Effects of somatostatin analogs on uptake of radiolabeled somatostatin analogs on imaging: a systematic review and meta-analysis

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that occur rarely in comparison with other malignant tumors (1). The incidence of NETs only contributes 0.5% of all malignancies (2). NETs originating from neuroendocrine cells disseminate throughout the body, and the most common site is the gastrointestinal tract, followed by the lung and pancreas (3). Somatostatin receptors (SSTRs), as members of the 7 transmembrane segment receptor superfamily, are overexpressed on most NETs and can bind somatostatin with high selectivity and affinity (4,5). Thus, SSTRs have become the therapeutic and diagnostic target in clinical conditions. Due to the low metabolic stability of natural somatostatin, many synthetic analogs such as octreotide, pasireotide, and lanreotide have been developed to improve the stability (6,7).

Iodine-123, Indium-111 (¹¹¹In), and Technetinum-99m (^99mTc)-labeled somatostatin analogs (SSAs) scintigraphy were the initial methods to visualize SSTRs-positive NETs with a detection rate ranging from 50% to 100% (8-11). However, these SSTRs imaging methods present some limitations in detecting liver lesions or small lesions because of the liver physiological uptake and the low resolution of gamma camera (12,13). Gallium-68 (⁶⁸Ga)-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-conjugated SSAs (⁶⁸Ga-DOTA-conjugated SSAs) such as ⁶⁸Ga-[DOTA-D-Phe¹-Tyr³-Thr⁸]-octreotide (⁶⁸Ga-DOTATATE), ⁶⁸Ga-[DOTA-D-Phe¹-Tyr³]-octreotide (⁶⁸Ga-DOTATOC), and ⁶⁸Ga-[DOTA-D-Phe¹-1-Nal³]-octreotide) (⁶⁸Ga-DOTANOC) were subsequently developed and opened a new horizon in imaging NETs. Positron emission tomography/computed tomography (PET/CT) with ⁶⁸Ga-DOTA-conjugated SSAs provides higher spatial resolution and more functional and anatomic data compared to single photon emission computed tomography (SPECT) and conventional imaging. Meanwhile, it also has better diagnostic sensitivity and specificity than fluorine-18 [¹⁸F]-fluorodeoxyglucose (¹⁸F-FDG) PET/CT for detecting NETs, resulting in significant management change (14-16). Up to now, ⁶⁸Ga-DOTA-conjugated SSAs PET/CT has been widely used in primary tumor localization, metastatic disease detection, and response monitoring, as well as predicting the treatment response for NET patients (17,18).

As the first-line therapy for functionally active NETs, SSAs play a prominent role in controlling hormonal symptoms and reducing tumor growth (5,19). Since nonradioactive SSAs treatment and SSTRs imaging involve the same receptors, high-dose SSA treatment prior to imaging could theoretically interfere with the uptake of radiolabeled SSAs by receptor internalization and saturation (20). Both the European Association of Nuclear Medicine (EANM) procedure guideline for ⁶⁸Ga-DOTA-conjugated peptides PET/CT and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) concept in ⁶⁸Ga-DOTATATE PET/CT recommend the time interval of 3–4 or 4–6 weeks between long-acting SSAs treatment and ⁶⁸Ga-DOTA-conjugated peptides PET/CT to avoid possible SSTR blockade (15,21). However, no clear or strong evidence has been provided to confirm the necessity of SSAs withdrawal before PET imaging. In contrast, recent studies investigating the effect of nonradioactive SSAs on uptake of ⁶⁸Ga-DOTA-conjugate peptides found reduced uptake in normal tissues, stable uptake in tumor sites, and improved tumor-to-background ratio (22-24). Therefore, in this systematic review and meta-analysis, we aimed to assess whether prior SSAs treatment affects the uptake of radiolabeled SSAs in normal organs and tumor lesions for patients with NETs. We present this article in accordance with the PRISMA-DTA reporting checklist (25) (available at https://qims.amegroups.com/article/view/10.21037/qims-23-477/rc).

