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Evaluating the diagnostic utility of [68Ga]Ga-Pentixafor in solid tumors: a systematic review

Saad Ruzzeh1 . Ahmed Saad Abdlkadir1 . Hasan Al-Alawi1 . Egesta Lopci2 . Mike Sathekge3,4 . Serin Moghrabi1 . Shahed Obeidat1 . Akram Al-Ibraheem 1,5 (D

Received: 10 June 2025 / Accepted: 28 July 2025 / Published online: 15 August 2025 @ The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine 2025

Abstract

The C-X-C motif chemokine receptor 4 (CXCR4) has emerged as a critical molecular imaging target in various malignan- cies due to its central role in tumor progression, metastasis, and resistance to therapy. Among the imaging modalities devel- oped to exploit this target, [68Ga]Ga-Pentixafor-a positron emission tomography (PET) radiopharmaceutical-has shown potential in diagnostic imaging. However, its diagnostic utility in solid tumors remains relatively underexplored, particularly in comparison to the widely utilized [18F]fluorodeoxyglucose ([18F]FDG) PET/CT. Comprehensive literature search was performed across PubMed, Scopus, Web of Science and Embase, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies included those reporting CXCR4-targeted PET imaging in solid tumors, with data on lesion detection, semiquantitative uptake values including maximum standardized uptake value (SUVmax) and tumor-to-background ratio (TBR). Data extraction focused on study design, patient demographics, tumor types, imaging protocols, and key findings. The quality of included studies was assessed using standardized risk-of-bias tools using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. This systematic review analyzed data from 26 studies, encompassing 831 patients with various solid malignancies to assess the diagnostic utility of [68Ga] Ga-Pentixafor PET/CT. Tracer uptake varied significantly among tumor types, with higher SUVmax values observed in adrenocortical carcinoma, small cell lung cancer, and desmoplastic small round cell tumors, while lower uptake was noted in breast cancer, glioblastoma, and melanoma. Certain malignancies, such as prostate cancer, pleural mesothelioma, and colorectal carcinoma, exhibited minimal or absent CXCR4 expression on PET imaging. A correlation between in vivo PET uptake and histopathologic CXCR4 expression was evident in specific tumor types, though heterogeneity in receptor expression was reported. When compared to [18F]FDG PET/CT, [68Ga]Ga-Pentixafor PET/CT demonstrated lower lesion detectability, highlighting its potential as a theranostic tool for CXCR4-targeted therapies rather than a primary diagnostic modality. [68Ga]Ga-Pentixafor PET/CT represents a promising, yet evolving, tool in oncology. While its diagnostic perfor- mance may not rival that of [18F]FDG PET/CT across all tumor types, its theranostic potential underscores its value in the precision medicine landscape.

Keywords CXCR4 · [68Ga]Ga-Pentixafor . PET/CT . Diagnostic imaging . Solid tumors . Molecular imaging

Introduction

The C-X-C motif chemokine receptor 4 (CXCR4) is an important molecular target in oncology, demonstrating over- expression in more than 20 different malignancies, encom- passing both hematological and solid tumors [1]. CXCR4 interacts with its ligand CXCL12, influencing crucial tumor behaviors, such as cell survival, angiogenesis, metastatic potential, and chemoresistance [2, 3]. These characteristics

have driven the development of CXCR4-targeting radiophar- maceuticals like [68Ga]Ga-Pentixafor, enabling non-inva- sive positron emission tomography/computed tomography (PET) imaging of CXCR4 expression and opening avenues for theranostic applications in precision oncology.

Clinically, CXCR4-targeted PET/CT imaging was ini- tially explored in hematological malignancies over a dec- ade ago [4], with subsequent investigations extending to solid malignancies. While extensive research supported by systematic reviews and meta-analyses exists for hema- tological cancers like lymphoma and multiple myeloma,

Fig. 1 Illustrates the selection process using the PRISMA flow diagram

Identification of studies via databases and registers

Identification

Records identified from Databases:

Scopus (n = 207) PubMed (n = 145) Web of science (n = 186)

Records removed before screening: Duplicate records removed (n = 232)

Total (n = 538)

Records screened (n = 306)

Records excluded (n = 258)

Screening

Reports assessed for eligibility (n = 48)

Reports excluded: Non-original research, e.g., case reports, articles, incomplete research and combining haematological and solid malignancies (n =22)

Included

Studies included in review (n = 26)

the application of [68Ga]Ga-Pentixafor PET/CT in solid tumors remains relatively less investigated [5-7]. Solid malignancies, including breast, lung, and pancreatic cancers, frequently exhibit CXCR4 expression, suggesting poten- tial diagnostic and therapeutic roles for CXCR4-targeted approaches [8]. Nonetheless, preliminary studies indicate substantial variability in tracer uptake among different tumor types and limited correlations with clinical outcomes [8, 9]. This variability, along with inconsistent imaging protocols, highlights the need for systematic evaluation in this domain.

[18F]fluorodeoxyglucose ([18F]FDG) PET/CT is widely employed for imaging solid malignancies; however, it pre- sents significant limitations related to specificity. FDG

uptake frequently occurs in inflammatory or infectious pro- cesses, resulting in false-positive interpretations [10]. Fur- thermore, several tumor types, including prostate cancer, mucinous adenocarcinomas, and low-grade neuroendocrine tumors, typically exhibit minimal FDG uptake, diminishing the diagnostic accuracy of FDG PET/CT in these scenarios [11]. In contrast, CXCR4-targeted imaging potentially offers a more specific molecular-level evaluation by directly visu- alizing the CXCR4 receptor, whose expression is closely associated with tumor aggressiveness, metastasis, and thera- peutic resistance [4].

Moreover, the significance of CXCR4 as a molecular target extends beyond its diagnostic utility; its importance

Fig. 2 QUADAS-2, Qual- ity Assessment of Diagnostic Accuracy Studies

Risk of bias domains

Study

Domains:

D1: Patient selection.

Judgement

D2: Index test.

☒ High

D3: Reference standard.

D4: Flow & timing.

☒ Some concerns

☒ Low

	D1	D2	D3	D4	Overall
Lapa et al. 2016 (A)	☒	☒	☒	☐	☒
Lapa et al. 2016 (B)	☒	☒	☒	☐	☒
Vag et al. 2016	☒	☒	☒	☒	☐
Lapa et al. 2017	☒	☒	☒	☒	☒
Bluemel et al. 2017	☒	☒	☒	☒	☒
Werner et al. 2017	☒	☒	☐	☐	☒
Vag et al. 2018	☒	☐	☐	☐	☐
Werner et al. 2019	☒	☐	☐	☒	☐
Breun et al. 2019	☒	☒	☐	☒	☒
Linde et al. 2021	☐	☐	☐	☒	☐
Weich et al. 2021	☐	☐	☐	☐	☐
Lewis et al. 2021	☐	☐	☒	☒	☐
Watts et al. 2022	☐	☒	☐	☒	☒
Jacobs et al. 2022	☐	☐	☐	☒	☐
Serfling et al. 2022	☒	☐	☐	☒	☒
Watts et al. 2023	☒	☐	☐	☒	☒
Mirshahvalad et al. 2023	☒	☐	☐	☒	☒
Hartrampf et al. 2023	☒	☒	☐	☒	☒
Hartlapp et al. 2023	☒	☒	☐	☒	☒
Waheed et al. 2024	☒	☒	☐	☒	☒
Liu et al. 2024	☒	☒	☐	☒	☒
Manafi-Farid et al. 2024	☐	☒	☐	☒	☒
Jena et al. 2024	☐	☒	☐	☒	☒
Dreher et al. 2024	☐	☒	☐	☒	☒
Madan et al. 2024	☒	☒	☒	☒	☒
Hadebe et al. 2024	☒	☒	☐	☐	☒

is largely driven by its potential theranostic applications in oncology. Theranostics integrates diagnostic imaging with targeted radionuclide therapy, enabling personalized treat- ment approaches. CXCR4-directed imaging with [68Ga] Ga-Pentixafor PET/CT facilitates the non-invasive visuali- zation of receptor expression, which can then guide patient selection for CXCR4-targeted radionuclide therapies, such as those using [177Lu] or [90Y]-labeled agents [12].

This systematic review aims to fill the gap by synthesiz- ing existing evidence on CXCR4-targeted imaging in solid tumors. It assesses the diagnostic performance of [68Ga]Ga- Pentixafor PET/CT, explores its potential as an alternative or complementary imaging modality and evaluates its role in guiding promising theranostic applications.

Methods

This review was reported according to the Preferred Report- ing Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. No ethical approval or informed consent was required.

Search strategy

We comprehensively and systematically searched three elec- tronic databases (PubMed, Web of Science, and Scopus) from their inception to 5-October 2024. The search utilized the following terms: (“68 Ga-pentixafor” or “CXCR4 imag- ing” or “pentixather”).

Eligibility criteria

The included studies comprised both prospective and retro- spective research investigating the role of [68Ga]Ga-Pen- tixafor PET in solid tumors, with a focus on those report- ing diagnostic performance or evaluating semiquantitative measures of tracer uptake, such as maximal standardized uptake value (SUVmax) and tumor-to-background ratio (TBR). Non-original research articles, including review articles, systematic reviews, case reports, and conference or meeting reports, were excluded from this systematic review. Studies conducted on non-human subjects or in vitro set- tings, as well as studies combining both hematologic and solid tumors, were also excluded. Lastly, studies published in languages other than English were excluded.

Screening and data extraction

Two authors (SR and HA), conducted the initial screening by evaluating the titles and abstracts of the records in Rayyan AI [14]. Following this, they independently performed a sec- ondary screening by thoroughly reviewing the full text of the

identified studies based on predetermined inclusion criteria. Subsequently, they independently extracted data from the included studies using a predesigned Microsoft Excel sheet. The extracted data included the title, year, authors, study location, study design, cancer type and subtype, sample size, age, and gender. Key variables assessed were compari- son with standard references, patient status and diagnostic performance outcomes. Semiquantitative PET measures, including median SUVmax and TBR for both primary and metastatic lesions, were collected for [68Ga]Ga-Pentixafor and compared with [18F]FDG PET when available (Fig. 1).

Risk of bias and quality assessment

The risk of bias and quality assessment of the included stud- ies were independently evaluated using the QUADAS-2 tool [15]. This tool assesses potential sources of bias in four key domains: patient selection, index test, reference standard, and flow and timing. Each domain was judged as having a low, high, or unclear risk of bias based on signalling ques- tions. Two independent reviewers performed the risk of bias assessment, with discrepancies resolved through discussion or consultation with a third reviewer when necessary. The overall quality of the studies was determined based on the degree of bias observed across domains. The evaluation was performed using Excel and Fig. 2 was generated using robvis (https://mcguinlu.shinyapps.io/robvis/) [16].

