Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial

Bart J T Reymen; Marike W van Gisbergen; Aniek J G Even; Catharina M L Zegers; Marco Das; Erik Vegt; Joachim E Wildberger; Felix M Mottaghy; Ala Yaromina; Ludwig J Dubois; Wouter van Elmpt; Dirk De Ruysscher; Philippe Lambin

doi:10.1016/j.ctro.2019.12.002

Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial

Bart J T Reymen, Marike W van Gisbergen, Aniek J G Even, Catharina M L Zegers, Marco Das, Erik Vegt, Joachim E Wildberger, Felix M Mottaghy, Ala Yaromina, Ludwig J Dubois, Wouter van Elmpt, Dirk De Ruysscher, Philippe Lambin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Nitroglycerin is proposed as an agent to reduce tumour hypoxia by improving tumour perfusion. We investigated the potential of nitroglycerin as a radio-sensitizer in non-small cell lung cancer (NSCLC) and the potential of functional imaging for patient selection.

Material and methods: Trial NCT01210378 is a single arm phase II trial, designed to detect 15% improvement in 2-year overall survival (primary endpoint) in stage IB-IV NSCLC patients treated with radical (chemo-) radiotherapy and a Transiderm-Nitro 5 patch during radiotherapy. Patients underwent dynamic contrast-enhanced CTs (DCE-CT) and HX4 (hypoxia) PET/CTs before and after nitroglycerin. Secondary endpoints were progression-free survival, toxicity and the prognostic value of tumour perfusion/hypoxia at baseline and after nitroglycerin.

Results: The trial stopped after a futility analysis after 42 patients. At median follow-up of 41 months, two-year and median OS were 58% (95% CI: 44-78%) and 38 months (95% CI: 22-54 months), respectively. Nitroglycerin could not reduce tumour hypoxia. DCE-CT parameters did not correlate with OS, whereas hypoxic tumours had a worse OS (p = 0.029). Changes in high-uptake fraction of HX4 and tumour blood flow were negatively correlated (r = -0.650, p = 0.022). The heterogeneity in treatment modalities and patient characteristics combined with a small sample size made further subgroup analysis of survival results impossible. Toxicity related to nitroglyerin was limited to headache (17%) and hypotension (2.4%).

Conclusion: Nitroglycerin did not improve OS of NSCLC patients treated with (chemo-)radiotherapy. A general ability of nitroglycerin to reduce hypoxia was not shown.

Original language	English
Pages (from-to)	49-55
Number of pages	7
Journal	Clinical and Translational Radiation Oncology
Volume	21
DOIs	https://doi.org/10.1016/j.ctro.2019.12.002
Publication status	Published - Mar 2020

Keywords

CARBOPLATIN
CHEMOTHERAPY
CONCURRENT
HX4
HYPOXIA
Hypoxia
Mitochondria
NECK-CANCER
NITRIC-OXIDE
NSCLC
Nitroglycerin
PET
Perfusion
RADIOTHERAPY
STAGE IIIA

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Cite this

Reymen, B. J. T., van Gisbergen, M. W., Even, A. J. G., Zegers, C. M. L., Das, M., Vegt, E., Wildberger, J. E., Mottaghy, F. M., Yaromina, A., Dubois, L. J., van Elmpt, W., De Ruysscher, D., & Lambin, P. (2020). Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial. Clinical and Translational Radiation Oncology, 21, 49-55. https://doi.org/10.1016/j.ctro.2019.12.002

@article{f61c764a61e84e4e968cf41a2b3d0dd4,

title = "Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial",

abstract = "Background: Nitroglycerin is proposed as an agent to reduce tumour hypoxia by improving tumour perfusion. We investigated the potential of nitroglycerin as a radio-sensitizer in non-small cell lung cancer (NSCLC) and the potential of functional imaging for patient selection.Material and methods: Trial NCT01210378 is a single arm phase II trial, designed to detect 15% improvement in 2-year overall survival (primary endpoint) in stage IB-IV NSCLC patients treated with radical (chemo-) radiotherapy and a Transiderm-Nitro 5 patch during radiotherapy. Patients underwent dynamic contrast-enhanced CTs (DCE-CT) and HX4 (hypoxia) PET/CTs before and after nitroglycerin. Secondary endpoints were progression-free survival, toxicity and the prognostic value of tumour perfusion/hypoxia at baseline and after nitroglycerin.Results: The trial stopped after a futility analysis after 42 patients. At median follow-up of 41 months, two-year and median OS were 58% (95% CI: 44-78%) and 38 months (95% CI: 22-54 months), respectively. Nitroglycerin could not reduce tumour hypoxia. DCE-CT parameters did not correlate with OS, whereas hypoxic tumours had a worse OS (p = 0.029). Changes in high-uptake fraction of HX4 and tumour blood flow were negatively correlated (r = -0.650, p = 0.022). The heterogeneity in treatment modalities and patient characteristics combined with a small sample size made further subgroup analysis of survival results impossible. Toxicity related to nitroglyerin was limited to headache (17%) and hypotension (2.4%).Conclusion: Nitroglycerin did not improve OS of NSCLC patients treated with (chemo-)radiotherapy. A general ability of nitroglycerin to reduce hypoxia was not shown.",

keywords = "CARBOPLATIN, CHEMOTHERAPY, CONCURRENT, HX4, HYPOXIA, Hypoxia, Mitochondria, NECK-CANCER, NITRIC-OXIDE, NSCLC, Nitroglycerin, PET, Perfusion, RADIOTHERAPY, STAGE IIIA",

author = "Reymen, {Bart J T} and {van Gisbergen}, {Marike W} and Even, {Aniek J G} and Zegers, {Catharina M L} and Marco Das and Erik Vegt and Wildberger, {Joachim E} and Mottaghy, {Felix M} and Ala Yaromina and Dubois, {Ludwig J} and {van Elmpt}, Wouter and {De Ruysscher}, Dirk and Philippe Lambin",

