CASE REPORT

Dennis H. Kraus, MD, Section Editor

USE OF BECAPLERMIN IN THE CLOSUREOF PHARYNGOCUTANEOUS FISTULAS

David M. Jakubowicz, MD,* Richard V. Smith, MD

Department of Otolaryngology, Albert Einstein College of Medicine-Montefiore Medical Center,

3400 Bainbridge Avenue, Bronx, NY 10467. E-mail: rsmith@montefiore.org

Accepted 23 November 2004

Published online 17 March 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20182

Abstract: Background. We report on the contribution of re-

combinant platelet-derived growth factor-BB (becaplermin) in

treating recalcitrant postlaryngectomy fistulas in two patients with

head and neck cancer.

Methods. Topical becaplermin was applied daily, with peri-

odic wound assessment and photodocumentation.

Results. The two patients with persistent fistula refractory to

conventional management have demonstrated rapid improve-

ment after topical application of becaplermin. Each wound ex-

hibited an exuberant granulation response, with a 50% decrease

in the size of wound at 1 week. The patients experienced even-

tual closure, with none having local recurrence of their cancer at

2 years’ follow-up.

Conclusions. Becaplermin seems to be a promising addition

to traditional methods of treatment for postlaryngectomy fistulas.

In patients with delayed healing, future studies will be required to

determine the overall efficacy of such biologic response modi-

fiers in the treatment of pharyngocutaneous fistulas and other

chronic wounds of the head and neck. A 2005 Wiley Periodicals,

Inc. Head Neck 27: 433–438, 2005

Keywords: complications; becaplermin; pharyngocutaneous

fistula; squamous cell carcinoma; laryngectomy, Regranex

This article is among the first to use recent

advances in wound healing to augment the tradi-

tional management of pharyngocutaneous fistu-

las. These fistulas fall into a category known as

‘‘chronic wound’’ or any nonhealing wound and/

or ulcer that has shown no granulation response

or change in size for 3 to 4 weeks despite con-

servative management.1 Other wounds of this cat-

egory include enterocutaneous fistulas, diabetic

foot ulcers, venous leg ulceration,2 and nonhealing

tympanic membrane perforations. The cost and

morbidity these wounds inflict on the patient are

enormous, and any improvement in treatment

will significantly improve quality of life. Tradi-

tionally, all fistulas have initially been treated

with daily wet-to-dry dressing changes. Grafts and

reconstructive flaps are used to facilitate closure

and lower the risk of further complications, such

as carotid blowout, but are second- or third-line

management options.

Both local and global factors contribute to poor

wound healing. Local ischemia, infection, tissue

maceration, or foreign bodies may retard wound

healing in even the ideal patient. Unfortunately,

most patients with head and neck cancer have

significant systemic issues such as advanced

age, poor nutrition, uncontrolled diabetes, renal

Correspondence to: R. V. Smith

*Current affiliation: Department of Surgery, Division of Otolaryngology,Maimonides Medical Center, Brooklyn, New York.

B 2005 Wiley Periodicals, Inc.

Becaplermin for Fistulas HEAD & NECK May 2005 433

disease, local radiotherapy, and steroid use that

further retard and complicate wound healing.2

A recent otolaryngologic trial has shown that

ototopical growth factors used after tympano-

plasty have shown vastly improved closure rates

at 8 days and 6 weeks in a double-blind control

trial.3 Similarly, a case series has shown patients

with persistent otorrhea 6 months after tympano-

plasty showed improved closure and drier ears.4

These studies used a combination of growth fac-

tors including epidermal growth factor (EGF),

basic fibroblast growth factor (bFGF), platelet-

derived growth factor (PDGF), and transforming

growth factor (TGF), which were obtained from

the lysates from keratinocytes in tissue culture.