Results

Study selection

A total of 538 records were initially identified from the three databases: Scopus (207), PubMed (145), and Web of Science (186). After removing 232 duplicate records, 306 studies were screened. Of these, 258 were excluded based on title and abstract screening. The remaining 48 full-text reports were assessed for eligibility, with 22 fur- ther excluded for being non-original research, incomplete studies, or combining haematological and solid malignan- cies. Ultimately, 26 studies met the inclusion criteria and were included in the review.

Characteristics of the included studies

The systematic review includes 26 studies [9, 17-41] inves- tigating the diagnostic utility of [68 Ga]Ga-Pentixafor PET/ CT across various solid tumors. The included studies were conducted across multiple countries, most from Germany, Iran, Netherlands, India, and South Africa. Both prospec- tive and retrospective study designs were represented, with a total of 831 patients analyzed. Sample sizes ranged from

Table 1 Characteristics of the included studies

Authors	Type of the study	Cancer type	Sample Size	Age (mean range)	Gender	Compared with	Patients compared
Lapa et al. 2016 [17]	Prosepctive	Lung cancer	10	63 (52-74)	5 males, 5 females	[68Ga]DOTATOC and [18F]FDG PET/CT	6 FDG, 5 DOTA- TOC
Lapa et al. 2016 [17]	Prosepctive	Glioblastoma	15	60 (48-71)	7 males, 8 females	[18F]FET PET/CT	15
Vag et al. 2016 [19]	Prosepctive	Solid cancers	21	63 (55-85)	–	[18F]FDG PET/ CT	10
Lapa et al. 2017 [20]	Prosepctive	Pleural mesothe- lioma	6	71 (53-89)	5 males, 1 female	[18F]FDG PET/ CT	4
Bluemel et al. 2017 [21]	Retrospective	Adrenocortical carcinoma	30	51.9 (26-77)	13 males, 17 females	[18F]FDG PET/ CT	30
Werner et al. 2017 [22]	Prosepctive	Neuroendocrine tumors (NET)	12	68 (48-82)	10 male, 2 female	[68Ga]DOTATOC and [18F]FDG PET/CT	12
Vag et al. 2018 [23]	Retrospective	Breast cancer	18	59 (38-77)	all females	[18F]FDG PET/ CT	8
Werner et al. 2019 [24]	Prosepctive	Solid cancers	19	71 (60-81)	11 males, 8 females	[18F]FDG PET/ CT	3
Breun et al. 2019 [25]	Prosepctive	Vestibular schwan- nomas	4	–	–	–	–
Linde et al. 2021 [26]	Retrospective	Esophageal cancer	10	70 (57-83)	8 males, 2 females	[18F]FDG PET/ CT	10
Weich et al. 2021 [27]	Retrospective	Neuroendocrine Carcinoma (NEC)	11	65 (45-80)	9 males, 2 females	[18F]FDG PET/ CT	11
Lewis et al. 2021 [9]	Retrospective	Solid cancers	145	58.8 (44-73)	89 males. 56 females	–	–
Jacobs et al. 2022 [28]	Retrospective	Gliomas	7	55 (21-75)	5 males, 2 females	–	–
Watts et al. 2022 [29]	Prosepctive	Rare Lung Malig- nancies	6	57 (41-74)	3 men, 3 women	–	–
Serfling et al. 2022 [30]	Retrospective	Solid cancers	93	59.6 (47-72)	49 males, 41 females	–	–
Watts et al. 2023 [31]	Prospective	Lung cancer	94	60.1 (50-70)	77 Males: 17 Females	–	–
Mirshahvalad et al. 2023 [32]	Prospective	Lung cancer	12	60 (53-67)	9 males, 3 females	[18F]FDG PET/ CT	12
Hartrampf et al. 2023 [33]	Retrospective	Solid cancers	50	63.7 (53-74)	31 males, 19 females	–	–
Hartlapp et al. 2023 [34]	Prospective	Small round cell tumor (DSRCT)	7	29 (8-43)	7 males	[18F]FDG PET/ CT	7
Waheed et al. 2024 [35]	Prospective	Glioblastoma mul- tiforme (GBM)	19	50 (28-67)	12 males, 7 females	–	–
Liu et al. 2024 [36]	Prospective	Nasopharyngeal Carcinoma	25	54 (27-77)	20 males, 5 women	[18F]FDG PET/ CT	25
Manafi-Farid et al. 2024 [37]	Prospective	Melanoma	12	60 (54-66)	6 males, 6 females	[18F]FDG PET/ CT	12
Jena et al. 2024 [38]	Prosepective	Sarcoma	10	24.7 (18-64)	7 males, 3 females	–	–
Dreher et al. 2024 [39]	Prospective	Solid cancers	142	59.5 (8-89)	79 males, 63 females	–	–
Madan et al. 2024 [40]	Prospective	Gliomas	30	44 (28-63)	20 males, 10 females	–	–
Hadebe et al. 2024 [41]	Prospective	Head and neck cancer	23 831	52.9 (42-64)	17 males, 6 females	[18F]FDG PET/ CT	16 186
		Total

[18F]FDG fluorine-18 fluorodeoxyglucose, [68 Ga]DOTATOC gallium-68 DOTA-D-Phe1-Tyr3-octreotide, [18F]FET fluorine-18 fluoroethyl- tyrosine, PET/CT positron emission tomography/computed tomography, NET neuroendocrine tumors, NEC neuroendocrine carcinoma, DSRCT desmoplastic small round cell tumor, GBM glioblastoma multiforme

Table 2 Distribution of included studies by cancer type, number of studies, and total number of patients undergoing [68Ga]Ga-Pentixafor PET/CT imaging

Cancer type		Number of studies	Num- ber of patients
Basket Studies (including different types of solid cancers)		6	470
Head and neck malignancies	Brain tumors	4	71
	Head and neck CA	2	48
	Vestibular schwannoma	1	4
Thoracic malignancies	Breast CA	1	18
	Lung CA	4	122
	Pleural mesothelioma	1	6
	Esophageal CA	1	10
Abdominal malignancies	Adrenocortical CA	1	30
	Neuroendocrine tumor (NET)	2	23
Others	Small round cell tumor	1	7
	Melanoma	1	12
	Sarcoma	1	10
	Total	26	831

CA carcinoma, NET neuroendocrine tumor

as few as 4 to as many as 145 patients per study. Patient ages also varied considerably, with reported ranges from 8 to 89 years. Gender distribution was relatively balanced across the studies. Out of these, 15 studies [17-24, 26, 27, 32, 34, 36, 37, 41] directly compared [68Ga]Ga-Pentixafor PET/CT with other PET tracers, including 12 with [18F]FDG PET/ CT, two with both [18F]FDG and [68Ga]DOTATOC PET/ CT, and one with [18F]FET PET/CT. Table 1 summarizes the characteristics of the included studies.

Risk of bias and quality assessment

In this systematic review, the risk of bias and quality of the included studies were evaluated using the QUADAS-2 tool, which assesses four main domains: patient selection, index test, reference standard, and flow and timing. The assess- ment, as illustrated in Fig. 2, indicated that the majority of included studies exhibited a low risk of bias across most domains. Nonetheless, certain concerns and occasional high risks were noted, especially related to the reference stand- ard domain, primarily due to methodological variations in defining and applying reference standards among the studies reviewed. Despite these variations, the overall methodologi- cal quality remained strong, particularly in aspects of patient selection, proper execution of the index test and consist- ent management of study flow and timing. Supplementary Table 1 presents a comprehensive evaluation and justifica- tion for the risk of bias judgments made for each included study.

Qualitative assessment

This systematic review evaluated 831 patients across various malignancies. Some included studies were designed as bas- ket studies [9, 19, 24, 30, 33, 39], incorporating multiple his- topathological types and primary tumor sites, while others focused specifically on head and neck, thoracic, abdominal, or rare malignancies. Basket studies accounted for the largest subgroup, comprising six studies with a total of 470 patients. Head and neck malignancies were investigated in five stud- ies, involving 71 patients with brain tumors, 48 patients with head and neck cancers, and four patients with vestibular schwannomas. Thoracic malignancies included breast cancer (18 patients), lung cancer (122 patients across four studies), pleural mesothelioma (6 patients), and esophageal cancer (10 patients). Abdominal malignancies were represented by two studies focusing on neuroendocrine tumors (23 patients) and one study on adrenocortical carcinoma (30 patients). Additionally, rare malignancies such as desmoplastic small round cell tumors (7 patients), melanoma (12 patients), and sarcoma (10 patients) were examined across three studies. Among these, 15 [17-24, 26, 27, 32, 34, 36, 37, 41] studies compared [68 Ga]Ga-Pentixafor PET/CT with other PET tracers: 12 studies compared it with [18F]FDG, one with [18F]FET, and two studies with both [68 Ga]Ga-DOTATOC and [18F]FDG (Table 2).

Basket studies (including different types of solid cancers)

Vag et al. (2016) [19] conducted a prospective study in Germany aiming to evaluate CXCR4-targeted PET probe in patients with solid cancers who had reported in vitro

Fig. 3 Ilustration of two patients imaged with [68 Ga]Ga-Pentixafor PET/CT. Comparison of CXCR4-directed immunohistochemistry (IHC) with [68 Ga]Ga-pentixafor PET/CT images of two patients. A, B, C Patient with adrenal cortical carcinoma with increased uptake in sites of disease on maximum intensity projection (MIP, A) and transaxial PET/CT (B), along with high CXCR4 expression on IHC

A

B

D

E

1

C

F

0

10

0

10

evidence of CXCR4 overexpression and to estimate its potential diagnostic value. The cohort included cases of pan- creatic cancer [3], laryngeal cancer [1], NSCLC [2], prostate cancer [1], melanoma [2], breast cancer [3], hepatocellular carcinoma [2], glioblastoma [1], sarcoma [5], and cancer of unknown primary [1]. Among these patients, 9 had not received prior therapy, while 12 had undergone treatment, including chemotherapy, radiotherapy, or surgery.

Imaging findings revealed that among the untreated patients, eight had identifiable primary tumors. In the treated group, local recurrence of primary tumors was observed in three cases. A total of 43 malignant lesions were analyzed, comprising 8 primary tumors, 3 locally recurrent tumors, and 32 metastases.

