The use of 5‐fluorouracil in the prevention of tendon adhesions: A systematic review

Abstract Background This systematic review aims to study the effectiveness of 5‐fluorouracil (5FU) in the reduction of tendon adhesions postsurgical repair. Method A systematic review was performed involving four databases, Cochrane, PubMed, MEDLINE, and Embase, looking for evidence of at least Level I or Level II (according to NHMRC) in the use of 5FU in tendon repairs in human or animal studies. Results Across the four databases 546 articles were identified. Of these 12 were identified as relevant, with a further two being excluded after in depth review. Conclusions Nine of the 10 studies showed that 5FU was effective at reducing tendon adhesions in their respective animal studies. One of the 10 studies showed no significant change compared to the control group.


| INTRODUC TI ON
The burden of tendon injuries places a tangible strain on the patient, the economy, and the hospital system. It is a significant source of socioeconomic stress and can have a pronounced effect on the daily life of those who suffer these injuries. 1 After the initial injury, tendon adhesions often further hamper recovery, with the injured tendon often permanently losing strength and functionality. 2 Despite this, a treatment that reliably, safely and effectively treats tendon adhesions still remains elusive.
Research into this area has produced many suggestions as to how this problem is best solved, recognizing that good surgical technique must go hand in hand with the modulation of the healing response. 3 In this regard, 5-fluorouracil has been identified as a drug that is able to modulate the immediate inflammatory response, from only a single application with no systemic side effects. 4 Indeed its use in ophthalmic surgery has similarly shown to produce a longterm reduction in the presence of scarring after glaucoma surgery. [5][6][7] It is with this in mind that the authors have undertaken a systematic review of the current literature to assess the effectiveness of the use of topical 5FU in a "single touch" technique on the reduction of adhesion formation in repaired tendons.

| ME THODS
This systematic review aims to investigate the following population, intervention, control, and outcome question: in humans, cadaveric, and animal models, undergoing tendon repairs, compared to control techniques, what is the efficacy of the use of 5FU in preventing postoperative tendon adhesions?
To address this, we performed a systematic review of the avail-  excluded because it was a non-randomized experiment looking at the correlation with reducing the coefficient of friction in unrepaired tendons with three synthetic agents including 5FU. Ten articles were then reviewed independently by two authors and data extracted.
An attempt was made to identify common outcome measure(s) across all studies analyzed. However several different clinical outcome measures were used for assessment including inflammatory response, work of flexion, synovial thickening, and tendon load.
Studies subject data, treatment dose, significance level, follow-up, and conclusions were analyzed. A P < .05 was a priori deemed statistically significant. The lack of subject-level specific data and heterogeneity in outcome reporting precluded meta-analysis.  Table 3. The focus on 5FU in these studies reflects the desire to modify the activity of fibroblasts, which play a vital role in the formation of adhesions. As an antimetabolite it modifies adhesion formation by inhibiting the proliferation of inflammatory cells and inhibits the invasion of fibroblasts from outside of the tendon, extrinsic fibroblasts. 2,11,13 Despite the initial necessity of the formation of scar tissue for the physical joining of the injured tendon, the studies in this review did not report that the use of 5FU resulted in a weaker tendon. The reduction of adhesions in the early phase of repair during immobilization with this agent in the studies is promising without compromising repair.

| RE SULTS
Nine of the 10 articles concluded that there was benefit to using   Although not all studies were designed with the same primary objective, most of them overlapped in the three main areas listed above. This is a representation of the outcomes measured in the nine positive articles

TA B L E 3 Continued
the studies that were assessed focused only on a window of up to 6 weeks without mobilization techniques.

| CON CLUS ION
Nine of the 10 articles assessed reported the benefits of 5FU in reducing tendon adhesions postsurgery. Thus, after reviewing the literature and finding congruency across the spectrum of relevant articles it can be asserted that 5FU is of benefit in reducing tendon adhesions and could well indeed find a place among the treatment approaches for reducing tendon adhesions. The results highlight this approach as an avenue that warrants further investigation in the way of human-focused trials.

CO N FLI C T O F I NTE R E S T
None.

AUTH O R CO NTR I B UTI O N
The main contributors to the article were ON and AS with constant input and guidance from the senior author DN. All the authors have read and approved the final manuscript.