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Gefitinib-Induced Paronychia:  Response to Autologous Platelet-Rich Plasma FREE

Soon-Hyo Kwon, MD; Jae-Woo Choi, MD; Jong-Soo Hong, MD; Sang-Young Byun, MD; Kyoung-Chan Park, MD, PhD; Sang-Woong Youn, MD, PhD; Chang-Hun Huh, MD, PhD; Jung-Im Na, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Dermatology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea.


Arch Dermatol. 2012;148(12):1399-1402. doi:10.1001/archdermatol.2012.3022.
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Background Paronychia has been reported in as many as 10% of patients treated with gefitinib. Although conservative management and treatment with topical or systemic antibiotics are beneficial, no effective method exists for intractable cases. Platelet-rich plasma (PRP) consists of a high concentration of platelets that promote wound healing through chemotaxis, cell proliferation, angiogenesis, and tissue remodeling.

Observations We herein report a refractory case of gefitinib-induced paronychia successfully treated with autologous PRP. A 68-year-old woman who had been diagnosed as having lung adenocarcinoma with multiple bone and brain metastases initiated gefitinib therapy at an oral dose of 250 mg/d. After 1 month, multiple paronychia with periungual granulation appeared on the nail fold of the first, second, and third toenails of both feet. Because the paronychia recurred repeatedly despite use of a topical antibiotic, topical corticosteroid, and short-term systemic antibiotic, she started PRP treatment. After 3 months, the lesion showed marked improvement with minimal pain or discharge.

Conclusion This case highlights the therapeutic challenges of using PRP to promote tissue repair in intractable gefitinib-induced paronychia and merits further investigation.

Figures in this Article

Gefitinib is a newer chemotherapeutic agent that inhibits tyrosine kinase activity of epidermal growth factor receptor, thus prohibiting the induction of cell proliferation, migration, and angiogenesis.1,2 Gefitinib-induced paronychia has been reported in as many as 10% of patients receiving gefitinib therapy.36 Although wet dressings, cushioning of the affected areas, topical or systemic antibiotics, and pain control are beneficial, no effective treatment has been documented for intractable cases.1

We herein report a recalcitrant case of gefitinib-induced paronychia successfully treated with autologous platelet-rich plasma (PRP). Platelet-rich plasma, consists of a high concentration of platelets and growth factors and promotes wound healing by influencing chemotaxis, cell proliferation, angiogenesis, and tissue remodeling.79 This case highlights the therapeutic challenges of using PRP to promote tissue repair in intractable gefitinib-induced paronychia and merits further investigation.

A 68-year-old woman was diagnosed as having adenocarcinoma of the lung with multiple bone and brain metastases. The cancer progressed despite the chemotherapy with gemcitabine hydrochloride and cisplatin. Four months after the first administration of chemotherapy, gefitinib therapy at an oral dose of 250 mg/d was initiated. One month later, multiple paronychia with periungual granulation appeared on the nail fold of the first, second, and third toenails of both feet (Figure 1). Short-term systemic antibiotic treatment with cefuroxime axetil for 5 days, wet dressings, and topical antibiotic therapy were started. Although the swelling, pain, and amount of discharge showed mild improvement with the oral antibiotics, the paronychia became aggravated repeatedly after the discontinuation of the antibiotic therapy. The patient received intermittent short-term oral administration of cefuroxime or cefradine for 1 year, but aggravation of the paronychia was observed once or twice a month. Doxycycline monohydrate therapy, at a dose of 200 mg/d, was initiated for 2 months, but the result was less satisfactory than with cephalosporins. Furthermore, periungual inflammation worsened in the use of topical desoximetasone (desoxymethasone). Unsuccessful attempts to treat the patient's gefitinib-induced paronychia led to the initiation of topical autologous PRP therapy.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. One month after the start of gefitinib treatment, multiple paronychia with periungual granulation, edema, and discharge appeared on the nail fold of the first, second, and third toenails of both feet.

