Clinical Investigation
Preoperative Prediction of Pathologic Response to Neoadjuvant Chemoradiotherapy in Patients With Esophageal Cancer Using 18F-FDG PET/CT and DW-MRI: A Prospective Multicenter Study

https://doi.org/10.1016/j.ijrobp.2019.12.038Get rights and content

Purpose

Accurate preoperative prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal cancer could enable omission of esophagectomy in patients with a pathologic complete response (pCR). This study aimed to evaluate the individual and combined value of 18F-fluorodeoxyglucose positron emission tomography with integrated computed tomography (18F-FDG PET/CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) during and after nCRT to predict pathologic response in patients with esophageal cancer.

Methods and Materials

In this multicenter prospective study, patients scheduled to receive nCRT followed by esophagectomy for esophageal cancer underwent 18F-FDG PET/CT and DW-MRI scanning before the start of nCRT, during nCRT, and before esophagectomy. Response to nCRT was based on histopathologic evaluation of the resection specimen. Relative changes in 18F-FDG PET/CT and DW-MRI parameters were compared between patients with pCR and non-pCR groups. Multivariable ridge regression analyses with bootstrapped c-indices were performed to evaluate the individual and combined value of 18F-FDG PET/CT and DW-MRI.

Results

pCR was found in 26.1% of 69 patients. Relative changes in 18F-FDG PET/CT parameters after nCRT (Δ standardized uptake value [SUV]mean,post P = .016, and Δ total lesion glycolysis post P = .024), as well as changes in DW-MRI parameters during nCRT (Δ apparent diffusion coefficient [ADC]during P = .008) were significantly different between pCR and non-pCR. A c-statistic of 0.84 was obtained for a model with ΔADCduring, ΔSUVmean,post, and histology in classifying patients as pCR (versus 0.82 for ΔADCduring and 0.79 for ΔSUVmean,post alone).

Conclusions

Changes on 18F-FDG PET/CT after nCRT and early changes on DW-MRI during nCRT can help identify pCR to nCRT in esophageal cancer. Moreover, 18F-FDG PET/CT and DW-MRI might be of complementary value in the assessment of pCR.

Introduction

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the preferred curative-intent treatment for patients with locally advanced esophageal cancer.1 Through tumor downsizing and downstaging, nCRT improves locoregional control and overall survival rates compared with surgery alone.2, 3, 4 Many studies have reported that the degree of tumor regression in response to nCRT is directly related to long-term survival, with pathologic complete responders having the most favorable long-term prognosis.3,5 The absence of viable tumor cells at the site of the primary tumor in pathologic complete responders raises the question of whether surgical resection is of benefit for patients who might have already been cured locoregionally by nCRT alone.6 Accurate prediction of pathologic complete response (pCR) before surgery could potentially allow patients to forgo surgery and would enable researchers to study the feasibility and outcome of an organ-preserving strategy after chemoradiotherapy. Conversely, patients with a poor response to nCRT are likely to benefit less or not at all from nCRT but are exposed to its side effects. Reliable identification of poor responders during nCRT may thus also be beneficial because ineffective therapy could be stopped or alternative treatment strategies (eg, additional neoadjuvant treatment or upfront surgery) could be explored.

Unfortunately, most studied modalities—including endoscopic biopsy, endoscopic ultrasonography, and computed tomography (CT)—yield unsatisfactory results for the evaluation of tumor response to nCRT.7, 8, 9, 10, 11 Metabolic and functional imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography with integrated computed tomography (18F-FDG PET/CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) may be more promising because they allow biological and microstructural characterization of tumors and visualization of treatment-induced changes before volumetric changes become apparent.9,12, 13, 14, 15, 16, 17, 18 However, the discriminatory ability of 18F-FDG PET/CT alone has been shown in a multitude of studies to be insufficient to guide clinical decision-making.14,19,20 The performance of DW-MRI and the quantitative apparent diffusion coefficient (ADC) are promising in predicting response to nCRT, although they have been demonstrated only in 2 small single-center pilot studies.16,17

A multimodality imaging approach, in comparison to single modality, may provide complementary value for predicting pathologic response, with the ultimate goal of optimally guiding individualized treatment decision-making. Therefore, the aim of this prospective multicenter study was to evaluate the individual and combined value of 18F-FDG PET/CT and DW-MRI during and after nCRT to predict pathologic response in patients who undergo nCRT for esophageal cancer, as well as to validate these findings for the prediction of survival.

