Clinical Delays and Comparative Outcomes in Younger and Older Adults with Colorectal Cancer: A Systematic Review

Round 1

Reviewer 1 Report

This is an interesting paper. The authors are transparent with the heterogeneity and biases of the available data for analyses. The main conclusion is important, that efforts to mitigate delays should focus on the pre-diagnostic interval. Current formatting obfuscates this.

Major concerns:

1.       There are numerous delays encompassed by the 39 included studies. Two are most relevant and include ‘symptoms to diagnosis’, and, ‘diagnosis to treatment’. The authors may wish to present papers and results that allow them to directly address these two intervals and then ‘other’ intervals. Currently, a number of overall interval studies are presented (line 206-215). It may be more effective to first present (symptom to diagnosis)  line 216. In the methods the authors may wish to consider using ‘Stage at presentation’ as a proxy for ‘symptom to diagnosis’ delay. These results on stage – the only metaanalysis in the study - could be included as a separate paragraph in the section presenting narrative results on ‘symptom to diagnosis’. The next section could then present data on ‘diagnosis to treatment’. The final section could present data on other intervals the authors deem important to review. If appropriate, decisions can be described in the methods that allow studies to be slotted into one of the above first two intervals. For example, the Majano study would use ‘first investigation’ as a proxy for ‘diagnosis’, and ignore the interval ‘first investigation to diagnosis’.  Figure 2 is then less important, or may still be presented but to support the above distillation of the studies to focus on the two intervals.

2.       If the authors agree with the above, the abstract and methods should be re-worded to emphasize this flow.

 The defining of stage III and IV as advanced should be tested using sensitivity analysis. In most series, 5-year survival for stage III colorectal patients is approximately 70% and drops to the single digits for stage IV patients. Stage I-III could be compared to IV in a sensitivity analysis and the results appropriately interpreted.

Minor concern:

 Approximately 75% of observations in the study come from the Gabriel 2017 study. This should be discussed and possibly included as a limitation.

Author Response

Thank you for your close reading of our manuscript. We appreciate the opportunity to continue with our submission to Current Oncology.  Please check the attachment for the reply.

Author Response File: Author Response.pdf

Reviewer 2 Report

Overall, this is a clear, concise, and well-written manuscript. The authors have performed an extensive literature review to compare delays and outcomes between younger and older adults with CRC. Sufficient information about the previous study findings is presented for readers to follow the present study rationale and procedures. The methods are generally appropriate, although the addition of a few variables would strengthen the conclusions if available. Overall, the results highlight the heterogeneous availability of literature on delay intervals in CRC. The authors must be congratulated on this herculean task of compiling the literature.

The two major conclusions reported by the authors are:

1. Fourteen studies (36%) found significantly longer delays among younger adults, and nine (23%) found shorter delays among younger patients.

2. Younger adults had higher odds of advanced stage (OR 1.76). Longer delays among younger adults with CRC occur before diagnosis.

The authors make a systematic contribution to the research literature in this area of investigation. Overall, this is a high-quality manuscript with implications for developing, developing, and implementing high-value research in combating the rising incidence of CRC in younger adults. Specific comments follow.

Major Comments:

1. Please mention in your limitations that the study did not assess the impact of the pandemic on delay intervals. Most literature on care delays has been published during the pandemic.

2. While very likely that younger adults face significant delays, the literature on pre-diagnostic delays includes very few younger adults. 

Author Response

Responses to Reviewer 2

Thank you for your close reading of our manuscript. We appreciate the opportunity to continue with our submission to Current Oncology. Please see the response below:

Major Comments:
1. Please mention in your limitations that the study did not assess the impact of the pandemic on delay intervals. Most literature on care delays has been published during the pandemic.

This has been added to the Discussion in the limitations section: 

We did not include studies reporting on care provided during the COVID-19 pandemic, and our results may not be applicable to delays experienced in this context.

2. While very likely that younger adults face significant delays, the literature on prediagnostic delays includes very few younger adults.

Thank you for the suggestions. We have added the following sentence to the limitations section:

As discussed, comparisons of pre-diagnostic intervals include few younger adults and conclusions with respect to these intervals are likely limited by low power.