Background
Gastric cancer is the fifth most common malignancy worldwide and the fourth most common cause of cancer-related death.1 For patients from Western countries with gastric cancer, the prognosis remains poor after surgery alone, and most cancers recur within 2 years after treatment.2,3 Evidence-based strategies that have been shown to improve treatment outcomes include postoperative chemoradiotherapy (CRT), as shown in the US Intergroup 0116 trial, and perioperative chemotherapy, as reported in the British MAGIC trial.4–6 One of the most recent and largest Western trials in gastric cancer was the CRITICS trial (ClinicalTrials.org identifier: NCT00407186), which compared perioperative chemotherapy with preoperative chemotherapy and postoperative CRT in patients who underwent gastric cancer surgery with D2 lymphadenectomy.7 After a median follow-up of 61.4 months, no significant differences in overall survival (OS) and event-free survival (EFS) were found between these 2 treatment strategies.8
Assessing health-related quality of life (HRQoL) in clinical trials is increasingly important because it addresses the impact of treatment from the patient’s perspective. Recent studies by Basch et al9 and Denis et al10 have shown that the use of HRQoL and related patient-reported outcome measures in clinical practice can contribute to improved OS. A few studies in gastric cancer also investigated the prognostic value of baseline HRQoL for OS.11,12
Most studies reporting HRQoL in patients with gastric cancer have focused on the effects of surgery alone13 or were limited to patients with advanced and metastatic (esophago-)gastric cancer. No studies have investigated the impact of (neo)adjuvant chemo(radio)therapy on HRQoL treated with curative intent. The primary aim of this study was to compare HRQoL in patients with resectable gastric cancer who, in the context of the CRITICS trial, received either perioperative chemotherapy or preoperative chemotherapy followed by postoperative CRT. The second objective was to investigate whether baseline HRQoL has a potential role in predicting OS and EFS in patients with resectable gastric or esophagogastric adenocarcinoma.
Patients and Methods
Protocol
The CRITICS trial was a randomized multicenter phase III trial in which patients with stage Ib–IVa resectable gastric or esophagogastric adenocarcinoma (AJCC Cancer Staging Manual, 6th edition) from the Netherlands, Sweden, and Denmark (n=788) were randomly assigned to preoperative chemotherapy followed by surgery and either postoperative chemotherapy or CRT. HRQoL was a secondary endpoint in the trial. A detailed description of the protocol has been reported previously and is provided in the supplemental eAppendix 2 (available with this article at JNCCN.org).7
HRQoL Assessment
HRQoL questionnaires were completed at baseline, after preoperative chemotherapy, after surgery, after postoperative chemotherapy or CRT, and at 12-month follow-up. HRQoL was assessed using the EORTC Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30)14 and the Quality-of-Life Questionnaire gastric cancer–specific module (EORTC QLQ-STO22).15 The 30-item EORTC QLQ-C30 consists of 5 multi-item functioning scales (physical functioning, role functioning, cognitive functioning, emotional functioning, and social functioning), 3 multi-item symptom scales (fatigue, nausea and vomiting, and pain), 6 single-item symptom scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a 2-item global QoL scale. Following EORTC guidelines, the scores of the QLQ-C30 are linearly transformed to scales of 0 to 100. Higher scores correspond to improved functioning for functioning scales, whereas for symptom scales, higher scores indicate more symptoms or problems. The QLQ-C30 summary score was calculated as the mean of the combined 13 QLQ-C30 scale scores (financial impact and global QoL excluded).16,17 For the summary score, higher scores indicate better HRQoL. The EORTC QLQ-STO22 includes 22 items assessing condition-specific symptoms and adverse effects.
Predefined endpoints selected on the basis of clinical relevance included dysphagia (QLQ-STO22), pain (QLQ-STO22), physical functioning (QLQ-C30), fatigue (QLQ-C30), and QLQ-C30 summary score (QLQ-C30). Recently, Giesinger et al18 published thresholds for clinical importance (TCIs) to increase the interpretability of the QLQ-C30 and make it more useful for clinical practice. The TCIs for the different QLQ-C30 function scales are physical functioning = 83, role functioning = 58, social functioning = 58, emotional functioning = 71, and cognitive functioning = 75; the TCIs for the symptom scales are fatigue = 39, pain = 25, nausea and vomiting = 8, insomnia = 50, dyspnea = 17, appetite loss = 50, constipation = 50, diarrhea = 17, and financial impact = 17.18 Scores below the TCI for function scales and scores above the TCI for symptom scales indicate problems or symptoms of clinical importance.