Methods

Our study was registered on the international prospective register of systematic reviews (PROSPERO) (CRD42022321650).

Search strategy

A literature search of the databases of PubMed, Embase, and Web of Science (WoS) was performed until March 12, 2022. Keywords were based on the following: (“neuroendocrine tumor” OR “NETs”) AND (“somatostatin receptor imaging” OR “somatostatin receptor Scintigraphy” OR “PET” OR “photon emission tomography” OR “SPECT” OR “single photon emission computed tomography”) AND (“somatostatin analogs” OR “SSA” OR “Lanreotide” OR “octreotide” OR “Pasireotide” OR “DOTATATE” OR “DOTATOC” OR “DOTANOC”).

Study selection

Studies investigating SSTR imaging before and after the commencement of SSA therapy were evaluated. The inclusion criteria were as follows: (I) clinical original studies regarding the alteration of uptake in normal organs and tumors between two SSTR images, which were performed prior to and after SSA treatment. (II) Patients had been confirmed with histologically well-differentiated NETs. Studies irrelevant to the topic were excluded, and case reports, conference abstracts, letters, editorial materials, and reviews were also excluded. When data overlapped among studies, the study with the most details was chosen. The included studies were written in English and performed on humans.

Data extraction

Two reviewers independently extracted data from the eligible studies about study characteristics (i.e., first author, publication year, country, study design) and patient characteristics (i.e., patient population, age, clinical setting, SSAs treatment, uptake characteristics, time intervals). Technical details (i.e., imaging modality, ligand, and injection dose) and any data regarding the tracer uptake in normal tissues and tumor lesions before and after SSAs treatment were also collected.

Quality assessment

The quality of the included studies was independently assessed by two reviewers according to the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2 revision) (26). The QUADAS-2 revision was used to evaluate the risk of bias for the following criteria: patient selection, first scan, second scan, and flow/timing, whereas applicability concerns were assessed for patient selection, first scan, and second scan (Table S1). Any discrepancies were resolved by discussion with a third reviewer.

Statistical analysis

The maximum standardized uptake value (SUVmax) of normal tissues including liver, spleen, adrenal glands, thyroid, and pituitary gland was extracted and individually pooled using a random effects model. Similarly, the uptake of tumor lesions categorized according to anatomical site (primary sites, liver, lymph nodes, and bone metastases) was also individually analyzed. Further, the measurements were compared between pretreatment and posttreatment scan. Stata version 15.0 (StataCorp., College Station, TX, USA) was used to conduct meta-regression analyses based on a linear mixed model for summarized mean SUVmax with 95% confidence intervals (CIs). The RevMan 5.3 software (Cochrane Collaboration, Copenhagen, Denmark) was used to evaluate the risk of bias. Heterogeneity between the studies was evaluated using the I² statistic, and the I² value greater than 50% was indicative of substantial heterogeneity (27).

Results

Literature search

The flow chart showed an overview of the search and selection process (Figure 1). A total of 6,928 records were identified, and 2,701 records were removed as duplication. After reviewing the title and abstract, 4,210 articles were excluded because they were cases, reviews, letters, conference abstracts, basic studies, or studies relevant to disease diagnosis or treatment. A total of 8 articles were excluded after full-text evaluation. Finally, 9 articles were eligible for this systematic review and meta-analysis (22-24,28-33).

Figure 1 Flow chart of study selection. PRRT, peptide receptor radionuclide treatment.

Study description

Table 1 summarizes the main characteristics of the included 9 studies. Among them, 6 studies were performed in Europe, 2 studies in Australia, and 1 in China; 3 studies were performed prospectively, whereas 6 studies had a retrospective study design; 7 studies involved intraindividual research, 1 interindividual research, and 1 combined inter-and intra-individual study design. Table 2 shows the imaging modalities of SSTRs among the 9 studies. The uptake of ⁶⁸Ga-DOTA-SSAs was assessed in 6 studies, especially ⁶⁸Ga-DOTATATE in 5 studies, whereas the other 3 studies investigated the uptake of ¹¹¹In or ^99mTc labeled SSAs. The injection activity of radiolabeled SSAs was heterogeneous and contained both weighted-based and fixed activities.

