Introduction
Meningiomas account for up to 40% of all intracranial tumors, representing the most frequently encountered primary brain tumors [
1]. These lesions are classified into three grades based on histological and molecular criteria defined by the 2021 World Health Organization (WHO) classification of central nervous system tumors [
2]. Microsurgical tumor resection with or without adjuvant radiation therapy (stereotactic radiosurgery or fractionated radiotherapy) is the established treatment of choice for the majority of symptomatic, space-occupying, or growing meningiomas [
3]. Since the extent of resection (EOR) has been shown to correlate with the risk of recurrence, surgery aims to achieve an optimal balance between maximal safe tumor removal and preservation of neurological function [
4,
5]. Recent outcome data from the NRG Oncology/RTOG 0539 trial prospectively validated favorable disease control rates and outcomes with a 10-year progression-free survival of up to 88% in patients receiving gross total tumor resection and observation [
6]. However, the importance of postoperative radiotherapy, especially in patients undergoing incomplete tumor resection, remains a matter of debate [
6]. Even in “benign” meningiomas WHO grade 1, a substantial subset of patients develops mid-to-long-term tumor recurrence or progressive disease and can even display atypical or malignant transformation at recurrence [
2,
7,
8], prompting more aggressive therapy including re-resection, radiotherapy, and experimental pharmacological therapies in refractory cases [
9,
10]. Early and accurate prediction of tumor recurrence in patients with meningioma WHO grade 1 therefore remains a pivotal component of clinical management, impacting recommendations for frequency of surveillance scans as well as indication and target volume delineation for adjuvant radiotherapy.
Historically, Simpson grading (SG) has been used as an intraoperative estimation for EOR; however, accuracy and prognostic significance of SG remain controversial [
11‐
14]. Contrast-enhancing MRI is nowadays routinely used to assess EOR and serves as the established imaging modality for further surveillance scans during postoperative follow-up [
3,
15,
16]. Nonetheless, structural imaging modalities such as MRI or CT scans have their limitations, especially in discriminating between viable tumor tissue, scars or post-therapeutic reactive changes, and struggle to estimate bony tumor involvement. In this context, functional imaging modalities such as the positron emission tomography (PET) are being increasingly applied to provide additional diagnostic information [
17].
Somatostatin receptor type 2 (SSTR2) is ubiquitously expressed in up to 100% of meningiomas and can be addressed by radiolabeled SSTR2 ligands such as [
68Ga]Gallium-DOTA-TATE, [
68Ga]Gallium-DOTA-TOC, and most recently [
18F]SiTATE [
18,
19]. Biopsy-controlled studies have validated SSTR2 PET/CT as a highly sensitive tool for detecting meningioma tissue and distinguishing between tumor and tumor-free tissue, which is superior to MRI [
20‐
23]. This enables differential diagnosis of MR morphologically ambiguous lesions [
24], provides an excellent opportunity to assess the extent of resection after surgery [
23,
25], and importantly also improves tumor delineation for radiation planning [
26‐
29]. In this context, new grading systems for EOR incorporating postoperative PET/CT or PET/MRI findings have already been proposed, but prospective validation is still lacking, and prognostic relevance of postoperative SSTR2 PET/CT for tumor recurrence ultimately remains unclear [
30].
In this single-center study, we describe a prospectively collected cohort of 46 patients with 49 meningiomas WHO grade 1 who were treated with microsurgical tumor resection and received postoperative [68Ga]Ga-DOTA-TATE PET/CT in addition to routinely used postoperative MRI to assess tumor residuals. We aim to prospectively evaluate the prognostic value of tumor remnants indicated by PET, compare it with postoperative MRI assessments, and discuss implications for adjuvant radiotherapy planning.
Discussion
Somatostatin receptor PET imaging has been shown to be highly sensitive in detecting tumor remnant after microsurgical tumor resection in patients with intracranial meningioma [
23,
25]. However, the prognostic importance of residual tumor as indicated by [
68Ga]Ga-DOTA-TATE PET/CT is so far unclear. Based on a prospective cohort of 46 patients with 49 meningiomas WHO grade 1 undergoing microsurgical tumor resection, we aimed to elaborate on the clinical relevance of tumor remnants on [
68Ga]Ga-DOTA-TATE PET/CT.
