Review Reports - The Role of SBRT in Oligometastatic Prostate Cancer: Where We Are and Where We Are Heading

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors, thank you for the opportunity to review your manuscript.

The review offers a clear overview of the biological rationale of oligometastatic disease and summarizes the main prospective trials exploring the role of SBRT as metastasis-directed therapy in prostate cancer. The effort to integrate available evidence with ongoing clinical trials is really useful.

I have few suggestions

The manuscript does not currently include a brief description of how the literature was selected. Even in the context of a narrative review, it would be helpful to add a short paragraph explaining how the studies discussed in the manuscript were identified and chosen (for example, databases consulted, approximate time frame, or general selection criteria).
The section 2 describing the technical and radiobiological principles of SBRT is clear, although it may be somewhat extensive for a review primarily focused on oligometastatic prostate cancer. A slight reduction or condensation of this introductory part could improve the overall flow of the manuscript.
Within the section 3 reviewing the clinical evidence, it may be more intuitive to present SABR-COMET first, as it represents the earliest prospective randomized trial supporting the ablative treatment approach in oligometastatic disease. This ordering would better reflect the chronological development of the field.
Table 2 is informative but could be improved with a few small adjustments: adding the systemic therapy administered in each study, which would help readers interpret the reported outcomes in the appropriate clinical context; correcting minor language inconsistencies (for example, “sincrónico / metacrónico” should be replaced with “synchronous / metachronous”).

Minor typographical issues
A careful proofreading of the manuscript is recommended, as a few minor typographical and stylistic inconsistencies are present in different sections.

In summary, this review provides a clear and timely overview of the current evidence supporting SBRT in oligometastatic prostate cancer. With a few minor revisions to improve clarity and presentation, the manuscript will represent a useful contribution to the literature.

Comments on the Quality of English Language

The English is generally clear, although a light proofreading could further improve the text, as a few expressions appear to reflect direct translation from Spanish; minor linguistic refinement would help ensure a more consistent academic style.

Author Response

Comment 1: The manuscript does not currently include a brief description of how the literature was selected. Even in the context of a narrative review, it would be helpful to add a short paragraph explaining how the studies discussed in the manuscript were identified and chosen (for example, databases consulted, approximate time frame, or general selection criteria).

Dear reviewer, thank you for pointing this out. We agree that a description of how the literature was selected is necessary and thus, we have described it from lines 63-70. We would like to add the paragraph here as well.

“This narrative review was conducted with the aim of summarizing current clinical evidence in oligometastatic prostate cancer, highlighting its efficacy, safety, and future directions in multidisciplinary management. Electronic databases as Pubmed/MEDLINE were used. Emphasis was placed on randomized clinical trials and meta-analyses referred to SBRT in oligometastatic prostate cancer. Additional relevant publications were identified through manual screening of reference lists of selected articles. Only English-language publications were included. ClinicalTrials.gov was used to identify ongoing relevant trials”.

Comment 2: The section 2 describing the technical and radiobiological principles of SBRT is clear, although it may be somewhat extensive for a review primarily focused on oligometastatic prostate cancer. A slight reduction or condensation of this introductory part could improve the overall flow of the manuscript.

Thank you for this appreciation. To avoid making this section too lengthy we have combined and summarized sections 2.2 and 2.3 in one (2.2) and we have also summarized section 2.4.

Comment 3: Within the section 3 reviewing the clinical evidence, it may be more intuitive to present SABR-COMET first, as it represents the earliest prospective randomized trial supporting the ablative treatment approach in oligometastatic disease. This ordering would better reflect the chronological development of the field.

Thank you for this valuable comment. We fully agree with the idea of discussing SABR-COMET trial before focusing on the studies specifically related to prostate cancer, and we have therefore modified the order.

Comment 4: Table 2 is informative but could be improved with a few small adjustments: adding the systemic therapy administered in each study, which would help readers interpret the reported outcomes in the appropriate clinical context; correcting minor language inconsistencies (for example, “sincrónico / metacrónico” should be replaced with “synchronous / metachronous”).

