Abstract
Purpose
18F-FDG uptake in irradiated non-tumour-affected oesophagus (NTO) on restaging PET is a potential surrogate for the measurement of radiation-induced inflammation. Radiation-induced inflammation itself has been shown to be of high prognostic relevance in patients undergoing preoperative radiochemotherapy (RCT) for locally advanced oesophageal cancer. We assessed the prognostic relevance of FDG uptake in the NTO in an independent cohort of patients treated with definitive RCT.
Methods
This retrospective evaluation included 72 patients with oesophageal squamous cell carcinoma treated with definitive RCT with curative intent. All patients underwent pretreatment and restaging FDG PET after receiving a radiation dose of 40–50 Gy. Standardized uptake values (SUVmax/SUVmean), metabolic tumour volume (MTV) and relative changes from pretreatment to restaging PET (∆SUVmax/∆SUVmean) were determined within the tumour and NTO. Univariate Cox regression with respect to overall survival (OS), local control (LC), distant metastases (DM) and treatment failure (TF) was performed. Independence of parameters was tested by multivariate Cox regression.
Results
∆SUVmax NTO and MTV were prognostic factors for all investigated clinical endpoints (OS, LC, DM, TF). Inclusion of clinical and PET tumour parameters in multivariate analysis showed that ∆SUVmax NTO was an independent prognostic factor. Furthermore, multivariate analysis of ∆SUVmax NTO using previously published cut-off values from preoperatively treated patients revealed that ∆SUVmax NTO was independent prognostic factor for OS (HR = 1.88, p = 0.038), TF (HR = 2.11, p = 0.048) and DM (HR = 3.02, p = 0.047).
Conclusion
NTO-related tracer uptake during the course of treatment in patients with oesophageal carcinoma was shown to be of high prognostic relevance. Thus, metabolically activity of NTO measured in terms of ∆SUVmax NTO is a potential candidate for future treatment individualization (i.e. organ preservation).
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References
Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992;326:1593–8.
Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA, Al-Sarraf M, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA. 1999;281:1623–7.
Sudo K, Xiao L, Wadhwa R, Shiozaki H, Elimova E, Taketa T, et al. Importance of surveillance and success of salvage strategies after definitive chemoradiation in patients with esophageal cancer. J Clin Oncol. 2014;32:3400–5.
Naik KB, Liu Y, Goodman M, Gillespie TW, Pickens A, Force SD, et al. Concurrent chemoradiotherapy with or without surgery for patients with resectable esophageal cancer: an analysis of the National Cancer Data Base. Cancer. 2017;123:3476–85.
Kranzfelder M, Schuster T, Geinitz H, Friess H, Büchler P. Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer. Br J Surg. 2011;98:768–83.
van Hagen P, Hulshof MCCM, van Lanschot JJB, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BPL, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–84.
Elimova E, Wang X, Etchebehere E, Shiozaki H, Shimodaira Y, Wadhwa R, et al. 18-fluorodeoxy-glucose positron emission computed tomography as predictive of response after chemoradiation in oesophageal cancer patients. Eur J Cancer. 2015;51:2545–52.
Malik V, Lucey JA, Duffy GJ, Wilson L, McNamara L, Keogan M, et al. Early repeated 18F-FDG PET scans during neoadjuvant chemoradiation fail to predict histopathologic response or survival benefit in adenocarcinoma of the esophagus. J Nucl Med. 2010;51:1863–9.
Palie O, Michel P, Ménard J-F, Rousseau C, Rio E, Bridji B, et al. The predictive value of treatment response using FDG PET performed on day 21 of chemoradiotherapy in patients with oesophageal squamous cell carcinoma. A prospective, multicentre study (RTEP3). Eur J Nucl Med Mol Imaging. 2013;40:1345–55.
Buscombe J. PET imaging of inflammation. Q J Nucl Med. 2014;58:284–9.
Hess S, Hansson SH, Pedersen KT, Basu S, Høilund-Carlsen PF. FDG-PET/CT in infectious and inflammatory diseases. PET Clin. 2014;9:497–519. vi–vii
Hennies S, Hermann RM, Gaedcke J, Grade M, Hess CF, Christiansen H, et al. Increasing toxicity during neoadjuvant radiochemotherapy as positive prognostic factor for patients with esophageal carcinoma. Dis Esophagus. 2014;27:146–51.
