Health-related quality of life analysis from ENTER, a randomized, controlled phase III trial of whole-brain radiotherapy with and without concurrent erlotinib in NSCLC with brain metastases

Introduction

Approximately 80% of lung cancer cases are reported as non-small cell lung cancer (NSCLC), which has an incidence of brain metastases (BM) of approximately 20–40%, and the incidence in patients harboring epidermal growth factor receptor (EGFR) mutations is higher (1,2). Patients with BM usually have a poor prognosis and experience a great symptomatic burden, including cognitive deficits, headaches, seizures, ataxia and speech and visual problems, which affect their health-related quality of life (HRQoL) (3). Moreover, the side effects related to antitumor treatment for BM, especially involving brain radiation or surgery, can likewise lead to severe impairment of HRQoL by limiting the patient’s ability to perform daily activities and changing neurocognitive processes (4). Therefore, patient-reported outcomes (PROs), including symptoms and HRQoL outcomes of treatment, are considered important when introducing new treatment strategies for BM, in addition to efficacy and safety endpoints (5). Given the worse prognosis of patients with BM and the impact of disease-related symptoms on patient HRQoL, maintaining or improving their quality of life (QoL) is of vital importance. It is not surprising that more patients would prefer treatments that improve QoL without prolonging life rather than one that improves survival slightly without symptomatic benefit (6,7). In addition, it is recommended to assess HRQoL in all prospective clinical comparative effectiveness studies (8).

Currently, whole-brain radiotherapy (WBRT) remains the standard treatment for NSCLC patients with multiple BMs (9); however, patients usually present limited efficacy when WBRT is determined as a single therapeutic modality, and it is controversially associated with a high risk of delayed neurotoxicity. Erlotinib, a first-generation tyrosine kinase inhibitors (TKI) drug with high blood-brain barrier (BBB) permeability, is capable of targeting BM in NSCLC with EGFR mutations and leads to radiosensitization (10-12). Combining erlotinib with WBRT can disrupt the BBB and elevate permeability into the surrounding brain parenchyma, creating the possibility of using erlotinib in combination with WBRT (12-14). The efficacy and safety of WBRT concurrent with erlotinib compared with WBRT was investigated in a multicenter, open-label, randomized, controlled phase 3 trial (ENTER), which has been reported previously (15). Although the results revealed that WBRT in combination with erlotinib did not improve intracranial progression-free survival (PFS) compared with WBRT alone in the overall population or in EGFR-mutant patients, it is worth mentioning that the combination therapy did not cause excessive cognitive function detriment, suggesting that it is safe to continue treatment with erlotinib in EGFR-mutated patients who have received brain radiotherapy during treatment.

Given the benefits of improving quality of life in evaluating cancer treatment strategies, here, we report PROs from ENTER, which were a secondary outcome of this trial. The patients’ HRQoL was assessed by using the 30-item Core Quality of Life Questionnaire (QLQ-C30) developed by the European Organization for Research and Treatment of Cancer (EORTC). We aimed to investigate whether self-reported symptoms deteriorate more slowly and whether more patients will have an improvement in global health status (GHS) and symptoms when treated with WBRT concurrent with erlotinib compared with WBRT alone. We present this article in accordance with the CONSORT reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-481/rc).

Methods

The ENTER trial (ClinicalTrials.gov identifier: NCT01887795) is a phase III clinical trial conducted at 10 centers in China to evaluate the efficacy and safety of WBRT plus concurrent erlotinib and WBRT-alone treatments in NSCLC patients with BM. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethical approval for conducting the trial was obtained prior to its commencement from Medical Ethics Committee of the Third Affiliated Hospital of the Third Military Medical University (year: 2013; No. 013). Each participant provided their written informed consent.

Study population

The eligibility criteria for the patients were an age of 18 years or above with histologically confirmed stage IV or recurrent NSCLC. In addition, contrast-enhanced magnetic resonance imaging (MRI) was required to demonstrate that there were two or more BM (the diameter of at least one lesion had to be >10 mm). Complete inclusion/exclusion criteria have been reported previously. Ethical approval for conducting the trial was obtained prior to its commencement from an independent institutional review board or ethics review committee at each study site.

