Health-related quality of life in the randomized phase 3 study of ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced urothelial carcinoma (RANGE)

Background To evaluate patient-reported outcomes with ramucirumab plus docetaxel, a regimen which improved progression-free survival in platinum-refractory advanced urothelial carcinoma (aUC). Methods RANGE—a randomized, double-blinded, phase 3 trial in patients with platinum-refractory aUC. Ramucirumab (10 mg/kg) plus docetaxel (75 mg/m2) or placebo plus docetaxel were administered every 21 days until disease progression or unacceptable toxicity. Patients received maximum 10 cycles of docetaxel. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EuroQoL five-dimensions (EQ-5D-5L) were administered at baseline, start of each cycle, and 30-day follow-up visit. A ≥ 10-point change in QLQ-C30 scores was considered meaningful. Rates of improved/stable scores were compared between treatment arms using Fisher’s exact test. Time to deterioration (TtD) was estimated and compared using Kaplan–Meier estimation and log-rank test. Results Of the 530 patients, ~ 97% patients in each arm provided baseline QLQ-C30 data. On-treatment compliance was ≥ 88% for first 8 cycles. Mean baseline QLQ-C30 scores were similar between arms, with global quality of life (QoL), fatigue, pain, and insomnia having greatest impairment. Postbaseline rates of improved/stable QLQ-C30 scores were similar between treatment arms except for greater improvement in pain score with ramucirumab. TtD of QLQ-C30 scales favored ramucirumab arm. Baseline EQ-5D-5L index and visual analogue scale scores were similar between arms, followed by relatively stable on-treatment scores. EQ-5D-5L scores worsened at post-discontinuation follow-up visit. Conclusions Ramucirumab plus docetaxel did not negatively impact QoL compared with docetaxel alone in platinum-refractory aUC. Improved TtD and tumor associated rates of pain favored ramucirumab treatment. Clinical trail registration NCT02426125. https://clinicaltrials.gov/ct2/show/NCT02426125. Date of registration: April 24th 2015


Background
Advanced/metastatic urothelial carcinoma (UC), including carcinomas arising in the bladder, urethra, ureter, and/or renal pelvis, has a poor prognosis. Median survival is approximately 12-14 months with standard first-line platinum-based chemotherapy for advanced/ metastatic disease [1]. Despite approvals of various targeted therapies for platinum-refractory advanced UC, most patients have limited treatment options as they experience disease progression. Ramucirumab plus docetaxel has shown higher response rate and improved progression-free survival (PFS) compared to placebo plus docetaxel in the platinum-refractory population [2,3]. In the refractory setting, quality of life (QoL) is an important factor in the treatment decision-making process for patients with cancer where symptom palliation is the primary goal of therapy [4,5]. Monitoring of QoL via patient-reported symptoms is also associated with better outcomes than observed with usual care [6].
The impact of treatment on QoL is not widely reported in refractory advanced UC (aUC), particularly for chemotherapy and anti-VEGFR-2 drug combination therapies. Therefore, we assessed the patient-reported outcomes (PROs) as secondary endpoints in the RANGE trial to evaluate the benefit-risk profile of the addition of ramucirumab to docetaxel from the patient perspective [3]. We hypothesized that patients would experience more symptomatic improvement without experiencing detriment in QoL.

Study design
The RANGE trial design and the outcome of its primary endpoint were previously published [2]. The trial was conducted during July 2015 and April 2017 and approved by appropriate review boards/ethics committees and followed the principles outlined in the Declaration of Helsinki. All patients provided written informed consent. This study adhered to the CONSORT guidelines.

Patient eligibility criteria
Eligibility criteria included patients with Eastern Cooperative Oncology Group (ECOG) performance status of zero or one and whose advanced disease progressed during or ≤ 14 months after first-line platinum-based chemotherapy. Patients may have also received one checkpoint inhibitor therapy prior to enrollment onto RANGE, in which case prior platinum-containing chemotherapy in ≤ 24 months was allowed. Patients were excluded if they had received a taxane previously [2].
Eligible patients were randomized to receive docetaxel (75 mg/m 2 , intravenously [IV]) plus ramucirumab (10 mg/kg, IV) or docetaxel plus placebo, administered on day 1 of each 21-day cycle. Randomization was stratified by geographic region (North America, East Asia, or Europe/other), ECOG performance status at baseline (0 or 1), and visceral metastasis (present or absent). Ramucirumab treatment continued until there was documented disease progression, toxicity or intolerance requiring discontinuation, withdrawal of consent, or noncompliance. Docetaxel could continue, if no prespecified discontinuation criteria were met, for up to six cycles with an additional four cycles allowed if an adequate treatment response was observed. Tumor responses were Keyword: Antiangiogenesis, Bladder cancer, Neoplasm metastatsis, Patient-reported outcomes, Quality of life, Ramucirumab, Urinary bladder neoplasm, Urothelial carcinoma assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [13].

