Head-to-Head Comparison between Peptide-Based Radiopharmaceutical for PET and SPECT in the Evaluation of Neuroendocrine Tumors: A Systematic Review

Round 1

Reviewer 1 Report

The work presents a systematic review.
The systematic review is, in overall methodology well conducted, and the paper well written.

However, the lack of statistics (namely the number of papers included in the review) prevents the systematic review to lead to scientific relevant results with improved scientific relevance when compared to each one of the analyzed papers.

The title and the introductory text are not clear about it, but the prevalence of such papers led the authors to a comparison PET vs SPECT, and the conclusions are influenced by the technical differences between these two imaging modalities, which is difficult to differenciate from the comparison between radiopharmaceuticals (that seems to be the main objective of the systematic review).

Furthermore, and still trusting the title and the introductory text, if the review focus on a comparison between SPECT and PET  radiopharmaceuticals, the inclusion of the (only) paper 111In and 99mTc radiopharmaceuticals can be challanged. The same would apply for a (missed by the authors) eventual paper comparing 68Ga and 64Cu.
Anyway, once again, the crucial fact is the low number of papers whatever are the subjects to be compared. Which tremendously prejudices the novelty and quality of the conclusions. 

Author Response

The work presents a systematic review.
The systematic review is, in overall methodology well conducted, and the paper well written.

Q1. However, the lack of statistics (namely the number of papers included in the review) prevents the systematic review to lead to scientific relevant results with improved scientific relevance when compared to each one of the analyzed papers.

R1. Our systematic review aims to evaluate the diagnostic ability of PET and SPECT tracers to manage patients with NET. However, based on the comments from the academic editors, we have implemented the discussion and the analysis of the available papers, also considering the advantages of PET and SPECT imaging for the clinical benefit in guiding to therapy with radionuclide. In this vision, although we were not able to add any statistical analysis (few papers), we have improved the content of the manuscript and included the utility to develop SPECT/PET tracers that can be translated in clinical practice.

Q2. The title and the introductory text are not clear about it, but the prevalence of such papers led the authors to a comparison PET vs SPECT, and the conclusions are influenced by the technical differences between these two imaging modalities, which is difficult to differenciate from the comparison between radiopharmaceuticals (that seems to be the main objective of the systematic review).

R2. We agree with the reviewer, indeed we reported this limitation in the discussion paragraph. However, the aim of this review is not underlined the differences in terms of diagnostic accuracy between PET and SPECT tracers but rather to understand how to use them to manage patients with NET, also in case of therapy with radionuclide. In this way, the discussion and the entire text was modified accordantly.  

Q3. Furthermore, and still trusting the title and the introductory text, if the review focus on a comparison between SPECT and PET  radiopharmaceuticals, the inclusion of the (only) paper 111In and 99mTc radiopharmaceuticals can be challanged. The same would apply for a (missed by the authors) eventual paper comparing 68Ga and 64Cu.

R3. In the present review, all type of tracers for SSTR imaging were considered, both for PET and SPECT. Indeed, also comparative studies between 68Ga and 64Cu-DOTA-TOC/NOC/TATE were included, although they were few (only 1 paper; Johnbeck et al, #ref22). Moreover, in the discussion section, as required by other reviewers, we have discussed the use of alternative tracers, such as radiolabeled SSTR-antagonist agents and metabolically ones (i.e., 18F-FDG and 18F-DOPA).

Q4. Anyway, once again, the crucial fact is the low number of papers whatever are the subjects to be compared. Which tremendously prejudices the novelty and quality of the conclusions. 

R4. Some additional comments have been included in the conclusion, hoping to improve the quality and novelty of the manuscript.

Reviewer 2 Report

Poletto et al. present here a systematic review on the use and evaluation of radoopharmaceuticals for neuroendocrine tumors. Even though the authors are presenting the work of others found on different database, the inclusion of only 30 published papers is not enough for a review. They also present the work of peptide based Radiopharmaceuticals and it is hard to understand why others have been excluded (small molecules, 18F-analogues, etc...). Furthermore, the chemical formula are most of time wrong and not representing to a high standard for the journal (wrong stereoselectivity, wrong oxidation states of the cationic metals and wrong chemical and coordination bonds). 

The paper shouldn't be published in it's current state.

