CASE‑1
Correspondence
A severe dermatologic adverse effect related with gefitinib: Case report and review of the literature ABSTRACT Gefitinib, a selective inhibitor of the epidermal growth factor receptor‑tyrosine kinase, it’s one of the most frequent drug‑related adverse effects (AEs) reported in literature is dermatologic AEs. We report, a case of severe cutaneous adverse reactions induced by gefitinib as second‑line treatment in a male patient with advanced non‑small cell lung cancer after 1 month of treatment. Although tumor shrunk and patient got benefit from the treatment, gefitinib had to be stopped right away. We managed the symptoms of rash with a variety of treatments, including topical ethacridine lactate, antihistamine and so on. After the rash improved, we found his tumor were progress. Then he took gefitinib again without severe skin toxicity or disease progression. We think the development of gefitinib‑induced rash may be a sign of effective and administrating it again maybe relieves the degree of rash. KEY WORDS: Dermatologic adverse effect, gefitinib, the epidermal growth factor inhibitor
INTRODUCTION
CASE REPORTS
Gefitinib (iressa), one of the epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors, is orally bioavailable, synthetic anilinoquinazoline that target adenosine triphosphate binding selectively and reversibly to the intracellular tyrosine kinase domain of the receptor, thus blocking EGFR signal transmission and inhibiting proliferation of the tumor cells.[1,2] The specificity of EGFR inhibitors (EGFRIs) for the target results in a much more favorable safety profile than most standard chemotherapy agents, with fewer non‑specific toxicities and no hematopoietic effects.[3] It has come to be more important drug for patients with locally advanced or metastatic non‑small cell lung cancer (NSCLC) with activating mutations of EGFR in all lines of therapy[4,5] and without that in second‑line therapy.[6,7]
A 58‑year‑old man who never smoked presented with severe cough and pain on the right lower extremity and hip joint and a performance status of approximately one. He had normal liver and renal functions and he had no history of hypersensitivity disease, excessive alcohol intake, drug abuse. A computed tomography (CT) scan of the chest confirmed a solitary, spiculated lesion in the right lower lung lobe. Tissues biopsy of the bronchoscopes revealed adenocarcinoma. He was diagnosed as having a primary NSCLC with multiple bone metastases. EGFR gene mutation analysis did not show the presence of any mutation. After 4 cycles Systemic chemotherapy with cisplatin and gemcitabine, he was confirmed disease progression with multiple pulmonary metastasis and brain metastasis. His serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)‑125 levels were all elevated, at 1441 ng/ml and 55.1 U/ml respectively. Then, he was treated with gefitinib 250 mg orally once daily. After 3 weeks, his cough and pain had improved and CT scan revealed lung tumor include primary and metastasis lesions shrinkage, some lesions disappeared. His serum CEA and CA‑125 were dramatically decreased to 400.7 ng/ml and 54.8 U/ml respectively. Evaluation of effect was partial response (PR). At that time, there are multiple and scattered acneiform eruptions with mild itching, distributing at orofacial and chest, without ulceration. However, on the 36th days after starting gefitinib, there were severe skin rashes appearing extensively. His skin
However, because of the important role of EGFR in the physiology of the skin, the treatment of EGFRIs can result in the dermatologic adverse effects (AEs) that have been more prevalent and described with a variety of manifestation.[2] Although these adverse reactions are rarely life‑threatening, they have a deep effect on patients’ quality‑of‑life including physical, financial, emotional and social well‑being.[8] They can lead to dose modification or discontinuation of life‑saving or prolonging treatment.[9] This has resulted in a growing concern in the dermatologic AEs associated with EGFRIs. Here, we reported a case with NSCLC, who suffered severe dermatologic AEs related with gefitinib. S110