Ten patients underwent [18F]FDG PET/CT. While all 27 lesions (2 primary and 25 metastatic) were detectable using [18F]FDG PET/CT, only 19 lesions were identified on [68 Ga]Ga-Pentixafor PET/CT, highlighting the lower detectability of CXCR4-targeted imaging.

Quantitative analysis demonstrated a mean SUVmax of 4.7 (range: 2.1-10.9) for [68 Ga]Ga-Pentixafor compared to a mean SUVmax of 13.8 for [18F]FDG. The mean TBR for [68 Ga]Ga-Pentixafor was 2.9, while it was 6.6 for [18F] FDG. Notably, the highest uptake with [68 Ga]GaPentixafor was observed in a patient with NSCLC (SUVmax: 10.9; TBR ratio: 8.4) and another with cancer of unknown primary (SUVmax: 13.8; TBR ratio: 8.1).

staining (C). D, E, F Patient diagnosed with a neuroendocrine car- cinoma, demonstrating no relevant uptake in the primary (D, E) and no relevant CXCR4 expression (IRS, 1). Magnification of IHC: × 400 Reproduced from Dreher et al. [39] licensed under a Creative Com- mons Attribution 4.0 International License http://creativecommons. org/licenses/by/4.0/

The study concluded that, despite in vitro evidence sup- porting CXCR4 overexpression in solid cancers, the in vivo detectability of [68 Ga]Ga-Pentixafor PET/CT was incon- sistent and generally lower compared to [18F]FDG PET/CT.

Werner et al. (2019) [24] published a prospective study in Germany evaluating the diagnostic potential of [68 Ga] Ga-Pentixafor PET/CT in 19 patients with solid tumors. All patients were newly diagnosed and treatment-naïve, includ- ing pancreatic adenocarcinoma [4], neuroendocrine tumors [2], cholangiocarcinoma [4], hepatocellular carcinoma [3], renal cell carcinoma [1], ovarian cancer [3], prostate cancer [1], and cancer of unknown origin [1]. In three subjects, additional [18F]FDG PET/CT imaging was performed within two weeks for staging purposes.

Among the included patients, primary tumors were visu- alized in all cases and evidence of metastases was found in 7/19 (36.8%) patients. By using [68 Ga]Ga-Pentixafor PET/ CT, 10/19 (52.6%) primary tumors and 14/49 (28.6%) meta- static lesions were detectable. Moreover [68 Ga]Ga-Pentix- afor failed to identify lesions in two of the three patients evaluated using [18F]FDG PET/CT, which detected metas- tases in two cases while [68 Ga]Ga-Pentixafor visualized metastases in only one patient.

Quantitative imaging results revealed a median SUVmax of 5.4 (range: 1.7-16.0) for [68 Ga]Ga-Pentixafor, com- pared to a higher median SUVmax of 14.3 for [18F]FDG. The median TBR for [68 Ga]Ga-Pentixafor was 2.6 (range: 0.8-7.4), while for [18F]FDG, it was 4.8 (range: 2.9-6.7).

Good correlation was noted between [68 Ga]Ga-Pentixafor uptake and histologically derived CXCR4 expression levels.

The study concluded that CXCR4-directed imaging with [68 Ga]Ga-Pentixafor may have limited applicability in the diagnosis of most solid cancer patients due to its suboptimal detection rates compared to [18F]FDG PET/CT.

Lewis et al. (2021) [9] investigated splenic CXCR4 expression using [68 Ga]Ga-Pentixafor in 145 patients with solid tumors across 27 cancer types. The largest subgroups included adrenal cancers (n=31), neuroendocrine tumors (n=25), and small cell lung cancer (SCLC, n=13). The mean age was 58.8 years, with 61.4% males. Limited-stage disease was seen in 19.3%, advanced-stage in 42.8%, and 37.9% had undetermined staging. The mean spleen SUVmax was 8.50, with a spleen-to-liver ratio of 6.19.

Authors concluded that splenic [68 Ga]Ga-Pentixafor uptake was not associated with stage of disease and clinical outcomes. No tumor entity showed especially high levels of spleen [68 Ga]Ga-Pentixafor uptake compared to others.

Serfling et al. (2022) [30] published a study involving 90 patients with histologically confirmed solid tumors evaluated the correlation between CXCR4-targeted [68Ga] Ga-Pentixafor PET/CT uptake in normal organs (spleen, kidneys, bone marrow, heart, and liver) and tumor burden metrics, including SUVmax, tumor volume (TV), and frac- tional tumor activity (FTA). Normal organ uptake showed no significant correlation with tumor burden parameters, sug- gesting an absence of a tumor sink effect. This finding indi- cates that, regardless of tumor load, normal organ dosimetry may remain consistent, which is significant for both diagnos- tic imaging and CXCR4-directed therapeutic applications.

In Hartrampf et al. (2023) [33] study, CXCR4-targeted [68Ga]Ga-Pentixafor PET/CT scans from 50 patients with solid tumors were reviewed by four independent observers to assess interobserver agreement on imaging parameters and eligibility for CXCR4-targeted radioligand therapy (RLT). Agreement rates ranged from fair to excellent across various metrics, including scan impressions, Intraclass Correlation Coefficient (ICC: 0.58), organ and lymph node (LN) involve- ment (ICC≥0.4), and CXCR4 density and metastases quan- tification (ICC≥0.65). Quantitative lesion measurements and eligibility decisions for CXCR4-RLT showed excellent concordance (ICC≥0.91). These findings support the clini- cal adoption of [68Ga]Ga-Pentixafor PET/CT for imaging and guiding CXCR4-targeted therapies.

Dreher et al. (2024) [39] conducted a prospective study in Germany to evaluate the in vivo expression of CXCR4 in solid tumors using [68 Ga]Ga-Pentixafor PET/CT, by cor- relating imaging findings with histopathological data. The study included 142 patients with a diverse range of malig- nancies, with the largest cohorts comprising adrenocorti- cal carcinoma (34 patients) (Fig. 3), neuroendocrine neo- plasms (30 patients), small cell lung cancer (14 patients),

and desmoplastic small round cell tumors (10 patients). Additional cases included non-small cell lung cancer (9 patients), hepatocellular carcinoma (8 patients), pancreatic cancer (8 patients), and pleural mesothelioma (6 patients), along with smaller subgroups of renal cell carcinoma [4], ovarian carcinoma [3], cholangiocarcinoma [3], and prostate cancer [2]. Single cases of Ewing sarcoma, osteosarcoma, mediastinal tumor, colorectal carcinoma, leiomyosarcoma, thyroid cancer, paraganglioma, angiosarcoma, stromal sar- coma, and neuroectodermal teratoma were also analyzed.

Overall, 152 [68Ga]Ga-pentixafor PET/CT scans were performed, discernible CXCR4 uptake above blood pool (TBR>1) was observed in 103 scans (67.8%), identifying a total of 462 lesions, including 52 primary tumors and 410 metastases. The imaging analysis reported a median SUV- max of 8.73 (range: 4.85-26.92) and TBR of 4.4 (range: 1.05-24.98), reflecting high image contrast. The highest radiotracer uptake (SUVmax) was observed in ovarian can- cer, followed by small cell lung cancer, desmoplastic small round cell tumor, and adrenocortical carcinoma. In contrast, tumors such as prostate, colorectal, and hepatocellular carci- nomas exhibited low or negligible CXCR4 expression, with uptake values close to background levels. Overall, CXCR4 expression appeared uniform across primary and metastatic lesions (P>0.999), except in pulmonary lesions, where a significant difference was observed (P=0.013).

Correlation with histopathology revealed a weak but statistically significant association between SUVmax and immunoreactive score (IRS) for CXCR4 expression (Spear- man’s p=0.328, P=0.018), supporting the tracer’s specific- ity. Furthermore, to assess suitability for CXCR4-targeted RLT, visual and quantitative evaluations were performed. Eligibility criteria by authors included intense tracer uptake (defined as an average SUVmax ≥ 10 across all segmented lesions) and widespread disease (at least five CXCR4- positive target lesions). Based on these parameters, 28% of patients were deemed potentially eligible for CXCR4- directed therapy. Among these, 12 scans (28.6%) exhibited a median SUVmax above 10, with adrenocortical carcinoma comprising the largest proportion (41.7%), followed by neuroendocrine neoplasms (33.3%), small cell lung cancer (16.7%), and desmoplastic small round cell tumors (8.3%).

Head and neck malignancies

Brain tumors Lapa et al. (2016) [18] designed a prospective study in Germany focusing on [68 Ga]Ga-Pentixafor PET/ CT imaging and histopathologic CXCR4 expression in 15 patients with glioblastoma. The median age of the cohort was 60 years interquartile range (IQR) 23, comprising 7 males and 8 females. The study utilized [18F]FET PET/CT for comparison. Among the tumors analyzed, 13 were pri- mary and 2 were recurrent, with all localized lesions.

The detection rate for [68 Ga]Ga-Pentixafor PET/CT was 13 out of 15, with two patients, one diagnosed with GBM and another with anaplastic astrocytoma IIIº, not display- ing uptake. Conversely, all patients with suspected primary and recurrent high-grade gliomas exhibited enhanced uptake with [18F]FET PET/CT. Imaging metrics revealed that [18F]FET had higher SUVmean and SUVmax (5.3±2.3) than [68 Ga]Ga-Pentixafor (3.9+2.0), while TBR values for [68 Ga]Ga-Pentixafor (4.1 ±1.3) were higher than for [18F]FET.

Histological evaluation confirmed CXCR4 expression in areas with high [68 Ga]Ga-Pentixafor uptake, whereas tumor regions with no apparent uptake showed low or no receptor expression. Among the 14 samples analyzed, CXCR4 expression varied, with two rated “weak”, six rated “moderate,” and five rated “strong.” A single sample from a patient with ischemic stroke was rated “negative,” and positive CXCR4 PET uptake in this case was attributed to macrophages and glial cells.

Jacobs et al. (2022) [28] conducted a study evaluating CXCR4 expression in glioblastoma tissue and its potential application for PET imaging with [68Ga]Ga-Pentixafor and targeted therapy using [177Lu]Lu-Pentixather. The study included a large-scale messenger ribonucleic acid (mRNA) dataset analysis (N=824), ex vivo immunohistochemical assessment of glioblastoma tissue (N= 191 tumors, 426 cores), and a correlation of in vivo PET imaging findings with resected tissue from seven patients with recurrent glio- blastoma. Results demonstrated substantial inter- and intra- tumoral heterogeneity in CXCR4 expression, with 78 cores (23 tumors) showing no staining, while 18 cores (5 tumors) had strong and extensive CXCR4 positivity. Immunohisto- chemistry confirmed that normal brain tissue lacked CXCR4 expression.

