Preliminary results from randomized control trial point toward the utility of neurotization in innervated breast reconstruction

We extend our congratulations to Dr. Bubberman and colleagues (1) on conducting one of the pioneering randomized control trials (RCTs) on sensory nerve coaptation in autologous breast reconstruction (ABR). Preliminary analysis of their study led the authors to conclude that sensory nerve coaptation leads to superior sensory recovery in deep inferior epigastric artery perforator (DIEP) flaps than controls without nerve coaptation. This is based on the findings that sensory nerve coaptation leads to increased sensitivity to Semmes-Weinstein monofilaments (SWM) and heat-pain perception at 24 months postoperatively compared to non-innervated breasts and that innervated breasts exhibited lowered touch thresholds without heightened risk of adverse events.

The authors deserve to be commended for their high quality of research, which represents a significant advancement in the field of breast reconstruction and holds great promise for improving patient outcomes. As they continue the study and move towards its completion, we believe there are four important points to be considered: differences between the control and intervention groups, the use of “as treated” analysis, the impact of irradiation, and the objective measures of sensation.

The first point is that in this preliminary analysis there are notable differences between the control and intervention groups. Specifically, a higher proportion of breasts in the control group underwent irradiation compared to the treatment group—approximately 47% versus 21%. There are also discrepancies in demographics, with the control group being older on average, and in reconstructive sequence, as the treatment group more frequently underwent immediate reconstruction. While these disparities may reflect the interim nature of this analysis of the RCT, it is crucial they are addressed and discussed in the final analysis.

The second point is that the authors employed an “as treated” analysis of patients enrolled in the study, which compromises the randomization of the interim results by reassigning patients, who were originally randomly assigned, in a non-blinded fashion. This introduces potential selection bias and confounding variables into the study. Although the authors compared complication rates between the “as treated” cohort and the “intention to treat” cohort, no further analysis was conducted. A comparison of sensation recovery outcomes between these two groups would have enhanced transparency, even if no statistical difference was found. The assumption that nerve coaptation failure never occurs underlines this “as treated” approach, threatening its validity. A previous study, written by Smeele and colleagues (2) from the same group explored the rate of coaptation failure in relation to various levels of surgeon experience with this technique. They found that failure rates ranged from 21% to 78%. Similarly, a systematic review and meta-analysis by Shiah and colleagues (3), which examined neurotization in ABR, reported a success rate of 90% across nine pooled studies. While this review covers a variety of neurotization techniques, over half of the studies included direct neurotization. These studies suggest that the failure rate of neurotization in ABR is not negligible, as Dr. Bubberman and colleagues assume in their preliminary “as treated” analysis.

The third point pertains to the ongoing debate about the impact that irradiation of breast tissue and skin has on sensation. The authors acknowledge the literature suggesting less favorable sensation in irradiated breast tissue, however, they also reference a prior study from their group which reported that breast sensibility is not significantly affected by radiation therapy. Specifically, Beugels and colleagues (4) found no statistically significant difference in sensation recovery in irradiated versus non-irradiated breasts on univariate or multivariate analysis. They propose that this may be due to the maximal excision of irradiated skin during mastectomy and reconstruction, thereby mitigating the effect that radiation has on sensation. While this explanation is plausible, several recent studies contradict this finding, reporting poorer sensation in irradiated breasts. For instance, Djohan and colleagues (5) identified a history of radiation therapy as a significant factor associated with decreased sensory recovery in patients who underwent neurotization in ABR. This discrepancy highlights the need for future controlled and randomized trials to thoroughly investigate the relationship between radiation therapy and breast sensation in ABR. Although addressing this issue was not the primary aim of the current study, Dr. Bubberman and colleagues are in a position to leverage their randomized data to conduct a sub-group analysis. By comparing irradiated versus non-irradiated breasts within both the treatment and control groups, they could provide valuable insights into the effects of radiation therapy on sensory recovery. We strongly encourage the authors to include such an analysis in their finalized study as it could significantly clarify the impact of radiation therapy on breast sensitivity in ABR.

Finally, the fourth point concerns the objective measures of sensation used in this RCT, as well as in the broader neurotization literature. The current study addresses tactile thresholds using SWM and a pressure-specified sensory device (PSSD), and thermal thresholds with a PATHWAY Model advanced thermal stimulator (ATS) device. However, there is no universally accepted methodology for objectively measuring sensation in the breast following breast reconstruction, leading to significant variation in reported outcomes. Shiah and colleagues (3) highlight this variation in their systematic review of 23 studies on neurotization in breast reconstruction. Consistent with the methods of Bubberman and colleagues, approximately 74% of studies utilized SWM as the primary assessment tool, by far the most common measure. Additionally, 52% of studies assessed temperature discrimination and, 13% used PSSD. Other measures included assessment of two-point discrimination with a Disk-Criminator (35% of studies), vibratory sensation with tuning forks (26%), sharp and dull sensation (22%), pain thresholds (17%), and somatosensory-evoked potentials (13%). While the variation in assessment tools is not a limitation specific to the current study, it underscores a broader issue in the field, namely, the lack of standardized measures for neurotization in innervated breast reconstruction. To enhance the relevance of these objective measures and better connect them with clinical outcomes, it would be beneficial to relate these assessments to patient-reported outcomes, such as those measured in the BREAST-Q questionnaire. Notably, a previous paper by Bijkerk and colleagues (6) from the same group found that BREAST-Q scores improved in patients who received sensory nerve coaptation. However, they also reported that the BREAST-Q at the time of the study (2016–2019) did not adequately capture sensation, indicating the need for a new, validated scale. In 2021, Tsangaris and colleagues (7) introduced the BREAST-Q Sensation Module to address this gap. Unfortunately, the current paper, initiated in 2019, predates this update and thus uses the BREAST-Q reconstructive module instead. The current study did not report BREAST-Q results in this interim analysis due to an inadequate sample size. Nonetheless, we commend the authors for incorporating the BREAST-Q to study patient-reported outcomes and recommend retrospectively applying the BREAST-Q Sensation Module at the study’s conclusion to better assess the impact of sensory nerve coaptation on sensation recovery.

We look forward to the forthcoming publication of the completed RCT. We commend Dr. Bubberman and colleagues for being among the first to conduct such a trial on neurotization in innervated breast reconstruction—a significant advancement in the effort to preserve sensation in ABR. This work represents an exciting next step forward in improving patient outcomes. We again emphasize the need for a standardized methodology to assess sensation in innervated breast reconstruction and encourage future RCTs to build upon this groundbreaking research and continue striving to enhance clinical outcomes.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article has undergone external peer review.

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Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-458/coif). The authors have no conflicts of interest to declare.

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References

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