Investigating the Chemokine Receptor 4 as Potential Theranostic Target in Adrenocortical Cancer Patients
Christina Bluemel, MD,* Stefanie Hahner, MD, Britta Heinze, PhD,f Martin Fassnacht, MD,1} Matthias Kroiss, MD,¿ Thorsten A. Bley, MD,§ Hans-Juergen Wester, PhD, ||| Saskia Kropf,1/ Constantin Lapa, MD,* Andreas Schirbel, PhD,* Andreas K. Buck, MD,* and Ken Herrmann, MD ***
Purpose: Adrenocortical carcinoma (ACC) is a rare but aggressive endo- crine tumor with limited treatment options. Preclinical studies con- firmed overexpression of the chemokine receptor 4 (CXCR4) in this cancer type. This study aimed to analyze the role of CXCR4 imaging using 68Ga-pentixafor for ACC staging and selection of patients for CXCR4-directed endoradiotherapy.
Methods: Thirty patients with histologically proven advanced, metastasized ACC underwent 18F-FDG PET/CT and 68Ga-pentixafor PET/CT within a time interval of 3 ± 4 days to evaluate suitability for CXCR4-directed endoradiotherapy. Scans were analyzed retrospectively for visual extent of ACC and SUVmax/mean of the tumor lesions. 68Ga-pentixafor PET was compared with 18F-FDG PET, the reference imaging standard. All patients were rated for suitability of CXCR4-directed endoradiotherapy considering patient’s history, previous treatment, and CXCR4 expression of FDG-positive lesions compared with background activity within the same organ.
Results: All patients had lesions that were positive for both 18F-FDG and 68 Ga-pentixafor PET and were rated as positive for disease. In 2 patients (7%), 68 Ga-pentixafor PET identified more lesions compared with 18F-FDG PET. In 5 patients (17%) and 10 patients (33%), complementary and comparable information, respectively, was provided by dual-tracer imaging. In 13 patients (43%), more tumor lesions were identified by 18F-FDG PET compared with 68Ga-pentixafor PET. The 18F-FDG uptake of the malignant lesions was significantly higher (P < 0.01) than the SUVmax/mean for 68Ga-pentixafor. Overall, 70% of the patients were rated as suitable or potentially suitable for CXCR4-directed treatment.
Conclusions: 68Ga-pentixafor allows in vivo imaging of CXCR4 expres- sion in patients with advanced ACC and may serve as companion diagnostic tool in selecting patients for potential CXCR4-directed endoradiotherapy. Seventy percent of the patients with advanced, metastasized ACC may
Received for publication June 27, 2016; revision accepted September 11, 2016.
From the *Department of Nuclear Medicine, ¡Division of Endocrinology, De- partment of Internal Medicine I, ¿Comprehensive Cancer Center, and §De- partment of Radiology, University Hospital of Würzburg, Würzburg; ||Pharmaceutical Radiochemistry, Technische Universität München, Munich; TScintomics GmbH, Fürstenfeldbruck, Germany; and ** De- partment of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
Author’s contributions: Conception and design: K.H., S.H., C.B., B.H .; development of methodology: K.H., C.B., M.F., S.H .; acquisition of data: K.H., C.B., T.A.B., A.K.B., M.K., S.H., B.H .; analysis and interpretation of data: K.H., C.B., C.L., T.A.B .; writing, review and/or revision of the manuscript: all authors; administrative, technical, or material support: A.K. B., A.S., S.K., H .- J.W .; supervision: K.H., A.K.B., H .- J.W., S.H., M.F.
Preliminary results were presented at the SNM (Society of Nuclear Medicine) and EANM (European Association of Nuclear Medicine) Meeting 2015. Four patients are included in a submission about preclinical data on CXCR4 expression in adrenocortical cancer (unpublished).
Conflicts of interest and sources of funding: S.K. is CEO of Scintomics; H .- J.W. is founder of Scintomics.
Correspondence to: Christina Bluemel, MD, Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Str 6, 97080 Würzburg, Germany. E-mail: bluemel_c@ukw.de.
