International Wound Journal ISSN 1742-4801
ORIGINAL ARTICLE
Foam dressing with epidermal growth factor for severe radiation dermatitis in head and neck cancer patients Jihyo Lee1 , Sang-wook Lee1 , Joon Pio Hong2 , Myeong Wha Shon1 , Seung-Hee Ryu1 & Seung Do Ahn1 1 Department of Radiation Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea 2 Department of Plastic and Reconstructive Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
Key words Dermatitis; Epidermal growth factor; Foam dressing; Radiotherapy
Lee J, Lee S-w, Hong JP, Shon MW, Ryu SH, Ahn SD. Int Wound J 2016; 13:390–393
Correspondence to
This study was conducted to evaluate the effects of foam dressing with human recombinant human epidermal growth factor (rhEGF) on the healing process in head and neck cancer patients who experience radiation-induced dermatitis (RID). Seven patients, including three with oropharyngeal, two with nasopharyngeal and one each with hypopharyngeal and laryngeal carcinoma, who underwent radiotherapy (RT) for head and neck cancer at the Asan Medical Center from March to December 2008 were prospectively included in this study. Patients who showed severe RID (more than wet desquamation) on the supraclavicular fossa or neck areas were treated by wound cleaning and debridement of granulation tissue, followed by daily rhEGF spray and foam dressing. Median time to stop exudates and reepithelialisation was 4 days. Within 14 days (median 8 days), all patients showed complete healing of RID and no longer required dressings. This new method of treatment with dressing containing rhEGF may have the potential to accelerate the healing process in patients with RID. A case–control study is needed to confirm this finding.
S-w Lee, MD, PhD Department of Radiation Oncology University of Ulsan College of Medicine Asan Medical Center 388-1 Pungnap-dong Songpa-gu Seoul 138-736 South Korea E-mail: [email protected]
doi: 10.1111/iwj.12317
Abstract
Introduction
Skin is a radiosensitive organ, and radiation-induced dermatitis (RID) is the first documented side effect of X-rays. The pathogenesis of radiation-induced injury to the skin involves the depletion of stem cells from the basal cell layer of the epidermis, aggravated by inflammatory cytokines and bacterial colonisation after secondary infection (1–4). Acute reactions to high-dose radiation include erythema, epilation, dark pigmentation, dry desquamation and moist desquamation (5). Acute skin reactions develop after radiotherapy (RT) doses of 35–45 Gy, with recovery of confluent moist desquamation usually requiring 3–4 weeks after completion of RT. The severity of RID is dependent on dose fractionation, total dose, dose rate, irradiated volume, radiation quality, anatomic site, use of chemotherapy and several host factors. RT of superficially located tumours often induces RID. For example, RID is a common acute complication in patients with head and neck cancer, with irradiated skin folds being high-risk areas because of a self-bolus effect. Treatment of RID in head and neck cancer patients is very important to maintain and complete RT. RID can cause discomfort and pain, and severe RID such as moist desquamation can cause pain, secondary infection and a break in RT that may limit 390
treatment results in patients with head and neck and gynecologic cancers (6,7). Thus, prevention and/or reduction of RID can enhance timely completion of RT. Clinical studies have failed to show that topical agents, such as aloe vera, hyaluronic acid, vitamin C, Biafine and mometasone furoate cream, have protective or therapeutic effects in breast, head and neck, and gynecologic cancer patients (8–13), indicating a need for new drugs or methods. Epidermal growth
Key Messages
• foam dressing with recombinant human epidermal growth factor (rhEGF) has the ability to accelerate the healing process in radiation-induced dermatitis (RID) • head and neck cancer patients who underwent RT were prospectively included • time to stop exudates and reepithelialisation was 4 days; within 14 days (median 8 days), patients showed complete healing of RID • foam dressing containing rhEGF was effective in accelerating the healing process
© 2014 The Authors International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
Lee et al.
