Objective: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. Methods: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. Results: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. Conclusion: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.

To alleviate symptoms, to extend survival, and to improve (or maintain) health-related quality of life (HRQoL) are the primary aims of metastatic breast cancer treatment [1,2], because these cancers are rarely curable [3,4,5]. Taxane, anthracycline, and S-1 are the choices for first-line chemotherapy among patients with HER2-negative metastatic breast cancer [6]. Taxane and anthracycline are both intravenously administered drugs, and the effects of these drugs on overall survival and HRQoL are shown to be equivalent [7]. These drugs are considered a first-line therapy option for advanced breast cancer [3,4,5]. In Japan, the orally administered drug S-1 - the compounding ingredient of tegafur, gimeracil, and oteracil - is widely used for various types of solid cancers [8,9,10,11,12,13,14,15].

In order to confirm that S-1 is noninferior to taxane regarding overall survival, and that S-1 is superior regarding HRQoL, the Selection of Effective Chemotherapy for Breast Cancer (SELECT BC) trial was conducted in Japan [16]. The trial demonstrated the noninferiority of S-1: the median survival time was 35.0 and 37.2 months in the S-1 and the taxane group, respectively (hazard ratio = 1.05 [95% confidence interval: 0.86-1.27], noninferiority p = 0.015). The SELECT BC trial set HRQoL as one of the secondary endpoints, with the hypothesis of superiority of S-1. In the trial, the patients were assessed longitudinally for several patient-reported outcome (PRO) measurements. Specifically, the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [17] and Patient Neurotoxicity Questionnaire (PNQ) [18] were administered.

Comparing S-1 and taxane using the mixed-effect model for repeated measures (MMRM) analysis on the QLQ-C30 yielded results as shown by Takashima et al. [16]. Briefly, S-1 was superior to taxane in 8 of 15 QLQ-C30 scales. Because this analysis compares the average value of each scale between treatment groups, we use the term “group-level (marginal) effect” for the results of the MMRM analysis. Since the recent publication of the guidelines on PROs by the Food and Drug Administration (FDA), the importance of individual-level effects has been demonstrated [19,20,21,22]. Here, we use the term “individual-level effect” if an individual patient's PRO score changes over a predetermined period of time so that it should be interpreted that the treatment might have some benefit [19]. In the FDA's guideline, using a priori responder definitions constructed with an anchor-based approach and showing cumulative distribution function (CDF) plots are thought to be useful techniques when interpreting PRO measurements.

One of the serious adverse events associated with administration of taxane is peripheral neuropathy [23]. In order to assess such chemotherapy-induced peripheral neuropathy (CIPN), there are several options, including both patient-reported and clinician-reported scales [24,25,26,27]. The PNQ is one of the PROs that assesses the severity of CIPN. The validation of the PNQ has been reported in Japan [27].

The aim of this paper is to analyze the PRO measurements from the SELECT BC trial in order to evaluate the clinical significance of S-1 versus taxane among patients with metastatic breast cancer.

Study Design and Participants

The SELECT BC trial was an open-label randomized controlled trial that was conducted in Japan [16]. There were 258 institutions involved, and 618 patients were enrolled from October 2006 to July 2010. The primary inclusion criteria for the SELECT BC trial have previously been reported [16]. After excluding 10 patients due to ineligibility, 608 patients were randomly assigned either to a taxane group (n = 301) or to an S-1 group (n = 307). The full analysis set comprised 592 patients in total (n = 286 and n = 306 for the taxane and the S-1 group, respectively), as 16 patients did not receive the assigned treatment.

To those allocated to the taxane group, the physician administered docetaxel (60-75 mg/m2, at intervals of 3 or 4 weeks) or paclitaxel (weekly 80-100 mg/m2 for 3 weeks and off for 1 week, or 175 mg/m2 at intervals of 3 or 4 weeks), taking into account the number of patient visits and treatment costs. The chosen treatment regimens were continued until disease progression or more than 6 courses of administration. In contrast, the treatment regimen for those in the S-1 group (40-60 mg, depending on the body surface area, twice daily for 28 days consecutively, and off for 14 days) was continued until disease progression or more than 4 courses had been administered. Continuation of first-line chemotherapy beyond the number of courses was allowed at the discretion of the physician. In cases of disease progression, adverse events that precluded the allocated treatment, or withdrawal from the allocated treatment by the patients, administering second-line chemotherapy was allowed by the protocol. The second-line therapy included chemotherapies that were generally accepted.