In vivo PET imaging of seven glioblastoma patients revealed variable [68Ga]Ga-Pentixafor uptake (mean SUV- max: 2.06; TBRmax: 65.6), with only one patient showing strong uptake corresponding to moderate-to-strong CXCR4 staining, while the others exhibited discrepancies between PET signal and histopathology. Despite this variability, the study suggests that patients with high CXCR4 expression on PET may be suitable candidates for CXCR4-directed radionuclide therapy, though caution is needed in directly translating ex vivo staining to PET uptake.

Waheed et al. (2024) [35] from India prospectively assessed the diagnostic potential of [68 Ga]Ga-Pentixafor PET/CT for imaging CXCR4 receptors in glioblastoma mul- tiforme (GBM) and its role in evaluating treatment response to R-CT. The study included 19 patients, divided into two groups. Group I (n=9) comprised presurgical patients who underwent scanning before surgery, while Group II (n= 10) included postsurgical patients scanned before and after R-CT (radio-chemotherapy).

In Group I, [68 Ga]Ga-Pentixafor uptake was observed in all primary tumors. The mean SUVmax, SUVmean, and SUVpeak were 4.5±1.6, 0.60±0.26, and 1.95±0.8, respec- tively, with a mean TBR of 6.9±4.6. In Group II, base- line imaging revealed residual disease in 9 of 10 patients, with corresponding mean SUVmax, SUVmean, SUVpeak, and TBR values of 4.4±1.6, 0.65±0.32, 2.04±0.85, and 5.96±3.5, respectively. Follow-up imaging after R-CT indi- cated significant changes, with a mean TBR increasing to 8.84±5.72 (P=0.05).

The study highlighted the utility of [68 Ga]Ga-Pentixafor in detecting CXCR4 receptors and suggested that SUVmax and TBR could serve as valuable prognostic indicators for R-CT outcomes in GBM patients.

Madan et al. (2024) [40] conducted a phase II prospective study in India to explore the potential role of [68 Ga]Ga- Pentixafor PET in guiding radiotherapy (RT) dose escalation for patients with grade 4 gliomas, including glioblastoma (GBM). The study included 30 biopsy-confirmed cases of grade 4 glioma. Post-operative MRI and [68 Ga]Ga-Pen- tixafor PET scans were performed for all patients to define gross tumor volumes (GTV) and planning target volumes (PTV) for a two-phase RT regimen. The phase-1 target area (PTV1) received a dose of 46 Gy in 23 fractions, while the phase-2 target area (PTV2) received 14 Gy in 7 fractions. PET-avid disease delineated as PTV-PET was treated with an escalated dose of 21 Gy in 7 fractions using simultaneous integrated boost (SIB), leading to a total dose of 67 Gy in 30 fractions for PTV-PET. All patients received concurrent and adjuvant temozolomide.

Analysis revealed a median overall survival (OS) of 23 months, with estimated 1-, 2-, and 3-year OS rates of 90%, 40%, and 17.8%, respectively. A significant associa- tion was observed between OS and the extent of surgery (p=0.04) and Karnofsky Performance Status (p=0.007). Importantly, no patients developed significant radiation necrosis, and treatment was well tolerated. However, the dose escalation guided by PET did not lead to a clear sur- vival benefit, highlighting the need for further investigation.

Head and neck cancers Hadebe et al. (2024) [41] presented a prospective study in South Africa to evaluate the diagnos- tic performance of CXCR4-directed imaging using [68 Ga] Ga-Pentixafor PET/CT in 23 patients with head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oro- pharynx, and nasopharynx. Among these, 17 patients were newly diagnosed, and 6 had recurrent disease. Sixteen patients also underwent [18F]FDG PET/CT as a standard reference for comparison. CXCR4 immunohistochemistry (IHC) staining was performed in 21 patients to correlate imaging findings with CXCR4 expression in tissue samples.

Most patients (91%) demonstrated visually detectable lesions on [68 Ga]Ga-Pentixafor PET/CT. However, the

avidity of [68 Ga]Ga-Pentixafor was generally lower than that of [18F]FDG PET/CT. Quantitative analysis revealed significantly higher SUVmax for [18F]FDG compared to [68 Ga]Ga-Pentixafor (16±6.7 vs. 5.8±2.6, p=0.011) and higher TBR values for [18F]FDG (4.9±2.3 vs. 2.36±1.4, p=0.014). Nasopharyngeal carcinoma exhibited the high- est tracer uptake among HNSCC subtypes, exceeding oro- pharyngeal and oral cavity malignancies.

CXCR4 IHC staining was positive in 15 out of 21 patients, with a statistically significant correlation observed between IHC staining intensity and [68 Ga]Ga-Pentixafor SUVmean (r=0.5, p=0.027). Notably, cervical lymph node metastases showed higher CXCR4 expression than primary lesions in some cases, as evidenced by greater [68 Ga]Ga- Pentixafor avidity in lymph nodes.

Although [68 Ga]Ga-Pentixafor PET/CT demonstrated lower diagnostic avidity compared to [18F]FDG PET/CT, it had specific advantages, including the absence of physiolog- ical brown fat uptake, which can obscure cervical lesions on [18F]FDG PET/CT. The study concluded that while [68 Ga] Ga-Pentixafor cannot replace [18F]FDG for routine diag- nostic use, it holds promise for selecting patients who may benefit from CXCR4-targeted therapies.

Liu et al. (2024) [36] designed a prospective study in China to evaluate the feasibility of [68 Ga]Ga-Pentixafor PET/CT as a diagnostic tool in nasopharyngeal carcinoma (NPC), comparing it with [18F]FDG PET/CT. The study enrolled 25 patients, including 21 undergoing initial staging and four assessed for recurrence. Both imaging modalities were performed within one week, and uptake in primary and metastatic lesions was quantitatively and qualitatively analyzed.

The detection rates for primary tumors were identical for [68 Ga]Ga-Pentixafor and [18F]FDG PET/CT (96% each, 24/25), with SUVmax values significantly lower for [68 Ga]Ga-Pentixafor than for [18F]FDG (8.13 ±2.78 vs. 14.25±6.45, p<0.01). Similarly, TBR values for [68 Ga] Ga-Pentixafor were lower than those for [18F]FDG (5.17±2.14 vs. 9.81±5.30, p<0.01). While tumor volumes derived from both tracers showed no significant difference (median TVpentixafor: 16.01 vs. TVFDG: 9.56, p=0.332), [68 Ga]Ga-Pentixafor demonstrated improved visualization of skull base and intracranial extension due to lower back- ground uptake in the brain.

Metastatic cervical lymph nodes (CLNs) were visual- ized effectively using both tracers, but SUVmax values for [68 Ga]Ga-Pentixafor were again lower than for [18F]FDG (6.86±2.63 vs.10.39±5.28, p<0.01). Although the detec- tion rates were comparable (96% for [68 Ga]Ga-Pentixafor vs. 98% for [18F]FDG, p=0.613), [68 Ga]Ga-Pentixafor identified fewer distant bone metastases, resulting in one staging underestimation.

Despite its lower uptake in primary and metastatic lesions compared to [18F]FDG, [68 Ga]Ga-Pentixafor PET/CT demonstrated unique advantages in delineating lesions near the skull base and intracranial regions. The study concluded that [68 Ga]Ga-Pentixafor is a promising imaging agent for NPC, particularly in selecting patients for CXCR4-directed endoradiotherapy.

Breun et al. (2019) [25] conducted a prospective study in Germany to assess the feasibility of CXCR4-targeted imaging of vestibular schwannomas (VS) using [68 Ga]Ga- Pentixafor PET/CT. The study included four patients with six VS lesions, of which two patients had neurofibromato- sis type 2 (NF2) with bilateral lesions (previously treated), while the other two had unilateral VS (one newly diagnosed and one untreated). All patients underwent [68 Ga]Ga-Pen- tixafor PET/CT prior to surgical resection.

The study demonstrated enhanced [68 Ga]Ga-Pentixafor uptake in all VS cases (100%). SUVmax and SUVmean values were reported as 3.8 +0.4 and 3.0±0.3, respec- tively, with corresponding TBRmax and TBRmean values of 5.0±1.7 and 4.0±1.4. Immunohistochemistry served as a reference standard and confirmed CXCR4 expression in tumors analyzed from three patients.

Authors highlight the potential utility of [68 Ga]Ga-Pen- tixafor PET/CT as a non-invasive imaging tool for assess- ing CXCR4 expression in vivo, particularly in NF2-mutated cases. This imaging modality could play a critical role in diagnosis, treatment planning, and further research into tar- geted therapies for vestibular schwannomas.

Thoracic malignancies

Lung cancer Lapa et al. (2016) [17] conducted a prospective study in Germany to investigate the potential role of [68 Ga] Ga-Pentixafor-PET/CT in assessing CXCR4 expression in small cell lung cancer (SCLC) and large cell neuroendo- crine carcinoma (LCNEC). The study included 10 patients, three with newly diagnosed disease and seven with prior treatment. Comparative imaging was performed using [18F] FDG PET/CT in six patients and [68Ga]DOTATOC PET/CT in five patients, targeting somatostatin receptor expression.

The findings showed that [68 Ga]Ga-Pentixafor-PET/CT was visually positive in 8 out of 10 patients, demonstrating strong tracer uptake in primary tumors, lymph nodes, and distant metastases. Notably, one patient with LCNEC and another with SCLC who had recently undergone combined chemoradiotherapy displayed negative results.

Compared to [68 Ga]DOTATOC (n=5), two out of five patients were positive on [68 Ga]Ga-Pentixafor but negative on SSTR imaging, two patients were positive on both scans, and one patient was negative on both modalities. Similarly, when compared to [18F]FDG (n =6), both [68 Ga]Ga- Pentixafor and [18F]FDG were positive in four out of six

patients, while the remaining two patients exhibited [18F] FDG-positive but CXCR4-negative lesions. On a lesion- based analysis, among the five patients who underwent [68 Ga]DOTATOC-PET, [68 Ga]Ga-Pentixafor identified a total of 55 lesions, significantly outperforming somatostatin receptor (SSTR-PET), which detected only 20 lesions. When compared to [18F]FDG (44 lesions), CXCR4-directed PET visualized 33 tumor lesions.

