Top

Published in:

01-01-2016 | Original Article

Phase II trial of epidermal growth factor ointment for patients with Erlotinib-related skin effects

Authors: In Gyu Hwang, Jung Hun Kang, Sung Yong Oh, Suee Lee, Sung-Hyun Kim, Ki-Hoon Song, Choonhee Son, Min Jae Park, Myung Hee Kang, Hoon Gu Kim, Jeeyun Lee, Young Suk Park, Jong Mu Sun, Hyun Jung Kim, Chan Kyu Kim, Seong Yoon Yi, Joung-Soon Jang, Keunchil Park, Hyo-Jin Kim

Published in: Supportive Care in Cancer | Issue 1/2016

Abstract

Purpose

The efficacy of erlotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated in patients with non-small cell lung cancer (NSCLC) and pancreatic cancer (PC). In the present study, we evaluated the effect of epidermal growth factor (EGF) ointment on erlotinib-related skin effects (ERSEs).

Methods

This was an open-label, non-comparative, multicenter, phase II trial. The patients included those diagnosed with NSCLC or PC who were treated with erlotinib. The effectiveness of the ointment was defined as follows: (1) grade 2, 3, or 4 ERSEs downgraded to ≤grade 1 or (2) grade 3 or 4 ERSEs downgraded to grade 2 and persisted for at least 2 weeks.

Results

Fifty-two patients from seven institutes in Korea were enrolled with informed consent. The final assessment included 46 patients (30 males, 16 females). According to the definition of effectiveness, the EGF ointment was effective in 36 (69.2 %) intention to treat patients. There were no statistically significant differences in the effectiveness of the EGF ointment by gender (p = 0.465), age (p = 0.547), tumor type (p = 0.085), erlotinib dosage (p = 0.117), and number of prior chemotherapy sessions (p = 0.547). The grading for the average National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) rating of rash/acne and itching improved from 2.02 ± 0.83 to 1.13 ± 0.89 and 1.52 ± 0.84 to 0.67 ± 0.90, respectively (p < 0.001). The most common reason for discontinuing the study was progression of cancer (37 %).

Conclusions

Based on the results, the EGF ointment is effective for ERSEs, regardless of gender, age, type of tumor, and dosage of erlotinib. The EGF ointment evenly improved all kinds of symptoms of ERSEs.

Clinical trial registration no.

ClinicalTrials.gov identifier: NCT01593995

Ciardiello F, Tortora G (2003) Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. Eur J Cancer 39:1348–1354CrossRefPubMed

Baselga J, Arteaga CL (2005) Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 23:2445–2459CrossRefPubMed

Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132CrossRefPubMed

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578CrossRefPubMed

Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345CrossRefPubMed

Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, You C (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12:735–742CrossRefPubMed

Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966CrossRefPubMed

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388CrossRefPubMed

Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334CrossRefPubMed

10.

Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, Ayoub J, Lago S, de Albuquerque RR, Gerogianni A, Cyjon A, Noble J, Laberge F, Chan RT, Fenton D, von Pawel J, Reck M, Shepherd FA (2006) Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 24:3831–3837CrossRefPubMed

11.

Lynch Jr TJ,, Kim ES, Eaby B, Garey J, West DP, Lacouture ME (2007) Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 12:610–621

12.

Li T, Perez-Soler R (2009) Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol 4:107–119CrossRefPubMed

13.

Joshi SS, Ortiz S, Witherspoon JN, Rademaker A, West DP, Anderson R, Rosenbaum SE, Lacouture ME (2010) Effects of epidermal growth factor receptor inhibitor-induced dermatologic toxicities on quality of life. Cancer 116:3916–3923CrossRefPubMed

14.

Galimont-Collen AF, Vos LE, Lavrijsen AP, Ouwerkerk J, Gelderblom H (2007) Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer 43:845–851CrossRefPubMed

15.

Thatcher N, Nicolson M, Groves RW, Steele J, Eaby B, Dunlop J, McPhelim J, Nijjar R, Ukachukwu I (2009) Expert consensus on the management of erlotinib-associated cutaneous toxicity in the U.K. Oncologist 14:840–847PubMed

16.

Gridelli C, Maione P, Amoroso D, Baldari M, Bearz A, Bettoli V, Cammilluzzi E, Crino L, De Marinis F, Di Pietro FA, Grossi F, Innocenzi D, Micali G, Piantedosi FV, Scartozzi M (2008) Clinical significance and treatment of skin rash from erlotinib in non-small cell lung cancer patients: results of an experts panel meeting. Crit Rev Oncol Hematol 66:155–162CrossRefPubMed

17.

