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Combination of IVIM-DWI and 3D-ASL for differentiating true progression from pseudoprogression of Glioblastoma multiforme after concurrent chemoradiotherapy: study protocol of a prospective diagnostic trial

Combination of IVIM-DWI and 3D-ASL for differentiating true progression from pseudoprogression of... Background: Standard therapy for Glioblastoma multiforme (GBM) involves maximal safe tumor resection followed with radiotherapy and concurrent adjuvant temozolomide. About 20 to 30% patients undergoing their first post-radiation MRI show increased contrast enhancement which eventually recovers without any new treatment. This phenomenon is referred to as pseudoprogression. Differentiating tumor progression from pseudoprogression is critical for determining tumor treatment, yet this capacity remains a challenge for conventional magnetic resonance imaging (MRI). Thus, a prospective diagnostic trial has been established that utilizes multimodal MRI techniques to detect tumor progression at its early stage. The purpose of this trial is to explore the potential role of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and three-dimensional arterial spin labeling imaging (3D-ASL) in differentiating true progression from pseudoprogression of GBM. In addition, the diagnostic performance of quantitative parameters obtained from IVIM-DWI and 3D-ASL, including apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), perfusion fraction (f), and cerebral blood flow (CBF), will be evaluated. Methods: Patients that recently received a histopathological diagnosis of GBM at our hospital are eligible for enrollment. The patients selected will receive standard concurrent chemoradiotherapy and adjuvant temozolomide after surgery, and then will undergo conventional MRI, IVIM-DWI, 3D-ASL, and contrast- enhanced MRI. The quantitative parameters, ADC, D, D*, f, and CBF, will be estimated for newly developed enhanced lesions. Further comparisons will be made with unpaired t-tests to evaluate parameter performance in differentiating true progression from pseudoprogression, while receiver-operating characteristic (ROC) analyses will determine the optimal thresholds, as well as sensitivity and specificity. Finally, relationships between these parameters will be assessed with Pearson’s correlation and partial correlation analyses. (Continued on next page) * Correspondence: [email protected]; [email protected] Equal contributors Department of Radiology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi’an 710038, China © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. BMC Medical Imaging (2017) 17:10 Page 2 of 7 (Continued from previous page) Discussion: The results of this study may demonstrate the potential value of using multimodal MRI techniques to differentiate true progression from pseudoprogression in its early stages to help decision making in early intervention and improve the prognosis of GBM. Trial registration: This study has been registered at ClinicalTrials.gov (NCT02622620) on November 18, 2015 and published on March 28, 2016. Keywords: Glioblastoma multiforme, True progression, Pseudoprogression, Intravoxel incoherent motion diffusion-weighted imaging, Diffusion weighted imaging, Perfusion, 3D arterial spin labeling Highlights for them are totally different. Tumor progression reflects treatment failure and the treatment plan should be Intravoxel incoherent motion (IVIM) magnetic adjusted accordingly [10], while pseudoprogression is resonance imaging (MRI) allows the simultaneous associated with a favorable prognosis and can improve acquisition of diffusion and perfusion parameters spontaneously with adjuvant TMZ. If the latter is mis- which reflect tumor cellularity and vascularity, diagnosed as true progression, the treatment efficacy can respectively. be underestimated, thus leading to the inappropriate Arterial spin labeling (ASL) and IVIM are two adjust of therapy. However, true progression can not be commonly used perfusion MRI techniques without easily differentiated from pseudoprogression with current introducing contrast agents and are considered as conventional MRI sequences. Therefore, new imaging safe and reliable methods. tools that can assist clinicians in effectively identifying true progression versus pseudoprogression within 6 months Background after concurrent chemoradiotherapy are needed, which Glioblastoma multiforme (GBM) is the most common will facilitate the selection of appropriate treatment or the malignant primary brain tumor in adults. A combination early termination of an invalid treatment plan. of radiation therapy with concurrent or adjuvant temo- There have been several studies in which researchers zolomide (TMZ) following maximum safe tumor resec- differentiated true progression from treatment effects by tion can significantly improve patients’ survival, and is using advanced MR imaging techniques, such as diffusion currently the standard treatment for GBM. Even with weighted magnetic resonance imaging (DWI) and dy- this standard treatment, the survival of GBM patients namic susceptibility-weighted contrast-enhanced (DSC) remains extremely poor and the overall median survival MRI. True progression exhibits significantly lower appar- time is 14–18 months after treatment [1, 2]. ent diffusion coefficient (ADC) values compared with GBM treatment efficacy is generally evaluated with pseudoprogression [11, 12], reflecting the high cellularity contrast-enhanced MRI in conjunction with clinical as- of progressed tumor. Considering that ADC values can be sessment. Only recently have radiologists and clinicians compromised by perfusion, Le Bihan et al. introduced an observed some transient treatment-induced changes intravoxel incoherent motion (IVIM) technique [13, 14]. after radiotherapy which demonstrate tumor progression Slow diffusion coefficient (D) is the diffusion parameter features in contrast-enhanced MRI such as progressive which reflects the diffusion coefficient for water while fast enlargement and new enhancement. However, these diffusion coefficient (D*) represents perfusion-related features mainly derive from postsurgical changes includ- diffusion. Fraction of fast ADC (f) is the perfusion fraction ing radiation effects, treatment-induced inflammation, linked to microcirculation