Copyright @ 2016 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0363-9762/17/4201-0e29
DOI: 10.1097/RLU.0000000000001435
be suitable for a CXCR4-directed treatment after failure of standard treatment options.
Key Words: adrenocortical cancer, chemokine receptor, CXCR4, in vivo imaging, PET/CT
(Clin Nucl Med 2017;42: e29-e34)
A drenocortical carcinoma (ACC) is a rare (incidence of 0.7-2.0 cases per million people per year)1,2 and aggressive endocrine tumor with an unfavorable prognosis (5-year survival rate ≤17% for stage IV).3,4 Relapse rates after radical surgery have been reported in single series as high as 85%.3,6 Besides local therapy (surgery, ra- diation therapy, radiofrequency ablation), systemic treatment with mitotane or cisplatin-based chemotherapy is available for adjuvant, recurrent, or metastatic disease.79 However, all available systemic therapies are only palliative and associated with disease response in only a minority of patients. Thus, there is an urgent need for new therapeutic targets. More recently, targeted endoradiotherapy has been explored, and preliminary clinical data reported a suffi- cient retention of iodometomidate and therapeutic efficacy with long-term disease stabilization in several patients.10-12 However, only a third of patients show sufficient uptake of iodometomidate, which is a prerequisite for treatment. 10,12,13
A promising potential target is the chemokine receptor 4 (CXCR4), which has been shown to be overexpressed in many types of hematopoietic and solid malignancies. This G protein-coupled receptor plays a central role in proliferation of cancer cells, tumor growth, vascularization, and metastasis development.14-17 Recently a CXCR4-directed PET ligand, 68Ga-pentixafor, was introduced, and promising results have been shown for imaging but also CXCR4-directed endoradiotherapy of patients with multiple my- eloma.18-21 Moreover, preclinical studies confirmed an overexpres- sion of CXCR4 in ACC cell lines.22 Accordingly, we hypothesized that CXCR4-directed PET imaging may help identify patients po- tentially qualifying for CXCR4-directed treatment strategies such as targeted endoradiotherapy with Lu-/ Y-pentixather.
Therefore, the aim of this study was (i) to evaluate the feasi- bility of the CXCR4-directed PET ligand 68Ga-pentixafor for in vivo visualization of CXCR4-expression in ACC patients and (ii) to de- termine the percentage of patients potentially suitable for future CXCR4-directed treatment concepts.
MATERIALS AND METHODS
Patients
From May 2014 to July 2015, 30 patients with histologically proven, metastasized ACC underwent 18F-FDG PET/CT and 68Ga- pentixafor PET/CT. 18F-FDG PET/CT was performed for standard follow-up restaging, whereas 68Ga-pentixafor PET/CT was performed to evaluate a potential therapeutic option. As previously reported for other 68Ga-labeled peptides,23 68Ga-pentixafor was ad- ministered under the conditions of pharmaceutical law (The German
Medicinal Products Act, AMG §13 2b) according to the German law and in accordance with the responsible regulatory body (Regierung von Oberfranken). All patients gave written informed consent prior to the investigations for receiving the 68Ga-pentixafor PET (on a compassionate use basis), as well as undergoing a standard 1 8F-FDG PET. Imaging data were retrospectively analyzed. A for- mal review for this retrospective analysis was waived by the ethics committee of the Universitätsklinikum Würzburg, Germany.
Synthesis of 68Ga-Pentixafor
Synthesis of 68Ga-pentixafor was performed in a fully automated, GMP-compliant procedure using a GRP module (SCINTOMICS GmbH, Fürstenfeldbruck, Germany) equipped with disposable single-use cassette kits (ABX, Radeberg, Germany). Method24,25 and standardized labeling sequence have been previously described.26 Prior to injection, the quality of 68Ga-pentixafor was assessed according to the standards described in the European Pharmacopoeia for 68Ga-edotreotide (European Pharmacopoeia; Monograph 01/2013:2482; available at www.edqm.eu).
