Abstract
Purpose of the Report:
[18F]FDG-PET is limited for assessment of central nervous system lymphoma (CNSL) due to physiologic tracer accumulation in the brain. We prospectively evaluated the novel PET tracer [68Ga]Pentixafor, which targets the C-X-C chemokine receptor 4 (CXCR4), for lesion visualization and response assessment of CNSL.
Materials and Methods:
Seven CNSL patients underwent [68Ga]Pentixafor-PET/MRI with contrast-enhanced (CE-MRI) and diffusion-weighted sequences. The accuracy of [68Ga]Pentixafor-PET for CNSL lesion detection relative to the CE-MRI reference standard was determined. Standardized uptake values (SUVmean and SUVmax), PET-based (PTV) and MRI-based (VOLMRI) tumor volumes, and apparent diffusion coefficients (ADCs) were assessed, and correlation coefficients calculated. Three SUVmax thresholds (41%, 50%, 70%) were evaluated for PTV definitions (PTV41%, PTV50%, and PTV70%) and tested against VOLMRI using paired-samples t-tests.
Results:
Twelve [68Ga]Pentixafor-PET/MRI examinations (including five follow-up scans) of seven patients were evaluated. [68Ga]Pentixafor-PET demonstrated 18 lesions, all of which were confirmed by CE-MRI; there were no false-positive lesions on PET (accuracy, 100%). PTV41% showed the highest concordance with lesion morphology, with no significant difference compared to VOLMRI (mean difference, −0.24 cm³; P=0.45). Correlation between ADCmean and SUVmean41% (r=0.68) was moderate. Changes in PTV41% on follow-up PET/MRI showed the same trend as VOLMRI changes, including progression of one lesion each in patient 1 (+456.0% PTV41% and +350.8% VOLMRI) and patient 3 (+110.4% PTV41% and +85.1% VOLMRI).
Conclusions:
[68Ga]Pentixafor-PET may be feasible for assessment and follow-up of CNSL. Future studies need to focus on testing its clinical value to distinguish between glioma and CNSL, and between radiation-induced inflammation and viable residual tumor.
Keywords: central nervous system lymphoma, CXCR4, Pentixafor, PET/MRI
INTRODUCTION
Central nervous system lymphoma (CNSL) is a rare form of Non-Hodgkin lymphoma (NHL) that can occur as a primary tumor (PCNSL; 3% of all brains tumors), or as a secondary manifestation of systemic lymphoma. Contrary to other brain tumors, surgical resection does not improve survival; however, histological confirmation by neurosurgical biopsy is commonly performed [1].
[18F]FDG-PET/CT is the recommended technique for staging and response assessment in most lymphomas –particularly aggressive subtypes such as diffuse large B-cell lymphoma (DLBCL)– because they show increased glucose metabolism [2]. However, since [18F]FDG shows pronounced physiologic accumulation in the brain, [18F]FDG-PET is not recommended for CNS lymphomas due to reduced tumor-to-background contrast. PET tracers currently investigated for CNS lymphomas include [18F]Fludarabine and [11C]Methionine [3,4], but no convincing clinical data exist. Thus, MRI currently remains the standard technique for preoperative assessment and follow-up of CNSL, despite its limited ability to distinguish between post-treatment pseudoprogression and true progression [1].
Because previous data showed that lymphomas express high levels of the G-protein-coupled chemokine receptor CXCR4, [68Ga]Pentixafor was recently developed as a PET tracer that specifically targets the CXCR4 receptor and has been applied to lymphoma, leukemia, and myeloma [5–7]. While [68Ga]Pentixafor cannot penetrate the intact blood-brain-barrier, the latter is impaired in patients with brain tumors [8]. Recently, a single study in 11 patients suggested that [68Ga]Pentixafor can be used for assessment of CNSL [9].
Our present PET/MRI study aims to (1) provide more evidence on the accuracy of [68Ga]Pentixafor-PET for CNSL detection; (2) provide the first images demonstrating CNSL treatment response assessment with [68Ga]Pentixafor-PET; and (3) determine the relationship between quantitative [68Ga]Pentixafor-PET and MRI metrics.