Quantitative analysis revealed a median SUVmax for primary lesions of 8.8 (range: 4.8-15.5) with [68 Ga]Ga- Pentixafor, compared to 9.9 (range: 4.7-38.1) for [18F]FDG and 9.1 (range: 4.7-13.5) for [68 Ga]DOTATOC. The TBR for [68 Ga]Ga-Pentixafor was 3.7 (range: 1.8-5.1), slightly higher than [18F]FDG at 3.2 (range: 1.4-8.7) and substan- tially greater than [68 Ga]DOTATOC at 0.7 (range: 0.4-1.0). For metastatic lesions, [68 Ga]Ga-Pentixafor demonstrated a median SUVmax of 10.0 (range: 6.5-19.4), while [18F]FDG showed a slightly higher median SUVmax of 11.2 (range: 4.9-19.3), and [68 Ga]DOTATOC exhibited the highest value at 17.6 (range: 16.7-18.5). The TBR for [68 Ga]Ga- Pentixafor was 3.2 (range: 2.4-8.3), compared to 3.5 (range: 1.5-8.6) for [18F]FDG and 1.5 (range: 1.3-1.6) for [68 Ga] DOTATOC.

This study highlighted the feasibility of non-invasive CXCR4 imaging with [68 Ga]Ga-Pentixafor-PET/CT in SCLC. The findings suggest its potential utility in identify- ing patients suitable for CXCR4-targeted therapies.

Watts et al. (2023) [31] from India conducted a prospec- tive study to evaluate the utility of [68 Ga]Ga-Pentixafor PET/CT for in vivo CXCR4 receptor mapping across vari- ous lung cancer subtypes, while correlating these findings with quantitative receptor density using immunochemistry techniques. The study included 94 patients, comprising 75 with non-small cell lung cancer (NSCLC); 54 squamous cell, 16 adenocarcinoma, 5 not otherwise specified (NOS) cancers, 14 with SCLC, and 5 with lung neuroendocrine tumors (NET).

[68 Ga]Ga-Pentixafor PET/CT demonstrated increased tracer uptake (SUVmax) in the primary lung tumor of all patients (100%). The tracer uptake followed the quantita- tive CXCR4 receptor density, with the order of expres- sion decreasing as follows: SCLC>NSCLC adenocar- cinoma> NSCLC squamous > NOS > lung NET. SCLC showed the highest SUVmax (mean: 10.3±5.0, range: 6.5-26.64), and correspondingly the highest mean fluores- cence intensity (MFI; 349.0±98.5). A significant correlation was observed between SUVmax and MFI values in NSCLC subtypes (squamous: r=0.697, p=0.001; adenocarcinoma: r=0.538, p=0.031), confirming specific CXCR4 recep- tor uptake. However, this correlation was not significant in SCLC (r=0.435, p=0.121) or NET (r=0.747, p=0.147), potentially due to small sample sizes.

The high sensitivity (85.7%) and specificity (78.1%) of [68 Ga]Ga-Pentixafor PET/CT were highlighted for dif- ferentiating SCLC from NSCLC, with an ROC (Receiver operating characteristic) cutoff SUVmax of 7.2. Similar performance was noted for distinguishing adenocarcinoma from squamous cell NSCLC (sensitivity: 87.5%, specific- ity: 71.4%, ROC cutoff SUVmax=6.7). These findings suggest that [68 Ga]Ga-Pentixafor PET/CT is a promising tool for response assessment and CXCR4-targeted radioli- gand therapy development in lung cancer.

Mirshahvalad et al. (2023) [32] from Iran prospectively conducted a study to compare the diagnostic performance of [68 Ga]Ga-Pentixafor PET/CT with the standard [18F]FDG PET/CT in patients with NSCLC. The study included 12 patients (mean age: 60±7 years; 9 males and 3 females), comprising 8 cases of adenocarcinoma and 4 cases of squamous cell carcinoma. Most patients (75%) were referred for primary staging, while the remaining 25% were evaluated for disease recurrence. The primary objective of the study was to assess whether [68 Ga] Ga-Pentixafor PET/CT could offer comparable or supe- rior diagnostic value in detecting and assessing NSCLC lesions.

Both imaging modalities successfully visualized all pri- mary tumors, demonstrating concordant visual findings for NSCLC primary lesions. Furthermore, [68 Ga]Ga-Pentixa- for PET/CT showed similar performance to [18F]FDG PET/ CT in detecting metastatic lesions, although [18F]FDG PET/ CT revealed significantly higher SUVmax and SUVmean values for malignant lesions (p<0.05). Despite this, [68 Ga] Ga-Pentixafor PET/CT displayed specific advantages, including the detection of two brain metastases that were missed by [18F]FDG PET/CT. Additionally, a lesion initially classified as suspicious for recurrence on [18F]FDG PET/CT was correctly identified as benign on [68 Ga]Ga-Pentixafor PET/CT, emphasizing its potential in resolving equivocal findings.

Out of 73 lesions detected across the cohort, 15 (21%) were interpreted differently between the two imaging modalities. Six lesions were identified as malignant only on [68 Ga]Ga-Pentixafor PET/CT, while nine lesions were identified as malignant only on [18F]FDG PET/CT. The remaining 58 lesions (79%) were concordant between the two modalities, with 36 interpreted as malignant and 22 as benign.

Quantitative analysis revealed median SUVmax values of 4.81 ±3.92 for [68 Ga]Ga-Pentixafor and 8.70±6.32 for [18F]FDG in primary lesions. For metastatic lesions, the median SUVmax was 4.50 ±2.23 for [68 Ga]Ga-Pentixa- for and 9.29 ±4.23 for [18F]FDG. The TBR also showed slightly lower values for [68 Ga]Ga-Pentixafor compared to [18F]FDG for both primary and metastatic lesions.

The authors concluded that [68 Ga]Ga-Pentixafor PET/ CT is a promising imaging modality for NSCLC, particu- larly in its ability to detect brain metastases and clarify ambiguous findings on [18F]FDG PET/CT. While the count statistics for [68 Ga]Ga-Pentixafor PET/CT were lower compared to [18F]FDG PET/CT, its complementary role in imaging NSCLC lesions highlights its potential for clinical application.

In 2022, Watts et al. [29] conducted a prospective study in India to evaluate the feasibility of [68 Ga]Ga-Pentixafor PET/CT in identifying CXCR4 receptor overexpression in rare lung malignancies and its correlation with histologic and histochemical findings. The study included six patients (mean age: 57 ±16.8 years; three males and three females), representing diverse malignancies. Three patients had rare primary lung tumors: hemangioendothelioma, sarcomatoid carcinoma, and hemangiopericytoma. The remaining three cases involved lung metastases originating from sarcoma, renal cell carcinoma, and an unknown primary tumor. Quan- titative findings were correlated with histopathology and CXCR4 fluorescence-activated cell sorting (FACS) analysis.

High tracer uptake was noted in all lung lesions. Among primary lung pathologies, the highest SUVmax (13.04) and corresponding MFI (682.0) were observed in the patient with histopathologic evidence of hemangioendothelioma. Patients with sarcomatoid carcinoma and hemangiopericytoma had SUVmax values of 6.34 and 3.0, with corresponding MFI values of 110.5 and 27.9, respectively. In patients with lung metastases, the highest SUVmax of 9.5 was reported in a sarcoma metastasis, followed by SUVmax values of 7.5 in metastases from an unknown primary and that of 6.0 in metastases from renal cell carcinoma, with corresponding MFI values of 191.2, 216.0, and 62.0, respectively.

Pearson correlation analysis revealed a strong relationship between SUVmax and MFI (r=0.90), SUVmax and the per- centage of stained CXCR4-positive cells (r=0.79), and MFI and the percentage of stained cells (r=0.72). These findings demonstrated the high specificity of [68 Ga]Ga-Pentixafor PET/CT in targeting in vivo CXCR4 receptor expression.

Pleural mesothelioma Lapa et al. (2017) [20] also con- ducted a prospective study to evaluate the potential role of [68 Ga]Ga-Pentixafor PET/CT as a theranostic tool target- ing CXCR4 expression in pleural mesothelioma. The study included six patients (median age: 71, IQR: 18; five males and one female), none of whom presented with extra-pleu- ral metastases. Comparative imaging was performed using [18F]FDG PET/CT in four patients.

Results revealed that none of the six patients exhibited relevant focal [68 Ga]Ga-Pentixafor-positive lesions on PET/ CT. This finding was consistent with immunohistochemical analysis, which failed to detect significant CXCR4 surface expression in the analyzed samples. Conversely, [18F]FDG

PET/CT identified viable tumor lesions in all four patients scanned, with a median SUVmax of 11.5 (range: 7.8-18.4), whereas the SUVmax for [68 Ga]Ga-Pentixafor ranged from 2.3 to 4.4, with a median of 3.9. TBRs for [68 Ga]Ga-Pentix- afor showed a median of 1.0 (range: 0.7-1.4), significantly lower than the TBRs for [18F]FDG, which had a median of 5.2 (range: 2.5-5.8).The study concluded that there is a widespread absence of CXCR4 expression in pleural meso- thelioma, as evidenced by imaging and immunohistochemi- cal analysis.

Breast cancer Vag et al. (2018) [23] from Germany retro- spectively assessed the utility of [68 Ga]Ga-Pentixafor PET/ CT in imaging CXCR4 expression in patients with primary and recurrent breast cancer. The study included 18 patients, among them 13 were newly diagnosed with primary breast carcinoma, five of whom had lymph node metastases, and two had distant metastases. Additionally, four patients had recurrent breast cancer, and one presented with axillary lymph node metastases of unknown primary origin. Com- parative imaging with [18F]FDG PET/CT was performed in eight patients (four with recurrent breast cancer and four with primary breast cancer).

Results revealed that [68 Ga]Ga-Pentixafor PET/CT visu- ally detected nine out of thirteen primary breast carcino- mas, while all cases of recurrent breast cancer and axillary metastases were detectable. However, lesions in two cases of invasive lobular carcinoma (ILC) and two cases of invasive carcinoma of no special type (NST) that were triple-negative (lacking hormone receptor and Human Epidermal Growth Factor Receptor 2 (HER2) expression) were undetectable with [68 Ga]Ga-Pentixafor PET/CT. In contrast, [18F] FDG PET/CT consistently demonstrated higher SUVmax values across all patients. Quantitative analysis showed a mean SUVmax of 3.0 for primary tumors on [68 Ga]Ga- Pentixafor PET/CT compared to 16.2 on [18F]FDG PET/ CT. Mean TBR were 2.4 for [68 Ga]Ga-Pentixafor and 3.2 for [18F]FDG.