Thank you for this appreciation. We have added the systemic therapy allowed in each study, improved the content of the Table and revised and corrected language inconsistences.

Comment 5: Minor typographical issues. A careful proofreading of the manuscript is recommended, as a few minor typographical and stylistic inconsistencies are present in different sections.

Thank you for this comment. We have reviewed the full manuscript in order to correct typographical inconsistences.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The authors review the biologic rationale/radiobiology of SBRT, prior clinical trials in SBRT for MDT in PCa, and future/pending trials. Overall, this is an excellent overview of the topic in prostate cancer.

Specific comments:

Line 46: definition of oligometastatic disease should be "less than three to five" (not between three and five).
Line 132: define the type of imaging use in STOMP -- relevant because it was not PSMA PET.
Organization question for 3.1 and 3.2: It seemed odd to me that the pan-cancer SABR-Comet study was discussed in section 3.2 after the prostate-specific ORIOLE and STOMP trial discussions in 3.1. Consider re-ordering for logical flow.
3.5 and 3.6 sections would benefit from more details regarding the patient selection characteristics in each study, this is conspicuously brief.
Organization question for 4.3: this section is called integration of the wolverine meta-analysis. However, it goes on past that (starting at line 288) to discuss other studies then trials in mCRPC. Consider additional section headers/separate sections for these different ideas discussed to match the style of the paper and section 4 in general.

Author Response

We would like to thank the reviewer for all the valuable comments.

Comment 1: Line 46: definition of oligometastatic disease should be "less than three to five" (not between three and five).

Dear reviewer, thank you for pointing this out. We agree and have therefore revised the definition to make it more accurate, as shown in line 46.

Comment 2: Line 132: define the type of imaging use in STOMP -- relevant because it was not PSMA PET.

Thank you for this appreciation. We have specified that the image use in the STOMP trial was Choline PET-CT (now line 151).

Comment 3: Organization question for 3.1 and 3.2: It seemed odd to me that the pan-cancer SABR-Comet study was discussed in section 3.2 after the prostate-specific ORIOLE and STOMP trial discussions in 3.1. Consider re-ordering for logical flow.

Line 125: 3.1. SABR-Comet: Proof of Concept for Ablative Treatment
Line 144: 3.2. STOMP and ORIOLE: Consolidating the MDT Paradigm in Prostate Cancer

Comment 4: 3.5 and 3.6 sections would benefit from more details regarding the patient selection characteristics in each study, this is conspicuously brief.

Thank you for pointing this out. Certainly, sections 3.5 and 3.6 needed to be improved. They have been modified in the manuscript but we also report them here:

3.5. RAVENS: a negative study of Ra223 combined with SBRT

The RAVENS phase II trial proposed that the addition of the alpha-emitter radium-223 dichloride (Ra223) to MDT potentially eliminated subclinical bone disease in omHSPC and, therefore, prolonged the time to progression. With this aim, 64 metachronous omHSPC patients with 1 to 3 bone metastases on conventional imaging or 1 to 5 on molecular imaging were randomized to receive SBRT to the metastases +/- Ra223 administered within 2 weeks after SBRT. Previous ADT had to have finished 6 months before enrolment. The primary endpoint was composite PFS. No improvement was found with the intensification strategy, with a median PFS of 11.8 months in the SBRT group versus 10.5 months in the combined therapy group (adjusted hazard ratio [aHR] 1.42; 95% CI, 0.79-2.56; p= 0.24).

The study revealed several noteworthy results regarding biomarkers. Pathogenic high-risk (“HiRi”) mutations (ATM, BRCA1/2, RB1, or TP53) were associated with poorer PFS (HR 5.95; 95% CI, 1.83–19.3; p=0.003), whereas higher levels of unique productive T-cell receptor rearrangements at 3 months were independently prognostic of improved PFS regardless of treatment arm (aHR 0.45; 95% CI, 0.21–0.96; p=0.04). Overall, treatment was well tolerated: 11% of patients experienced grade 3 treatment-related adverse events (no grade 4–5), with 6% in the SBRT arm compared to 17% in the SABR + Ra223 arm.