The technique for obtaining PRP has been previously described by Na et al.10 Twenty milliliters of the patient's venous blood was drawn in a syringe prefilled with 3mL anticoagulant solution (anticoagulant citrate dextrose solution formula A; Baxter Healthcare Corp). The blood was centrifuged at 160 g for 10 minutes. After the first spin, the bottom concentrate of red blood cells was discarded and the supernatant was centrifuged again at 400 g for another 10 minutes. Next, the resulting pellet of platelets was mixed with 3mL supernatant to produce 3 mL of PRP. To release the growth factors contained in platelets, the PRP was frozen in liquid nitrogen and thawed at room temperature. Three milliliters of PRP was distributed equally into 10 syringes and provided to the patient. Afterwards, the resulting platelet lysate was stored at −20°C and thawed at room temperature 30 minutes before administration. The patient applied 0.3 mL of PRP daily to the wound at home. The wound was occluded with an adhesive tape after PRP application.

One month after the start of the PRP treatment, the wound showed much improvement with minimal to no pain or discharge (Figure 2). The PRP treatment was continued for 3 months, while the edema and granulation tissue gradually subsided without any exacerbation (Figure 3). After 3 months of PRP treatment, gefitinib therapy was discontinued owing to the tumor's poor response to the chemotherapeutic agent.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. One month after initiation of platelet-rich plasma treatment, the paronychia showed much improvement with minimal to no pain and discharge. Although granulation tissue still remained, its size decreased considerably compared with that of Figure 1.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Three months after initiation of platelet-rich plasma (PRP) treatment, no granulation tissue remained. During the 3 months of PRP treatment, the edema and granulation tissue gradually subsided without any exacerbation.

Autologous PRP is a portion of the plasma containing a high concentration of platelets and growth factors.7 Several studies have reported the effectiveness of autologous PRP in the treatment of acute wounds and nonhealing chronic wounds.1114 Because of its potential to enhance wound healing, autologous PRP is widely used for implantation and bone regeneration in dentistry, oral-maxillofacial surgery, and orthopedic surgery and for soft tissue wound healing in plastic surgery.8,15,16

Gefitinib-induced paronychia involving the great toes is often the first sign, usually starting at 4 to 8 weeks after the initiation of the treatment.17 To prevent gefitinib-induced paronychia, friction and pressure on the nail fold must be minimized as much as possible. Wearing comfortable-sized shoes, cushioning appropriate areas, and applying wet dressings once the signs and symptoms of paronychia appear are recommended for relief of symptoms.18 Although gefitinib-induced paronychia does not involve an infectious cause, the risk for secondary infection is increased because of the defective skin barrier in the lesion, thus explaining the use of topical antibiotics.19 Topical corticosteroids have been prescribed in severe cases of periungual inflammation, but their efficacy is still unclear.5

Systemic antistreptococcal therapy can be used if secondary infection is suspected, but the response has been insignificant.19,20 In 2 cases where cultures of the periungual abscesses yielded Staphylococcus aureus, a favorable response was seen with minocycline hydrochloride use, but the paronychia persisted.4,5 Only with the discontinuation of gefitinib therapy did the paronychia improve. Furthermore, a case report has shown rapid and successful treatment of paronychia induced by cetuximab, an epidermal growth factor receptor inhibitory monoclonal antibody, with use of doxycycline monohydrate, 100 mg for 6 weeks.20 However, paronychia in this patient was refractory to doxycycline treatment, with even with a higher dose and longer treatment period.

Because paronychia can mimic the clinical presentation of an ingrown nail, surgical treatments including partial nail bed excision and total nail extraction with destruction of nail matrix have been performed with little benefit and have led to permanent nail loss.19 Large granulomatous papules have been reported to be successfully treated with electrodesiccation.5

Although most of the treatments of gefitinib-induced paronychia mentioned in this report are mainly conservative in that they focus on symptomatic relief or prevention and treatment of secondary bacterial infection, PRP directly affects wound-healing mechanisms. Platelet-rich plasma contains growth factors such as platelet-derived growth factor, transforming growth factor β1, vascular endothelial growth factor, and insulinlike growth factor 1. As a result, PRP enhances wound-healing mechanisms such as chemotaxis, cell proliferation, angiogenesis, and extracellular matrix deposition and remodeling.8,9 Moreover, these growth factors have been reported to enhance human mesenchymal stem cell proliferation and differentiation into various cell types, including fibroblasts, endothelial cells, adipocytes, and osteocytes.21,22