Study procedures

The patients who fulfilled the inclusion criteria and signed the informed consent form were randomly assigned (in a 1:1 ratio) to either the WBRT plus concurrent erlotinib arm (WBRT + erlotinib arm) or the WBRT-alone arm (WBRT arm). Patients received either WBRT (20 fractions of 40 Gy) concurrent with oral erlotinib (150 mg/day, induction erlotinib for 6 days, then concurrent with WBRT) or WBRT alone until unacceptable toxicity developed. It is permissible to reduce or interrupt the dose of erlotinib if severe or intolerable drug toxicity occurs. Dose reductions first to 100 mg/day are recommended and then second to 50 mg/day. Standard first-line systemic therapy continues after completion of WBRT. EGFR-mutated patients received erlotinib continued. EGFR wild-type adenocarcinoma or squamous carcinoma patients receive cisplatin-based chemotherapy in combination with pemetrexed or paclitaxel, respectively.

PRO assessments

The European Organization for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire (EORTC QLQ-C30) was used in this study to assess the HRQoL of patients, which is currently the most widely used international measure of the quality of survival of cancer patients (16). The questionnaire includes a GHS/quality of life (QoL) scale, five functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, nausea/vomiting and pain) and six individual scales (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). A linear transformation was applied to standardize raw scores for all scales and single-item measures to a range of 0 to 100, where higher scores on the overall health status and the five functional subscales indicated better functioning, while higher scores on the symptom and economic scales indicated more severe functioning. Worsening or improvement of symptoms was considered to have occurred when the change (increase or decrease) in score from baseline was ≥10, and symptoms were considered stable when the score was in between (17,18). In addition, time to deterioration referred to the time from randomization to the first deterioration in QoL (≥10 points decrease on functional scales and ≥10 points increase on symptom scales or items), with death as a competing event. Completion of baseline questionnaires prior to the first dose, with subsequent questionnaires completed at the end of WBRT, immediately 1 month after initiation of treatment, and then every 2 months until intra- or extracranial disease progression or death.

Statistical analysis

The participant population undergoing PROs analysis included all patients who completed the PROs instrument with at least one time point other than the baseline questionnaire. Compliance referred to the proportion of patients completing at least one PROs questionnaire at each visit among those who were expected to complete these questionnaires (excluding those missing by design, i.e., those who could not complete the questionnaire owing to death, discontinuation, or no visit scheduled).

For each scale, differences in mean change between arms from baseline to the five planned time points were compared using least squares to provide a complete profile of QoL behavior. Positive values indicate improvement in functional scales and worsening in symptom scales. If a participant had a missing value for a certain time point, all the data of that participant were deleted. For time to deterioration, all available questionnaires were assessed. Kaplan-Meier analysis was used to evaluate the deterioration curves for each arm, and the log-rank test was used to determine hazard ratio (HR) and 95% confidence intervals (CI). All statistical analyses were performed using SPSS 25.0 and GraphPad 8.0.

Results

Patients

From 7 August 2013 to 25 November 2016, 224 patients from 10 centers in China were randomly assigned to the two treatment arms, and 220 patients received the treatment; among all these patients, 1 patient in the WBRT + erlotinib arm was excluded due to noncompletion of the baseline questionnaire. Thus, 114 patients in the WBRT arm and 105 patients in the WBRT + erlotinib arm were included in the PROs analysis (CONSORT diagram shown in Figure S1). As previously reported, baseline characteristics were well balanced in both treatment arms, and mean baseline QoL scores were mostly similar in both arms (Table 1). The data cutoff date was August 31, 2017.

