were operated as soon as possible, whereas patients in the nCRT group underwent surgery 4–6 weeks after completion of nCRT. Patients with carcinomas at or above the level of the carina underwent a transthoracic esophagectomy with two-field lymphadenectomy, whereas patients with carcinomas below the carina, either had a transthoracic esophagectomy with two-field lymphadenectomy or had a transhiatal esophagectomy with upper abdominal and lower mediastinal lymphadenectomy, depending on patient characteristics and local preferences. For patients with carcinomas involving the esophagogastric junction, a transhiatal esophagectomy was recommended. HRQOL measurement Cancer-specific HRQOL was assessed using the EORTC-QLQ-C30, a validated self-completed questionnaire designed for cancer patients [12]. Tumor-specific HRQOL was assessed using the EORTC-QLQ-OES24 self-completed questionnaire [13]. The EORTC-QLQ-OES24 was used to allow for comparison with baseline and 12 months postoperative questionnaires, as the currently used derivative, EORTC QLQ-OES18, was not available at that time. During long-term follow-up assessment, the K-BILD questionnaire was added to assess pulmonary effects of radiotherapy. The K-BILD is a self-completed validated questionnaire for interstitial lung disease patients [14]. The self-completed questionnaires were mailed to all patients who were alive after a minimum follow-up of 6 years after surgery. Patients who had not completed the questionnaires within 1 month were reminded two times by telephone. To allow for examination of HRQOL over time, questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores from the earlier short-term HRQOL study (follow-up ≤1 year after surgery) [6]. Before the analysis, end points were predefined by consensus discussion with experienced medical oncologists, upper-GI surgical oncologists and nurse practitioners. End points were defined based on clinical relevance and hypothesized relation with long-term outcome of nCRT. Primary end points were physical functioning (QLQ-C30), eating problems (QLQ-OES24) and total respiratory problems (K-BILD). Secondary end points were global quality of life and fatigue (both QLQ-C30). Statistical analysis Patients who were alive during long-term follow-up assessment (July 2015) were included in the analysis. Pretreatment patient characteristics were compared using Student’s t-test or Mann–Whitney U test for continuous characteristics, whereas χ2 test or Fisher’s exact test was used for comparison of categorical characteristics. Questionnaire scale scores were transformed into a 0–100 scale as was described previously [14, 15]. Baseline (questionnaire) scores of the two treatment groups were compared using Student’s t test. Over-time differential effects between the treatment groups and longitudinal differences of the follow-up measurements were investigated using mixed modeling analysis. If no statistically significant differential effects were found between both groups, results of the combined groups are reported. Mixed modeling allows for inclusion of questionnaires from subjects with different numbers of completed measurements and thereby enables analysis of all available data [16]. Hence, all available questionnaires were included in the analyses. Mean changes between groups and over time differential effects were described. Cohen’s d (CD) effect sizes were calculated to assess clinical relevance of the effects and to enable standardized comparison between different outcome variables. CD effect sizes were derived from the β-estimates in the mixed modeling procedure. CD values of 0.2, 0.5 and 0.8 reflect small, medium and large effects, respectively [17]. Values >0.5 indicate clinically relevant effects [18]. As multiple comparisons correction, P < 0.025 was considered statistically significant for the mixed models analyses (the main analyses included two comparisons and thus a Bonferroni correction of 0.05/2 was applied), whereas P < 0.05 was considered statistically significant for clinical characteristics and baseline score comparisons. All P-values are two-sided. Data were analyzed using SPSS version 21.0. Results Of the 368 patients included in the CROSS trial, 123 (33%) were still alive (70 nCRT plus surgery, 53surgery alone). Median follow-up was 105 months. Patients in the nCRT group were older, but there were no other statistically significant differences in pretreatment clinicopathologic characteristics between the groups (Table 1). The majority of patients was male (76% and 77%, respectively), most patients had an adenocarcinoma (73% and 76%, respectively) and most tumors were clinically staged as cT3 (77% and 76%, respectively). Most patients had suspected locoregional lymph node metastases (54% and 69%, respectively). Due to an administrative error, 32 of the long-term survivors did not receive baseline HRQOL questionnaires. These patients were not excluded from the analysis, because their pretreatment characteristics were not significantly different from the total study group (data not shown), and follow-up questionnaires were correctly mailed and completed [6]. Table 1. Clinicopathologic characteristics of patients with potentially curable esophageal or esophagogastric junction cancer, according to treatment allocationa Characteristic  nCRT plus surgery  Surgery alone  P-value  (N = 70)  (N = 53)  Follow-up—months        Median  104  105  0.635   IQ range  90–116  87–117    Age at randomization—yr.         Median  60  57  0.024   IQ range  55–65  51–62    Male sex—no. (%)  53 (76)  41 (77)  0.832  Tumor type—no. (%)      0.205   Adenocarcinoma  51 (73)  40 (76)     Squamous cell carcinoma  19 (27)  11 (21)     Other  0  2 (4)    Tumor location—no. (%)b      0.571   Esophagus         Proximal and middle third  12 (18)  6 (12)     Distal third  36 (54)  32 (62)     Esophagogastric junction  19 (28)  14 (27)     Missing data  3  1    Clinical T stage—no. (%)c      0.965   cT1/cT2  16 (23)  12 (24)     cT3  53 (77)  39 (76)     Could not be determinedd  1  2    Clinical N stage—no. (%)e      0.116   N0  31 (46)  16 (31)     N1  37 (54)  35 (69)    Could not be determinedd  2  2    WHO performance status—no. (%)f      0.425   0  57 (81)  46 (87)     1  13 (19)  7 (13)    Characteristic  nCRT plus surgery  Surgery alone  P-value  (N = 70)  (N = 53)  Follow-up—months        Median  104  105  0.635   IQ range  90–116  87–117    Age at randomization—yr.         Median  60  57  0.024   IQ range  55–65  51–62    Male sex—no. (%)  53 (76)  41 (77)  0.832  Tumor type—no. (%)      0.205   Adenocarcinoma  51 (73)  40 (76)     Squamous cell carcinoma  19 (27)  11 (21)     Other  0  2 (4)    Tumor location—no. (%)b      0.571   Esophagus         Proximal and middle third  12 (18)  6 (12)     Distal third  36 (54)  32 (62)     Esophagogastric junction  19 (28)  14 (27)     Missing data  3  1    Clinical T stage—no. (%)c      0.965   cT1/cT2  16 (23)  12 (24)     cT3  53 (77)  39 (76)     Could not be determinedd  1  2    Clinical N stage—no. (%)e      0.116   N0  31 (46)  16 (31)     N1  37 (54)  35 (69)    Could not be determinedd  2  2    WHO performance status—no. (%)f      0.425   0  57 (81)  46 (87)     1  13 (19)  7 (13)    a Percentages may not add up to 100 because of rounding. WHO denotes World Health Organization. b Tumor length and location were determined by means of endoscopy. c Clinical tumor (cT) stage was assessed by means of endoscopic ultrasonography or computed tomography (CT) and was classified according to the International Union against Cancer (UICC) tumor-node-metastasis (TNM) classification, 6th edition. d This category included patients in whom the tumor could not be fully investigated by means of a transducer for endoscopic ultrasonography owing to a stenosis caused by the tumor. e Clinical lymph