We could show that [68Ga]Ga-DOTA-TATE PET/CT suggestive for residual tumor after resection was prognostic for tumor progression and associated with lower progression-free survival. In addition, our data demonstrated a strong correlation between the localization of tumor progression and postoperative tumor remnants as indicated by PET. Importantly, all patients with negative postoperative PET findings after resection remained recurrence-free until data base closure. On a cautionary note, patients with and without tumor remnants on postoperative PET were heterogeneously treated as 7 patients in our study population received adjuvant FSRT after PET findings were suggestive for tumor remnants and followingly remained progression-free. However, in our subgroup analysis of patients homogeneously treated with a watch-and-wait approach after tumor resection, PET remained prognostic for tumor progression with an even higher positive predictive value of 33%. In comparison, both SG and MRI proved insufficient for distinguishing patients who developed tumor recurrence or progression from those who did not.
Age, sex distribution, and histology in our study population were characteristic for meningiomas, and different tumor localizations were evenly distributed. A tumor recurrence rate of 14% at 4.3 years was in line with previous publications reporting recurrence rates of 6–23% 5 years after gross total tumor resection [
6,
35]. As the study population exclusively consisted of “benign” WHO grade 1 meningiomas, one would expect an increased tumor recurrence or progression rate with longer follow-up [
8]. In this context, one would assume that the positive predictive value of PET findings indicating residual tumor in predicting tumor progression may increase with a longer follow-up period. Of note, unspecific tracer uptake has been previously described during the first weeks after glioma resection [
36]. In [
68Ga]Ga-DOTA-TATE PET/CT after meningioma resection, possible transient tracer uptake has not been demonstrated yet. However, image acquisition should be performed not within the first 2 weeks after surgery to avoid possible unspecific tracer uptake and false-positive findings.
Beside histopathologic and molecular tumor characteristics, early and accurate assessment of residual meningioma tissue remains of clinical importance, as it potentially changes adjuvant patient management. In this regard, information about tumor remnants on PET not only helps clinicians in accurately prognosticating the risk of progression/recurrence for their patients but could potentially impact the decision to start adjuvant radiotherapy. Based on our results, every third patient with PET/CT findings indicative for tumor remnant and treated with surgery and observation developed local tumor progression during follow-up. Hence, we suggest that postoperative SSR PET should at least be added to the portfolio of postoperative imaging modalities to optimize assessment of EOR and subsequently guide clinical decision-making in patients with otherwise borderline radiotherapy indications. Patients with negative PET are highly unlikely to develop tumor recurrence and can therefore be monitored with extended surveillance scan intervals. Patients with positive PET findings should be monitored closely with reduced surveillance scan intervals for timely detection of tumor progress. Importantly, however, adjuvant radiotherapy indications should be critically evaluated and not solely based on postoperative PET findings but rather on a case-by-case basis, given the overall low tumor progression rate in patients with meningioma WHO grade 1. Especially for tumor localizations like parafalcine lesions with involvement of the superior sagittal sinus or skull base meningiomas, where complete tumor resection is often difficult to achieve, postoperative PET seems to be a helpful add-on to better estimate EOR and the risk for tumor progression. Adjuvant radiotherapy can be considered in these patients. This is particularly important, as recurrent meningiomas have an increased risk of progression and the potential to display atypical or malignant transformation at recurrence, necessitating more aggressive therapy associated with increased morbidity [
2,
7]. Furthermore, early re-resection of tumor residuals should be carefully evaluated; however, complex localizations and preservation of neurological function seem to limit its benefit [
37]. On a side note, one has to assume that in light of improving imaging modalities for assessment of EOR, many so-called local tumor recurrences, meaning recurrences without prior evidence of tumor remnants on MRI, rather depict slow tumor progressions when additional PET scans are taken into account, and careful consideration is warranted when reporting on such outcomes.