Compliance rates with patient-reported instrument

Compliance rates for each treatment arm are shown in Table S1. The QoL questionnaire compliance rate decreased gradually with treatment duration due to disease progression and death. At 1, 3 and 5 months, 86.8%, 69.0% and 66.3% reported QoL scores in the WBRT arm, compared with 85.7%, 68.8% and 61.5%, respectively, in the WBRT + erlotinib arm.

Changes in QoL from baseline

Figure 1 displays the absolute mean differences in GHS/QoL and functioning scales scores from baseline. For the WBRT arm, mean GHS/QoL scores were above baseline at month 5 and slightly deteriorated in the WBRT + erlotinib arm, but the least-squares mean difference between the two arms of GHS/QoL scores was not significantly different at all time points. Similarly, differences in the least squares means of all functional and symptom scales scores between the two arms were not significantly different at all time points (Figure S2). In the subset of 109 EGFR-mutated patients, the same results were observed in all QoL scales (Figures S3,S4).

Figure 1 Mean change from baseline in GHS/QoL and functioning scales scores by visit. (A) GHS/QoL scores; (B) physical function scores; (C) role function scores; (D) emotional function scores; (E) cognitive function scores; (F) social function scores. Data points represent means, and error bars denote SEM. WBRT, whole-brain radiotherapy; SEM, standard error of the mean; GHS, global health status; QoL, quality-of-life.

Previous studies have reported a decline in neurocognitive function and an increase in self-reported cognitive dysfunction along with a significant decline in QoL within 3 months after WBRT, with a peak at 4 months (19,20). In addition, the observed endpoint for QoL reporting in previous classical studies of EGFR-TKIs for advanced NSCLC was usually set at 3–5 months (21,22), and the median time to worsening of major lung cancer symptoms in patients treated with erlotinib was also approximately 3–5 months (23). Therefore, we chose the 5th month after starting treatment to compare each group with its own baseline. Additionally, compliance at this time point was above 60%, ensuring a meaningful sample size and minimizing data loss due to disease progression/death.

Self-assessed QoL scores were assessed separately for both arms at the 5-month time point relative to their own pretreatment baseline. As shown in Figure 2A, after month 5, in the GHS/QoL and all functional scales, neither arm had a statistically significant change in scores compared to their own pretreatment baseline. Interestingly, at this time point, both arms improved (lower scores) on most symptom scales. The WBRT arm showed improvements in nausea/vomiting (P=0.003), while the WBRT + erlotinib arm had improved scores in fatigue (P=0.01), nausea/vomiting (P=0.02), pain (P=0.04) and insomnia (P=0.01) (Figure 2B). As shown in Figure 2C,2D, compared to the WBRT arm, patients in the combination treatment arm improved on more QoL scales [26.67% (4/15) vs. 6.67% (1/15)]. Analysis of the EGFR-mutated subgroup showed that from baseline to month 5, the WBRT arm showed improvements in fatigue (P=0.03), with improvements in fatigue (P=0.006), nausea/vomiting (P=0.01), pain (P=0.002) and insomnia (P=0.01) in the WBRT + erlotinib arm (Figure 2E,2F).

Figure 2 Changes from baseline in GHS/QoL, functional scale scores and symptom scale scores after 5 months. Higher functional scale scores represent better functioning, whereas higher symptom subscale scores indicate more symptoms; higher GHS/QoL represents better health status/QoL. (A) GHS/QoL and functional scale scores; (B) symptom scale scores; (C) GHS/QoL and functional scale scores in the EGFR-mutated subgroup; (D) symptom scale scores in the EGFR-mutated subgroup; (E) proportion of scales with higher QoL scores than baseline in the WBRT arm after 5 months; (F) proportion of scales with higher QoL scores than baseline in the WBRT + erlotinib arm after 5 months. Data points represent means, and error bars denote SEM. WBRT, whole-brain radiotherapy; EGFR, epidermal growth factor receptor; LS, least squares; SEM, standard error of the mean; GHS, global health status; QoL, quality-of-life.