node (N) stage was assessed by means of endoscopic ultrasonography, CT or 18F-fluorodeoxyglucose positron-emission tomography and was classified according to UICC TNM classification, 6th edition. f WHO performance status scores are on a scale of 0–5, with lower numbers indicating better performance status; 0 indicates fully active, and 1 unable to carry out heavy physical work. Bold values reflect statistically significantly differences. Overall response rate to the HRQOL questionnaires in the 123 long-term survivors was 89% (Table 2). In the nCRT-group response rate was 94%, whereas in the surgery alone group this was 83% (P = 0.07). Mean scores of all HRQOL domains of the EORTC-questionnaires and K-BILD questionnaire are reported in Tables 3 and 4, respectively. Table 2. Patients’ eligible for quality-of-life assessment, returning the quality-of-life questionnaire, deceased, not returning the quality-of-life questionnaire because they were too ill or because of random reasons at each measurement point Status  Pretreatment  12 months postoperatively  Long-term follow-up (>6 years postoperatively)  Eligible  123  123  123   nCRT+surgery  70  70  70   Surgery alone  53  53  53  Returned total (% of eligible)  83 (67)  79 (64)  110 (89)   nCRT+surgery (%)  57 (81)  49 (70)  66 (94)   Surgery alone (%)  26 (49)  30 (57)  44 (83)  Deceased  N/A  N/A  N/A  Too ill  0  1  1  Randomly missing/other  40a  43  12  Status  Pretreatment  12 months postoperatively  Long-term follow-up (>6 years postoperatively)  Eligible  123  123  123   nCRT+surgery  70  70  70   Surgery alone  53  53  53  Returned total (% of eligible)  83 (67)  79 (64)  110 (89)   nCRT+surgery (%)  57 (81)  49 (70)  66 (94)   Surgery alone (%)  26 (49)  30 (57)  44 (83)  Deceased  N/A  N/A  N/A  Too ill  0  1  1  Randomly missing/other  40a  43  12  a Of whom 32 due to administrative error. Table 3. Mean scores for all domains in the two EORTC questionnaires according to treatment group   Pretreatment   12 months postoperatively   Long-term follow-up (>6 years postoperatively)     nCRT plus surgery  Surgery alone  nCRT plus surgery  Surgery alone  nCRT plus surgery  Surgery alone  QLQ-C30                 Global quality of life  76 (19)  73 (15)  76 (17)  77 (22)  76 (22)  78 (19)  Functional scales                 Physical  96 (9)  94 (8)  89 (16)  91 (10)  86 (16)  86 (20)     Role  88 (27)  85 (22)  80 (25)  78 (23)  82 (24)  82 (25)     Emotional  68 (24)  67 (18)  86 (17)  79 (20)  87 (18)  84 (22)     Cognitive  92 (17)  85 (19)  88 (18)  83 (19)  85 (19)  84 (20)     Social  85 (23)  81 (21)  90 (16)  78 (24)  87 (20)  80 (24)  Symptom scores                 Fatigue  13 (17)  16 (21)  25 (20)  20 (15)  27 (22)  22 (24)     Nausea and vomiting  5 (11)  6 (12)  11 (16)  15 (20)  7 (14)  10 (21)     Pain  12 (19)  14 (22)  6 (11)  18 (20)  10 (20)  10 (17)     Dyspnea  5 (12)  2 (9)  16 (22)  11 (18)  19 (25)  14 (21)     Insomnia  23 (26)  20 (31)  14 (23)  16 (25)  20 (27)  20 (27)     Loss of appetite  10 (24)  7 (17)  10 (19)  10 (18)  12 (23)  15 (28)     Constipation  8 (19)  1 (6)  8 (20)  11 (20)  10 (17)  5 (12)     Diarrhea  2 (11)  0 (0)  16 (24)  18 (23)  16 (24)  17 (26)     Financial worries  7 (18)  9 (24)  9 (19)  13 (26)  12 (25)  11 (28)  QLQ-OES24                 Eating problems  29 (27)  33 (28)  24 (21)  29 (27)  20 (20)  22 (23)     Emotional problemsa  36 (25)  48 (18)  29 (20)  33 (23)  29 (22)  25 (24)     Dysphagia  74 (33)  63 (35)  83 (28)  69 (38)  82 (31)  76 (36)     Deglutition  16 (27)  9 (16)  16 (26)  13 (19)  12 (20)  18 (22)     Swallowing of saliva  18 (34)  11 (23)  14 (30)  10 (22)  10 (25)  17 (32)     Aspiration  14 (27)  7 (14)  18 (28)  16 (23)  13 (24)  18 (25)     GI symptoms (24)a  16 (19)  21 (16)  21 (22)  25 (25)  20 (19)  25 (30)     GI symptoms (18)  10 (20)  7 (13)  19 (26)  22 (27)  19 (24)  26 (32)     Pain  16 (20)  23 (27)  8 (14)  9 (15)  8 (16)  7 (11)     Dry mouth  8 (21)  12 (19)  17 (25)  14 (23)  17 (25)  13 (24)     Trouble with taste  7 (19)  9 (24)  9 (21)  8 (14)  8 (20)  8 (23)     Trouble with coughing  13 (21)  12 (21)  17 (21)  20 (21)  17 (24)  18 (27)     Trouble with speaking  4 (17)  0 (0)  12 (27)  10 (26)  9 (22)  11 (22)     Hair lossa  0 (0)  0 (0)  13 (17)  33 (33)  8 (23)  0 (0)    Pretreatment   12 months postoperatively   Long-term follow-up (>6 years postoperatively)     nCRT plus surgery  Surgery alone  nCRT plus surgery  Surgery alone  nCRT plus surgery  Surgery alone  QLQ-C30                 Global quality of life  76 (19)  73 (15)  76 (17)  77 (22)  76 (22)  78 (19)  Functional scales                 Physical  96 (9)  94 (8)  89 (16)  91 (10)  86 (16)  86 (20)     Role  88 (27)  85 (22)  80 (25)  78 (23)  82 (24)  82 (25)     Emotional  68 (24)  67 (18)  86 (17)  79 (20)  87 (18)  84 (22)     Cognitive  92 (17)  85 (19)  88 (18)  83 (19)  85 (19)  84 (20)     Social  85 (23)  81 (21)  90 (16)  78 (24)  87 (20)  80 (24)  Symptom scores                 Fatigue  13 (17)  16 (21)  25 (20)  20 (15)  27 (22)  22 (24)     Nausea and vomiting  5 (11)  6 (12)  11 (16)  15 (20)  7 (14)  10 (21)     Pain  12 (19)  14 (22)  6 (11)  18 (20)  10 (20)  10 (17)     Dyspnea  5 (12)  2 (9)  16 (22)  11 (18)  19 (25)  14 (21)     Insomnia  23 (26)  20 (31)  14 (23)  16 (25)  20 (27)  20 (27)     Loss of appetite  10 (24)  7 (17)  10 (19)  10 (18)  12 (23)  15 (28)     Constipation  8 (19)  1 (6)  8 (20)  11 (20)  10 (17)  5 (12)     Diarrhea  2 (11)  0 (0)  16 (24)  18 (23)  16 (24)  17 (26)     Financial worries  7 (18)  9 (24)  9 (19)  13 (26)  12 (25)  11 (28)  QLQ-OES24                 Eating problems  29 (27)  33 (28)  24 (21)  29 (27)  20 (20)  22 (23)     Emotional problemsa  36 (25)  48 (18)  29 (20)  33 (23)  29 (22)  25 (24)     Dysphagia  74 (33)  63 (35)  83 (28)  69 (38)  82 (31)  76 (36)     Deglutition  16 (27)  9 (16)  16 (26)  13 (19)  12 (20)  18 (22)     Swallowing of saliva  18 (34)  11 (23)  14 (30)  10 (22)  10 (25)  17 (32)     Aspiration  14 (27)  7 (14)  18 (28)  16 (23)  13 (24)  18 (25)     GI symptoms (24)a  16 (19)  21 (16)  21 (22)  25 (25)  20 (19)  25 (30)     GI symptoms (18)  10 (20)  7 (13)  19 (26)  22 (27)  19 (24)  26 (32)     Pain  16 (20)  23 (27)  8 (14)  9 (15)  8 (16)  7 (11)     Dry mouth  8 (21)  12 (19)  17 (25)  14 (23)  17 (25)  13 (24)     Trouble with taste  7 (19)  9 (24)  9 (21)  8 (14)  8 (20)  8 (23)     Trouble with coughing  13 (21)  12 (21)  17 (21)  20 (21)  17 (24)  18 (27)     Trouble with speaking  4 (17)  0 (0)  12 (27)  10 (26)  9 (22)  11 (22)     Hair lossa  0 (0)  0 (0)  13 (17)  33 (33)  8 (23)  0 (0)  Scores are presented as mean. Standard deviations are shown between parentheses. a Domains were removed after validation and refinement of the QLQ-OES24 into the QLQ-OES18 questionnaire. EORTC, European organization for research and treatment of cancer. Table 4. Mean scores for all domains in the K-BILD questionnaire according to treatment group   >6 years postoperatively     nCRT plus surgery  Surgery alone  P-value  Psychologic symptoms  86 (19)  87 (17)  0.95  Breathlessness and activity  73 (23)  77 (23)  0.41  Chest symptoms  89 (17)  93 (16)  0.24  Total  81 (18)  83 (17)  0.69    >6 years postoperatively     nCRT plus surgery  Surgery alone  P-value  Psychologic symptoms  86 (19)  87 (17)  0.95  Breathlessness and activity  73 (23)  77 (23)  0.41  Chest symptoms  89 (17)  93 (16)  0.24  Total  81 (18)  83 (17)  0.69  Primary end points Pretreatment, there were no statistically significant differences in physical functioning between both groups (P = 0.32). Effects over time were comparable in both groups (P = 0.46). Physical functioning had declined 12 months after surgery compared with baseline (−6, P < 0.001; CD −0.37, 95% CI −0.58 to − 0.16), and stayed stable during long-term follow-up (−3, P = 0.10; CD −0.19, 95% CI −0.42 to 0.04, Figure 1A). Figure 1. View largeDownload slide Mean scores with standard deviations for (A) physical functioning, (B) eating problems (primary end points), (C) global quality of life and (D) fatigue (secondary end points) according to treatment allocations. Figure 1. View largeDownload slide Mean scores with standard deviations for (A) physical functioning, (B) eating problems (primary end points), (C) global quality of life and (D) fatigue (secondary end points) according to treatment allocations. Baseline eating problems scores and overall changes over time were comparable in both groups (P = 0.52, P = 0.90, respectively). Twelve months postoperatively, eating problems were comparable to baseline (−4, P = 0.24; CD −0.18, 95% CI −0.48 to 0.12) and remained stable after long-term follow-up (−5, P = 0.09; CD −0.20, 95% CI −0.43 to 0.03). Compared with baseline, a significant improvement was reported after long-term follow-up (−9, P = 0.011; CD −0.37, 95% CI −0.66 to −0.09, Figure 1B). After long-time follow-up, there were no statistically significant differences in overall respiratory problems between both groups (P = 0.69; CD 0.08, 95%CI −0.32 to 0.48). Secondary end points No statistically significant differences in global quality of life were found at baseline (P = 0.35), and no differential effects between both groups over time-up were detected (P = 0.57). One year after surgery, scores were comparable to baseline (+2, P = 0.56; CD 0.08, 95%CI −0.20 to 0.37) and no statistically significant improvement was found after long-term follow-up compared with 12 months postoperatively (+2, P = 0.96; CD 0.01, 95%CI −0.24 to 0.26). Baseline fatigue levels were comparable in both groups (P = 0.60) and all effects over time were comparable between the groups (P = 0.48). One year after surgery, fatigue levels had worsened compared with baseline (+9, P < 0.001; CD 0.39, 95% CI 0.16–0.62), and remained stable during long-term follow-up (+2, P = 0.24; CD 0.12, 95%CI −0.08 to 0.31). Influence of missing baseline questionnaires In order to investigate the effect of missing baseline questionnaires, the availability of baseline questionnaires was included as control variable in a separate analysis. This did not influence the described trends in HRQOL trajectory (data not shown). Discussion There were no clinically relevant differential effects in HRQOL between long-term survivors of esophageal or esophagogastric junctional cancer treated with nCRT and surgery, compared with surgery alone. In both groups, eating problems improved compared with 1-year postoperative levels, whereas physical functioning, global HRQOL and fatigue remained at the same level. Physical functioning and fatigue were not restored to pretreatment levels and corresponding effect sizes were clinically relevant (CD −0.56 and 0.51, respectively). These results indicate a lasting impact of surgery, regardless of the use of nCRT. Earlier studies have shown that adding nCRT to surgery does not adversely impact postoperative HRQOL. However, most of these studies have been criticized by their non-randomized designs and small sample sizes, which make them prone for selection bias and limit their ability to detect small but potentially clinically relevant differences [7−9]. Methodological strengths of the current study include its randomized design and low attrition rate after long-term follow-up, thereby minimizing the risks of selection and attrition bias. Furthermore, the availability of pretreatment and 1-year postoperative data enabled investigation of change trajectories. Notably, none of the previous studies focused on long-term follow-up [7−9]. Late side-effects of radiotherapy can develop years after initial treatment, with the lungs being the most radiosensitive organ in the chest. Symptomatic radiotherapy-induced pulmonary fibrosis is reported in up to 10% of patients after thoracic radiotherapy. Its incidence depends on the total radiation dose, the irradiated lung volume and the use of chemotherapy. Especially concurrent chemotherapy is associated with an increased incidence of (chemo-)radiotherapy induced pulmonary fibrosis. Symptoms include dyspnea, chest pain, cough, malaise and weight loss, which may exert profound effects on HRQOL, thereby underlining the relevance of effect studies [10]. The finding that adding nCRT to surgery does not adversely impact postoperative HRQOL, confirms the relatively low toxicity of the CROSS regimen [2, 6]. Interestingly, an earlier study found a lasting impairment in physical functioning and dyspnea after chemoradiotherapy, compared with surgery alone. These conflicting results can be explained by the higher dose of radiotherapy (66 Gy) and the more toxic chemotherapeutic agents that were applied in that study (5-FU/cisplatinum) [19]. It should be noted that novel radiotherapy techniques applied in the CROSS trial have likely also reduced therapy-related complications. Besides the improvement in survival, the absent impact on HRQOL is an important argument to apply the CROSS regimen as regimen of first choice [3]. Although no impact of nCRT on HRQOL was apparent, both treatment groups experienced long-lasting impact of esophagectomy on HRQOL. The reported deterioration in physical functioning and fatigue might also be explained by increasing age. However, studies that used a matched reference population also reported reduced long-term HRQOL [20, 21]. Moreover, pretreatment HRQOL data were obtained after patients had been confronted with the diagnosis of esophageal cancer, when they already were suffering from disease symptoms and were psychologically affected by their recent diagnosis. Consequently, pretreatment HRQOL levels probably represent an underestimation of patients’ HRQOL levels before diagnosis, thereby further emphasizing the (negative) impact of esophagectomy. The lasting deterioration in HRQOL is in line with earlier studies [5, 21, 22]. Our short-term analysis on all included patients showed impaired physical functioning and fatigue 1 year after surgery [6]. The current analysis in long-term survivors shows comparable results, indicating that these symptoms last. This suggests that impairment cannot be attributed to a selected group of patients (e.g. patients with subclinical disease recurrence), as was suggested earlier [20]. A recent study investigated HRQOL in patients who were alive 10 years after surgical treatment. Although these patients underwent primary surgery, results are in line with those of the current study, showing that long-term HRQOL remains substantially impaired [21]. These findings not only call for long-term supportive care including long-lasting rehabilitation such as cognitive behavior therapy for patients with lasting fatigue [23], but also for new treatment strategies with optimal preservation of HRQOL. Definitive chemoradiotherapy without esophagectomy has been evaluated for patients with squamous cell carcinoma. Locoregional recurrence rates and long-term survival were found to be inferior, when compared with (nCRT followed by) surgery. Therefore, definitive chemoradiotherapy with active surveillance and salvage surgery for non-responders is a treatment option [4]. Furthermore, the effects of minimally invasive and hybrid surgical techniques, and an active surveillance strategy after nCRT (instead of standard esophagectomy) on HRQOL should be investigated [24, 25]. Limitations of the current study include its relatively small sample size. This is inevitable in long-term follow-up studies investigating diseases with poor survival. The current study provides the largest available dataset on long-term HRQOL after nCRT, and its sample size has sufficient power to detect clinically relevant differences. Nevertheless, the ability of this dataset to