Yuan‑Qing Li, Hong Sun, Dong Xue Department of Integration of TCM and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China For correspondence: Dr. Hong Sun, Department of Integration of TCM and Western Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, China. E-mail: sunhong2273@ 163.com Dr. Yuan-Qing Li, Department of Integration of TCM and Western Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District 100142, Beijing, China. E-mail: liyuanqing2999@ 126.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.119123 PMID: *** Quick Response Code:
Journal of Cancer Research and Therapeutics - Supplement 2 - 2013 - Volume 9
Li, et al.: Dermatologic adverse effect of gefitinib
had been red and swelling so serious that cannot illegible appearance. The rash’s manifestation was diverse, including erythema, acneiform rash and pustular rash and local crusting, some sites showed a lichenoid changes. Patient had not complained of any clinical symptoms such as fever, nausea, diarrhea, abdominal pain or fatigue and he had taken no other medications or supplements. Thus, gefitinib‑induced heavy degree skin injury was suspected [Figures 1‑3]. After stopping gefitinib, he received combined therapies, which included administrating loratadine tablets, 10 mg, once a day, smearing with 0.1% ethacridine lactate topically, and so on. After 1 week, the symptoms significantly relieved, the rashes subsided gradually, only remain erythema, pigmentation, crusting and desquamation. Then, antiallergic medication was stopped. After 1 month stopped treatment of gefitinib, the rashes on the face and chest disappeared, no obvious pigmentation, only little crust were scattered in his limbs. Reviewing a chest CT, it showed lesion in the right lung and lymphnodes similar, but metastasis lesions in the both of lung larger than before. Head magnetic resonance
imaging showed similar with before. His CEA was 199 ng/ml and CA‑125 was 94.75 U/ml. Then, gefitinib 250 mg once daily was started again with carefully monitoring of cutaneous AEs. After 1 month, there was little acneiform rash scattered on the side of his nose with mild itch, no rashes on the body and the extremities [Figures 4 and 5]. The CT showed that the mass in the right lower lung lobe and pulmonary metastatic nodules were diminished further. His CEA was 87.84 ng/ml and CA‑125 was 22.02 U/ml. The comprehensive evaluation of effect was PR again. The patient got benefit from gefitinib once again with tolerated skin rash. DISCUSSION Skin rash has been documented as one of the most common adverse reactions in patients receiving EGFRIs. In fact, the incidence of rash in patients treated with these new agents ranges from 50% to 100%. [3,10,11] The common reported EGFRIs‑induced dermatologic AEs are acneiform‑like rash (also described as a papulopustular rash), pruritus, xerosis, fissures, desquamation, nail changes (mostly
Figure 1: Extensive erythema, local acneiform rash, pustular rash and exudate on his trunk
Figure 2: Diffuse painful erythema and edema on his upper extremity that affecting daily activities
Figure 3: Serious papulopustular eruption on the face, with edema, erythema and eschar
Figure 4: After 1 month started gefitinib again, there was a little acneform rash scattered only on the side of his nose with mild itch
Journal of Cancer Research and Therapeutics - Supplement 2 - 2013 - Volume 9
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Li, et al.: Dermatologic adverse effect of gefitinib
Figure 5: There was no rash on his hands and extremities, only remained a little skin pigmentation
paronychia, brittle nails), trichomegaly, hyperpigmentation, telangiectases, alopecia.[12,13] A papulopustular rash is the most common cutaneous toxicity of EGFRIs, affecting up to 90% of patients.[14] The severity of rash is mild to moderate. A small number of Grade 3‑4 will significantly affect the quality‑of‑life for some patients, some even effect tumor treatment. Grade 3‑4 dermatologic AEs occurred in 1.6% of gefitinib‑treated patients.[3] Some studies have reported that the emergence and extent of the rash is correlated with tumor response and the overall survival.