MATERIAL AND METHODS
Patients
Patients with histologically proven primary or secondary CNSL were included in this prospective proof-of-principle study. Approval by the local Ethics Committee (no. 1866/2019) and written informed patient consent were obtained. Exclusion criteria were: age <18 years; pregnancy; breast-feeding; and known contraindications to MRI. Patients were treated by according to Good Clinical Practice guidelines.
Image acquisition
Patients underwent [68Ga]Pentixafor-PET/MRI on a simultaneous hybrid system (Biograph mMR, Siemens, Erlangen, Germany) at the earliest possible time point after presentation / diagnosis of CNSL. PET/MRI of the head was performed 60 min after intravenous administration of 150 MBq of [68Ga]Pentixafor, with 30 min acquisition time, three iterations and 21 subsets, a 256×256 matrix, and a voxel size of 1.40×1.40 ×2.03 mm³, using the point-spread function-based reconstruction algorithm HD-PET. [68Ga]Pentixafor was synthesized as previously described [6]. Attenuation correction (AC) was done using the model-based approach incorporating spatially variant bone information into MR-based AC based using an axial 2-point Dixon T1-weighted VIBE SPAIR 3D sequence, as implemented in the acquisition software version VE11P.
An axial RESOLVE DWI sequence (b-50, b-1000) with apparent diffusion coefficient (ADC) mapping and an isotropic FLAIR sequence were obtained. An isotropic T1-weighted MPRAGE sequence was acquired before and after injection of extracellular Gd-based contrast media (CE-MRI).
Qualitative image analysis
A board-certified radiologist and a board-certified nuclear medicine physician evaluated all PET/MRIs in random order. The [68Ga]Pentixafor-PET and diagnostic MRI components were read separately, blinded to each other and to pathology and clinical reports. For PET, focal tracer accumulations within the brain that were visibly distinct from the surrounding background uptake were rated as PET-positive, and annotated. Similarly, lesions with contrast enhancement on CE-MRI were rated as positive, and annotated; in case of subtle/equivocal enhancement, other MRI sequences were used for confirmation.
Quantitative image analysis
[68Ga]Pentixafor-PET-based tumor volumes (PTV) were generated for each individual lesion. Because –contrary to [18F]FDG-PET, where a 41% SUVmax threshold is recommended by the European Association of Nuclear Medicine (EANM)– no threshold is established for PTV generation on [68Ga]Pentixafor-PET, three thresholds (41%, 50%, and 70% SUVmax) were evaluated. PTV41%, PTV50% and PTV70% were tested against morphological tumor volumes determined by manual lesion segmentation on CE-MRI (VOLMRI). SUVmean was calculated for each PTV, and also for a 2-cm cubic volume within the contralateral cerebral hemisphere (in a normal-appearing area on MRI) to calculate tumor-to-background ratios (TBR: lesion SUVmax / contralateral SUVmean). Mean ADCs (ADCmean, x10−6 mm2/s) were measured based on VOLMRI. All measurements were performed using LIFEx 6.0 (https://lifexsoft.org/).
Statistical analyses
Accuracy of [68Ga]Pentixafor-PET was defined as rate of agreement with MRI. Pearson correlation coefficients were used to determine relationships between PTVs and VOLMRI, and paired-samples t-tests were used to compare means. Correlations of SUVmean and TBR with ADCmean were also investigated. Due to our hypothesis-generating study design, no correction for multiple testing was applied. The specified significance level was P<0.05. Statistical tests were performed using SPSS 24.0 (SPSS Inc., Chicago, IL, USA).
RESULTS
Seven patients (four women and three men; 54.9±15.0 years) were enrolled: five with PCNSL, and two with secondary CNSL (Table 1). Patient 1 underwent five [68Ga]Pentixafor-PET/MRIs within 16 months; patient 3 underwent [68Ga]Pentixafor-PET/MRI twice. Therefore, 12 PET/MRI examinations were available for analysis.
Table 1.