Foam dressing with EGF for radiation dermatitis
factor (EGF) acts to maintain tissue homeostasis by regulating epithelial cell proliferation, growth and migration. Thus, EGF plays an important role in wound healing and tissue generation and may be useful in the treatment of radiation-induced oral mucositis (14,15). The clinical effects of recombinant human epidermal growth factor (rhEGF) have not been assessed in patients with RID. We have, therefore, investigated the effects of rhEGF on the healing process in head and neck cancer patients with RID. Patients and methods Patient characteristics
From March to December 2008, seven head and neck cancer patients who underwent RT with curative intent at the Department of Radiation Oncology of Asan Medical Center were treated with a new dressing method for severe RID. The clinical characteristics of these seven patients, comprising five males and two females, of median age 59 years (range, 46–66 years), are described in Table 1. According to the 1997 American Joint Committee on Cancer (AJCC) staging classification, one patient (14%) had stage II, three (43%) had stage III and three (43%) had stage IV disease. RT was delivered as 2 Gy daily fractions, with a dose prescription for planning target volume as in International Commission on Radiation Units (ICRU) Report 50, for 5 days/week, for a total dose of 70 Gy. Six of the seven patients received concurrent chemotherapy. Radiation fields included the neck or supraclavicular area and the radiation dose to these areas was at least 46 Gy. Prior to starting the new dressing procedure, a medical history was taken from each patient. Dressings were changed once per day, 5 days/week (Monday to Friday) by one nurse (JH Lee), and the skin lesions were examined every day. Pictures of the wound, wound size, clinical appearance of the wound bed, nature and amount of wound exudate, odour, and wound pain were recorded every day. Signs of clinical infection in the wound site were monitored by a nurse and a primary physician. All patients provided oral informed consent.
once with rhEGF (Nepidermin® , Daewoong Pharmaceutical Co. Ltd, Seoul, South Korea); after 5 minutes, the wound was covered with Medifoam® (Ildong Co., Seoul, South Korea). Study design
The study was designed to explore the healing effects and safety of applying a topical rhEGF spray with a secondary foam dressing in seven patients experiencing RID. RID healing time was defined as the number of days until the achievement of complete skin integrity. Degree of wound healing was determined by examination of the reaction size and appearance of the RID area. Wounds that showed complete reepithelialisation, along with the complete absence of moist desquamation and disappearance of pain, were considered healed. Wound site infection was assessed by the presence of erythema, change in the nature of drainage from serous to purulent, odour, and systemic signs of infection including fever and leukocytosis. A swab of the wound was taken for culture before treatment and whenever signs of infection were detected. The Mann–Whitney U-test was used to assess differences in dermatitis scores. Results
No toxicity was associated with the use of the dressing containing rhEGF, and none of the patients experienced allergic reactions. Compliance was 100% during wound dressing for RID, and all patients completed this procedure without interruption. RID was classified by the common toxicity criteria (CTC) grading system (Table 2). Figure 1 illustrates a patient who showed an ulcerative moist desquamation in two areas of the neck. Healing and reepithelialisation time in patients with severe moist desquamation was much reduced compared with historical controls. Disappearance of exudate and reepithelialisation took 4–5 days. The number of dressings ranged from two to ten (median 6), and complete healing of RID took 6–14 days (median 8 days). None of these patients showed signs of wound infection or fever during the course of treatment. Discussion
Dressing methods
Moist desquamation wounds were fully opened and cleansed by gentle washing for more than 10 minutes with cotton balls soaked in cooled (4∘ C) 0⋅9% normal saline, followed by cleansing with 0⋅5% chlorhexidine. The wound was sprayed
Radiation researchers have known about radiation-induced skin reactions for over 100 years, with RID being a common acute complication of RT of the neck and supraclavicular area. The degree of RID depends on the fractionation schedule, accumulated dose, anatomically dependent areas (skin folds), radiation
Table 1 Patient baseline characteristics and healing outcomes Number of patients 1 2 3 4 5 6 7
Age/sex 46/F 59/M 46/F 62/M 49/M 66/M 65/M
Diagnosis
Pathology
Stage
Aim of RT
Nasopharynx Base of tongue Nasopharynx Tonsil Tonsil Pyriform sinus Glottis
Undifferentiated carcinoma Squamous cell carcinoma Undifferentiated carcinoma Squamous cell carcinoma Squamous cell carcinoma Squamous cell carcinoma Squamous cell carcinoma
T4N3aM0 T4N1M0 T4N1M0 T2N2bM0 T2N2cM0 T3N1M0 T2N0M0
Definitive Definitive Definitive Definitive Definitive Definitive Definitive
Dermatitis grade
Time to reepithelialisation (days)
Number of dressing
Time to healing (days)
G3 G3 G4 G3 G3 G4 G3
4 4 5 5 4 5 4
6 4 10 6 2 7 5
6 8 14 10 6 10 8
F, female; M, male. © 2014 The Authors International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
391
Lee et al.