[15] The emergence of the rash may be the performance of treatment effective. Some even suggested that the response of treatment of EGFRIs is possibly improved by increasing the doses until the acne‑like rash emerge. However, such speculation has not been confirmed yet. Some multiple studies with cetuximab[16,17] and erlotinib[18‑20] showed positive correlation of rash with response rates and survival. Data from a Phase II trial with ABX‑EGF showed a trend between the severity of rash and progression‑free survival. [21] The retrospective analysis of panitumumab confirmed an association between clinically graded skin toxicity and patient‑reported outcome, quality‑of‑life, longer progression‑free survival and overall survival. The authors suggest that skin reactions should be treated while continuing EGFR‑targeted therapy.[22] However, other studies were not drawn the conclusion of the correlation between skin rash and efficacy of anti‑EGFR therapy. [23‑27] In the large Phase II monotherapy trials, IDEAL 1 and 2, 250 mg/d and 500 mg/d gefitinib were evaluated in 200 patients with NSCLC.[25] The response rates in 250 mg/d group and 500 mg/d group were 12% and 9%, symptom control rate were 43% and 35% respectively. The occurrence and the severity of the rash in both groups were dose‑related, but the response rate was not dose‑related or any correlation between rash and tumor response rate. It might indicate that the emergence of the rash cannot guarantee a response. So there would be further studies to determine the clinical significance of these results. Though potential treatment suggestions for EGFRI‑associated dermatologic AEs have been evaluated in clinical trials, standard guidelines have not been published so far.[28,29] S112
However, a series of recent randomized controlled trials investigating the prophylactic role of oral antibiotics, such as minocycline and doxycycline, yielded encouraging results.[30] Some recommended that prophylactic treatment, such as local or systemic use of antibiotics, should be given at the beginning of targeted therapy.[31] Prophylactic treatment for skin toxicity observed in patients received panitumumab, compared with medication after skin reactions occurring the occurrence rates of the skin adverse reaction over Grade 2 were 29% and 62% respectively. It shows drug prevention impact on quality‑of‑life was significantly lower than that of the latter.[32] For this case, the treatment of gefitinib induced serious dermatologic AE, which is really rare. During the early phase the cutaneous adverse reactions only manifested as limited acne‑like rash. However, with the administration of gefitinib persistently, the severe cutaneous adverse reactions broke out in a few days. The rashes almost involved with the whole body skin, especially on the face. A variety of rash forms were coexist, accompanied by swelling, oozing, crusting and peeling and local infection. The patient’s daily life was limited, which seriously affected the quality‑of‑life. Although the anti‑tumor therapy was effective, we had to interrupt the treatment of gefitinib. After stopped the treatment of gefitinib and administrated actively, the rash was improved significantly in the short term. We analyzed that the reason is contributed to not only interruption of the treatment of gefitinib, but also the reasonable and effective medicines. It also showed that the EGFRIs‑induced cutaneous adverse reactions are reversible and can be controlled effectively. The efficacy of the anti‑allergic agents and antibiotic treatment is still pending and need to further studies. However, it is positive and necessary that using these drugs in the severe stages of the rash, which can control the systemic inflammatory response and prevent more serious skin infections. Patients took gefitinib again after the tumor progressed, but there were no serious dermatologic AE appearing. Patient got clinical benefit again from the treatment of gefitinib. That may indicate that dermatologic AE can relieve after administrating gefitinib again. On the whole, the treatment of EGFRIs is widely using in clinical and its benefit is significant. However, its dermatologic AE may eventually lead to some patient compliance reduced, interfere with normal treatment, dose reduction or even interrupt tumor treatment, in severe cases it affect quality of life significantly.[33,34] Although the incidence of severe grades is not often, we should pay enough attention to it. For reducing its adverse impact and deriving more clinical benefits, it needs more studies to confirm some results and establish the standard of EGFRIs‑related dermatologic AE as soon as possible. REFERENCES 1. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002;7 Suppl 4:2‑8. 2. Su Z. Epidermal growth factor receptor mutation‑guided treatment Journal of Cancer Research and Therapeutics - Supplement 2 - 2013 - Volume 9