Author Response

Q1. Poletto et al. present here a systematic review on the use and evaluation of radiopharmaceuticals for neuroendocrine tumors. Even though the authors are presenting the work of others found on different database, the inclusion of only 30 published papers is not enough for a review.

R1. The present systematic review aims to assess the head-to-head comparison between PET and SPECT tracers for NET imaging, in clinical studies and their utility in clinical practice. By using the standard methodology for systematic review, no more than 30 studies were selected. This result highlights that more data should be collected in the future in order to test the utility of SPECT and PET agents for the management of patients with NETs.

Q2. They also present the work of peptide based Radiopharmaceuticals and it is hard to understand why others have been excluded (small molecules, 18F-analogues, etc...).

R2. The present studies was focused only on agonist of SSTR, being already used in clinical practice. However, some comments about other tracers for NET (i.e., antagonist of SSTR and others) have been included in the discussion/conclusion section.

Q3. Furthermore, the chemical formula are most of time wrong and not representing to a high standard for the journal (wrong stereoselectivity, wrong oxidation states of the cationic metals and wrong chemical and coordination bonds). 

R3. Chemical formulas have been corrected.

Reviewer 3 Report

Thank you for your submitting your review on the use of SPECT and PET tracers in NET.

The following changes / clarifications are suggested:

Please revise the title to more clearly reflect the comparison between SPECT and PET tracers in the detection of NET.

Materials and Methods:

Search strategy: more relevant publications may have been detected by not limiting the search to specific tracers and by broadening the search terms to “Somatostatin Receptor imaging” / “SSTR-PET” or “SRS”, for example.

Considering the 2020 PRISMA checklist, details of various aspects thereof

are not clear from the methodology. Kindly clarify the following:

The search strategy is not reproducible as the dates, filters and other limits considered are not clearly outlined. Outcomes and assessment of possible bias, exploration of possible heterogeneity and evaluation of robustness are not clearly detailed.

The Results and Discussion section should start with short summaries and assessments of the studies that were included with reference to possible bias and an interpretation provided.

Results should link to the aim stated and therefor it is expected that details pertaining to diagnostic accuracy and the role of imaging in the monitoring of treatment response evaluation would be addressed.  The pharmaceutical profile of agents (as described in 3.1) is probably not needed.

Novelty: It is now well accepted that Somatostatin Receptor imaging with PET outperforms SPECT imaging. The 2018 Appropriate Use Criteria published in the JNM already stated that all indications for ¹¹¹In-octreotide should be replaced with ⁶⁸Ga-SSTR imaging. It is the impact on clinical management and any subsequent changes in patient outcomes that probably require more attention now.

Table 1 should ideally include an outcome/ interpretation of the comparison as an additional last column.

Table 2 is very difficult to read and should probably be replaced by Table 3, which provides easy diagnostic comparisons at a glance.

Important omissions from this paper include reference to the use of ¹⁸F-FDG PET, SSR antagonist imaging (JR11 and LM3), ¹⁸F-DOPA, ¹²³I-MIBG and some of the newer agents linked to Cu-64 (eg SARTATE).

A few examples of important recent publications on such comparisons that were omitted, include the following:

·      Zhu W, Cheng Y, Wang X, Yao S, Bai C, Zhao H, Jia R, Xu J, Huo L. Head-to-head comparison of 68Ga-DOTA-JR11 and 68Ga-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors: a prospective study. Journal of Nuclear Medicine. 2020 Jun 1;61(6):897-903.

·      Piccardo A, Fiz F, Bottoni G, Ugolini M, Noordzij W, Trimboli P. Head‐to‐head comparison between 18F‐DOPA PET/CT and 68Ga‐DOTA peptides PET/CT in detecting intestinal neuroendocrine tumours: A systematic review and meta‐analysis. Clinical Endocrinology. 2021 Oct;95(4):595-605.

·      Liu X, Li N, Jiang T, Xu H, Ran Q, Shu Z, Wu J, Li Y, Zhou S, Zhang B. Comparison of gallium-68 somatostatin receptor and 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of neuroendocrine tumours: A systematic review and meta-analysis. Hell J. Nucl. Med. 2020 May 1;23:188-200.

Author Response

Thank you for your submitting your review on the use of SPECT and PET tracers in NET.

The following changes / clarifications are suggested:

Q1. Please revise the title to more clearly reflect the comparison between SPECT and PET tracers in the detection of NET.

