5-fluorouracil Versus Placebo in Periocular Full Thickness Skin Grafts
| Status: | Terminated |
|---|---|
| Conditions: | Skin Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 89 |
| Updated: | 2/1/2019 |
| Start Date: | August 25, 2016 |
| End Date: | January 25, 2019 |
A Prospective, Randomized, Double-blinded Comparison of the Use of 5-fluorouracil Versus Placebo in Periocular Full Thickness Skin Grafts.
Full thickness skin grafts are an essential tool in surgery around the eyelids for
reconstruction or rehabilitation following injury or surgery. Common conditions where skin
grafts are needed include cicatricial ectropion, restoration of eyelid function after tumor
removal, burns to the eyelids, or trauma. Early complications, occurring in the first 2 weeks
after surgery, are rare: wound dehiscence, necrosis, infection, bleeding, partial or complete
graft failure. However, late postoperative complications generally categorized as "scarring"
(including graft hypertrophy and contraction, keloid formation, and hypo/hyper pigmentation)
can limit the success and acceptability of the procedure by patients. Scars form following
any insult to the deep dermis as a result of wound healing. Factors such as age, skin type,
racial pigmentation, genetics, and sex may influence fibroblast proliferation as part of the
healing response, resulting in a suboptimal result. Graft contraction is perhaps the most
worrisome result, since it can result in failure of the initial surgery and may require
additional surgery to correct. Many treatments have been used to manage these complications:
corticosteroid injection, cryotherapy, pressure therapy, radiotherapy, laser therapy,
silicone based products, and antimetabolite therapy. One such antimetabolite, 5-fluorouracil
(5-FU), has been used over the last 15 years as an adjunct or primary treatment to modulate
wound healing and scar formation. Other studies have demonstrated safety for cutaneous and
subcutaneous injection in the periocular region. However, no controlled studies exist. This
prospective, randomized, and double-blinded clinical study will evaluate the use and benefit
of 5-FU versus saline in patients undergoing skin grafting for periocular reconstruction. The
decision for the need for skin grafting will be at the discretion of the attending surgeon
and will be made separate from enrollment in the study. Surgery will be performed as
indicated. The study medication or placebo (normal saline) will be administered 2-3 weeks
after surgery and then every 2-3 weeks afterwards for up to a total of 4 injections. After
the injections, regular scheduled follow-up will be at 3, 6, and 12 months post-op. Outcomes
at each study visit (up to 12 months post-operatively) include graft size, color, contour,
and complications between study treatment group and placebo group.
reconstruction or rehabilitation following injury or surgery. Common conditions where skin
grafts are needed include cicatricial ectropion, restoration of eyelid function after tumor
removal, burns to the eyelids, or trauma. Early complications, occurring in the first 2 weeks
after surgery, are rare: wound dehiscence, necrosis, infection, bleeding, partial or complete
graft failure. However, late postoperative complications generally categorized as "scarring"
(including graft hypertrophy and contraction, keloid formation, and hypo/hyper pigmentation)
can limit the success and acceptability of the procedure by patients. Scars form following
any insult to the deep dermis as a result of wound healing. Factors such as age, skin type,
racial pigmentation, genetics, and sex may influence fibroblast proliferation as part of the
healing response, resulting in a suboptimal result. Graft contraction is perhaps the most
worrisome result, since it can result in failure of the initial surgery and may require
additional surgery to correct. Many treatments have been used to manage these complications:
corticosteroid injection, cryotherapy, pressure therapy, radiotherapy, laser therapy,
silicone based products, and antimetabolite therapy. One such antimetabolite, 5-fluorouracil
(5-FU), has been used over the last 15 years as an adjunct or primary treatment to modulate
wound healing and scar formation. Other studies have demonstrated safety for cutaneous and
subcutaneous injection in the periocular region. However, no controlled studies exist. This
prospective, randomized, and double-blinded clinical study will evaluate the use and benefit
of 5-FU versus saline in patients undergoing skin grafting for periocular reconstruction. The
decision for the need for skin grafting will be at the discretion of the attending surgeon
and will be made separate from enrollment in the study. Surgery will be performed as
indicated. The study medication or placebo (normal saline) will be administered 2-3 weeks
after surgery and then every 2-3 weeks afterwards for up to a total of 4 injections. After
the injections, regular scheduled follow-up will be at 3, 6, and 12 months post-op. Outcomes
at each study visit (up to 12 months post-operatively) include graft size, color, contour,
and complications between study treatment group and placebo group.
