Sage Journals: Discover world-class research

Abstract

Introduction

The somatostatin receptor (SSTR) standardized uptake value (SUVmax_sstr) obtained by [⁶⁸Ga]Ga-edotreotide positron emission tomography-computed tomography ([⁶⁸Ga]Ga-SSTR PET/CT) helps recognize patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who are at a high risk for adverse outcomes. This observational cohort study was conducted to verify whether the SSTR representative tumor volume (RTV_sstr) can provide incremental prognostic information over conventional PET/CT parameters in patients with metastatic disease.

Methods

We retrospectively evaluated patients (48% female) with metastatic GEP-NETs who underwent [⁶⁸Ga]Ga-SSTR PET/CT between January 2022 and November 2023. The mean SUVmax_sstr, mean RTV_sstr (cm³; 42% threshold), and total RTV_sstr were recorded. Thereafter, patients were followed up for 22.9 (range: 8-42) months. The PET/CT results were compared to the progression free survival (PFS).

Results

Sixty patients (59 ± 5 years) were enrolled. Only the mean and total RTV_sstr values were predictive in the multivariate analysis. Kaplan-Meier survival analysis for both the mean and total RTV_sstr demonstrated a significantly better PFS in patients presenting with lower than greater values (P = 0.001 and P = 0.007, respectively; log-rank test). SUVmax_sstr was not appropriate for predicting PFS.

Conclusion

The mean or total RTV_sstr represents a valuable volumetric parameter able to predict outcomes in patients with GEP-NETs that are metastatic at onset. The degree of the SSTR representative tumor burden, rather than the maximal SSTR representation at single voxel, has a predominant value for influencing the response to therapy in this cohort.

Keywords

metastatic GEP-NET PET/CT quantitative assessment volumetric parameters survival

Introduction

Neuroendocrine tumors (NETs) encompass a group of extremely heterogeneous neoplasms that can affect different organs, with an estimated incidence of ≤ 1/100.000 cases. Their clinical behavior is generally indolent.^1,2 Although gastroenteropancreatic (GEP) NETs have a low tendency to metastasize, they can progress quickly once they diffuse. Conversely, those derived from the small intestine with inherently higher malignant potential have a slow growth pattern when metastatic at onset.³ Generally, GEP-NETs are well- or moderately differentiated; few cases, such as aggressive neuroendocrine carcinoma (NEC), remain poorly differentiated.^4-6 Several prognostic factors may differently affect the survival and outcome of patients with NETs, even with similar stage and grade, representing a clinical challenge. Although most patients exhibit controlled disease during long-term follow-up,^7,8 assessing the location and extent of GEP-NETs is critical for management, especially in patients who are multi-metastatic at onset. For these patients, the awareness and quantification of the true tumor burden can address questions regarding therapy. While useful for evaluating location, extent and therapy response of NETs, some studies have demonstrated the limited value of morphological imaging and conventional parameters for predicting survival and outcome.^9,10 Molecular imaging, as a part of morpho-functional imaging based on tumor somatostatin receptor (SSTR) overexpression, constitutes a novel imaging modality whose goal is to increase sensitivity for the detection of micro-metastases and ability to quantitate tumor burden, even diffuse. Among others, such as [⁶⁸Ga]Ga-DOTA-TOC/NOC/TATE/EDOTREOTIDE, [⁶⁸Ga]Ga-SSTR positron emission tomography-computed tomography (PET/CT) has shown a high affinity for SSTR subtype 2,¹¹ enabling the diagnosis of NETs with a very high sensitivity and accuracy,^12,13 especially in patients with metastatic disease.^14,15 Limited data are currently available concerning the new PET/CT quantitative parameters for the prediction of disease outcome and survival in patients with NETs. Aside from the traditional use of maximum standardized uptake (SUVmax) value, a PET/CT volumetric parameter based on SSTR distribution - SSTR representative tumor volume (RTV_sstr) - has recently been implemented for inclusive tumor assessment.^16-18 We aim to retrospectively investigate the correlation between the SSTR-based PET/CT functional parameters (SUVmax_sstr and RTV_sstr) and PFS in patients with metastatic GEP-NETs at staging. In fact, tumor burden volumetric indicators may assess the whole representative tumor volume rather than the single voxel hyper-metabolic activity addressing treatment planning and prognosis, especially in metastatic GEP NET at onset. Existing studies mainly focused on patients that had already received a first-line therapeutic approach.^14,16-18

Materials and Methods

Patients

We retrospectively reviewed the data of 229 patients with a positive biopsy for GEP-NET who underwent baseline [⁶⁸Ga]Ga-edotreotide PET/CT scanning between January 2022 and November 2023. The inclusion criteria were an age ≥18 years at entry, and primary GEP-NET with G1 or G2 grading that was metastatic at onset. The exclusion criteria were having previously undergone surgery for GEP-NET, and formerly receiving peptide receptor radionuclide therapy (PRRT), chemotherapy, or somatostatin analogs (SSAs). We also excluded patients with grade 3 NEC, multiple endocrine neoplasia, and those with ≤ 6 months of follow-up after PET/CT (apart from those with early tumor progression). A flowchart of patient selection is shown in Figure 1. Diagnoses were confirmed in accordance with the WHO 5^th ed. (2019) classification.