capture long-term complications that are present in a minority of patients is limited. Patients in the nCRT-group were slightly older than patients in the surgery alone group. However, survivors were selected from randomized groups with similar baseline characteristics, suggesting that this difference in age is a result of the experimental treatment (nCRT), rather than of selection bias [2, 3]. Moreover, it does not seem plausible that the higher age has positively influenced HRQOL. Furthermore, patients completed questionnaires at one point in time, which introduced different follow-up times between patients who were included at different time points. However, there were no differences in median follow-up time between both groups and it is unlikely that treatment-related HRQOL still changes substantially after more than 6 years of follow-up. Therefore, we feel that the effect of differences in follow-up duration on HRQOL outcome is negligible. Since this trial included relatively few patients with poor performance status (patients with WHO >2 were excluded) and high age (patients >75 years were also excluded), the results cannot be extrapolated to other categories of more vulnerable patients. The effect of the CROSS regimen on (long term) HRQOL in more vulnerable subgroups of patients remains to be investigated. Finally, the EORTC-QLQ-OES24 has been revised into the EORTC-QLQ-OES18, with refinement of the hypothesized scales and removal of two single items [13]. To allow for comparison with baseline and 12 months postoperative questionnaires, we used the EORTC-QLQ-OES24. We believe that this did not limit the validity of the results, because the eating problems domain was retained in its original form. In conclusion, no impact of nCRT is apparent on long-term HRQOL compared with surgery alone. In addition to the improvement in long-term survival and the absent impact on postoperative recovery, these results support the view that nCRT can be considered as a standard care for patients with locally advanced esophageal or esophagogastric junctional cancer. Funding Dutch Cancer Foundation (KWF Kankerbestrijding, no grant number applicable). Disclosure EWS: Royalties from Springer for book on prediction models. JJBvL: Dutch Cancer Foundation (KWF Kankerbestrijding), the Coolsingel Stichting, Erasmus MC/MRace fund. All remaining authors have declared no conflicts of interest. References 1 Sjoquist KM, Burmeister BH, Smithers BM et al.   Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol  2011; 12( 7): 681– 692. Google Scholar CrossRef Search ADS PubMed  2 van Hagen P, Hulshof MC, van Lanschot JJ et al.   Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med  2012; 366( 22): 2074– 2084. Google Scholar CrossRef Search ADS PubMed  3 Shapiro J, van Lanschot JJ, Hulshof MC et al.   Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol  2015; 16( 9): 1090– 1098. Google Scholar CrossRef Search ADS PubMed  4 Lordick F, Mariette C, Haustermans K et al.   Oesophageal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol  2016; 27(Suppl 5): v50– v57. Google Scholar CrossRef Search ADS   5 Scarpa M, Valente S, Alfieri R et al.   Systematic review of health-related quality of life after esophagectomy for esophageal cancer. World J Gastroenterol  2011; 17( 42): 4660– 4674. Google Scholar CrossRef Search ADS PubMed  6 Noordman BJ, Verdam MGE, Lagarde SM et al.   Impact of neoadjuvant chemoradiotherapy on health related quality of life in esopageal or junctional cancer: results from the randomized CROSS trial. J Clin Oncol  2017. 7 Blazeby JM, Sanford E, Falk SJ et al.   Health-related quality of life during neoadjuvant treatment and surgery for localized esophageal carcinoma. Cancer  2005; 103( 9): 1791– 1799. Google Scholar CrossRef Search ADS PubMed  8 Hauser C, Patett C, von Schoenfels W et al.   Does neoadjuvant treatment before oncologic esophagectomy affect the postoperative quality of life? A prospective, longitudinal outcome study. Dis Esophagus  2015; 28( 7): 652– 659. Google Scholar CrossRef Search ADS PubMed  9 Reynolds JV, McLaughlin R, Moore J et al.   Prospective evaluation of quality of life in patients with localized oesophageal cancer treated by multimodality therapy or surgery alone. Br J Surg  2006; 93( 9): 1084– 1090. Google Scholar CrossRef Search ADS PubMed  10 Abratt RP, Morgan GW, Silvestri G, Willcox P. Pulmonary complications of radiation therapy. Clin Chest Med  2004; 25( 1): 167– 177. Google Scholar CrossRef Search ADS PubMed  11 Sobin LH, Gospodarowicz MK, Wittekind C et al.   TNM Classification of Malignant Tumors . New York: Wiley-Liss 2002. 12 Aaronson NK, Ahmedzai S, Bergman B et al.   The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst  1993; 85( 5): 365– 376. Google Scholar CrossRef Search ADS PubMed  13 Blazeby JM, Conroy T, Hammerlid E et al.   Clinical and psychometric validation of an EORTC questionnaire module, the EORTC QLQ-OES18, to assess quality of life in patients with oesophageal cancer. Eur J Cancer . 2003; 39( 10): 1384– 1394. Google Scholar CrossRef Search ADS PubMed  14 Patel AS, Siegert RJ, Brignall K et al.   The development and validation of the King's Brief Interstitial Lung Disease (K-BILD) health status questionnaire. Thorax  2012; 67( 9): 804– 810. Google Scholar CrossRef Search ADS PubMed  15 Fayers PM, Aaronson NK, Bjordal K et al.   The EORTC QLQ-C30 Scoring Manual , 3rd edition. Brussels: European Organisation for Research and Treatment of Cancer 2001. 16 Twisk J, de Vente W. Attrition in longitudinal studies. How to deal with missing data. J Clin Epidemiol  2002; 55( 4): 329– 337. Google Scholar CrossRef Search ADS PubMed  17 Cohen J, Statistical Power Analysis for the Behavorial Sciences . Hillsdale, NJ: Erlbaum 1988. 18 Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care  2003; 41( 5): 582– 592. Google Scholar PubMed  19 Hurmuzlu M, Aarstad HJ, Aarstad AK et al.   Health-related quality of life in long-term survivors after high-dose chemoradiotherapy followed by surgery in esophageal cancer. Dis Esophagus  2011; 24( 1): 39– 47. Google Scholar CrossRef Search ADS PubMed  20 Derogar M, Lagergren P. Health-related quality of life among 5-year survivors of esophageal cancer surgery: a prospective population-based study. J Clin Oncol  2012; 30: 413– 418. Google Scholar CrossRef Search ADS PubMed  21 Schandl A, Lagergren J, Johar A, Lagergren P. Health-related quality of life 10 years after oesophageal cancer surgery. Eur J Cancer  2016; 69: 43– 50. Google Scholar CrossRef Search ADS PubMed  22 Lagergren P, Avery KN, Hughes R et al.   Health-related quality of life among patients cured by surgery for esophageal cancer. Cancer  2007; 110( 3): 686– 693. Google Scholar CrossRef Search ADS PubMed  23 Gielissen MF, Verhagen S, Witjes F, Bleijenberg G. Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol  2006; 24: 4882– 4887. Google Scholar CrossRef Search ADS PubMed  24 Putora PM, Bedenne L, Budach W et al.   Oesophageal cancer: exploring controversies overview of experts' opinions of Austria, Germany, France, Netherlands and Switzerland. Radiat Oncol  2015; 10( 1): 116. Google Scholar CrossRef Search ADS PubMed  25 Noordman BJ, Shapiro J, Spaander MC et al.   Accuracy of detecting residual disease after CROSS neoadjuvant chemoradiotherapy for esophageal cancer (preSANO Trial): rationale and protocol. JMIR Res Protoc  2015; 4: e79. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Impact of neoadjuvant chemoradiotherapy on health-related quality of life in long-term survivors of esophageal or junctional cancer: results from the randomized CROSS trial

Loading next page...
 
/lp/ou_press/impact-of-neoadjuvant-chemoradiotherapy-on-health-related-quality-of-hXlLPS9TCB
Publisher
Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
eISSN
1569-8041
D.O.I.