The study concluded that [68 Ga]Ga-Pentixafor PET/CT demonstrated significantly lower tumor detectability com- pared to [18F]FDG PET/CT. Consequently, CXCR4-targeted imaging may not be suitable as a general diagnostic tool for breast cancer imaging.

Esophageal cancer In 2021, Linde et al. (2021) [26] from Germany designed a retrospective study to evaluate the potential of [68 Ga]Ga-Pentixafor PET/CT for imaging CXCR4 expression in esophageal cancer. The study involved 10 patients (median age: 70 years, IQR: 13; eight males and two females) diagnosed with localized esophageal cancer, comprising three adenocarcinomas and seven squamous cell carcinomas. Comparative imaging was performed using [18F]FDG PET/CT.

Patient-based analysis revealed comparable results between [68 Ga]Ga-Pentixafor and [18F]FDG PET/CT in 4 out of 10 patients. Lesion-based analysis identified a total of 26 lesions, of which 14 showed positive uptake for both tracers. Interestingly, five lesions were [18F]FDG positive but [68 Ga]Ga-Pentixafor negative, whereas seven lesions were [68 Ga]Ga-Pentixafor positive but [18F]FDG negative. Quantitatively, the mean SUVmax for [68 Ga]Ga-Pentixafor PET/CT was 4.7±2.5, while it was higher for [18F]FDG PET/CT at 6.9±4.6.

The study concluded that imaging CXCR4 expression in esophageal cancer using [68 Ga]Ga-Pentixafor PET/CT is feasible but exhibits heterogeneity. While [68 Ga]Ga-Pen- tixafor PET/CT may not fully replace [18F]FDG PET/CT, it demonstrated potential as a complementary imaging tool, particularly for identifying lesions that were FDG-negative. The findings also suggest that CXCR4 could serve as a promising target for endoradiotherapy in selected cases.

Abdominal malignancies

Adrenocortical cancer Bluemel et al. (2017) [21] conducted a retrospective study in Germany to assess the potential role of CXCR4 as a theranostic target in adrenocortical carci- noma (ACC) patients using [68 Ga]Ga-Pentixafor PET/CT. The study involved 30 patients, all of whom had undergone various treatments.

In comparison with the standard [18F]FDG PET/CT, [68 Ga]Ga-Pentixafor PET/CT showed diverse results. [18F]FDG PET/CT revealed extensive disease, with 93% of patients presenting distant metastases, 43% with peritoneal or mesenteric tumors, 40% with retroperitoneal lesions, 30% with lymph node involvement, and 40% with local recur- rences. [68 Ga]Ga-Pentixafor PET/CT findings were com- parable to [18F]FDG PET/CT in 33% of patients, identified additional lesions in 7% of cases, and provided complemen- tary information on lesion number and intensity in 17% of patients. However, [18F]FDG PET/CT detected more lesions with higher uptake than [68 Ga]Ga-Pentixafor in 43% of the patients. Notably, 40% of [18F]FDG-avid metastatic lesions showed no significant [68 Ga]Ga-Pentixafor uptake, while 13% of [68 Ga]Ga-Pentixafor-avid lesions lacked [18F]FDG uptake, including some brain metastases.

Quantitative analysis showed a mean SUVmax of 8.4±5.5 (range: 1.7-34.2) for [68 Ga]Ga-Pentixafor and 12.5 ±7.8 (range: 2.2-47.0) for [18F]FDG. Based on CXCR4 expression patterns, 57% of patients were deemed suitable by authors, 13% potentially suitable, and 30% not suitable for CXCR4-directed therapies. The study high- lighted that CXCR4 overexpression is present in a significant subset of metastatic ACC cases, suggesting that CXCR4- targeted treatment strategies could provide a promising

therapeutic option for patients with advanced disease and limited response to standard treatments.

Neuroendocrine tumor (NET) Werner et al. (2017) [22] conducted a prospective study in Germany to investigate the expression of CXCR4 in gastro-entero-pancreatic neu- roendocrine tumors (GEP-NET) using a triple-tracer com- parative approach involving [68 Ga]Ga-Pentixafor PET/ CT, [68 Ga]DOTATOC PET/CT and [18F]FDG PET/ CT. The study included 12 patients with various NET subtypes, including ileum NET (n=4), pancreatic NET (n=3), gastric NET (n=2), rectum NET (n=1), esopha- geal NET (n=1), and mixed adenoneuroendocrine carci- noma of the colon (n= 1).

At the time of imaging, 4 patients had newly diagnosed disease, while 8 had previously undergone various thera- pies but had not received treatment for at least four weeks. The primary tumor was present in 75% of subjects, and 11 out of 12 patients presented with metastatic disease. The imaging was primarily conducted for staging and thera- peutic planning.

[68 Ga]Ga-Pentixafor PET/CT visualized tumor lesions in 6 out of 12 subjects, identifying 69 lesions. In con- trast, [68 Ga]DOTATOC PET/CT detected 245 lesions, while [18F]FDG PET/CT identified 127 lesions. Notably, [68 Ga]Ga-Pentixafor failed to detect any lesions in well- differentiated G1 NETs, but visualized tumor sites in 50% of G2 and 80% of G3 cases.

The study highlighted that SSTR-directed PET [68 Ga] DOTATOC was the best imaging modality for well-differ- entiated G1 and G2 NETs. In contrast, CXCR4-directed PET ([68 Ga]Ga-Pentixafor) demonstrated a higher detection rate in poorly differentiated and dedifferenti- ated tumors (G3). These findings suggest that [68 Ga]Ga- Pentixafor PET/CT may serve as a non-invasive diagnostic tool and a potential readout for CXCR4-targeted endora- diotherapy in advanced, SSTR-negative, dedifferentiated NETs.

In 2021 Weich et al. [27] designed a retrospective study in Germany to evaluate the diagnostic utility of CXCR4- directed [68 Ga]Ga-Pentixafor PET/CT in patients with newly diagnosed, poorly differentiated (GEP-NETs). The study included 11 treatment-naïve patients. Tumor locations included the stomach (n=3), pancreas (n=2), esophagus (n=2), ileum (n=1), rectum (n=1), and two patients with unknown primary tumors. The primary objectives of the study were staging and therapy planning.

The results showed that [68 Ga]Ga-Pentixafor PET/CT visualized tumor lesions in 10 out of 11 patients, detecting a total of 42 lesions, including both primary tumors and metastatic sites. However, it was outperformed by [18F]FDG PET/CT, which identified tumor sites in all 11 patients and detected significantly more lesions (102 vs. 42; total lesions,

n=107, p<0.001). This included sites of primary and meta- static disease.

Quantitative analysis revealed a mean SUVmax of 7.7±2.2 for [68 Ga]Ga-Pentixafor compared to 13.3±8.5 for [18F]FDG. Similarly, TBR was higher for [18F]FDG (8.8±6.9) than for [68 Ga]Ga-Pentixafor (4.7±1.0). The findings highlighted the superior sensitivity of [18F]FDG PET/CT compared to [68 Ga]Ga-Pentixafor PET/CT for detecting poorly differentiated neuroendocrine tumors.

Others

Desmoplastic small round cell tumors (DSRCT) Hartlapp et al. (2023) [34] conducted a prospective study in Ger- many to evaluate the clinical potential of CXCR4-directed imaging and endoradiotherapy in desmoplastic small round cell tumors (DSRCT), a rare and aggressive malignancy. The study included seven male patients with EWSR1-WT1 fusion-positive DSRCT, with a mean age of 29 years (range: 8-43 years). All patients presented with extensive disease at the time of imaging.

The imaging protocol involved both [68 Ga]Ga-Pen- tixafor PET/CT and the standard [18F]FDG PET/CT for comparison. The results demonstrated significant [68 Ga] Ga-Pentixafor uptake in tumor lesions for all seven patients, confirming CXCR4 overexpression. Of the 61 tumor lesions identified, 60 lesions (98.4%) showed uptake on [18F]FDG PET/CT, while 57 lesions (93.4%) exhibited uptake on [68 Ga]Ga-Pentixafor PET/CT. Concordant uptake of both tracers was observed in 56 lesions. However, discordant pat- terns were noted in three patients, with some lesions being [18F]FDG-positive but CXCR4-negative and others being CXCR4-positive but [18F]FDG-negative. For instance, two patients had discordant uptake patterns in isolated metasta- ses (lymph node or peritoneal metastases), highlighting the complementary diagnostic value of CXCR4 imaging.

Quantitative analysis revealed significant differences between the two modalities. The median SUVpeak was higher for [18F]FDG compared to [68 Ga]Ga-Pentixafor (5.7, range: 1.5-16.6, vs. 4.7, range: 1.7-10.3; p <0.001). Similarly, the median TBR was higher for [18F]FDG (3.8, range: 0.9-9.2, vs. 2.9, range: 0.7-5.9; p<0.001). Despite these differences, the study underscored the unique ability of [68 Ga]Ga-Pentixafor to identify lesions with CXCR4 over- expression, which could serve as a biomarker for potential therapeutic targeting.

In terms of treatment, four patients underwent CXCR4- directed endoradiotherapy using [90Y]Pentixather after pre- therapeutic dosimetry with [177Lu]Pentixather. The results showed a significant decrease in tumor metabolic activity on post-therapy [18F]FDG PET/CT, indicating a measurable therapeutic response. The treatment was well-tolerated, with

manageable hematotoxicity, supporting its feasibility in this young, organ-fit patient population.

Malignant melanoma Manafi-Farid et al. (2024) [37] from Iran shared a prospective pilot study to assess the diagnos- tic value of [68 Ga]Ga-Pentixafor PET/CT in malignant melanoma. The study involved 12 patients (mean age: 60±6 years; 6 males and 6 females) who were all previously classified as stage III or higher. Among these, two patients were referred for initial staging, two for detecting recur- rence, and eight for evaluating the extent of metastases.

The imaging protocol utilized both [68 Ga]Ga-Pentixafor PET/CT and the standard [18F]FDG PET/CT for compari- son. [68 Ga]Ga-Pentixafor detected lesions in all patients, identifying a total of 101 tumoral lesions, including two primary tumors, one recurrence, 16 locoregional metasta- ses, and 82 distant metastases. However, this represented a detection rate of only 42% compared to [18F]FDG PET/CT, which visualized 236 lesions, including two primary tumors, two recurrent lesions, 29 locoregional metastases, and 203 distant metastases. Notably, [68 Ga]Ga-Pentixafor PET/CT successfully identified a documented brain metastasis, which was missed on [18F]FDG PET/CT, highlighting its potential for detecting brain lesions due to the lack of physiological cerebral uptake.