Figure 1.

Flowchart of patient collection. Not enrolled: previous surgery, radioligand therapy, chemotherapy, somatostatin analogues. Excluded: PET negative, insufficient follow-up, Multi Endocrine Neoplasia

A complete baseline standard evaluation including clinical and laboratory data, as well as chest, abdomen, and pelvis CT or magnetic resonance (MRI) was performed in all patients. Data such as histological specimen, Ki67 values, tumor grading, and WHO classification were collected from patients’ medical records.

The Basilicata Independent Ethics Committee (CEUR) and IRCCS CROB review board approved the study (approval number: #2022-001470; date: February 15, 2022). All patients who underwent PET/CT provided written informed consent according to the Declaration of Helsinki. The reporting of this study conforms to the REMARK and STROBE guidelines.^19,20 All patients’ details were de-identified.

Imaging Technique

Patients received [⁶⁸Ga]Ga-edotreotide intravenously (median:185; range: 111-333 MBq; weight-based). PET and modulated low-dose CT were performed with a PET/CT scanner (GE Discovery VCT scanner; Waukesha, WI, USA) that combined a PET scanner and Light Speed VCT 64 row multidetector computed tomography (MDCT) system. MDCT (pitchx 1.5; 120 mAs; 120 kVp) was performed without contrast medium, 60 minutes after tracer injection. PET scanning ensured 6 to 8 beds per patient depending on patient height, encompassing the whole skeleton (3 min per bed position). Raw PET data were reconstructed with and without attenuation correction into transverse, sagittal, and coronal images. Attenuation correction was based on CT attenuation coefficients, which were determined by iterative reconstruction. The raw CT data were reconstructed into transverse images with a 3.75-mm (1.25-mm when needed) section thickness. Sagittal and coronal CT images were generated by reconstructing the transverse data.

Imaging Evaluation

PET/CT studies were read, in consensus, by 3 experienced nuclear medicine physicians with 15 years of expertise. We reviewed all images using a PET/CT fusion software (Volumetrix for PET-CT and AW volume share 4.5; GE Healthcare, Waukesha, WI, USA). The examiners first evaluated the CT images. Lesion sizes were visually estimated and measured at two or more maximum diameters using vendor-provided software (Volumetrix for PET-CT). Every lesion ≥1.0 cm in maximal transverse or sagittal dimensions, with soft tissue/abdominal window settings, was considered a target lesion. The CT volume computation, when requested, was based on diameter assessment according to the formula: (V = d craniocaudal × d antero-posterior × d lateral × π/6); the lesions were assumed to be ellipsoid.

The PET studies were evaluated both visually and semi-quantitatively. Subsequently, the body weight corrected SUVmax_sstr and SSTR expression representative tumor volume (RTV_sstr; cm³; 42% threshold) were computed using the same vendor-provided software. The RTV_sstr was defined as the volume at which the SUV was ≥42% of the SUVmax_sstr. The 42% threshold derives from a segmentation method, and it is a relative threshold for distinguishing the tumor from surrounding healthy tissue automatically.²¹ Additionally, the most representative mean SUVmax (MSUVmax: mean of the highest values of the target lesions), mean RTV_sstr (MRTV_sstr: mean RTV_sstr of target lesions), and total RTV_sstr (TRTV_sstr: sum of RTV_sstr of target lesions) were calculated.

In brief, focal or diffuse [⁶⁸Ga]Ga-edotreotide uptake at a location that mismatched with normal anatomy or physiology was deduced to be abnormal and ultimately indicated a GEP-NET. A merged score based on MSUVmax_sstr and TRTV_sstr aggregation was used for patients’ supplementary stratification.

Follow-Up Assessment

Receiver operating characteristic (ROC) curve analysis was used to determine the cut-off points for MSUVmax_sstr, TRTV_sstr and MRTV_sstr; accordingly, patients were categorized into two groups. The disease status was followed up for 22.9 (range: 8-42) months thereafter. Clinical and hematological parameters during scheduled or unscheduled visits, diagnostic imaging (i.e., CT, MRI) findings, and phone interviews were used for patients’ evaluation.

Surrogate endpoints included therapy regimen changes due to evidence of non-response (even clinical), progression, and/or disease-related death. PET/CT findings and clinical parameters were related to the disease outcome (progression free survival; PFS). PFS was expressed as the time from PET/CT until end point occurrence or the time of the last censor.