PET/CT Imaging Studies
All 18F-FDG PET/CT and 68Ga-pentixafor PET/CT scans were obtained on a dedicated PET/CT scanner (Siemens Biograph mCT 64; Siemens Medical Solutions, Erlangen, Germany) within a mean time interval of 3 ± 4 days (range, 1-22 days). Patients with a time interval of more than 28 days between 18F-FDG PET/CT and 68Ga-pentixafor PET/CT were excluded from the retrospective analysis.
Before the acquisition of 18F-FDG PET/CT, patients fasted for at least 6 hours prior to injection of a dose of 302 ± 23 MBq (range, 256-354 MBq). Patients’ blood glucose levels had to be less than 180 mg/dL. The image acquisition from head to midthigh started 60 minutes after tracer injection. Corresponding diagnostic-dose CT scans with (23 patients [77%]) or without contrast enhancement (4 patients [13%]) for diagnostic issue and attenuation correction were obtained (210 mAs, 120 keV, 512 x 512 matrix,5-mm slice thickness, increment of 5 mm/s, rotation time of 0.5 second, and pitch index of 1.4; CAREDOSE 4D; Siemens Medical Solutions, Erlangen, Germany). In 3 patients (10%), CT was performed as a low-dose CT without contrast enhancement.
Prior to obtaining 68Ga-pentixafor scans, patients fasted at least 4 hours. Injected activity was in mean 127 ± 23 MBq (range, 87-156 MBq), and image acquisition started 60 minutes post injec- tion in accordance with the recently published dosimetry study.20 Corresponding CT scans for attenuation correction were acquired using a low-dose protocol (35 mAs, 120 keV, a 512 x 512 matrix, 5-mm slice thickness, increment of 5 mm/s, rotation time of 0.5 sec- ond, and pitch index of 0.8).
PET emission data both for 18F-FDG PET and 68Ga- pentixafor PET were acquired in 3D mode with a 200 x 200 matrix with 2- to 3-minute emission time per bed position. After decay and scatter correction, PET data were reconstructed iteratively with attenuation correction using a dedicated software (Siemens E-soft).
PET and CT Analysis
All PET scans were analyzed separately by 2 nuclear medicine physicians (C.B., K.H.) with at least 5 years’ experience. All PET scans were analyzed qualitatively and interpreted in a binary visual fashion as positive or negative for disease. CT information was added after identification of tumor lesions to determine the location (local recurrence, lymph node metastases, lung or liver metastases, etc). CT scans were analyzed separately by an experienced radiologist.
The primary readout was the detection rate of 18F-FDG PET. Diagnostic information provided by CT was separately assessed. 68 Ga-pentixafor PET/CT was compared with the reference imag- ing standard 18F-FDG PET/CT to assess if all lesions highly sug- gestive of disease showed a CXCR4 expression. Lesions with uptake highly suspected to be false positive (eg, due to inflamma- tion) were not compared with 68Ga-pentixafor PET/CT. In the present study, 18F-FDG PET/CT was used as standard of refer- ence based on previous publications for staging and restaging of ACC patients.27-29 A lesion on PET was rated as positive if the up- take was higher compared with the background activity within the same organ or tissue. Secondary readout for 18F-FDG PET and 68Ga-pentixafor PET was the semiquantitative tracer uptake as expressed by SUVmax and SUV mean for the tumor lesion with the highest uptake per organ. The SUVmax was assessed by a 3D volume of interest and the SUV mean by a 2D ROI with a diam- eter of 1.5 cm around the hottest pixel. If the hottest lesions were not the same one in the 68Ga-pentixafor PET and 18F-FDG PET, 2 le- sions in 1 organ were reported.
Finally, all patients were rated as suitable, potentially suitable, or not suitable for CXCR4-directed therapy with 177Lu/Y-pentixather based on patient’s history, previous treatment, and CXCR4 expres- sion of FDG-positive lesions. Patients were rated as suitable if all le- sions suggestive of a potential site of disease showed a CXCR4 expression higher than surrounding healthy tissue and liver. Patients were rated as potentially suitable if the majority of lesions showed a high CXCR4 expression.