3.6. LUNAR: the addition of neoadjuvant 177Lu-PNT2002 to SBRT

The LUNAR trial evaluated the role of administering two cycles of the PSMA-targeted radioligand Lutetium-177 (177Lu-PNT2002) before SBRT in oligorrecurrent-HSPC. 87 patients with 1-5 lesions identified by PSMA-PET and no ADT within 6 months before enrollement were included. Primary endpoint was PFS. At a median follow-up of 22 months, adding lutetium to SBRT significantly improved PFS: 17.6 months (95% CI, 15–not reached) versus 7.4 months (95% CI, 6.0–13.5) with SBRT alone (HR 0.37; 95% CI, 0.22–0.61; P < 0.0001).

Local control was excellent, with in-field progression observed in 2% of the SBRT-alone arm versus 0% in the combined therapy group. Safety was generally favourable, with grade 3 adverse events limited to lymphopenia (4.8% in the SBRT group vs 6.7% in the lutetium + SBRT group), and no grade 4–5 events observed.

Comment 5: Organization question for 4.3: this section is called integration of the wolverine meta-analysis. However, it goes on past that (starting at line 288) to discuss other studies then trials in mCRPC. Consider additional section headers/separate sections for these different ideas discussed to match the style of the paper and section 4 in general.

Thank you for this valuable comment. Certainly, section 4 would benefit from some reorganization. We have therefore divided it into the following four sections to better align with the content of the studies in each of them:

“4.1. Oligometastatic Disease States: Oligorecurrence, Oligopersistence, and Oligoprogression

4.2. Hormone-Sensitive Prostate Cancer. Integration of the Wolverine Meta-Analysis

4.3. Hormone-Sensitive Prostate Cancer. Combination of SBRT with Systemic Therapy

4.4. Hormone-Resistant Prostate Cancer”

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

1. Heterogeneity in Definitions of Oligometastatic Disease

The manuscript correctly acknowledges that definitions of oligometastatic prostate cancer vary across studies (typically ≤3 vs ≤5 lesions). However, this issue could be discussed in greater depth. A clearer explanation of how different definitions influence patient selection, outcomes, and interpretation of clinical trials would improve the scientific value of the review.

2. Imaging Modalities and Staging Bias

The manuscript notes that imaging techniques varied across trials and that PSMA-PET was not mandatory in many studies. Given the increasing role of PSMA-PET in clinical practice, the review should more thoroughly discuss how differences in imaging sensitivity may introduce staging bias and affect reported outcomes.

3. Integration with Modern Systemic Therapies

Many of the early MDT trials were conducted before the widespread use of androgen receptor pathway inhibitors (ARPIs). This limitation is mentioned but deserves further discussion, particularly regarding how SBRT should be integrated with current standards of care that include ARPIs and combination systemic therapy.

4. Standardization of SBRT Dose and Fractionation

Dose and fractionation schedules vary substantially across studies. The manuscript would benefit from a clearer synthesis of commonly used regimens and a discussion of whether any consensus or preferred approaches are emerging in clinical practice.

5. Tables and Data Presentation

Table 2 summarizes several clinical trials but appears dense and somewhat difficult to interpret. The authors may consider simplifying the table structure, clearly defining abbreviations, and ensuring consistency in reported endpoints across studies.

Minor Comments

Some sections of the manuscript contain minor grammatical inconsistencies and stylistic issues, likely related to translation or editing. A thorough language revision is recommended.
A few terms appear in mixed language (e.g., “sincrónico” / “metacrónico”), which should be standardized to English terminology.
Several abbreviations should be defined at their first occurrence in the text, even if they are later included in the abbreviation list.
The manuscript could benefit from improved flow between sections, particularly when transitioning from clinical evidence to disease-state classifications.
Some references appear to be repeated or cited inconsistently, and the reference list should be carefully checked for formatting consistency.

