PONE-D-23-02061Early death after a diagnosis of metastatic solid cancer – raising awareness and identifying risk factors from the SEER database.PLOS ONE

Dear Dr. Urban,

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We have completed the review process for your manuscript titled "Early death after a diagnosis of metastatic solid cancer – raising awareness and identifying risk factors from the SEER database." (Manuscript ID: PONE-D-23-02061), and I would like to thank you for submitting your work to PLOS ONE.

Your manuscript was reviewed by two independent experts in the field. I have carefully considered the reviewers' feedback, which provided valuable insights into the strengths and weaknesses of your work. The reviewers' comments have highlighted both the potential for major revisions and concerns leading to a recommendation for rejection. I will summarize the reviewers' evaluations and provide guidance regarding the next steps for your manuscript.

Reviewer 1:

Reviewer 1 has provided a thorough review and identified several significant issues that need to be addressed. The reviewer has pointed out areas where clarification, further analysis, or additional experiments are necessary to strengthen the paper's claims. The reviewer's suggestions and constructive criticism offer a clear path towards improving the manuscript. I highly encourage you to carefully consider these comments and implement the proposed revisions in order to enhance the scientific rigor and overall quality of your work.

Reviewer 2:

Reviewer 2, on the other hand, expressed reservations about the manuscript and recommended rejection. While their feedback may appear discouraging, it is important to note that scientific opinions can vary, and reviewer evaluations do not always align. However, their concerns cannot be overlooked, and it is essential to carefully address them in any revision attempt. Please take their comments into consideration and attempt to address their main concerns to the best of your ability.

Considering the time in which the paper was under review, and the varying evaluations from the reviewers, I propose that you make a broad and substantial modification of the paper, in accordance with the comments of both reviewers. By addressing their concerns, you will have the opportunity to strengthen your work and increase its chances of acceptance.

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Once again, I appreciate your dedication and the significant effort you have put into your research. I look forward to receiving your revised manuscript.

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Rita De Sanctis

Academic Editor

PLOS ONE

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Dr Urban reports receiving consulting fees from Merck, Sharpe & Dohme, Roche Israel, Takeda, Nucleai, Rhenium Oncotest, and lecture fees from Astrazeneca, Merck, Sharpe & Dohme, Roche, Takeda, Bristol Myers Squibb, and Merck Seronoe. Dr Globus reports receiving lecture fees from Pfizer Lilly, Roche, Astra Zeneca, Novartis, Gilead, and Merck, Sharpe & Dohme, consulting fees from Lilly, Gilead and Novartis, and expenses for conferences from Pfizer, Medison, Rhenium Onctotest, and Gilead. Dr Sagie, Levina, and Brachana report no potential conflicting interests.   

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The Authors present the results of a very interesting analysis of the SEER database. The methods are sound and the results - the main of which is, one fifth of de novo diagnosed cancer patients die withih the first two months since diagnosis - deserve dissemination.

I can offer the following comments:

- the analysis spans from 2004 to 2016. Twelve years in which the early death rate decreased by 4%. Which are Authors' expectations for the last 6 years, 2017-2023, taking into account also the pandemic period?

- Table 1, the results do not match with the text (e.g., 54.3% of those with early dying appear to be women, but the same figures was reported for men in the text). In the same Table, what does the p-value for race refer to? there seem to be major differences in terms of ethnicities in the overall population, but no in the early vs non early mortalty groups (e.g., 80.2% of patients with early morality was white, compared with 78.2% in those without early mortality - a difference unlikely to be significant). Can the Authors carefully reconsider all data?

- the Authors should always clarify that their findings apply to patients with de novo diagnosed metastatic solid cancer (see for instance the first paragraph of the Discussion, this is not clear).

Minor:

- Why does the Introduction start with a word on cancer death rate in the US? (the Authors are from Israel and Cyprus). Can this be generalized?

- Can the Authors expand on the SEER database?

- in the sentence (Results section) 'Patients that died early were older (70 vs 65), more frequently male (54.3% vs 51.5%), had lower income (56.8% vs 54.9% had an income below $65K a year) and more frequently had brain (15% vs 12.9%), lung (49.2% vs 33.5%) and liver metastasis (33.5% vs 28%).', do the Authors mean 'than those who died after two months since diagnosis'?

- Quality of figures should be improved.

