original articles 14. Spitzer WO, Dobson AJ, Hall J et al. Measuring the quality of life of cancer patients: a concise QL-Index for use by physicians. J Chronic Dis 1981; 34: 585–597. 15. Dingemans A-MC, Groen HJM, Herder J et al. A randomized phase II study of paclitaxel-carboplatin-bevacizumab (PCB) with or without nitroglycerin patches (NTG) in patients ( pts) with stage IV nonsquamous non-small cell lung cancer (NSCLC): Nvalt 12 (NCT01171170). J Clin Oncol 2014; 32: 5s. 16. Reinmuth N, Meyer A, Hartwigsen D et al. Randomized, double-blind phase II study to compare nitroglycerin plus oral vinorelbine plus cisplatin with oral vinorelbine plus cisplatin alone in patients with stage IIIB/IV non-small cell lung cancer (NSCLC). Lung Cancer 2014; 83: 363–368.
Annals of Oncology 17. Cooper WA, Lam DCL, O’Toole SA, Minna JD. Molecular biology of lung cancer. J Thora Dis 2013; 5: S479–S490. 18. Gandara DR, Kawaguchi T, Crowley J et al. Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. J Clin Oncol 2009; 27: 3540–3546. 19. Lara PN, Redman MW. The hazards of randomized phase II trials. Ann Oncol 2012; 23: 7–9. 20. Maitland ML, Hudoba C, Snider KL, Ratain MJ. Analysis of the yield of phase II combination therapy trials in medical oncology. Clin Cancer Res 2010; 16: 5296–5302.
Annals of Oncology 26: 2286–2293, 2015 doi:10.1093/annonc/mdv370 Published online 7 September 2015
A randomized phase II study comparing paclitaxel– carboplatin–bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170)† A.-M. C. Dingemans1*, H. J. M. Groen2, G. J. M. Herder3, J. A. Stigt4, E. F. Smit5,6, I. Bahce5, J. A. Burgers6, B. E. E. M. van den Borne7, B. Biesma8, A. Vincent9, V. van der Noort9 & J. G. Aerts10,11 on behalf of the NVALT study group 1
Department of Respiratory Disease, Maastricht University Medical Center, Maastricht; 2Department of Respiratory Disease, University Medical Center Groningen, Groningen; Department of Respiratory Disease, Sint Antonius Hospital, Nieuwegein; 4Department of Respiratory Disease, Isala Hospital, Zwolle; 5Department of Respiratory Disease, VU Medical Center, Amsterdam; 6Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam; 7Department of Respiratory Disease, Catharina Hospital, Eindhoven; 8Department of Respiratory Disease, Jeroen Bosch Hospital’s, Hertogenbosch; 9Department of Biostatistics, Netherlands Cancer Institute, Amsterdam; 10 Department of Respiratory Disease, Amphia Hospital, Breda; 11Department of Respiratory Disease, University Medical Center Rotterdam, Rotterdam, The Netherlands 3
Received 2 July 2015; revised 17 August 2015; accepted 18 August 2015
Background: Nitroglycerin (NTG) increases tumor blood flow and oxygenation by inhibiting hypoxia-inducible-factor (HIF)-1. A randomized phase II study has shown improved outcome when NTG patches were added to vinorelbine/ cisplatin in patients with advanced nonsmall-cell lung cancer (NSCLC). In addition, there is evidence that the combination of bevacizumab and HIF-1 inhibitors increases antitumor activity. Patients and methods: In this randomized phase II trial, chemo-naive patients with stage IV nonsquamous NSCLC were randomized to four cycles of carboplatin (area under the curve 6)–paclitaxel (200 mg/m2)–bevacizumab 15 mg/kg on day 1 every 3 weeks with or without NTG patches 15 mg (day −2 to +2) followed by bevacizumab with or without NTG until progression. Response was assessed every two cycles. Primary end point was progression-free survival (PFS). The study was powered (80%) to detect a decrease in the hazard of tumor progression of 33% at α = 0.05 with a two-sided log-rank test when 222 patients were enrolled and followed until 195 events were observed. Results: Between 1 January 2011 and 1 January 2013, a total of 223 patients were randomized; 112 control arm and 111 experimental arm; response rate was 54% in control arm and 38% in experimental arm. Median [95% confidence interval (CI)] PFS in control arm was 6.8 months (5.6–7.3) and 5.1 months (4.2–5.8) in experimental arm, hazard ratio (HR) 1.27 (95% CI 0.96–1.67). Overall survival (OS) was 11.6 months (8.8–13.6) in control arm and 9.4 months (7.8–11.3) in experimental arm, HR 1.02 (95% CI 0.71–1.46). In the experimental arm, no additional toxicity was observed except headache (6% versus 52% in patients treated with NTG). *Correspondence to: Dr Anne-Marie C. Dingemans, Department of Pulmonary Medicine, Maastricht University Medical Center, PO Box 5800, Maastricht 6202 AZ, The Netherlands. Tel: +31-43-387-1318; E-mail:
[email protected] †
This study was presented in part at ASCO 2014 ( poster) and ESMO 2014 ( poster).