which has been successfully and ischemia [3, 4]. This phenomenon is referred to as applied to glioma grading and to differentiate recurrent pseudoprogression. Chemotherapy with TMZ signifi- tumors from treatment-related changes [15, 16]. DSC is a cantly increased the rate of pseudoprogression [5, 6]. It T2*-weighted technique to measure relative cerebral is reported that half of the patients with high-grade blood volume (rCBV) and lower mean rCBV values in gliomas after chemoradiotherapy showed an enlarged pseudoprogression was previously used to differentiate enhancement area on contrast-enhanced T1-weighted from true progression [17]. However, radiotherapy and magnetic resonance (MR) images, of which 20 to 30% chemotherapy for GBM destroy blood–brain barrier, were pseudoprogression [7–9]. allowing gadolinium-based contrast agents to leak into the While both tumor progression and pseudoprogression interstitial fluid, which may lead to the underestimation of exhibit progressive enlargement and new enhancement rCBV with DSC [18]. Three-dimensional arterial spin within a radiation field [3], the treatment and prognosis labeling (3D-ASL) is another non-invasive and contrast Liu et al. BMC Medical Imaging (2017) 17:10 Page 3 of 7 agent-free perfusion imaging method to measure cere- Methods/Design bral blood flow (CBF) [19]. The diagnostic perform- This prospective single institution observational study ance of 3D-ASL has been found to be equivalent to will include two case groups and has been approved by DSC MRI in assessing brain tumor perfusion, particu- the Ethics Committee of Tangdu Hospital (TDLL- larly for those patients not suitable for DSC because 20151013). The scheme of the current trial is presented of renal failure [20]. in Fig. 1. Despite the application of IVIM and 3D-ASL in glioma study, there still lacks study in which IVIM is combined Patient Selection with 3D-ASL in the same GBM patient cohort to evalu- Inclusion criteria ate their efficacy of differentiate true tumor progression Patients that recently received a histopathological diag- from pseudoprogression as a consequnence of radioche- nosis of GBM from Tangdu Hospital are considered for motherapy for GBM. enrollment in the present study. The criteria for selec- Therefore, the current prospective diagnostic trial was tion are: (1) a recent histopathologic diagnosis of GBM designed to evaluate the ability of IVIM-DWI and 3D- according to criteria of the World Health Organization; ASL to distinguish true tumor progression from pseudo- (2) total or partial resection of the enhanced tumor com- progression in GBM. The diagnostic performance of the ponent; (3) baseline contrast-enhanced MRI performed quantitative parameters obtained from IVIM-DWI and within 24 ~ 48 h after surgery; (4) standard radiation 3D-ASL will also be compared. therapy with concurrent TMZ and six cycles of adjuvant Fig. 1 Flowchart of the current prospective diagnostic trial Liu et al. BMC Medical Imaging (2017) 17:10 Page 4 of 7 TMZ after surgery; (5) follow-up IVIM-DWI and 3D- WI, USA) with an 8-channel head coil. Conventional ASL performed on the same 3 T MRI scanner within MRI, DWI with 13 b-values (0 ~ 1500 s/mm ), 3D-ASL, 6 months after the completion of radiation therapy with and contrast-enhanced MRI will be arranged in regular concurrent TMZ, when pseudoprogression is prevalent sequence for each patient’s first follow-up visit. Conven- [21], however as a long project, we will follow up glioma tional MRI sequences will include spin-echo T1-weighted patients as long as possible;(6) Without receiving cor- imaging, fast spin-echo T2-weighted imaging, and fluid- ticosteroid management at 3 days before imaging;(7) the attenuated inversion recovery imaging (FLAIR). The IVIM presence of newly developed enhanced lesions or en- DWI will be performed prior to gadolinium injection with larged enhanced lesions within the radiation field; (8) a single-shot diffusion-weighted spin-echo echo-planar surgical resection of enhanced tissue or adequate clini- sequence using 13 different b-values: 0, 10, 20, 30, 50, 80, coradiologic follow-up to definitively diagnose true pro- 100, 200, 300, 500, 800, 1000, and 1500s/mm .These gression or pseudoprogression according to Response b-values were selected to cover both initial pseudo Assessment in Neuro-Oncology (RANO) criteria [22]. diffusion decay (b < 200 s/mm ) and molecular diffu- sion decay (b ≥ 200 s/mm ) [24].Intotal,20 axial Exclusion criteria slices covering the entire brain will be obtained. The Subjects will be excluded based on any of the following following MR imaging parameters will be used: field conditions: (1) without contrast-enhanced MRI per- of view (FOV) = 256 × 256 mm , slice thickness = 5 mm, formed within 24 ~ 48 h after surgery; (2) absence of slice gap = 1.5 mm, repetition time (TR) = 3000 ms, echo newly developed enhanced lesions or enlarged enhanced time (TE) = minimum, matrix =128 × 128. The total lesions after the end of radiation therapy with concur- acquisition time will be 5 min and 45 s. rent TMZ; (3) non-standard treatment after surgery; or A 3D spiral fast spin echo (FSE) sequence will be used (4) patient does not complete clinicoradiologic follow-up to obtain 3D-ASL perfusion images. The MRI parameters or surgical resection of enhanced tissue to definitively will be: 512 sampling points on eight spiral arms, spatial diagnose true progression or pseudoprogression. resolution = 3.64 mm, TR = 4590 ms, TE = 10.5 ms, slice thickness = 4.0 mm, number of slices = 40, FOV = 240 × IVIM model 240 mm , number of excitations (NEX) = 3.0. The total DWI dada will be analyzed using the same protocol as acquisition time will be 4 min. described in our previous publication [15]. DWI will be Finally, a contrast-enhanced T1-weighted spin echo analyzed with an IVIM model (Eq. 1), where S0 and S(b) sequence will be performed in the transverse, sagittal, are the signal intensities of attenuation at a b-value of 0 s/ and coronal planes following a bolus injection of 0.1 mmol/ 2 2 mm and at a b-value > 0 s/mm , respectively. D is the kg of gadodiamide (Omniscan; GE Healthcare, Co. diffusion parameter which reflects the diffusion coefficient Cork, Ireland). for water, D* represents perfusion-related diffusion and f is the perfusion fraction linked to microcirculation. Image