Foam dressing with EGF for radiation dermatitis
(A)
(B)
(C)
(D)
Figure 1 Photographs of a representative patient with T1-stage glottis cancer who received definitively aimed radiotherapy. (A) Severe radiation dermatitis developed on the skin of the anterior neck area. Radiation therapy was interrupted and dressing was started (day 1). (B) On day 3, reepithelialisation was initiated, which markedly decreased pain in the skin wound. (C) On day 5, the moist wound had healed when radiation therapy was restarted. (D) on day 7, the patient had completely recovered from the radiation-induced skin wound.
Table 2 Grading system by common toxicity criteria (CTC) for RID Grade
Symptom
0 1 2
None Faint erythema or dry desquamation Moderate to brisk erythema or a patchy moist desquamation, mostly confined to skin folds and creases; moderate edema Confluent moist desquamation ≥1⋅5 cm diameter and not confined to skin folds; pitting edema Skin necrosis or ulceration of full thickness dermis; may include bleeding not induced by minor trauma or abrasion
3 4
RID, radiation-induced dermatitis.
beam quality and individual differences among patients (12,16). The incidence of severe RID has been markedly reduced by the use of megavoltage RT, which has skin-sparing effects, and by advanced RT planning techniques. However, when the target volume is located superficially, the skin receives an unavoidably high radiation dose. The combination of RT and chemotherapy further aggravates RID (16–18), resulting in dose-limiting toxicities in many head and neck cancer patients. Moreover, severe RID can cause radiation-induced fibrosis and may temporally interrupt RT, decreasing the radiation control rate (9). Prolonged overall RT can have a negative impact on treatment outcomes in head and neck cancer patients (19). RT of the skin can easily damage proliferating cells, especially in the basal cell layer. High doses of radiation to the skin can result in severe erythema and moist desquamation, with the 392
progression of severe RID involving the development of ulcers and/or necrosis (16). Moist desquamation is believed to result from the inability of basal cells to proliferate rapidly enough to supply cells for the epidermis, resulting in exposure of the dermis. Thus, early intervention for RID, when there are more residual proliferative cells in the basal layer, can result in more rapid recovery. Topical application of corticosteroids has shown a therapeutic effect in patients with acute RID (20,21). Hydrocortisone cream can decrease mild RID, such as irritated or inflamed skin, but is not recommended in the treatment of moist desquamation because it may enhance infection. Gentian violet has been used to prevent secondary infection in patients with moist desquamation because of its antifungal and antiseptic effects. However, gentian violet causes skin drying and can result in tightness, restricting movement in some patients. Moreover, cell proliferation, especially of fibroblasts and keratinocytes, may be reduced in dried skin. Gentian violet also stains the skin and clothes of patients, which is not aesthetically acceptable. Other topical agents, including Biafine, chamomile cream, almond ointment and topical vitamin C have not been shown to be effective. The effects of several growth factors, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), fibroblast growth factor (FGF), keratinocyte growth factor (KGF) and EGF, have been studied in the healing of intractable wounds (22–26). EGF has been shown, in animal models, to accelerate recovery from oral or intestinal mucosal damage induced by irradiation (27–29). Moreover, EGF spray has a healing effect in head and neck
© 2014 The Authors International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
Lee et al.