Section snippets

Methods and Materials

Three high-volume institutions participated in this multicenter prospective study, including the University Medical Center Utrecht, the University of Texas MD Anderson Cancer Center, and the Netherlands Cancer Institute. The study has been approved by the institutional review board of each institution separately, and all patients provided their written informed consent. The study was registered with ClinicalTrials.gov, number NCT02125448.

Study population

Between October 2013 and July 2017, a total of 82 consecutive patients with newly diagnosed esophageal cancer who underwent standard diagnostic workup signed informed consent forms. A total of 13 patients were excluded from the analysis (withdrawal from study participation [n = 4], unexpected distant metastatic disease [n = 3], no tumor signal on the baseline 18F-FDG PET/CT or DW-MRI [n = 3], small tumor volume [<2 mL, n = 2], and refusal of surgery [n = 1]). The remaining 69 patients, with a

Discussion

This international, multicenter, prospective study was designed to assess the predictive value of quantitative changes on 18F-FDG PET/CT and DW-MRI scans acquired during and after nCRT in patients with esophageal cancer. Changes in 18F-FDG PET/CT parameters after nCRT (ΔSUVmean,post and ΔTLGpost) and changes in DW-MRI parameters during nCRT (ΔADCduring) discriminate well between pathologic complete responders (TRG 1) and non-pCR (TRG 2-4) in esophageal cancer. Moreover, 18F-FDG PET/CT and

Conclusions

Our study shows that quantitative ADC changes from baseline to interim DW-MRI scans and SUVmean changes from baseline to follow-up 18F-FDG PET/CT scans can help identify pCR to nCRT in patients with esophageal cancer. However, additional larger prospective studies, as well as other combined multimodal approaches, are needed to validate these results, especially regarding the potentially complementary value of 18F-FDG PET/CT and DW-MRI imaging parameters.

References (43)

  • E. Elimova et al.

    18-fluorodeoxy-glucose positron emission computed tomography as predictive of response after chemoradiation in oesophageal cancer patients

    Eur J Cancer

    (2015)
  • B.J. Noordman et al.

    Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): A prospective multicenter, diagnostic cohort study

    Lancet Oncol

    (2018)
  • J.A. Ajani et al.

    Oesophageal preservation in locally advanced oesophageal cancer

    Lancet Oncol

    (2018)
  • P.S. van Rossum et al.

    Imaging of oesophageal cancer with FDG-PET/CT and MRI

    Clin Radiol

    (2015)
  • P. van Hagen et al.

    Preoperative chemoradiotherapy for esophageal or junctional cancer

    N Engl J Med

    (2012)
  • T. Steffen et al.

    Recurrence patterns and long-term results after induction chemotherapy, chemoradiotherapy, and curative surgery in patients with locally advanced esophageal cancer

    Ann Surg

    (2019)
  • B.J. Noordman et al.

    Active surveillance in clinically complete responders after neoadjuvant chemoradiotherapy for esophageal or junctional cancer

    Dis Esophagus

    (2017)
  • M. Westerterp et al.

    Esophageal cancer: CT, endoscopic US, and FDG PET for assessment of response to neoadjuvant therapy—Systematic review

    Radiology

    (2005)
  • C. Yip et al.

    Performance of different imaging modalities in assessment of response to neoadjuvant therapy in primary esophageal cancer

    Dis Esophagus

    (2016)
  • S. Ngamruengphong et al.

    Assessment of response to neoadjuvant therapy in esophageal cancer: An updated systematic review of diagnostic accuracy of endoscopic ultrasonography and fluorodeoxyglucose positron emission tomography

    Dis Esophagus

    (2010)
  • D.-M. Koh et al.

    Diffusion-weighted MRI in the body: Applications and challenges in oncology

    Am J Roentgenol

    (2007)
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    Alicia S. Borggreve Lucas Goense made equal contributions to this study.

    This research was partially funded by Elekta Inc and by National Institutes of Health/National Cancer Institute Cancer Center support grant P30CA016672.

    Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

    Disclosures: R.v.H. and J.P.R. are proctoring surgeons for Intuitive Surgical Inc and train other surgeons in robot-assisted minimally invasive esophagectomy. J.J.W. receives research funding from Elekta Inc. S.H.L. receives research funding from Elekta Inc, Genentech, Hitachi Chemicals, New River Labs, and Beyond Spring Pharmaceuticals and is a member of the Advisory Board of AstraZeneca. All of the above are not in conflict with the research in question. All other authors have nothing to disclose.

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