Analysis of QoL response

Figure 3 depicts the QoL response outcomes for both treatment arms after month 5. Fewer patients in the WBRT + erlotinib arm experienced deterioration in physical and role functioning, and more patients reported deterioration in emotional and cognitive functioning compared to the WBRT arm, but none reached statistical significance. There were limited differences between the two arms in the distribution of improved, stable, and deteriorated scores on other symptom scales, except for a greater proportion of patients with deteriorating diarrhea in the WBRT + erlotinib arm (P=0.009). In the EGFR-mutated subgroup, similarly more patients in the WBRT + erlotinib arm reported deteriorating diarrhea (P=0.03), while no statistically significant differences were observed in all other scales.

Figure 3 Proportions of patients with improved, stable, and deteriorated after 5 months. (A) Overall population; (B) EGFR-mutated subgroup. WBRT, whole-brain radiotherapy; EGFR, epidermal growth factor receptor; GHS, global health status; QoL, quality-of-life.

Analysis of time to deterioration

Compared to the WBRT arm, the WBRT + erlotinib arm showed significant delays in time to deterioration in role function (4.4 vs. 7.0 months, HR =0.74; 95% CI, 0.54–1.00; P=0.03), insomnia (7.0 vs. 4.7 months, HR =0.72; 95% CI, 0.53–0.98; P=0.02), and constipation (12.7 vs. 9.3 months, HR =0.70; 95% CI, 0.51–0.96; P=0.02) symptom scales and showed a trend in delaying the GHS/QoL (5.0 vs. 4.8 months, HR =0.79; 95% CI, 0.58–1.07; P=0.09). No significant differences were observed in the time to deterioration in other functional and symptomatic scales between the two arms (Figures 4,5).

Figure 4 Time to deterioration in GHS/QoL, functional scale. (A) GHS/QoL scores; (B) physical function scores; (C) role function scores; (D) emotional function scores; (E) cognitive function scores; (F) social function scores. WBRT, whole-brain radiotherapy; HR, hazard ratio; CI, confidence interval; GHS, global health status; QoL, quality-of-life.

Figure 5 Time to deterioration in symptom scale. (A) Fatigue; (B) nausea and vomiting; (C) pain; (D) dyspnea; (E) insomnia; (F) appetite loss; (G) constipation; (H) diarrhea; (I) financial difficulties. WBRT, whole-brain radiotherapy; HR, hazard ratio; CI, confidence interval.

Discussion

This study showed that both treatments improved/maintained HRQoL in NSCLC patients with multiple BMs. The simultaneous addition of erlotinib during radiotherapy did not reduce QoL scores nor improve partial functions and symptoms compared to WBRT alone. WBRT combined with erlotinib was equally well tolerated in the EGFR-mutated population. To our knowledge, this is the largest analysis of PROs in a phase III study of WBRT combined with EGFR-TKIs in NSCLC patients with BM.

While the focus remains on maximizing survival outcomes, clinicians recognize that the maintenance of QoL and cognitive function are among the primary goals in treating patients with BM (24). WBRT, which is an important tool for BM treatment, has been controversial, with previous research suggesting that WBRT may improve QoL and cognitive function through tumor control (25), and others concluding that despite improved intracranial tumor control rates, QoL and cognitive function deteriorate significantly in patients undergoing WBRT (26,27). Although the application of stereotactic radiosurgery (SRS) in the administration of multiple BMs is expanding with the increasing sophistication of radiotherapy machines and image-guided devices, it is undeniable that the rate of distant intracranial failure is higher in patients treated with SRS alone than WBRT for patients with high risk factors for intracranial metastasis, and thus WBRT treatment remains significant value of research and application for its ability to target unknown microscopic intracranial disease (28). A survey of 1,000 Chinese oncologists from different regions and hospital grades showed that WBRT combined with TKIs remains the preferred regimen for patients with BM >4 due to patient heterogeneity, technical limitations, and conflicting study results (29). In an era when targeted therapy has led to significantly longer survival in EGFR-mutant NSCLC patients with BM, more patients are likely to experience the neurological QoL impact of WBRT, making the assessment of QoL for such patients particularly important (30).