Critically, improved target volume delineation based upon PET scans may come with an increased disease control rate, but also lower toxicities due to personalized dose distribution [
27,
38]. In our cohort, patients received radiotherapy based on both MRI and PET-guided therapy planning, and all of them remained progression-free. GTVs delineated based on PET were significantly higher than MRI GTV and superior in detecting bony tumor involvement, providing a rationale to include PET for radiation planning. Additionally, PET enables detection of distant foci otherwise not evident on MRI scans which can consequently be included in the respective target volume planning. Simultaneous somatostatin receptor PET/MRI, combining high soft tissue resolution structural imaging with metabolic and cellular features from PET/CT, may be an even more accurate option for assessing postoperative tumor remnants [
39]. However, its lack of availability hinders the widespread use of such devices. Moreover, given the fact that the skull serves as excellent reference for the fusion process, PET/CT seems comparable to PET/MRI in cranial imaging.
Considering its daily application,
68Gallium-labeled somatostatin receptor ligands are associated with several limitations. Especially the
68Ge/
68Ga generators, although enabling in-house production without need of an on-site cyclotron, currently remain cost intensive. The ligands show low activity amounts and a short half-life. Here, the [
18F]SiTATE tracer provides a promising alternative that may advance the widespread use of SSTR ligands and overcome the drawbacks of
68Gallium-labeled ligands [
17,
19,
40]. It is highly selective for the SSTR receptor subtype 2 with only minor or no affinity to SSTR types 1 and 3–5 [
41]. Furthermore, the significantly lower positron energy of
18F compared to
68Ga (mean positron energy 0.25 vs. 0.83 MeV) leads to a better spatial resolution in PET imaging due to a shorter positron range (mean range 0.6 vs. 3.5 mm). The cyclotron-based synthesis of
18F allows for significantly higher activities per synthesis. In combination with the longer half-life compared to
68Ga (110 vs. 68 min), a higher number of patients can be examined per day, and transportation of [
18F]SiTATE to other additional imaging sites is manageable (satellite principle) [
42].
This, in turn, is relevant from a health economics’ perspective. As SSTR2 PET and its associated ligands become more cost-effective and can be offered on a widespread basis, a reduction in the frequency of postoperative surveillance scans via MRI considering its limitations in predicting tumor recurrence has to be evaluated. In this context, further cost-effectiveness analyses are warranted.
The limitations of our study included the limited sample size and different adjuvant treatment strategies that were applied in our patient cohort depending on extent of resection. No additional sample size calculations and success thresholds for survival data were defined a priori, possibly introducing bias. Large prospective studies are needed to validate our promising findings in this preliminary study and take postoperative treatment strategies into account.
Histological grading, DNA methylation profiling, and copy number analyses have been shown to predict the recurrence risk in meningioma, in addition to WHO grading and extent of resection, and were shown to be helpful in accurately identifying patients at high risk for tumor recurrence [
43,
44]. Interestingly, studies could show that only 20% of all meningiomas WHO grade 1 demonstrated a methylation profile associated with higher risk for recurrence [
45]. Most meningiomas WHO grade 1, therefore, remained at low risk for recurrence even when incorporating DNA methylation profiling. Nevertheless, missing molecular characterizations including DNA methylation profiling in our study cohort of meningiomas WHO grade 1 could possibly represent confounding factors.
Future studies will need to assess the prognostic relevance of [
68Ga]Ga-DOTA-TATE PET/CT in higher grade meningiomas WHO grades 2 and 3. A previously published small retrospective analysis on patients with WHO grades 2 and 3 meningiomas undergoing radiotherapy only found metabolic tumor volume on PET prior to radiotherapy to be predictive for progression-free survival [
46]. Especially in meningiomas WHO grade 2, where the role of adjuvant radiotherapy is still a subject of discussion when complete tumor resection is provided, accurate assessment of EOR and knowledge of its prognostic value will prove crucial for risk stratification and consequently optimal patient management [
3]. In this regard, the question of watch-and-wait versus radiotherapy is currently being addressed by the ROAM/EORTC-1308 trial (ISRCTN71502099).
In conclusion, our data show that [68Ga]Ga-DOTA-TATE PET/CT is highly effective in revealing postoperative tumor residuals in patients with meningioma WHO grade 1, and superior to commonly used MRI and Simpson grading. Importantly, negative PET findings were strongly associated with a decreased risk for tumor progression and higher progression-free survival. In patients with tumor remnants, PET improved adjuvant radiotherapy planning for surgically resected meningiomas.
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