Patient characteristics
| ID | Sex / Age | Tumor | PET/MRI scans | Histological diagnosis | Therapy regimen |
|---|---|---|---|---|---|
| 1 | M / 49 | PCNSL, 1 lesion | (1) Baseline: post 2 cycles of CHT (2) 8 week follow-up: post 4 cycles of CHT (3) 25 week follow-up: post WBRT after disease progression (4) 35 week follow-up: no therapeutical intervention since last follow-up (5) 54 week follow-up: no therapeutical intervention since last follow-up |
Primary CNS high-grade B-cell lymphoma | CHT with high-dose MTX, WBRT[11] |
| 2 | F / 56 | PCNSL, no lesion | (1) Baseline: 4 cycles of CHT (2) 15 week follow-up: post 5 cycles of CHT and autologous stem cell transplantation |
Primary CNS high-grade B-cell lymphoma | CHT with high-dose MTX[12] |
| 3 | F / 30 | SCNSL, 2 lesions | (1) Baseline at 2nd recurrence: post surgery+CHT at primary DLBCL manifestation, CHT at 1st recurrence and 1 cycle of CHT at 2nd recurrence (2) 5 week follow-up: post 2 cycles of CHT |
Secondary CNS high-grade B-cell lymphoma | CHT with R-CHOP, high-dose MTX |
| 4 | M / 65 | PCNSL, no lesion | (1) Baseline: post 1 cycle of CHT | Primary CNS high-grade B-cell lymphoma | CHT with high-dose MTX |
| 5 | F / 54 | SCNSL, 1 lesion | (1) Baseline at 1st recurrence: post CHT at primary DLBCL manifestation, 1 cycle of CHT at 1st recurrence | Secondary CNS high-grade B-cell lymphoma | CHT with R-CHOP, high-dose MTX |
| 6 | F / 51 | PCNSL, 7 lesions | (1) Baseline: pretreatment | Primary CNS high-grade B-cell lymphoma | CHT with high-dose MTX |
| 7 | M / 79 | PCNSL, 2 lesions | (1) Baseline: post 1 cycle of CHT | Primary CNS high-grade B-cell lymphoma | CHT with high-dose MTX |
Abbreviations: M male; F female; CHT chemotherapy; MTX methotrexate; PCNSL primary central nervous system lymphoma; CNS central nervous system; WBRT whole brain radiotherapy
[68Ga]Pentixafor-PET demonstrated 18 focal CNSL lesions with increased tracer uptake in 5/7 patients (10/12 PET/MRI examinations), all of which were confirmed by CE-MRI (Fig. 1).The remaining two patients had undergone biopsy before imaging, and showed only linear [68Ga]Pentixafor uptake along the trepanation defects, as confirmed by MRI. No additional lesions without [68Ga]Pentixafor uptake were visible on MRI; consequently, [68Ga]Pentixafor-PET accuracy was 100%.
Figure 1.
A 54-year-old female patient (no. 5) with secondary CNSL adjacent to the left interventricular foramen (arrows). The lesion shows marked focal tracer uptake on [68Ga]Pentixafor-PET and contrast enhancement on T1-weighted CE-MRI, as well as moderately hyperintense signal on the DWI and FLAIR images. On the ADC map, diffusivity is similar to that of the surrounding brain tissue.
Quantitative PET/MRI metrics are provided in Table 2. T-tests revealed no significant difference between VOLMRI and PTV41% (mean difference, −0.24 cm³; 95% confidence interval [CI], −0.91 to +0.42 cm³; P=0.45), but significant differences between VOLMRI and PTV50% (mean difference, −1.36 cm³; 95% CI, −2.71 to −0.10 cm³; P=0.048) and between VOLMRI and PTV70% (mean difference, −3.68 cm³; 95% CI, −7.0 to −0.37 cm³; P=0.032). Correlations between ADCmean and SUVmean41% (r=0.68), SUVmean50% (r=0.68), and SUVmean70% (r=0.68); and between ADCmean and TBR (r=0.61), were moderate.
Table 2.