10.1093/annonc/mdx726
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone. Patients and methods Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4-Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30). Results After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen’s d −0.37, P = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen’s d −0.56 and 0.51, respectively, both P < 0.001). Conclusions Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care. Trial registration number Netherlands Trial Register NTR487. esophageal cancer, neoadjuvant chemoradiotherapy, health-related quality of life Key Message In addition to the earlier described improvement in overall and disease-free survival and the absent impact on early recovery, this study indicates that neoadjuvant chemoradiotherapy plus surgery does not impact long-term HRQOL, compared with surgery alone. This supports the view that this multimodality treatment can be considered as a standard of care for patients with esophageal cancer. Introduction Esophageal cancer is characterized by frequent locoregional and distant recurrence. The 5-year overall survival rate rarely exceeds 40% after primary surgery. In order to improve locoregional control and overall survival, neoadjuvant chemo(radio)therapy has been investigated in many clinical trials [1]. The ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial compared a carboplatin and paclitaxel based neoadjuvant chemoradiotherapy (nCRT) regimen plus surgery with surgery alone. Eight centers in the Netherlands participated. After a minimum follow-up of 5 years, a clinically relevant and statistically significant benefit in overall- and progression-free survival rates was shown for the multimodality group. Treatment-related toxicity and postoperative complication rate were acceptable [2, 3]. Based on these results, nCRT followed by surgery according to the CROSS regimen is a standard care in many countries [4]. The increasing emphasis on patient-reported outcome measures and health-related quality of life (HRQOL) leads to a more prominent role of these measures as end points in clinical trials. Thus far, HRQOL has received limited attention in the field of esophageal cancer, but the wide introduction of nCRT and the associated increased survival emphasize the need for high-quality HRQOL data from these patients. It is known that esophagectomy has profound and lasting impact on patients’ HRQOL [5, 6]. The short-term HRQOL analysis of the CROSS trial (follow-up ≤1 year) showed that adding nCRT to surgery does not adversely impact postoperative HRQOL [6], which is in line with results from earlier retrospective studies [7–9]. However, follow-up of these studies did not exceed 24 months [6–9]. Importantly, side-effects of radiotherapy can develop years after treatment, with the lungs being the most radiosensitive organ in the chest [10]. Therefore, long-term HRQOL data from patients treated with nCRT plus surgery are desired. The aim of this sub-study of the CROSS trial was to compare HRQOL in long-term survivors (>6 years) who received nCRT plus surgery or surgery alone. Methods Details of this randomized trial have been reported previously [2, 3]. Briefly, patients with locally advanced (clinical stage T1N1M0 or T2-3N0-1M0, 6th edition of the Union for International Cancer Control TNM cancer staging) [11] esophageal or esophagogastric junctional squamous cell carcinoma or adenocarcinoma were eligible. Patients were randomized between nCRT plus surgery and surgery alone. The study protocol was approved by the ethical committees of the participating centers, and ethical approval for long-term HRQOL measurement was provided by the medical ethical committee of the Erasmus MC. All included patients provided written informed consent. Procedures Patients assigned to nCRT were treated with carboplatin (AUC 2 mg/ml/min) and paclitaxel (50 mg/m2 of body-surface area) for five weekly cycles. Concomitant radiation therapy was given in 23 fractions of 1.8 Gy (41.4 Gy total). Patients assigned to surgery alone were operated as soon as possible, whereas patients in the nCRT group underwent surgery 4–6 weeks after completion of nCRT. Patients with carcinomas at or above the level of the carina underwent a transthoracic esophagectomy with two-field lymphadenectomy, whereas patients with carcinomas below the carina, either had a transthoracic esophagectomy with two-field lymphadenectomy or had a transhiatal esophagectomy with upper abdominal and lower mediastinal lymphadenectomy, depending on patient characteristics and local preferences. For patients with carcinomas involving the esophagogastric junction, a transhiatal esophagectomy was recommended. HRQOL measurement Cancer-specific HRQOL was assessed using the EORTC-QLQ-C30, a validated self-completed questionnaire designed for cancer patients [12]. Tumor-specific HRQOL was assessed using the EORTC-QLQ-OES24 self-completed questionnaire [13]. The EORTC-QLQ-OES24 was used to allow for comparison with baseline and 12 months postoperative questionnaires, as the currently used derivative, EORTC QLQ-OES18, was not available at that time. During long-term follow-up assessment, the K-BILD questionnaire was added to assess pulmonary effects of radiotherapy. The K-BILD is a self-completed validated questionnaire for interstitial lung disease patients [14]. The self-completed questionnaires were mailed to all patients who were alive after a minimum follow-up of 6 years after surgery. Patients who had not completed the questionnaires within 1 month were reminded two times by telephone. To allow for examination of HRQOL over time, questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores from the earlier short-term HRQOL study (follow-up ≤1 year after surgery) [6]. Before the analysis, end points were predefined by consensus discussion with experienced medical oncologists, upper-GI surgical oncologists and nurse practitioners. End points were defined based on clinical relevance and hypothesized relation with long-term outcome of nCRT. Primary end points were physical functioning (QLQ-C30), eating problems (QLQ-OES24) and total respiratory problems (K-BILD). Secondary end points were global quality of life and fatigue (both QLQ-C30). Statistical analysis Patients who were alive during long-term follow-up assessment (July 2015) were included in the analysis. Pretreatment patient characteristics were compared using Student’s t-test or Mann–Whitney U test for continuous characteristics, whereas χ2 test or Fisher’s exact test was used for comparison of categorical characteristics. Questionnaire scale scores were transformed into a 0–100 scale as was described previously [14, 15]. Baseline (questionnaire) scores of the two treatment groups were compared using Student’s t test. Over-time differential effects between the treatment groups and longitudinal differences of the follow-up measurements were investigated using mixed modeling analysis. If no statistically significant differential effects were found between both groups, results of the combined groups are reported. Mixed modeling allows for inclusion of questionnaires from subjects with different numbers of completed measurements and thereby enables analysis of all available data [16]. Hence, all available questionnaires were included in the analyses. Mean changes between groups and over time differential effects were described. Cohen’s d (CD) effect sizes were calculated to assess clinical relevance of the effects and to enable standardized comparison between different outcome variables. CD effect sizes were derived from the β-estimates in the mixed modeling procedure. CD values of 0.2, 0.5 and 0.8 reflect small, medium and large effects, respectively [17]. Values >0.5 indicate clinically relevant effects [18]. As multiple comparisons correction, P < 0.025 was considered statistically significant for the mixed models analyses (the main analyses included two comparisons and thus a Bonferroni correction of 0.05/2 was applied), whereas P < 0.05 was considered statistically significant for clinical characteristics and baseline score comparisons. All P-values are two-sided. Data were analyzed using SPSS version 21.0. Results Of the 368 patients included in the CROSS trial, 123 (33%) were still alive (70 nCRT plus surgery, 53surgery alone). Median follow-up was 105 months. Patients in the nCRT group were older, but there were no other statistically significant differences in pretreatment clinicopathologic characteristics between the groups (Table 1). The majority of patients was male (76% and 77%, respectively), most patients had an adenocarcinoma (73% and 76%, respectively) and most tumors were clinically staged as cT3 (77% and 76%, respectively). Most patients had suspected locoregional lymph node metastases (54% and 69%, respectively). Due to an administrative error, 32 of the long-term survivors did not receive baseline HRQOL questionnaires. These patients were not excluded from the analysis, because their pretreatment characteristics were not significantly different from the total study group (data not shown), and follow-up questionnaires were correctly mailed and completed [6]. Table 1. Clinicopathologic characteristics of patients with potentially curable esophageal or esophagogastric junction cancer, according to treatment allocationa Characteristic  nCRT plus surgery  Surgery alone  P-value  (N = 70)  (N = 53)  Follow-up—months        Median  104  105  0.635   IQ range  90–116  87–117    Age at randomization—yr.         