Author Response

We would like to thank the reviewer for all the valuable comments.

Heterogeneity in Definitions of Oligometastatic Disease

Dear reviewer, thank you for pointing this out. We agree that different definitions of oligometastatic disease and variations in the number of metastases permitted may have a critical impact in the results and that a further explanation may be advisable. We have therefore added a paragraph delving deeper into this topic.

“These differences can influence studies outcomes, as trials with stricter criteria tend to include patients with lower disease burden and potentially better prognosis, whereas broader definitions allow inclusion of patients with more extensive oligometastatic disease. It is therefore essential to consider these definitional variations, as they can affect both the applicability of the results and cross-trial comparisons”.

Imaging Modalities and Staging Bias

Thank you for pointing this out. We have included a paragraph discussing studies that compare PSMA-PET with other imaging techniques. Certainly, these results may justify the potential staging biases in the available trials of SBRT in oligometastatic prostate cancer patients.

“Different retrospective and prospective trials have shown superior lesions detection rate of PSMA PET when compared with conventional imaging (both CT and even whole-body Magnetic Resonance Imaging). Besides, for PSA ≤1ng/ml, a meta-analysis and a systematic review showed higher lesions detection rate with PSMA PET compared to choline PET/CT. These results were confirmed by the phase III study of Panagiotidis et al. For these reasons, given the staging methods used in the available clinical trials, the results should be interpreted with caution due to the potential bias in metastasis detection”.

Integration with Modern Systemic Therapies

Dear reviewer, thank you for this appreciation. We agree that, in addition to highlighting the scientific evidence supporting the use of ARPIs, it is important to address how they can be integrated with SBRT. We have incorporated the recommendations from the major clinical practice guidelines regarding this issue.

Standardization of SBRT Dose and Fractionation

“The most commonly used regimens ranged from single-fraction treatments of 16–24 Gy to hypofractionated schedules of 27–36 Gy in three fractions or 30–50 Gy in five fractions. For bone metastases, regimens around 27-36 Gy in three fractions or 30–40 Gy in five fractions were commonly used, whereas doses for visceral lesions typically ranged between 35–50 Gy in five fractions. Despite the heterogeneity, doses and fractionations are aligned with the recommendations of the main clinical practice guidelines. The ESTRO guidelines for spinal metastases recommend delivering a biologically effective dose (BED₁₀) of at least 50Gy. More specifically, for bone metastases, international guidelines propose 20-24Gy in single fraction, 27–30Gy in 3 fractions and 30–35Gy in 5 fractions. For lung and liver metastases, higher doses are advisable (BED₁₀>100Gy)”.

Tables and Data Presentation

Thank you for this comment. We agree that the content and presentation of Table 2 could be improved. We have revised, simplified and improved the content to make it less dense and of higher quality.

Minor Comments

Some sections of the manuscript contain minor grammatical inconsistencies and stylistic issues, likely related to translation or editing. A thorough language revision is recommended.
A few terms appear in mixed language (e.g., “sincrónico” / “metacrónico”), which should be standardized to English terminology.
Several abbreviations should be defined at their first occurrence in the text, even if they are later included in the abbreviation list.
The manuscript could benefit from improved flow between sections, particularly when transitioning from clinical evidence to disease-state classifications.
Some references appear to be repeated or cited inconsistently, and the reference list should be carefully checked for formatting consistency.

Dear reviewer, thank you for all these comments. We have carefully reviewed the manuscript in order to solve grammatical and language inconsistences. We have also checked and corrected all the references in order to follow the journal stylish recommendation and to avoid inconsistences.