Wolff HA, Raus I, Jung K, Schüler P, Herrmann MK, Hennies S, et al. High-grade acute organ toxicity as a positive prognostic factor in primary radiochemotherapy for anal carcinoma. Int J Radiat Oncol Biol Phys. 2011;79:1467–78.
Zschaeck S, Hofheinz F, Zöphel K, Bütof R, Jentsch C, Schmollack J, et al. Increased FDG uptake on late-treatment PET in non-tumour-affected oesophagus is prognostic for pathological complete response and disease recurrence in patients undergoing neoadjuvant radiochemotherapy. Eur J Nucl Med Mol Imaging. 2017;44:1813–22.
Li Y, Lin Q, Luo Z, Zhao L, Zhu L, Sun L, et al. Value of sequential 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in prediction of the overall survival of esophageal cancer patients treated with chemoradiotherapy. Int J Clin Exp Med. 2015;8:10947–55.
van den Hoff J, Lougovski A, Schramm G, Maus J, Oehme L, Petr J, et al. Correction of scan time dependence of standard uptake values in oncological PET. EJNMMI Res. 2014;4:18.
Hofheinz F, Pötzsch C, Oehme L, Beuthien-Baumann B, Steinbach J, Kotzerke J, et al. Automatic volume delineation in oncological PET. Evaluation of a dedicated software tool and comparison with manual delineation in clinical data sets. Nuklearmedizin. 2012;51:9–16.
Hofheinz F, Langner J, Petr J, Beuthien-Baumann B, Steinbach J, Kotzerke J, et al. An automatic method for accurate volume delineation of heterogeneous tumors in PET. Med Phys. 2013;40:082503.
R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing.
Brower JV, Chen S, Bassetti MF, Yu M, Harari PM, Ritter MA, et al. Radiation dose escalation in esophageal cancer revisited: a contemporary analysis of the National Cancer Data Base, 2004 to 2012. Int J Radiat Oncol Biol Phys. 2016;96:985–93.
de Geus-Oei L-F, Slingerland M. PET-guided treatment algorithms in oesophageal cancer: the promise of the near future! J Thorac Dis. 2017;9:2736–9.
Ku GY, Kriplani A, Janjigian YY, Kelsen DP, Rusch VW, Bains M, et al. Change in chemotherapy during concurrent radiation followed by surgery after a suboptimal positron emission tomography response to induction chemotherapy improves outcomes for locally advanced esophageal adenocarcinoma. Cancer. 2016;122:2083–90.
Vallböhmer D, Hölscher AH, Dietlein M, Bollschweiler E, Baldus SE, Mönig SP, et al. [18F]-Fluorodeoxyglucose-positron emission tomography for the assessment of histopathologic response and prognosis after completion of neoadjuvant chemoradiation in esophageal cancer. Ann Surg. 2009;250:888–94.
Piessen G, Petyt G, Duhamel A, Mirabel X, Huglo D, Mariette C. Ineffectiveness of 18F-fluorodeoxyglucose positron emission tomography in the evaluation of tumor response after completion of neoadjuvant chemoradiation in esophageal cancer. Ann Surg. 2013;258:66–76.
Metser U, Rashidi F, Moshonov H, Wong R, Knox J, Guindi M, et al. (18)F-FDG-PET/CT in assessing response to neoadjuvant chemoradiotherapy for potentially resectable locally advanced esophageal cancer. Ann Nucl Med. 2014;28:295–303.
Kong F-MS, Ritter T, Quint DJ, Senan S, Gaspar LE, Komaki RU, et al. Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. Int J Radiat Oncol Biol Phys. 2011;81:1442–57.
Löck S, Perrin R, Seidlitz A, Bandurska-Luque A, Zschaeck S, Zöphel K, et al. Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging. Radiother Oncol. 2017;124:533–40.
Lemarignier C, Di Fiore F, Marre C, Hapdey S, Modzelewski R, Gouel P, et al. Pretreatment metabolic tumour volume is predictive of disease-free survival and overall survival in patients with oesophageal squamous cell carcinoma. Eur J Nucl Med Mol Imaging. 2014;41:2008–16.
Desbordes P, Ruan S, Modzelewski R, Pineau P, Vauclin S, Gouel P, et al. Predictive value of initial FDG-PET features for treatment response and survival in esophageal cancer patients treated with chemo-radiation therapy using a random forest classifier. PLoS One. 2017;12:e0173208.
Ma J, Wang Z, Wang C, Chen E, Dong Y, Song Y, et al. Individualized radiation dose escalation based on the decrease in tumor FDG uptake and normal tissue constraints improve survival in patients with esophageal carcinoma. Technol Cancer Res Treat. 2017;16:75–80.
