Long-Term Oncological Outcomes in Metastatic Prostate Cancer Patients Who Are Able to Maintain/Recover Ongoing Anticancer Therapy After SARS-CoV-2 Infection—Results of the MEET-URO 22 Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The objective of this report was to evaluate the long-term oncological outcomes of patients with metastatic PC who were undergoing medical therapy at the time of contracting SARS-CoV-2 and who resumed/continued medical therapy after recovery. A critical flaw of the study is the lack of a direct comparison group (e.g., a metastatic PC patient population that did not contract SARS-CoV-2).  Comparing survival outcomes in this patient population to similar patient populations reported in the literature does not constitute a scientific study. In addition to the flawed study design, there is no substantive information on the timing, duration and severity of the SARS-CoV-2 infections the study population experienced. 

Finally, the authors appear to be confused about their study conclusion. The second to last sentence in the abstract states, "SARS-CoV-2 infection does not appear to have had an adverse effect on long-term oncological outcomes". However, the last sentence of the manuscript reads as follows, "Our findings suggest that SARS-CoV-2 infection negatively impacts long-term oncological outcomes for patients who had been able to maintain/resume their own anticancer therapy after recovering from the infection." These two statements are in complete disagreement with each other and suggests the authors are unsure of their study results.

Author Response

• A critical flaw of the study is the lack of a direct comparison group (e.g., a metastatic PC patient population that did not contract SARS-CoV-2).  Comparing survival outcomes in this patient population to similar patient populations reported in the literature does not constitute a scientific study. In addition to the flawed study design, there is no substantive information on the timing, duration and severity of the SARS-CoV-2 infections the study population experienced. 

Reply: We fully acknowledge the limitations of our work, as highlighted by the reviewer in the comments. All these limitations have been recognized in the discussion. (lines 467-483)

 

• The authors appear to be confused about their study conclusion. The second to last sentence in the abstract states, "SARS-CoV-2 infection does not appear to have had an adverse effect on long-term oncological outcomes". However, the last sentence of the manuscript reads as follows: "Our findings suggest that SARS-CoV-2 infection negatively impacts long-term oncological outcomes for patients who had been able to maintain/resume their own anticancer therapy after recovering from the infection." These two statements are in complete disagreement with each other and suggest the authors are unsure of their study results.

Reply: Thanks for this observation. The confusion was due a typo error, which was corrected in the revised version of the manuscript (line 495)

Reviewer 2 Report

Comments and Suggestions for Authors

1. It is recommended to incorporate multivariate analysis to evaluate the independent effects of infection severity, duration, and other relevant factors on survival outcomes.
2. A stratification of tumor treatment modalities is advised, with comparative analyses of survival outcomes post-infection across different treatment types, including ARPI, chemotherapy, and ADT.
3. It is suggested to provide a detailed rationale for the sample size estimation to enhance methodological transparency.
4. The conclusion that "SARS-CoV-2 infection negatively impacts long-term oncological outcomes" appears inconsistent with the overall findings presented in the manuscript and should be reconsidered for accuracy.

Author Response

• It is recommended to incorporate multivariate analysis to evaluate the independent effects of infection severity, duration, and other relevant factors on survival outcomes.

Reply: Thanks for this suggestion. We performed the suggested multivariate analysis as described in the revised manuscript. (line 164 – lines 304-307). The analysis was not performed in mHSPC population due to the small number of patients evaluated.

• A stratification of tumor treatment modalities is advised, with comparative analyses of survival outcomes post-infection across different treatment types, including ARPI, chemotherapy, and ADT.

Reply: We are grateful for this suggestion. A comparison of post-infection survival outcomes was performed by aggregating treatment types as commented (ARPI, chemo, and ADT). (table 4)

• It is suggested to provide a detailed rationale for the sample size estimation to enhance methodological transparency.

Reply: We fully agree with this observation. However, the high heterogeneity of ongoing treatments at the time of SARS-CoV-2 infection (different treatment lines, different agents) made it impossible to estimate a preliminary sample size.