Reviewer #2: This a retrospective study based on available SEER data, investigating factors of early mortality (2-months) in solid tumors. As a general comment, I believe that the clinical question regarding the drivers of early mortality is crucial, but it is extremely difficult to assess in a cohort of patients with different solid tumors. Indeed, the biology, the response to treatments, the diagnostic process as well as symptoms and possible complication cancer and treatment related significantly differ across cancer subtypes. Therefore, it is difficult to draw generalized conclusions for all solid tumors. In addition, treatment information is missing, and as well as adverse events that may have a role in early mortality. Another missing element that can affect mortality is comorbidities status: patients with a compromised general status or organ impairment due to other diseases are expected to be more likely to rapid decline. An example is COPD in patients with lung cancer: I expect that a patient with an obstructive lung disease and lung cancer is more likely to develop respiratory failure than a patient with normal respiratory function at the time of the cancer diagnosis. In addition, the choice of cut-off of 2 months have created an intrinsic selection bias for aggressive cancer more likely to develop rapid progression. Indeed, authors in the discussion states that 2 months is the usual cut-off to see response in patients in solid tumors. If the baseline is date of biopsy as it seems, this means that patients had the time to probably received 1 cycle of therapy (in average, 1-2 weeks for pathology report, 3-4 weeks to have genomic profile/biological characterization of the tumor). With 2 months as cut-off, many patients with potentially early death are missed. Ideally, for accuracy, the cut-off for early death should be defined according to the cancer subtype.

Another issue difficult to overcome in this type of analyses is the following: how is cancer-related death defined? This information should be included in the methods since it is the main objective of the study. In cancer patients, death can be associated with different scenarios including organ failure due to cancer invasion, or secondary consequences of the cancer dissemination (i.e. hypercoagulative state, compression issues etc..). This element is difficult to retrieve from SEER published data.

Authors specified that they included only metastatic de novo, but they do not explain why. This choice introduces another selection bias: there is a potential underestimation of early death in those cancer subtype who are less likely to present as de novo (for example, head and neck cancer, that are actually expected to progress rapidly and be lethal for loco-regional complications).

The results are consistent with what expected: higher prevalence of pancreatic cancer and lung cancer, presence of visceral metastases, advanced age, and lower income were associated with early death (the latter element, very relevant form policy standpoint and has not been properly commented in the discussion). In the discussion section, it is not clear what is the main finding (new finding) and comments on clinical implications are questionable. In my opinion, palliative support needs to be activated in all patients with symptoms, in parallel to the active treatment regardless of if patient it is at risk of early death. I provide a similar argument for invasive diagnostic procedure: for the “primum non nocere” principle, less invasive procedures should be considered for all patients. Liquid biopsy can be diagnostic only for some cancer subtype (i.e. colon cancer, lung cancer) and it is not validated for all type of solid tumors, and in those case in which is validated, it has been performed as standard of care and routinely at the diagnosis for all patients. On the other hand, if a patient is considered ineligible for any active treatment for performance status/organ impairments, nor invasive nor non-invasive (but high cost) procedures should be recommended. This decision needs to be established case by case and cannot be generalized. There are some situations in which the effectiveness of the cancer treatment is impressive and the toxicity burden relatively low (for example immunotherapy in melanoma), where the treatment can significantly improve survival of patients also in case of extensive organs involvement. Therefore, I do not believe we can extrapolate from this analysis any factor that can drive or help the difficult decision of omission of active treatment, that should be taken with the patient, after extensive discussion, and influenced by many different variables.

I suggest running a median survival for all de novo patients, similarly as it has been done in this paper recently published on JNCI, https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djad020/7086066. Another way to improve the quality of the work and the message delivered could be to limit the analysis to a few cancers subtype with a similar prognosis.

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Reviewer #1: Yes: Luca Giacomelli

Reviewer #2: No

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Early death after a diagnosis of metastatic solid cancer – raising awareness and identifying risk factors from the SEER database.

PONE-D-23-02061R1

Dear Dr. Urban,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Mirosława Püsküllüoğlu, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The Authors did a great job in addressing my comments and those of the other reviewer. I think that this paper will be a major contribution to the field.

Reviewer #2: Thanks so much for the detailed response.

I do not have additional comments.

All point have been properly addressed.

The early mortality in solid tumor is an important data that is missing in literature.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Luca Giacomelli

Reviewer #2: No

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