All independent ethics committees of the participating sites approved the protocol and its modifications, and all patients provided written informed consent.

PRO Assessment

In the SELECT BC trial, some institutions were excluded for HRQoL assessments due to feasibility issues. In this paper, we restrict our analysis to the patients in those institutions where HRQoL assessments were conducted. The patients responded to the EORTC QLQ-C30 (version 3) and PNQ at baseline and 3, 6, and 12 months after the start of protocol treatment.

The QLQ-C30 is one of the most widely used questionnaires for assessing HRQoL among cancer patients. It is composed of 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), 1 global health status/QoL scale, and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each functional scale, symptom scale, and single item is converted into a 0-100 scale with a scoring manual [28]. A lower score on a functional scale stands for a lower level of functioning (unhealthy level of functioning), and a lower score on the global health status/QoL scale stands for a lower QoL, while a higher score on a symptom scale or for an item stands for a higher level of symptoms. On assessing the group-level effect in the SELECT BC trial, S-1 was found to perform better than taxane in terms of all 5 functional scales, pain, financial difficulties, and global health status/QoL [16]. Recently, a single summary score of the QLQ-C30 was developed and validated [29]. It is a linear combination of the 13 scales (all subscales except for global health status/QoL and financial difficulties). For supporting the results of the 15 scales, the EORTC Quality of Life Group recommends using the QLQ-C30 summary score.

The PNQ is a simple questionnaire for assessing CIPN, composed of 2 items: one regarding sensory neuropathy and the other regarding motor neuropathy. Each item ranges from grade A (no neuropathy) to grade E (very severe neuropathy). The PNQ grades A-C can be clearly separated from grades D and E: the former indicate the absence of symptoms interfering with activities of daily living, while the latter capture CIPN symptoms which interfere with activities of daily living.

Statistical Analysis

In this study, we included patients who have scores on at least 1 QLQ-C30 scale or for 1 item of the PNQ. We conducted these analyses for those on treatment, because we are interested in the effect of first-line chemotherapy, not treatment policies, on the QoL and CIPN captured by the QLQ-C30 and PNQ. In the original report of the SELECT BC trial, a subgroup analysis suggested that taxane was more effective than S-1 among patients with triple-negative breast cancer [16]. Therefore, we conducted a post hoc subgroup analysis focused on triple-negative breast cancer.

For the QLQ-C30, we conducted a responder analysis that compared time to be a “responder” between treatment groups for each scale or item by the Cox regression model, with only treatment group as a covariate. A patient was defined as a responder if the patient's PRO score changed more than the a priori responder definition. However, there is no single or certain definition of a responder [30,31,32,33]. Traditionally, the definition of response was set at 10 [30]; for example, a patient whose score increased (or decreased) by 10 points or more from baseline was said to have deteriorated (or improved) on a symptom scale. Because a guideline published by Cocks et al. [31] is often used [34,35], we followed the guideline as per the definition of response. It reported clinically relevant mean differences in each QLQ-C30 scale score based on a meta-analytic approach, and we used the medium mean difference for the definition of response. We imputed intermittent missing values by the last-observation-carried-forward method, and we treated a patient who died as a responder at the point of death when conducting the time-to-deterioration analysis.

As a sensitivity analysis, we created a continuous CDF plot: the horizontal axis displays the score change from baseline, and the vertical axis shows the proportion of patients whose score changes from baseline at the score or lower. Because there is no definite responder definition, as stated above, we need to evaluate the CDF plot carefully [20], for it has a supplementary or alternative role in responder analysis [19]. For completeness, we also drew the CDF plot of the QLQ-C30 summary score.

For the PNQ, we compared time to deterioration between the treatment groups for each scale by Cox regression. According to the nature of the PNQ items, we defined deterioration as measures of grade D or E. When considering CIPN, researchers are often interested in learning whether the worst grade during follow-up differs between groups. As such, we presented the distributions of worst-grade measures on the PNQ of each item for each treatment group, and compared them by the χ2 test.

