Letter to the Editor: “Quality of life and functional outcomes after rectal sparing approaches following neoadjuvant therapy for rectal cancer: a prospective cohort multicentre study”

Dear Editor,

We read with great interest the prospective multicenter cohort study by Gavaruzzi et al evaluating quality of life (QoL) and functional outcomes after rectal-sparing strategies (local excision [LE] or watch-and-wait [WW]) following neoadjuvant therapy for rectal cancer^[1^]. The authors should be commended for prioritizing patient-reported outcomes in a setting where organ preservation is increasingly pursued and where harmonized outcome reporting has been advocated^[2^]. Recent evidence syntheses comparing LE and WW after neoadjuvant therapy suggest broadly comparable rectum-preservation and oncologic outcomes, while functional trade-offs remain central to decision-making^[3^].

We would like to seek clarification on a few analytic and interpretative points that may help readers to better understand the between-strategy comparisons – particularly within the clinical complete response (cCR) subgroup.

First, in Figure 3 (cCR subgroup), the LE versus WW comparison for “blood and mucus in stool” appears statistically different already at baseline (T1), and the overall difference over time may therefore partly reflect a pre-intervention imbalance rather than a post-approach effect^[1^]. Could the authors clarify whether the mixed-effects models were parameterized to estimate (1) differences in change from baseline, or (2) differences in mean scores averaged across all time points? If the latter, it might be informative to provide baseline-adjusted group-by-time contrasts (LE vs WW at T2 and T3, with confidence intervals) or a change-from-T1 analysis, to help distinguish persistent baseline symptoms from any incremental effect associated with LE.

Second, a meaningful proportion of patients underwent additional procedures during follow-up (e.g., completion surgery after LE, including completion total mesorectal excision, and salvage interventions after local regrowth in WW)^[1^]. Because such intercurrent events can materially affect bowel function and QoL – and deterioration has been observed when WW patients ultimately require surgery^[4^] – it would be helpful to specify how these patients contributed to the T2/T3 patient-reported outcome estimates. Were analyses conducted strictly by initial strategy, censored at the time of completion/salvage surgery, or reclassified according to subsequent management? Sensitivity analyses excluding patients who underwent completion/salvage total mesorectal excision, or modeling surgery as a time-varying exposure, could further inform interpretation.

Third, the study evaluates multiple patient-reported outcome instruments and domains across several time points, and Figure 3 notes that P values were not adjusted for multiplicity^[1^]. Even with a stricter significance threshold, readers may benefit from knowing whether a primary PRO endpoint (or a hierarchical testing plan) was prespecified, and whether interpretation prioritized effect sizes and minimal important differences over nominal P values, consistent with contemporary PRO analysis recommendations^[5^].

Overall, we believe these clarifications would strengthen interpretability and comparability of this valuable work and help clinicians and patients navigate the nuanced trade-offs between LE and WW after neoadjuvant therapy. We thank the authors for their important contribution.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

This research was funded by the China Scholarship Council.

Author contributions

Writing – original draft: M.J. and M.Q. Writing – review and editing: Z.L.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Zhen Liu accepts full responsibility for the work, had access to the data, and controlled the decision to publish.

Provenance and peer review

Not commissioned.

Data availability statement

Not applicable.

AI disclosure

The authors acknowledge the use of OpenAI’s language model for grammar and language refinement during the writing process. The work has been reported in line with the TITAN criteria^[6^].