cancer patients with severe oral mucositis (14). We hypothesised that local EGF application to skin wounds would stimulate the proliferation of basal epithelial stem cells as well as fibroblasts of the submucosa. Wound dressing offers various benefits for damaged skin, including pain reduction, handling of secretions, and protection from mechanical and biological hazards (bacterial and viral contamination). Although various dressing methods, from open to moist dressing, have been used to treat RID, there is as yet no standard dressing method. Wound reepithelialisation is much faster with moist than with dry wound dressing (30). A moist environment of the wound is also important for lysing necrotic tissue and enhancing the phagocytosis of necrotic debris and bacteria (17). Among the moist dressing types used to treat RID are transparent, hydrocolloid and hydrogel dressings (31). We used a foam dressing to absorb exudates, hydrate wounds and prevent their adherence. In conclusion, our results suggest that the use of a topical rhEGF and hydrofoam dressing may have the potential to accelerate the healing of skin wounds caused by RT. Further randomised controlled trials exploring the efficacy of this intervention compared with a common standard of care are needed to determine a standard dressing method for RID. References 1. Vuong T, Franco E, Lehnert S, Lambert C, Portelance L, Nasr E, Faria S, Hay J, Larsson S, Shenouda G, Souhami L, Wong F, Freeman C. Silver leaf nylon dressing to prevent radiation dermatitis in patients undergoing chemotherapy and external beam radiotherapy to the perineum. Int J Radiat Oncol Biol Phys 2004;59:809–14. 2. Archambeau JO, Pezner R, Wasserman T. Pathophysiology of irradiated skin and breast. Int J Radiat Oncol Biol Phys 1995;31:1171–85. 3. Hopewell JW. The skin: its structure and response to ionizing radiation. Int J Radiat Biol 1990;57:751–73. 4. Hilderley L. Skin care in radiation therapy. A review of the literature. Oncol Nurs Forum 1983;10:51–6. 5. Ertekin MV, Tekin SB, Erdogan F, Karslioglu I, Gepdiremen A, Sezen O, Balci E, Gündogdu C. The effect of zinc sulphate in the prevention of radiation-induced dermatitis. J Radiat Res 2004;45:543–8. 6. Hansen O, Overgaard J, Hansen HS, Overgaard M, Hoyer M, Jorgensen KE, Bastholt L, Berthelsen A. Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiother Oncol 1997;43:47–51. 7. Van den Bogaert W, Van der Leest A, Rijnders A, Delaere P, Thames H, van der Schueren E. Does tumor control decrease by prolonging overall treatment time or interrupting treatment in laryngeal cancer? Radiother Oncol 1995;36:177–82. 8. Fisher J, Scott C, Stevens R, Marconi B, Champion L, Freedman GM, Asrari F, Pilepich MV, Gagnon JD, Wong G. Randomized phase III study comparing Best Supportive Care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97–13. Int J Radiat Oncol Biol Phys 2000;48:1307–10. 9. Williams MS, Burk M, Loprinzi CL, Hill M, Schomberg PJ, Nearhood K, O’Fallon JR, Laurie JA, Shanahan TG, Moore RL, Urias RE, Kuske RR, Engel RE, Eggleston WD. Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity. Int J Radiat Oncol Biol Phys 1996;36:345–9. 10. Liguori V, Guillemin C, Pesce GF, Mirimanoff RO, Bernier J. Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy. Radiother Oncol 1997;42:155–61.
Foam dressing with EGF for radiation dermatitis
11. Halperin EC, Gaspar L, George S, Darr D, Pinnell S. A double-blind, randomized, prospective trial to evaluate topical vitamin C solution for the prevention of radiation dermatitis. CNS Cancer Consortium. Int J Radiat Oncol Biol Phys 1993;26:413–6. 12. Bostrom A, Lindman H, Swartling C, Berne B, Bergh J. Potent corticosteroid cream (mometasone furoate) significantly reduces acute radiation dermatitis: results from a double-blind, randomized study. Radiother Oncol 2001;59:257–65. 13. Kouvaris JR, Kouloulias VE, Plataniotis GA, Balafouta EJ, Vlahos LJ. Dermatitis during radiation for vulvar carcinoma: prevention and treatment with granulocyte-macrophage colony-stimulating factor impregnated gauze. Wound Repair Regen 2001;9:187–93. 14. Wu HG, Song SY, Kim YS, Oh YT, Lee CG, Keum KC, Ahn YC, Lee SW. Therapeutic effect of recombinant human epidermal growth factor (RhEGF) on mucositis in patients undergoing radiotherapy, with or without chemotherapy, for head and neck cancer: a double-blind placebo-controlled prospective phase 2 multi-institutional clinical trial. Cancer 2009;115:3699–708. 