Outcomes and assessments
Assessment of PROs, a secondary endpoint of the RANGE trial, was conducted through use of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), version 3 and the EuroQoL five-dimensions, 5 level (EQ-5D-5L) questionnaire, which measure QoL (functional domains and symptoms) and health status, respectively [14,15]. Patients completed the questionnaires only if there were cross-culturally validated translations in which they were fluent. Prior to any extensive contact with clinical personnel, patients were asked to complete the questionnaires at baseline, prior to the start of each cycle, and within 30 days after treatment discontinuation (follow-up). QLQ-C30 data were scored according to the EORTC guidelines, using a 0-100 scale with higher scores for global QoL and functional scales representing better QoL and lower scores for symptom scales representing less burden. A ≥ 10-point change was considered clinically meaningful [16]. EQ-5D-5L index values were based on the value set for England with a range of -0.281 to 1, with zero representing death and one representing perfect health [17]. Additionally, patients indicated their current health status by marking on a visual analogue scale (VAS) ranging from 0 (worst-imaginable health state) to 100 (best-imaginable health state) [15].

Statistical analysis
Analyses were conducted in the intention-to-treat (ITT) population except for descriptive statistics that were limited to the number of patients who provided data at a given assessment. Compliance rates were calculated based on the number of patients expected to provide data at a given assessment (i.e., those patients still receiving study therapy). Descriptive statistics were used to summarize data, including change from baseline as well as for the EQ-5D-5L scores. QLQ-C30 scores were classified as improved or worsened if change from baseline was ≥ 10 points; change < 10 points was classified as stable. For each scale at each postbaseline assessment, the proportion of patients with improved or stable scores was compared using the Fisher's exact test. Time to sustained deterioration (TtD) was defined as time from randomization date to first worsening of ≥ 10 points with no subsequent non-worsened assessment relative to baseline. If there were no subsequent assessments, the patient was classified as deteriorated. The follow-up assessment after treatment discontinuation could not be considered as a subsequent non-worsened assessment. Patients without deterioration were censored at the last non-deteriorated assessment. Kaplan-Meier method was used to estimate the probability of TtD, and unstratified log-rank test was used to investigate significance between treatment groups. Univariable Cox regression analysis was performed to test the association of treatment with TtD. No adjustments were made for multiplicity, but p-values < 0.05 were used to identify potential trends. These analyses discussed here were performed on the ITT population at the time of the OS database lock [3]. All the analyses were conducted using SAS software (SAS, Version 9.1.2 or higher).

RANGE patients and questionnaire compliance
In the randomly assigned patients (N = 530, ITT population) from the 727 screened for eligibility ( Fig. 1), baseline characteristics were similar between treatment arms (Table 1). At baseline, 254 (96.6%) of patients in the ramucirumab arm and 260 (97.4%) in the placebo arm provided QLQ-C30 and EQ-5D-5L data ( Table 2). For the first 8 cycles, compliance was ≥ 88% for both the QLQ-C30 and EQ-5D-5L, ( Table 2). The most common reasons for noncompliance were failure by the site to administer and patient refusal to complete the questionnaires ( Fig. 1). At the post-discontinuation followup visit, compliance was lower overall, with 52-54% of patients providing data. When grouped by those who provided data at follow-up and those who did not, the groups were similar in baseline patient characteristics, time on therapy, BOR, and reasons for discontinuation.