Lacouture ME, Maitland ML, Segaert S, Setser A, Baran R, Fox LP, Epstein JB, Barasch A, Einhorn L, Wagner L, West DP, Rapoport BL, Kris MG, Basch E, Eaby B, Kurtin S, Olsen EA, Chen A, Dancey JE, Trotti A (2010) A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Support Care Cancer 18:509–522CrossRefPubMed

18.

Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, Rigas J, Clark GM, Santabarbara P, Bonomi P (2004) Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22:3238–3247CrossRefPubMed

19.

Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812CrossRefPubMed

20.

Hong JP, Kim YW, Jung HD, Jung KI (2006) The effect of various concentrations of human recombinant epidermal growth factor on split-thickness skin wounds. Int Wound J 3:123–130CrossRefPubMed

21.

Kwon YB, Kim HW, Roh DH, Yoon SY, Baek RM, Kim JY, Kweon H, Lee KG, Park YH, Lee JH (2006) Topical application of epidermal growth factor accelerates wound healing by myofibroblast proliferation and collagen synthesis in rat. J Vet Sci 7:105–109PubMedCentralCrossRefPubMed

22.

Oh SY, Hwang IG, Lee J, Park MJ, Lee S, Kim S, Song K, Son CH, Kang JH, Kim HG, Park YS, Sun J, Kim HJ, Kim CK, Yi SY, Jang J, Kim HJ (2014) Phase II trial of epidermal growth factor ointment for patients with erlotinib-related skin effects. Annals of Oncology 25(supplement4): iv471-477.

23.

Jatoi A, Rowland K, Sloan JA, Gross HM, Fishkin PA, Kahanic SP, Novotny PJ, Schaefer PL, Johnson DB, Tschetter LK, Loprinzi CL (2008) Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer 113:847–853PubMedCentralCrossRefPubMed

24.

Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10.

25.

Reguiai Z, Bachet JB, Bachmeyer C, Peuvrel L, Beylot-Barry M, Bezier M, Boucher E, Chevelle C, Colin P, Guimbaud R, Mineur L, Richard MA, Artru P, Dufour P, Gornet JM, Samalin E, Bensadoun RJ, Ychou M, Andre T, Dreno B, Bouche O (2012) Management of cutaneous adverse events induced by anti-EGFR (epidermal growth factor receptor): a French interdisciplinary therapeutic algorithm. Support Care Cancer 20:1395–1404CrossRefPubMed

26.

Cohen S (1962) Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 237:1555–1562PubMed

27.

Nanney LB (1990) Epidermal and dermal effects of epidermal growth factor during wound repair. J Investig Dermatol 94:624–629CrossRefPubMed

28.

Brown GL, Curtsinger 3rd L, Brightwell JR, Ackerman DM, Tobin GR, Polk Jr HC,, George-Nascimento C, Valenzuela P, Schultz GS (1986) Enhancement of epidermal regeneration by biosynthetic epidermal growth factor. J Exp Med 163:1319–1324

29.

Brown GL, Curtsinger LJ, White M, Mitchell RO, Pietsch J, Nordquist R, von Fraunhofer A, Schultz GS (1988) Acceleration of tensile strength of incisions treated with EGF and TGF-beta. Ann Surg 208:788–794PubMedCentralCrossRefPubMed

30.

Hong JP, Lee SW, Song SY, Ahn SD, Shin SS, Choi EK, Kim JH (2009) Recombinant human epidermal growth factor treatment of radiation-induced severe oral mucositis in patients with head and neck malignancies. Eur J Cancer Care (Engl) 18:636–641CrossRef

31.

Wu HG, Song SY, Kim YS, Oh YT, Lee CG, Keum KC, Ahn YC, Lee SW (2009) 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 115:3699–3708CrossRefPubMed

32.

Valenzuela-Silva CM, Tuero-Iglesias AD, Garcia-Iglesias E, Gonzalez-Diaz O, Del Rio-Martin A, Yera Alos IB, Fernandez-Montequin JI, Lopez-Saura PA (2013) Granulation response and partial wound closure predict healing in clinical trials on advanced diabetes foot ulcers treated with recombinant human epidermal growth factor. Diabetes Care 36:210–215PubMedCentralCrossRefPubMed

33.

Shin JU, Park JH, Cho BC, Lee JH (2012) Treatment of epidermal growth factor receptor inhibitor-induced acneiform eruption with topical recombinant human epidermal growth factor. Dermatology 225:135–140CrossRefPubMed

34.

Dancey J, Sausville EA (2003) Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2:296–313CrossRefPubMed

35.

Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, Wechsler J, Lhomme C, Escudier B, Boige V, Armand JP, Le Chevalier T (2005) Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6:491–500CrossRefPubMed

36.

Perez-Soler R, Delord JP, Halpern A, Kelly K, Krueger J, Sureda BM, von Pawel J, Temel J, Siena S, Soulieres D, Saltz L, Leyden J (2005) HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 10:345–356CrossRefPubMed

37.

Tsimboukis S, Merikas I, Karapanagiotou EM, Saif MW, Syrigos KN (2009) Erlotinib-induced skin rash in patients with non-small-cell lung cancer: pathogenesis, clinical significance, and management. Clin Lung Cancer 10:106–111CrossRefPubMed

38.

Ocvirk J, Heeger S, McCloud P, Hofheinz RD (2013) A review of the treatment options for skin rash induced by EGFR-targeted therapies: evidence from randomized clinical trials and a meta-analysis. Radiol Oncol 47:166–175PubMedCentralCrossRefPubMed

39.

Baas JM, Krens LL, Guchelaar HJ, Ouwerkerk J, de Jong FA, Lavrijsen AP, Gelderblom H (2012) Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review. Cancer Treat Rev 38:505–514CrossRefPubMed

40.

Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB, Eaby-Sandy B, Murphy BA (2011) Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19:1079–1095PubMedCentralCrossRefPubMed

41.

Scope A, Agero AL, Dusza SW, Myskowski PL, Lieb JA, Saltz L, Kemeny NE, Halpern AC (2007) Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 25:5390–5396CrossRefPubMed

42.

Abdullah SE, Haigentz Jr M,, Piperdi B (2012) Dermatologic toxicities from monoclonal antibodies and tyrosine kinase inhibitors against EGFR: pathophysiology and management. Chemother Res Pract 2012:351210

43.

Tan EH, Chan A (2009) Evidence-based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Ann Pharmacother 43:1658–1666CrossRefPubMed

44.

Hashimoto H, Iwasa S, Yanai T, Honma Y, Kato K, Hamaguchi T, Yamada Y, Shimada Y, Namikawa K, Tsutsumida A, Yamazaki N, Yamamoto H (2013) A double-blind, placebo-controlled study of the safety and efficacy of vitamin K1 ointment for the treatment of patients with cetuximab-induced acneiform eruption. Jpn J Clin Oncol 43:92–94CrossRefPubMed

45.

Tomkova H, Pospiskova M, Zabojnikova M, Kohoutek M, Serclova M, Gharibyar M, Sternbersky J (2013) Phytomenadione pre-treatment in EGFR inhibitor-induced folliculitis. J Eur Acad Dermatol Venereol 27:514–519CrossRefPubMed

46.

Jo JC, Hong YS, Kim KP, Lee JL, Kim HJ, Lee MW, Lim SB, Yu CS, Kim JC, Kim JH, Kim TW (2013) Topical vitamin K1 may not be effective in preventing acneiform rash during cetuximab treatment in patients with metastatic colorectal cancer. Eur J Dermatol 23:77–82PubMed

Title: Phase II trial of epidermal growth factor ointment for patients with Erlotinib-related skin effects
Authors: In Gyu Hwang
Jung Hun Kang
Sung Yong Oh
Suee Lee
Sung-Hyun Kim
Ki-Hoon Song
Choonhee Son
Min Jae Park
Myung Hee Kang
Hoon Gu Kim
Jeeyun Lee
Young Suk Park
Jong Mu Sun
Hyun Jung Kim
Chan Kyu Kim
Seong Yoon Yi
Joung-Soon Jang
Keunchil Park
Hyo-Jin Kim
Publication date: 01-01-2016
Publisher: Springer Berlin Heidelberg
Published in: Supportive Care in Cancer / Issue 1/2016
Print ISSN: 0941-4355
Electronic ISSN: 1433-7339
DOI: https://doi.org/10.1007/s00520-015-2783-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Clinical trial registration no.

Please log in to get access to this content

Other articles of this Issue 1/2016

Defining cancer-related fatigue for biomarker discovery

Is febrile neutropenia prophylaxis with granulocyte-colony stimulating factors economically justified for adjuvant TC chemotherapy in breast cancer?

Treatment complexity: a description of chemotherapy and supportive care treatment visits in patients with advanced-stage cancer diagnoses

Sleep complaints in survivors of pediatric brain tumors

Indigenous cancer patient and staff attitudes towards unmet needs screening using the SCNAT-IP

Developing a clinical pathway for the identification and management of anxiety and depression in adult cancer patients: an online Delphi consensus process

Keynote webinar | Spotlight on antibody–drug conjugates in cancer