Li, et al.: Dermatologic adverse effect of gefitinib
for lung cancers: Where are we now? Thorac Cancer 2011;2:1‑6. 3. Ricciardi S, Tomao S, de Marinis F. Toxicity of targeted therapy in non‑small‑cell lung cancer management. Clin Lung Cancer 2009;10:28‑35. 4. Yang C, Fukuoka M, Mok TS, et al. Final Overall Survival (OS) Results from a Phase III, Randomised, Open‑Label, First‑Line Study of Gefitinib (G) v Carboplatin/Paclitaxel (C/P) in Clinically Selected Patients with Advanced Non‑Small Cell Lung Cancer (NSCLC) in Asia (IPASS). Abstract LBA2. ESMO; 2010. 5. Huang Z, Wang Z, Bai H, Wu M, An T, Zhao J, et al. The detection of EGFR mutation status in plasma is reproducible and can dynamically predict the efficacy of EGFR‑TKI. Thorac Cancer 2012;3:334‑40. 6. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non‑small‑cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008;372:1809‑18. 7. Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non‑small‑cell lung cancer. J Clin Oncol 2009;27:6251‑66. 8. Joshi SS, Ortiz S, Witherspoon JN, Rademaker A, West DP, Anderson R, et al. Effects of epidermal growth factor receptor inhibitor‑induced dermatologic toxicities on quality of life. Cancer 2010;116:3916‑23. 9. Agha R, Kinahan K, Bennett CL, Lacouture ME. Dermatologic challenges in cancer patients and survivors. Oncology (Williston Park) 2007;21:1462‑72. 10. Wagner LI, Lacouture ME. Dermatologic toxicities associated with EGFR inhibitors: The clinical psychologist’s perspective. Impact on health‑related quality of life and implications for clinical management of psychological sequelae. Oncology (Williston Park) 2007;21:34‑6. 11. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004;22:77‑85. 12. Chen AP, Setser A, Anadkat MJ, Cotliar J, Olsen EA, Garden BC, et al. Grading dermatologic adverse events of cancer treatments: The common terminology criteria for adverse events version 4.0. J Am Acad Dermatol 2012;67:1025‑39. 13. Balagula Y, Rosen ST, Lacouture ME. The emergence of supportive oncodermatology: The study of dermatologic adverse events to cancer therapies. J Am Acad Dermatol 2011;65:624‑35. 14. Pérez‑Soler R, Delord JP, Halpern A, Kelly K, Krueger J, Sureda BM, et al. HER1/EGFR inhibitor‑associated rash: Future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 2005;10:345‑56. 15. Peréz‑Soler R, Saltz L. Cutaneous adverse effects with HER1/ EGFR‑targeted agents: Is there a silver lining? J Clin Oncol 2005;23:5235‑46. 16. Saltz L, Kies M, Abbruzzese JL, Needle M. The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 2003;22:204. 17. Racca P, Fanchini L, Caliendo V, Ritorto G, Evangelista W, Volpatto R, et al. Efficacy and skin toxicity management with cetuximab in metastatic colorectal cancer: Outcomes from an oncologic/dermatologic cooperation. Clin Colorectal Cancer 2008;7:48‑54. 18. Herbst RS, Prager D, Hermann R. TRIBUTE: A phase III trial of erlotinib HCL (OSI‑774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non‑small cell lung cancer (NSCLC). J Clin Oncol 2004;22:617. 19. Gatzemeier U, Pluzanska A, Szczesna A. Results of a phase III trial of erlotinib (OSI‑774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non‑small cell lung cancer (NSCLC). J Clin Oncol 2004;22:617. Journal of Cancer Research and Therapeutics - Supplement 2 - 2013 - Volume 9
20. Pérez‑Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. Determinants of tumor response and survival with erlotinib in patients with non – Small‑cell lung cancer. J Clin Oncol 2004;22:3238‑47. 21. Rowinsky EK, Schwartz GH, Gollob JA, Thompson JA, Vogelzang NJ, Figlin R, et al. Safety, pharmacokinetics, and activity of ABX‑EGF, a fully human anti‑epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 2004;22:3003‑15. 22. Peeters M, Siena S, Van Cutsem E, Sobrero A, Hendlisz A, Cascinu S, et al. Association of progression‑free survival, overall survival, and patient‑reported outcomes by skin toxicity and KRAS status in patients receiving panitumumab monotherapy. Cancer 2009;115:1544‑54. 23. Tejpar S, Peeters M, Humbler Y. The EVEREST study: Relationship between efficacy and K‑ras mutation status in patients with irinotecan‑refractory mCRC treated with irinotecan and standard or escalating doses of cetuximab. Ann Oncol 2008;19 Suppl Vi: 14. 