Can Tc-99m-PSMA SPECT/CT Be Used as Accessible Alternative for Diagnosis of Biochemically Recurrent Prostate Cancer? A Prospective Study

Round 1

Reviewer 1 Report (Previous Reviewer 3)

Comments and Suggestions for Authors

I believe that the revised version of the manuscript is academically more rigorous and scientifically improved. I thank the authors for their contributions.

Author Response

Comment 1: I believe that the revised version of the manuscript is academically more rigorous and scientifically improved. I thank the authors for their contributions.

Response 1: We thank the reviewer for the positive evaluation of the revised manuscript. We also appreciate the constructive feedback provided throughout the review process, which has significantly strengthened the manuscript.

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

Manuscript ‘Can Tc-99m-PSMA SPECT/CT be used as accessible alternative for diagnosis of biochemically recurrent prostate cancer? A prospective study.’ by Milos et al.

 

This paper describes the findings of a prospective SPECT/CT study for restaging of prostate cancer, using Tc-99m-PSMA SPECT/CT as an alternative to PSMA PET/CT. The results are encouraging the use of the former, especially in developing countries with resource limited  nuclear medicine departments. The prospective nature of this study is a strong selling point.

Although the findings of this study are certainly of clinical interest and the paper seems to have been reviewed before, there are still some issues that need to be addressed. This reviewer therefor judges revision necessary because of the following major and minor reasons:

 

Major:

• Materials and methods. Why were the 95 patients excluded from the study. Please add a Figure 1 showing a flow diagram of patients included and excluded.
• Materials and methods. Image interpretation an scoring should be more elaborated, since there are no recommended scoring systems for Tc-99m-PSMA SPECT/CT. Just mentioning that any uptake that cannot be attributed to physiogical uptake or benign processes is not sufficient.
• Results and discussion. The radical prostatectomy and the radiation therapy groups seem not to be quite comparable, with the prostatectomy group showing signs of more aggressive behavior. This should be discussed more in detail.
• In order to shorten the discussion, results of the retrospective studies and effects of ADT on it can be taken together because most of them are comparable to the results of the present study.
• The section highlighted in yellow comprising lines 458-467 should be moved to the limitations section starting at line 475.

 

Minor:

• Lines 197-198 can be left out.
• Line 381: ‘This can explained by the fact that detection rate’ should be This can be explained by the fact that the detection rate’
• Line 436: please add ‘due to higher spatial resolution’ (of PET/CT compared to SPECT/CT).
• Lines 440-443: ‘A very limited number of studies is reporting on head-to-head comparison of Tc-99m-PSMA SPECT/CT and PSMA PET/CT in the detection of prostate cancer. In one such study reporting on detection rates in 28 patients, 25 out of 28 had abnormal Ga-68-PSMA PET/CT findings’.

Author Response

Major comments:

Comment 1:  Materials and methods. Why were the 95 patients excluded from the study. Please add a Figure 1 showing a flow diagram of patients included and excluded.

Response 1: Thank you for the comment. We have addressed this point by adding Figure 1, a flow diagram of patient selection, and by clarifying the study population in the Materials and Methods section. The revised text now explains that out of 227 consecutive referred patients, 132 fulfilled the study criteria and were included in the final analysis, while 95 were excluded according to the predefined inclusion and exclusion criteria. These criteria are listed in Section 2.1, and the newly added flow diagram summarizes the inclusion and exclusion process.

Comment 2:  Materials and methods. Image interpretation an scoring should be more elaborated, since there are no recommended scoring systems for Tc-99m-PSMA SPECT/CT. Just mentioning that any uptake that cannot be attributed to physiogical uptake or benign processes is not sufficient.