Quality assessment

Following the revised QUADAS-2 tool, we assessed the quality of included studies (Figure 2). For interindividual design studies, SSTRs imaging of the SSAs untreated group was regarded as the first scan while that of the SSAs treated group as the second scan. For intraindividual studies, pretreatment and posttreatment SSTRs imaging were defined as first and second scan, respectively. Almost all studies had a low risk of bias in patient selection. Only 1 study had an unclear risk of bias in patient selection and applicability concerns because 3 patients had undergone the first scan after a 24-hour period of octreotide withdrawal (28). Two studies showed unclear risk in the applicability concerns of patient selection because of the interindividual comparison design (30,32). Since the first and second scan results were measured independently, we graded the risk of bias and applicability concerns in both scans as low risk. Regarding the flow and timing, some studies had unclear risk because the time intervals between 2 scans were heterogeneous or they were interindividual studies (22,29,30,32,33).

Figure 2 Quality assessment of diagnostic studies-2 revision evaluation of the risk of bias and applicability concerns among the 9 studies.

Main findings of included studies

Table 3 provides an overview of the effect of SSAs treatment on radiolabeled SSAs uptake. The radiolabeled SSAs uptake decreased in the liver in patients after SSAs treatment in all studies (22-24,28,30-33). The same trend was also observed in the spleen in almost all studies, whereas only 1 study showed that the spleen-to-muscle ratio of ^99mTc-hydrazinonicotinyl-Tyr3-octreotide (^99mTc-HYNIC-TOC) did not significantly change following SSAs therapy (22,23,28,30,31,33). No convincing data revealed that SSAs treatment significantly changed the uptake of radiolabeled SSAs in the adrenal gland, kidney, pituitary gland, bone, and parotid gland. A total of 3 studies suggested that radiolabeled SSAs uptake might be decreased in the thyroid after SSAs treatment (22,23,31). Meanwhile, 8 studies evaluated the effect of SSAs treatment on tumor uptake of radiolabeled tracer, and among them, 3 showed increased tumor uptake after SSAs treatment whereas the remaining did not show any significant effect (22-24,28,30-33). In 5 studies, the tumor-to-liver/background ratio increased significantly after SSAs treatment (23,24,28,29,31).

Meta-analysis of SUVmax in normal organs and tumors

A total of 6 studies investigated the effect of SSAs on the uptake of the ⁶⁸Ga-labeled SSAs. Among these, 5 studies presented detailed data about the uptake of ⁶⁸Ga-DOTATATE in healthy organs and tumors. We further extracted and pooled these data and performed meta-analysis. Figure 3 displays the pooled SUVmax prior to and after SSAs treatment in the liver (Figure 3A) and spleen (Figure 3B). The SUVmax of the liver prior to SSAs treatment was 9.56 (95% CI: 9.17–9.95, I²=85.9%) and decreased to 7.62 (95% CI: 7.24–8.00, I²=93.3%) following SSAs therapy. The corresponding parameters were 25.74 (95% CI: 24.61–26.88, I²=77.9%) and 20.39 (95% CI: 19.29–21.49, I²=80.3%) for spleen. As shown in Figure S1 and Figure S2, the summarized SUVmax of the adrenal gland, thyroid, and pituitary gland before SSAs treatment were 18.63 (95% CI: 17.68–19.58), 4.52 (95% CI: 4.10–4.95), and 3.99 (95% CI: 3.66–4.31), respectively. After SSAs treatment, the summarized parameters of these normal tissues were 17.81 (95% CI: 16.62–19.01), 3.03 (95% CI: 2.65–3.40), and 5.58 (95% CI: 4.83–6.33), respectively. SUVmax significantly decreased in the liver (P=0.001) and spleen (P=0.006) following SSAs treatment whereas no significant change was noted in the adrenal gland (P=0.83), thyroid (P=0.07), and pituitary gland (P=0.33) (Figure 4A). With regard to tumor uptake, pooled parameters before and after SSAs treatment are demonstrated in Figure S3 and Figure S4. The uptake of the hottest lesion did not differ significantly between pre-and post-treatment scans (28.14±14.3 vs. 29.28±14.51, P=0.37). In addition, neither primary tumor sites nor metastases showed significant differences after SSAs treatment (Figure 4B).