analysis Considering that D* is significantly larger than D [14, 23]. All imaging data will be transferred to a GE ADW4.6 The contribution of D* to signal decay can be neglected workstation. All of the IVIM-DWI and 3D-ASL parame- with a b-value > 200 s/mm . Thus, Eq. (1) can then be sim- ters will be measured by two experienced neuroradiologist plified, and the estimation of D can be obtained by using in consensus (SYZ, TQ, with 9 and 8 years of clinical ex- only b values larger than 200 s/mm , with a simple linear perience in neuroradiology), who are blinded to the clin- fit Eq. (2), then D* and f will be generated with low b-values ical outcome. The conventional plain, contrast-enhanced by using a nonlinear regression algorithm based on Eq. (1). MRI scans will be carefully reviewed to detect if there are newly developed enhanced lesions within the radiation SbðÞ =S0 ¼ f expðÞ −b  DþðÞ 1−f expðÞ −b  D ð1Þ field. The section containing the maximum diameter of the enhanced lesion will be selected for subsequent re- SbðÞ =S0 ¼ expðÞ −bD ð2Þ gions of interest (ROI) analysis. ROI will be manually ex- The ADC value will be derived from a monoexponential tracted to cover as much of the solid parts of the equation with all b-values by Eq. (3). enhanced lesions as possible on a single section, while avoiding large vessels and hemorrhagic, ischemic, cystic, SbðÞ =S0 ¼ exp −ðÞ ADC  b ð3Þ and necrotic areas according to the anatomical contrast images. The ROI will be transferred to the IVIM Image acquisition parametric maps. Diffusion and perfusion parameter Upon completion of radiation therapy with concurrent maps of the IVIM will be generated automatically and TMZ, follow-up MRI scans will be performed with a the parameters will be obtained from the ROI, includ- 3.0 T MRI system (MR750; GE Healthcare, Milwaukee, ing mean ADC, D, D*,and f. Liu et al. BMC Medical Imaging (2017) 17:10 Page 5 of 7 ROIanalysisfor 3D-ASL will be performedina Primary outcome measure manner similar to that of IVIM-DWI. A single con- trast section containing the maximum diameter of the (1) Differences in diffusion-related parameters between enhanced lesion will be selected, and an ROI will be true tumor progression and pseudoprogression drawn around the entire enhanced lesion, while avoid- according to the different fitting model ing large vessels and hemorrhagic, ischemic, cystic, D and ADC will be derived from biexponential and and necrotic areas according to the anatomical con- monoexponential models, respectively. We trast images. The ROI will be transferred to the 3D- hypothesized that true tumor progression and ASL parametric maps. the mean CBF parameters will pseudoprogression can be distinguished based on be generated automatically. these two values and true tumor progression can exhibit significantly lower mean D and ADC values Follow-up and lesion diagnosis compared with pseudoprogression. In addition, we Serial follow-up MRI assessments will be performed hypothesized that D, which separates perfusion approximately 2 months after the completion of effects, will be a more promising parameter in standard radiation therapy with concurrent TMZ. distinguishing true tumor progression from Disease progression will be definited according to pseudoprogression compared with ADC which can RANO criteria or histopathology of surgical resection. be compromised by perfusion. If the size of the enhanced lesions remain unchanged (2) Differences in perfusion-related parameters between or show a decrease for at least 6 months, pseudo- true progression and pseudoprogression progression will be defined. On the contrary, if the Data regarding D*, f, and CBF will be summarized. enhanced lesions exhibit a gradual increase in size for We hypothesized that D*, f, and CBF will at least 6 months, true progression will be defined. significantly differ between true tumor progression Radiological evaluation will be made by two authors and pseudoprogression and Mean D*, f, and CBF in consensus (SYZ, TQ with 9 and 8 years of clinical values will be signifcantly lower for experience in neuroradiology).. Pseudoprogression pseudoprogression than for true progression. will be defined as some treatment effects with the (3) Diagnostic Performance of the IVIM and 3D-ASL complete absence of tumor. Recurrent tumor will be Parameters defined as any amount of tumor. Pathologic evalu- Receiver operating characteristic (ROC) analyses ation will be made by an experienced neuropatholo- will determine corresponding cutoff points for gist (WZ, with 26 years of clinical experience in differentiating true tumor progression from neuropathology). pseudoprogression based on ADC, D, D*, f, and CBF values. In addition, sensitivity, specificity, and Sample size calculation and statistics area under curve (AUC) for identifying true A sample size calculation was performed with refer- progression will be calculated in each case when ence to a previous study that had a sensitivity of 71.0% pseudoprogression is differentiated. We will make a and a specificity of 75.0% [16]. With a permissible comparison among all the IVIM and 3D-ASL pa- error of 0.1 and an alpha significance level of 0.05, a rameters to identify which has the best sensitivity/ sample size of 50 patients per group was enough to specificity with regards to early diagnosis. get satisfying statistic power. (4) Establishment of Clinical prediction model Numerical variables will be expressed as the mean Single factor analysis will show which covariates ± standard deviation (SD). Student’s t-test will be affect the judgment of newly developed enhanced or used to assess significant differences in the above enlarged enhanced lesions, such as age, gender, mentioned parameters between the true tumor pro- radiation dose, karnofsky performance score, lesion gression and the pseudoprogression cases. Receiver region and imaging characteristics. A logistic operating characteristic (ROC) analyses will deter- regression equation will be performed to identify mine corresponding specificity, sensitivity and cutoff those covariates, IVIM and 3D-ASL parameters that points for differentiating true tumor progression from contribute to the diagnostic differentiation between pseudoprogression based on ADC, D, D*, f,and CBF true progression and pseudoprogression. values. Associations between f, D, and