Progression was recognized as the presence of a new lesion, or relapse of a previous existing lesion; in the case of missing information, the date of unscheduled new SSA treatment was considered.

Statistical Analysis

Continuous data were expressed as percentage, mean ± SD, or median, as appropriate. Correlation analysis was used to assess the relationship between variables, when requested. To differentiate patients at high risk of main events, the optimal cut-offs for MSUVmax_sstr, MRTV_sstr and TRTV_sstr were derived from the ROC analysis. Further survival ROC analyses for the 3 parameters, considering time dependance and censoring, were performed via the Nearest Neighbor Estimation (NNE)²² method and using the Kaplan-Meier estimator (R software-CRAN packages survivalROC and timeROC). The ROC analysis was also performed for any other parameter, if requested. PFS curves were constructed via the Kaplan-Meier method to account for censored survival times and were compared using the log-rank test. A P-value <.05 was considered statistically significant. Survival analysis was performed by Cox proportional hazard regression analysis. The proportional hazard assumption of the Cox model was checked separately for each covariate. The Ki-67 values and age at diagnosis, intended as continuous variables, as well as PET parameters, were also included in a multivariate analysis. All statistical analyses were performed using both medcalc® and R software-CRAN packages.

Results

Patient Characteristics

Sixty patients (29 females, 31 males; 59 ± 5 years) were included in the study. All patients underwent SSAs therapy (octreotide LAR 30 mg or lanreotide 120 mg) after the [⁶⁸Ga]Ga-edotreotide PET/CT study. Thirty-eight pancreatic and 22 gastro-intestinal (stomach, ileum, and large bowel) tissue specimens were used in this study. The mean Ki-67 was 3.8% ± 6.0%; 39 and 21 patients were classified as G1 and G2, respectively. Individual data are summarized in Table 1.

Table 1.

Individual Data of Metastatic GEP-NET Patients

Characteristics	Value
Total number of patients	60
Age at diagnosis, year (median), range	59 (19-84)
Established by referral observer
Scan positive for metastatic NET (%)	60 (100)
Distant nodal involvement (%)	16 (27)
Parenchyma involvement (%)	14 (24)
Bone involvement (%)	7 (11)
Other (%)	23 (38)
Ki-67
≤2% (%)	39 (65)
>2% (%)	21 (35)
Localization
Pancreatic (%)	38 (63)
Gastro-enteric (%)	22 (37)
Patient outcome
Stable or significant response (%)	38 (63)
Progression (%)	5 (8)
Therapy regimen change (%)	10 (17)
Death (%)	7 (12)

GEP-NET, Gastroenteropancreatic-Neuroendocrine Tumor; Ki-67, protein; Parenchyma, as per liver, spleen, etc. Other, iuxta-regional massive involvement (related to primary lesion, N2).

Imaging Evaluation

Scans were positive in all patients. Pathological lympho-nodes were detected in 27% of patients whereas 24% had parenchymal concern. Bone involvement occurred in 11% and 38% of patients had two or more anatomical districts affected or soft tissue/muscular disease. The MSUVmax_sstr, MRTV_sstr and mean TRTV_sstr were 6.09 ± 4.8, 14.77 ± 18.7 cm³, and 39.63 ± 68.0 cm³, respectively. The ROC curve analysis, recognizing MSUVmax_sstr, MRTV_sstr and TRTV_sstr cutoff values for PFS, are shown in Figure 2. The area under the curve (AUC) for MSUVmax_sstr was 0.603 (95% CI: 0.47-0.73), and the established cut off value was ≥3.33. The AUC for MRTV_sstr and TRTV_sstr were 0.715 (95% CI: 0.58-0.82) and 0.756 (95% CI: 0.62-0.85), whereas the cut-off values were >20.1 cm³ and >33.7 cm³, respectively. This analysis was performed to maximize differences among positive patients and allow sensitive dichotomization. Data from the NNE and Kaplan-Meier estimator ROC analyses substantially confirmed the abovementioned findings and are reported in Supplemental Figures 1 and 2.

Figure 2.

ROC curve analysis establishing the cut off value of total RTV_sstr, mean RTV_sstr and mean SUVmax_sstr for predicting Progression Free Survival. The cut off value of total RTV_sstr (A), mean RTV_sstr (B) and SUVmax_sstr (C) for stratifying patients was >33.7 (cm3), >20.1 (cm3) and ≥3.33, respectively

Clinical Endpoints, Follow-Up, and Correlations

Twenty-two of 60 patients (36%) reached the endpoint, 5 showed progression, 10 had therapy regimen changes, and 7 died. The median follow-up duration was 22.9 (range: 8-42) months.