R1. The title has been changed for reflecting the comparison between PET and SPECT agents.

Materials and Methods:

Search strategy: more relevant publications may have been detected by not limiting the search to specific tracers and by broadening the search terms to “Somatostatin Receptor imaging” / “SSTR-PET” or “SRS”, for example.

Q2. Considering the 2020 PRISMA checklist, details of various aspects thereof are not clear from the methodology. Kindly clarify the following:

The search strategy is not reproducible as the dates, filters and other limits considered are not clearly outlined. Outcomes and assessment of possible bias, exploration of possible heterogeneity and evaluation of robustness are not clearly detailed.

R2.  The methodology has been implemented as requested by the reviewer. Nevertheless, the present manuscript is not a meta-analysis but a systematic reviews, therefore heterogeneity, possible bias and robustness cannot be assesses, as for studies included statistical analysis. However, we have included the CASP in order to evaluate the quality of the studies. In this way, we have included more sentences about the quality of selected papers, in the results section.

Q3. The Results and Discussion section should start with short summaries and assessments of the studies that were included with reference to possible bias and an interpretation provided.

R4. In the limitation has been implemented in the discussion section. Moreover, the CAPS results have been more discussed in the results section.

Q5. Results should link to the aim stated and therefor it is expected that details pertaining to diagnostic accuracy and the role of imaging in the monitoring of treatment response evaluation would be addressed.  The pharmaceutical profile of agents (as described in 3.1) is probably not needed.

R5. We decided to include also the description and pharmaceutical profile of the agents in order to include a synthetic overview of the available tracers. Not only from a chemical point of view, but also considering the current commercial situation and availability. In our opinion this overview can be useful to show how a diagnostic agent could be produced and how is important to have a SPECT and PET tracer for a theragnostic purpose. Indeed, not all the peptides’ analogues are commercially available. For example, 68Ga-DOTATATE and 68Ga-DOTANOC are not commercialized, though guidelines don’t state the preferential use of 68Ga-DOTATOC over the other. Moreover, the different radionuclide may affect the availability of the different radiotracers. 99mTc and 68Ga generators are commercially available and therefore the radiolabeling can be made on-site. Conversely, 64Cu and 111In requires the presence of a cyclotron or should be commercially acquired.

The choice between SPECT and PET agents is, therefore, linked to some situations: 1) availability, costs and supply. Here we have tried to discuss the opportunity to use one or another one for letting to manage patients with neuroendocrine cancer, everywhere.

Q6. Novelty: It is now well accepted that Somatostatin Receptor imaging with PET outperforms SPECT imaging. The 2018 Appropriate Use Criteria published in the JNM already stated that all indications for ¹¹¹In-octreotide should be replaced with ⁶⁸Ga-SSTR imaging. It is the impact on clinical management and any subsequent changes in patient outcomes that probably require more attention now.

R6. Please see the comments #R5. However, in the Appropriate Use Criteria, agents radiolabeled with 99mTc are not mentioned. We have had in mind that PET is not available worldwide, indeed SPECT is more available. Therefore, alternative tracers, also for SPECT with a more favorable radioprotection and synthetical characteristics (mainly 99mTc) should be considered, for the equity of treatments. A sentence has been added in the conclusion paragraph.

Q7. Table 1 should ideally include an outcome/interpretation of the comparison as an additional last column.

R7. The table 1 has been implemented.

Q8. Table 2 is very difficult to read and should probably be replaced by Table 3, which provides easy diagnostic comparisons at a glance.

R8. We have included Table 2, in case of additional analysis for the false positive and false negative rate. We believe that the inclusion of this data would be helpful in case of future meta-analysis (when more data will be available).

