Dermatologic adverse events to targeted therapies in lower gi cancers: Clinical presentation and management

Current Treatment Options in Oncology

Volumn 14, Issue 3, 2013, Pages 389-404

  Belum, Viswanath Reddy ^a   Cercek, Andrea ^a   Sanz Motilva, Virginia ^b   Lacouture, Mario E ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b HOSPITAL UNIVERSITARIO 12 DE OCTUBRE   (Spain)

Author keywords

Aflibercept; Antiangiogenic; Bevacizumab; Cetuximab; Colorectal; Dermatologic adverse events; EGFR inhibitors; Panitumumab; Regorafenib; VEGF VEGFR inhibitors

Indexed keywords

4 AMINOBUTYRIC ACID RECEPTOR STIMULATING AGENT; AFLIBERCEPT; AMMONIUM LACTATE; ANTIINFECTIVE AGENT; AVEENO; BEVACIZUMAB; BIOTIN; CEFADROXIL; CETUXIMAB; CLOBETASOL; CORTICOSTEROID; DIPHENHYDRAMINE; DOXYCYCLINE; EPIDERMAL GROWTH FACTOR RECEPTOR; HYDROXYZINE; KERATOLYTIC AGENT; LANOLIN ALCOHOL; LIDOCAINE; MINOCYCLINE; MINOXIDIL; NONSTEROID ANTIINFLAMMATORY AGENT; OPIATE; PANITUMUMAB; PERMANGANATE POTASSIUM; POVIDONE IODINE; PSEUDOMONIC ACID; REGORAFENIB; SALICYLIC ACID; SILVER NITRATE; TRIAMCINOLONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANICREAM; VASCULOTROPIN;

ACNEIFORM RASH; ALOPECIA; BEDTIME DOSAGE; CELL DIFFERENTIATION; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; CRYOTHERAPY; DRY SKIN; ENZYME ACTIVATION; ENZYME INHIBITION; ERYTHRODERMA; HAND FOOT SYNDROME; HUMAN; HYDRATION; HYPERPIGMENTATION; HYPERTRICHOSIS; LIFESTYLE MODIFICATION; METASTASIS; METASTATIC COLORECTAL CANCER; MOLECULARLY TARGETED THERAPY; MUCOSA INFLAMMATION; MUCOSAL BLEEDING; NASAL VESTIBULITIS; NOSE DISEASE; PARONYCHIA; PATIENT COUNSELING; PATIENT EDUCATION; PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN BINDING; PRURITUS; PYOGENIC GRANULOMA; QUALITY OF LIFE; RASH; REVIEW; SIGNAL TRANSDUCTION; SKIN CARE; SKIN EXFOLIATION; SKIN FISSURE; SKIN ULCER; STOMATITIS; TREATMENT OUTCOME; TRICHOMEGALY; WOUND HEALING IMPAIRMENT;

ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; GASTROINTESTINAL NEOPLASMS; HUMANS; MOLECULAR TARGETED THERAPY; PHENYLUREA COMPOUNDS; PYRIDINES; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; RECOMBINANT FUSION PROTEINS; SKIN;

EID: 84884209653     PISSN: 15272729     EISSN: 15346277     Source Type: Journal    
DOI: 10.1007/s11864-013-0254-4     Document Type: Review

References (73)