Response 2:  We have substantially expanded Section 2.4 (Image interpretation). The revised manuscript now states that image interpretation was based on a visual and morphologic assessment using combined SPECT and low-dose CT findings, performed on a lesion-by-lesion basis and then summarized at the patient level. We also clarified that interpretation included assessment of lesion intensity, focality, anatomic location, and correlation with low-dose CT morphology. In addition, we now specify lesion-specific criteria for positivity, including different thresholds for pelvic/retroperitoneal lymph nodes, extra-pelvic lymph nodes, prostate bed lesions after radical prostatectomy, intraprostatic lesions after radiation therapy, and bone/soft-tissue lesions, with visual comparison to blood-pool or liver activity and correlation with low-dose CT findings. This expanded description has replaced the previous brief statement that pathological uptake was defined only as uptake not attributable to physiologic or benign processes.

Comment 3:  Results and discussion. The radical prostatectomy and the radiation therapy groups seem not to be quite comparable, with the prostatectomy group showing signs of more aggressive behavior. This should be discussed more in detail.

Response 3: In the revised manuscript, we have added a paragraph in the Discussion clarifying that the radical prostatectomy and radiation therapy groups represent different clinical entities. We now emphasize that the radical prostatectomy group showed several indicators of more aggressive disease, including a predominance of ISUP grade 3–5 tumors and frequent adverse pathological features such as positive surgical margins, extracapsular extension, and seminal vesicle invasion. We also note that this group had a higher proportion of metastatic disease, despite a lower overall recurrence detection rate compared with the radiation therapy group. These points are now explicitly discussed, and we state that the comparison between the two cohorts should be interpreted with caution. 

Comment 4:  In order to shorten the discussion, results of the retrospective studies and effects of ADT on it can be taken together because most of them are comparable to the results of the present study.

Response 4:  As suggested, to shorten the Discussion, we combined several retrospective studies [23–26] and the effects of ADT on PSMA kinetics [27,28] into a compact paragraph, while still highlighting the overall detection rates and the main similarities and differences between those studies and the present study.

Comment 5:  The section highlighted in yellow comprising lines 458-467 should be moved to the limitations section starting at line 475.

Response 5:  In the revised manuscript we have moved the key technological limits of SPECT/CT to limitation section, as suggested.

Minor comments

Comment 6: 

Lines 197-198 can be left out.

Line 381: ‘This can explained by the fact that detection rate’ should be This can be explained by the fact that the detection rate’

Line 436: please add ‘due to higher spatial resolution’ (of PET/CT compared to SPECT/CT).

Lines 440-443: ‘A very limited number of studies is reporting on head-to-head comparison of Tc-99m-PSMA SPECT/CT and PSMA PET/CT in the detection of prostate cancer. In one such study reporting on detection rates in 28 patients, 25 out of 28 had abnormal Ga-68-PSMA PET/CT findings’.

Response 6:  Thank you for helping us improve the overall quality of the manuscript. All suggested minor textual revisions have now been incorporated into the revised version.

Round 2

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

The comments have been sufficiently addressed by the authors, thus improving the quality of the paper. In addition to this, its value for the standing practice in developing countries warrants publication in Diagnostics.

 

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript reports a single-centre prospective cohort of 144 men with biochemical recurrence (BCR) of prostate cancer undergoing Tc-99m-PSMA SPECT/CT, with PSA-stratified detection rates and an ROC-derived PSA cut-off for optimal performance. The topic is clinically relevant, particularly for resource-limited settings. The sample size is reasonable and the imaging and follow-up protocol are clearly described.

 

Major comments

- Definition of biochemical recurrence and inclusion criteria

• BCR is defined (Introduction, page 2) as PSA ≥0.2 ng/ml after prostatectomy or ≥2 ng/ml after radiotherapy, citing guideline-based thresholds.

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• However, the inclusion criteria also allow patients initially treated with androgen deprivation therapy (ADT) alone (Table 1 shows 19% ADT as “initial treatment”, page 3), without specifying the PSA threshold for BCR in this setting. This is not standard and may introduce heterogeneity.

• In addition, the Methods state “two consecutive measurements of rising PSA levels… minimum 6 months after initial treatment” but do not clearly reconcile this with the numerical BCR thresholds given in the Introduction, or how these rules were applied to the ADT group

-Reference standard and classification of TP/TN/FP/FN

• The follow-up criteria combine histopathology, other imaging (CT/MRI/repeat SPECT), and PSA response to therapy after lesions identified on Tc-99m-PSMA SPECT/CT (Section 2.5, page 4). This risks incorporation bias, as the index test partially guides the reference standard (e.g., lesions treated because they were SPECT-positive, then PSA falls).