corresponding CBF and ADC will be assessed with Pearson’s correl- Secondary outcome measures ation and partial correlation analyses, respectively. SPSS 17.0 software (SPSS Inc, Chicago, IL, USA) will (1) Correlations among imaging parameters be used for all statistical analyses and p <0.05 indi- Correlation coefficients between f and cate statistical significance. corresponding CBF values, and between D derived Liu et al. BMC Medical Imaging (2017) 17:10 Page 6 of 7 from the biexponential model and corresponding that encompassed the entire lesion and targeted the areas ADC values derived from the monoexponential of maximal abnormality is used to measure the parame- model, will be calculated. It is hypothesized that ters rather than a pixel-to-pixel method. This method may both sets of correlations will be significant. not reflect the intraregional tumor heterogeneity. How- ever, these techniques are rapid, reproducible, simple, and Discussion are commonly used in clinical practice. Third, pathologic In patients with GBM after concurrent chemoradiother- sampling regions lacks strict pathologic correlation of the apy, it is important to differentiate pseudoprogression image-based segmentation with surgical specimens, as from true progression to choose appropriate treatment shown by Hu et al. [10]. However, in clinical practice, such and predict prognosis. In both situations, conventional quantitative correlation is very difficult to achieve. MRI usually shows enhanced lesion with or without Abbreviations mass effect, so it cannot be conclusive. Few studies have 3D-ASL: Three-dimensional arterial spin labeling imaging; ADC: Apparent examined the combination of IVIM and 3D-ASL im- diffusion coefficient; AUC: Area under curve; CBF: Cerebral blood flow; aging for distinguishing true progression from pseudo- D*: Fast diffusion coefficient; D: Slow diffusion coefficient; DSC: Dynamic susceptibility-weighted contrast-enhanced; f: Perfusion fraction; FA: Fractional progression of GBM, The current study attempts to anisotropy; FOV: Field of view; FSE: Fast spin echo; GBM: Glioblastoma validate perfusion and diffusion parameters derived from multiforme; IVIM-DWI: Intravoxel incoherent motion diffusion-weighted IVIM and 3D-ASL to determine whether an enlarged imaging; MRI: Magnetic resonance imaging; NEX: Number of excitations; ROC: Receiver-operating characteristic; TMZ: Temozolomide; SD: Standard contrast-enhanced lesion was caused by true progression deviation; TE: Echo time; TR: Repetition time or by pseudoprogression. Advantages and disadvantages of this study are discussed below. Acknowledgements We would like to thank Prof. Shang Lei from the department of statistics of Compared to recently published studies in gliomas the Fourth Military Medical University for the insightful discussions on the [15, 25], more and higher b values are used in our study, sample size calculation and Prof. Wang Zhe from the department of as more b values in segment of low b values can improve pathology of the Fourth Military Medical University for pathologic evaluation. the accuracy of the pseudodiffusion, while higher b Funding values can better eliminate the perfusion-related diffu- This study is financially supported by the Natural Science Foundation of sion; thus it can in turn generate a more realistic mo- Shanxi Province (No. 2008 K13-04 to Dr. Cui GB) and Science and lecular diffusion coefficient value. Perfusion imaging of Technology Development of Shanxi Province (2014JZ2-007 to Dr. Cui GB). The funding source has estimated the feasibility of the study, but has no role brain tumors, which mainly includes DSC-MR perfusion in the collection, analysis, or interpretation of the data or in the decision to techniques, has been used for the diagnosis of glioma submit the manuscript for publication. recurrence and radiation necrosis [26–28]. However, the use of intravenous contrast media is a major limitation Availability of data and materials The datasets supporting the conclusions of this article are available in the in the routine clinical application of this method, since ClinicalTrials.gov, NCT02622620, https://www.clinicaltrials.gov/. contrast media extravasation can result in a decreased rCBV for high-grade tumors. The 3D-ASL is one sub- Authors’ contributions method of ASL. It had been widely used in gliomas WW and CGB conceived the idea. All authors participated in the design of this study. LZC, YLF and WW drafted the manuscript. HYC, NHY, YY, SQ, TQ, grading and had reliable results with DSC. In this tech- SYZ, and LZC provided critical revisions and important intellectual nique, the contrast agent used is labeled arterial blood contributions to the manuscript. All of the authors contributed to, read, and water proximal to the brain. Without intravenous approved the final manuscript. contrast media, 3D-ASL imaging could be particularly Competing interests relevant for the long-term follow-up of gliomas follow- The authors declare that they have no competing interests. ing radiation, including those with renal insufficiency or severe allergies. Several reports [26–28] have suggested Consent for publication that combining information derived from different tech- Not applicable. niques increases diagnostic performance not only for the Ethics approval and consent to participate identifcation of brain tumors but also for assessing the This study was approved by the Ethics Committee of Tangdu Hospital response to treatment. Because each parameter can (TDLL-20151013) and written informed consent will be obtained from all show different aspects of tumor biology, the combin- participants before starting the trial. ation of parameters may have added value compared Received: 28 July 2016 Accepted: 25 January 2017 with single-parameter measurements. We are expecting that combination of IVIM-DWI and 3D-ASL imaging has an acceptable accuracy in differenti- References 1. Ho VK, et al. 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Combination of IVIM-DWI and 3D-ASL for differentiating true progression from pseudoprogression of Glioblastoma multiforme after concurrent chemoradiotherapy: study protocol of a prospective diagnostic trial

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Springer Journals
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Copyright © 2017 by The Author(s).