15. Hong JP, Lee SW, Song SY, Ahn SD, Shin SS, Choi EK, Kim JH. Recombinant human epidermal growth factor treatment of radiation-induced severe oral mucositis in patients with head and neck malignancies. Eur J Cancer Care (Engl) 2009;18:636–41. 16. Sitton E. Early and late radiation-induced skin alterations. Part II: Nursing care of irradiated skin. Oncol Nurs Forum 1992;19:907–12. 17. Mak SS, Molassiotis A, Wan WM, Lee IY, Chan ES. The effects of hydrocolloid dressing and gentian violet on radiation-induced moist desquamation wound healing. Cancer Nurs 2000;23:220–9. 18. O’Rourke ME. Enhanced cutaneous effects in combined modality therapy. Oncol Nurs Forum 1987;14:31–5. 19. Horiot JC, Le Fur R, N’Guyen T, Chenal C, Schraub S, Alfonsi S, Gardani G, Van Den Bogaert W, Danczak S, Bolla M. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992;25:231–41. 20. Bjornberg A, Hellgren L, Magnusson B, Mattsson I, Rosengren B. Topical treatment of radiation dermatitis with bethamethasone17-valerate, vaseline and eucerine--a double-blind comparison. Clin Radiol 1967;18:463–4. 21. Bjoernberg A, Hellgren L, Olsson S. Treatment of radiation dermatitis with fluocinolone acetonide. Acta Radiol Ther Phys Biol 1965;3:129–34. 22. Braund R, Hook S, Medlicott NJ. The role of topical growth factors in chronic wounds. Curr Drug Deliv 2007;4:195–204. 23. Robson MC, Mustoe TA, Hunt TK. The future of recombinant growth factors in wound healing. Am J Surg 1998;176(2A Suppl):80S–2. 24. Goldman R. Growth factors and chronic wound healing: past, present, and future. Adv Skin Wound Care 2004;17:24–35. 25. Steed DL. Modifying the wound healing response with exogenous growth factors. Clin Plast Surg 1998;25:397–405. 26. Lee SW, Moon SY, Kim YH, Hong JP. The use of recombinant human epidermal growth factor to promote healing for chronic radiation ulcer. Int Wound J 2007;4:216–20. 27. Lee SW, Jung KI, Kim YW, Jung HD, Kim HS, Hong JP. Effect of epidermal growth factor against radiotherapy-induced oral mucositis in rats. Int J Radiat Oncol Biol Phys 2007;67:1172–8. 28. Lee KK, Jo HJ, Hong JP, Lee SW, Sohn JS, Moon SY, Yang SH, Shim H, Lee SH, Ryu SH, Moon SR. Recombinant human epidermal growth factor accelerates recovery of mouse small intestinal mucosa after radiation damage. Int J Radiat Oncol Biol Phys 2008;71:1230–5. 29. Ryu SH, Kim YH, Lee SW, Hong JP. The preventive effect of recombinant human growth factor (rhEGF) on the recurrence of radiodermatitis. J Radiat Res 2010;51:511–7. 30. Hom DB, Adams G, Koreis M, Maisel R. Choosing the optimal wound dressing for irradiated soft tissue wounds. Otolaryngol Head Neck Surg 1999;121:591–8. 31. Wickline MM. Prevention and treatment of acute radiation dermatitis: a literature review. Oncol Nurs Forum 2004;31:237–47.
© 2014 The Authors International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
393
ORIGINAL ARTICLE
Foam dressing with epidermal growth factor for severe radiation dermatitis in head and neck cancer patients Jihyo Lee1 , Sang-wook Lee1 , Joon Pio Hong2 , Myeong Wha Shon1 , Seung-Hee Ryu1 & Seung Do Ahn1 1 Department of Radiation Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea 2 Department of Plastic and Reconstructive Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
Key words Dermatitis; Epidermal growth factor; Foam dressing; Radiotherapy
Lee J, Lee S-w, Hong JP, Shon MW, Ryu SH, Ahn SD. Int Wound J 2016; 13:390–393
Correspondence to
This study was conducted to evaluate the effects of foam dressing with human recombinant human epidermal growth factor (rhEGF) on the healing process in head and neck cancer patients who experience radiation-induced dermatitis (RID). Seven patients, including three with oropharyngeal, two with nasopharyngeal and one each with hypopharyngeal and laryngeal carcinoma, who underwent radiotherapy (RT) for head and neck cancer at the Asan Medical Center from March to December 2008 were prospectively included in this study. Patients who showed severe RID (more than wet desquamation) on the supraclavicular fossa or neck areas were treated by wound cleaning and debridement of granulation tissue, followed by daily rhEGF spray and foam dressing. Median time to stop exudates and reepithelialisation was 4 days. Within 14 days (median 8 days), all patients showed complete healing of RID and no longer required dressings. This new method of treatment with dressing containing rhEGF may have the potential to accelerate the healing process in patients with RID. A case–control study is needed to confirm this finding.