• The manuscript states that “because all patients in the study met criteria for BCR… results were interpreted as false negative if there was no pathological uptake.” True negative was defined as PSA lowering without treatment after a negative SPECT/CT (page 4). This is logically inconsistent: if all patients truly had BCR at inclusion, there should be no “true negatives”.

• In the ROC analysis, the authors report 117 TP, 22 FN, and 5 TN, with no FP (page 6). It is unclear how the 5 TN are compatible with the initial inclusion of only BCR cases.

-References: cite this article in comparison with the role of PET in LN detection in BC  doi: 10.1016/j.euo.2025.03.019.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This is a well-conceived and clinically valuable study that addresses an important question of using Tc-99m-PSMA SPECT/CT as a potential surrogate imaging modality for detecting BCR in prostate cancer. The manuscript is clearly written, and the prospective design is a significant strength. The findings on the performance of Tc-99m-PSMA SPECT/CT are promising and relevant, especially for resource-limited settings.

However, the discussion would benefit from explicitly acknowledging a key technological limitation of SPECT/CT: the lack of standardized semiquantitative metrics (e.g., SUVmax, SUVmean). This limit’s objective assessment of tracer avidity, reduces precision in lesion characterization, and hinders reliable monitoring of treatment response over time, areas where PET/CT clearly maintains an advantage. Although newer SPECT systems are exploring relevant quantitative approaches, these remain neither standardized nor widely available.

 

Abstract:

Line 24: This creates a confusing overlap at the 3.0 ng/ml threshold. To avoid ambiguity, it is advised to consider the following intervals: 0.2 to <3.0 ng/ml; 3.0 to <7.0 ng/ml; and ≥7.0 ng/ml.

Line 26: The reported optimal PSA cutoff (>2.8 ng/ml) requires more explanation. Was a ROC curve used? If so, provide the AUC and confidence intervals.

Line 28: The conclusion that Tc-99m-PSMA SPECT/CT being a powerful diagnostic tool, is stronger than the data justify, particularly given the low detection rate at lower PSA levels.

 

Introduction:

Line 50: (after few weeks) should be (after a few weeks).

Line 56: (becoming increasingly important tool) should be (becoming an increasingly important tool).

Line 67-68: The statement could be made more precise. While several studies have explored Tc-99m-PSMA SPECT/CT, systematic evaluations of its diagnostic performance at very low PSA levels (e.g., <0.5 ng/mL, 0.5–1.0 ng/mL) remain limited. Clarifying this gap would better justify the study’s focus.

71-73: Reference. Also, the argument for using Tc-99m-PSMA SPECT/CT as an alternative to PET/CT lacks justification. Elaborate on why SPECT/CT is more available and affordable. Consider its advantages in accessibility and cost, including lower equipment and operational expenses, longer tracer half-life for easier distribution, and wider scanner availability in community hospitals and developing region.

 

Methods:

Line 83: Were all 190 patients diagnosed with BCR based on standard criteria (which you defined in the introduction) before the scan?

Line 89: There is a serious chronological inconsistency. The study is stated to have been conducted from January 2024 to January 2025, yet one of the provided ethics approval numbers has a date of 29.09.202.

Please state the reference standard used.

Line 94: Including androgen deprivation therapy (ADT) along with radical prostatectomy and radiation therapy as an initial treatment can be methodologically problematic. ADT is rarely a definitive initial monotherapy for localized disease. Its use can confound PSA kinetics and PSMA expression. In addition, a patient rising on PSA after ADT alone is in a state of castration-resistant progression, which is a different clinical entity than BCR following curative-intent therapy (surgery/radiation).

Line 102: this is redundant with the inclusion criteria no.2.

Line 103: Provide a clear, quantitative definition based on established clinical guidelines (e.g., CKD-EPI eGFR < 30 mL/min/1.73m²) with reference.