Figure 3 Forest plots of SUVmax before and after SSAs treatment. (A) SUVmax in the liver. (B) SUVmax in the spleen. SUVmax, maximum standardized uptake value.

Figure 4 Pooled SUVmax change between the first and second scan. (A) SUVmax change in normal tissues. (B) SUVmax change in tumor lesions. Plots indicate the pooled SUVmax with 95% confidence intervals. *, statistical significance. SUVmax, maximum standardized uptake value.

Discussion

This meta-analysis summarizes the effect of SSAs therapy prior to imaging on the uptake of radiolabeled SSAs for NETs patients. We detected significantly decreased tracer uptake in the liver and spleen after SSAs treatment, especially uptake of ⁶⁸Ga-labeled SSAs. Conversely, no significant change was observed in primary tumor sites or metastatic lesions.

SSAs, as synthetic SSAs targeting SSTRs, have been widely applied in NETs imaging and therapy (34). The rationale is the tumor cell receptor-mediated internalization of the radio- or non-radiolabeled SSAs and their retention in the cytoplasm (21). Theoretically, treatment with nonradioactive SSAs could result in possible SSTRs occupancy and blockade, and then interfere with the interpretation of radiolabeled SSAs imaging. Velikyan et al. found that different doses of octreotide (0, 50, 250, and 500 µg) administered immediately before ⁶⁸Ga-DOTATOC PET/CT imaging affected the ⁶⁸Ga-DOTATOC uptake, revealing a blocking or saturation effect at higher amounts of SSA (35). Thus, current SSTRs imaging guidelines recommended the discontinuation of SSAs therapy prior to imaging to avoid possible decreased radioactive SSAs uptake (15). However, most of our included studies reported inconsistent results, of which 3 studies showed a significant increase in tumor lesions after SSAs treatment, whereas in 5 studies, the difference of tumor uptake was not significant. Taken together, our pooled results indicate that SUVmax of primary tumors or metastases did not change significantly after SSAs treatment. The plausible explanation may be the fast SSTRs recovery in NETs within a short time frame, compared to that in normal organs (36,37). Although our findings may represent the worst-case scenario, they may indicate that nonradioactive SSAs treatment has little effect on the tumor uptake of radiolabeled SSAs on SSTRs imaging.

In contrast to the change of tumor uptake after SSAs, our results showed that the SUVmax of ⁶⁸Ga-labeled tracer in the liver and spleen were significantly decreased on the posttreatment scan with an approximately 20% reduction, whereas no significant difference was observed in other normal tissues including the adrenal, thyroid, and pituitary glands. These findings are almost in agreement with previously reported relevant studies. In a prospective study with intraindividual design, Aalbersberg et al. reported significantly decreased SUVmax in the liver (10.15 vs. 9.08, P<0.001) and spleen (25.77 vs. 22.35, P<0.001) after SSAs, with a reduction of about 10% (23). A recent study showed a higher reduction of 25% and 20% in physiologic spleen and liver accumulation, respectively, similar to our findings (23). It should be noted that following SSAs therapy, the thyroid uptake also decreased although the difference did not reach statistical significance due to the small sample size. Some studies also investigated the uptake difference in the kidney, parotid gland, and bone between 2 PET/CT scans, but these data were too scarce to be pooled in this meta-analysis. The different tendency between tumor and liver or spleen uptake may be due to different SSTRs recycling kinetics mainly consisting of receptor internalization and expression after SSAs therapy (37). Interestingly, a recent study that investigated the time-dependent extended effect of SSAs on the tumor versus normal tissue uptake of ⁶⁸Ga-DOTATOC found that tumor SUV decreased significantly from baseline to 1 hour post-injection but subsequently increased to baseline level at 4 hours whereas the uptake in the liver and spleen remained significantly below baseline level at 7 hours, suggesting faster SSTRs recycling in tumors than in normal tissues (33). In addition, the difference in inherent receptor density could also lead to the different thresholds for receptor saturation in normal tissues and tumors (38,39).