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

Title - clearly depicting the essence of the study - No Remarks

Abstract - a concise summary of the manuscript - No remarks

Introduction - an in-depth analysis of the literature on the subject with focus on MDT and SBRT, which seamlessly integrates with Paragraph 2 - SBRT: technical and radiobiologic principles - No remarks

SBRT: technical and radiobiologic principles - a concise technical description of the SBRT concept - further solidifying its role in MDT in oligo-met state in PC - No remarks

Current clinical evidence of SBRT in oligometastasic disease - a review of the founding studies in SBRT usage in PC - a comprehensive analysis of MDT with included SBRT in different clinical scenarios. Especially beneficial for the manuscript, in this reviewer`s opinion, is the global assessment on safety and effectiveness in all this different studies - No remarks

Role of SBRT according to the subtype of oligometastasic prostate 250 cancer patient - in this chapter additional nuances are discussed - Oligorecurrence, Oligopersistence, and Oligoprogression as different clinical entities; hsPC and hrPC - this further enhance and clarify SBRT role - No remarks

Critical evaluation of current evidence - a cornerstone paragraph which discusses the significant heterogeneity in the literature, regarding usage of SBRT as a MDT in PC, as well as solidifying the need for future large-scale studies with standardized protocol. Those findings are further discussed in next chapter 6. Future directions with results from ongoing phase III trials - No Remarks

7. Conclusions - with a step-by-step approach, the authors have substantiated their conclusions, as well as future directions for development - No remarks

Author Response

We would like to thank the reviewer for their careful report and their comments section by section.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Nu Major Comments

1. Discussion of Heterogeneity in Oligometastatic Definitions

The authors have expanded the discussion regarding the variability in definitions of oligometastatic disease (≤3 vs ≤5 lesions) and its implications for clinical trials and patient selection. This addition improves the manuscript and highlights an important methodological issue when interpreting results across studies.

However, the discussion could be strengthened by briefly referencing the ESTRO/EORTC consensus classification of oligometastatic disease, which is increasingly used to standardize definitions in the literature.

2. Imaging Modalities and Staging Bias

The additional paragraph addressing the role of PSMA-PET and potential staging bias is appropriate and improves the critical interpretation of the available evidence.

This is particularly relevant because several early trials relied on conventional imaging or choline PET, which may underestimate the true metastatic burden.

The authors may consider briefly emphasizing that improved imaging sensitivity may partly explain differences in outcomes between earlier and more recent trials.

3. Integration of SBRT with Modern Systemic Therapy

The manuscript now better addresses the interaction between SBRT and contemporary systemic therapies such as ARPIs, which is an important aspect of current clinical practice.

The discussion appropriately mentions ongoing trials and guideline recommendations. This section now provides a more balanced view of SBRT within the modern multimodal treatment paradigm.

4. SBRT Dose and Fractionation

The authors have improved the discussion of dose and fractionation schedules and included ranges commonly used in clinical practice.

This clarification is helpful for readers. However, the authors may consider summarizing the most frequently used regimens in a concise sentence or small table to improve readability.

Minor Comments

The presentation of Table 2 has improved compared to the previous version, but the table still contains a large amount of information. Some simplification or clearer alignment of endpoints might further enhance readability.
The manuscript has improved in terms of language, but a final professional language edit would still be beneficial to correct minor grammatical inconsistencies.
Ensure that all abbreviations are defined at first occurrence, even if they appear later in the abbreviation list.
Some transitions between sections (particularly between the evidence review and the classification of oligometastatic disease states) could still be slightly smoother.
The reference list should be checked once more to ensure consistent formatting according to journal guidelines.

Overall Recommendation

The authors have satisfactorily addressed the main concerns raised in the initial review, and the manuscript has improved in clarity and

I recommend minor revision before acceptance.

Author Response

Dear Reviewer, thank you for your valuable comments, which have helped us improve the quality of our manuscript.

Major Comments

Discussion of Heterogeneity in Oligometastatic Definitions

Dear reviewer, thank you for pointing this out. It is of high importance that future trials select specific oligometastatic subgroups as their potential prognosis differ. We have discussed it in the manuscript to highlight its relevance.