In oculofacial surgery, full thickness skin grafts are a fundamental tool used to restore
function to the eyelid. This can be required after removal of skin cancer, correction of
eyelid malposition such as cicatricial eyelid ectropion (the eyelid edge is pulled away from
the eye), retraction (the eyelid is pulled lower than normal, exposing more of the eye to the
air), scar formation (such as a medial pulling or web), or trauma with loss of tissue. These
conditions affect patients of all ages, ranging from newborns to nonagenarians. Skin grafting
in the periorbital area is relatively safe, although complications may arise. The most common
and challenging complication scarring and graft shrinkage. This can lead to requiring
additional surgery to add additional skin or to improve the appearance of the graft. In
addition to the morbidity of another surgery, some patients have limited or no additional
skin available (e.g. young patients, burn patients). The eyelid skin is the thinnest of the
body, so only thin skin can be used as donor material. However, the amount of skin available
for this purpose is very little.
There are limited options for preventing graft shrinkage and scarring in this situation. The
oldest and most commonly used technique is injection of steroid medication. Steroids decrease
proliferation of a fibroblast cells, which create collagen and glycosaminoglycan, two
proteins created by the body that contract and cause graft shrinkage. Data in literature
shows that one form of steroid, triamcinolone, is effective for this purpose. However, there
is a risk of embolization of this solid steroid material that care rarely cause blindness. In
addition, in the periocular area, steroids can elevate eye (intraocular) pressure (that can
cause glaucoma in some cases) and accelerate the formation of cataracts.
Another medication used for this purpose is 5-fluorouracil (5-FU). This is an antimetabolite
(a drug that inhibits another chemical that is part of normal processes) that works by
irreversibly inhibiting the enzyme thymidylate synthetase resulting in impaired DNA
synthesis. This reduces fibroblast proliferation and inhibits collagen type 1 production
which is a key protein in scar formation. This medication is commonly used in ophthalmology
after glaucoma filtration surgery. In this usage, it is injected under the conjunctiva to
prevent scarring around the surgical site.
There have been two retrospective studies that have investigated the safety and efficacy of
5-FU injected in periorbital skin grafts with or without Kenalog. The first (Massry 2011)
used post-operative injections of a 50:50 mixture of 5-FU and triamcinolone for correction of
medial canthal webs. In 2 patients, they found it to be safe and effective. The author noted
he has used it previously for other scar management cases and was "very pleased with the
results and [had] negligible side-effect[s]." The same author performed another study using
5-FU for skin grafts. This study evaluated 19 patients who had skin grafts for various
purposes and were injected following surgery (similar to our protocol). This study
demonstrated safety of the injection, with no cases of complication. The author concluded
that the 5-FU is effective with "minimal scarring, high patient and surgeon satisfaction, and
few complications." However, there was no comparison group to truly evaluate the effect. With
only two retrospective studies by the same author, there is no strong evidence that it is
effective, although safety has been demonstrated.
The investigators therefore propose a randomized controlled prospective study to evaluate the
outcomes of periocular skin grafts with or without the use of 5-FU injected in the
post-operative period. Patients will be recruited from the investigators' practices who need
full thickness skin grafts for reconstruction after cancer removal, pre-existing scarring,
eyelid malposition, or trauma. Patients will be introduced to the study, and will come back
for detailed explanation and consent. The injection medication will be prepared by the Mass
Eye and Ear Research Pharmacy and labeled for this double-blinded study. Injections will be
given 2-3 weeks after surgery and up to 4 times (also every 2-3 weeks). Measurements and
photographs of the skin graft will be taken at each visit (following injections, at 3, 6, and
12 months) to monitor for complications. Patients will be followed for at least 12 months.