Descriptive summaries
Mean baseline scores for both questionnaires were similar between treatment arms (Table 3). With high scores being favorable for global QoL and functional domains of the QLQ-C30, the lowest mean scores were reported for global QoL, indicating the domain with greatest impairment at baseline. With low scores being favorable for symptoms, the highest mean scores were reported for fatigue, pain, and insomnia, indicating the symptoms of greatest burden at baseline.
When considering high-level assessment of QoL and health status, no clear differences were observed between the treatment arms for changes in mean scores from baseline of the QLQ-C30 global QoL scale, EQ-5D-5L index, and EQ-5D-5L VAS (Fig. 2a-c). Although scores within arms worsened over time, the mean changes for on-treatment assessments were small. Similar patterns of no differences between arms in changes from baseline were observed for the other QoL scales, with the exception of pain (Additional file 1: Figure S1). For the functional scales, worsened scores over time were observed for physical and role functioning. For symptom scales, fatigue, dyspnea, and diarrhea had the greatest worsening over time. In the case of pain, improved scores were observed in the ramucirumab arm over the first five cycles, while scores worsened in the placebo arm. Additional file 1: Figure S2 summarizes the distribution of EQ-5D-5L responses over time. At baseline, the highest levels of impairment (i.e., moderate or more severe) were reported for pain/discomfort. In general, the distributions of responses for all dimensions were similar over time for on-treatment assessments (Additional file 1: Figure S2A-E). For all scales, change from baseline was worst at the post-discontinuation follow-up assessment. Thus, in general, findings of the QLQ-C30 and the EQ-5D-5L were consistent.

Rates of improved or stable scores
The proportion of patients whose QoL scores improved, remained stable, or deteriorated from baseline at each postbaseline assessment are shown in Fig. 4, for the scales with the greatest impairment at baseline; Additional file 1: Figure S4 depicts these results for all other scales. For each scale, rates of improved/stable were similar between treatment arms in early cycles. Of note, a higher proportion of patients in the ramucirumab arm had either improved or stable pain scores at cycles 4, 5, and 7 compared to the placebo arm (Fig. 4d). Indeed, across all cycles, the pain scale, relative to the other scales ( Fig. 3a and Additional file 1: S4), exhibited consistency with respect to having the greatest proportion of patients with improvement in pain within the ramucirumab arm.

Exploratory analyses
Considering all prespecified analyses, the consistency of the pain results prompted an exploratory analysis evaluating the association with best overall response to treatment (Fig. 5). Because the global QoL scale provides the most holistic assessment, it was similarly evaluated. During the first four cycles, the range of patients achieving complete response (CR)/partial response (PR) with improved global QoL was 17.6-25.0% for ramucirumab and 10.8-21.6% for placebo; the range for patients with stable disease (SD) was 9.6-17.3% for ramucirumab and 10.0-21.8% for placebo (Fig. 5a). During the first four cycles, the range of patients achieving CR/PR with   improved pain was 29.4-30.9% for ramucirumab and 13.5-27.0% for placebo; the range for patients with SD was 17.3-28.8% for ramucirumab and 16.4-29.1% for placebo (Fig. 5b). In general, a higher proportion of patients who achieved CR/PR had improved pain scores in the ramucirumab arm versus the placebo arm. No apparent difference in pain palliation was seen between arms for patients who achieved SD. Similar results were observed for improved global QoL between ramucirumab versus placebo arms in patients who achieved CR/PR and SD (Fig. 5).