[68Ga]Pentixafor-PET/MRI metrics of patients with PCNSL lesions according to MRI
| ID | Scan | Lesion | SUVmax | SUVmean 41% | PTV 41% | SUVmean 50% | PTV 50% | SUVmean 70% | PTV 70% | TBR | VOL MRI | ADC mean |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 1 | 1 | 4.5 | 2.85 | 5.57 | 3.12 | 4.19 | 3.7 | 1.86 | 34.62 | 7.47 | 204 |
| 1 | 2 | 1 | 5.93 | 3.95 | 30.97 | 4.19 | 26.15 | 4.68 | 14.16 | 49.42 | 33.66 | 818 |
| 1 | 3 | 1 | 1.44 | 0.88 | 1.73 | 0.98 | 1.21 | 1.17 | 0.48 | 8.00 | 3.568 | 151 |
| 1 | 4 | 1 | 1.59 | 0.96 | 1.36 | 1.07 | 0.94 | 1.3 | 0.35 | 7.57 | 2.965 | 94 |
| 1 | 5 | 1 | 1.42 | 0.82 | 1.32 | 0.94 | 0.93 | 1.16 | 0.31 | 9.47 | 0.738 | 218 |
| 3 | 1 | 1 | 5.18 | 3.27 | 2.89 | 3.56 | 2.19 | 4.22 | 0.92 | 25.90 | 2.42 | 792 |
| 3 | 1 | 2 | 4.95 | 3.14 | 2.57 | 3.43 | 1.95 | 4.07 | 0.86 | 24.75 | 1.89 | 729 |
| 3 | 2 | 1 | 6.49 | 4.11 | 6.08 | 4.5 | 4.57 | 5.3 | 2.01 | 34.16 | 4.48 | 757 |
| 5 | 1 | 1 | 2.1 | 1.29 | 0.595 | 1.42 | 0.43 | 1.73 | 0.160 | 14.00 | 0.43 | 424 |
| 6 | 1 | 1 | 9.83 | 6.32 | 31.52 | 6.77 | 25.31 | 7.9 | 10.60 | 51.74 | 34.14 | 820 |
| 6 | 1 | 2 | 5.5 | 3.38 | 2.08 | 3.75 | 1.47 | 4.5 | 0.59 | 28.95 | 2.23 | 799 |
| 6 | 1 | 3 | 3.86 | 2.38 | 1.42 | 2.6 | 1.05 | 3.14 | 0.39 | 20.32 | 1.29 | 562 |
| 6 | 1 | 4 | 2.75 | 1.63 | 1.3 | 1.84 | 0.87 | 2.24 | 0.31 | 14.47 | 1.03 | 712 |
| 6 | 1 | 5 | 2.29 | 1.38 | 1.7 | 1.51 | 1.24 | 1.84 | 0.42 | 12.05 | 2.12 | 687 |
| 6 | 1 | 6 | 4.95 | 3.03 | 1.77 | 3.33 | 1.28 | 4.04 | 0.49 | 26.05 | 1.55 | 442 |
| 6 | 1 | 7 | 1.5 | 0.91 | 0.91 | 0.99 | 0.66 | 1.23 | 0.22 | 7.89 | 0.93 | 566 |
| 7 | 1 | 1 | 0.46 | 0.27 | 1.53 | 0.3 | 1.15 | 0.37 | 0.36 | 2.56 | 0.23 | 322 |
| 7 | 1 | 2 | 0.39 | 0.25 | 1.81 | 0.27 | 1.45 | 0.32 | 0.72 | 2.17 | 0.35 | 289 |
| Mean ± SD | 3.62 ±2.50 | 2.27 ±1.62 | 5.40 ±9.51 | 2.48 ±1.74 | 4.28 ±7.88 | 2.94 ±2.01 | 1.96 ±3.88 | 20.78 ±14.87 | 5.64 ±10.43 | 521.44 ±256.18 |
In patient 1, changes on the four post-treatment [68Ga]Pentixafor-PET scans relative to the respective prior scan were +456.0% (consistent with clinical progression after 2 chemotherapy cycles), −94.4%, −21.4%, and −2.9% for PTV41% (consistent with response after chemotherapy completion and whole-brain radiotherapy (WBRT); and +350.8%, −89.4%, −16.9%, and −75.1% for VOLMRI, respectively. In patient 3, follow-up PTV41% and VOLMRI increased by +110.4% and +85.1% for lesion 1, respectively; whereas the second lesion had resolved.
DISCUSSION
The results of our study –the second to apply [68Ga]Pentixafor-PET to CNSL– provide further evidence that CXCR4 imaging may have a role for assessment of this type of brain tumor. Similar to results by Herhaus et al. [9], [68Ga]Pentixafor-PET showed perfect accuracy for CNSL detection, with high lesion-to-background contrast, and without false-positive findings within the brain. Apart from tumor and physiologic uptake (e.g. venous sinuses), only linear [68Ga]Pentixafor uptake along the trepanation defects of the skull was noted, probably due to an inflammatory reaction.