Median  60  57  0.024   IQ range  55–65  51–62    Male sex—no. (%)  53 (76)  41 (77)  0.832  Tumor type—no. (%)      0.205   Adenocarcinoma  51 (73)  40 (76)     Squamous cell carcinoma  19 (27)  11 (21)     Other  0  2 (4)    Tumor location—no. (%)b      0.571   Esophagus         Proximal and middle third  12 (18)  6 (12)     Distal third  36 (54)  32 (62)     Esophagogastric junction  19 (28)  14 (27)     Missing data  3  1    Clinical T stage—no. (%)c      0.965   cT1/cT2  16 (23)  12 (24)     cT3  53 (77)  39 (76)     Could not be determinedd  1  2    Clinical N stage—no. (%)e      0.116   N0  31 (46)  16 (31)     N1  37 (54)  35 (69)    Could not be determinedd  2  2    WHO performance status—no. (%)f      0.425   0  57 (81)  46 (87)     1  13 (19)  7 (13)    Characteristic  nCRT plus surgery  Surgery alone  P-value  (N = 70)  (N = 53)  Follow-up—months        Median  104  105  0.635   IQ range  90–116  87–117    Age at randomization—yr.         Median  60  57  0.024   IQ range  55–65  51–62    Male sex—no. (%)  53 (76)  41 (77)  0.832  Tumor type—no. (%)      0.205   Adenocarcinoma  51 (73)  40 (76)     Squamous cell carcinoma  19 (27)  11 (21)     Other  0  2 (4)    Tumor location—no. (%)b      0.571   Esophagus         Proximal and middle third  12 (18)  6 (12)     Distal third  36 (54)  32 (62)     Esophagogastric junction  19 (28)  14 (27)     Missing data  3  1    Clinical T stage—no. (%)c      0.965   cT1/cT2  16 (23)  12 (24)     cT3  53 (77)  39 (76)     Could not be determinedd  1  2    Clinical N stage—no. (%)e      0.116   N0  31 (46)  16 (31)     N1  37 (54)  35 (69)    Could not be determinedd  2  2    WHO performance status—no. (%)f      0.425   0  57 (81)  46 (87)     1  13 (19)  7 (13)    a Percentages may not add up to 100 because of rounding. WHO denotes World Health Organization. b Tumor length and location were determined by means of endoscopy. c Clinical tumor (cT) stage was assessed by means of endoscopic ultrasonography or computed tomography (CT) and was classified according to the International Union against Cancer (UICC) tumor-node-metastasis (TNM) classification, 6th edition. d This category included patients in whom the tumor could not be fully investigated by means of a transducer for endoscopic ultrasonography owing to a stenosis caused by the tumor. e Clinical lymph node (N) stage was assessed by means of endoscopic ultrasonography, CT or 18F-fluorodeoxyglucose positron-emission tomography and was classified according to UICC TNM classification, 6th edition. f WHO performance status scores are on a scale of 0–5, with lower numbers indicating better performance status; 0 indicates fully active, and 1 unable to carry out heavy physical work. Bold values reflect statistically significantly differences. Overall response rate to the HRQOL questionnaires in the 123 long-term survivors was 89% (Table 2). In the nCRT-group response rate was 94%, whereas in the surgery alone group this was 83% (P = 0.07). Mean scores of all HRQOL domains of the EORTC-questionnaires and K-BILD questionnaire are reported in Tables 3 and 4, respectively. Table 2. Patients’ eligible for quality-of-life assessment, returning the quality-of-life questionnaire, deceased, not returning the quality-of-life questionnaire because they were too ill or because of random reasons at each measurement point Status  Pretreatment  12 months postoperatively  Long-term follow-up (>6 years postoperatively)  Eligible  123  123  123   nCRT+surgery  70  70  70   Surgery alone  53  53  53  Returned total (% of eligible)  83 (67)  79 (64)  110 (89)   nCRT+surgery (%)  57 (81)  49 (70)  66 (94)   Surgery alone (%)  26 (49)  30 (57)  44 (83)  Deceased  N/A  N/A  N/A  Too ill  0  1  1  Randomly missing/other  40a  43  12  Status  Pretreatment  12 months postoperatively  Long-term follow-up (>6 years postoperatively)  Eligible  123  123  123   nCRT+surgery  70  70  70   Surgery alone  53  53  53  Returned total (% of eligible)  83 (67)  79 (64)  110 (89)   nCRT+surgery (%)  57 (81)  49 (70)  66 (94)   Surgery alone (%)  26 (49)  30 (57)  44 (83)  Deceased  N/A  N/A  N/A  Too ill  0  1  1  Randomly missing/other  40a  43  12  a Of whom 32 due to administrative error. Table 3. Mean scores for all domains in the two EORTC questionnaires according to treatment group   Pretreatment   12 months postoperatively   Long-term follow-up (>6 years postoperatively)     nCRT plus surgery  Surgery alone  nCRT plus surgery  Surgery alone  nCRT plus surgery  Surgery alone  QLQ-C30                 Global quality of life  76 (19)  73 (15)  76 (17)  77 (22)  76 (22)  78 (19)  Functional scales                 Physical  96 (9)  94 (8)  89 (16)  91 (10)  86 (16)  86 (20)     Role  88 (27)  85 (22)  80 (25)  78 (23)  82 (24)  82 (25)     Emotional  68 (24)  67 (18)  86 (17)  79 (20)  87 (18)  84 (22)     Cognitive  92 (17)  85 (19)  88 (18)  83 (19)  85 (19)  84 (20)     Social  85 (23)  81 (21)  90 (16)  78 (24)  87 (20)  80 (24)  Symptom scores                 Fatigue  13 (17)  16 (21)  25 (20)  20 (15)  27 (22)  22 (24)     Nausea and vomiting  5 (11)  6 (12)  11 (16)  15 (20)  7 (14)  10 (21)     Pain  12 (19)  14 (22)  6 (11)  18 (20)  10 (20)  10 (17)     Dyspnea  5 (12)  2 (9)  16 (22)  11 (18)  19 (25)  14 (21)     Insomnia  23 (26)  20 (31)  14 (23)  16 (25)  20 (27)  20 (27)     Loss of appetite  10 (24)  7 (17)  10 (19)  10 (18)  12 (23)  15 (28)     Constipation  8 (19)  1 (6)  8 (20)  11 (20)  10 (17)  5 (12)     Diarrhea  2 (11)  0 (0)  16 (24)  18 (23)  16 (24)  17 (26)     Financial worries  7 (18)  9 (24)  9 (19)  13 (26)  12 (25)  11 (28)  QLQ-OES24                 Eating problems  29 (27)  33 (28)  24 (21)  29 (27)  20 (20)  22 (23)     Emotional problemsa  36 (25)  48 (18)  29 (20)  33 (23)  29 (22)  25 (24)     Dysphagia  74 (33)  63 (35)  83 (28)  69 (38)  82 (31)  76 (36)     Deglutition  16 (27)  9 (16)  16 (26)  13 (19)  12 (20)  18 (22)     Swallowing of saliva  18 (34)  11 (23)  14 (30)  10 (22)  10 (25)  17 (32)     Aspiration  14 (27)  7 (14)  18 (28)  16 (23)  13 (24)  18 (25)     GI symptoms (24)a  16 (19)  21 (16)  21 (22)  25 (25)  20 (19)  25 (30)     GI symptoms (18)  10 (20)  7 (13)  19 (26)  22 (27)  19 (24)  26 (32)     Pain  16 (20)  23 (27)  8 (14)  9 (15)  8 (16)  7 (11)     Dry mouth  8 (21)  12 (19)  17 (25)  14 (23)  17 (25)  13 (24)     Trouble with taste  7 (19)  9 (24)  9 (21)  8 (14)  8 (20)  8 (23)     Trouble with coughing  13 (21)  12 (21)  17 (21)  20 (21)  17 (24)  18 (27)     Trouble with speaking  4 (17)  0 (0)  12 (27)  10 (26)  9 (22)  11 (22)     Hair lossa  0 (0)  0 (0)  13 (17)  33 (33)  8 (23)  0 (0)    Pretreatment   12 months postoperatively   Long-term follow-up (>6 years postoperatively)     nCRT plus surgery  Surgery alone  nCRT plus surgery  Surgery alone  nCRT plus surgery  Surgery alone  QLQ-C30                 Global quality of life  76 (19)  73 (15)  76 (17)  77 (22)  76 (22)  78 (19)  Functional scales                 Physical  96 (9)  94 (8)  89 (16)  91 (10)  86 (16)  86 (20)     Role  88 (27)  85 (22)  80 (25)  78 (23)  82 (24)  82 (25)     Emotional  68 (24)  67 (18)  86 (17)  79 (20)  87 (18)  84 (22)     Cognitive  92 (17)  85 (19)  88 (18)  83 (19)  85 (19)  84 (20)     Social  85 (23)  81 (21)  90 (16)  78 (24)  87 (20)  80 (24)  Symptom scores                 Fatigue  13 (17)  16 (21)  25 (20)  20 (15)  27 (22)  22 (24)     Nausea and vomiting  5 (11)  6 (12)  11 (16)  15 (20)  7 (14)  10 (21)     Pain  12 (19)  14 (22)  6 (11)  18 (20)  10 (20)  10 (17)     Dyspnea  5 (12)  2 (9)  16 (22)  11 (18)  19 (25)  14 (21)     Insomnia  23 (26)  20 (31)  14 (23)  16 (25)  20 (27)  20 (27)     Loss of appetite  10 (24)  7 (17)  10 (19)  10 (18)  12 (23)  15 (28)     Constipation  8 (19)  1 (6)  8 (20)  11 (20)  10 (17)  5 (12)     Diarrhea  2 (11)  0 (0)  16 (24)  18 (23)  16 (24)  17 (26)     Financial worries  7 (18)  9 (24)  9 (19)  13 (26)  12 (25)  11 (28)  QLQ-OES24                 Eating problems  29 (27)  33 (28)  24 (21)  29 (27)  20 (20)  22 (23)     Emotional problemsa  36 (25)  48 (18)  29 (20)  33 (23)  29 (22)  25 (24)     