All statistical analyses were performed with SAS (version 9.4). We used the SGPLOT Procedure of SAS for creating all the graphs. We conducted many tests because HRQoL is multifaceted. Therefore, we have to interpret the p values conservatively. For simplicity and from the viewpoint of exploratory analysis, we treat p values <0.05 as statistically significant.

Characteristics of the Patients

Of the 592 patients with a full analysis set, 386 patients, who completed at least 1 QLQ-C30 scale or 1 item of the PNQ, were analyzed in this paper; 176 were in the taxane group, and 210 were in the S-1 group. Table 1 shows the baseline characteristics of the PRO analysis population. In total, there were 99 patients who were estrogen receptor negative and progesterone receptor negative. There were no significant differences in baseline characteristics between the treatment groups within the PRO analysis population.

Table 1

Baseline characteristics of the PRO analysis patients

Baseline characteristics of the PRO analysis patients
Baseline characteristics of the PRO analysis patients

Questionnaire Response Rate

We calculated the proportions of those who were on first-line treatment and responded to the questionnaire. The response rates at each response time point were 100% (386/386) at the start of follow-up (by the definition of our PRO analysis population), 90.9% (279/307) at 3 months, 87.0% (180/207) at 6 months, and 86.9% (86/99) at 12 months after the start of protocol treatment. The questionnaire response rate in the S-1 group was higher (90.3%) than in the taxane group (81.1%) at 12 months.

EORTC QLQ-C30

Figures 1 and 2 show the results of the time-to-deterioration and the time-to-improvement analysis, respectively. It was shown that S-1 had a clinically better effect on 6 scales: the scores on physical, role, and social functioning, as well as financial difficulties, had deteriorated more slowly in the S-1 group than in the taxane group (Fig. 1), and global health status/QoL and the symptom of constipation had improved more rapidly in the S-1 group than in the taxane group (Fig. 2). The subgroup analysis among patients with triple-negative breast cancer showed a significant delay in deterioration of nausea and vomiting in the taxane group compared with the S-1 group (hazard ratio = 2.3, p < 0.01). In the other scales, there were no significant differences between the treatment groups in this subgroup analysis (p > 0.1).

Fig. 1

Results of the responder (time-to-deterioration) analysis of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30, showing estimated hazard ratios with the taxane group as the reference group. A hazard ratio <1 means that there was slower deterioration in the S-1 group than in the taxane group. QoL, quality of life; HR, hazard ratio; CI, confidence interval.

Fig. 1

Results of the responder (time-to-deterioration) analysis of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30, showing estimated hazard ratios with the taxane group as the reference group. A hazard ratio <1 means that there was slower deterioration in the S-1 group than in the taxane group. QoL, quality of life; HR, hazard ratio; CI, confidence interval.

Close modal
Fig. 2

Results of the responder (time-to-improvement) analysis of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30, showing estimated hazard ratios with the S-1 group as the reference group. A hazard ratio <1 means that there was more rapid improvement in the S-1 group than in the taxane group. QoL, quality of life; HR, hazard ratio; CI, confidence interval.

Fig. 2

Results of the responder (time-to-improvement) analysis of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30, showing estimated hazard ratios with the S-1 group as the reference group. A hazard ratio <1 means that there was more rapid improvement in the S-1 group than in the taxane group. QoL, quality of life; HR, hazard ratio; CI, confidence interval.

Close modal

Figure 3 shows the CDF plots of global health status/QoL and the QLQ-C30 summary score 6 months after the start of protocol treatment. The appearance of the CDF plots does not change substantially at 3 or 12 months, which is why we decided to focus on the CDF plots at 6 months only. Note that it is preferable that the CDF plot trend to the right for global health status/QoL and the QLQ-C30 summary score. The CDF plots of global health status/QoL overlap in the area where the change from baseline is negative, while they are apart from each other in the area where the change from baseline is positive. This suggests that S-1 tends to improve the global health status/QoL, but the degree of deterioration is similar with S-1 and taxane. Therefore, the CDF plot of global health status/QoL seemed to be consistent with the findings from the aforementioned responder analyses. On the other hand, the CDF plot of the QLQ-C30 summary score suggests that the degree of deterioration is lower in the S-1 group but that of improvement is similar in the two groups. This is probably because the QLQ-C30 summary score excludes global health status/QoL [29].