Regarding the ROC, re-focus the results on the detection rates (sensitivity) at low PSA levels. Emphasize that while the test is highly specific, its sensitivity is limited at PSA levels below 2.8 ng/mL, which is precisely the population where imaging guidance is most challenging.

Line 280: Inconsistency of reference formatting.

 

Figures: The figures’ legends are very brief and lack sufficient context. Try to expand specifying relevant patient’s history and lesion details, along with any annotations. Additionally, it would be important to indicate which tool or method was used to confirm BCR in each figure.

 

 

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Reviewer Comments 

The study is generally well designed and focuses on a clinically interesting and relevant topic. I would like to congratulate the authors for their efforts in this field. I believe that, with the following suggestions, the scientific quality and methodological robustness of the manuscript can be significantly improved.

1. Methodologically inappropriate grouping of treatment modalities

In the current study, patients who received radiotherapy and those who underwent radical prostatectomy were evaluated within the same group. This approach does not seem methodologically appropriate. These two treatment modalities differ substantially in terms of both biological effects and recurrence dynamics. Therefore, this comparison is rather like comparing apples and oranges.

2. Insufficient pathological data

Although transrectal ultrasound–guided biopsy pathology was included in the analysis, the pathological data obtained after radical prostatectomy (RRP) were not adequately evaluated.

In particular, the following parameters should also be included and analyzed, as they are highly relevant for prognosis and recurrence:

• Perineural invasion

• Lymphovascular invasion

• Surgical margin status

• Extracapsular extension

• Seminal vesicle invasion

3. Inappropriate comparison of recurrence patterns

Biochemical recurrence after radical prostatectomy and recurrence after radiotherapy should not be considered as the same biological process. These two conditions should be analyzed separately using different recurrence definitions and criteria.

However, the current sample size appears insufficient to allow for meaningful subgroup analyses.

4. Sample size and statistical power

The current sample size seems inadequate, especially for intergroup comparisons and subgroup analyses.

Therefore, it is strongly recommended to:
increase the number of patients, ensure better homogeneity of the subgroups, and, if possible, consider multicenter data inclusion.

5. Publishability perspective

Although the topic of the study is valuable, in its current form, the manuscript appears methodologically and statistically insufficient for publication in an ESCI-indexed journal.

Comments on the Quality of English Language

Reviewer Comments 

The study is generally well designed and focuses on a clinically interesting and relevant topic. I would like to congratulate the authors for their efforts in this field. I believe that, with the following suggestions, the scientific quality and methodological robustness of the manuscript can be significantly improved.

1. Methodologically inappropriate grouping of treatment modalities

In the current study, patients who received radiotherapy and those who underwent radical prostatectomy were evaluated within the same group. This approach does not seem methodologically appropriate. These two treatment modalities differ substantially in terms of both biological effects and recurrence dynamics. Therefore, this comparison is rather like comparing apples and oranges.

2. Insufficient pathological data

Although transrectal ultrasound–guided biopsy pathology was included in the analysis, the pathological data obtained after radical prostatectomy (RRP) were not adequately evaluated.

In particular, the following parameters should also be included and analyzed, as they are highly relevant for prognosis and recurrence:

• Perineural invasion

• Lymphovascular invasion

• Surgical margin status

• Extracapsular extension

• Seminal vesicle invasion

3. Inappropriate comparison of recurrence patterns

Biochemical recurrence after radical prostatectomy and recurrence after radiotherapy should not be considered as the same biological process. These two conditions should be analyzed separately using different recurrence definitions and criteria.

However, the current sample size appears insufficient to allow for meaningful subgroup analyses.

4. Sample size and statistical power

The current sample size seems inadequate, especially for intergroup comparisons and subgroup analyses.

Therefore, it is strongly recommended to:
increase the number of patients, ensure better homogeneity of the subgroups, and, if possible, consider multicenter data inclusion.

5. Publishability perspective

Although the topic of the study is valuable, in its current form, the manuscript appears methodologically and statistically insufficient for publication in an ESCI-indexed journal.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf