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.