Recently, a single recombinant PDGF-BB

(becaplermin) has gained United States Food and

Drug Administration approval for the treatment

of diabetic foot ulcers.5 The medication has been

shown to increase complete healing, reduce ul-

cer size, and reduce the need for amputation.6,7

Furthermore, in case reports, becaplermin has

shown promise in resolving chronic orbital ulcer-

ation after exenteration for melanoma8 and im-

proving healing in a chronic neck wound after

radiation therapy.9 Given its success in treating

other chronic wounds, we hypothesized that it

would be equally efficacious in wounds of the

head and neck. To test this hypothesis, we used

daily becaplermin gel (0.01%) in addition to tradi-

tional twice-daily dressing changes in two patients

with pharyngocutaneous fistulas refractory to

medical management.

PATIENTS

Patient 1. A 46-year-old woman was transferred

to our institution with a T3N2B squamous cell

carcinoma of the larynx, having undergone emer-

gent tracheotomy for respiratory obstruction. Her

comorbities included human immunodeficiency

virus, hepatitis B and C, chronic obstructive

pulmonary disease, asplenia, and polysubstance

abuse on methadone maintenance. She had lost

70 pounds in the year before treatment and was

cachectic. Preoperative thyroid function testing

revealed a thyroid-stimulating hormone level of

0.010 mIU/L and free thyroxine (T4) of 1.0 ng/dl.

This patient was then seen at our institution’s

multidisciplinary tumor board, where it was de-

cided that she was not a candidate for chemo-

therapy because of her poor immunologic status

and general medical condition. Therefore, the con-

sensus was to proceed with surgical management.

She underwent a total laryngectomy, left modi-

fied radical neck dissection, left hemithyroidec-

tomy, right selective neck dissection, mediastinal

dissection, and left pectoralis major reconstruc-

tion with primary tracheoesophageal puncture

(TEP; the practice of the senior author). She had

an uneventful postoperative course, started oral

feedings on the sixth day, and was discharged

home on the seventh postoperative day with a dry

wound without erythema. Two days later, she re-

turned to the emergency department with a com-

plete dehiscence of the pectoralis flap and a large

salivary fistula. She was initially treated with

twice-daily wet-to-dry dressing changes without

any improvement. On postoperative day 13, the

patient underwent debridement of the necrotic

pectoralis major flap and a second pectoralis ma-

jor flap reconstruction. By postoperative day 4

from the return, she had another large wound

dehiscence develop with pharyngocutaneous fis-

tula. Despite 3 weeks of twice-a-day wet-to-dry

dressing changes and pectoralis reconstruction,

she showed no improvement in the size or se-

verity of the fistula (Figure 1).

After a lengthy discussion with the patient

regarding risks and benefits, she agreed to topical

becaplermin 0.01% application every day, in addi-

tion to the previous treatment regimen. A rapid

decrease was seen in the size of the fistula, and

exuberant granulation response was found from

the pectoralis flap, which had been absent pre-

viously. Less tissue growth was seen from the

nascent tissue. By 4 days after the initiation of

treatment, the size of defect was decreased by

75% (Figure 2). A week into treatment, the fistula

FIGURE 1. Patient 1 before treatment.

HEAD & NECK May 2005434 Becaplermin for Fistulas

continued to decrease in size, and tissue augmen-

tation progressed (Figure 3). The lateral aspect of

the wound started to develop a cutaneous cover-

age, and the split-thickness skin graft was com-

pletely healed. Treatment continued for 2 weeks

total with some additional improvement and

minimal salivary flow through the fistula.

Treatment was stopped because the patient

was transferred to a nursing home, where themed-

ication could neither be obtained nor adminis-

tered. Eighteen months after the procedure, the

patient’s fistula is closed. She can tolerate oral

feedings, speak with a good tracheoesophageal

puncture (TEP) voice, and lives recurrence-free.

Case 2. A 71-year-old man with T3N2B squa-

mous cell carcinoma of the larynx with chronic

obstructive pulmonary disease and renal failure

initially underwent an incomplete course of con-

comitant chemotherapy and radiation. The pa-

tient’s severe mucositis and pneumonia required

cessation of the laryngeal preservation protocol.

