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

Marianne E. Pavel, Simron Singh, Jonathan R. Strosberg, Lida Bubuteishvili-Pacaud, Evgeny Degtyarev, Maureen P. Neary, Carlo Carnaghi, Jiri Tomasek, Edward Wolin, Markus Raderer, Harald Lahner, Juan W. Valle, Rodney Pommier, Eric Van Cutsem, Margot E.T. Tesselaar, Gianfranco Delle Fave, Roberto Buzzoni, Matthias Hunger, Jennifer Eriksson, David CellaJean François Ricci, Nicola Fazio, Matthew H. Kulke, James C. Yao

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalThe Lancet Oncology
DOIs
StateAccepted/In press - 2017

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Neuroendocrine Tumors
Placebos
Quality of Life
Lung
Disease-Free Survival
Neoplasms
Random Allocation
Therapeutics
Pharmaceutical Preparations
Everolimus
Poisons
Somatostatin
Disease Progression
Outcome Assessment (Health Care)
Survival

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Pavel, Marianne E.; Singh, Simron; Strosberg, Jonathan R.; Bubuteishvili-Pacaud, Lida; Degtyarev, Evgeny; Neary, Maureen P.; Carnaghi, Carlo; Tomasek, Jiri; Wolin, Edward; Raderer, Markus; Lahner, Harald; Valle, Juan W.; Pommier, Rodney; Van Cutsem, Eric; Tesselaar, Margot E.T.; Fave, Gianfranco Delle; Buzzoni, Roberto; Hunger, Matthias; Eriksson, Jennifer; Cella, David; Ricci, Jean François; Fazio, Nicola; Kulke, Matthew H.; Yao, James C.

In: The Lancet Oncology, 2017.

Research output: Contribution to journalArticle

Pavel, ME, Singh, S, Strosberg, JR, Bubuteishvili-Pacaud, L, Degtyarev, E, Neary, MP, Carnaghi, C, Tomasek, J, Wolin, E, Raderer, M, Lahner, H, Valle, JW, Pommier, R, Van Cutsem, E, Tesselaar, MET, Fave, GD, Buzzoni, R, Hunger, M, Eriksson, J, Cella, D, Ricci, JF, Fazio, N, Kulke, MH & Yao, JC 2017, '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', The Lancet Oncology. https://doi.org/10.1016/S1470-2045(17)30471-0
Pavel, Marianne E. ; Singh, Simron ; Strosberg, Jonathan R. ; Bubuteishvili-Pacaud, Lida ; Degtyarev, Evgeny ; Neary, Maureen P. ; Carnaghi, Carlo ; Tomasek, Jiri ; Wolin, Edward ; Raderer, Markus ; Lahner, Harald ; Valle, Juan W. ; Pommier, Rodney ; Van Cutsem, Eric ; Tesselaar, Margot E.T. ; Fave, Gianfranco Delle ; Buzzoni, Roberto ; Hunger, Matthias ; Eriksson, Jennifer ; Cella, David ; Ricci, Jean François ; Fazio, Nicola ; Kulke, Matthew H. ; Yao, James C. / 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. In: The Lancet Oncology. 2017.
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title = "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",
abstract = "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.",
author = "Pavel, {Marianne E.} and Simron Singh and Strosberg, {Jonathan R.} and Lida Bubuteishvili-Pacaud and Evgeny Degtyarev and Neary, {Maureen P.} and Carlo Carnaghi and Jiri Tomasek and Edward Wolin and Markus Raderer and Harald Lahner and Valle, {Juan W.} and Rodney Pommier and {Van Cutsem}, Eric and Tesselaar, {Margot E.T.} and Fave, {Gianfranco Delle} and Roberto Buzzoni and Matthias Hunger and Jennifer Eriksson and David Cella and Ricci, {Jean Fran{\cc}ois} and Nicola Fazio and Kulke, {Matthew H.} and Yao, {James C.}",
year = "2017",
doi = "10.1016/S1470-2045(17)30471-0",
language = "English (US)",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",

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TY - JOUR

T1 - Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4)

T2 - A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

AU - Pavel, Marianne E.

AU - Singh, Simron

AU - Strosberg, Jonathan R.

AU - Bubuteishvili-Pacaud, Lida

AU - Degtyarev, Evgeny

AU - Neary, Maureen P.

AU - Carnaghi, Carlo

AU - Tomasek, Jiri

AU - Wolin, Edward

AU - Raderer, Markus

AU - Lahner, Harald

AU - Valle, Juan W.

AU - Pommier, Rodney

AU - Van Cutsem, Eric

AU - Tesselaar, Margot E.T.

AU - Fave, Gianfranco Delle

AU - Buzzoni, Roberto

AU - Hunger, Matthias

AU - Eriksson, Jennifer

AU - Cella, David

AU - Ricci, Jean François

AU - Fazio, Nicola

AU - Kulke, Matthew H.

AU - Yao, James C.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

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