Statistical Analysis
Qualitative parameters of CT, 18F-FDG PET, and 68Ga-pentixafor PET were descriptively compared. Quantitative values were expressed as mean ± SD or median and range as appropriate. Comparisons of related metric measurements were performed using Wilcoxon signed ranks test. All statistical tests were performed using SPSS Statistics version 22 (IBM). The bars shown represent the SEM. P < 0.05 was considered statistically significant.
RESULTS
Patients
The mean patient age was 51.9 ± 12.2 years (range, 26.3- 77.2 years). Mean duration of disease at time of PET imaging was 2.6 ± 2.9 years (range, 0.3-13.0 years). Patients were previously treated with surgery (29 patients [97%]), mitotane (29 patients [97%]), radiotherapy (7 patients [23%]), systemic chemotherapy (23 patients [77%]), and/or tyrosine kinase inhibitors (2 patients [7%]). The detailed patient characteristics are shown in Table 1. At time of F-FDG PET/CT, 22 patients (73%) had progressive and 4 patients (13%) had stable disease. One pa- tient showed mixed response, and another one responded to therapy (7%), whereas 2 patients (7%) had no previous imaging for comparison available.
Diagnostic Information Provided by 18F-FDG and 68Ga-Pentixafor PET and CT
In summary, all 18F-FDG and 68Ga-pentixafor PET (100%) scans were rated visually positive for potential site of disease. In the reference standard 18F-FDG PET/CT, 12 patients (40%) had local recurrence, 13 patients (43%) had peritoneal or mesenterial tumor lesions, 12 patients (40%) had a retroperitoneal tumor manifestation, 9 patients (30%) had lymph node metastases, and 28 patients (93%) had distant metastases. The most common distant metastases were lung metastases (23 patients [77%]), liver
| No. of Patients | % of All Patients | Mean ± SD (Range) | |
|---|---|---|---|
| Age, y | 51.9 ±12.2 (26.3-77.2) | ||
| Sex | |||
| Female | 17 | 57% | |
| Male | 13 | 43% | |
| Survival time, y | 2.6 ± 2.9 (0.3-13) | ||
| Therapy | |||
| Tumor resection | 29 | 97% | |
| Mitotane | 29 | 97% | |
| Chemotherapy | 23 | 77% | |
| Radiotherapy | 7 | 23% | |
| Tyrosine kinase inhibitor | 2 | 7% | |
| Cortisol and/or aldosterone secretion at time of diagnosis | |||
| Yes | 11 | 37% | |
| No | 6 | 20% | |
| Unknown | 13 | 43% | |
metastases (20 patients [67%]), and bone metastases (7 patients [23%]). Two patients had a metastasis affecting the contralat- eral adrenal gland (7%), and 2patients had multiple pleural metastases (7%).
Visual comparison of both tracers resulted in comparable findings in 10 patients (33%). In 13 patients (43%), 8F-FDG PET identified more lesions with high uptake compared with 68Ga-pentixafor PET. In 2 patients (7%), 68Ga-pentixafor PET (Fig. 1) identified more metastatic lesions. In 5 patients (17%), 68Ga-pentixafor PET and 18F-FDG PET provided complementary
information regarding the number and intensity of lesions. An ex- ample is given in Figure 2. In 2 patients (7%), distant metastases (lung) were detected only by CT and not by PET. In 2 patients (7%), me- tastases in an additional location (liver, tumor lesion in the inferior vena cava, lung) were detected only by CT. In 15 patients (59%), CT detected additional (small) FDG-negative lesions in locations with also FDG-positive metastases (11 patients, lung; 2 patients, liver; 2 patients [retro], peritoneal).