Q9. Important omissions from this paper include reference to the use of ¹⁸F-FDG PET, SSR antagonist imaging (JR11 and LM3), ¹⁸F-DOPA, ¹²³I-MIBG and some of the newer agents linked to Cu-64 (eg SARTATE). A few examples of important recent publications on such comparisons that were omitted, include the following:

• Zhu W, Cheng Y, Wang X, Yao S, Bai C, Zhao H, Jia R, Xu J, Huo L. Head-to-head comparison of 68Ga-DOTA-JR11 and 68Ga-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors: a prospective study. Journal of Nuclear Medicine. 2020 Jun 1;61(6):897-903.
• Piccardo A, Fiz F, Bottoni G, Ugolini M, Noordzij W, Trimboli P. Head‐to‐head comparison between 18F‐DOPA PET/CT and 68Ga‐DOTA peptides PET/CT in detecting intestinal neuroendocrine tumours: A systematic review and meta‐analysis. Clinical Endocrinology. 2021 Oct;95(4):595-605.
• Liu X, Li N, Jiang T, Xu H, Ran Q, Shu Z, Wu J, Li Y, Zhou S, Zhang B. Comparison of gallium-68 somatostatin receptor and 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of neuroendocrine tumours: A systematic review and meta-analysis. Hell J. Nucl. Med. 2020 May 1;23:188-200.

R9. As already reported for the Reviewer 2, some comments about other radiopharmaceutical agents for NET have been included in the discussion/conclusion section. Moreover, as suggested by the reviewer, additional papers have been mentioned.

Round 2

Reviewer 1 Report

Although the text was significantly improved, the major obstacle for scientific soundness leading to a publication remains: the number of papers considered in the review is too short.
I would recommend to re-perform the paper selection process, so finally more statistically relevant ground is achieved to ensure relevant conclusions.  

Author Response

Q1. Although the text was significantly improved, the major obstacle for scientific soundness leading to a publication remains: the number of papers considered in the review is too short.

R1. A new literature search was made, by adding other 7 papers to the previous version. We have made a search by interviewing three database (Scopus, WoS and Pubmed) with the following and combined terms: “Somatostatin receptor imaging”; “Somatostatin receptor imaging” AND “Functional”; “Somatostatin receptor imaging” AND “SPECT”; “Somatostatin receptor imaging” AND “PET”.  The papers have been detailed across the text. Moreover other 4 papers were discussed, although they cover different topic from the performance comparison.

Q2. I would recommend to re-perform the paper selection process, so finally more statistically relevant ground is achieved to ensure relevant conclusions.  

R2. Please see the R#1

Reviewer 2 Report

In their revised version the authors have improved the discussion section and included some of the comments made by all the reviewers. However it is still lacking a subsequent number of publications in the field to obtain better results in terms of statistics and discussion. Without it, the work is not suited for the journal as a review article. Secondly it is very disappointing to see that the chemical formula are still wrong and that the coordination bonds around the metal centers are not drawn properly, which is even worst than in the authors first draft. It is not acceptable for researchers in the field of nuclear medicine who present the work of metal based radiopharmaceuticals. I strongly suggest that the authors perform a significant improvement in the writing of their review before resubmission anywhere, which would benefit the all community. 

Author Response

In their revised version the authors have improved the discussion section and included some of the comments made by all the reviewers.

Q1. However it is still lacking a subsequent number of publications in the field to obtain better results in terms of statistics and discussion. Without it, the work is not suited for the journal as a review article.

R1. A new literature search was made, by adding other 7 papers to the previous version. We have made a search by interviewing three database (Scopus, WoS and Pubmed) with the following and combined terms: “Somatostatin receptor imaging”; “Somatostatin receptor imaging” AND “Functional”; “Somatostatin receptor imaging” AND “SPECT”; “Somatostatin receptor imaging” AND “PET”.  The papers have been detailed across the text. Moreover other 4 papers were discussed, although they cover different topic from the performance comparison.

Q2. Secondly it is very disappointing to see that the chemical formula are still wrong and that the coordination bonds around the metal centers are not drawn properly, which is even worse than in the authors first draft. It is not acceptable for researchers in the field of nuclear medicine who present the work of metal based radiopharmaceuticals.

R2. The chemical formulas were deleted.

Reviewer 3 Report

Thank you for addressing and clarifying several points.

The following issues remain:

Search strategy: Bias is still introduced by searching for specific tracers, instead of using broader terms to depict somatostatin receptor imaging/ functional/SPECT/PET NET imaging.

Despite inclusion of additional references, Fig 5 (record selection) remained unchanged.

PRISMA guidelines 2020 checklist: some explanations for omission have been provided. However, many aspects that relate to the methodology and the results are still inadequately explained.(In particular Points 10-16 in the checklist).

The Results and Discussion section should start with short summaries and assessments of the studies that were included with reference to possible bias and an interpretation provided.

