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

Clin Transl Radiat Oncol. 2019 Dec 13:21:49-55. doi: 10.1016/j.ctro.2019.12.002. eCollection 2020 Mar.

Authors

Affiliations

¹ Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
² The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
³ Institute of Data Science, Maastricht University, The Netherlands.
⁴ Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
⁵ Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶ Department of Nuclear Medicine, University Hospital, RWTH Aachen University, Aachen, Germany.
⁷ The D-Lab & The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

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: BF, blood flow; BV, blood volume; CI, confidence interval; CoR, coefficient of repeatability; DCE-CT, dynamic contrast-enhanced CT; FHV, fraction of hypoxic volume hypoxic fraction of the GTV; GTV, gross tumour volume; GTVln, gross tumour volume of the lymph nodes; GTVp, gross tumour volume of the primary tumour; HX4; HX4, 2-nitroimidazole [18F]-HX4 (flortanidazole, 3-[18F]fluoro-2-(4-((2-nitro-1Himidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-propan-1-ol); HX4-HF, HX4 hypoxic fraction; HX4-HV, HX4 hypoxic volume; Hypoxia; INDAR, individualized accelerated radiotherapy; IQR, interquartile range; LRPFS, loco-regional progression free survival; MFS, metastasis-free survival; Mitochondria; NO, nitric oxide; NSCLC; NSCLC, non-small cell lung cancer; Nitroglycerin; OS, overall survival; PET, positron emission tomography; Perfusion; SUVmax, maximum standardised uptake value; SUVmean, mean standardised uptake value; TBR, tumour-to-blood ratio; TTD, total tumour dose.