The age and Ki-67 values, settled as continuous variables, were not significantly associated with the outcome (shown in Table 2). The proportional hazard assumption was not rejected for any of the other covariates included in the Cox model (P = ns for all covariates). Better PFS was associated with lower MRTV_sstr and TRTV_sstr values, which significantly contributed to the outcome prediction (P = 0.006, HR: 3.25, 95% CI: 1.39-7.56 and P = 0.0008, HR: 4.17, 95% CI: 1.80-9.66, respectively). Overall model fit in multivariate analysis (P = 0.0003); age at diagnosis slightly contributed to the model (HR: 1.04) whereas TRTV_sstr impacted significantly (HR: 5.31). The Kaplan-Meier survival analysis for SUVmax_sstr did not demonstrate a significant difference in PFS (P = 0.07, log-rank test; Figure 3). The composite score, based on MSUVmax_sst (SUVmax_sst - and SUVmax_sst +: below and above the cut-off, respectively) and TRTV_sstr (RTV_sstr - and RTV_sstr +: below and above the cut-off, respectively) aggregation, allowed for grouping of patients into 4 categories with distinct survival. Data are shown in Figure 4.

Table 2.

Univariate Cox Proportional Hazard Regression Analysis

	HR	95% CI	P-value
Total RTVsstr (cm³)^a	4.17	1.80-9.66	0.0008
Mean RTVsstr (cm³)^a	3.25	1.39-7.56	0.006
Mean SUVmaxsstr^a	2.28	0.89-5.83	0.08
Ki-67^b	1.73	0.74-4.04	0.20
Age^b	2.16	0.87-5.33	0.09

^aDichotomized variables on ROC analysis basis.

^bContinuous variable.

HR, hazard ratio; CI, confidence interval; SSTR, somatostatin receptor; RTVsstr, sstr expression representative tumor volume; SUVmaxsstr, sstr maximum standardized uptake value.

Figure 3.

Kaplan-Meier survival graphs indicate a significant difference in PFS between the group of patients categorized by RTV_sstr. Figure 2. (A) Kaplan-Meier graph of total RTV_sstr and PFS showing total RTV_sstr above (dotted line) and below (solid line) the cut off of >33.7 (cm3). Low RTV_sstr is coupled with prolonged Progression Free Survival (P = 0.0008, log-rank test). Figure 2. (B) Kaplan-Meier graph of mean RTV_sstr and PFS with mean RTV_sstr above (dotted line) and below (solid line) the cut off of >20.1 (cm3); P = 0.006. Figure 2. (C) Kaplan-Meier graph of mean SUVmax_sstr and PFS with mean SUVmax_sstr above (dotted line) and below (solid line) the cut off of ≥3.33; P = ns

Figure 4.

Survival by aggregation of total RTV_sstr and mean SUVmax_sstr values. Kaplan-Meier graph of both total RTV_sstr and mean SUVmax_sstr and Progression Free Survival. RTV_sstr + and RTV_sstr - indicate values of total RTV_sstr above and below the cut off of >33.7 (cm3), respectively. SUVmax_sstr + and SUVmax_sstr - indicate values of mean SUVmax_sstr above and below the cut-off, respectively; (P = 0.07 across categories, log-rank test)

Among the 24 patients with the SUVmax_sst - RTV_sstr - combination, 20 showed a response, two experienced progression, and two died. In group presenting with the SUVmax_sst + RTV_sstr - combination (22), 15 demonstrated responses, 6 had therapy change and one showed progression. In the SUVmax_sst - RTV_sstr + group (2) one patient showed progression, and one died. Among the 12 patients categorized as SUVmax_sst + RTV_sstr +, 3 showed a response, 4 had therapy change, one showed progression and 4 died.