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Medicine & Public Health; Imaging / Radiology
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Abstract

Background: Standard therapy for Glioblastoma multiforme (GBM) involves maximal safe tumor resection followed with radiotherapy and concurrent adjuvant temozolomide. About 20 to 30% patients undergoing their first post-radiation MRI show increased contrast enhancement which eventually recovers without any new treatment. This phenomenon is referred to as pseudoprogression. Differentiating tumor progression from pseudoprogression is critical for determining tumor treatment, yet this capacity remains a challenge for conventional magnetic resonance imaging (MRI). Thus, a prospective diagnostic trial has been established that utilizes multimodal MRI techniques to detect tumor progression at its early stage. The purpose of this trial is to explore the potential role of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and three-dimensional arterial spin labeling imaging (3D-ASL) in differentiating true progression from pseudoprogression of GBM. In addition, the diagnostic performance of quantitative parameters obtained from IVIM-DWI and 3D-ASL, including apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), perfusion fraction (f), and cerebral blood flow (CBF), will be evaluated. Methods: Patients that recently received a histopathological diagnosis of GBM at our hospital are eligible for enrollment. The patients selected will receive standard concurrent chemoradiotherapy and adjuvant temozolomide after surgery, and then will undergo conventional MRI, IVIM-DWI, 3D-ASL, and contrast- enhanced MRI. The quantitative parameters, ADC, D, D*, f, and CBF, will be estimated for newly developed enhanced lesions. Further comparisons will be made with unpaired t-tests to evaluate parameter performance in differentiating true progression from pseudoprogression, while receiver-operating characteristic (ROC) analyses will determine the optimal thresholds, as well as sensitivity and specificity. Finally, relationships between these parameters will be assessed with Pearson’s correlation and partial correlation analyses. (Continued on next page) * Correspondence: [email protected]; [email protected] Equal contributors Department of Radiology, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi’an 710038, China © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. BMC Medical Imaging (2017) 17:10 Page 2 of 7 (Continued from previous page) Discussion: The results of this study may demonstrate the potential value of using multimodal MRI techniques to differentiate true progression from pseudoprogression in its early stages to help decision making in early intervention and improve the prognosis of GBM. Trial registration: This study has been registered at ClinicalTrials.gov (NCT02622620) on November 18, 2015 and published on March 28, 2016. Keywords: Glioblastoma multiforme, True progression, Pseudoprogression, Intravoxel incoherent motion diffusion-weighted imaging, Diffusion weighted imaging, Perfusion, 3D arterial spin labeling Highlights for them are totally different. Tumor progression reflects treatment failure and the treatment plan should be Intravoxel incoherent motion (IVIM) magnetic adjusted accordingly [10], while pseudoprogression is resonance imaging (MRI) allows the simultaneous associated with a favorable prognosis and can improve acquisition of diffusion and perfusion parameters spontaneously with adjuvant TMZ. If the latter is mis- which reflect tumor cellularity and vascularity, diagnosed as true progression, the treatment efficacy can respectively. be underestimated, thus leading to the inappropriate Arterial spin labeling (ASL) and IVIM are two adjust of therapy. However, true progression can not be commonly used perfusion MRI techniques without easily differentiated from pseudoprogression with current introducing contrast agents and are considered as conventional MRI sequences. Therefore, new imaging safe and reliable methods. tools that can assist clinicians in effectively identifying true progression versus pseudoprogression within 6 months Background after concurrent chemoradiotherapy are needed, which Glioblastoma multiforme (GBM) is the most common will facilitate the selection of appropriate treatment or the malignant primary brain tumor in adults. A combination early termination of an invalid treatment plan. of radiation therapy with concurrent or adjuvant temo- There have been several studies in which researchers zolomide (TMZ) following maximum safe tumor resec- differentiated true progression from treatment effects by tion can significantly improve patients’ survival, and is using advanced MR imaging techniques, such as diffusion currently the standard treatment for GBM. Even with weighted magnetic resonance imaging (DWI) and dy- this standard treatment, the survival of GBM patients namic susceptibility-weighted contrast-enhanced (DSC) remains extremely poor and the overall median survival MRI. True progression exhibits significantly lower appar- time is 14–18 months after treatment [1, 2]. ent diffusion coefficient (ADC) values compared with GBM treatment efficacy is generally evaluated with pseudoprogression [11, 12], reflecting the high cellularity contrast-enhanced MRI in conjunction with clinical as- of progressed tumor. Considering that ADC values can be sessment. Only recently have radiologists and clinicians compromised by perfusion, Le Bihan et al. introduced an observed some transient treatment-induced changes intravoxel incoherent motion (IVIM) technique [13, 14]. after radiotherapy which demonstrate tumor progression Slow diffusion coefficient (D) is the diffusion parameter features in contrast-enhanced MRI such as progressive which reflects the diffusion coefficient for water while fast enlargement and new enhancement. However, these diffusion coefficient (D*) represents perfusion-related features mainly derive from postsurgical changes includ- diffusion. Fraction of fast ADC (f) is the perfusion fraction ing radiation effects, treatment-induced inflammation, linked to microcirculation which has been successfully and ischemia [3, 4]. This