Statistical Analysis
Data were analyzed on an intention-to-treat basis. Patient characteristics are presented as proportions: mean [SD] in case of a normal distribution or median (interquartile range) in case of a skewed distribution. Differences in baseline characteristics and HRQoL were compared using independent-sample t tests (continuous variables) and chi-square tests (categorical variables).
Linear mixed modeling was used to assess differences between the treatment groups over time and at each time point. We constructed a model with a random intercept and an autoregressive covariance structure. Improvement of the fit of the models was compared based on the maximum likelihood fits. When the overall model with time included as continuous variable was found to be significant, a new model was constructed with time included as a categorical variable to compare differences between time points. Because a large proportion of patients in both groups did not complete HRQoL questionnaires at all time points, the missing at-random assumption was probably not supported. Therefore, a variable indicating the missing data pattern of each individual and the interaction with treatment was tested. Differences over time between the groups in mean change scores were accompanied by Cohen’s effect size.19 An effect size of 0.20 was considered to be small, 0.50 was considered to be moderate and clinically significant, and 0.80 was considered to be large.20
OS was defined as the time from randomization to the time of death from any cause or to the time of last follow-up (censoring). EFS was defined as the time from randomization until disease progression, irresectable disease at surgery, tumor recurrence after potentially curative surgery, or death from any cause. Kaplan-Meier survival curves, stratified for HRQoL thresholds, were plotted for EFS and OS. Statistical significance above and below the HRQoL thresholds was calculated using log-rank tests. To investigate the factors influencing EFS and OS, Cox proportional hazards analyses were performed. First, univariate analyses were constructed (including age, sex, WHO performance status, Lauren classification, and all the QLQ-C30 scales), and then a multivariate model was constructed using a backward selection procedure, including only the statistically significant variables. Proportional hazards assumptions were tested by interpretation of the survival plots for every model.
Sensitivity analyses were performed to assess differences in HRQoL over time between the per-protocol subgroup and the intention-to-treat group by conducting linear-mixed modeling in the per-protocol cohort, consisting of those patients who actually started the postoperative treatment.
To investigate the association between the decline in HRQoL at each follow-up moment and OS, univariate Cox survival analyses were applied. For these analyses, we included HRQoL decline from baseline as both a continuous variable (are larger declines associated with survival outcomes?) and a dichotomous variable (is a clinically relevant decline of >10 points associated with survival?).
Further, we compared the proportion of patients who experienced a clinically relevant decline in HRQoL (decline >10 points) between treatments.21 All analyses were performed in SPSS Stattistics, version 26.0 (IBM Corp). All tests were 2-sided with an assumed significance level of P<.05.
Results
At least 1 evaluable questionnaire was available for 645 patients (82% of 788 randomized patients; Figure 1). Baseline characteristics of patients who completed the baseline questionnaire were well balanced (Table 1). At baseline, 301 (77%) patients in the chemotherapy group versus 298 (75%) patients in the CRT group completed the questionnaires. At 12-month follow-up, 92 (31%) patients in the chemotherapy group versus 83 (28%) patients in the CRT group completed the questionnaires. A decrease in the number of completed questionnaires was seen over time, but no between-group difference in questionnaire compliance rates was observed (Figure 1).
CONSORT diagram.
Abbreviations: CRT, chemoradiotherapy; HRQoL, health-related quality of life.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7057
CONSORT diagram.
Abbreviations: CRT, chemoradiotherapy; HRQoL, health-related quality of life.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7057
CONSORT diagram.
Abbreviations: CRT, chemoradiotherapy; HRQoL, health-related quality of life.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7057
Baseline Characteristicsa
HRQoL Between Treatment Groups
Between-group differences in mean change at the different time points compared with baseline are shown in supplemental eTable 1. After postoperative treatment, patients in the chemotherapy group had significantly fewer dysphagia complaints compared with those in the CRT group (mean difference, 8.3; ES, 0.38; P=.01; Figure 2). Patients in the chemotherapy group had significantly better physical functioning after postoperative treatment compared with those receiving CRT (mean difference, 5.4; ES, 0.42; P=.02; Figure 2). No significant differences between the chemotherapy and CRT groups over time were observed for pain, fatigue, or the QLQ-C30 summary score (Figure 2).
Mean scores with standard deviations for predefined endpoints in the chemotherapy and CRT groups: (A) dysphagia, (B) physical functioning, (C) pain, (D) fatigue, and (E) QLQ-C30 summary score.