Because there are no established criteria for generation of PTVs on [68Ga]Pentixafor-PET, we compared three relative SUVmax thresholds in analogy to those listed in the EANM guideline 1.0 for [18F]FDG-PET-based metabolic tumor volumes (MTV): 41%, 50%, and 70%. Contrary to PTV50% and PTV70%, there was no significant difference between PTV41% and VOLMRI, suggesting that PTV41% reflects the actual CNSL volume on [68Ga]Pentixafor-PET. While this means that for pre-therapeutic CNSL assessment, there is no rationale for using PTV41% over VOLMRI, this may possibly differ for treatment response assessment; in patients 1 and 3, changes on follow-up [68Ga]Pentixafor-PET/MRI were more pronounced for PTV41% than for VOLMRI. Also, in clinical practice, SUVs rather than PTV are utilized for response assessment, and future studies need to focus on their clinical value to distinguish between radiation-induced inflammation and viable residual tumor.
Contrary to Herhaus et al. [9], our PET/MRI protocol included DWI, a technique that relies on tissue diffusivity for signal generation. DWI-based ADC measurements indirectly reflect tumor cell density [6], and enable assessment of treatment-induced necrosis. One limitation of DWI is the sensitivity of ADC measurements to intralesional hemorrhage, which can occur in CNSL particularly after treatment. Contrary to previous findings in the bone marrow of chronic lymphocytic leukemia patients [6], we observed significant, moderate correlations between ADCmean and [68Ga]Pentixafor SUVmean as well as TBR, suggesting a possible relationship between cellularity and CXCR4 receptor density in CNSL, but also suggesting that [68Ga]Pentixafor-PET and DWI provide complementary information.
CXCR4 is activated through its ligand CXCL12, which activates mitogen-activated protein (MAP) kinase and phosphatidylinositol 3 (PI3) kinase pathway [5]. The CXCR4/CXCL12 axis mediates tumor cell migration [6]. Novel therapies such as the Bruton’s tyrosine kinase inhibitor ibrutinib, the CXCR4 inhibitor plerixafor, and CXCR4-directed endoradiotherapy with [177Lu]Pentixather are designed to target the CXCR4/CXCL12 pathway [10]. A CXCR4-specific diagnostic imaging test therefore has high clinical potential, not just for imaging but also for treatment response assessment. Findings in patients 1 and 3 suggest that [68Ga]Pentixafor-PET may possibly also be useful for response assessment (Fig. 2), although more data are clearly needed.
Figure 2.
A 49-year-old male patient (no. 1) with recurrent PCNSL of the right thalamus that shows high [68Ga]Pentixafor uptake correlated to- the pathological contrast enhancement on the T1-weighted CE-MRI. [68Ga]Pentixafor-PET-based metabolic tumor volumes (PTV41% shown) showed good concordance with morphologic tumor volumes (VOLMRI) both at baseline and after treatment demonstrating progression under chemotherapy with high-dose methotrexate and treatment response after WBRT.
In conclusion, our small [68Ga]Pentixafor-PET/MRI proof-of-principle study provides further evidence for the feasibility of this technique for CNSL lesion detection, and first images of [68Ga]Pentixafor-PET-based response assessment. PET and MRI may possibly provide complementary information in CNSL.
ACKNOWLEDGEMENTS
The study was supported by the research budget of the Medical University of Vienna. We sincerely thank the PET/MRI staff, in particular Julia Kesselbacher and Benedikt Schmiedinger, for their technical help in conducting this study. This study was performed within the PhD thesis of Angelika M. Starzer with the title “Immune monitoring in cancer patients” in the N790 doctoral program at the Medical University Vienna, Austria.
Funding: This study was funded by the research budget of the Medical University of Vienna.
AMS has received travel support from Pharma Mar. ASB has research support from Daiichi Sankyo and Roche, honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo as well as travel support from Roche, Amgen, Daiichi Sankyo and AbbVie.
MP has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen. The following for-profit companies have supported clinical trials and contracted research conducted by MP with payments made to his institution: Böhringer-Ingelheim, Bristol-Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dome, Novocure, GlaxoSmithKline, AbbVie. MEM received speaker honoraria and research support from Siemens, and speaker honoraria from Bristol Myers Squibb.
GW received restricted travel grants from NX Development Corp.
Footnotes
Conflicts of interest:
All other authors report no conflicts of interest concerning this specific publication.
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