Pretreatment metabolic tumour volume in stage IIIA/B non-small-cell lung cancer uncovers differences in effectiveness of definitive radiochemotherapy schedules: analysis of the ESPATUE randomized phase 3 trial
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According to the ACRIN 6668/RTOG 0235 trial, pretreatment metabolic tumour volume (MTV) as detected by 18F-fluorodeoxyglucose PET/CT is a prognostic factor in patients with stage III non-small-cell lung cancer (NSCLC) after definitive radiochemotherapy (RCT). To validate the prognostic value of MTV in patients with stage III NSCLC after RCT, we analysed mature survival data from the German phase III trial ESPATUE.
This analysis included patients who were staged by PET/CT and who were enrolled in the ESPATUE trial, a randomized study comparing definitive RCT (arm A) with surgery (arm B) after induction chemotherapy and RCT in patients with resectable stage IIIA/IIIB NSCLC. Patients refusing surgery and those with nonresectable disease were scheduled to receive definitive RCT. MTV was measured using a fixed threshold-based approach and a model-based iterative volume thresholding approach. Data were analysed using proportional hazards models and Kaplan-Meier survival functions.
MTV as a continuous variable did not reveal differences in survival between the 117 patients scheduled to receive definitive RCT and all 169 enrolled patients who underwent pretreatment PET/CT (p > 0.5). Five-year survival rates were 33% (95% CI 17–49%) in patients scheduled for definitive RCT with a high MTV (>95.4 ml) and 32% (95% CI: 22–42%) in those with a low MTV. The hazard ratio for survival was 0.997 (95% CI 0.973–1.022) per 10-ml increase in MTV and the slope was significantly shallower than that in the ACRIN 6668/RTOG 0235 trial (random effects model, p = 0.002). There were no differences in MTV size distributions between the ACRIN and ESPATUE trials (p = 0.97).
Patients with stage III NSCLC and a large MTV in whom definitive RCT had a particularly good survival in the ESPATUE trial. Treatment individualization according to MTV is not supported by this study. The ESPATUE and ACRIN trials differed by the use of cisplatin-containing induction chemotherapy and an intensified radiotherapy regimen that were particularly effective in patients with large MTV disease.
KeywordsMTV Prognostic marker Stage III Induction NSCLC
The ESPATUE trial was supported by grant no. 70-3070-Eb from German Cancer Aid. The West German Cancer Center at University Hospital Essen is supported by the Oncology Centre of Excellence Program of German Cancer Aid (grant no. 110534) and by the German Federal and State governments via the German Cancer Consortium (DKTK).
Compliance with ethical standards
Conflicts of interest
W. Eberhardt received honoraria from Eli Lilly, Boehringer Ingelheim, Pfizer, Novartis, Roche, Merck, Bristol-Myers Squibb, Amgen, GlaxoSmithKline, Aestellas, Bayer, Teva, Merck Serono, Daichi Sankyo and Hexal, and is a consultand or advisor to Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Roche, Merck, Bristol-Myers Squibb, Aestellas, Bayer, Teva, Daichi Sankyo. Research Funding and Eli Lilly (Inst).
T. Gauler received Honoraria from Eli Lilly, Boehringer Ingelheim, Merck Serono, Novartis, Roche, Pfizer, Bayer, MSD Oncology, Bristol-Myers Squibb, Symphogen and GlaxoSmithKline, is a consultand or advisor to MSD Oncology, Merck Serono, Novartis, and Eli Lilly, and received travel, accommodation and other expenses from Boehringer Ingelheim and Merck Serono.
M. Schuler received honoraria from Alexion Pharmaceuticals, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Eli Lilly, Novartis and Pfizer, is a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Celgene, Bristol-Myers Squibb, Novartis, IQWiG and Eli Lilly, and received research funding from Boehringer Ingelheim (Inst), Novartis (Inst) and Bristol-Myers Squibb (Inst). Patents, Royalties, Other intellectual property: patents (University Hospital Essen).
D. Theegarten is an advisory board member of E. Lilly.
C. Pöttgen received honoraria from Roche Pharma and Boehringer Ingelheim (speakers bureau).
All other authors declare no conflicts of interest.
All procedures performed were in accordance with the ethical standards of the institutional research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments. This secondary analysis was approved by the lead ethics committee of the Medical Faculty of the University Duisburg-Essen in September 2016.
- 2.Ohri N, Duan F, Machtay M, Gorelick JJ, Snyder BS, Alavi A, et al. Pretreatment FDG-PET metrics in stage III non-small cell lung cancer: ACRIN 6668/RTOG 0235. J Natl Cancer Inst. 2015;107(4). https://doi.org/10.1093/jnci/djv004.
- 4.Salavati A, Duan F, Snyder BS, Wei B, Houshmand S, Khiewvan B, et al. Optimal FDG PET/CT volumetric parameters for risk stratification in patients with locally advanced non-small cell lung cancer: results from the ACRIN 6668/RTOG 0235 trial. Eur J Nucl Med Mol Biol. 2017;44:1969–83.CrossRefGoogle Scholar
- 5.Bradley JD, Hu C, Komaki RU, Masters G, Blumenschein GR, Schild SE, et al. Long-term results of RTOG 0617: a randomized phase 3 comparison of standard dose versus high dose conformal chemoradiation therapy +/− cetuximab for stage III NSCLC. Int J Radiat Oncol Biol Phys. 2017;99(Suppl):S105.CrossRefGoogle Scholar
- 6.Eberhardt WE, Pöttgen C, Gauler TC, Friedel G, Veit S, Heinrich V, et al. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol. 2015;33:4194–201.CrossRefGoogle Scholar
- 7.Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, et al. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016;34:953–62.CrossRefGoogle Scholar
- 11.www.onkozert.de/aktuelles_180309.htm. Accessed 19 January 2019.
- 13.Chiang A, Thibault I, Warner A, Rodrigues G, Palma D, Soliman H, et al. A comparison between accelerated hypofractionation and stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC): results of a propensity score-matched analysis. Radiother Oncol. 2016;118:478–84.CrossRefGoogle Scholar
- 14.Pöttgen C, Gauler T, Bellendorf A, Guberina M, Bockisch A, Schwenzer N, et al. Standardized uptake decrease on [18F]-fluorodeoxyglucose positron emission tomography after neoadjuvant chemotherapy is a prognostic classifier for long-term outcome after multimodality treatment: secondary analysis of a randomized trial for resectable stage IIIA/B non-small-cell lung cancer. J Clin Oncol. 2016;34:2526–33.CrossRefGoogle Scholar
- 17.Machtay M, Duan F, Siegel BA, Snyder BS, Gorelick JJ, Reddin JS, et al. Prediction of survival by [18F]fluorodeoxyglucose positron emission tomography in patients with locally advanced non-small-cell lung cancer undergoing definitive chemoradiation therapy: results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol. 2013;31(30):3823–30.CrossRefGoogle Scholar
- 26.Vokes EE, Herndon JE 2nd, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007;25:1698–704.CrossRefGoogle Scholar
- 31.Pöttgen C, Stuschke M, Graupner B, Theegarten D, Gauler T, Jendrossek V, et al. Prognostic model for long-term survival of locally advanced non-small-cell lung cancer patients after neoadjuvant radiochemotherapy and resection integrating clinical and histopathologic factors. BMC Cancer. 2015;15:363.CrossRefGoogle Scholar