Biomedical Engineering Reference
In-Depth Information
adverse reactions such as this has been around 40% as reported
in two studies (35,170).
A similar time interval of the effects of a single dose of 5-FU
was demonstrated in an in vivo study by Uppal et al. (204),
which showed suppression of fi broblasts 4 weeks after 5-FU
treatment. These studies suggest a treatment interval of 1 month
might be appropriate. However, that has not been an effective
treatment protocol in the author's experience. In fact, much
more frequent injections (1-3 times per week) have proven to
be much more successful.
Based on pharmacokinetic studies, Haurani et al. (205)
report that 5-FU remains in the soft tissue for less than 10 days
and in the bloodstream for less than 20 minutes. Perhaps these
dynamics are more signifi cant than the time of suppression of
fi broblasts. It is metabolized and excreted by the kidney.
Uppal et al. (204) conducted a study of 11 patients with
keloids using a single application of 5-FU (25 mg/cc) for
5 minutes to the open wound following excision of keloid. The
wound was then fl ushed with saline prior to suturing with
5-0 nylon sutures. The patient served as its own control with a
second keloid excision being soaked with saline for 5 minutes
before suturing. Clinical assessment of the scars using a
numerical scoring system showed 50% improvement at
6 months compared with the control scars. Biopsies of scars at
1 month showed signifi cant reduction (
p
<0.01) in cellular
markers for cell proliferation, infl ammation, and TGF-
intralesional 5-fu
Of all the various antimetabolites that have been studied for
use as IL agents to treat keloids and hypertrophic scars, 5-FU
stands out as a uniquely effective agent.
In 1989, the senior author (REF) began a clinical investiga-
tion of the use of IL 5-FU in the management of hypertrophic
scars and keloids. Patients were initially treated with IL injec-
tions of 5-FU (50 mg/cc) in the range of 2-50 mg per treat-
ment. Monthly treatment intervals were used at the onset, but
this was found to be ineffective. Gradually, the intervals were
decreased to as frequently as three times weekly until there was
a clinical response. Once a signifi cant response was seen, the
treatment interval was gradually tapered to twice a week, once
per week, and then once every 2 weeks. Follow-up treatments
were resumed at the fi rst signs of an infl ammatory response.
Generally an injection interval of once weekly was successful
for most patients, but in general the more infl amed and indu-
rated the scar is, the more frequent the injection interval needed
to be. Through trial and error, it was found that the addition of
0.1 cc Kenalog 10 mg/cc alleviated some of the pain of injection
as well as increased the clinical effi cacy. A standard treatment
protocol is to combine 0.1 cc of Kenalog 10 mg (1 mg Kenalog)
with 0.9 cc 5-FU (45 mg) in the same syringe, making sure that
the Kenalog is well dispersed in the 5-FU. The author's initial
9-year experience involving as many as 5000 injections in
approximately 1000 scars was reported in 1999 (188).
Systemic administration of 5-FU can cause anemia, leuco-
penia, and thrombocytopenia. No systemic side effects have
been reported even with doses of 90 mg 5-FU or higher per
treatment session (35,170,188,189).
In the early 1980s, 5-FU was investigated as an adjunct to
glaucoma fi ltering surgery to inhibit scarring after the surgical
procedure (190-193) and has become a routine adjuvant as
the safety and effi cacy were demonstrated in a long-term mul-
ticenter study of 5-FU in trabeculectomy surgery (194).
It has an inhibitory effect on TGF-
1.
In vivo studies have shown 5-FU to have a dose-dependent
toxicity to fi broblasts (206). A dose of 25 mg/cc as used in this
study was considered subtoxic, but an average loss of 5% of
cells was found in tissue culture in this study. 5-FU has been
shown to halt cell growth at any stage (207) of the cell, but no
general toxicity was seen as wounds healed normally. Macro-
phage numbers were not altered.
Costa et al. (208) reported 50% improvement in 85% of
patients at 1 year after treatment with 5-FU. A recurrence rate
of 4.7% was seen at 1 year (209).
Davison et al. (199) performed a retrospective review of
patient charts having 102 keloids treated from 1999 to 2006.
There were 52 patients who were treated with 5-FU (37 mg)
combined with TAC (2.5 or 10 mg) in the same syringe with-
out excision and 4-week intervals. This group had an average
of 81% reduction in lesion volume. Those treated using the
same regimen without excision averaged 92% improvement
and those treated with excision followed by TAC averaged 73%
improvement. Symptoms resolved in 93% of patients treated
with 5-FU.
Apikian and Goodman (210) demonstrated improvement
in keloids in two patients treated with IL 5-FU.
Gupta and Kalra (211) have shown safety and effi cacy in
using 5-FU as an individual agent in the treatment of small
symptomatic keloids in 24 patients. Weekly treatments of
50-150 mg of 5-FU were used. Symptoms resolved completely
in over 70% of their patients and one-third had greater than
75% fl attening of the treated keloid. Keloids
β
-induced type I collagen
gene expression in human fi broblasts (195) and subsequent
collagen deposition. De Waard et al. (196) have shown inhibi-
tion of fi broblast proliferation and collagen synthesis by 5-FU.
In vitro studies have shown a dose-related reduction by 5-FU
in both keloid fi broblast proliferation and fi broblast-populated
collagen lattice (197). It also inhibits proliferation and myofi -
broblast differentiation in dupuytren fi broblasts in vitro (198).
5-FU is an antimetabolite drug in the pyrimidine class. It
interrupts both DNA and RNA synthesis at several levels, includ-
ing the inhibition of thymidylate synthetase (199). This blocks
the change of uridine to thymidine, which affects the biosynthe-
sis of fi broblast DNA, which results in the inhibition of cell pro-
liferation (200). 5-FU relies on thymidylate synthase activity to
initiate apoptosis. Studies have shown pathologically low rates
of apoptosis among keloid scars (201). Bulstrode et al. (202)
have demonstrated that 5-FU selectively inhibits collagen syn-
thesis. In animal studies, 5-FU has been shown to inhibit fi bro-
blast proliferation and accelerate degradation of hypertrophic
scar collagen (196).
Occleston et al. (203) have shown that type I collagen, fi bro-
nectin, and cell migration were inhibited by 5-FU for 48 days.
β
5 years in dura-
tion had a greater tendency to fl atten (55%). Kontochristopou-
los et al. (212) also studied 5-FU as monotherapy in 20 patients
having more than 75 keloids. Injections of 5-FU (50 mg/cc)
were performed at weekly intervals for an average of seven
treatments. Maximum volume was 2.0 cc and average was
0.3 cc. A reduction in keloid volume was seen in 95% of
patients, with 8 having more than 50% reduction and 8 having
greater than 75% reduction and 1 having 100%. Recurrences
≤
