Elsevier

The Lancet Oncology

Volume 18, Issue 10, October 2017, Pages 1411-1422
The Lancet Oncology

Articles
Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(17)30471-0Get rights and content

Summary

Background

In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint.

Methods

RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy—General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (± 1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783.

Findings

Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27–19·35) with everolimus and 9·23 months (5·52–not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55–1·21; log-rank p=0·31).

Interpretation

HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer.

Funding

Novartis Pharmaceuticals.

Introduction

Neuroendocrine tumours (NETs) are biologically and clinically heterogeneous tumours that arise from neuroendocrine cells throughout the body, mainly from the gastrointestinal tract and lungs. Most NETs are non-functional, meaning that they are not associated with symptoms of hormonal hypersecretion.1 Most patients with NETs are diagnosed at a late stage of the disease.2 Median overall survival for patients with metastatic well-differentiated NETs varies substantially by tumour origin, ranging from 14 months for cancers originating in the colon to 103 months for disease originating in the small intestine.3 Treatment goals for patients with unresectable or metastatic NETs include control of secretory symptoms (if the tumour is functional), control of tumour growth, improvement in survival, and preservation of health-related quality of life (HRQOL) for as long as possible.4

Research in context

Evidence before this study

We searched PubMed for articles published between Jan 1, 1990, and Jan 13, 2017, with the terms: “neuroendocrine tumors” OR “neuroendocrine tumours”; “health-related quality of life” OR “quality of life”; “EQ-5D”; “association” OR “correlation”; “disease progression” OR “progression-free survival”; AND “oncology” OR “cancer” OR “tumor” OR “tumour”. Our search retrieved one study reporting health-related quality of life (HRQOL) and baseline and end-of-treatment utility values in patients with neuroendocrine tumours (NETs) treated with everolimus. However, the study had no control group; thus, it does not provide definite evidence on the effect of everolimus on HRQOL in NETs. Moreover, although three systematic literature reviews have been published on HRQOL in NETs, evidence is scant with respect to specific NET subtypes—eg, those of gastrointestinal and lung origin. We identified one publication on health status utilities for pre-progression and post-progression health states in NETs; however, these were derived from time trade-off experiments using health state vignettes rather than from HRQOL questionnaires administered to patients. We identified six further studies reporting that delayed disease progression is associated with improved HRQOL, but none were done in patients with NETs.

Added value of this study

We present a prespecified secondary analysis of HRQOL in the RADIANT-4 trial. To our knowledge, our analysis is the first to assess the effect of everolimus versus placebo on HRQOL in patients with NETs and the first to investigate the effect of disease progression on HRQOL and utilities in NETs. Time to definitive deterioration of the Functional Assessment of Cancer Therapy—General (FACT-G) total score (by ≥7 points) did not differ between the everolimus and placebo groups.

Implications of all the available evidence

Approval of everolimus by the US Food and Drug Administration and the European Medicines Agency in 2016 for the treatment of patients with progressive, well-differentiated, non-functional NETs of gastrointestinal or lung origin that are unresectable, locally advanced, or metastatic was based on data from RADIANT-4, showing longer progression-free survival with everolimus than with placebo. Together with our secondary findings from RADIANT-4, we provide potentially practice-changing evidence that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. As more treatments become available for NETs, with no evidence for optimum sequencing, the decline in HRQOL and utility after disease progression shows the importance of considering HRQOL, along with progression-free survival, as a meaningful and patient-relevant endpoint in clinical trials of advanced NETs.

In addition to clinical benefit, assessment of patient-reported outcomes such as HRQOL is recognised as important to capture treatment-related and disease-related outcomes that are experienced directly by patients. Treatment-related toxic effects and pain caused by metastases or progressive disease can contribute to deterioration of HRQOL.4 As new treatment options emerge for non-curable advanced NETs, maintenance of HRQOL is an important treatment goal, and studies on HRQOL can aid in treatment selection. HRQOL is also important for health technology assessment agencies, because it can be used as an assessment of health status (utility) in cost-effectiveness evaluations of new interventions.