Fig. 3

Cumulative distribution function plots of global health status/quality of life and the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 summary score 6 months after the start of treatment, showing the change score from baseline in the S-1 group (solid line) and the taxane group (broken line). The plot preferably trends to the right for both scales. QoL, quality of life.

Fig. 3

Cumulative distribution function plots of global health status/quality of life and the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 summary score 6 months after the start of treatment, showing the change score from baseline in the S-1 group (solid line) and the taxane group (broken line). The plot preferably trends to the right for both scales. QoL, quality of life.

Close modal

PNQ

The responder analysis of the PNQ showed that S-1 had a significant effect compared with taxane, such that it slows the appearance of patient-reported serious (grade D and E) adverse effects of sensory neuropathy (hazard ratio = 0.45 [95% confidence interval: 0.24-0.86], p = 0.01). Although the same tendency was observed for motor neuropathy (hazard ratio = 0.53 [95% confidence interval: 0.25-1.13], p = 0.09), no significant difference between the treatment groups was seen. These results were not observed in the subgroup analysis among patients with triple-negative breast cancer (p > 0.5).

Table 2 shows the distribution of worst-grade measures on the PNQ while on treatment. There was a substantial difference in the frequency of worst-grade measures of sensory neuropathy between the treatment groups. It is worth noting that over one-third of the patients in the S-1 group answered that they had no numbness, pain, or tingling of the hands or feet (grade A of sensory scale) during the 12 months since the start of first-line chemotherapy.

Table 2

Comparison of the distribution of maximum (worst)-grade measures on the Patient Neurotoxicity Questionnaire at 12 months between the S-1 and the taxane group

Comparison of the distribution of maximum (worst)-grade measures on the Patient Neurotoxicity Questionnaire at 12 months between the S-1 and the taxane group
Comparison of the distribution of maximum (worst)-grade measures on the Patient Neurotoxicity Questionnaire at 12 months between the S-1 and the taxane group

In this study, we evaluated the clinical significance of S-1 versus taxane among metastatic breast cancer patients by analyzing phase III randomized SELECT BC trial data. As expected, the orally administered S-1 is superior to taxane in many QLQ-C30 scales and in sensory neuropathy on the PNQ. Taxane is an established option of treatment for metastatic breast cancer patients, but the side effect of neuropathy is a common problem with the administration of taxane. It is therefore necessary that we assess taxane-induced patient-reported neuropathy prospectively [23]. Recently, results of clinical trials for metastatic breast cancer have been reported [36,37] and quality-of-life data from the PALOMA-3 trial were analyzed using a method similar to the one used in this paper [38,39]. In the PALOMA-3 trial, palbociclib in combination with fulvestrant was compared to fulvestrant plus placebo. The median progression-free survival with palbociclib plus fulvestrant was reported to be 9.5 months [36], which is almost the same as that with S-1 (9.6 months) in the SELECT BC trial [16]. With respect to quality of life, palbociclib plus fulvestrant delayed the deterioration of global health status/QoL and pain symptoms [38]. When we censored patients who died in the same manner as those reported on by Harbeck et al. [38], the number of patients who had deteriorations in global health status/QoL was 53 (25.2%) in the S-1 group and 48 (27.3%) in the taxane group, which did not differ much from the values of the PALOMA-3 trial. However, regarding the symptom of pain, the number of patients who had deteriorated was 35 (16.7%) in the S-1 group and 39 (22.2%) in the taxane group, and these numbers seem smaller than the deterioration rate of 39.1% in the palbociclib-plus-fulvestrant group of the PALOMA-3 trial. With respect to pain relief, S-1 or taxane could be better than palbociclib plus fulvestrant.

Group-level effects of S-1 versus taxane therapy were reported among the main findings of the SELECT BC trial [16]. The usual MMRM analysis concluded that S-1 showed effects superior to taxane with respect to 8 scales of the QLQ-C30: global health status/QoL, 5 functional scales (physical, role, emotional, cognitive, and social), and 2 symptom scales (pain and financial difficulties). In this paper, using responder analysis we showed that S-1 was superior to taxane with respect to 5 of these 8 scales. One symptom scale (constipation) also showed a better effect of S-1. These findings may be summarized as follows: individual-level effects may indicate group-level effects, but not vice versa.