phenomenon is referred to as applied to glioma grading and to differentiate recurrent pseudoprogression. Chemotherapy with TMZ signifi- tumors from treatment-related changes [15, 16]. DSC is a cantly increased the rate of pseudoprogression [5, 6]. It T2*-weighted technique to measure relative cerebral is reported that half of the patients with high-grade blood volume (rCBV) and lower mean rCBV values in gliomas after chemoradiotherapy showed an enlarged pseudoprogression was previously used to differentiate enhancement area on contrast-enhanced T1-weighted from true progression [17]. However, radiotherapy and magnetic resonance (MR) images, of which 20 to 30% chemotherapy for GBM destroy blood–brain barrier, were pseudoprogression [7–9]. allowing gadolinium-based contrast agents to leak into the While both tumor progression and pseudoprogression interstitial fluid, which may lead to the underestimation of exhibit progressive enlargement and new enhancement rCBV with DSC [18]. Three-dimensional arterial spin within a radiation field [3], the treatment and prognosis labeling (3D-ASL) is another non-invasive and contrast Liu et al. BMC Medical Imaging (2017) 17:10 Page 3 of 7 agent-free perfusion imaging method to measure cere- Methods/Design bral blood flow (CBF) [19]. The diagnostic perform- This prospective single institution observational study ance of 3D-ASL has been found to be equivalent to will include two case groups and has been approved by DSC MRI in assessing brain tumor perfusion, particu- the Ethics Committee of Tangdu Hospital (TDLL- larly for those patients not suitable for DSC because 20151013). The scheme of the current trial is presented of renal failure [20]. in Fig. 1. Despite the application of IVIM and 3D-ASL in glioma study, there still lacks study in which IVIM is combined Patient Selection with 3D-ASL in the same GBM patient cohort to evalu- Inclusion criteria ate their efficacy of differentiate true tumor progression Patients that recently received a histopathological diag- from pseudoprogression as a consequnence of radioche- nosis of GBM from Tangdu Hospital are considered for motherapy for GBM. enrollment in the present study. The criteria for selec- Therefore, the current prospective diagnostic trial was tion are: (1) a recent histopathologic diagnosis of GBM designed to evaluate the ability of IVIM-DWI and 3D- according to criteria of the World Health Organization; ASL to distinguish true tumor progression from pseudo- (2) total or partial resection of the enhanced tumor com- progression in GBM. The diagnostic performance of the ponent; (3) baseline contrast-enhanced MRI performed quantitative parameters obtained from IVIM-DWI and within 24 ~ 48 h after surgery; (4) standard radiation 3D-ASL will also be compared. therapy with concurrent TMZ and six cycles of adjuvant Fig. 1 Flowchart of the current prospective diagnostic trial Liu et al. BMC Medical Imaging (2017) 17:10 Page 4 of 7 TMZ after surgery; (5) follow-up IVIM-DWI and 3D- WI, USA) with an 8-channel head coil. Conventional ASL performed on the same 3 T MRI scanner within MRI, DWI with 13 b-values (0 ~ 1500 s/mm ), 3D-ASL, 6 months after the completion of radiation therapy with and contrast-enhanced MRI will be arranged in regular concurrent TMZ, when pseudoprogression is prevalent sequence for each patient’s first follow-up visit. Conven- [21], however as a long project, we will follow up glioma tional MRI sequences will include spin-echo T1-weighted patients as long as possible;(6) Without receiving cor- imaging, fast spin-echo T2-weighted imaging, and fluid- ticosteroid management at 3 days before imaging;(7) the attenuated inversion recovery imaging (FLAIR). The IVIM presence of newly developed enhanced lesions or en- DWI will be performed prior to gadolinium injection with larged enhanced lesions within the radiation field; (8) a single-shot diffusion-weighted spin-echo echo-planar surgical resection of enhanced tissue or adequate clini- sequence using 13 different b-values: 0, 10, 20, 30, 50, 80, coradiologic follow-up to definitively diagnose true pro- 100, 200, 300, 500, 800, 1000, and 1500s/mm .These gression or pseudoprogression according to Response b-values were selected to cover both initial pseudo Assessment in Neuro-Oncology (RANO) criteria [22]. diffusion decay (b < 200 s/mm ) and molecular diffu- sion decay (b ≥ 200 s/mm ) [24].Intotal,20 axial Exclusion criteria slices covering the entire brain will be obtained. The Subjects will be excluded based on any of the following following MR imaging parameters will be used: field conditions: (1) without contrast-enhanced MRI per- of view (FOV) = 256 × 256 mm , slice thickness = 5 mm, formed within 24 ~ 48 h after surgery; (2) absence of slice gap = 1.5 mm, repetition time (TR) = 3000 ms, echo newly developed enhanced lesions or enlarged enhanced time (TE) = minimum, matrix =128 × 128. The total lesions after the end of radiation therapy with concur- acquisition time will be 5 min and 45 s. rent TMZ; (3) non-standard treatment after surgery; or A 3D spiral fast spin echo (FSE) sequence will be used (4) patient does not complete clinicoradiologic follow-up to obtain 3D-ASL perfusion images. The MRI parameters or surgical resection of enhanced tissue to definitively will be: 512 sampling points on eight spiral arms, spatial diagnose true progression or pseudoprogression. resolution = 3.64 mm, TR = 4590 ms, TE = 10.5 ms, slice thickness = 4.0 mm, number of slices = 40, FOV = 240 × IVIM model 240 mm , number of excitations (NEX) = 3.0. The total DWI dada will be analyzed using the same protocol as acquisition time will be 4 min. described in our previous publication [15]. DWI will be Finally, a contrast-enhanced T1-weighted spin echo analyzed with an IVIM model (Eq. 1), where S0 and S(b) sequence will be performed in the transverse, sagittal, are the signal intensities of attenuation at a b-value of 0 s/ and coronal planes following a bolus injection of 0.1 mmol/ 2 2 mm and at a b-value > 0 s/mm , respectively. D is the kg of gadodiamide (Omniscan; GE Healthcare, Co. diffusion parameter which reflects the diffusion coefficient Cork, Ireland). for water, D* represents perfusion-related