In the current report, no clinically meaningful differences were found between the two arms for 15-item QoL scale scores at all follow-up time points. This finding suggested that the continuation of erlotinib in patients treated with WBRT, including those with EGFR mutations, appears to be safe and that the combination treatment did not result in a decrease in the QoL of patients. One previous study has shown a progressive deterioration in patients’ self-reported cognitive ability over time up to 6 months after treatment with WBRT (31). However, other study have demonstrated that QoL in patients with a better prognosis [Karnofsky Performance Status (KPS) scores of 70 or better] improves after WBRT (32). Yaneva et al. used the EORTC QLQ-C30 to assess the QoL of patients with KPS scores greater than 70 before and after WBRT treatment. HRQoL improved significantly after radiotherapy, as did all domains of function and symptoms except dyspnea, diarrhea, and financial difficulties (33). This finding is consistent with ours in that WBRT did not impair patients’ QoL. All patients in our study had pretreatment KPS scores above 70, and GHS/QoL scores remained generally stable in both arms during the follow-up period (<5-point change from baseline in both arms until month 9). There is further evidence that WBRT is potentially beneficial for BM patients with good performance status. Self-reported cognitive function scores decreased from baseline in both arms at 1 month after initiating treatment, continued to decrease in the combined treatment arm at month 3, gradually returned to pretreatment levels and remained stable in the WBRT arm, and gradually recovered and moved closer to baseline levels in the combined treatment arm at month 5. The administration of BM treatment may lead to transient neurocognitive dysfunction due to peritumor tissue edema and absorption of tumor lysis products, and increased treatment pressure may result in a slightly prolonged duration of this process. However, for both treatments, WBRT alone and WBRT with concurrent erlotinib, this effect was eliminated by the fifth month because the tumor was controlled and cognitive function was well recovered.

In this trial, at month 5 after the initiation of radiotherapy, the WBRT arm showed improvement in nausea/vomiting symptom scores relative to pretreatment baseline, while the WBRT + erlotinib arm showed greater improvement in fatigue, nausea/vomiting, pain, and insomnia, an advantage of the combination therapy that was also observed in EGFR-mutated patients. The time to deterioration was also assessed in all patients in this analysis, and the combination therapy delayed the time to deterioration of role function, insomnia and constipation symptoms compared to WBRT alone. This may be attributed to patients in the combination therapy arm receiving EGFR-TKIs earlier, achieving initial control of tumor load earlier, and adapting their lifestyle to oral targeted drugs earlier. In addition, patients in the combination therapy arm only needed to pay for an additional 4 weeks of EGFR-TKIs compared to the WBRT alone arm, which, in general, did not result in an excessive financial burden, and our study also showed no significant difference in scores on the financial difficulties scale between the two groups. At month 5, worsening of diarrhea symptoms was observed in a higher proportion of patients in the combination therapy arm in both the overall and EGFR-mutated populations. Diarrhea was one of the most common adverse events with erlotinib, as reported in previous study, but was mostly of degree 1 or 2 and was managed by administration of antidiarrheal medication and dose reduction without interruption of dosing (34). In this study, with continued drug administration, the diarrhea gradually relieved, and the impact on QoL gradually decreased, slowly returning to baseline levels. In addition, the slightly higher incidence of acneiform rash and dry skin adverse events reported in our previous study (15) in the WBRT + erlotinib arm were not reflected in their GHS/QoL and did not affect functional or symptom scales. Our previous report and other studies have shown that radiotherapy combined with EGFR-TKIs has not prolonged PFS or overall survival (OS) (15,35), but as mentioned above, the present study demonstrated that the combination treatment was not excessively toxic and was more beneficial in improving some QoL scales, which may be due to the mutual complementarity of the two treatments, and it is evident that the combination treatment is a potential treatment option for patients with BM in terms of QoL.

