A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial

Background: We sought to determine whether the substantial benefits of topical nitroglycerin with first- line, platinumbased, doublet chemotherapy in advanced nonsmall- cell lung cancer ( NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. Patients and methods: Patients starting one of five, prespecified, platinum- based doublets as first- line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression- free survival ( PFS) was the primary end point. Results: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine ( 79%) or carboplatin and paclitaxel ( 18%). The final analysis included 345 events in 372 participants with a median follow- up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [ median 5.0 versus 4.8 months, hazard ratio ( HR) = 1.07, 95% confidence interval ( CI) 0.86- 1.32, P = 0.55], overall survival ( median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79- 1.24, P = 0.94), or objective tumor response ( 31% versus 30%, relative risk = 1.03, 95% CI 0.82- 1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. Conclusion: The addition of topical nitroglycerin to carboplatin- based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further.