Quantitative analysis revealed significantly lower SUV values for [68 Ga]Ga-Pentixafor compared to [18F] FDG. The mean SUVmax for [68 Ga]Ga-Pentixafor was 2.72 ±1.33, compared to 11.41 ±14.79 for [18F]FDG. Similarly, the mean TBR for [68 Ga]Ga-Pentixafor was 1.25±0.61, compared to 4.32±5.47 for [18F]FDG. These findings underline the lower sensitivity and tumor-to-back- ground contrast provided by [68 Ga]Ga-Pentixafor PET/CT.

In terms of diagnostic performance, [68 Ga]Ga-Pentixa- for PET/CT showed a sensitivity of 41.8%, a positive predic- tive value of 87.4%, and an accuracy of 39.4% for detecting regional and distant metastases. Despite its limited sensi- tivity and lesion detection capabilities compared to [18F] FDG PET/CT, [68 Ga]Ga-Pentixafor demonstrated a distinct advantage in identifying brain metastases due to the absence of cerebral uptake. The authors concluded that [68 Ga]Ga- Pentixafor PET/CT has limited potential as a primary diag- nostic tool in melanoma compared to [18F]FDG PET/CT.

Sarcoma Jena et al. (2024) [38] conducted a prospective study in India to explore the potential of [68 Ga]Ga-Pen- tixafor PET/CT for in vivo mapping of CXCR4 receptor expression as a radiotheranostic target in bone and soft tis- sue sarcomas. The study included 10 patients (mean age: 24.7±14.2 years; range: 18-64 years), comprising seven males and three females. Histological subtypes consisted of seven osteosarcomas, and one each of chondrosarcoma,

Table 3 Summary of key findings from studies assessing [68Ga]Ga-Pentixafor PET/CT imaging in solid tumors

Study	Cancer type	Key findings	Comparator findings
Vag et al. (2016)	Mixed solid tumors	CXCR4 PET showed inconsistent tumor detection despite known CXCR4 overexpression in vitro. Clinical utility remains limited by variable tracer uptake	Lower detection and significantly lower SUVmax and TBR com- pared to FDG PET
Werner et al. (2019)	Mixed solid tumors	CXCR4 PET imaging revealed moderate lesion detection across various solid tumors. Limited clinical applicability due to over- all suboptimal tracer uptake	Substantially lower lesion detectability and lower SUVmax com- pared to FDG PET
Lewis et al. (2021)	Mixed solid tumors	Splenic uptake of CXCR4 PET tracer showed no association with cancer stage or clinical outcomes. Its clinical significance remains uncertain	N/A
Serfling et al. (2022)	Mixed solid tumors	No correlation was observed between normal-organ uptake and overall tumor burden using CXCR4 PET. Normal-organ dosim- etry may be unaffected by tumor load	N/A
Hartrampf et al. (2023)	Mixed solid tumors	CXCR4 PET imaging demonstrated excellent interobserver agree- ment regarding eligibility for CXCR4-targeted therapy. Supports potential clinical adoption for therapy guidance	N/A
Dreher et al. (2024)	Mixed solid tumors	CXCR4 PET imaging showed variable uptake across multiple solid malignancies. Approximately 28% of patients were eligible for CXCR4-targeted therapy based on uptake criteria	N/A
Lapa et al. (2016)	Glioblastoma	CXCR4 PET imaging successfully visualized aggressive glioblas- toma lesions, with uptake correlating strongly to tumor grade. Its uptake could serve as a non-invasive marker for aggressive glioblastomas	Lower SUVmax but improved tumor-to-background ratios (TBR) compared to FET PET
Jacobs et al. (2022)	Glioblastoma	Glioblastoma exhibited substantial heterogeneity in CXCR4 expression, limiting the universal utility of CXCR4 PET imag- ing. Some lesions showed discrepancies between PET uptake and histology	N/A
Waheed et al. (2024)	Glioblastoma	CXCR4 PET uptake reliably predicted patient response to radio- chemotherapy in glioblastoma. It serves as a potential prognos- tic imaging biomarker for therapy monitoring	N/A
Madan et al. (2024)	Glioblastoma	CXCR4 PET imaging effectively aided radiotherapy dose escala- tion planning in grade IV gliomas. However, no clear survival benefit from dose escalation was observed	N/A
Hadebe et al. (2024)	Head & Neck	CXCR4 PET showed notably higher uptake in nasopharyngeal carcinoma than in other head and neck cancer subtypes. It may facilitate patient selection for CXCR4-targeted therapeutic strategies	Lower SUVmax, TBR, and lesion detectability compared to FDG PET
Liu et al. (2024)	Nasopharyngeal carcinoma	CXCR4 PET had lower SUVmax in primary tumors but uniquely improved visualization of lesions at the skull base and intracra- nial regions. It could be especially valuable for tumor delinea- tion in challenging anatomical areas	Lower overall lesion detectability and lower SUVmax compared to FDG PET, yet superior intracranial lesion detection

Table 3 (continued)

Study	Cancer type	Key findings	Comparator findings
Breun et al. (2019)	Vestibular Schwannoma	All vestibular schwannomas demonstrated robust CXCR4 PET tracer uptake. CXCR4 imaging could thus be potentially valuable for treatment planning and tumor characterization in vestibular schwannoma	N/A
Lapa et al. (2016)	Lung cancer	CXCR4 PET was highly effective, identifying lesions in most patients with SCLC and LCNEC. It has potential as an imag- ing biomarker and therapy selection tool for CXCR4-targeted approaches in lung neuroendocrine carcinomas	Superior lesion detection compared to DOTATOC PET and similar lesion detectability to FDG PET
Watts et al. (2023)	Lung cancer	Small cell lung cancer demonstrated significantly higher CXCR4 PET tracer uptake compared to non-small cell lung cancer. CXCR4 PET could be useful for differentiating lung cancer subtypes non-invasively	N/A
Mirshahvalad et al. (2023)	Lung cancer	CXCR4 PET was particularly effective in detecting brain metas- tases missed by conventional imaging in NSCLC patients. However, its sensitivity for extracranial lesions was lower than FDG PET	Lower sensitivity and lower SUVmax compared to FDG PET, except for superior brain lesion detection
Watts et al. (2022)	Lung cancer	Rare lung malignancies consistently exhibited high tracer uptake on CXCR4 PET, suggesting its suitability for these tumors. It highlights potential as a diagnostic and therapeutic biomarker in uncommon lung malignancies	N/A
Lapa et al. (2017)	Pleural mesothelioma	CXCR4 PET failed to demonstrate significant tracer uptake in pleural mesothelioma, suggesting limited clinical relevance. CXCR4 imaging may not be suitable for mesothelioma evalua- tion	Significantly inferior to FDG PET in lesion detectability and tracer uptake
Vag et al. (2018)	Breast cancer	CXCR4 PET showed limited detectability and low uptake in breast cancer lesions. Its use as a general diagnostic imaging modality for breast cancer appears minimal	Significantly lower detection rates and SUVmax values compared to FDG PET
Linde et al. (2021)	Esophageal cancer	CXCR4 PET imaging was feasible but demonstrated significant heterogeneity in uptake among esophageal cancer patients. It could serve as a complementary imaging approach for detecting FDG-negative lesions	Detected certain FDG-negative lesions but generally lower overall uptake compared to FDG PET
Bluemel et al. (2017)	Adrenocortical carcinoma	High CXCR4 uptake was observed in adrenocortical carcinoma, suggesting significant potential for CXCR4-targeted therapy. CXCR4 PET might assist in identifying therapy candidates in advanced ACC cases	Comparable lesion detection to FDG PET, with complementary lesion visualization capabilities
Werner et al. (2017)	Neuroendocrine tumors	CXCR4 PET demonstrated higher tracer uptake specifically in high-grade neuroendocrine tumors. It could potentially identify patients suitable for CXCR4-targeted therapies in dedifferenti- ated NETs	Lower detection rate compared to DOTATOC and FDG PET in well-differentiated NETs
Weich et al. (2021)	Neuroendocrine tumors	High tracer uptake was seen predominantly in poorly differenti- ated neuroendocrine neoplasms using CXCR4 PET. The modal- ity could facilitate targeted therapy selection in these aggressive tumors	Significantly lower lesion detectability and SUVmax compared to FDG PET

Table 3 (continued)

			com-		FET desmo-
	FDG PET		detectability		tumor-to-background ratio, cancer, DSRCT
	to
			lesion	lesions
	compared				lung
				brain	cell
			overall
				for	TBR
			and
	capability			better	value, non-small
			SUVmax	yet	NSCLC
				PET,	uptake
findings	detection		lower
				FDG
Comparator	lesion			to
	Similar		Significantly	pared N/A	standardized carcinoma,
Key findings			in
	uptake in	This strong therapeutic	detectability	uptake, suggesting imaging modal- therapeutic metastases CXCR4	SUVmax maximum cell neuroendocrine
	uniformly strong tracer	cell tumors (DSRCT). as a biomarker and	demonstrated generally low	strong CXCR4 tracer theranostic target. This selection for targeted in detecting brain Despite this limitation,	fluorodeoxyglucose, cancer, LCNEC large available
		round suitability		as a patient potential lesions.	FDG cell lung where carcinoma
	demonstrated	small suggests its	imaging DSRCT	showed potential facilitate unique melanoma in sarcoma	tomography, small included adrenocortical
	PET		PET in	lesions showed	SCLC
		desmoplastic uptake	target	Sarcoma excellent could malignant approaches effectively	emission are ACC
	CXCR4		CXCR4	ity PET	PET tumor,
					positron [18F]FET
			melanoma		4, PET or neuroendocrine
Cancer type	DSRCT		Malignant	Sarcoma	receptor type DOTA-D-Phe1-Tyr3-octreotide, with [18F]FDG NET
			(2024)		DOTATOC results tumor,
	(2023)				chemokine cell
			et al.	(2024)	imaging round
	al.
	et				C-X-C small
				et al.
Study	Hartlapp		Manafi-Farid	Jena	CXCR4 fluoroethyltyrosine, Comparative plastic

leiomyosarcoma, and synovial sarcoma. Among the cohort, three patients exhibited metastatic lesions.