Lesion-Based and Semiquantitative Comparison of 18F-FDG and 68Ga-Pentixafor
The hottest lesion per metastatic location or organ was ana- lyzed semiquantitatively. In 7 patients (23%), the lesion with the highest uptake in 8F-FDG PET did not correspond with 68Ga-pentixafor PET, and therefore 2 lesions per organ were analyzed. The evaluated target lesions per patient ranged from 1 to 9 lesions (mean, 4 ± 2) accounting for a total of 112 lesions. In 12 patients (40%), 15 18F-FDG-avid metastatic lesions (13%) did not show an increased uptake in the 68Ga-pentixafor PET. In 4 patients (13%), 4 68Ga-pentixafor-avid lesions (4%) did not show an increased 18F-FDG uptake (eg, brain metastasis). The corresponding mean SUVmax value for 18F-FDG was 12.5 ± 7.8 (range, 2.2-47.0) and thus higher (P < 0.01) than the SUVmax for 68Ga-pentixafor (mean, 8.4 ± 5.5; range, 1.7-34.2). Detailed results are summarized in Table 2.
Patients Suitable for 177 Lu/90Y-Pentixather Therapy
Including patients’ history and the results of the 68Ga- pentixafor scan, 17 (57%) of 30 patients were rated as suitable, and 4 patients (13%) as potentially suitable for a CXCR4-directed treatment. In these patients, the uptake of 68Ga-pentixafor in the tumor lesions was comparable to or significantly higher than in the 18F-FDG scan. In 9 patients (30%), the FDG-avid tumor lesions demonstrated no or only a faint uptake in
A
B
D
F
C
E
68Ga-Pentixafor PET/CT
18F-FDG PET/CT
A
B
D
F
F
F
C
E
68Ga-Pentixafor PET/CT
18F-FDG PET/CT
the 68Ga-pentixafor scan. These patients were rated as not suitable for CXCR4-directed treatment.
DISCUSSION
68Ga-pentixafor PET/CT is feasible for the in vivo detection of metastatic ACC. However, 18F-FDG PET/CT provided a superior detection rate than 68Ga-pentixafor PET/CT with visually higher up- take in 43% of patients. This finding is in agreement with a previous study in a mixed population of 10 patients with solid tumors reporting a superior visual detectability for 18F-FDG compared with 68Ga-pentixafor.27 Interestingly, in multiple myeloma (n = 14 pa- tients) 68Ga-pentixafor PET/CT identified more lesions than 1 8F-FDG PET/CT in 50% of patients, and also a significantly higher uptake of 68Ga-pentixafor was documented.19
Only in 7% of the ACC patients 68Ga-pentixafor PET/CT identified more lesions, whereas both imaging methods provided complementary information in 15%, respectively. 68Ga-pentixafor uptake often differed between lesions of the same individual, indi- cating some heterogeneous CXCR4 expression of the tumor. Com- parison of tracer uptake in different tumor lesions did not reveal significant differences between local recurrence in the tumor bed and distant metastases, suggesting that the level of CXCR4 mem- brane expression is not per se higher in distant metastases.
As already known,28 sensitivity of PET for detection of small lesions was lower compared with CT for both PET imaging modal- ities. In 7% of the patients, distant metastases (particularly lung me- tastases) were identified only by CT because of their small size. In 59% of the patients, additional PET-negative lesions were found by CT in PET-positive locations. The combination of both full-dose CT and 18F-FDG PET was superior to either method alone. This fits well to the results of previously published studies reporting a significant impact on patient management.28,29 In regard to our find- ings, 18F-FDG PET/CT, preferably combined with a contrast-enhanced CT, should remain the criterion standard for staging and restaging of
ACC and cannot be replaced by 68Ga-pentixafor PET/CT. 68Ga- pentixafor PET/CT is also not suitable for discrimination between ACC and adrenal incidentaloma, because CXCR4 overexpression has also been seen in aldosterone-producing adenoma.3
The results of our in vivo analysis demonstrate that CXCR4 overexpression is present in a significant subgroup of metastatic ACC, and therefore CXCR4-directed treatment concepts might be a future option in patients with advanced ACC and tumor progress under standard treatment. Overall 57% of the ACC pa- tients were rated as suitable or 13% as potentially suitable for CXCR4-diretected endoradiotherapy using Lu/Y-pentixather. Recently, a proof of concept has been published for CXCR4-targeted endoradiotherapy in 3 patients with multiple myeloma.19,20,31 In these patients, a remarkable therapeutic effect was shown by pretreat- ment and posttreatment 18F-FDG PET/CT.31 Endoradiotherapy was well tolerated and safe, but in ACC or other solid cancers, this treatment may have limitations because of its adverse effects. CXCR4/CXCL12 is involved not only in hematopoietic malig- nancies but also in physiological processes including hematopoi- esis, organogenesis, and immunity. The stem cell compartment of normal tissue especially the bone marrow might be affected, resulting in the need of posttherapeutic stem cell transplantation for rescue of bone marrow. Therefore, this treatment option may currently be regarded as a potential last-line therapy. Unless proven as unnecessary, a prerequisite for treatment should be the availabil- ity of hematopoietic stem cells. So far, none of the patients in this study received a 177Lu/90Y-pentixather therapy.