“Besides, the consensus from the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC) classified oligometastatic disease into nine subgroups with potential prognostic differences. The classification first distinguishes between a genuine scenario, in which patients have no previous history of polymetastases, in contrast to the induced oligometastatic subgroup. Within the genuine state, patients are further categorized into de novo oligometastatic disease, when oligometastases are diagnosed for the first time, and repeat oligometastatic disease. The de novo scenario is further divided into synchronous and metachronous states, depending on whether the metastases appeared within or more than 6 months after the diagnosis of the primary tumour. Additional subgroups are established based on the presence of systemic therapy at the time of progression and on whether the lesions represent persistence or true progression of disease. Given the potential prognostic differences among these subgroups, their inclusion within the same study may introduce bias making it important to distinguish between them in future studies”.

Imaging Modalities and Staging Bias

The additional paragraph addressing the role of PSMA-PET and potential staging bias is appropriate and improves the critical interpretation of the available evidence.

This is particularly relevant because several early trials relied on conventional imaging or choline PET, which may underestimate the true metastatic burden.

The authors may consider briefly emphasizing that improved imaging sensitivity may partly explain differences in outcomes between earlier and more recent trials.

Thank you for this appreciation. We agree these imaging sensitivity differences may partially explain outcomes variations between trials and, therefore, we have highlighted it briefly in the manuscript.

“The improved sensitivity of molecular imaging and, specially, PSMA PET, may influence outcomes differences between previous studies and recent ones and this should be taken into account when interpreting the results of the phase III clinical trials that are still ongoing”

Integration of SBRT with Modern Systemic Therapy

The manuscript now better addresses the interaction between SBRT and contemporary systemic therapies such as ARPIs, which is an important aspect of current clinical practice.

The discussion appropriately mentions ongoing trials and guideline recommendations. This section now provides a more balanced view of SBRT within the modern multimodal treatment paradigm.

Dear reviewer, thank you very much for this comment.

SBRT Dose and Fractionation

The authors have improved the discussion of dose and fractionation schedules and included ranges commonly used in clinical practice.

This clarification is helpful for readers. However, the authors may consider summarizing the most frequently used regimens in a concise sentence or small table to improve readability.

Thank you for this comment. We have specified in a sentence that 30Gy in 3 fractions was the most commonly used treatment scheme (when nodal or bone metastases were treated). However, there was considerable heterogeneity, making it difficult to provide more specific regimens as predominant. We hope that the reported ranges, together with the inclusion of the most commonly used regimen in the available trials could be adequate.

Minor Comments

1. The presentation of Table 2 has improved compared to the previous version, but the table still contains a large amount of information. Some simplification or clearer alignment of endpoints might further enhance readability.

Dear reviewer, thank you for pointing this out. We have reduced the table by eliminating the “local control” column as it was a secondary objective and it was not reported in all of the studies. The year column was also avoided and we have summarized the information reported in the “primary endpoint” column. The whole Table has been reviewed in order to make it clearer.

2. The manuscript has improved in terms of language, but a final professional language edit would still be beneficial to correct minor grammatical inconsistencies.

The manuscript has been checked to correct grammatical inconsistences.

3. Ensure that all abbreviations are defined at first occurrence, even if they appear later in the abbreviation list.

Thank you for this appreciation. Certainly, a few abbreviations were not defined at first occurrence. We have checked and corrected the inconsistencies related to this matter.

4. Some transitions between sections (particularly between the evidence review and the classification of oligometastatic disease states) could still be slightly smoother.

Thank you for this comment. We agree with you and, therefore, we have made some adjustments to improve the transition between these sections.

5. The reference list should be checked once more to ensure consistent formatting according to journal guidelines.

Dear reviewer, we have checked the reference list after the changes made to ensure that the format complied with the journal’s requirements.

Author Response File: Author Response.docx