Dysphagia  74 (33)  63 (35)  83 (28)  69 (38)  82 (31)  76 (36)     Deglutition  16 (27)  9 (16)  16 (26)  13 (19)  12 (20)  18 (22)     Swallowing of saliva  18 (34)  11 (23)  14 (30)  10 (22)  10 (25)  17 (32)     Aspiration  14 (27)  7 (14)  18 (28)  16 (23)  13 (24)  18 (25)     GI symptoms (24)a  16 (19)  21 (16)  21 (22)  25 (25)  20 (19)  25 (30)     GI symptoms (18)  10 (20)  7 (13)  19 (26)  22 (27)  19 (24)  26 (32)     Pain  16 (20)  23 (27)  8 (14)  9 (15)  8 (16)  7 (11)     Dry mouth  8 (21)  12 (19)  17 (25)  14 (23)  17 (25)  13 (24)     Trouble with taste  7 (19)  9 (24)  9 (21)  8 (14)  8 (20)  8 (23)     Trouble with coughing  13 (21)  12 (21)  17 (21)  20 (21)  17 (24)  18 (27)     Trouble with speaking  4 (17)  0 (0)  12 (27)  10 (26)  9 (22)  11 (22)     Hair lossa  0 (0)  0 (0)  13 (17)  33 (33)  8 (23)  0 (0)  Scores are presented as mean. Standard deviations are shown between parentheses. a Domains were removed after validation and refinement of the QLQ-OES24 into the QLQ-OES18 questionnaire. EORTC, European organization for research and treatment of cancer. Table 4. Mean scores for all domains in the K-BILD questionnaire according to treatment group   >6 years postoperatively     nCRT plus surgery  Surgery alone  P-value  Psychologic symptoms  86 (19)  87 (17)  0.95  Breathlessness and activity  73 (23)  77 (23)  0.41  Chest symptoms  89 (17)  93 (16)  0.24  Total  81 (18)  83 (17)  0.69    >6 years postoperatively     nCRT plus surgery  Surgery alone  P-value  Psychologic symptoms  86 (19)  87 (17)  0.95  Breathlessness and activity  73 (23)  77 (23)  0.41  Chest symptoms  89 (17)  93 (16)  0.24  Total  81 (18)  83 (17)  0.69  Primary end points Pretreatment, there were no statistically significant differences in physical functioning between both groups (P = 0.32). Effects over time were comparable in both groups (P = 0.46). Physical functioning had declined 12 months after surgery compared with baseline (−6, P < 0.001; CD −0.37, 95% CI −0.58 to − 0.16), and stayed stable during long-term follow-up (−3, P = 0.10; CD −0.19, 95% CI −0.42 to 0.04, Figure 1A). Figure 1. View largeDownload slide Mean scores with standard deviations for (A) physical functioning, (B) eating problems (primary end points), (C) global quality of life and (D) fatigue (secondary end points) according to treatment allocations. Figure 1. View largeDownload slide Mean scores with standard deviations for (A) physical functioning, (B) eating problems (primary end points), (C) global quality of life and (D) fatigue (secondary end points) according to treatment allocations. Baseline eating problems scores and overall changes over time were comparable in both groups (P = 0.52, P = 0.90, respectively). Twelve months postoperatively, eating problems were comparable to baseline (−4, P = 0.24; CD −0.18, 95% CI −0.48 to 0.12) and remained stable after long-term follow-up (−5, P = 0.09; CD −0.20, 95% CI −0.43 to 0.03). Compared with baseline, a significant improvement was reported after long-term follow-up (−9, P = 0.011; CD −0.37, 95% CI −0.66 to −0.09, Figure 1B). After long-time follow-up, there were no statistically significant differences in overall respiratory problems between both groups (P = 0.69; CD 0.08, 95%CI −0.32 to 0.48). Secondary end points No statistically significant differences in global quality of life were found at baseline (P = 0.35), and no differential effects between both groups over time-up were detected (P = 0.57). One year after surgery, scores were comparable to baseline (+2, P = 0.56; CD 0.08, 95%CI −0.20 to 0.37) and no statistically significant improvement was found after long-term follow-up compared with 12 months postoperatively (+2, P = 0.96; CD 0.01, 95%CI −0.24 to 0.26). Baseline fatigue levels were comparable in both groups (P = 0.60) and all effects over time were comparable between the groups (P = 0.48). One year after surgery, fatigue levels had worsened compared with baseline (+9, P < 0.001; CD 0.39, 95% CI 0.16–0.62), and remained stable during long-term follow-up (+2, P = 0.24; CD 0.12, 95%CI −0.08 to 0.31). Influence of missing baseline questionnaires In order to investigate the effect of missing baseline questionnaires, the availability of baseline questionnaires was included as control variable in a separate analysis. This did not influence the described trends in HRQOL trajectory (data not shown). Discussion There were no clinically relevant differential effects in HRQOL between long-term survivors of esophageal or esophagogastric junctional cancer treated with nCRT and surgery, compared with surgery alone. In both groups, eating problems improved compared with 1-year postoperative levels, whereas physical functioning, global HRQOL and fatigue remained at the same level. Physical functioning and fatigue were not restored to pretreatment levels and corresponding effect sizes were clinically relevant (CD −0.56 and 0.51, respectively). These results indicate a lasting impact of surgery, regardless of the use of nCRT. Earlier studies have shown that adding nCRT to surgery does not adversely impact postoperative HRQOL. However, most of these studies have been criticized by their non-randomized designs and small sample sizes, which make them prone for selection bias and limit their ability to detect small but potentially clinically relevant differences [7−9]. Methodological strengths of the current study include its randomized design and low attrition rate after long-term follow-up, thereby minimizing the risks of selection and attrition bias. Furthermore, the availability of pretreatment and 1-year postoperative data enabled investigation of change trajectories. Notably, none of the previous studies focused on long-term follow-up [7−9]. Late side-effects of radiotherapy can develop years after initial treatment, with the lungs being the most radiosensitive organ in the chest. Symptomatic radiotherapy-induced pulmonary fibrosis is reported in up to 10% of patients after thoracic radiotherapy. Its incidence depends on the total radiation dose, the irradiated lung volume and the use of chemotherapy. Especially concurrent chemotherapy is associated with an increased incidence of (chemo-)radiotherapy induced pulmonary fibrosis. Symptoms include dyspnea, chest pain, cough, malaise and weight loss, which may exert profound effects on HRQOL, thereby underlining the relevance of effect studies [10]. The finding that adding nCRT to surgery does not adversely impact postoperative HRQOL, confirms the relatively low toxicity of the CROSS regimen [2, 6]. Interestingly, an earlier study found a lasting impairment in physical functioning and dyspnea after chemoradiotherapy, compared with surgery alone. These conflicting results can be explained by the higher dose of radiotherapy (66 Gy) and the more toxic chemotherapeutic agents that were applied in that study (5-FU/cisplatinum) [19]. It should be noted that novel radiotherapy techniques applied in the CROSS trial have likely also reduced therapy-related complications. Besides the improvement in survival, the absent impact on HRQOL is an important argument to apply the CROSS regimen as regimen of first choice [3]. Although no impact of nCRT on HRQOL was apparent, both treatment groups experienced long-lasting impact of esophagectomy on HRQOL. The reported deterioration in physical functioning and fatigue might also be explained by increasing age. However, studies that used a matched reference population also reported reduced long-term HRQOL [20, 21]. Moreover, pretreatment HRQOL data were obtained after patients had been confronted with the diagnosis of esophageal cancer, when they already were suffering from disease symptoms and were psychologically affected by their recent diagnosis. Consequently, pretreatment HRQOL levels probably represent an underestimation of patients’ HRQOL levels before diagnosis, thereby further emphasizing the (negative) impact of esophagectomy. The lasting deterioration in HRQOL is in line with earlier studies [5, 21, 22]. Our short-term analysis on all included patients showed impaired physical functioning and fatigue 1 year after surgery [6]. The current analysis in long-term survivors shows comparable results, indicating that these symptoms last. This suggests that impairment cannot be attributed to a selected group of patients (e.g. patients with subclinical disease recurrence), as was suggested earlier [20]. A recent study investigated HRQOL in patients who were alive 10 years after surgical treatment. Although these patients underwent primary surgery, results are in line with those of the current study, showing that long-term HRQOL remains substantially impaired [21]. These findings not only call for long-term supportive care including long-lasting rehabilitation such as cognitive behavior therapy for