• The conclusion that "SARS-CoV-2 infection negatively impacts long-term oncological outcomes" appears inconsistent with the overall findings presented in the manuscript and should be reconsidered for accuracy.
• Reply: Thanks for this observation. The confusion was due a typo error, which was corrected in the revised version of the manuscript (line 495)

Reviewer 3 Report

Comments and Suggestions for Authors

This study explores an important and novel clinical question and provides valuable data. However, the major issues mentioned above, particularly the contradictions in the core conclusions and the inadequate handling of selection bias, are significant shortcomings of the manuscript. Only after the authors satisfactorily address these issues, especially by revising the conclusions, fully discussing limitations, and improving the rigor of the results interpretation, will the manuscript be worthy of acceptance.

The specific content is as follows:

1. There are inconsistencies in the abstract (Lines 48-50 and 72-74), discussion (Lines 474-476), and conclusion (Lines 483-485). This constitutes a serious logical fallacy. Based on the data and discussion throughout the text, the intended message should be "no negative impact." The author must carefully proofread and revise the entire text to ensure that the conclusions are consistent with the data and discussion sections. The current conclusion section is seriously misleading to the reader.
2. A key limitation of this study is its patient selection. The study only included patients who survived infection and were able to recover/maintenance therapy (76.8% of the initial cohort). This means that the results are not applicable to the entire mPC population infected with SARS-CoV-2, but only to a subgroup with relatively better prognosis.
3. Patients who died from the infection (12.6%) or were unable to resume treatment after recovery due to their physical condition (10.6%) were excluded from the long-term outcome analysis. This inevitably introduces a significant selection bias. The authors need to emphasize this point more clearly in the discussion and limitations sections, explicitly stating that the findings of this study can only be extrapolated to a group of patients whose clinical condition is sufficiently stable after infection and who are able to continue anti-cancer treatment. Comparing the survival data of this study with a matched cohort of uninfected SARS-CoV-2 patients, or conducting some exploratory analysis with patients unable to resume treatment as a control group, would greatly strengthen the argument, but given the retrospective nature of the study, this may be difficult to achieve. At the very least, it must be adequately discussed in the text.
4. The authors repeatedly compared the survival data from this study with data from historical pivotal clinical trials, concluding that the results were "consistent." While this provides useful background information, caution is advised.These comparisons were not randomized, and the study cohort differed significantly from strictly controlled clinical trial populations in baseline characteristics, lines of treatment, and follow-up. For example, the piPFS and OS data for mCRPC patients receiving first-line ARPI therapy appear promising, but this largely reflects the generally good prognosis of this patient population (first-line treatment, ARPI-sensitive) rather than demonstrating that infection has no impact. It is recommended to adjust the wording, changing from "Our results were consistent with these data." to a more cautious statement, such as "In the selected patients who were able to resume treatment, the survival outcomes we observed were similar to the range of historical data reported in pivotal clinical trials, suggesting that SARS-CoV-2 infection may not have led to a significant deterioration in long-term oncology outcomes in these patients." Meanwhile, explanations regarding situations where direct comparisons were not possible should be strengthened.
5. The caption in Figure 1 is unclear. The bar charts in the figure need clearer labels to explain the specific grouping each bar represents (e.g., "Treatment evolution by hospitalization status" and "Treatment evolution by treatment type"). The current state makes it difficult for readers to understand intuitively.
6. Figure 2-6 is informative, but some text is too small or overlaps; readability should be optimized.
7. The introduction could more concisely state the purpose of this study and the gaps it fills. While the discussion is comprehensive, it is somewhat lengthy, and some background information on ADT and TMPRSS2 could be simplified to better focus on the main findings of this study.
8. Line 194, Please confirm that "SPPS" is not a typo for "SPSS".
9. The manuscript is generally readable, but there are some minor grammatical and expressive inaccuracies. It is recommended that it be polished by a native English speaker or a professional editing service.

Author Response

1. There are inconsistencies in the abstract (Lines 48-50 and 72-74), discussion (Lines 474-476), and conclusion (Lines 483-485). This constitutes a serious logical fallacy. Based on the data and discussion throughout the text, the intended message should be "no negative impact." The author must carefully proofread and revise the entire text to ensure that the conclusions are consistent with the data and discussion sections. The current conclusion section is seriously misleading to the reader.

