Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Chee KG, Nguyen DV, Brown M, Gandara DR, Wun T, Lara PN Jr. Positron emission tomography and improved survival in patients with lung cancer: the Will Rogers phenomenon revisited. Arch Intern Med. 2008;168:1541–9.

    Article  PubMed  Google Scholar 

  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.

  3. Bazan JG, Duan F, Snyder BS, Horng D, Graves EE, Siegel BA, et al. Metabolic tumor volume predicts overall survival and local control in patients with stage III non-small cell lung cancer treated in ACRIN 6668/RTOG0235. Eur J Nucl Med Mol Imaging. 2017;44:17–24.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google 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.

    Article  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  8. Goeckenjan G, Sitter H, Thomas M, Branscheid D, Flentje M, Griesinger F, et al. Prevention, diagnosis, therapy, and follow-up of lung cancer: interdisciplinary guideline of the German Respiratory Society and the German Cancer Society. Pneumologie. 2011;65:39–59.

    Article  CAS  PubMed  Google Scholar 

  9. Pöttgen C, Eberhardt W, Stamatis G, Stuschke M. Definitive radiochemotherapy versus surgery within multimodality treatment in stage III non-small cell lung cancer (NSCLC) – a cumulative meta-analysis of the randomized evidence. Oncotarget. 2017;8:41670–8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Patel AP, Crabtree TD, Bell JM, Guthrie TJ, Robinson CG, Morgensztern D, et al. National patterns of care and outcomes after combined modality therapy for stage IIIA non-small-cell lung cancer. J Thorac Oncol. 2014;9:612–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. www.onkozert.de/aktuelles_180309.htm. Accessed 19 January 2019.

  12. Rami-Porta R, Bolejack V, Crowley J, Ball D, Kim J, Lyons G, et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10:990–1003.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  15. Erdi YE, Mawlawi O, Larson SM, Imbriaco M, Yeung H, Finn R, et al. Segmentation of lung lesion volume by adaptive positron emission tomography image thresholding. Cancer. 1997;80(12 Suppl):2505–9.

    Article  CAS  PubMed  Google Scholar 

  16. Jentzen W. An improved iterative thresholding method to delineate PET volumes using the delineation-averaged signal instead of the enclosed maximum signal. J Nucl Med Technol. 2015;43:28–35.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Faraggi D, Simon R. A simulation study of cross-validation for selecting an optimal cutpoint in univariate survival analysis. Stat Med. 1996;15:2203–13.

    Article  CAS  PubMed  Google Scholar 

  19. Schwarzer G, Carpenter JR, Rücker G. Meta-analysis with R (use-R!). Heidelberg: Springer; 2015.

    Book  Google Scholar 

  20. Cheebsumon P, Boellaard R, de Ruysscher D, van Elmpt W, van Baardwijk A, Yaqub M, et al. Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology. EJNMMI Res. 2012;2:56.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Koo TR, Moon SH, Lim YJ, Kim JY, Kim Y, Kim TH, et al. The effect of tumor volume and its change on survival in stage III non-small cell lung cancer treated with definitive concurrent chemoradiotherapy. Radiat Oncol. 2014;9:283.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Warner A, Dahele M, Hu B, Palma DA, Senan S, Oberije C, et al. Factors associated with early mortality in patients treated with concurrent chemoradiation therapy for locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2015;94:612–20.

    Article  PubMed  Google Scholar 

  23. Stinchcombe TE, Morris DE, Moore DT, Bechtel JH, Halle JS, Mears A, et al. Post-chemotherapy gross tumor volume is predictive of survival in patients with stage III non-small cell lung cancer treated with combined modality therapy. Lung Cancer. 2006;52:67–74.

    Article  PubMed  Google Scholar 

  24. Ahmed I, Ferro A, Baby R, Malhotra J, Cohler A, Langenfeld J, et al. Modern induction chemotherapy before chemoradiation for bulky locally-advanced nonsmall cell lung cancer improves survival. J Cancer Res Ther. 2016;12:952–8.

    Article  CAS  PubMed  Google Scholar 

  25. Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005;23:5883–91.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  27. Saber A, Hiltermann TJN, Kok K, Terpstra MM, de Lange K, Timens W, et al. Mutation patterns in small cell and non-small cell lung cancer patients suggest a different level of heterogeneity between primary and metastatic tumors. Carcinogenesis. 2017;38:144–51.

    CAS  PubMed  Google Scholar 

  28. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376:2109–21.

    Article  CAS  PubMed  Google Scholar 

  29. Even AJG, Reymen B, La Fontaine MD, Das M, Mottaghy FM, Belderbos JSA, et al. Clustering of multi-parametric functional imaging to identify high-risk subvolumes in non-small cell lung cancer. Radiother Oncol. 2017;125:379–84.

    Article  PubMed  Google Scholar 

  30. Wu J, Gensheimer MF, Dong X, Rubin DL, Napel S, Diehn M, et al. Robust intratumor partitioning to identify high-risk subregions in lung cancer: a pilot study. Int J Radiat Oncol Biol Phys. 2016;95:1504–12.

    Article  PubMed  PubMed Central  Google 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.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Conant RC, Ashby WR. Every good regulator of a system must be a model of that system. Int J Syst Sci. 1970;1:89–97.

    Article  Google Scholar 

  33. Bensch F, van der Veen EL, Lub-de Hooge MN, Jorritsma-Smit A, Boellaard R, Kok IC, et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018;24:1852–8.

    Article  CAS  PubMed  Google Scholar 

  34. Huang W, Fan M, Liu B, Fu Z, Zhou T, Zhang Z, et al. Value of metabolic tumor volume on repeated 18F-FDG PET/CT for early prediction of survival in locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy. J Nucl Med. 2014;55:1584–90.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

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).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, West German Cancer Center, University of Duisburg-Essen Medical School, Hufelandstr. 55, 45122, Essen, Germany

    Maja Guberina, Martin Stuschke, Thomas Gauler & Christoph Pöttgen

  2. Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen Medical School, 45122, Essen, Germany

    Wilfried Eberhardt & Martin Schuler

  3. German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45122, Essen, Germany

    Martin Stuschke, Clemens Aigner, Martin Schuler & Ken Herrmann

  4. Department of Thoracic Surgery, Ruhrlandklinik, University of Duisburg-Essen Medical School, 45239, Essen, Germany

    Clemens Aigner & Georgios Stamatis

  5. Department of Pathology, West German Cancer Center, University of Duisburg-Essen Medical School, 45122, Essen, Germany

    Dirk Theegarten

  6. Department of Nuclear Medicine, West German Cancer Center, University of Duisburg-Essen Medical School, 45122, Essen, Germany

    Walter Jentzen & Ken Herrmann

Authors
  1. Maja Guberina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wilfried Eberhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Stuschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Gauler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Clemens Aigner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Schuler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Georgios Stamatis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dirk Theegarten
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Walter Jentzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ken Herrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christoph Pöttgen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Stuschke.

Ethics declarations

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.

Ethical approval

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guberina, M., Eberhardt, W., Stuschke, M. et al. 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. Eur J Nucl Med Mol Imaging 46, 1439–1447 (2019). https://doi.org/10.1007/s00259-019-4270-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-019-4270-x

Keywords

Search

Navigation