Discussion

The quintessence of current NET therapy is based on long-acting SSAs. The data derived from some studies has shown that the long-term administration of octreotide LAR inhibits tumor growth in midgut NETs with low-volume metastatic disease, with a time to progression twice as long as the placebo arm²³; conversely, patients with G1-G2 high-volume disease, a relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy, PRRT, everolimus, or sunitinib after progression on SSAs.²⁴ Overall, therapeutic approaches are beneficial for GEP-NETs while the achievement of more precise treatment, tailored to the specific risk stratification and tumor burden, may represent a clinical challenge. Although these tumors have a rather favorable prognosis,^16-18,25 they can exhibit various clinical features and outcomes. This setting imposes the need for suitable prognostic indicators that are generally missing in NET management. A new PET/CT volumetric parameter, expressed as MRTV_sstr or TRTV_sstr, was found to be useful for prognostication in patients with metastatic GEP-NETs. Higher MRTV_sstr and TRTV_sstr values can be used to identify patients with a poor prognosis; additionally, RTV_sstr seemed to have better prognostic significance than SUVmax_sstr in this metastatic setting. These findings have already been described in metastatic NET. In fact, PET/TC volumetric parameters were depicted as quantitative imaging biomarkers for whole-body tumor burden, demonstrating potential for the assessment of treatment response among 32 patients, and were also correlated with health-related quality of life.^14,15 Our data resembled the findings of Toriihara et al¹⁶ who reported RTV_sstr as a valid indicator performing better than SUVmax_sstr when related to PFS in patients with well differentiated NETs. However, the study enrolled 92 patients with metastases who underwent surgery. Similar results have been recently reported by Abou-azar et al²⁶ in patients with metastatic GEP/NET who had undergone surgical debulking. In our study we excluded patients who had received excisional or debulking surgery to rule out its impact on setting homogeneity and outcome, if any. Some authors^27-31 investigated pretherapeutic [⁶⁸Ga]Ga-SSTR PET tumor uptake and volumetric parameters in patients undergoing ⁹⁰Y-DOTATOC and [¹⁷⁷Lu]Lu-DOTATATE PRRT. They found that high tracer-avid tumor volume predicts better outcomes in patients with NET treated with PRRT, although its value as a prognosticator was only partially confirmed. Conversely, the value of PET/CT volumetric assessment in NETs has been recently reported, even using fluorine-18-fluorodeoxyglucose [(18)F]FDG.³² Other authors³³ demonstrated the prognostic value of volumetric indices in patients with NETs (all types), including metastatic or locally advanced disease, regarding both PFS and disease-specific mortality. This scenario again endorses the need for tumor burden indicators to predict outcomes in patients with NETs. Ohnona et al.³⁴ indicated the total functional tumor volume measured by [⁶⁸Ga]Ga-SSTR PET as a relevant prognostic biomarker in patients with all stages of well-differentiated pancreatic NETs. At present, few trials have compared the prognostic values of SUVmax and TRTV_sstr at staging in metastatic GEP-NET.^18,35,36 Separately, a low SUVmax on [⁶⁸Ga]Ga-SSTR PET was associated with poor prognosis in well-differentiated GEP-NET, predicting early failure on SSA monotherapy. Additionally, through SUVmax, [⁶⁸Ga]Ga-SSTR PET/CT influenced the management of patients with NETs, leading to a change in treatment decisions.³⁷ Ambrosini et al¹⁷ also reported that a high [⁶⁸Ga]Ga-DOTANOC SUVmax correlates with better outcomes in stage III or IV pancreatic NETs. Our study was conducted in a homogeneous cohort of patients who were metastatic at onset and did not undergo a priori second line therapy (see PRRT or chemotherapy), apart from SSA analogs.

Here, RTV_sstr (expressed as the mean or total) is a volumetric parameter and prognostic indicator of PFS; it predicts worst outcomes when higher and appears to work better than SUVmax_sstr for metastatic GEP-NETs. Furthermore, lower TRTV_sstr values appear to be protective when aggregated with MSUVmax_sstr for prognostics on a per-patient basis, since patients with a low TRTV_sstr tend to have a longer PFS irrespective of MSUVmax_sstr. SUVmax remains a validated measure, which limits its power to the detection of the hyper-metabolic activity of the tumor at single site (the site most representative of SSTR concentration), even when computing that of multiple selected target lesions. Therefore, it does not consider the whole representative tumor volume, but the higher grade of receptor expression. Conversely, the TRTV_sstr encompasses the tumor SSTR representation through the entire volume of all target lesions above a minimum threshold, designed to exclude background activity. Hence, it represents the true tumor burden. The well-known tumor heterogeneity of NETs might translate to tracer uptake heterogeneity between lesions of the same histological subtype, impacting quantitative, non-volumetric, appraisal. To date, few imaging-derived prognostic parameters have been translated into routine clinical practice. For example, some authors³⁸ reported that the combined use of [⁶⁸Ga]Ga-SSTR and [¹⁸F]F-FDG PET/CT is of value in the diagnostic workup of pancreatic G2 NETs with an aggregate sensitivity of 99.2%; however, it is not used daily. Indeed, the PET/CT methodology and number of tracers used have been recognized to precisely assess heterogeneity and the whole tumor burden in both solid tumors and hematological malignancies.^39-42 In our study, there was a correlation between small tumor volumes -representing SSTR expression- and the best response to subsequent therapy. Patients presenting with higher MRTV_sstr and TRTV_sstr values demonstrated shorter PFS than patients with lower values. The MRTV_sstr and TRTV_sstr were reported for completeness, using different wording to represent the same phenomenon. We found that SUVmax and other patient characteristics were not predictive. Notably, the prognosis of patients with a higher TRTV_sstr worsened irrespective of SUVmax_sstr. Generally, the whole tumor burden and its heterogeneity cannot be comprehensively depicted by a series of single “hypermetabolic” voxels (highest uptake of target lesions in a district). Accordingly, the MSUVmax does not seem to have affected the outcome of our patients. From a patho-physiological point of view, these findings are not surprising as SUVmax conveys an index of cell SSTR expression within a well-defined and circumscribed voxel, though registered in several representative districts. RTV_sstr may reflect GEP-NET variegated pathological features such as the degree of SSTR expression, number of neoplastic cells, degree of cellularity of lesions, and number of histological architectures (which can include trabeculae, nests, glandular formation, gyriform, and pseudorosettes) better than MSUVmax.^43-46 In this complex environment, the comprehensive volumetric indices such as the MRTV_sstr and TRTV_sstr work better than SUVmax for avoiding pitfalls in interpretation. Moreover, this setting could be eligible for current PRRT in a theragnostic approach, that may require exact knowledge of the tumor burden. The prognostic impact of [⁶⁸Ga]Ga-SSTR PET/CT volumetric parameters in patients with metastatic GEP-NETs remains to be completely established. In this context, our results demonstrate that RTV_sstr may be predictive in this setting, endorsing the use of [⁶⁸Ga]Ga-SSRT PET/CT volumetric parameters in daily clinical practice.