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, Cancer incidence and mortality worldwide: IARC CancerBase No. 10 [Internet]. Lyon: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr. Accessed April 1, 2013.
2. American Cancer Society, Inc. Colorectal Cancer: What are the key statistics about colorectal cancer? 2013. Available from: http://www.cancer.org/ cancer/colonandrectumcancer/detailedguide/colorectal-cancer-key-statistics. Accessed on April 1, 2013.
3. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23(16):3697-705.
4. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539-44.
5. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658-64.
6. Borner M, Koeberle D, Von Moos R, et al. Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK. Ann Oncol. 2008;19(7):1288-92.
7. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008;26(21):3523-9.
8. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(14):2311-9.
9. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-12.
10. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302.
11. Carpenter G, Cohen S. Epidermal growth factor. Annu Rev Biochem. 1979;48:193-216.
12. Yao M, Shuin T, Misaki H, Kubota Y. Enhanced expression of c-myc and epidermal growth factor receptor (C-erbB-1) genes in primary human renal cancer. Cancer Res. 1988;48(23):6753-7.
13. Ennis BW, Lippman ME, Dickson RB. The EGF receptor system as a target for antitumor therapy. Cancer Invest. 1991;9(5):553-62.
14. Albanell J, Rojo F, Averbuch S, et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol. 2002;20(1):110-24.
15. Jost M, Kari C, Rodeck U. The EGF receptor - an essential regulator of multiple epidermal functions. Eur J Dermatol. 2000;10(7):505-10.
16. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040-8.
17. Cetuximab [package insert]. Branchburg, NJ: Bristol Myers Squibb Company; 2012 (accessed from: http://www.accessdata.fda.gov/drugsatfda-docs/label/2012/ 125084s225lbl.pdf, on April 1, 2013).
18. Panitumumab [package insert]. Thousand Oaks, CA: Amgen Inc.; 2006-2012. Available from: http://www.accessdata.fda.gov/drugsatfda-docs/label/2012/ 125147s0148lbl.pdf. Accessed on April 1, 2013).
19. Van Doorn R, Kirtschig G, Scheffer E, Stoof TJ, Giaccone G. Follicular and epidermal alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor. Br J Dermatol. 2002;147(3):598-601.
20. 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):1425-33.
21. Perez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist. 2005;10(5):345-56.
22. 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):657-70.
23. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol. 2005;23(22):5235-46.
24. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408-17.
25. Luu M, Lai SE, Patel J, Guitart J, Lacouture ME. Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib. Photodermatol Photoimmunol Photomed. 2007;23(1):42-5.
26. Jacot W, Bessis D, Jorda E, et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours. Br J Dermatol. 2004;151(1):238-41.
27. Jatoi A, Green EM, Rowland Jr KM, Sargent DJ, Alberts SR. Clinical predictors of severe cetuximab-induced rash: observations from 933 patients enrolled in north central cancer treatment group study N0147. Oncology. 2009;77(2):120-3.
28. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-12.
29. Roe E, Garcia Muret MP, Marcuello E, Capdevila J, Pallares C, Alomar A. Description and management of cutaneous side effects during cetuximab or erlotinib treatments: a prospective study of 30 patients. J Am Acad Dermatol. 2006;55(3):429-37.
30. Eilers Jr RE, Gandhi M, Patel JD, et al. Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy. J Natl Cancer Inst. 2010;102(1):47-53.First study that highlighted the increased prevalence of infections, especially bacterial, in patients receiving EGFR inhibitors. Of note, the authors did not find an association between the use of corticosteroids or prophylactic antibiotics (used to treat the EGFR rash) and an increase in the risk of cutaneous infections.
31. Eames T, Grabein B, Kroth J, Wollenberg A. Microbiological analysis of epidermal growth factor receptor inhibitor therapy-associated paronychia. J Eur Acad Dermatol Venereol. 2010;24(8):958-60.A retrospective study that investigated and summarized the microbial agents associated with the development of paronychia, a nail condition that could potentially affect quality of life in cancer patients treated with EGFR inhibitors. Findings from this study provide justification for empiric antibiotic use to treat such infections.
32. Eaby B, Culkin A, Lacouture ME. An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors. Clin J Oncol Nurs. 2008;12(2):283-90.
33. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669-76.
34. Di Lorenzo G, Porta C, Bellmunt J, et al. Toxicities of targeted therapy and their management in kidney cancer. Eur Urol. 2011;59(4):526-40.
35. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21(1):60-5.
36. Bevacizumab [package insert]. South San Francisco, CA: Genentech, Inc.; 2011. Available from: http://www.accessdata.fda.gov/drugsatfda-docs/label/2011/ 125085s225lbl.pdf. Accessed on April 1, 2013.
37. Aflibercept [package insert]. Bridgewater, NJ: Sanofi Aventis US LLC.; 2012. Available from: http://products.sanofi.us/zaltrap/zaltrap.pdf. Accessed on April 1, 2013.
38. Regorafenib [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2013 (accessed from: http://labeling.bayerhealthcare.com/html/products/ pi/Stivarga-PI.pdf, on Apr 1, 2013).
39. Ellis LM. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol. 2006;33(5 Suppl 10):S1-7.
40. Wozel G, Sticherling M, Schon MP. Cutaneous side effects of inhibition of VEGF signal transduction. J Dtsch Dermatol Ges. 2010;8(4):243-9.
41. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843-50.
42. Chen HX, Gore-Langton RE, Cheson BD. Clinical trials referral resource: Current clinical trials of the anti-VEGF monoclonal antibody bevacizumab. Oncology (Williston Park). 2001;15(8):1017, 1020, 1023-1016.
43. Pegram MD, Reese DM. Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. Semin Oncol. 2002;29(3 Suppl 11):29-37.
