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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

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

In recent years, multiple studies have demonstrated the value of volumetric FDG-PET/CT parameters as independent prognostic factors in patients with non-small cell lung cancer (NSCLC). We aimed to determine the optimal cut-off points of pretreatment volumetric FDG-PET/CT parameters in predicting overall survival (OS) in patients with locally advanced NSCLC and to recommend imaging biomarkers appropriate for routine clinical applications.

Methods

Patients with inoperable stage IIB/III NSCLC enrolled in ACRIN 6668/RTOG 0235 were included. Pretreatment FDG-PET scans were quantified using semiautomatic adaptive contrast-oriented thresholding and local-background partial-volume-effect-correction algorithms. For each patient, the following indices were measured: metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUVmax, SUVmean, partial-volume-corrected TLG (pvcTLG), and pvcSUVmean for the whole-body, primary tumor, and regional lymph nodes. The association between each index and patient outcome was assessed using Cox proportional hazards regression. Optimal cut-off points were estimated using recursive binary partitioning in a conditional inference framework and used in Kaplan-Meier curves with log-rank testing. The discriminatory ability of each index was examined using time-dependent receiver operating characteristic (ROC) curves and corresponding area under the curve (AUC(t)).

Results

The study included 196 patients. Pretreatment whole-body and primary tumor MTV, TLG, and pvcTLG were independently prognostic of OS. Optimal cut-off points were 175.0, 270.9, and 35.5 cm3 for whole-body TLG, pvcTLG, and MTV, and were 168.2, 239.8, and 17.4 cm3 for primary tumor TLG, pvcTLG, and MTV, respectively. In time-dependent ROC analysis, AUC(t) for MTV and TLG were uniformly higher than that of SUV measures over all time points. Primary tumor and whole-body parameters demonstrated similar patterns of separation for those patients above versus below the optimal cut-off points in Kaplan-Meier curves and in time-dependent ROC analysis.

Conclusion

We demonstrated that pretreatment whole-body and primary tumor volumetric FDG-PET/CT parameters, including MTV, TLG, and pvcTLG, are strongly prognostic for OS in patients with locally advanced NSCLC, and have similar discriminatory ability. Therefore, we believe that, after validation in future trials, the derived optimal cut-off points for primary tumor volumetric FDG-PET/CT parameters, or their more refined versions, could be incorporated into routine clinical practice, and may provide more accurate prognostication and staging based on tumor metabolic features.

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Author information

Authors and Affiliations

  1. Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Ali Salavati, Sina Houshmand, Benjapa Khiewvan & Abass Alavi

  2. Department of Radiology, University of Minnesota, Minneapolis, MN, USA

    Ali Salavati

  3. Department of Biostatistics and Center for Statistical Sciences, Brown University School of Public Health, Providence, RI, USA

    Fenghai Duan

  4. Center for Statistical Sciences, Brown University School of Public Health, Providence, RI, USA

    Bradley S. Snyder

  5. Department of Biostatistics, Rollins School of Public Health, Emory University, Atlanta, GA, USA

    Bo Wei

  6. Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Benjapa Khiewvan

  7. American College of Radiology, ACR Center for Research and Innovation, Philadelphia, PA, USA

    Adam Opanowski

  8. Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD, USA

    Charles B. Simone II

  9. Mallinckrodt Institute of Radiology and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St, Louis, MO, USA

    Barry A. Siegel

  10. Department of Radiation Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH, USA

    Mitchell Machtay

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  1. Ali Salavati
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  2. Fenghai Duan
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  3. Bradley S. Snyder
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  9. Barry A. Siegel
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  11. Abass Alavi
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Corresponding authors

Correspondence to Ali Salavati or Abass Alavi.

Ethics declarations

Funding

The ACRIN 6668/RTOG 0235 Trial receives funding from the National Cancer Institute through the grants U01 CA079778 and UO1 CA080098.

Conflict of interest

None.

Ethical approval

Patients consented to the original prospective study, which was approved by the local institutional review board of each participating institution.

Appendix

Appendix

Table 5 Description of pre-treatment FDG-PET/CT measures (SUV, MTV, TLG) for the whole-body, primary tumor and lymph node regions
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Table 6 Univariable and multivariable Cox proportional hazard regression models for overall survival (OS) using continuous pre-treatment FDG-PET/CT measures (SUV, MTV, and TLG) from the whole body, primary tumor and lymph node regions. Partial-volume-effect-corrected measures are italicized and denoted by the prefix pvc
Full size table
Table 7 Estimated area under the time-dependent (cumulative sensitivity/dynamic specificity) receiver operating characteristic curve (AUC), along with 95% confidence interval, corresponding to 2-year overall survival (OS) for whole body and primary tumor FDG-PET/CT measures, along with corresponding differences. Partial-volume-effect-corrected measures are italicized and denoted by the prefix pvc. 95% confidence intervals were derived from the bootstrap technique (n = 2000)
Full size table
Table 8 Univariable and Multivariable Cox proportional hazard regression models for local-regional control (LRC) using continuous pre-treatment FDG-PET/CT measures (SUV, MTV, and TLG) from the whole body, primary tumor and lymph node regions. Partial-volume-effect-corrected measures are italicized and denoted by the prefix pvc. In analyzing time to locoregional failure, some of the FDG-PET/CT parameters demonstrated extreme departures from the proportional hazards assumption, which is integral to the Cox model. To remedy this, for the affected features, models with time-dependent coefficients were fit through an appropriate interaction with time
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Table 9 Univariable Cox proportional hazards regression models using timing of locoregional failure (LRF) from baseline (how soon from registration the patient experienced LRF) to predict overall survival (OS) among the subset of patients who experienced LRF (n = 69). Survival time was defined from the date of LRF to either death or patient censoring. The median survival time of this subset was 9.0 months
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Fig. 4
figure 4

Area under the time-dependent (cumulative sensitivity/dynamic specificity) receiver operating characteristic curve (AUC(t)) corresponding to overall survival (OS) over the range of observed follow-up time, demonstrating the discriminatory abilities of whole-body (A) and primary tumor parameters (B)

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Fig. 5
figure 5

(A) Scatterplot of whole-body SUVmean versus pvcSUVmean (B) Plot of percentage of difference between whole-body SUVmean and pvcSUVmean by tumor size (C) Scatterplot of whole-body TLG versus pvcTLG (D) Plot of percentage of difference between whole-body TLG and pvcTLG by tumor size

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Salavati, A., Duan, F., Snyder, B.S. 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 Imaging 44, 1969–1983 (2017). https://doi.org/10.1007/s00259-017-3753-x

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