Table 1 should ideally include an outcome/ interpretation of the comparison as an additional last column. This was probably not clearly communicated. The idea was to add a column which provides the reader with an idea of the overall interpretation of the study, i.e Tracer X outperformed tracer Y by detecting more lesions/ changing staging/ changing management.

Table 2 could rather be provided as supplementary material.

Selected omissions and references have been added.

The only additional included publication is the one by Zhu et al 2020. The additional two suggested meta-analyses include several studies based on head-to head comparisons.

·      Piccardo A, Fiz F, Bottoni G, Ugolini M, Noordzij W, Trimboli P. Head‐to‐head comparison between 18F‐DOPA PET/CT and 68Ga‐DOTA peptides PET/CT in detecting intestinal neuroendocrine tumours: A systematic review and meta‐analysis. Clinical Endocrinology. 2021 Oct;95(4):595-605.

·      Liu X, Li N, Jiang T, Xu H, Ran Q, Shu Z, Wu J, Li Y, Zhou S, Zhang B. Comparison of gallium-68 somatostatin receptor and 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of neuroendocrine tumours: A systematic review and meta-analysis. Hell J. Nucl. Med. 2020 May 1;23:188-200.

Author Response

Thank you for addressing and clarifying several points.

The following issues remain:

Q1. Search strategy: Bias is still introduced by searching for specific tracers, instead of using broader terms to depict somatostatin receptor imaging/ functional/SPECT/PET NET imaging.

R1. A new literature search was made, by adding other 7 papers to the previous version. We have made a search by interviewing three database (Scopus, WoS and Pubmed) with the following and combined terms: “Somatostatin receptor imaging”; “Somatostatin receptor imaging” AND “Functional”; “Somatostatin receptor imaging” AND “SPECT”; “Somatostatin receptor imaging” AND “PET”.  The papers have been detailed across the text. Moreover other 4 papers were discussed, although they cover different topic from the performance comparison.

Q2. Despite inclusion of additional references, Fig 5 (record selection) remained unchanged. PRISMA guidelines 2020 checklist: some explanations for omission have been provided. However, many aspects that relate to the methodology and the results are still inadequately explained.(In particular Points 10-16 in the checklist).

R2. Figure 5, now renamed as Figure 1 has updated in accordance with the new search strategy. However, based on the PRISMA statement, many required information are missing across the text of the selected articles and are often more relative to meta-analysis rather than the systematic review. Indeed some additional data have been included, as much as possible.   

Q3. The Results and Discussion section should start with short summaries and assessments of the studies that were included with reference to possible bias and an interpretation provided.

R3. Additional data about the summary of each included paper has been included in the results paragraph.

Q4. Table 1 should ideally include an outcome/ interpretation of the comparison as an additional last column. This was probably not clearly communicated. The idea was to add a column which provides the reader with an idea of the overall interpretation of the study, i.e Tracer X outperformed tracer Y by detecting more lesions/ changing staging/ changing management.

R4. Table 1 has been corrected in accordance with the suggestions of the Reviewer.

Q5. Table 2 could rather be provided as supplementary material.

R5. We prefer to leave it in the main text.

Q6. Selected omissions and references have been added.

The only additional included publication is the one by Zhu et al 2020. The additional two suggested meta-analyses include several studies based on head-to head comparisons.

• Piccardo A, Fiz F, Bottoni G, Ugolini M, Noordzij W, Trimboli P. Head‐to‐head comparison between 18F‐DOPA PET/CT and 68Ga‐DOTA peptides PET/CT in detecting intestinal neuroendocrine tumours: A systematic review and meta‐analysis. Clinical Endocrinology. 2021 Oct;95(4):595-605.
• Liu X, Li N, Jiang T, Xu H, Ran Q, Shu Z, Wu J, Li Y, Zhou S, Zhang B. Comparison of gallium-68 somatostatin receptor and 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of neuroendocrine tumours: A systematic review and meta-analysis. Hell J. Nucl. Med. 2020 May 1;23:188-200.

R6. Both the papers have been included in the discussion section: Ref 38 and Ref 39

Round 3

Reviewer 1 Report

Comments were well addressed and the paper improved

Author Response

Q1. Comments were well addressed and the paper improved.

R1. We are thankful to the Reviewer for the kind comments about the new version of the mansucript.