This study included patients with GEP-NETs who strictly fulfilled the inclusion criteria and were enrolled at staging. It was performed at a single research center in collaboration with academic Hospitals, explaining the limited patient number. Moreover, the complete impact on PFS of subsequent and supportive therapies, if any, has not been ascertained.

Conclusion

Quantitative assessment by RTV_sstr rather than SUVmax, on [⁶⁸Ga]Ga-SSTR PET/CT may be helpful for managing patients with metastatic GEP-NET. In this setting, the response to subsequent therapy appears to depend upon the tumor burden volume, rather than the magnitude of SSTR expression.

Supplemental Material

Supplemental Material - Ga-68-Edotreotide PET/CT SSTR Total Tumor Volume as a Predictor of Outcome in Patients With Metastatic Gastroenteropancreatic Neuroendocrine Tumors

Supplemental Material for Ga-68-Edotreotide PET/CT SSTR Total Tumor Volume as a Predictor of Outcome in Patients With Metastatic Gastroenteropancreatic Neuroendocrine Tumors by Rosj Gallicchio, Mariarita Milella, Alessia Giordano, Mauro Cives, Rebecca Storto, Anna Nardelli, Giovanni Calice, Matteo Landriscina, Giovanni Storto in Cancer Control.

Footnotes

Acknowledgments

The Authors wish to thank Mrs. Piccolella A. and Mr. Volpicelli F. for their valuable contribution to performing the studies.

ORCID iDs

Giovanni Calice

Giovanni Storto

Ethical Consideration

Basilicata Ethics Committee (Potenza, Italy) and IRCCS CROB institutional review board gave approval for the study (approval number: #2022-001470). All patients undergoing PET/CT signed an informed consent form in accordance with the Declaration of Helsinki.

Consent to Participate

All patients undergoing PET/CT gave their informed consent according to the Declaration of Helsinki.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; they have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work has been funded by Ministero della Salute, ricerca corrente 2025.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data that generated the manuscript are guarded in digital form by the corresponding author and are available upon request, if any.*

Supplemental Material

Supplemental material for this article is available online.

Appendix

References

Cives

Strosberg

. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin. 2018;68(6):471-487. doi:10.3322/caac.21493

Ahmed

. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol. 2020;12(8):791-807. doi:10.4251/wjgo.v12.i8.791

Halfdanarson

Rabe

Rubin

Petersen

. Pancreatic neuroendocrine tumors (PNETs): incidence prognosis and recent trend toward improved survival. Ann Oncol. 2008;19(10):1727-1733. doi:10.1093/annonc/mdn351

Hendifar

Marchevsky

Tuli

. Neuroendocrine tumors of the lung: current challenges and advances in the diagnosis and management of well-differentiated disease. J Thorac Oncol. 2017;12(3):425-436. doi:10.1016/j.jtho.2016.11.2222

Lloyd

Osamura

Kloppel

Rosai

. WHO Classification of Tumors of Endocrine Organs. Geneva: WHO Press; 2017.

Díez

Teulé

Salazar

. Gastroenteropancreatic neuroendocrine tumors: diagnosis and treatment. Ann Gastroenterol. 2013;26(1):29-36.

Hallet

Law

Cukier

Saskin

Liu

Singh

. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology metastatic presentation and outcomes. Cancer. 2015;121:589-597. doi:10.1002/cncr.29099

Zandee

deHerder

. The evolution of neuroendocrine tumor treatment reflected by ENETS guidelines. Neuroendocrinology. 2018;106:357-365. doi:10.1159/000486096

Sadowski

Neychev

Millo

, et al. Prospective study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. J Clin Oncol. 2016;34(6):588-596. doi:10.1200/JCO.2015.64.0987

10.

Schmid-Tannwald

Morelli

, et al. Comparison of abdominal MRI with diffusion-weighted imaging to 68Ga-DOTATATE PET/CT in detection of neuroendocrine tumors of the pancreas. Eur J Nucl Med Mol Imaging. 2013;40(6):897-907. doi:10.1007/s00259-013-2371-5

11.