Given that there was no evidence of decreased tumor uptake but significant reduction in the liver or spleen uptake, several included studies consistently demonstrated the improved tumor-to-liver or background ratio after SSAs treatment. In spite of the prominent heterogeneity of NETs, this finding may be generalized to all types of this tumor. Aalbersberg et al. reported increased tumor-to-liver ratio for SUVmax in all lesions after SSA, including abdominal, liver, lymph node, and bone lesions (23). The increased ratio not only facilitates tumor detection but also provides obvious implications for peptide receptor radionuclide treatment (PRRT). Firstly, the improved tumor-to-background or liver ratio perhaps increases the likelihood of being suitable for PRRT. Then, nonradioactive SSAs pretreatment may decrease the uptake of ¹⁷⁷Lu- or ⁹⁰Y-SSAs in normal tissues, especially in the spleen, thus reducing potential radiation exposure and adverse side effects on normal tissues (40). However, the amount of peptide administered during PRRT is much higher than that for ⁶⁸Ga-SSAs PET/CT, thus further research is needed to confirm our findings in PRRT (39). Apart from these, the change in tumor-to-liver or -spleen ratio was also used as a valid marker for evaluating the disease status in some studies (41-43). Clinicians should be aware of the effect of SSAs on the tumor-to-background ratio on SSTRs imaging, in case of misdiagnosis as disease progression during response assessment.

Consistent with previous studies, our systematic review and meta-analysis that supports no withdrawal of SSAs treatment prior to SSTRs imaging might affect the procedure guideline for ⁶⁸Ga-DOTA-SSAs PET/CT. If continuation of SSAs treatment prior to SSTRs imaging is undertaken, it is of great benefit to patients by controlling the symptoms and reducing the risk of tumor growth. There is also no need for patients to use short-acting SSAs instead that has to be administrated 3 times daily for preparation of SSTRs imaging. Meanwhile, the nuclear medicine department can have flexible schedules for SSTRs imaging without having to adhere to the SSAs administration time.

Our study has some limitations. Firstly, the number of included articles was relatively small, especially for pooled analysis, which might be a possible source of bias. Secondly, prominent heterogeneity of the study design was found among included studies, such as SSAs treatment, time intervals between 2 scans, and from the last injection to posttreatment scan, which significantly affected the reliability of pooled results. In addition, the study quality including patient selection, various radiolabeled SSAs, and diverse imaging outcomes also made contributions to the high heterogeneity. Thirdly, the included studies used different radiolabeled SSAs tracers, scanners, and scanning methods, thus the imaging interpretation and parameter measurement may be inconsistent among studies.

Conclusions

SSAs therapy prior to imaging resulted in a significant reduction in the liver and spleen uptake, but did not decrease the uptake of radiolabeled SSAs in tumor primary or metastatic sites as well as other normal tissues. These findings have significant implications for procedure guidelines of SSTRs imaging and support the unnecessary discontinuation of SSAs prior to radiolabeled SSAs imaging (Table 4). Further prospective, multicenter, and long-term prospective longitudinal studies with a large sample are also needed to better determine the effect of SSAs therapy on the uptake of radiolabeled SSAs in normal organs and tumor lesions.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (No. 81901776) and the Post-Doctor Research Project, West China Hospital, Sichuan University (No. 2023HXBH075).

Footnote

Reporting Checklist: The authors have completed the PRISMA-DTA reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-23-477/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-477/coif). The authors report that this work was supported by the National Natural Science Foundation of China (No. 81901776) and the Post-Doctor Research Project, West China Hospital, Sichuan University (No. 2023HXBH075).

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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