Abbreviations: chemo, chemotherapy; CRT, chemoradiotherapy; QLQ-C30, EORTC Quality-of-Life Questionnaire-Core 30.
*Significant difference based on linear mixed modeling.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7057
Mean scores with standard deviations for predefined endpoints in the chemotherapy and CRT groups: (A) dysphagia, (B) physical functioning, (C) pain, (D) fatigue, and (E) QLQ-C30 summary score.
Abbreviations: chemo, chemotherapy; CRT, chemoradiotherapy; QLQ-C30, EORTC Quality-of-Life Questionnaire-Core 30.
*Significant difference based on linear mixed modeling.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7057
Mean scores with standard deviations for predefined endpoints in the chemotherapy and CRT groups: (A) dysphagia, (B) physical functioning, (C) pain, (D) fatigue, and (E) QLQ-C30 summary score.
Abbreviations: chemo, chemotherapy; CRT, chemoradiotherapy; QLQ-C30, EORTC Quality-of-Life Questionnaire-Core 30.
*Significant difference based on linear mixed modeling.
Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7057
For the total sample, across all predefined endpoints we found a deterioration in HRQoL over time, which was almost restored at 12-month follow-up (Figure 2). The ES for all predefined endpoints at 12-month follow-up were <0.20, indicating that the remaining differences between baseline and 12-month follow-up were small and not clinically relevant (supplemental eTable 1).
At 12 months of follow-up, patients with a locoregional recurrence experienced significantly more complaints of dysphagia compared with those without a locoregional recurrence (P=.003). Furthermore, insomnia was significantly more often present in patients with a locoregional recurrence (P=.042).
Sensitivity Analyses
The per-protocol analyses showed similar associations between treatment groups and HRQoL outcomes (data not shown). After postoperative treatment, the proportion of patients who experienced a clinically relevant decline in HRQoL (>10 points) did not significantly differ between the chemotherapy and CRT groups (54% vs 62%; P=.170). At 12 months of follow-up, almost one-third of patients still showed a clinically relevant decline from baseline HRQoL, ranging from 31% in the chemotherapy group to 38% in the CRT group (P=.412).
Baseline Prognostic Factors
At baseline, the HRQoL questionnaire scores did not differ significantly between treatment groups (data not shown). Therefore, baseline prognostic analyses were performed for the entire sample.
At baseline, patients with worse physical functioning, role functioning, and social functioning and more nausea, pain, insomnia, appetite loss, and constipation had a significantly shorter median OS compared with those with scores indicating better functioning or fewer symptoms (Table 2).
Univariate and Multivariate Analyses of Baseline Factors Affecting OS and EFS
For physical functioning, nausea, and appetite loss, significantly fewer patients with a score of clinical importance completed all treatments compared with those who had a score without clinical importance. Thus, compliance was worse in patients who experienced worse physical functioning and more complaints of nausea and appetite loss.
Multivariate Analysis
In multivariate analyses, worse social functioning (hazard ratio [HR], 2.20; 95% CI, 1.36–3.55; P=.001), nausea (HR, 1.89; 95% CI, 1.39–2.56; P<.001), worse WHO performance status (HR, 1.55; 95% CI, 1.13–2.13; P=.007), and histologic subtype (diffuse vs intestinal: HR, 1.94; 95% CI, 1.42–2.67; P<.001; mixed vs intestinal: HR, 2.35; 95% CI, 1.35–4.12; P=.003) were significantly associated with worse EFS and OS (Table 2).
Clinically relevant declines in HRQoL across all time points were not associated with survival outcomes. However, at 12 months of follow-up, larger declines (HR, 1.02; 95% CI, 1.00–1.04) and a clinically relevant decline (HR, 2.04; 95% CI, 1.18–3.53) were associated with worse OS.
Discussion
In this study, we observed that patients with worse HRQoL at baseline were associated with worse EFS and OS. Furthermore, we found that patients receiving postoperative chemotherapy had significantly better physical functioning and less dysphagia compared with those receiving postoperative CRT. Because the CRITICS trial did not show a significant difference in OS, the results of this study are of additional value.