The study demonstrated increased [68 Ga]Ga-Pentixafor uptake in all primary sarcoma lesions, with notable visu- alization of CXCR4 receptor expression. Metastatic lesions were also detected in three patients using [68 Ga]Ga-Pen- tixafor PET/CT imaging, further emphasizing its utility in identifying disease extent. Quantitative analysis revealed a mean SUVmax of 4.80± 1.0 (range: 3.9-7.7, median: 4.75) in primary lesions and a mean TBR of 1.84± 1.3 (range: 1.1-3.2, median: 1.8), indicating high-contrast imaging capability.

The study’s findings suggest that [68 Ga]Ga-Pentixafor PET/CT offers detailed visualization of nuclear and cyto- plasmic CXCR4 receptor expression in sarcomas, delivering high-contrast PET/CT images (Table 3).

Discussion

This systematic review highlights the emerging role of [68 Ga]Ga-Pentixafor PET/CT in imaging CXCR4 expres- sion in solid tumors. While its application in precision oncology demonstrates both promise and limitations.

Several studies in this review highlight a correlation between CXCR4 expression in histopathological assays (e.g., immunohistochemistry, mRNA) and [68 Ga]Ga-Pen- tixafor PET uptake, particularly in high-grade, aggressive malignancies [21, 24, 29]. This supports the role of CXCR4 PET imaging as a non-invasive biomarker for patient selec- tion in CXCR4-targeted therapies. However, significant het- erogeneity in receptor expression has been observed across tumors, leading to variability in PET uptake [39]. While some studies report strong alignment between in vivo PET findings and ex vivo CXCR4 staining, others demonstrate discordant results, particularly in glioblastoma and pancre- atic cancer, where [68 Ga]Ga-Pentixafor uptake does not always reflect histologic receptor density [24, 28]. These inconsistencies may stem from differences in tumor micro- environment, receptor internalization, or tracer kinetics; underscoring the need for standardized thresholds and fur- ther validation to refine the clinical applicability of CXCR4 PET imaging.

Although [68Ga]Ga-Pentixafor PET/CT demonstrates lower lesion detectability and semiquantitative uptake com- pared to [18F]FDG PET/CT in most solid tumors [23, 26, 32, 36, 41], its value extends beyond diagnostic accuracy alone. The ability to identify CXCR4 expression in aggres- sive and treatment-resistant cancers positions it as a thera- nostic tool rather than a direct competitor to [18F]FDG PET/ CT.

Table 4 Clinical suitability and diagnostic utility of [68 Ga]Ga-Pentixafor PET/CT imaging across different solid cancer subtypes, highlighting potential applications in guiding CXCR4-targeted radionuclide therapies

Cancer subtype	Suitability for CXCR4 imaging Clinical clarification
Small Cell Lung Cancer (SCLC)	Highly promising	Consistently high CXCR4 uptake suggests strong potential for guiding targeted radionuclide therapies
Adrenocortical Carcinoma (ACC)	Highly promising	Frequent strong tracer accumulation, indicating suitability for theranostic applications, particularly in advanced or metastatic disease
Desmoplastic Small Round Cell Tumors (DSRCT)	Highly promising	Uniformly elevated CXCR4 expression observed; promis- ing candidate for CXCR4-directed radionuclide therapy
High-grade neuroendocrine tumors	Promising	Significant uptake noted, especially in aggressive or poorly differentiated neuroendocrine tumors; potentially useful for therapy selection
Glioblastoma Multiforme (GBM) (selected cases)	Conditionally promising	Variable uptake; strong CXCR4 expression primarily in aggressive or recurrent tumors, making it useful in selected cases for therapy guidance and radiotherapy planning
Breast cancer	Limited	Generally low or inconsistent CXCR4 expression; inferior to FDG PET in lesion detection and clinical utility
Mesothelioma	Limited	Negligible or absent tracer uptake, indicating limited clini- cal relevance of CXCR4 imaging in this subtype
Malignant melanoma	Limited	Low sensitivity and inferior lesion detection compared to FDG PET; limited utility except in the detection of brain metastases
Esophageal cancer	Limited	Markedly heterogeneous uptake limits its utility as a rou- tine diagnostic tool; may only have niche applications
Non-Small Cell Lung Cancer (NSCLC)	Generally limited	Overall lower lesion detectability than FDG PET; however, shows advantage in brain metastases detection due to reduced background uptake in the brain

CXCR4 expression exhibits marked inter- and intra- tumoral heterogeneity, with distinct patterns of uptake observed across different malignancies. Certain tumor types, such as adrenocortical carcinoma, small cell lung cancer, and desmoplastic small round cell tumors, demonstrate strong CXCR4 expression, reflected in high [68Ga]Ga-Pentixafor uptake [21, 31, 34]. Others, including pancreatic adenocar- cinoma, cholangiocarcinoma, and high-grade NETs, exhibit moderate tracer avidity [22, 27]. Conversely, cancers such as breast carcinoma, glioblastoma, and melanoma display more limited CXCR4 expression, resulting in lower uptake values [23, 28, 37].

At the opposite end of the spectrum, several malignan- cies, including prostate cancer, pleural mesothelioma, colorectal carcinoma, liposarcoma, and stromal sarcoma, demonstrate little to no detectable CXCR4 expression [20, 39]. Additionally, a high proportion of negative scans has been reported in renal cell carcinoma, ovarian carcinoma, hepatocellular carcinoma, and pancreatic cancer [24], fur- ther underscoring the inconsistencies in CXCR4 expression among solid tumors.

These findings highlight the selective applicability of [68Ga]Ga-Pentixafor PET/CT, reinforcing that while it may not serve as a universal diagnostic tool, it holds significant

potential in guiding CXCR4-targeted therapies. Identify- ing malignancies with high CXCR4 expression may enable better patient selection for theranostic approaches, optimiz- ing treatment strategies for tumors that demonstrate strong receptor expression while minimizing unnecessary imaging in cases with negligible uptake (Table 4).

[68 Ga]Ga-Pentixafor PET/CT has shown clinical util- ity in specific oncologic contexts, particularly in aggressive tumors and cases where conventional imaging faces limita- tions. A notable advantage is its ability to detect CXCR4 overexpression in high-grade GEP-NETs, with elevated tracer uptake observed in poorly differentiated subtypes [22, 31]. This underscores its potential for guiding patient selec- tion in CXCR4-targeted precision therapies. Additionally, its application in brain tumor imaging is particularly valuable, as high physiological uptake of [18F]FDG in normal brain tissue can hinder tumor delineation. Evidence suggests that [68 Ga]Ga-Pentixafor PET/CT enhances lesion detectability in intracranial malignancies, making it a viable alternative for evaluating CXCR4-expressing brain tumors [34, 37].

Large-scale studies, such as those conducted by Dreher et al. (2024) [39], illustrate how the inclusion of diverse tumor types can impact diagnostic outcomes, empha- sizing the influence of tumor heterogeneity on imaging

performance. Furthermore, none of the included studies reported comprehensive diagnostic accuracy metrics, such as true positive, true negative, sensitivity, and specificity, which limits the ability to derive robust performance benchmarks. These variations highlight a critical limitation in interpreting pooled data from mixed cancer populations, as differences in tumor biology and receptor expression may confound overall diagnostic accuracy.

Given the limited patient populations with tumors exhib- iting strong CXCR4 expression-such as adrenocortical carcinoma, small cell lung cancer, and desmoplastic small round cell tumors-the clinical impact and commercial fea- sibility of [68 Ga]Ga-Pentixafor could be constrained. To enhance its broader applicability and overcome potential limitations, future research should explore several direc- tions. Firstly, systematic investigations into CXCR4 expres- sion across more common malignancies or aggressive cancer subtypes could identify larger patient groups that might ben- efit from CXCR4-targeted imaging and therapy. Secondly, studies evaluating the role of [68 Ga]Ga-Pentixafor PET/CT in treatment response assessment, prognosis determination, and patient stratification for combination therapies could establish additional clinical niches. Lastly, the development and validation of improved CXCR4 ligands with enhanced pharmacokinetics, higher tumor-to-background contrast, and optimized dosimetry profiles might significantly expand clinical adoption, ultimately strengthening the position of CXCR4-targeted radiopharmaceuticals within precision oncology.

Conclusion

In conclusion, [68 Ga]Ga-Pentixafor PET/CT represents a promising yet evolving tool in oncology. While its diagnostic performance may not rival that of [18F]FDG PET/CT across all tumor types, its unique advantages in specific scenarios and its theranostic potential underscore its value in the preci- sion medicine landscape. Continued research and innovation will be essential to fully realize its role in clinical practice.

Supplementary Information The online version contains supplemen- tary material available at https://doi.org/10.1007/s12149-025-02093-w.

Acknowledgements The authors would like to thank the Department of Nuclear Medicine at King Hussein Cancer Center for their support in conducting this work. No specific grant or institutional funding was received for this study.

Funding This research received no specific funding from any agency in the public, commercial, or not-for-profit sectors.

Data availability This article is based on previously published data. The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of interest The authors declare that they have no conflicts of interest.

Ethical approval Not applicable. This is a systematic review of pub- lished literature and does not involve any new studies with human par- ticipants or animals.

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Authors and Affiliations

Saad Ruzzeh1 . Ahmed Saad Abdlkadir1 . Hasan Al-Alawi1 . Egesta Lopci2 . Mike Sathekge3,4 . Serin Moghrabi1. Shahed Obeidat1 . Akram Al-Ibraheem 1,5 (D

☒ Akram Al-Ibraheem aibraheem@khcc.jo; akramalibrahim@gmail.com		Shahed Obeidat so.14734@khcc.jo
Saad Ruzzeh sr.16472@khcc.jo	1	Department of Nuclear Medicine, King Hussein Cancer Center (KHCC), Amman, Jordan
Ahmed Saad Abdlkadir ahmedshukri92@hotmail.com	2	Aiuto - Medicina Nucleare, Dipartimento Di Diagnostica Per Immagini, IRCCS - Humanitas Research Hospital, Milan,
Hasan Al-Alawi		Italy
hassanmohalalawi@gmail.com	3	Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
Egesta Lopci
egesta.lopci@humanitas.it; egesta.lopci@gmail.com	4	Nuclear Medicine Research Infrastructure (NuMeRI), Pretoria, South Africa
Mike Sathekge
mike.sathekge@up.ac.za; sathekgemike@gmail.com	5	School of Medicine, University of Jordan, Amman, Jordan

Serin Moghrabi Sm.16471@khcc.jo