Koukouraki

Strauss

Georgoulias

, et al. Evaluation of the pharmacokinetics of 68Ga-DOTATOC in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy. Eur J Nucl Med. 2006;33:460-466. doi:10.1007/s00259-005-0006-1

12.

Deppen

Blume

Bobbey

, et al. 68Ga-DOTATATE compared with 111In-DTPA-Octreotide and conventional imaging for pulmonary and gastroenteropancreatic neuroendocrine tumors: a systematic review and meta-analysis. J Nucl Med. 2016;57(6):872-878. doi:10.2967/jnumed.115.165803

13.

Bartolomei

Berruti

Falconi

, et al. Clinical management of neuroendocrine neoplasms in clinical practice: a formal consensus exercise. Cancers (Basel). 2022;14:2501. doi:10.3390/cancers14102501

14.

Ohlendorf

Henkenberens

Brunkhorst

, et al. Volumetric 68Ga-DOTA-TATE PET/CT for assessment of whole-body tumor burden as a quantitative imaging biomarker in patients with metastatic gastroenteropancreatic neuroendocrine tumors. Q J Nucl Med Mol Imaging. 2020;66:361-371. doi:10.23736/S1824-4785.20.03238-0

15.

Ohlsson

Gålne

Trägårdh

Malmström

Sundlöv

Almquist

. Relationship between somatostatin receptor expressing tumour volume and health-related quality of life in patients with metastatic GEP-NET. Neuroendocrinol. 2022;34(6):e13139. doi:10.1111/jne.13139

16.

Toriihara

Baratto

Nobashi

, et al. Prognostic value of somatostatin receptor expressing tumor volume calculated from (68)Ga-DOTATATE PET/CT in patients with well-differentiated neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2019;46(11):2244-2251. doi:10.1007/s00259-019-04455-9

17.

Ambrosini

Campana

Polverari

, et al. Prognostic value of 68Ga-DOTANOC PET/CT SUVmax in patients with neuroendocrine tumors of the pancreas. J Nucl Med. 2015;56:1843-1848. doi:10.2967/jnumed.115.162719

18.

Lee

Kim

. Prognostic value of maximum standardized uptake value in 68Ga-Somatostatin receptor positron emission tomography for neuroendocrine tumors: a systematic review and meta-analysis. Clin Nucl Med. 2019;44(10):777-783. doi:10.1097/RLU.0000000000002694

19.

McShane

Altman

Sauerbrei

, et al. Reporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer. 2005;93(4):387-391.

20.

von

Altman

Egger

, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147:573-577.

21.

Erdi

Mawlawi

Larson

, et al. Segmentation of lung lesion volume by adaptive positron emission tomography image thresholding. Cancer. 1997;80:2505-2509.

22.

Heagerty

Lumley

Pepe

. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000;56(2):337-344. doi:10.1111/j.0006-341x.2000.00337.x

23.

Rinke

Muller

Schade-Brittinger

, et al. Placebo-controlled double-blind prospective randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J Clin Oncol. 2009;27:4656-4663.

24.

Del Rivero

Perez

Kennedy

, et al. Systemic therapy for tumor control in metastatic well-differentiated Gastroenteropancreatic neuroendocrine tumors: ASCO guideline. J Clin Oncol. 2023;41(32):5049-5067. doi:10.1200/JCO.23.01529

25.

Panzuto

Boninsegna

Fazio

, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol. 2011;29(17):2372-2377. doi:10.1200/JCO.2010.33.0688

26.

Abou-Azar

Tobias

Feinberg

, et al. DOTATATE PET CT tumor volume as a predictor of surgical outcome in patients with metastatic gastroenteropancreatic neuroendocrine tumors. Surgical Oncology Insight. 2025;2(Issue 2 June 2025):100141. doi:10.1016/j.soi.2025.100141

27.

Pauwels

Van Binnebeek

Vandecaveye

, et al. Inflammation-based index and (68)Ga-DOTATOC PET-derived uptake and volumetric parameters predict outcome in neuroendocrine tumor patients treated with (90)Y-DOTATOC. J Nucl Med. 2020;61(7):1014-1020. doi:10.2967/jnumed.119.236935

28.

Ortega

Wong

Schaefferkoetter

, et al. Quantitative 68Ga-DOTATATE PET/CT parameters for the prediction of therapy response in patients with progressive metastatic neuroendocrine tumors treated with 177Lu-DOTATATE. J Nucl Med. 2021;62(10):1406-1414. doi:10.2967/jnumed.120.256727

29.

Durmo

Filice

Fioroni

, et al. Predictive and prognostic role of pre-therapy and interim 68Ga-DOTATOC PET/CT parameters in metastatic advanced neuroendocrine tumor patients treated with PRRT. Cancers (Basel). 2022;14(3):592. doi:10.3390/cancers14030592

30.