note = "{\textcopyright} 2019 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.",

year = "2020",

month = mar,

doi = "10.1016/j.ctro.2019.12.002",

language = "English",

volume = "21",

pages = "49--55",

journal = "Clinical and Translational Radiation Oncology",

issn = "2405-6308",

publisher = "Elsevier Ireland Ltd",

}

Reymen, BJT , van Gisbergen, MW , Even, AJG , Zegers, CML, Das, M, Vegt, E, Wildberger, JE , Mottaghy, FM , Yaromina, A , Dubois, LJ , van Elmpt, W , De Ruysscher, D & Lambin, P 2020, 'Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial', Clinical and Translational Radiation Oncology, vol. 21, pp. 49-55. https://doi.org/10.1016/j.ctro.2019.12.002

TY - JOUR

T1 - Nitroglycerin as a radiosensitizer in non-small cell lung cancer

T2 - Results of a prospective imaging-based phase II trial

AU - Reymen, Bart J T

AU - van Gisbergen, Marike W

AU - Even, Aniek J G

AU - Zegers, Catharina M L

AU - Das, Marco

AU - Vegt, Erik

AU - Wildberger, Joachim E

AU - Mottaghy, Felix M

AU - Yaromina, Ala

AU - Dubois, Ludwig J

AU - van Elmpt, Wouter

AU - De Ruysscher, Dirk

AU - Lambin, Philippe

PY - 2020/3

Y1 - 2020/3

N2 - Background: Nitroglycerin is proposed as an agent to reduce tumour hypoxia by improving tumour perfusion. We investigated the potential of nitroglycerin as a radio-sensitizer in non-small cell lung cancer (NSCLC) and the potential of functional imaging for patient selection.Material and methods: Trial NCT01210378 is a single arm phase II trial, designed to detect 15% improvement in 2-year overall survival (primary endpoint) in stage IB-IV NSCLC patients treated with radical (chemo-) radiotherapy and a Transiderm-Nitro 5 patch during radiotherapy. Patients underwent dynamic contrast-enhanced CTs (DCE-CT) and HX4 (hypoxia) PET/CTs before and after nitroglycerin. Secondary endpoints were progression-free survival, toxicity and the prognostic value of tumour perfusion/hypoxia at baseline and after nitroglycerin.Results: The trial stopped after a futility analysis after 42 patients. At median follow-up of 41 months, two-year and median OS were 58% (95% CI: 44-78%) and 38 months (95% CI: 22-54 months), respectively. Nitroglycerin could not reduce tumour hypoxia. DCE-CT parameters did not correlate with OS, whereas hypoxic tumours had a worse OS (p = 0.029). Changes in high-uptake fraction of HX4 and tumour blood flow were negatively correlated (r = -0.650, p = 0.022). The heterogeneity in treatment modalities and patient characteristics combined with a small sample size made further subgroup analysis of survival results impossible. Toxicity related to nitroglyerin was limited to headache (17%) and hypotension (2.4%).Conclusion: Nitroglycerin did not improve OS of NSCLC patients treated with (chemo-)radiotherapy. A general ability of nitroglycerin to reduce hypoxia was not shown.

AB - Background: Nitroglycerin is proposed as an agent to reduce tumour hypoxia by improving tumour perfusion. We investigated the potential of nitroglycerin as a radio-sensitizer in non-small cell lung cancer (NSCLC) and the potential of functional imaging for patient selection.Material and methods: Trial NCT01210378 is a single arm phase II trial, designed to detect 15% improvement in 2-year overall survival (primary endpoint) in stage IB-IV NSCLC patients treated with radical (chemo-) radiotherapy and a Transiderm-Nitro 5 patch during radiotherapy. Patients underwent dynamic contrast-enhanced CTs (DCE-CT) and HX4 (hypoxia) PET/CTs before and after nitroglycerin. Secondary endpoints were progression-free survival, toxicity and the prognostic value of tumour perfusion/hypoxia at baseline and after nitroglycerin.Results: The trial stopped after a futility analysis after 42 patients. At median follow-up of 41 months, two-year and median OS were 58% (95% CI: 44-78%) and 38 months (95% CI: 22-54 months), respectively. Nitroglycerin could not reduce tumour hypoxia. DCE-CT parameters did not correlate with OS, whereas hypoxic tumours had a worse OS (p = 0.029). Changes in high-uptake fraction of HX4 and tumour blood flow were negatively correlated (r = -0.650, p = 0.022). The heterogeneity in treatment modalities and patient characteristics combined with a small sample size made further subgroup analysis of survival results impossible. Toxicity related to nitroglyerin was limited to headache (17%) and hypotension (2.4%).Conclusion: Nitroglycerin did not improve OS of NSCLC patients treated with (chemo-)radiotherapy. A general ability of nitroglycerin to reduce hypoxia was not shown.

KW - CARBOPLATIN

KW - CHEMOTHERAPY

KW - CONCURRENT

KW - HX4

KW - HYPOXIA

KW - Hypoxia

KW - Mitochondria

KW - NECK-CANCER

KW - NITRIC-OXIDE

KW - NSCLC

KW - Nitroglycerin

KW - PET

KW - Perfusion

KW - RADIOTHERAPY

KW - STAGE IIIA

U2 - 10.1016/j.ctro.2019.12.002

DO - 10.1016/j.ctro.2019.12.002

M3 - Article

C2 - 32021913

SN - 2405-6308

VL - 21

SP - 49

EP - 55

JO - Clinical and Translational Radiation Oncology

JF - Clinical and Translational Radiation Oncology

ER -