S-w Lee, MD, PhD Department of Radiation Oncology University of Ulsan College of Medicine Asan Medical Center 388-1 Pungnap-dong Songpa-gu Seoul 138-736 South Korea E-mail: [email protected]
doi: 10.1111/iwj.12317
Abstract
Introduction
Skin is a radiosensitive organ, and radiation-induced dermatitis (RID) is the first documented side effect of X-rays. The pathogenesis of radiation-induced injury to the skin involves the depletion of stem cells from the basal cell layer of the epidermis, aggravated by inflammatory cytokines and bacterial colonisation after secondary infection (1–4). Acute reactions to high-dose radiation include erythema, epilation, dark pigmentation, dry desquamation and moist desquamation (5). Acute skin reactions develop after radiotherapy (RT) doses of 35–45 Gy, with recovery of confluent moist desquamation usually requiring 3–4 weeks after completion of RT. The severity of RID is dependent on dose fractionation, total dose, dose rate, irradiated volume, radiation quality, anatomic site, use of chemotherapy and several host factors. RT of superficially located tumours often induces RID. For example, RID is a common acute complication in patients with head and neck cancer, with irradiated skin folds being high-risk areas because of a self-bolus effect. Treatment of RID in head and neck cancer patients is very important to maintain and complete RT. RID can cause discomfort and pain, and severe RID such as moist desquamation can cause pain, secondary infection and a break in RT that may limit 390
treatment results in patients with head and neck and gynecologic cancers (6,7). Thus, prevention and/or reduction of RID can enhance timely completion of RT. Clinical studies have failed to show that topical agents, such as aloe vera, hyaluronic acid, vitamin C, Biafine and mometasone furoate cream, have protective or therapeutic effects in breast, head and neck, and gynecologic cancer patients (8–13), indicating a need for new drugs or methods. Epidermal growth
Key Messages
• foam dressing with recombinant human epidermal growth factor (rhEGF) has the ability to accelerate the healing process in radiation-induced dermatitis (RID) • head and neck cancer patients who underwent RT were prospectively included • time to stop exudates and reepithelialisation was 4 days; within 14 days (median 8 days), patients showed complete healing of RID • foam dressing containing rhEGF was effective in accelerating the healing process
© 2014 The Authors International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
Lee et al.
Foam dressing with EGF for radiation dermatitis
factor (EGF) acts to maintain tissue homeostasis by regulating epithelial cell proliferation, growth and migration. Thus, EGF plays an important role in wound healing and tissue generation and may be useful in the treatment of radiation-induced oral mucositis (14,15). The clinical effects of recombinant human epidermal growth factor (rhEGF) have not been assessed in patients with RID. We have, therefore, investigated the effects of rhEGF on the healing process in head and neck cancer patients with RID. Patients and methods Patient characteristics
From March to December 2008, seven head and neck cancer patients who underwent RT with curative intent at the Department of Radiation Oncology of Asan Medical Center were treated with a new dressing method for severe RID. The clinical characteristics of these seven patients, comprising five males and two females, of median age 59 years (range, 46–66 years), are described in Table 1. According to the 1997 American Joint Committee on Cancer (AJCC) staging classification, one patient (14%) had stage II, three (43%) had stage III and three (43%) had stage IV disease. RT was delivered as 2 Gy daily fractions, with a dose prescription for planning target volume as in International Commission on Radiation Units (ICRU) Report 50, for 5 days/week, for a total dose of 70 Gy. Six of the seven patients received concurrent chemotherapy. Radiation fields included the neck or supraclavicular area and the radiation dose to these areas was at least 46 Gy. Prior to starting the new dressing procedure, a medical history was taken from each patient. Dressings were changed once per day, 5 days/week (Monday to Friday) by one nurse (JH Lee), and the skin lesions were examined every day. Pictures of the wound, wound size, clinical appearance of the wound bed, nature and amount of wound exudate, odour, and wound pain were recorded every day. Signs of clinical infection in the wound site were monitored by a nurse and a primary physician. All patients provided oral informed consent.