Compared with systemic antibiotic therapy, with which long-term use causes problems with resistance, topical PRP treatment can be used continuously for a long period. Therefore, PRP may be a good treatment modality for long-term and maintenance therapy in those patients taking gefitinib for months to years. In addition, autologous PRP is easy to obtain and can be prepared at a low cost. Moreover, only a slight decline in the level of growth factors was found when PRP was stored at −20°C for 10 days.23 Thus, PRP treatment can be used in an outpatient setting, and patients can apply the PRP themselves at home if it is stored in household refrigerator. Finally, because autologous PRP is derived from the patient's own blood, it does not carry any risk of allergic reaction. Because PRP is made in liquid, an occlusive material such as an adhesive bandage was used to enhance its absorption.

We report the successful treatment of gefitinib-induced paronychia with autologous PRP. This newer chemotherapeutic agent is becoming more prevalent in its use against malignant neoplasms, and the adverse effects involving the nail often lead to discontinuation of the therapy. Therefore, dermatologists must manage gefitinib-induced paronychia properly. Autologous PRP consists of abundant growth factors that can help wound healing and restoration of tissue. Platelet-rich plasma is easy to obtain at a low cost without the risk of allergic reaction. This case highlights the therapeutic success of using autologous PRP to promote tissue repair in intractable gefitinib-induced paronychia and merits further research.

Correspondence: Jung-Im Na, MD, PhD, Department of Dermatology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Korea (vividna@gmail.com).

Accepted for Publication: July 11, 2012.

Published Online: September 17, 2012. doi:10.1001/archdermatol.2012.3022

Author Contributions: All of the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kwon, Park, Youn, Huh, and Na. Acquisition of data: Kwon, Byun, and Na. Analysis and interpretation of data: Kwon, Choi, Hong, and Na. Drafting of the manuscript: Kwon and Na. Critical revision of the manuscript for important intellectual content: Park, Youn, Huh, and Na. Administrative, technical, and material support: Choi, Byun, and Hong. Study supervision: Kwon, Park, Youn, Huh, and Na.

Financial Disclosure: None reported.

Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.  J Am Acad Dermatol. 2006;55(4):657-670
PubMed   |  Link to Article
Jost M, Kari C, Rodeck U. The EGF receptor: an essential regulator of multiple epidermal functions.  Eur J Dermatol. 2000;10(7):505-510
PubMed
Lee MW, Seo CW, Kim SW,  et al.  Cutaneous side effects in non–small cell lung cancer patients treated with Iressa (ZD1839), an inhibitor of epidermal growth factor.  Acta Derm Venereol. 2004;84(1):23-26
PubMed   |  Link to Article
Chang GC, Yang TY, Chen KC, Yin MC, Wang RC, Lin YC. Complications of therapy in cancer patients: case 1: paronychia and skin hyperpigmentation induced by gefitinib in advanced non–small-cell lung cancer.  J Clin Oncol. 2004;22(22):4646-4648
PubMed   |  Link to Article
Dainichi T, Tanaka M, Tsuruta N, Furue M, Noda K. Development of multiple paronychia and periungual granulation in patients treated with gefitinib, an inhibitor of epidermal growth factor receptor.  Dermatology. 2003;207(3):324-325
PubMed   |  Link to Article
Nakano J, Nakamura M. Paronychia induced by gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor.  J Dermatol. 2003;30(3):261-262
PubMed
Lacci KM, Dardik A. Platelet-rich plasma: support for its use in wound healing.  Yale J Biol Med. 2010;83(1):1-9
PubMed
Rozman P, Bolta Z. Use of platelet growth factors in treating wounds and soft-tissue injuries.  Acta Dermatovenerol Alp Panonica Adriat. 2007;16(4):156-165
PubMed
Eppley BL, Woodell JE, Higgins J. Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing.  Plast Reconstr Surg. 2004;114(6):1502-1508
PubMed
Na JI, Choi JW, Choi HR,  et al.  Rapid healing and reduced erythema after ablative fractional carbon dioxide laser resurfacing combined with the application of autologous platelet-rich plasma.  Dermatol Surg. 2011;37(4):463-468
PubMed   |  Link to Article
Kazakos K, Lyras DN, Verettas D, Tilkeridis K, Tryfonidis M. The use of autologous PRP gel as an aid in the management of acute trauma wounds.  Injury. 2009;40(8):801-805
PubMed   |  Link to Article
Driver VR, Hanft J, Fylling CP, Beriou JM.Autologel Diabetic Foot Ulcer Study Group.  A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers.  Ostomy Wound Manage. 2006;52(6):68-70, 72, 74
PubMed
Akingboye AA, Giddins S, Gamston P, Tucker A, Navsaria H, Kyriakides C. Application of autologous derived-platelet rich plasma gel in the treatment of chronic wound ulcer: diabetic foot ulcer.  J Extra Corpor Technol. 2010;42(1):20-29
PubMed
Hom DB, Linzie BM, Huang TC. The healing effects of autologous platelet gel on acute human skin wounds.  Arch Facial Plast Surg. 2007;9(3):174-183
PubMed   |  Link to Article
Alsousou J, Thompson M, Hulley P, Noble A, Willett K. The biology of platelet-rich plasma and its application in trauma and orthopaedic surgery: a review of the literature.  J Bone Joint Surg Br. 2009;91(8):987-996
PubMed   |  Link to Article
Eppley BL, Pietrzak WS, Blanton M. Platelet-rich plasma: a review of biology and applications in plastic surgery.  Plast Reconstr Surg. 2006;118(6):147e-159e
PubMed  |  Link to Article   |  Link to Article
Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update.  J Am Acad Dermatol. 2008;58(4):545-570
PubMed   |  Link to Article
Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225.  Br J Dermatol. 2001;144(6):1169-1176
PubMed   |  Link to Article
Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors.  Ann Oncol. 2005;16(9):1425-1433
PubMed   |  Link to Article
Shu KY, Kindler HL, Medenica M, Lacouture M. Doxycycline for the treatment of paronychia induced by the epidermal growth factor receptor inhibitor cetuximab.  Br J Dermatol. 2006;154(1):191-192
PubMed   |  Link to Article
Mishra A, Tummala P, King A,  et al.  Buffered platelet-rich plasma enhances mesenchymal stem cell proliferation and chondrogenic differentiation.  Tissue Eng Part C Methods. 2009;15(3):431-435
PubMed   |  Link to Article
Kumar S, Chanda D, Ponnazhagan S. Therapeutic potential of genetically modified mesenchymal stem cells.  Gene Ther. 2008;15(10):711-715
PubMed   |  Link to Article
Liu YS, Zhou YS, Zhu SS. Effect of in vitro storage on the biological activity of human platelet-rich plasma [in Chinese].  Beijing Da Xue Xue Bao. 2008;40(1):34-38
PubMed

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. One month after the start of gefitinib treatment, multiple paronychia with periungual granulation, edema, and discharge appeared on the nail fold of the first, second, and third toenails of both feet.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. One month after initiation of platelet-rich plasma treatment, the paronychia showed much improvement with minimal to no pain and discharge. Although granulation tissue still remained, its size decreased considerably compared with that of Figure 1.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Three months after initiation of platelet-rich plasma (PRP) treatment, no granulation tissue remained. During the 3 months of PRP treatment, the edema and granulation tissue gradually subsided without any exacerbation.