A limitation of the study is that because of the retrospective design no biopsies of the lesions were performed for histopatho- logic correlation of the imaging results. So far, no follow-up of the patients is available. Further evaluation has to be performed to assess if CXCR4 overexpression also in ACC is a poor prognostic factor as shown for other cancer types.32
In conclusion, 68Ga-pentixafor is suitable for in vivo imaging of CXCR4 expression in metastatic ACC and therefore a useful
| 18F-FDG SUV, max | 68 Ga-Pentixafor SUV max | P | 18F-FDG SUV, mean | 68 Ga-Pentixafor SUV mean | P | |
|---|---|---|---|---|---|---|
| Local recurrence | ||||||
| n =13 | 0.152 | 0.087 | ||||
| Mean ± SD | 11.6± 7.4 | 8.3 ± 3.4 | 8.6±5.5 | 5.9 ±2.7 | ||
| Min | 5.5 | 4.5 | 3.8 | 3.0 | ||
| Max | 32.9 | 18.0 | 25.1 | 13.9 | ||
| Peritoneal/mesenterial | ||||||
| n = 14 | 0.016 | 0.013 | ||||
| Mean ± SD | 9.9± 6.6 | 6.3 ± 3.7 | 7.5±4.9 | 4.3 ± 2.6 | ||
| Min | 3.3 | 2.3 | 2.7 | 1.2 | ||
| Max | 23.6 | 14.6 | 17.5 | 9.5 | ||
| Retroperitoneal | ||||||
| n = 15 | 0.233 | 0.125 | ||||
| Mean ± SD | 13.7 ± 6.6 | 11.5 ±8.7 | 10.5 ± 6.6 | 7.2 ± 4.6 | ||
| Min | 4.3 | 2.7 | 3.3 | 2.1 | ||
| Max | 25.5 | 34.2 | 29.8 | 19.0 | ||
| Lymph nodes | ||||||
| n =10 | 0.074 | 0.028 | ||||
| Mean ± SD | 11.1 ±4.6 | 6.8 ± 6.0 | 7.2±2.0 | 4.4 ± 3.3 | ||
| Min | 5.5 | 2.3 | 4.6 | 1.8 | ||
| Max | 19.3 | 22.9 | 10.3 | 12.8 | ||
| Distant | ||||||
| n = 60 | <0.01 | <0.01 | ||||
| Mean ± SD | 13. ±8.8 | 8.4 ± 4.8 | 9.1 ±6.8 | 5.5 ±3.7 | ||
| Min | 2.2 | 1.7 | 0.9 | 0.5 | ||
| Max | 47.0 | 27.4 | 40.8 | 20.9 | ||
| All lesions | ||||||
| n =112 | <0.01 | <0.01 | ||||
| Mean ± SD | 12.5± 7.8 | 8.4 ± 5.5 | 8.8 ±6.1 | 5.5 ± 3.6 | ||
| Min | 2.2 | 1.7 | 0.9 | 0.5 | ||
| Max | 47.0 | 34.2 | 40.8 | 20.9 |
tool for identification of patients potentially benefiting from CXCR4-directed endoradiotherapy. More than 50% of the patients qualified for a CXCR4-directed treatment.
ACKNOWLEDGMENTS
The authors thank Simone Seifert, Simone Groß, Michael Schulze-Glück (members of the nuclear medicine PET team) for their support and assistance.
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