Gålne

Sundlöv

Enqvist

Sjögreen Gleisner

Larsson

Trägårdh

. Retrospective evaluation of the predictive value of tumour burden at baseline [(68) Ga]Ga-DOTA-TOC or -TATE PET/CT and tumour dosimetry in GEP-NET patients treated with PRRT. EJNMMI Rep. 2024;8(1):24. doi:10.1186/s41824-024-00210-y

31.

Shin

Kim

Yoo

, et al. Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy. Eur Radiol. 2025;35(5):2559-2568. doi:10.1007/s00330-024-11116-5

32.

Chan

Hayes

Karfis

, et al. [(18)F]FDG metabolic tumor volume as a prognostic marker in neuroendocrine neoplasm: a multicenter study. J Nucl Med. 2025;66(7):1012-1017. doi:10.2967/jnumed.124.269031

33.

Tirosh

Papadakis

Millo

, et al. Prognostic utility of total (68)Ga-DOTATATE-avid tumor volume in patients with neuroendocrine tumors. Gastroenterology. 2018;154(4):998-1008.e1. doi:10.1053/j.gastro.2017.11.008

34.

Ohnona

Nataf

Gauthe

, et al. Prognostic value of functional tumor burden on 68Ga-DOTATOC PET/CT in patients with pancreatic neuro-endocrine tumors. Neoplasma. 2019;66(1):140-148. doi:10.4149/neo_2018_180328N209

35.

Lee

Eads

Pryma

. ⁶⁸Ga-DOTATATE positron emission tomography-computed tomography quantification predicts response to somatostatin analog therapy in gastroenteropancreatic neuroendocrine. Oncologist. 2021;26(1):21-29. doi:10.1634/theoncologist.2020-0165

36.

Teker

Elboga

. Is SUVmax a useful marker for progression-free survival in patients with metastatic GEP-NET receiving (177)Lu-DOTATATE therapy? Hell J Nucl Med. 2021;24(2):122-131. doi:10.1967/s002449912352

37.

Virgolini

Gabriel

Kroiss

, et al. Current knowledge on the sensitivity of the (68)Ga-somatostatin receptor positron emission tomography and the SUVmax reference range for management of pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2016;43(11):2072-2083. doi:10.1007/s00259-016-3395-4

38.

Paiella

Landoni

Tebaldi

, et al. Dual-Tracer (68Ga-DOTATOC and 18F-FDG-)-PET/CT scan and G1-G2 nonfunctioning pancreatic neuroendocrine tumors: a single-center retrospective evaluation of 124 nonmetastatic resected cases. Neuroendocrinology. 2022;112(2):143-152. doi:10.1159/000514809

39.

Storto

Nicolai

Salvatore

. [18F] FDG-PET-CT for early monitoring of tumor response: when and why. Q J Nucl Med Mol Imaging. 2009;53(2):167-180.

40.

Nappi

Gallicchio

Simeon

, et al. [F-18] FDG-PET/CT parameters as predictors of outcome in inoperable NSCLC patients. Radiol Oncol. 2015;49(4):320-326. doi:10.1515/raon-2015-0043

41.

Storto

De Renzo

Pellegrino

, et al. Assessment of metabolic response to radioimmunotherapy with 90Y-ibritumomab tiuxetan in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Radiology. 2010;254(1):245-252. doi:10.1148/radiol.09090603

42.

Gallicchio

Giordano

Milella

, et al. Ga-68-Edotreotide positron emission tomography/computed tomography somatostatin receptors tumor volume predicts outcome in patients with primary gastroenteropancreatic neuroendocrine tumors. Cancer Control. 2023;30:10732748231152328. doi:10.1177/10732748231152328

43.

Şentürk

Acar

Yildirim

Çakir

Küçükkartallar

Vatansev

. Clinicopathological characteristics of gastroenteropancreatic neuroendocrine tumors: 10 years of experience from a single center. Pancreas. 2022;51(2):159-163. doi:10.1097/MPA.0000000000001981

44.

Riss

Scheuba

Strobel

. Endocrine and neuroendocrine tumors. Chirurg. 2021;92(11):996-1002. doi:10.1007/s00104-021-01512-8

45.

Watanabe

Fujishima

Komoto

, et al. Somatostatin receptor 2 expression profiles and their correlation with the efficacy of somatostatin analogues in gastrointestinal neuroendocrine tumors. Cancers (Basel). 2022;14(3):775. doi:10.3390/cancers14030775

46.

, et al. The correlation between [(68)Ga]DOTATATE PET/CT and cell proliferation in patients with GEP-NENs. Mol Imaging Biol. 2019;21(5):984-990. doi:10.1007/s11307-019-01328-3

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.27 MB