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
[email protected].
original articles
Annals of Oncology
Conclusion: Adding NTG to first-line carboplatin–paclitaxel–bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC. Key words: nonsmall-cell lung cancer, nitroglycerin, bevacizumab, VEGF
introduction Tumor hypoxia is a well-known factor negatively influencing outcome in many solid tumors, including nonsmall-cell lung cancer (NSCLC) [1, 2]. Hypoxia-inducible factor (HIF)-1 is the major factor regulating the response to hypoxia. HIF-1 directly activates vascular endothelial growth factor (VEGF) and VEGFreceptor [1, 2]. Bevacizumab, a monoclonal antibody against VEGF, interacts with this pathway by blocking VEGF. A landmark phase III study has shown that the addition of bevacizumab to carboplatin–paclitaxel in NSCLC leads to improved overall survival (OS) [3]. However, clinical outcome of NSCLC patients still remains unsatisfactory. One explanation may be persistent tumor hypoxia and activation of compensatory survival pathways that negatively impact outcome [4, 5]. Preclinical studies have shown that nitric oxide-donating drugs, such as nitroglycerin (NTG), may decrease hypoxia and HIF expression and increase tumor blood flow and consequently drug delivery [6]. In addition, it has been shown in a small patient study that NTG treatment decreases VEGF through reduction of HIF-1α [7]. In a randomized phase II study in patients with advanced NSCLC (n = 120), NTG patches were added to vinorelbine/ cisplatin [8]. In the NTG-treated patients, the response rate increased from 42% in the control arm to 72% and both time to progression and OS significantly increased. Furthermore,
combinations of bevacizumab and HIF-1 inhibitors may constitute an attractive therapeutic strategy [9]. The aim of the current study is to evaluate whether the addition of NTG patches to firstline bevacizumab containing chemotherapy improves progression-free survival (PFS) in patients with stage IV nonsquamous NSCLC.
patients and methods NVALT12 is a multicenter randomized open-label parallel group phase II trial conducted by the Dutch Lung Physician Society (NVALT). Chemo-naive patients with stage IV nonsquamous NSCLC were randomized between paclitaxel–carboplatin–bevacizumab with or without NTG patches after stratification for histology (adeno/nonadenocarcinoma), EGFR-mutation status (mutated, wild-type, unknown), gender and center. Inclusion criteria were stage IV nonsquamous NSCLC, no prior systemic treatment (except adjuvant chemotherapy >1 year ago and prior treatment with an EGFR TKI for patients with an activating EGFR mutation), age ≥18 years, WHO performance status of 0–2, measurable disease according to Response Evaluation Criteria in Solid Tumor (RECIST 1.1), adequate bone marrow and liver and renal function. Exclusion criteria included: clinically significant cardiovascular disease; hemoptysis ≥grade 2; tumor invading major blood vessels; HIV infection or chronic hepatitis B or C; active clinically serious infection; symptomatic brain metastases; organ allograft; evidence of bleeding diathesis; previous or active concurrent cancer except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors or curatively treated >2 years before study entry; nonhealing
Patients randomly assigned n = 223
Paclitaxel-carboplatin-bevacizumab Allocated to intervention Received allocated intervention Did not receive allocated intervention Death (n = 2) (n = 2) Clinical deterioration (n = 2) Protocol violation
(n = 112) (n = 107) (n = 5)
Lost to follow-up Discontinued intervention Progression Adverse event Patient refusal Death Other
(n = 1) (n = 110)
Analyzed Excluded from analysis
(n = 83) (n = 16) (n = 3) (n = 5) (n = 3)
(n = 112) (n = 0)
Paclitaxel-carboplatin-bevacizumab NTG Allocated to intervention Received allocated intervention Did not receive allocated intervention Death (n = 1) Clinical deterioration (n = 2)
(n = 111) (n = 107) (n = 4)
Lost to follow-up Discontinued intervention Progression Adverse event Patient refusal Protocol violation Death Other
(n = 0) (n = 111)
Analyzed Excluded from analysis
(n = 72) (n = 20) (n = 5) (n = 20) (n = 7) (n = 5)
(n = 111) (n = 0)
Figure 1. CONSORT diagram.
Volume 26 | No. 11 | November 2015
doi:10.1093/annonc/mdv370 |
original articles wound; abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months; radiotherapy within 4 weeks (palliative radiotherapy for bone lesions