Tables

References

Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.  J Am Acad Dermatol. 2006;55(4):657-670
PubMed   |  Link to Article
Jost M, Kari C, Rodeck U. The EGF receptor: an essential regulator of multiple epidermal functions.  Eur J Dermatol. 2000;10(7):505-510
PubMed
Lee MW, Seo CW, Kim SW,  et al.  Cutaneous side effects in non–small cell lung cancer patients treated with Iressa (ZD1839), an inhibitor of epidermal growth factor.  Acta Derm Venereol. 2004;84(1):23-26
PubMed   |  Link to Article
Chang GC, Yang TY, Chen KC, Yin MC, Wang RC, Lin YC. Complications of therapy in cancer patients: case 1: paronychia and skin hyperpigmentation induced by gefitinib in advanced non–small-cell lung cancer.  J Clin Oncol. 2004;22(22):4646-4648
PubMed   |  Link to Article
Dainichi T, Tanaka M, Tsuruta N, Furue M, Noda K. Development of multiple paronychia and periungual granulation in patients treated with gefitinib, an inhibitor of epidermal growth factor receptor.  Dermatology. 2003;207(3):324-325
PubMed   |  Link to Article
Nakano J, Nakamura M. Paronychia induced by gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor.  J Dermatol. 2003;30(3):261-262
PubMed
Lacci KM, Dardik A. Platelet-rich plasma: support for its use in wound healing.  Yale J Biol Med. 2010;83(1):1-9
PubMed
Rozman P, Bolta Z. Use of platelet growth factors in treating wounds and soft-tissue injuries.  Acta Dermatovenerol Alp Panonica Adriat. 2007;16(4):156-165
PubMed
Eppley BL, Woodell JE, Higgins J. Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing.  Plast Reconstr Surg. 2004;114(6):1502-1508
PubMed
Na JI, Choi JW, Choi HR,  et al.  Rapid healing and reduced erythema after ablative fractional carbon dioxide laser resurfacing combined with the application of autologous platelet-rich plasma.  Dermatol Surg. 2011;37(4):463-468
PubMed   |  Link to Article
Kazakos K, Lyras DN, Verettas D, Tilkeridis K, Tryfonidis M. The use of autologous PRP gel as an aid in the management of acute trauma wounds.  Injury. 2009;40(8):801-805
PubMed   |  Link to Article
Driver VR, Hanft J, Fylling CP, Beriou JM.Autologel Diabetic Foot Ulcer Study Group.  A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers.  Ostomy Wound Manage. 2006;52(6):68-70, 72, 74
PubMed
Akingboye AA, Giddins S, Gamston P, Tucker A, Navsaria H, Kyriakides C. Application of autologous derived-platelet rich plasma gel in the treatment of chronic wound ulcer: diabetic foot ulcer.  J Extra Corpor Technol. 2010;42(1):20-29
PubMed
Hom DB, Linzie BM, Huang TC. The healing effects of autologous platelet gel on acute human skin wounds.  Arch Facial Plast Surg. 2007;9(3):174-183
PubMed   |  Link to Article
Alsousou J, Thompson M, Hulley P, Noble A, Willett K. The biology of platelet-rich plasma and its application in trauma and orthopaedic surgery: a review of the literature.  J Bone Joint Surg Br. 2009;91(8):987-996
PubMed   |  Link to Article
Eppley BL, Pietrzak WS, Blanton M. Platelet-rich plasma: a review of biology and applications in plastic surgery.  Plast Reconstr Surg. 2006;118(6):147e-159e
PubMed  |  Link to Article   |  Link to Article
Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update.  J Am Acad Dermatol. 2008;58(4):545-570
PubMed   |  Link to Article
Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225.  Br J Dermatol. 2001;144(6):1169-1176
PubMed   |  Link to Article
Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors.  Ann Oncol. 2005;16(9):1425-1433
PubMed   |  Link to Article
Shu KY, Kindler HL, Medenica M, Lacouture M. Doxycycline for the treatment of paronychia induced by the epidermal growth factor receptor inhibitor cetuximab.  Br J Dermatol. 2006;154(1):191-192
PubMed   |  Link to Article
Mishra A, Tummala P, King A,  et al.  Buffered platelet-rich plasma enhances mesenchymal stem cell proliferation and chondrogenic differentiation.  Tissue Eng Part C Methods. 2009;15(3):431-435
PubMed   |  Link to Article
Kumar S, Chanda D, Ponnazhagan S. Therapeutic potential of genetically modified mesenchymal stem cells.  Gene Ther. 2008;15(10):711-715
PubMed   |  Link to Article
Liu YS, Zhou YS, Zhu SS. Effect of in vitro storage on the biological activity of human platelet-rich plasma [in Chinese].  Beijing Da Xue Xue Bao. 2008;40(1):34-38
PubMed

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