diffusion and f is the perfusion fraction linked to microcirculation. Image analysis Considering that D* is significantly larger than D [14, 23]. All imaging data will be transferred to a GE ADW4.6 The contribution of D* to signal decay can be neglected workstation. All of the IVIM-DWI and 3D-ASL parame- with a b-value > 200 s/mm . Thus, Eq. (1) can then be sim- ters will be measured by two experienced neuroradiologist plified, and the estimation of D can be obtained by using in consensus (SYZ, TQ, with 9 and 8 years of clinical ex- only b values larger than 200 s/mm , with a simple linear perience in neuroradiology), who are blinded to the clin- fit Eq. (2), then D* and f will be generated with low b-values ical outcome. The conventional plain, contrast-enhanced by using a nonlinear regression algorithm based on Eq. (1). MRI scans will be carefully reviewed to detect if there are newly developed enhanced lesions within the radiation SbðÞ =S0 ¼ f expðÞ −b  DþðÞ 1−f expðÞ −b  D ð1Þ field. The section containing the maximum diameter of the enhanced lesion will be selected for subsequent re- SbðÞ =S0 ¼ expðÞ −bD ð2Þ gions of interest (ROI) analysis. ROI will be manually ex- The ADC value will be derived from a monoexponential tracted to cover as much of the solid parts of the equation with all b-values by Eq. (3). enhanced lesions as possible on a single section, while avoiding large vessels and hemorrhagic, ischemic, cystic, SbðÞ =S0 ¼ exp −ðÞ ADC  b ð3Þ and necrotic areas according to the anatomical contrast images. The ROI will be transferred to the IVIM Image acquisition parametric maps. Diffusion and perfusion parameter Upon completion of radiation therapy with concurrent maps of the IVIM will be generated automatically and TMZ, follow-up MRI scans will be performed with a the parameters will be obtained from the ROI, includ- 3.0 T MRI system (MR750; GE Healthcare, Milwaukee, ing mean ADC, D, D*,and f. Liu et al. BMC Medical Imaging (2017) 17:10 Page 5 of 7 ROIanalysisfor 3D-ASL will be performedina Primary outcome measure manner similar to that of IVIM-DWI. A single con- trast section containing the maximum diameter of the (1) Differences in diffusion-related parameters between enhanced lesion will be selected, and an ROI will be true tumor progression and pseudoprogression drawn around the entire enhanced lesion, while avoid- according to the different fitting model ing large vessels and hemorrhagic, ischemic, cystic, D and ADC will be derived from biexponential and and necrotic areas according to the anatomical con- monoexponential models, respectively. We trast images. The ROI will be transferred to the 3D- hypothesized that true tumor progression and ASL parametric maps. the mean CBF parameters will pseudoprogression can be distinguished based on be generated automatically. these two values and true tumor progression can exhibit significantly lower mean D and ADC values Follow-up and lesion diagnosis compared with pseudoprogression. In addition, we Serial follow-up MRI assessments will be performed hypothesized that D, which separates perfusion approximately 2 months after the completion of effects, will be a more promising parameter in standard radiation therapy with concurrent TMZ. distinguishing true tumor progression from Disease progression will be definited according to pseudoprogression compared with ADC which can RANO criteria or histopathology of surgical resection. be compromised by perfusion. If the size of the enhanced lesions remain unchanged (2) Differences in perfusion-related parameters between or show a decrease for at least 6 months, pseudo- true progression and pseudoprogression progression will be defined. On the contrary, if the Data regarding D*, f, and CBF will be summarized. enhanced lesions exhibit a gradual increase in size for We hypothesized that D*, f, and CBF will at least 6 months, true progression will be defined. significantly differ between true tumor progression Radiological evaluation will be made by two authors and pseudoprogression and Mean D*, f, and CBF in consensus (SYZ, TQ with 9 and 8 years of clinical values will be signifcantly lower for experience in neuroradiology).. Pseudoprogression pseudoprogression than for true progression. will be defined as some treatment effects with the (3) Diagnostic Performance of the IVIM and 3D-ASL complete absence of tumor. Recurrent tumor will be Parameters defined as any amount of tumor. Pathologic evalu- Receiver operating characteristic (ROC) analyses ation will be made by an experienced neuropatholo- will determine corresponding cutoff points for gist (WZ, with 26 years of clinical experience in differentiating true tumor progression from neuropathology). pseudoprogression based on ADC, D, D*, f, and CBF values. In addition, sensitivity, specificity, and Sample size calculation and statistics area under curve (AUC) for identifying true A sample size calculation was performed with refer- progression will be calculated in each case when ence to a previous study that had a sensitivity of 71.0% pseudoprogression is differentiated. We will make a and a specificity of 75.0% [16]. With a permissible comparison among all the IVIM and 3D-ASL pa- error of 0.1 and an alpha significance level of 0.05, a rameters to identify which has the best sensitivity/ sample size of 50 patients per group was enough to specificity with regards to early diagnosis. get satisfying statistic power. (4) Establishment of Clinical prediction model Numerical variables will be expressed as the mean Single factor analysis will show which covariates ± standard deviation (SD). Student’s t-test will be affect the judgment of newly developed enhanced or used to assess significant differences in the above enlarged enhanced lesions, such as age, gender, mentioned parameters between the true tumor pro- radiation dose, karnofsky performance score, lesion gression and the pseudoprogression cases. Receiver region and imaging characteristics. A logistic operating characteristic (ROC) analyses will deter- regression equation will be performed to identify mine corresponding specificity, sensitivity and cutoff those covariates, IVIM and 3D-ASL parameters that points for