This study is the largest clinical trial in gastric cancer comparing HRQoL in patients who underwent curative treatment using neoadjuvant and adjuvant therapy. Most studies reporting on HRQoL in esophagogastric cancer involve patients receiving palliative systemic therapy or surgery alone.11–13,22,23 The recently published systematic review by Ter Veer et al23 reports that an increasing number of randomized controlled trials include HRQoL as an endpoint for advanced esophagogastric cancer, but the quality of the studies is still limited. One of the studies that does investigate HRQoL in patients undergoing curative treatment is the CROSS trial,24 in which patients with potentially curable esophageal or junctional cancer received either neoadjuvant CRT followed by surgery or surgery alone.25 In line with our results, a deterioration in HRQoL scores was described. Despite the fact that there were 22% junction tumors and that patients were treated using neoadjuvant CRT and surgery, the same course of HRQoL was seen over time, with a near return to baseline levels of HRQoL after 12 months. The CROSS trial also looked at physical functioning and fatigue as HRQoL outcome measures based on the QLQ-C30 and reported very similar mean scores after neoadjuvant CRT to those reported after postoperative CRT in the CRITICS trial. The recently published systematic review by van den Boorn et al13 found that most studies reporting HRQoL in patients with gastric cancer were based on surgery alone and that more studies in HRQoL reflecting contemporary treatment strategies need to be conducted. They concluded that surgery in patients with gastric cancer did not yield a clinically relevant difference in HRQoL at 12 months of follow-up compared with baseline. Therefore, our study adds important information about the impact of the current treatment strategies on HRQoL.
An important finding from our analyses is that worse HRQoL at baseline is associated with OS and EFS in patients with gastric cancer receiving multimodality treatment. In the multivariate analysis, worse social functioning, nausea, WHO performance status, and histologic subtype (Lauren classification) remained significantly associated with OS and EFS. Park et al11 also observed that baseline social functioning predicts survival in patients with advanced gastric cancer treated using first-line chemotherapy. Chau et al12 investigated the prognostic value of pretreatment HRQoL in patients with locally advanced or metastatic esophagogastric cancer, and concluded that pretreatment physical functioning, role functioning, and global QoL significantly predicted survival. These findings provide consistent evidence supporting the potential usefulness of taking baseline HRQoL into account in doctor–patient communication and in shared decision-making about the choice of treatment.
We are the first to apply the HRQoL thresholds recently developed by Giesinger et al18 for defining clinically relevant HRQoL scores. Interpreting the linearly transformed scores (0–100 scales) from the EORTC QLQ-C30 can be challenging for clinicians. Use of these thresholds may make HRQoL scores more understandable and more actionable for clinicians.
A limitation of our study was the decreasing response rate to the HRQoL questionnaires over time. The decrease in completed questionnaires can be explained by dropout during the study. Only 60% of patients began postoperative treatment due to toxicity/complications, progression, patient refusal to continue treatment, poor condition, and death.8 Other studies investigating perioperative chemotherapy in gastric cancer have also noted relatively low compliance rates.6,26–28 Nevertheless, at each time point, the number of completed questionnaires was appropriate between the groups. In addition, patients were randomized upfront, so when comparing the groups at time points other than baseline there remains some uncertainty about the comparability of the treatments among the groups. We chose this design deliberately to prevent patient selection during preoperative and postoperative treatment and after surgery. Moreover, upfront randomization reflects daily clinical practice, where management decisions must be made before the start of any treatment.
A strength of this study is its novel focus on HRQoL in patients who underwent curative treatment for gastric cancer with both surgery and (neo)adjuvant treatment. HRQoL has been examined in gastric cancer, but this examination has primarily focused on patients who underwent treatment in the palliative phase or those who only underwent surgery. In addition, the relatively large sample size increased the power to detect clinically relevant differences between the groups.
Conclusions
Our findings indicate that HRQoL is poorer after postoperative CRT compared with postoperative chemotherapy, but that HRQoL returns to baseline levels in both groups at 12 months of follow-up. We also found that pretreatment HRQoL is associated significantly with (event-free) survival in curatively treated patients with gastric cancer. Pretreatment HRQoL can therefore play a potentially important role in clinical decision-making and in shaping the patient’s expectations of treatment efficacy. In addition, it can be of importance in individual risk stratification and tailored supportive care.
Ongoing clinical trials, including TOPGEAR (ClinicalTrials.gov identifier: NCT01924819) and CRITICS II (NCT02931890), are investigating neoadjuvant regimens in which chemotherapy or CRT or a combination of both is given preoperatively. In these trials, assessment of HRQoL will continue to add to our understanding of the impact of emerging treatment strategies on both clinical outcomes and the effects of treatment on the functional health, symptom experience, and well-being of patients from their perspective.
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