If effective, this medication could change the post-operative management of skin grafts,
reduce complications and reoperations.
function to the eyelid. This can be required after removal of skin cancer, correction of
eyelid malposition such as cicatricial eyelid ectropion (the eyelid edge is pulled away from
the eye), retraction (the eyelid is pulled lower than normal, exposing more of the eye to the
air), scar formation (such as a medial pulling or web), or trauma with loss of tissue. These
conditions affect patients of all ages, ranging from newborns to nonagenarians. Skin grafting
in the periorbital area is relatively safe, although complications may arise. The most common
and challenging complication scarring and graft shrinkage. This can lead to requiring
additional surgery to add additional skin or to improve the appearance of the graft. In
addition to the morbidity of another surgery, some patients have limited or no additional
skin available (e.g. young patients, burn patients). The eyelid skin is the thinnest of the
body, so only thin skin can be used as donor material. However, the amount of skin available
for this purpose is very little.
There are limited options for preventing graft shrinkage and scarring in this situation. The
oldest and most commonly used technique is injection of steroid medication. Steroids decrease
proliferation of a fibroblast cells, which create collagen and glycosaminoglycan, two
proteins created by the body that contract and cause graft shrinkage. Data in literature
shows that one form of steroid, triamcinolone, is effective for this purpose. However, there
is a risk of embolization of this solid steroid material that care rarely cause blindness. In
addition, in the periocular area, steroids can elevate eye (intraocular) pressure (that can
cause glaucoma in some cases) and accelerate the formation of cataracts.
Another medication used for this purpose is 5-fluorouracil (5-FU). This is an antimetabolite
(a drug that inhibits another chemical that is part of normal processes) that works by
irreversibly inhibiting the enzyme thymidylate synthetase resulting in impaired DNA
synthesis. This reduces fibroblast proliferation and inhibits collagen type 1 production
which is a key protein in scar formation. This medication is commonly used in ophthalmology
after glaucoma filtration surgery. In this usage, it is injected under the conjunctiva to
prevent scarring around the surgical site.
There have been two retrospective studies that have investigated the safety and efficacy of
5-FU injected in periorbital skin grafts with or without Kenalog. The first (Massry 2011)
used post-operative injections of a 50:50 mixture of 5-FU and triamcinolone for correction of
medial canthal webs. In 2 patients, they found it to be safe and effective. The author noted
he has used it previously for other scar management cases and was "very pleased with the
results and [had] negligible side-effect[s]." The same author performed another study using
5-FU for skin grafts. This study evaluated 19 patients who had skin grafts for various
purposes and were injected following surgery (similar to our protocol). This study
demonstrated safety of the injection, with no cases of complication. The author concluded
that the 5-FU is effective with "minimal scarring, high patient and surgeon satisfaction, and
few complications." However, there was no comparison group to truly evaluate the effect. With
only two retrospective studies by the same author, there is no strong evidence that it is
effective, although safety has been demonstrated.
The investigators therefore propose a randomized controlled prospective study to evaluate the
outcomes of periocular skin grafts with or without the use of 5-FU injected in the
post-operative period. Patients will be recruited from the investigators' practices who need
full thickness skin grafts for reconstruction after cancer removal, pre-existing scarring,
eyelid malposition, or trauma. Patients will be introduced to the study, and will come back
for detailed explanation and consent. The injection medication will be prepared by the Mass
Eye and Ear Research Pharmacy and labeled for this double-blinded study. Injections will be
given 2-3 weeks after surgery and up to 4 times (also every 2-3 weeks). Measurements and
photographs of the skin graft will be taken at each visit (following injections, at 3, 6, and
12 months) to monitor for complications. Patients will be followed for at least 12 months.
If effective, this medication could change the post-operative management of skin grafts,
reduce complications and reoperations.
Inclusion Criteria:
- Outpatients
- Ages 18 to 89 years of age
- Has a condition (e.g. trauma, skin/tissue defect, scar) requiring a skin graft for
repair
- Sufficient education to understand study procedures and to give consent
Exclusion Criteria:
- Women lactating, pregnant or planning to get pregnant in the near future
- Immunosuppression/immunocompromise or serious/active infections
- Dihydropyrimidine dehydrogenase enzyme deficiency
- Severe hepatic or renal impairment or failure
- Unable to give consent or understand the study
We found this trial at
1
site
243 Charles St
Boston, Massachusetts 02114
Boston, Massachusetts 02114
(617) 523-7900
Phone: 518-221-0414
Massachusetts Eye & Ear Infirmary Whether you see our physicians at Mass. Eye and Ear's...
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