differentiating true tumor progression from contribute to the diagnostic differentiation between pseudoprogression based on ADC, D, D*, f,and CBF true progression and pseudoprogression. values. Associations between f, D, and corresponding CBF and ADC will be assessed with Pearson’s correl- Secondary outcome measures ation and partial correlation analyses, respectively. SPSS 17.0 software (SPSS Inc, Chicago, IL, USA) will (1) Correlations among imaging parameters be used for all statistical analyses and p <0.05 indi- Correlation coefficients between f and cate statistical significance. corresponding CBF values, and between D derived Liu et al. BMC Medical Imaging (2017) 17:10 Page 6 of 7 from the biexponential model and corresponding that encompassed the entire lesion and targeted the areas ADC values derived from the monoexponential of maximal abnormality is used to measure the parame- model, will be calculated. It is hypothesized that ters rather than a pixel-to-pixel method. This method may both sets of correlations will be significant. not reflect the intraregional tumor heterogeneity. How- ever, these techniques are rapid, reproducible, simple, and Discussion are commonly used in clinical practice. Third, pathologic In patients with GBM after concurrent chemoradiother- sampling regions lacks strict pathologic correlation of the apy, it is important to differentiate pseudoprogression image-based segmentation with surgical specimens, as from true progression to choose appropriate treatment shown by Hu et al. [10]. However, in clinical practice, such and predict prognosis. In both situations, conventional quantitative correlation is very difficult to achieve. MRI usually shows enhanced lesion with or without Abbreviations mass effect, so it cannot be conclusive. Few studies have 3D-ASL: Three-dimensional arterial spin labeling imaging; ADC: Apparent examined the combination of IVIM and 3D-ASL im- diffusion coefficient; AUC: Area under curve; CBF: Cerebral blood flow; aging for distinguishing true progression from pseudo- D*: Fast diffusion coefficient; D: Slow diffusion coefficient; DSC: Dynamic susceptibility-weighted contrast-enhanced; f: Perfusion fraction; FA: Fractional progression of GBM, The current study attempts to anisotropy; FOV: Field of view; FSE: Fast spin echo; GBM: Glioblastoma validate perfusion and diffusion parameters derived from multiforme; IVIM-DWI: Intravoxel incoherent motion diffusion-weighted IVIM and 3D-ASL to determine whether an enlarged imaging; MRI: Magnetic resonance imaging; NEX: Number of excitations; ROC: Receiver-operating characteristic; TMZ: Temozolomide; SD: Standard contrast-enhanced lesion was caused by true progression deviation; TE: Echo time; TR: Repetition time or by pseudoprogression. Advantages and disadvantages of this study are discussed below. Acknowledgements We would like to thank Prof. Shang Lei from the department of statistics of Compared to recently published studies in gliomas the Fourth Military Medical University for the insightful discussions on the [15, 25], more and higher b values are used in our study, sample size calculation and Prof. Wang Zhe from the department of as more b values in segment of low b values can improve pathology of the Fourth Military Medical University for pathologic evaluation. the accuracy of the pseudodiffusion, while higher b Funding values can better eliminate the perfusion-related diffu- This study is financially supported by the Natural Science Foundation of sion; thus it can in turn generate a more realistic mo- Shanxi Province (No. 2008 K13-04 to Dr. Cui GB) and Science and lecular diffusion coefficient value. Perfusion imaging of Technology Development of Shanxi Province (2014JZ2-007 to Dr. Cui GB). The funding source has estimated the feasibility of the study, but has no role brain tumors, which mainly includes DSC-MR perfusion in the collection, analysis, or interpretation of the data or in the decision to techniques, has been used for the diagnosis of glioma submit the manuscript for publication. recurrence and radiation necrosis [26–28]. However, the use of intravenous contrast media is a major limitation Availability of data and materials The datasets supporting the conclusions of this article are available in the in the routine clinical application of this method, since ClinicalTrials.gov, NCT02622620, https://www.clinicaltrials.gov/. contrast media extravasation can result in a decreased rCBV for high-grade tumors. The 3D-ASL is one sub- Authors’ contributions method of ASL. It had been widely used in gliomas WW and CGB conceived the idea. All authors participated in the design of this study. LZC, YLF and WW drafted the manuscript. HYC, NHY, YY, SQ, TQ, grading and had reliable results with DSC. In this tech- SYZ, and LZC provided critical revisions and important intellectual nique, the contrast agent used is labeled arterial blood contributions to the manuscript. All of the authors contributed to, read, and water proximal to the brain. Without intravenous approved the final manuscript. contrast media, 3D-ASL imaging could be particularly Competing interests relevant for the long-term follow-up of gliomas follow- The authors declare that they have no competing interests. ing radiation, including those with renal insufficiency or severe allergies. Several reports [26–28] have suggested Consent for publication that combining information derived from different tech- Not applicable. niques increases diagnostic performance not only for the Ethics approval and consent to participate identifcation of brain tumors but also for assessing the This study was approved by the Ethics Committee of Tangdu Hospital response to treatment. Because each parameter can (TDLL-20151013) and written informed consent will be obtained from all show different aspects of tumor biology, the combin- participants before starting the trial. ation of parameters may have added value compared Received: 28 July 2016 Accepted: 25 January 2017 with single-parameter measurements. We are expecting that combination of IVIM-DWI and 3D-ASL imaging has an acceptable accuracy in differenti- References 1. Ho VK, et al. 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