Although generally considered a gold-standard endpoint, overall survival in clinical trials of NETs might take a long time to assess because of long-term survival of patients with NETs post progression.5 Progression-free survival, a surrogate endpoint, is accepted increasingly in trials of NETs and has been recommended as a primary endpoint in clinical trials.6 In a review of published literature, an association was noted between progression-free survival and overall survival in NETs,7, 8 but no formal study has investigated the possible effect of disease progression on HRQOL. The relation between HRQOL, utility, and tumour progression has been assessed in several other malignant diseases suggesting that delayed progression results in superior HRQOL; however, this association has not been shown in NETs, in which patients often have indolent disease and, thus, good WHO performance status before initiation of treatment.

Everolimus is a potent oral inhibitor of mTOR.9 In the phase 3 RADIANT-4 trial,10 in patients with advanced, progressive, non-functional NETs of lung and gastrointestinal origin, everolimus resulted in longer progression-free survival than did placebo treatment. Based on safety and efficacy data from RADIANT-4, everolimus was approved for the treatment of advanced, progressive, non-functional, well-differentiated NETs of gastrointestinal or lung origin by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2016.

A secondary endpoint of the RADIANT-4 study was to compare HRQOL and WHO performance status between treatment groups. Here, we report the results of these analyses and those investigating the extent to which disease progression, irrespective of treatment assignment, is associated with a decline in HRQOL and utility scores.

Section snippets

Study design and participants

RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 study done in 97 centres in 25 countries worldwide (appendix pp 4–7).10 Adult patients (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or grade 2) NETs of lung or gastrointestinal origin. Additional key inclusion criteria included: WHO performance status 0 or 1; adequate bone marrow function

Results

Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled to the study; 205 patients were allocated everolimus and 97 patients were assigned placebo. Table 1 presents baseline and disease characteristics of patients, which are reported in more detail elsewhere.10 The median age of all patients was 63 years (range 22–86).

At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 patients allocated placebo completed either fully or partly the FACT-G questionnaire.

Discussion

The analysis of FACT-G total scores in patients with advanced, progressive, non-functional NETs of lung or gastrointestinal origin who were enrolled in the randomised, phase 3 RADIANT-4 trial shows that despite toxic effects of active cancer treatment (eg, adverse events with some risk for grade 3–4 adverse events and discontinuations because of adverse events), HRQOL is maintained in patients treated with everolimus, with no statistically or clinically relevant differences compared with

References (43)

  • MH Kulke et al.

    Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting

    J Clin Oncol

    (2011)
  • S Singh et al.

    Association between time to disease progression end points and overall survival in patients with neuroendocrine tumors

    Gastrointest Cancer

    (2014)
  • M Ter-Minassian et al.

    Association of progression-free survival with overall survival (OS) in patients (pts) with neuroendocrine tumor (NET) treated with somatostatin analogs

    Proc Am Soc Clin Oncol

    (2015)
  • D Lebwohl et al.

    Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases

    Ann NY Acad Sci

    (2013)
  • JC Yao et al.

    Phase III prospective randomized comparison trial of depot octreotide plus interferon alfa-2b versus depot octreotide plus bevacizumab in patients with advanced carcinoid tumors: SWOG S0518

    J Clin Oncol

    (2017)
  • K Webster et al.

    The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: properties, applications, and interpretation

    Health Qual Life Outcomes

    (2003)
  • KJ Yost et al.

    Combining distribution- and anchor-based approaches to determine minimally important differences: the FACIT experience

    Eval Health Prof

    (2005)
  • CA Bellera et al.

    Variables with time-varying effects and the Cox model: some statistical concepts illustrated with a prognostic factor study in breast cancer

    BMC Med Res Methodol

    (2010)
  • JG Ibrahim et al.

    Missing data methods in longitudinal studies: a review

    Test (Madr)

    (2009)
  • BF Kurland et al.

    Longitudinal data with follow-up truncated by death: match the analysis method to research aims

    Stat Sci

    (2009)
  • B Ratitch et al.

    Missing data in clinical trials: from clinical assumptions to statistical analysis using pattern mixture models

    Pharm Stat

    (2013)
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