44. Motl S. Bevacizumab in combination chemotherapy for colorectal and other cancers. Am J Health Syst Pharm. 2005;62(10):1021-32.
45. Man XY, Yang XH, Cai SQ, et al. Expression and localization of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 in human epidermal appendages: a comparison study by immunofluorescence. Clin Exp Dermatol. 2009;34(3):396-401.
46. Gavrilovic IT, Balagula Y, Rosen AC, et al. Characteristics of oral mucosal events related to bevacizumab treatment. Oncologist. 2012;17(2):274-8.
47. Belum VR, Wu S, Lacouture ME. Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis. Invest New Drugs. 2013;31(4):1078-86.
48. • Nardone B, Hensley JR, Kulik L, et al. The effect of hand-foot skin reaction associated with the multikinase inhibitors sorafenib and sunitinib on health-related quality of life. J Drugs Dermatol. 2012;11(11):e61-5.An important study which showed that the development of hand-foot skin reaction with the VEGF inhibitors sorafenib and sunitinib, negatively impacts patients' quality of life. The study also found that the NCI-CTCAE grading correlates with health-related quality of life.
49. Jatoi A, Nguyen PL. Do patients die from rashes from epidermal growth factor receptor inhibitors? A systematic review to help counsel patients about holding therapy. Oncologist. 2008;13(11):1201-4.
50. Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol. 2009;4(2):107-19.
51. Galimont-Collen AF, Vos LE, Lavrijsen AP, Ouwerkerk J, Gelderblom H. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer. 2007;43(5):845-51.
52. Jatoi A. Sunshine and rash: testing the role of sunscreen to prevent epidermal growth factor receptor inhibitor-induced rash. Support Cancer Ther. 2007;4(4):198-202.
53. Bhojani N, Jeldres C, Patard JJ, et al. Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma. Eur Urol. 2008;53(5):917-30.
54. Chuang P, Langone AJ. Clobetasol ameliorates aphthous ulceration in renal transplant patients on sirolimus. Am J Transplant. 2007;7(3):714-7.
55. Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005;6(7):491-500.
56. Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist. 2008;13(9):1001-11.
57. Chu D, Lacouture ME, Fillos T, Wu S. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol. 2008;47(2):176-86.
58. Scope A, Agero AL, Dusza SW, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol. 2007;25(34):5390-6.
59. Jatoi A, Rowland K, Sloan JA, et al. 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. 2008;113(4):847-53.
60. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(8):1351-7.This study investigated the benefit of pre-emptive use of a sunscreen, moisturizer, hydrocortisone 1% cream, and oral doxycycline 100 mg BID in mCRC patients treated with panitumumab. The authors noted a >50% reduction (29% vs 62% in the reactive group) in the incidence of ≥grade 2 rash and a significant delay in its onset, without any additional untoward events.
61. Jatoi A, Thrower A, Sloan JA, et al. Does sunscreen prevent epidermal growth factor receptor (EGFR) inhibitor-induced rash? Results of a placebo-controlled trial from the North Central Cancer Treatment Group (N05C4). Oncologist. 2010;15(9):1016-22.
62. Jatoi A, Dakhil SR, Sloan JA, et al. Prophylactic tetracycline does not diminish the severity of epidermal growth factor receptor (EGFR) inhibitor-induced rash: results from the North Central Cancer Treatment Group (Supplementary N03CB). Support Care Cancer. 2011;19(10):1601-7.
63. Grande R, Narducci F, Bianchetti S, et al. Pre-emptive skin toxicity treatment for anti-EGFR drugs: evaluation of efficacy of skin moisturizers and lymecycline. A phase II study. Support Care Cancer. Jan 13 2013.
64. Ren Z, Zhu K, Kang H, et al. A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma. J Clin Oncol. 2012;30 (suppl; abstr 4008). A large-scale study, which showed a statistically significant reduction (by 24%) of all grade hand-foot skin reaction in patients prophylactically treated with a urea-based cream.
65. Scope A, Lieb JA, Dusza SW, et al. A prospective randomized trial of topical pimecrolimus for cetuximab-associated acnelike eruption. J Am Acad Dermatol. 2009;61(4):614-20.
66. Ocvirk J. Management of cetuximab-induced skin toxicity with the prophylactic use of topical vitamin K1 cream. Radiol Oncol. 2010;44(4):265-6.
67. Perez-Soler R, Zou Y, Li T, Ling YH. The phosphatase inhibitor menadione (vitamin K3) protects cells from EGFR inhibition by erlotinib and cetuximab. Clin Cancer Res. 2011;17(21):6766-77. In this preclinical study, authors demonstrated the ability of menadione (vitamin K3; when applied topically and at nontoxic concentrations), to confer a protective effect on human keratinocytes and abate the EGFR inhibitory effect of erlotinib in skin.
68. Lopez-Ilasaca M, Schiene C, Kullertz G, Tradler T, Fischer G, Wetzker R. Effects of FK506-binding protein 12 and FK506 on autophosphorylation of epidermal growth factor receptor. J Biol Chem. 1998;273(16):9430-4.
69. Kanazawa S, Yamaguchi K, Kinoshita Y, Muramatsu M, Komiyama Y, Nomura S. Aspirin reduces adverse effects of gefitinib. Anticancer Drugs. 2006;17(4):423-7.
70. Kanazawa S, Yamaguchi K, Kinoshita Y, et al. Effect of low-dose aspirin for skin rash associated with erlotinib therapy in patients with lung cancer. Platelets. 2009;20(1):70-1.
71. Wong SF, Lindgren A, Mummaneni M, et al. A prospective crossover pilot study to evaluate the use of a topical wound gel in patients with cutaneous toxicity caused by epidermal growth factor receptor inhibitors. J Support Oncol. 2010;8(5):202-8.
72. Katzer K, Tietze J, Klein E, Heinemann V, Ruzicka T, Wollenberg A. Topical therapy with nadifloxacin cream and prednicarbate cream improves acneiform eruptions caused by the EGFR-inhibitor cetuximab - A report of 29 patients. Eur J Dermatol. 2010;20(1):82-4.
73. Onoda T, Ono T, Dhar DK, Yamanoi A, Nagasue N. Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent and -independent apoptosis in human colon cancer cells. Int J Cancer. 2006;118(5):1309-15.