Preoperative thyroid function testing showed a

free T4 level of 0.5 and thyroid-stimulating

hormone level of 11.3. After recovery from his

treatment, he underwent a total laryngectomy

with right selective neck dissection and primary

TEP for persistent disease. Oral feeding was

initiated on postoperative day 10. On day 11, he

had a small suprastomal dehiscence develop. The

patient aggressively suctioned his stoma, and by

day 12, had a significant suprastomal wound

dehiscence and fistula. He also suctioned out his

TEP, although this was separate from his pha-

FIGURE 4. Patient 2 before treatment. FIGURE 5. Patient 2 on day 4 of treatment.

FIGURE 2. Patient 1 on day 4 of treatment. FIGURE 3. Patient 1 on day 9 of treatment.

Becaplermin for Fistulas HEAD & NECK May 2005 435

ryngocutaneous fistula and was managed with a

catheter through which feedings were adminis-

tered. The TEP was not believed to be the cause

or the origin of the fistula. Over the ensuing few

days, despite twice-daily dressing changes, the

wound continued to dehisce, and the size of fistula

increased. One month after surgery, the patient

had a large lateral dehiscence that communi-

cated with the pharynx and by that time a patent

TEP site (Figure 4) with no evidence of clinical

improvement or granulation. After careful dis-

cussion with the patient and family, topical be-

caplermin was added to the dressing changes.

Again, improvement in wound healing was noted

immediately. A rubber catheter was placed

through the TEP site for alimentation, and sa-

liva could be seen through the residual wound

(Figure 5). The wound further improved with

a decrease in fistula size and overall health of the

surrounding tissue. The treatment course lasted

2 weeks total and was halted when the patient

was transferred to the same nursing home as

patient number 1 (Figure 6). The patient is now

18 months posttreatment, tolerating oral feed-

ings, and speaking through his TEP, with no

evidence of disease and with complete closure

of fistula.

DISCUSSION

Normal wound healing requires the careful or-

chestration of multiple different cell lines whose

efforts result in a thin, mature scar. Disruption

of this biologic cascade can have catastrophic

results for the patient. In the patient with head

and neck cancer, this disruption may result in

leakage of saliva and the development of a

chronic fistula. Daily treatment with becapler-

min gel seems promising in these patients and

may become a welcome addition to the medical

armamentarium in the treatment of this mor-

bid complication.

Chronic wounds differ from other wounds by

remaining at an early stage of wound healing,

never organizing sufficiently to allow deposition

of collagen.10 Serum extracted from these wounds

shows gross deficiencies in peptide growth factors

and an imbalance between proteolytic enzymes

and their inhibitors. Growth factor deficiencies

found in serum from chronic wounds include

PDGF along with BFGF, EGF, and TGF-h.11 Data

suggest that these deficiencies result not from a

lack of production but rather an increased degra-

dation of wound healing factors by proteolytic

enzymes.3 These differences halt the organizing

wound at an immature, catabolic state, which is

inherently weak and prone to failure.

PDGF is a 31-kDa dimeric glycoprotein that

serves a potent chemotactic factor for inflamma-

tory cells.12 It is composed of two polypeptide

chains (A and B) that combine to form three dif-

ferent disulfide linked forms (AA, AB, BB). These

chains are synthesized from large precursors that

are enzymatically cleaved to the active form. Hu-

man platelets have all three dimers (65% AA, 23%

BB, and 12% AA). PDGF is primarily involved in

the inflammatory and proliferative phases of

wound healing, being initially released during

platelet lysis at the site of injury. PDGF-AA levels

peak at 36 hours after initial full-thickness in-

sult.1 It attracts hematopoietic cells to the site

of injury, mediates localized vasoconstriction, and

functions as a potent mitogen for mesenchymal

cells, including fibroblasts and vascular smooth

muscle cells. Other cells that produce PDGF in-

clude placental cells, fibroblasts, vascular smooth

muscle,13 and endothelial cells.7

PDGF-BB is the only recombinant growth fac-

tor licensed for use in the United States and

indicated only for diabetic foot ulcers. It is a ho-

modimer formed by transfecting the human B

chain into yeast. Application in acute and chronic

wounds results in a marked increase of PDGF-

AA levels.14 Compared with placebo, becaplermin

gel 100 Ag/g significantly increased the incidence

of complete wound closure in diabetic foot ulcers

by 43% and time to closure by 32% with no in-

crease in wound infection or adverse events over

placebo.6 Another trial using becaplermin in pres-

sure ulcers also found significantly reduced ulcer

FIGURE 6. Patient 2 on day 9 of treatment.

