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Page 8 of 10 Dengsoe et al. Plast Aesthet Res 2024;11:25 https://dx.doi.org/10.20517/2347-9264.2024.20

found no evidence of adverse survival among patients who started adjuvant chemotherapy up until 90 days
[11]
after surgery compared with patients starting chemotherapy within 31 days after surgery .
Similarly, another retrospective study including 2,594 patients suggests that adjuvant chemotherapy is
[33]
equally effective up to 12 weeks after surgery . This is in contrast to the findings in a meta-analysis by Yu
et al. involving seven studies and 34,097 patients. They found a 15% decrease in overall survival for every
four-week delay in the delivery of adjuvant chemotherapy and commented that adjuvant chemotherapy
should optimally be initiated 4 weeks after surgery . Another meta-analysis by Biagi et al. including 14,327
[14]
[34]
patients found a 6% decrease in overall survival for every four-week delay . The biggest mean difference in
time from surgery to initiation of adjuvant therapy between patients receiving immediate free flap
reconstruction and patients receiving mastectomy only found in this systematic review was two weeks.
Applying the findings of the two meta-analyses, a two-week delay would theoretically result in a 2%-7%
decrease in overall survival.

The included studies underline the importance of careful patient selection. These studies and the literature
in general extensively describe immediate free flap reconstruction as a potentially complex procedure that
[35]
carries a considerable risk of surgical complications . Additionally, a majority of the studies agree that
complications - especially major complications resulting in re-operation - lead to some degree of delay in
the initiation of adjuvant therapy. Based on this, it is obvious that the development of postoperative
complications, rather than the type of procedure performed, determines the initiation of adjuvant therapy.
When dealing with complex and, to some extent, fragile microsurgical procedures, it is especially important
to minimize the amount of patient-related risk factors associated with postoperative complications, such as
comorbidity, smoking, and high BMI. This is achieved by careful patient selection. Another way of reducing
the risk of postoperative complications is to use per-operative modalities, which can assist the surgeon in
intraoperative decision making. One example could be ICG-A, which is a well-known imaging modality
that can be applied to visualize the per-operative tissue perfusion. Per-operative application of ICG-A has
been reported to correlate with a decreased rate of complications and loss of reconstruction .
[36]

Study limitations
This review carries certain limitations that should be acknowledged. Most of the studies included in this
study can be described as case-control studies, generally recognized as providing an intermediate level of
evidence. Randomized controlled studies are recognized to provide the highest level of evidence but cannot
be conducted in this setting due to obvious ethical reasons. Two of the included studies [22,24] are multicenter
studies, and especially, O’Connell et al. provide eligible data based on a substantial study population,
resulting in statistically solid and reliable results . The remaining studies are all single-center studies and
[24]
are based on significantly smaller study populations, especially in the free-flap case group. All studies were
retrospective, leaving the possibility of recall bias and record accuracy. Lastly, it is worth noticing that 20
articles had to be excluded during the process of abstract screening and full-text screening because it was
not possible to obtain the full text versions. These articles could have contributed with relevant findings and
reflections on the subject.

CONCLUSION
This study proposes that immediate autologous microsurgical reconstruction is associated with a longer
time to initiation of adjuvant therapy compared to mastectomy-only, varying from 2 to 14 days. Based on
this, the clinical significance of the difference between free flap reconstruction and mastectomy-only is
predicted to be minimal or non-existing in most cases. Adjuvant therapy was initiated after four to ten
weeks in most cases - regardless of reconstruction or not - and there were only few examples of delays of