The Role of PET and SPECT Imaging in Prostate Cancer Targeted Alpha Therapy: When and How?

Round 1

Reviewer 1 Report

Thank you for this manuscript which discusses a topic of high interest (TAT). Comments:

-The manuscript fails to address the significant disease heterogeneity in mCRPC. The role of FDG PET in addition to PSMA PET should be discussed in the setting of assessment for eligibility to treatment with PSMA targeted therapies, as well as prognostication. Please consider discussing in more depth disease heterogeneity, how it can be detected by molecular imaging, and how it impacts treatment decision, as well as the imaging criteria used to determine choice of therapy.

-The introduction is too long, and discusses topics that are not particularly relevant to the content of the manuscript.

- The manuscript needs English language review, there are many syntax errors that need attention, to name a few:  

Line 42: “and the advantageous of withdrawal” should be “and the advantage of withdrawal”

Line 76-77: “nowadays the therapeutical chance has been bettered the overall survival in these patients” needs review

Line 142: “nanomatherials” should be changed to “nanomaterials”

 

-In the introduction, consider mentioning that Lu-177 is a beta minus emitter, to contrast it with the alpha emitters.

-In page 4, the difference between SPECT and PET is poorly explained, and it is not mentioned that each positron decay results in 2 photons emitted in opposite direction.

-Fig 1: Are the planar images post-Lu-177 PSMA 617 (C) obtained on the same patient imaged by Ga-PSMA-11 (A and B)? If so, how do you explain the different distribution of disease? What’s the time interval between the PET and the therapy? Why we don’t see all these osseous metastases on PET?

-Lines 223-230, can you please provide a reference for the discussion of “synthetic lethality”?

-Lines 287-288, consider changing “Bone metastasis in mCRPC are FDG-avid” to “metastases from CRPC have higher likelihood of being FDG avid”, since there is significant disease heterogeneity, and not all mCRPC lesions are FDG-avid.

-In terms of patient selection for a particular therapy, the diagnostic/therapeutic pair have to share the same biological target. This is the core concept of theranostics, and for this reason, bone scintigraphy (Tc-99m MDP), or F-18 NaF are used to assess eligibility for treatment with Xofigo. It is confusing in the manuscript how F-18 Choline and PSMA PET are listed under the discussion of Xofigo without clarifying that they shouldn’t be used to assess eligibility or choice of treatment. Example: PSMA+/bone scan- bone lesions should be treated with Pluvicto not Xofigo.

-Lines 334-336: Attention to the following sentence: “Only a small number of clinical trials, early dosimetry attempts, and some retrospective observational studies have examined PSMA-targeting alpha-particle therapy (TAT). These include anti-PSMA antibodies such as J591 and PSMA targeted small molecules such as MIP-1095, PSMA I & T, and PSMA-617 labeled with alpha or beta particle emitting isotopes”; PSMA targeted molecules labeled with beta emitting isotopes are not TAT, please consider taking out beta from this sentence.

-In table 1, please abbreviate the summary for the 7^th listed trial NCT04225910, and 10^th listed trial NCT04833517

-Lines 453-456: “Also, in the PSMA field the 68Ga labeled tracers have been the most validated and as such the European Association of Urology and National Cancer Comprehensive Network have included 68Ga-PSMA PET/CT in NCCN Guidelines Insights”. F18-DCFPyL or Pylarify is also included in NCCN guidelines.

-Lines 468-470: “some previous papers concerning beta-emitting- therapy describes the 68Ga-PSMA uptake in lesions as a specific criteria, that should be 1.5 times higher than liver uptake”. In VISION trial which was behind the FDA approval of Pluvicto, patients were considered eligible if they had uptake on PSMA PET higher than liver (not 1.5 times), and that’s what we use clinically.

-Line 475: Please explain the mechanism of action/target of “68Ga-NODAGA PET/CT”

-Lines 493-495: “99mTc-PSMA- I&S has been tested at various clinical stages, showing at low PSA levels inferior detection rates with respect to PET-imaging whereas, at higher PSA levels provides higher”. First, the sentence is weak. Second, it implies that at high PSA level Tc-99m PSMA SPECT has higher detection rate than PET, which is not the case, please revise.

Author Response

We would like to thank you for the comments. 

Since the reviewers did not agree on the length of the manuscript, we had to choose to eliminate many things or lengthen many others to homogenize the manuscript and seek agreement between various points of view. Particularly:

The introduction has been shortened and English language review has been done. 