once with rhEGF (Nepidermin® , Daewoong Pharmaceutical Co. Ltd, Seoul, South Korea); after 5 minutes, the wound was covered with Medifoam® (Ildong Co., Seoul, South Korea). Study design
The study was designed to explore the healing effects and safety of applying a topical rhEGF spray with a secondary foam dressing in seven patients experiencing RID. RID healing time was defined as the number of days until the achievement of complete skin integrity. Degree of wound healing was determined by examination of the reaction size and appearance of the RID area. Wounds that showed complete reepithelialisation, along with the complete absence of moist desquamation and disappearance of pain, were considered healed. Wound site infection was assessed by the presence of erythema, change in the nature of drainage from serous to purulent, odour, and systemic signs of infection including fever and leukocytosis. A swab of the wound was taken for culture before treatment and whenever signs of infection were detected. The Mann–Whitney U-test was used to assess differences in dermatitis scores. Results
No toxicity was associated with the use of the dressing containing rhEGF, and none of the patients experienced allergic reactions. Compliance was 100% during wound dressing for RID, and all patients completed this procedure without interruption. RID was classified by the common toxicity criteria (CTC) grading system (Table 2). Figure 1 illustrates a patient who showed an ulcerative moist desquamation in two areas of the neck. Healing and reepithelialisation time in patients with severe moist desquamation was much reduced compared with historical controls. Disappearance of exudate and reepithelialisation took 4–5 days. The number of dressings ranged from two to ten (median 6), and complete healing of RID took 6–14 days (median 8 days). None of these patients showed signs of wound infection or fever during the course of treatment. Discussion
Dressing methods
Moist desquamation wounds were fully opened and cleansed by gentle washing for more than 10 minutes with cotton balls soaked in cooled (4∘ C) 0⋅9% normal saline, followed by cleansing with 0⋅5% chlorhexidine. The wound was sprayed
Radiation researchers have known about radiation-induced skin reactions for over 100 years, with RID being a common acute complication of RT of the neck and supraclavicular area. The degree of RID depends on the fractionation schedule, accumulated dose, anatomically dependent areas (skin folds), radiation
Table 1 Patient baseline characteristics and healing outcomes Number of patients 1 2 3 4 5 6 7
Age/sex 46/F 59/M 46/F 62/M 49/M 66/M 65/M
Diagnosis
Pathology
Stage
Aim of RT
Nasopharynx Base of tongue Nasopharynx Tonsil Tonsil Pyriform sinus Glottis
Undifferentiated carcinoma Squamous cell carcinoma Undifferentiated carcinoma Squamous cell carcinoma Squamous cell carcinoma Squamous cell carcinoma Squamous cell carcinoma
T4N3aM0 T4N1M0 T4N1M0 T2N2bM0 T2N2cM0 T3N1M0 T2N0M0
Definitive Definitive Definitive Definitive Definitive Definitive Definitive
Dermatitis grade
Time to reepithelialisation (days)
Number of dressing
Time to healing (days)
G3 G3 G4 G3 G3 G4 G3
4 4 5 5 4 5 4
6 4 10 6 2 7 5
6 8 14 10 6 10 8
F, female; M, male. © 2014 The Authors International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
391
Lee et al.
Foam dressing with EGF for radiation dermatitis
(A)
(B)
(C)
(D)
Figure 1 Photographs of a representative patient with T1-stage glottis cancer who received definitively aimed radiotherapy. (A) Severe radiation dermatitis developed on the skin of the anterior neck area. Radiation therapy was interrupted and dressing was started (day 1). (B) On day 3, reepithelialisation was initiated, which markedly decreased pain in the skin wound. (C) On day 5, the moist wound had healed when radiation therapy was restarted. (D) on day 7, the patient had completely recovered from the radiation-induced skin wound.
Table 2 Grading system by common toxicity criteria (CTC) for RID Grade
Symptom
0 1 2
None Faint erythema or dry desquamation Moderate to brisk erythema or a patchy moist desquamation, mostly confined to skin folds and creases; moderate edema Confluent moist desquamation ≥1⋅5 cm diameter and not confined to skin folds; pitting edema Skin necrosis or ulceration of full thickness dermis; may include bleeding not induced by minor trauma or abrasion
3 4
RID, radiation-induced dermatitis.
beam quality and individual differences among patients (12,16). The incidence of severe RID has been markedly reduced by the use of megavoltage RT, which has skin-sparing effects, and by advanced RT planning techniques. However, when the target volume is located superficially, the skin receives an unavoidably high radiation dose. The combination of RT and chemotherapy further aggravates RID (16–18), resulting in dose-limiting toxicities in many head and neck cancer patients. Moreover, severe RID can cause radiation-induced fibrosis and may temporally interrupt RT, decreasing the radiation control rate (9). Prolonged overall RT can have a negative impact on treatment outcomes in head and neck cancer patients (19). RT of the skin can easily damage proliferating cells, especially in the basal cell layer. High doses of radiation to the skin can result in severe erythema and moist desquamation, with the 392
progression of severe RID involving the development of ulcers and/or necrosis (16). Moist desquamation is believed to result from the inability of basal cells to proliferate rapidly enough to supply cells for the epidermis, resulting in exposure of the dermis. Thus, early intervention for RID, when there are more residual proliferative cells in the basal layer, can result in more rapid recovery. Topical application of corticosteroids has shown a therapeutic effect in patients with acute RID (20,21). Hydrocortisone cream can decrease mild RID, such as irritated or inflamed skin, but is not recommended in the treatment of moist desquamation because it may enhance infection. Gentian violet has been used to prevent secondary infection in patients with moist desquamation because of its antifungal and antiseptic effects. However, gentian violet causes skin drying and can result in tightness, restricting movement in some patients. Moreover, cell proliferation, especially of fibroblasts and keratinocytes, may be reduced in dried skin. Gentian violet also stains the skin and clothes of patients, which is not aesthetically acceptable. Other topical agents, including Biafine, chamomile cream, almond ointment and topical vitamin C have not been shown to be effective. The effects of several growth factors, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), fibroblast growth factor (FGF), keratinocyte growth factor (KGF) and EGF, have been studied in the healing of intractable wounds (22–26). EGF has been shown, in animal models, to accelerate recovery from oral or intestinal mucosal damage induced by irradiation (27–29). Moreover, EGF spray has a healing effect in head and neck
© 2014 The Authors International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
Lee et al.