HEAD & NECK May 2005436 Becaplermin for Fistulas

volume and increased healing.7 Furthermore, in

one cost-benefit study, consistent use of this prod-

uct resulted in a 9% decreased risk of amputa-

tions at a cost of $19 per ulcer-free month.15

Becaplermin (Regranex; OMJ Pharmaceuti-

cals, San German, PR) is packaged as a 0.1% gel

and comes in 2, 7.5, and 15 g sizes. For the two

larger sizes, the wound will require about a

0.25-cm length of gel for every square centimeter

of wound. The gel is applied with a cotton swab to

the wound in a thin layer, and a sterile saline-

moistened gauze is applied. The gauze is removed

after 12 hours, and the wound is gently rinsed

with saline. Saline-moistened gauze without

medication is then applied for the rest of the

evening, and the cycle is repeated the subse-

quent day. A normal treatment course lasts until

the wound closes or 4 months elapse, whichever

comes first.16

Contraindications to its use include known hy-

persensitivity to any component of this product

(eg, parabens) and known neoplasm(s) at the

site(s) of application.

Patients receiving becaplermin gel, placebo

gel, and good ulcer care alone had a similar in-

cidence of ulcer-related adverse events such as

infection, cellulitis, or osteomyelitis.16 However,

erythematous rashes occurred in 2% of patients

treated with becaplermin gel and placebo and

none in patients receiving good ulcer care alone.

The incidence of cardiovascular, respiratory, mus-

culoskeletal, and central peripheral nervous sys-

tem disorders was not different across all treat-

ment groups. Mortality rates were also similar

across all treatment groups. Patients treated with

becaplermin gel did not have neutralizing anti-

bodies against becaplermin develop.16

Becaplermin, or any growth factor, has the po-

tential to induce proliferation of mutated and nor-

mal cells. This is a significant issue when dealing

with postlaryngectomy fistulas. Although it has

been proposed as a tumor marker, PDGF has

been shown to have no proliferative effects on

cloned squamous cell carcinomas17 or dysplastic

epithelium.18 Still, we would advise caution when

using this product in any patient with a close or

frankly positive tumor margin. Furthermore, its

long-term effect on tissue altered by radiation,

smoking, or alcohol and possible development of

metachronous or second primaries would be a fu-

ture avenue of research.

One previous postoncologic use of becaplermin

was a melanoma patient with a chronic orbital

ulcer after exenteration. This ulcer persisted for

15 months despite twice-a-day dressing changes

and discontinuation of the prosthesis. Topical ap-

plication of becaplermin for 3 weeks resulted in

complete wound healing without any evidence

of recurrence.7

In the two patients presented in the article,

becaplermin applied once a day resulted in sig-

nificant wound augmentation with 50% or greater

closure within 4 days and greater response by

1 week in wounds with no improvement over pre-

vious 2 to 3 weeks. Unfortunately, the medication

alone did not precipitate immediate closure of the

fistula during the treatment period. Despite the

limited treatment course in this study, all wounds

eventually closed. Dilution of the growth factor in

the region of greatest salivary flow may hamper

the efficacy of this medication. Salivary diversion

may help with this issue, although it was not used

in these patients. Many chronic wound trials use

the product for 4 months before considering that

a wound failed medically.19

CONCLUSION

In refractory cases of pharyngocutaneous fistu-

las, becaplermin may provide a safe, nonsurgical

means to expedite wound healing. This medi-

cation has proven effective in treating chronic

wounds below the clavicle. This study shows how

in selected cases topical application results in

a vigorous granulation response and improved

wound healing. Although becaplermin seems

quite promising in patients with delayed healing,

future studies will be required to determine the

overall efficacy of such biologic response mod-

ifiers in the treatment of pharyngocutaneous

fistulas and other chronic wounds of the head

and neck.

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HEAD & NECK May 2005438 Becaplermin for Fistulas