In the era of targeted therapies, EGFR-TKIs have become the first-line treatment for EGFR-mutated patients with NSCLC, and timely WBRT treatment is equally necessary for patients with symptomatic BM due to its large size, peritumoral edema and mass effect. However, current studies evaluating the effects of WBRT combined with EGFR-TKIs on neurocognitive function and QoL in such patients are still limited. The present study provides good evidence that the combination of erlotinib during WBRT in EGFR-mutant patients is safe and does not reduce QoL. It is important to note that the treatment landscape for patients with BM from NSCLC has changed since the start of this trial, with more third-generation EGFR-TKIs with high BBB permeability proven to better control intracranial disease, and the use of these targeted agents may lead to different outcomes than those of patients in this trial. Also, WBRT is currently rarely used upfront, due to toxicity concerns and the higher intracranial activity of osimertinib and other newer drugs. Under osimertinib, WBRT is frequently deferred. At the same time, with the development of precision radiotherapy techniques, increasing evidence supports that a higher risk-benefit ratio may be obtained with SRS in patients with selective 4–10 BMs (36). More precise radiotherapy patterns for BM in combination with third-generation EGFR-TKIs may result in more favorable QoL benefits, and we look forward to ongoing studies of three generations of EGFR-TKIs in combination with SRS to reveal the answer (NCT03535363, NCT03769103, NCT03497767).

We note several limitations of this analysis. First, there was a limited follow-up period to evaluate PROs and a decline in patient compliance in later stages. High attrition rates due to disease progression and health deterioration are difficult to avoid in QoL studies of patients with BM, but patient compliance in our study is still within acceptable levels compared to other studies (22,37,38). The findings of the present study still have some guidance value for the treatment of such patients (37,39). Second, only the EORTC QLQ-C30 questionnaire was used to assess QoL in this study (although it is the most commonly used instrument in oncology clinical trials), and it has been suggested that utilizing a cancer subtype-specific questionnaire, such as the EORTC QoL Questionnaire-Brain Neoplasm (QLQ-BN20), in combination with the core questionnaire, can collect more specific information for a more multidimensional assessment of QoL (40). In recent years, QoL has become an equally important consideration in treatment decision selection as objective efficacy, and it should be prospectively included in future randomized clinical trials of patients with BM from NSCLC, even as a primary endpoint, while the selection of appropriate brain-specific instruments to capture the benefit or toxicity of brain-directed therapy and the selection of instruments with lower problem burden to improve compliance in BM patients who may already have neurocognitive dysfunction at the time of diagnosis are issues that need to be addressed in future study design. Third, this study only involved Chinese patients. Different ethnic and cultural groups may lead to differences in HRQoL assessment in some aspects, and the representativeness of this study results in Western populations may be limited.

Conclusions

In conclusion, as evaluated by the EORTC QLQ-C30 instrument, the simultaneous addition of erlotinib during WBRT did not decrease the QoL in NSCLC patients with BM and resulted in improvements on more QoL scales and slower deterioration of some self-reported symptoms compared to WBRT alone. In the EGFR-mutated population, WBRT with concurrent erlotinib was also well tolerated.

Acknowledgments

We appreciate everyone who participated in the study, including the patients and their families. We also acknowledge the nurses and other clinical staff members who provided crucial assistance.

Funding: This work was supported by grants from the National Natural Science Foundation of China (Nos. 82273572 and 82002448), the Project of Chongqing Technology Innovation and Application Development (No. CSTC2021jscx-gksb-N0022), the Science and Technology Innovation Medical Development Foundation of Beijing (No. KC2021-JX-0186-11), Health Commission Science and Technology Foundation of Guizhou Province (No. gzwkj 2022-028), and Science and Technology Foundation of Guizhou Province (Outstanding Young Scientists of Guizhou Province) (No. Qiankeherencai-YQK[2023]021).

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-481/rc

Trial Protocol: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-481/tp

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-481/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-481/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-481/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethical approval for conducting the trial was obtained prior to its commencement from Medical Ethics Committee of the Third Affiliated Hospital of the Third Military Medical University (Year: 2013; No. 013). Each participant provided their written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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