Line 42: “and the advantageous of withdrawal” has been substituted with “and the advantage of withdrawal”

Line 76-77: “nowadays the therapeutical chance has been bettered the overall survival in these patients” has been substituted with “has been bettered over time”

Line 142: “nanomatherials” has been changed with “nanomaterials”

 In the introduction has been yet mentioned Lutetium 177Lu vipivotide, see line 112.

The difference between SPECT and PET was better explained.

PET/CT and Lu-scintigraphy were obtained on the same patient. As a matter of fact, the discrepancy between PET/CT's findings and those of Lu-based scintigraphy might be explained by the too long interval of time occurred between the diagnostic phase and the therapeutic procedure (2 months) in a subject with rapidly progressive disease. In this patient, PET/CT was not repeated before the administration of 177Lu-PSMA due to shortage of tracer's availability. This case underlines the importance of a short gap of time in the 2 steps of the theranostic approaches (diagnostic and therapeutic phases), as now clearly stated in the legend to Figure 1.  

Lines 223-230, has been provided a reference for the discussion of “synthetic lethality”.

We have changed the sentence  following your suggestion (Lines 287-288).

In the new version, we have changed some sentences in order to clarify the possible role of choline PET and PSMA PET in the selection of patients for treatment with Xofigo: the first in terms of prognosis, the second in terms of visceral metastasis detection.

We modified the test accordingly (Lines 334-336).

"In table 1, please abbreviate the summary for the 7^th listed trial NCT04225910, and 10^th listed trial NCT04833517". Thank you for your suggestion. However, this table reports the information reported by Authors in the clinicaltrials.gov and, therefore, we would avoid several changes.

We modified the sentence “the 68Ga labeled tracers have been widely validated” and we cited the recently published Version 1.2023 of NCCN guidelines. “However, concerning the optimal setting for baseline assessment pre-treatment with 177Lu-PSMA-617 in NCCN Guidelines [DOI: 10.6004/jnccn.2022.0063], the panel discussed the fact that the 2 FDA approved PSMA imaging agents—68Ga-PSMA-11 and 18F-piflufolastat PSMA—share the same PSMA binding motif with each other and with 177Lu-PSMA-617, suggesting that all approved PSMA PET imaging agents should be acceptable “

We reported more details about VISION trial eligibility criteria.

We included a brief description of “68Ga-NODAGA PET/CT”  in the text.

We revised the sentence in order to clarify this aspect (Lines 493-495).

Best regards

Author Response File: Author Response.docx

Reviewer 2 Report

The review discusses the current state of Targeted Alpha Therapy (TAT) in prostate cancer, particularly in mCRPCT, covering a collection of related publications in recent years. However, as a potential review paper, it requires a major revision in terms of presentation and writing. Detailed comments are as follows.

1. To improve the readability, it is suggested the long pragraphs (in the sections of introduction/discussion/...) should be split into short paragraphs.

2. The organisation of the manuscript needs to be improved significantly. As a review paper, it is especially difficult to follow the authors' presentation without a clear taxonomy/structure. Schematic diagrams may be helpful for easier understanding.

3. Some subsection titles are not descriptive.

4. There exist some typos/grammar issues.

Author Response

We would like to thank you for the comments. 

Since the reviewers did not agree on the length of the manuscript, we had to choose to eliminate many things or lengthen many others to homogenize the manuscript and seek agreement between various points of view.

English language review has been done.

Best regards

 

Author Response File: Author Response.pdf

Reviewer 3 Report

This review paper is well written. These are several comments:

On Page 12, "Imaging" section should include CT and MRI. It should also mention the limitations of these modalities and also mention FDG-PET/CT and FAPI.

In line 117, "177Lu" is not superscripted, and similarly, in line 139, "211At" is not superscripted. Others should be reviewed in their entirety.

 

Author Response

We would like to thank you for the comments.

Since the reviewers did not agree on the length of the manuscript, we had to choose to eliminate many things or lengthen many others to homogenize the manuscript and seek agreement between various points of view.

Superscripts have been revised throughout the manuscript.

Best regards

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The authors failed to respond to my comments regarding the manuscript structure (e.g., point 1 and point 2 in my 1st round review report). One obvious caveat is that there is only one super-long paragraph in sections 1, 2 and 3.

Author Response

We thank the reviewer very much and hope that these changes make our text clearer as requested

Author Response File: Author Response.docx