24. Karthaus M, Speiss G, Hofheinz R. Management of epidermal‑growth factor receptor inhibitor‑related skin toxicity: A first‑line, phase II study (20060314) of panitumumab with FOLFIRI in the treatment of metastatic colorectal cancer. Ann Oncol 2009;20 Suppl 7:Vii12. 25. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non‑small cell lung cancer: A randomized trial. JAMA 2003;290:2149‑58. 26. Cohen EE, Rosen F, Stadler WM, Recant W, Stenson K, Huo D, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980‑7. 27. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22:133‑42. 28. Burtness B, Anadkat M, Basti S, Hughes M, Lacouture ME, McClure JS, et al. NCCN Task Force Report: Management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Canc Netw 2009;7 Suppl 1:S5‑21. 29. Potthoff K, Hofheinz R, Hassel JC, Volkenandt M, Lordick F, H a r t ma n n J T, et al. I n t erd is c ipl in a r y ma n ag e m e nt o f EGFR‑inhibitor‑induced skin reactions: A German expert opinion. Ann Oncol 2011;22:524‑35. 30. Scope A, Agero AL, Dusza SW, Myskowski PL, Lieb JA, Saltz L, et al. Randomized double‑blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab‑associated acne‑like eruption. J Clin Oncol 2007;25:5390‑6. 31. Herbst RS, LoRusso PM, Purdom M, Ward D. Dermatologic side effects associated with gefitinib therapy: Clinical experience and management. Clin Lung Cancer 2003;4:366‑9. 32. Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, 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;28:1351‑7. 33. Lacouture ME. The growing importance of skin toxicity in EGFR inhibitor therapy. Oncology (Williston Park) 2009;23:194, 196. 34. Lacouture ME, Mitchell E, Shearer H, et al. Impact of pre‑emptive skin toxicity (ST) treatment on panitumumab (pmab)‑related skin toxicities and quality of life (QOL) in patients (pts) with metastatic colorectal cancer (mCRC). Results from STEPP. Gastrointestinal Cancer Symposium, 15‑17 January, (Abstr 291), San Francisco, CA, 2009.
Cite this article as: Li Y, Sun H, Xue D. A severe dermatologic adverse effect related with gefitinib: Case report and review of the literature. J Can Res Ther 2013;9:110-3. Source of Support: Nil, Conflict of Interest: No.
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Correspondence
A severe dermatologic adverse effect related with gefitinib: Case report and review of the literature ABSTRACT Gefitinib, a selective inhibitor of the epidermal growth factor receptor‑tyrosine kinase, it’s one of the most frequent drug‑related adverse effects (AEs) reported in literature is dermatologic AEs. We report, a case of severe cutaneous adverse reactions induced by gefitinib as second‑line treatment in a male patient with advanced non‑small cell lung cancer after 1 month of treatment. Although tumor shrunk and patient got benefit from the treatment, gefitinib had to be stopped right away. We managed the symptoms of rash with a variety of treatments, including topical ethacridine lactate, antihistamine and so on. After the rash improved, we found his tumor were progress. Then he took gefitinib again without severe skin toxicity or disease progression. We think the development of gefitinib‑induced rash may be a sign of effective and administrating it again maybe relieves the degree of rash. KEY WORDS: Dermatologic adverse effect, gefitinib, the epidermal growth factor inhibitor
INTRODUCTION
CASE REPORTS
Gefitinib (iressa), one of the epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors, is orally bioavailable, synthetic anilinoquinazoline that target adenosine triphosphate binding selectively and reversibly to the intracellular tyrosine kinase domain of the receptor, thus blocking EGFR signal transmission and inhibiting proliferation of the tumor cells.[1,2] The specificity of EGFR inhibitors (EGFRIs) for the target results in a much more favorable safety profile than most standard chemotherapy agents, with fewer non‑specific toxicities and no hematopoietic effects.[3] It has come to be more important drug for patients with locally advanced or metastatic non‑small cell lung cancer (NSCLC) with activating mutations of EGFR in all lines of therapy[4,5] and without that in second‑line therapy.[6,7]