patients with lasting fatigue [23], but also for new treatment strategies with optimal preservation of HRQOL. Definitive chemoradiotherapy without esophagectomy has been evaluated for patients with squamous cell carcinoma. Locoregional recurrence rates and long-term survival were found to be inferior, when compared with (nCRT followed by) surgery. Therefore, definitive chemoradiotherapy with active surveillance and salvage surgery for non-responders is a treatment option [4]. Furthermore, the effects of minimally invasive and hybrid surgical techniques, and an active surveillance strategy after nCRT (instead of standard esophagectomy) on HRQOL should be investigated [24, 25]. Limitations of the current study include its relatively small sample size. This is inevitable in long-term follow-up studies investigating diseases with poor survival. The current study provides the largest available dataset on long-term HRQOL after nCRT, and its sample size has sufficient power to detect clinically relevant differences. Nevertheless, the ability of this dataset to capture long-term complications that are present in a minority of patients is limited. Patients in the nCRT-group were slightly older than patients in the surgery alone group. However, survivors were selected from randomized groups with similar baseline characteristics, suggesting that this difference in age is a result of the experimental treatment (nCRT), rather than of selection bias [2, 3]. Moreover, it does not seem plausible that the higher age has positively influenced HRQOL. Furthermore, patients completed questionnaires at one point in time, which introduced different follow-up times between patients who were included at different time points. However, there were no differences in median follow-up time between both groups and it is unlikely that treatment-related HRQOL still changes substantially after more than 6 years of follow-up. Therefore, we feel that the effect of differences in follow-up duration on HRQOL outcome is negligible. Since this trial included relatively few patients with poor performance status (patients with WHO >2 were excluded) and high age (patients >75 years were also excluded), the results cannot be extrapolated to other categories of more vulnerable patients. The effect of the CROSS regimen on (long term) HRQOL in more vulnerable subgroups of patients remains to be investigated. Finally, the EORTC-QLQ-OES24 has been revised into the EORTC-QLQ-OES18, with refinement of the hypothesized scales and removal of two single items [13]. To allow for comparison with baseline and 12 months postoperative questionnaires, we used the EORTC-QLQ-OES24. We believe that this did not limit the validity of the results, because the eating problems domain was retained in its original form. In conclusion, no impact of nCRT is apparent on long-term HRQOL compared with surgery alone. In addition to the improvement in long-term survival and the absent impact on postoperative recovery, these results support the view that nCRT can be considered as a standard care for patients with locally advanced esophageal or esophagogastric junctional cancer. Funding Dutch Cancer Foundation (KWF Kankerbestrijding, no grant number applicable). Disclosure EWS: Royalties from Springer for book on prediction models. JJBvL: Dutch Cancer Foundation (KWF Kankerbestrijding), the Coolsingel Stichting, Erasmus MC/MRace fund. All remaining authors have declared no conflicts of interest. References 1 Sjoquist KM, Burmeister BH, Smithers BM et al.   Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol  2011; 12( 7): 681– 692. Google Scholar CrossRef Search ADS PubMed  2 van Hagen P, Hulshof MC, van Lanschot JJ et al.   Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med  2012; 366( 22): 2074– 2084. Google Scholar CrossRef Search ADS PubMed  3 Shapiro J, van Lanschot JJ, Hulshof MC et al.   Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol  2015; 16( 9): 1090– 1098. Google Scholar CrossRef Search ADS PubMed  4 Lordick F, Mariette C, Haustermans K et al.   Oesophageal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol  2016; 27(Suppl 5): v50– v57. Google Scholar CrossRef Search ADS   5 Scarpa M, Valente S, Alfieri R et al.   Systematic review of health-related quality of life after esophagectomy for esophageal cancer. World J Gastroenterol  2011; 17( 42): 4660– 4674. Google Scholar CrossRef Search ADS PubMed  6 Noordman BJ, Verdam MGE, Lagarde SM et al.   Impact of neoadjuvant chemoradiotherapy on health related quality of life in esopageal or junctional cancer: results from the randomized CROSS trial. J Clin Oncol  2017. 7 Blazeby JM, Sanford E, Falk SJ et al.   Health-related quality of life during neoadjuvant treatment and surgery for localized esophageal carcinoma. Cancer  2005; 103( 9): 1791– 1799. Google Scholar CrossRef Search ADS PubMed  8 Hauser C, Patett C, von Schoenfels W et al.   Does neoadjuvant treatment before oncologic esophagectomy affect the postoperative quality of life? A prospective, longitudinal outcome study. Dis Esophagus  2015; 28( 7): 652– 659. Google Scholar CrossRef Search ADS PubMed  9 Reynolds JV, McLaughlin R, Moore J et al.   Prospective evaluation of quality of life in patients with localized oesophageal cancer treated by multimodality therapy or surgery alone. Br J Surg  2006; 93( 9): 1084– 1090. Google Scholar CrossRef Search ADS PubMed  10 Abratt RP, Morgan GW, Silvestri G, Willcox P. Pulmonary complications of radiation therapy. Clin Chest Med  2004; 25( 1): 167– 177. Google Scholar CrossRef Search ADS PubMed  11 Sobin LH, Gospodarowicz MK, Wittekind C et al.   TNM Classification of Malignant Tumors . New York: Wiley-Liss 2002. 12 Aaronson NK, Ahmedzai S, Bergman B et al.   The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst  1993; 85( 5): 365– 376. Google Scholar CrossRef Search ADS PubMed  13 Blazeby JM, Conroy T, Hammerlid E et al.   Clinical and psychometric validation of an EORTC questionnaire module, the EORTC QLQ-OES18, to assess quality of life in patients with oesophageal cancer. Eur J Cancer . 2003; 39( 10): 1384– 1394. Google Scholar CrossRef Search ADS PubMed  14 Patel AS, Siegert RJ, Brignall K et al.   The development and validation of the King's Brief Interstitial Lung Disease (K-BILD) health status questionnaire. Thorax  2012; 67( 9): 804– 810. Google Scholar CrossRef Search ADS PubMed  15 Fayers PM, Aaronson NK, Bjordal K et al.   The EORTC QLQ-C30 Scoring Manual , 3rd edition. Brussels: European Organisation for Research and Treatment of Cancer 2001. 16 Twisk J, de Vente W. Attrition in longitudinal studies. How to deal with missing data. J Clin Epidemiol  2002; 55( 4): 329– 337. Google Scholar CrossRef Search ADS PubMed  17 Cohen J, Statistical Power Analysis for the Behavorial Sciences . Hillsdale, NJ: Erlbaum 1988. 18 Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care  2003; 41( 5): 582– 592. Google Scholar PubMed  19 Hurmuzlu M, Aarstad HJ, Aarstad AK et al.   Health-related quality of life in long-term survivors after high-dose chemoradiotherapy followed by surgery in esophageal cancer. Dis Esophagus  2011; 24( 1): 39– 47. Google Scholar CrossRef Search ADS PubMed  20 Derogar M, Lagergren P. Health-related quality of life among 5-year survivors of esophageal cancer surgery: a prospective population-based study. J Clin Oncol  2012; 30: 413– 418. Google Scholar CrossRef Search ADS PubMed  21 Schandl A, Lagergren J, Johar A, Lagergren P. Health-related quality of life 10 years after oesophageal cancer surgery. Eur J Cancer  2016; 69: 43– 50. Google Scholar CrossRef Search ADS PubMed  22 Lagergren P, Avery KN, Hughes R et al.   Health-related quality of life among patients cured by surgery for esophageal cancer. Cancer  2007; 110( 3): 686– 693. Google Scholar CrossRef Search ADS PubMed  23 Gielissen MF, Verhagen S, Witjes F, Bleijenberg G. Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol  2006; 24: 4882– 4887. Google Scholar CrossRef Search ADS PubMed  24 Putora PM, Bedenne L, Budach W et al.   Oesophageal cancer: exploring controversies overview of experts' opinions of Austria, Germany, France, Netherlands and Switzerland. Radiat Oncol  2015; 10( 1): 116. Google Scholar CrossRef Search ADS PubMed  25 Noordman BJ, Shapiro J, Spaander MC et al.   Accuracy of detecting residual disease after CROSS neoadjuvant chemoradiotherapy for esophageal cancer (preSANO Trial): rationale and protocol. JMIR Res Protoc  2015; 4: e79. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve Freelancer

DeepDyve Pro

Price
FREE
$49/month

$360/year
Save searches from
Google Scholar,
PubMed
Create lists to
organize your research
Export lists, citations
Read DeepDyve articles
Abstract access only
Unlimited access to over
18 million full-text articles
Print
20 pages/month
PDF Discount
20% off