cancer patients with severe oral mucositis (14). We hypothesised that local EGF application to skin wounds would stimulate the proliferation of basal epithelial stem cells as well as fibroblasts of the submucosa. Wound dressing offers various benefits for damaged skin, including pain reduction, handling of secretions, and protection from mechanical and biological hazards (bacterial and viral contamination). Although various dressing methods, from open to moist dressing, have been used to treat RID, there is as yet no standard dressing method. Wound reepithelialisation is much faster with moist than with dry wound dressing (30). A moist environment of the wound is also important for lysing necrotic tissue and enhancing the phagocytosis of necrotic debris and bacteria (17). Among the moist dressing types used to treat RID are transparent, hydrocolloid and hydrogel dressings (31). We used a foam dressing to absorb exudates, hydrate wounds and prevent their adherence. In conclusion, our results suggest that the use of a topical rhEGF and hydrofoam dressing may have the potential to accelerate the healing of skin wounds caused by RT. Further randomised controlled trials exploring the efficacy of this intervention compared with a common standard of care are needed to determine a standard dressing method for RID. References 1. Vuong T, Franco E, Lehnert S, Lambert C, Portelance L, Nasr E, Faria S, Hay J, Larsson S, Shenouda G, Souhami L, Wong F, Freeman C. Silver leaf nylon dressing to prevent radiation dermatitis in patients undergoing chemotherapy and external beam radiotherapy to the perineum. Int J Radiat Oncol Biol Phys 2004;59:809–14. 2. Archambeau JO, Pezner R, Wasserman T. Pathophysiology of irradiated skin and breast. Int J Radiat Oncol Biol Phys 1995;31:1171–85. 3. Hopewell JW. The skin: its structure and response to ionizing radiation. Int J Radiat Biol 1990;57:751–73. 4. Hilderley L. Skin care in radiation therapy. A review of the literature. Oncol Nurs Forum 1983;10:51–6. 5. Ertekin MV, Tekin SB, Erdogan F, Karslioglu I, Gepdiremen A, Sezen O, Balci E, Gündogdu C. The effect of zinc sulphate in the prevention of radiation-induced dermatitis. J Radiat Res 2004;45:543–8. 6. Hansen O, Overgaard J, Hansen HS, Overgaard M, Hoyer M, Jorgensen KE, Bastholt L, Berthelsen A. Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiother Oncol 1997;43:47–51. 7. Van den Bogaert W, Van der Leest A, Rijnders A, Delaere P, Thames H, van der Schueren E. Does tumor control decrease by prolonging overall treatment time or interrupting treatment in laryngeal cancer? Radiother Oncol 1995;36:177–82. 8. Fisher J, Scott C, Stevens R, Marconi B, Champion L, Freedman GM, Asrari F, Pilepich MV, Gagnon JD, Wong G. Randomized phase III study comparing Best Supportive Care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97–13. Int J Radiat Oncol Biol Phys 2000;48:1307–10. 9. Williams MS, Burk M, Loprinzi CL, Hill M, Schomberg PJ, Nearhood K, O’Fallon JR, Laurie JA, Shanahan TG, Moore RL, Urias RE, Kuske RR, Engel RE, Eggleston WD. Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity. Int J Radiat Oncol Biol Phys 1996;36:345–9. 10. Liguori V, Guillemin C, Pesce GF, Mirimanoff RO, Bernier J. Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy. Radiother Oncol 1997;42:155–61.
Foam dressing with EGF for radiation dermatitis
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