The responder analysis conducted in this paper is different from conventional methods such as the MMRM in several points. The most important difference is the parameter that each analysis method targets (estimand). Usually, the MMRM is used to compare least-squares means between treatment groups at the last visit. This estimand is the difference in averages of quality-of-life scores between treatment groups if all the patients continued the randomized treatment until the last visit without dropout [40]. The estimand of responder analysis is the difference in proportions of responder patients (or hazard ratios of time to respond) between treatment groups while on treatment. The estimand of MMRM analysis may not be of interest when lots of treatment switching or deaths occur until the last visit, while that of responder analysis avoids this problem by including these events in the definition of responders. The advantage of MMRM analysis is that it uses all the observed quality-of-life scores; on the other hand, responder analysis may involve loss of information due to dichotomization into responders and nonresponders. However, as was shown in this paper, researchers can emphasize a treatment effect within subscales which showed a significant difference not only by MMRM but also by responder analysis. Each method estimates different estimands and has advantages and disadvantages; therefore, we recommend that both results are shown for quality-of-life data.

As we noted, the definition of response is arbitrary. Therefore, we conducted sensitivity analyses by changing the definitions into the conventional 10-point scale and using another definition reported by Bedard et al. [33]. The results of the sensitivity analysis do not change our conclusions qualitatively. Because the 0-100 scale of the QLQ-C30 is discrete, the small change in response definition does not affect the results. This can also be demonstrated by the CDF plots (Fig. 3). For example, the CDF plots of global health status/QoL are apart a change score of about 0 to 30 from baseline. In our primary analysis, we used 10 points as the definition of response for global health status/QoL, but we can expect that a response definition around 10 points does not affect the result. We consider that CDF plots are useful as a supplemental tool and as a sensitivity analysis tool for responder analysis.

One limitation of the on-treatment analysis we conducted is the possibility of posttreatment selection bias. The presence of bias is due to selections (restrictions) on patients who are on first-line treatment. Patients who are healthy enough to tolerate the chemotherapies tend to contribute to the analysis, so the proportions of deteriorated patients in each treatment group may be underestimated. However, our main aim was to compare PRO measurements between treatment groups, not to estimate the probability of deteriorated patients in each treatment group. Therefore, we believe that this bias has little effect on our conclusions. Another limitation may include that some of the results above may be false positive due to the multiplicity testing problem. This problem is inherent when considering outcome measures consisting of multidomains such as HRQoL. If HRQoL measurements are the primary endpoint, we surely need to care for multiple testing by selecting the most important domain, statistically adjusting the multiple testing with, for instance, the Bonferroni method or the closed testing procedure, or using the summary score. In this paper, we exploratorily analyzed HRQoL measurements, which are secondary endpoints in the SELECT BC trial. To confirm our results, we consider that more trials are needed, but we believe that our findings are important for choosing first-line chemotherapy for metastatic breast cancer.

In this paper, we showed that first-line S-1 therapy may have a clinical benefit for metastatic breast cancer patients with respect to 3 functional scales, 2 symptomatic scales, and global health status/QoL on the QLQ-C30. Moreover, a benefit from S-1 was also seen with respect to patient-reported neuropathy on the PNQ. These findings should be of importance for choosing first-line chemotherapy among patients with metastatic breast cancer.

This study was funded by the Comprehensive Support Project (CSP) of the Public Health Research Foundation. The research fund was provided to the CSP by Taiho Pharmaceutical Co., Ltd., under the study contract. Finally, we appreciate the participation of those in the SELECT BC trial, and all the investigators and study collaborators.

Y.O. has received consulting fees from Taiho Pharmaceutical. H.M. has received personal fees as honoraria from AstraZeneca, Novartis Pharma, and Taiho Pharmaceutical, and research funds from Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Nippon Kayaku, Novartis Pharma, Pfizer Japan, and Sanofi. The other authors declare that they have no conflict of interest.

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