2. Reply: Thanks for this observation. The confusion was due a typo error, which was corrected in the revised version of the manuscript (line 495)

1. A key limitation of this study is its patient selection. The study only included patients who survived infection and were able to recover/maintenance therapy (76.8% of the initial cohort). This means that the results are not applicable to the entire mPC population infected with SARS-CoV-2, but only to a subgroup with relatively better prognosis.

Reply: We fully agree. This limitation was acknowledged in the revised manuscript. (lines 471-474)

1. Patients who died from the infection (12.6%) or were unable to resume treatment after recovery due to their physical condition (10.6%) were excluded from the long-term outcome analysis. This inevitably introduces a significant selection bias. The authors need to emphasize this point more clearly in the discussion and limitations sections, explicitly stating that the findings of this study can only be extrapolated to a group of patients whose clinical condition is sufficiently stable after infection and who are able to continue anti-cancer treatment. Comparing the survival data of this study with a matched cohort of uninfected SARS-CoV-2 patients, or conducting some exploratory analysis with patients unable to resume treatment as a control group, would greatly strengthen the argument, but given the retrospective nature of the study, this may be difficult to achieve. At the very least, it must be adequately discussed in the text.

Reply: We fully agree. This limitation was acknowledged in the revised manuscript. (lines 481-483)

1. The authors repeatedly compared the survival data from this study with data from historical pivotal clinical trials, concluding that the results were "consistent." While this provides useful background information, caution is advised.These comparisons were not randomized, and the study cohort differed significantly from strictly controlled clinical trial populations in baseline characteristics, lines of treatment, and follow-up. For example, the piPFS and OS data for mCRPC patients receiving first-line ARPI therapy appear promising, but this largely reflects the generally good prognosis of this patient population (first-line treatment, ARPI-sensitive) rather than demonstrating that infection has no impact. It is recommended to adjust the wording, changing from "Our results were consistent with these data." to a more cautious statement, such as "In the selected patients who were able to resume treatment, the survival outcomes we observed were similar to the range of historical data reported in pivotal clinical trials, suggesting that SARS-CoV-2 infection may not have led to a significant deterioration in long-term oncology outcomes in these patients." Meanwhile, explanations regarding situations where direct comparisons were not possible should be strengthened.

Reply: Thanks for this constructive suggestion. These considerations were incorporated and detailed in the revised manuscript. (abstract-simple summary- discussion)

1. The caption in Figure 1 is unclear. The bar charts in the figure need clearer labels to explain the specific grouping each bar represents (e.g., "Treatment evolution by hospitalization status" and "Treatment evolution by treatment type"). The current state makes it difficult for readers to understand intuitively.

Reply: To improve readability, data described in the figure were detailed in the table 2

1. Figure 2-6 is informative, but some text is too small or overlaps; readability should be optimized.

Reply: We agree. The figures were moved to the appendix to increase their size and readability.

1. The introduction could more concisely state the purpose of this study and the gaps it fills. While the discussion is comprehensive, it is somewhat lengthy, and some background information on ADT and TMPRSS2 could be simplified to better focus on the main findings of this study.

Reply: We agree. The introduction was shortened and discussion simplified

1. Line 194, Please confirm that "SPPS" is not a typo for "SPSS".

Reply: We agree. The error was corrected

1. The manuscript is generally readable, but there are some minor grammatical and expressive inaccuracies. It is recommended that it be polished by a native English speaker or a professional editing service.

Reply: We agree. The text was extensively revised

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Authors have adequately addressed the limitations of their study design in the discussion section. In methods section of the abstract, they need to clearly state that the 151 metastatic PC patients in their study have a history of a SARS-CoV-2 infection.

Comments on the Quality of English Language

none

Author Response

In methods section of the abstract, they need to clearly state that the 151 metastatic PC patients in their study have a history of a SARS-CoV-2 infection.

Response: We agree. The abstract was modified accordingly.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have responded to and revised their comments one by one. Therefore, I recommend that it be published.

Author Response

The authors have responded to and revised their comments one by one. Therefore, I recommend that it be published.

Reply: Thank you for your endorsement