Discussion
QoL is of utmost importance when considering therapeutic options for patients in the palliative setting [4,18]. There can be concerns when a second agent is added to chemotherapy if gains in efficacy are also accompanied by increased toxicity [19], such as in the RANGE study where there were numerically higher rates of any-grade diarrhea, decreased appetite, nausea, and stomatitis in the ramucirumab plus docetaxel arm compared with the placebo plus docetaxel arm [3]. Thus, evaluating the effects on QoL through PROs when ramucirumab plus docetaxel was compared to placebo plus docetaxel was a key secondary endpoint in the RANGE trial. While on therapy, patients in the placebo plus docetaxel arm generally maintained global QoL and health status. Results were similar for the ramucirumab plus docetaxel arm, suggesting no detrimental impact. Worsening at the 30-day follow-up visit in both treatment arms was potentially associated with the negative impact of disease progression, which was the most common reason for treatment discontinuation. The longer PFS was consistent with trend for longer TtD in global QoL in the ramucirumab plus docetaxel arm. These findings may be In our study, all of the more specific aspects of QoL were at least maintained in the ramucirumab plus docetaxel arm relative to the placebo plus docetaxel arm. The strongest trend of delay in deterioration among the functional scales favoring ramucirumab plus docetaxel was for physical functioning which addresses mobility and self-care. Fatigue and insomnia were two of the most prominent symptoms reported by patients at baseline. Changes in fatigue were similar between arms, with patients more likely to report worsening. Insomnia scores generally remained similar both between and within arms.
Of all of the dimensions assessed by the QLQ-C30 and the EQ-5D-5L, pain may be the one most closely associated with disease symptoms and treatment efficacy, with less confounding by toxicity of treatment [20][21][22].
At baseline, the mean score for pain from the QLQ-C30 indicated high levels of pain and < 30% of patients reported no pain or discomfort on the EQ-5D-5L. All analyses of pain from the QLQ-C30 suggested a differential effect between arms. In the descriptive summaries, mean scores generally improved for the ramucirumab plus docetaxel arm, but worsened for the placebo plus docetaxel arm. At later cycles, more patients in the ramucirumab plus docetaxel arm reported improved or stable pain scores. The HR for TtD was 0.79 (95% CI 0.61, 1.0). In the exploratory analysis conducted, patients treated with ramucirumab plus docetaxel, who achieved a complete or partial response, often reported improvement in pain. The observed relative benefit in pain palliation may be associated with the greater extent of tumor shrinkage among responders and longer duration of response seen in the ramucirumab plus docetaxel arm. The association of symptom palliation with tumor response in other populations has been previously reported [23,24]. Recent phase 3 studies of immune checkpoint inhibitors in similar study populations also assessed QoL [25,26]. Although trial designs differed, the control arms were single-agent chemotherapy, and QoL was assessed with the QLQ-C30. However, different analysis approaches limit comparisons across the studies. In general, chemotherapy-based regimens were associated with within-arm worsening in global QoL over time and checkpoint inhibitors were associated with no within-arm improvement or worsening. In KEYNOTE-045, the HR for time to first  deterioration in global QoL was0.72, indicating a longer time to first deterioration for pembrolizumab compared to chemotherapy [25]. In IMvigor211, the HR for time to sustained deterioration in global QoL was not reported, but median values were the same for atezoluzimab and chemotherapy [26].The HR for time to sustained deterioration in global QoL in RANGE was 0.887, trending for a longer time to deterioration for ramucirumab plus docetaxel compared to chemotherapy (docetaxel). In RANGE, the addition of ramucirumab to chemotherapy did not further worsen QoL but demonstrated withinarm improvements in pain scores. Both RANGE and KEYNOTE-045 [25] observed a worsening of QoL associated with disease progression. This supports our findings that disease-related symptoms may have a more prominent effect on QoL in this setting.
This study used robust analytical methods. The analysis was prespecified and completion rate of questionnaires was high during the study. The ramucirumab and placebo groups were similar at baseline in PROs and patient and disease characteristics. This study showed no deterioration of QoL with addition of ramucirumab, with consistency observed across QLQ-C30 global QoL scale, EQ-5D-5L index, and VAS scores. The completion rate at the post-discontinuation follow-up visit in our study was comparable to other studies in advanced cancer [27,28]. In our study slightly more than half of patients provided post-discontinuation data, limiting the characterization of QoL and health status for that time period.
Limitations in the study include PRO instruments, patient characteristics, and incomplete follow-up data. Although cancer-specific and the most widely used in aUC trials, the QLQ-C30 is not specific to UC. No validated tumor-specific module to supplement the QLQ-C30 is available for use to assess additional concerns of aUC patients [29,30]. With the baseline eligibility criterion of ECOG performance status of zero or one, there is less opportunity for patients to report improvements in PROs. As is common in advanced cancer trials, early discontinuation of patients results in non-random missing data; therefore, we attempted to minimize the impact by conducting cycle-by-cycle analysis to explore data trend instead of focusing on only certain cycle as a snapshot. We also made the general assumption that patients who discontinued therapy likely have worsened QoL, as might be expected with disease progression which was most common reason for study discontinuation. While PRO completion rates were lower at follow-up, characteristics and outcomes of patients who provided follow-up data were similar to those who did not. However, despite these limitations, trends in differences between arms were observed that were consistent with other clinical outcomes.
As the term itself suggests, PROs are reported by patients themselves without any interpretation from a physician or anyone else. PROs can be used to support evaluation of response to treatment and to increase clinician-patient engagement [31]. Integration of PROs to the care demonstrated a survival benefit in patients with cancer compared with patients undergoing usual care (median 31.2 months vs. median 26.0 months, p = 0.03) [6]. In addition, PROs provide patients with a mechanism to self-report symptoms, minimize a decline in QoL, reduce hospitalization and emergency room admissions, and prolonged time on chemotherapy [32]. As newer agents become available for aUC, PRO/QoL data should be provided to help clinicians make informed treatment decisions [33][34][35].

Conclusions
In summary, QoL outcomes of the phase 3 RANGE trial presented here provided additional insights regarding no negative impact of ramucirumab plus docetaxel on QoL compared with placebo plus docetaxel. The association of pain palliation with tumor response and disease control observed in this study may be used when considering therapeutic choices for advanced UC.