Todor Krastev

AFT for the treatment of fibrosis and scar-related conditions

This chapter uncovers new and intriguing qualities of AFT which reach beyond its obvious volume correction capabilities and explores its feasibility in the treatment of fibrosis and scars. This systematic review and meta-analysis demonstrated, like in other indications a high rate of patient (91%) and surgeon (89%) satisfaction after only 1.3 AFT procedures. The most notable findings are in outcomes measured by specific scar assessment scales such as the POSAS, which showed significant improvements in the overall scores of both the patient and observer categories, with the most pronounced difference in the scar stiffness and pliability. This suggests possible regenerative and fibrosis-reducing effects of AFT in scars and scar-tissue related conditions, which is the first convincing evidence to confirm regenerative effects of AFT from experimental research. Finally, exciting findings were noted in patients with painful scars treated with AFT, which showed a remarkable reduction in VAS scores of 3.5 points. These positive effects of AFT were not compromised by many clinical risks as the rate of complications was low- 6.4%. This means that AFT seems to be a promising treatment for fibrosis and scar-related conditions owing to its mechanical and possibly regenerative properties that these conditions profit from.

PART TWO
Chapter 5 | Efficacy of AFT in correcting contour deformities of the breast

Being the most widely studied subject in AFT, this chapter covers the wide array of congenital and acquired contour deformities of the breast that can profit from AFT treatment. Even though the predominantly positive and encouraging results of individual studies on the matter, may tempt the plastic surgeon into accepting AFT as proven effective and safe procedure, it should be noted that the evidence to back these claims is unreliable due to the fragmented, heterogeneous data from an abundant body of literature on the subject that is difficult to interpret. This chapter aimed to solve this problem through an extensive data extraction, standardisation and pooling into meta-analyses. The results demonstrated, similarly to the other indication, a high patient (94%) and surgeon (96%) satisfaction, high satisfaction scores (7.4-7.5/10) and Breast-Q scores (73/100) after only 1.5 AFT sessions. Volume retention was 52% at one year of follow-up, though long-term data is of limited quality. Only 5% of procedures resulted in clinical complications and 8.6% of breasts required biopsy due to abnormal clinical or radiological findings. These findings reflect that AFT is an effective and safe procedure for the correction of contour deformities of the breast. However, the oncological safety is still an issue that requires further investigation based on oncological cohorts with longer follow-up.

Chapter 6 | Oncological safety of AFT in breast cancer patients

This chapter consists of one of the first systematic review in the past decade that addressed the highly relevant topic on the oncological safety of AFT. Due to the scarcity of cohort studies at that moment and insufficient reporting of oncological outcomes, no meta-analysis could be warranted. Descriptive analysis revealed locoregional recurrence (LRR) incidence rates ranging between 1.35-2.19 events per year of oncological follow-up. Although the evidence is inconclusive, it did not show alarmingly high rates of LRR events after AFT, but underlines the urgent need for larger studies with control groups and longer follow-up.

Chapter 7 | Long-term results on the oncological safety of AFT in breast cancer patients

To address the issues raised by the previous chapter, a large matched-cohort study was set up in the Netherlands involving 300 breasts (in 282 patients) affected by disfiguring deformities after breast cancer treatment, which were reconstructed with AFT. In addition, 300 non-exposed controls were selected from a larger sample in the local oncological database, thereby matching the intervention cases on relevant baseline characteristics and recurrence-free follow-up. After five years of follow-up post-AFT, 8 and 11 LRR events were noted in the AFT and control groups, respectively. This resulted in a hazard ratio of 0.63, without significant difference between the groups (p=0.329). Similarly, no increased LRR rates were seen in all subgroups and in addition, AFT was not associated with increased distant recurrence and mortality rates. With respect to the overall mortality and the breast-cancer related mortality, this was quite the opposite- control patients exhibited a significantly higher rates than AFT patients. This phenomenon has also been reported in a number of cohort studies published in the past. As this could not be explained by multivariable regression analyses as well as sensitivity analyses, there is a possibility of a protective effect of AFT on mortality or more probably confounding by factors not investigated by the current and past studies. To conclude, this study demonstrates that AFT does not seem to be associated with an increased risk of LRR, which confirms the results of previous studies.

Chapter 8 | Meta-analysis on the oncological safety of AFT after breast cancer

This final paper aimed to provide conclusive evidence on the oncological risks of AFT by means of a meta-analysis of all published studies, including the matched cohort study described in Chapter 7. It consolidates oncological data from 59 studies (over 4,000 patients) consisting of seven matched cohorts, nine cohorts and 43 case-series. Separate meta-analyses were performed for each study design, in order to obtain convincing evidence by taking into account all relevant published data. The first and most important meta-analysis involved the matched-cohorts, revealing an incidence rate difference (IRD) between AFT and control groups of -0.2% per year, meaning that control patients experience on average 0.2% more LRR events per year than AFT patients. This difference was however not significant (p=0.419). Furthermore, non-matched cohorts displayed a similar IRD of -0.3% per year, which was significantly lower in AFT patients (p=0.035). Finally, meta-analysis of the remaining case-series obtained a mean raw LRR incidence rate of 0.7% per year, which falls within reported ranges of large historical cohorts (0.8-1.3%). By assessing the totality of the evidence, exposure to AFT does not seem to result in increased rate of LRR in the breast cancer patient. To be able accurately assess the oncological risks of specific subgroups or the timing of AFT, further steps need to be undertaken such as starting international collaboration toward an individual patient data meta-analysis.

Chapter 9 | Discussion and future perspectives

This chapter includes the general discussion that encompasses the findings of this thesis with respect to the efficacy and safety of AFT for the variety of indications. In addition, gaps in the current knowledge are identified that warrant investigation by future studies.