Yap WK, Chang YC, Hsieh CH, Chao YK, Chen CC, Shih MC, et al. Favorable versus unfavorable prognostic groups by post-chemoradiation FDG-PET imaging in node-positive esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. Eur J Nucl Med Mol Imaging. 2018;45:689–98.
Cremonesi M, Garibaldi C, Timmerman R, Ferrari M, Ronchi S, Grana CM, et al. Interim 18F-FDG-PET/CT during chemo-radiotherapy in the management of oesophageal cancer patients. A systematic review. Radiother Oncol. 2017;125:200–12.
Bütof R, Hofheinz F, Zöphel K, Stadelmann T, Schmollack J, Jentsch C, et al. Prognostic value of pretherapeutic tumor-to-blood standardized uptake ratio in patients with esophageal carcinoma. J Nucl Med. 2015;56:1150–6.
van den Hoff J, Oehme L, Schramm G, Maus J, Lougovski A, Petr J, et al. The PET-derived tumor-to-blood standard uptake ratio (SUR) is superior to tumor SUV as a surrogate parameter of the metabolic rate of FDG. EJNMMI Res. 2013;3:77.
Zschaeck S, Löck S, Leger S, Haase R, Bandurska-Luque A, Appold S, et al. FDG uptake in normal tissues assessed by PET during treatment has prognostic value for treatment results in head and neck squamous cell carcinomas undergoing radiochemotherapy. Radiother Oncol. 2017;122:437–44.
Freilich J, Hoffe SE, Almhanna K, Dinwoodie W, Yue B, Fulp W, et al. Comparative outcomes for three-dimensional conformal versus intensity-modulated radiation therapy for esophageal cancer. Dis Esophagus. 2015;28:352–7.
Wu Z, Xie C, Hu M, Han C, Yi J, Zhou Y, et al. Dosimetric benefits of IMRT and VMAT in the treatment of middle thoracic esophageal cancer: is the conformal radiotherapy still an alternative option? J Appl Clin Med Phys. 2014;15:93–101.
Ling TC, Slater JM, Nookala P, Mifflin R, Grove R, Ly AM, et al. Analysis of intensity-modulated radiation therapy (IMRT), proton and 3D conformal radiotherapy (3D-CRT) for reducing perioperative cardiopulmonary complications in esophageal cancer patients. Cancers. 2014;6:2356–68.
Ypsilantis P-P, Siddique M, Sohn H-M, Davies A, Cook G, Goh V, et al. Predicting response to neoadjuvant chemotherapy with PET imaging using convolutional neural networks. PLoS One. 2015;10:e0137036.
Nakajo M, Jinguji M, Nakabeppu Y, Nakajo M, Higashi R, Fukukura Y, et al. Texture analysis of 18F-FDG PET/CT to predict tumour response and prognosis of patients with esophageal cancer treated by chemoradiotherapy. Eur J Nucl Med Mol Imaging. 2017;44:206–14.
Niedzielski JS, Yang J, Stingo F, Liao Z, Gomez D, Mohan R, et al. A novel methodology using CT imaging biomarkers to quantify radiation sensitivity in the esophagus with application to clinical trials. Sci Rep. 2017;7:6034.
Funding
This work was partly supported by the Major Projects of Fujian Natural Science Foundation (no. 2008-59-11), the Nature Science Foundation of China (no. 81101066), the Xiamen City Science and Technology Project guidance (3502Z20134004) and the Berliner Krebsgesellschaft (ZSF201720).
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S.Z. provided ideas for the study. S.Z., Y.L. and F.H. performed the analysis and drafted the manuscript. F.H. designed the figures and calculated the underlying statistics. Y.L., C.L. and W.H. were responsible for treatment, imaging, collection of patient data and follow-up. C.F., P.G., S.Z. and Y.L. provided ideas, supervised the analysis and interpretation of the data and reviewed the manuscript. All authors read and approved the final manuscript.
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Li, Y., Hofheinz, F., Furth, C. et al. Increased evidence for the prognostic value of FDG uptake on late-treatment PET in non-tumour-affected oesophagus in irradiated patients with oesophageal carcinoma. Eur J Nucl Med Mol Imaging 45, 1752–1761 (2018). https://doi.org/10.1007/s00259-018-3996-1
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DOI: https://doi.org/10.1007/s00259-018-3996-1