A 58‑year‑old man who never smoked presented with severe cough and pain on the right lower extremity and hip joint and a performance status of approximately one. He had normal liver and renal functions and he had no history of hypersensitivity disease, excessive alcohol intake, drug abuse. A computed tomography (CT) scan of the chest confirmed a solitary, spiculated lesion in the right lower lung lobe. Tissues biopsy of the bronchoscopes revealed adenocarcinoma. He was diagnosed as having a primary NSCLC with multiple bone metastases. EGFR gene mutation analysis did not show the presence of any mutation. After 4 cycles Systemic chemotherapy with cisplatin and gemcitabine, he was confirmed disease progression with multiple pulmonary metastasis and brain metastasis. His serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)‑125 levels were all elevated, at 1441 ng/ml and 55.1 U/ml respectively. Then, he was treated with gefitinib 250 mg orally once daily. After 3 weeks, his cough and pain had improved and CT scan revealed lung tumor include primary and metastasis lesions shrinkage, some lesions disappeared. His serum CEA and CA‑125 were dramatically decreased to 400.7 ng/ml and 54.8 U/ml respectively. Evaluation of effect was partial response (PR). At that time, there are multiple and scattered acneiform eruptions with mild itching, distributing at orofacial and chest, without ulceration. However, on the 36th days after starting gefitinib, there were severe skin rashes appearing extensively. His skin
However, because of the important role of EGFR in the physiology of the skin, the treatment of EGFRIs can result in the dermatologic adverse effects (AEs) that have been more prevalent and described with a variety of manifestation.[2] Although these adverse reactions are rarely life‑threatening, they have a deep effect on patients’ quality‑of‑life including physical, financial, emotional and social well‑being.[8] They can lead to dose modification or discontinuation of life‑saving or prolonging treatment.[9] This has resulted in a growing concern in the dermatologic AEs associated with EGFRIs. Here, we reported a case with NSCLC, who suffered severe dermatologic AEs related with gefitinib. S110
Yuan‑Qing Li, Hong Sun, Dong Xue Department of Integration of TCM and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China For correspondence: Dr. Hong Sun, Department of Integration of TCM and Western Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, China. E-mail: sunhong2273@ 163.com Dr. Yuan-Qing Li, Department of Integration of TCM and Western Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District 100142, Beijing, China. E-mail: liyuanqing2999@ 126.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.119123 PMID: *** Quick Response Code:
Journal of Cancer Research and Therapeutics - Supplement 2 - 2013 - Volume 9
Li, et al.: Dermatologic adverse effect of gefitinib
had been red and swelling so serious that cannot illegible appearance. The rash’s manifestation was diverse, including erythema, acneiform rash and pustular rash and local crusting, some sites showed a lichenoid changes. Patient had not complained of any clinical symptoms such as fever, nausea, diarrhea, abdominal pain or fatigue and he had taken no other medications or supplements. Thus, gefitinib‑induced heavy degree skin injury was suspected [Figures 1‑3]. After stopping gefitinib, he received combined therapies, which included administrating loratadine tablets, 10 mg, once a day, smearing with 0.1% ethacridine lactate topically, and so on. After 1 week, the symptoms significantly relieved, the rashes subsided gradually, only remain erythema, pigmentation, crusting and desquamation. Then, antiallergic medication was stopped. After 1 month stopped treatment of gefitinib, the rashes on the face and chest disappeared, no obvious pigmentation, only little crust were scattered in his limbs. Reviewing a chest CT, it showed lesion in the right lung and lymphnodes similar, but metastasis lesions in the both of lung larger than before. Head magnetic resonance
imaging showed similar with before. His CEA was 199 ng/ml and CA‑125 was 94.75 U/ml. Then, gefitinib 250 mg once daily was started again with carefully monitoring of cutaneous AEs. After 1 month, there was little acneiform rash scattered on the side of his nose with mild itch, no rashes on the body and the extremities [Figures 4 and 5]. The CT showed that the mass in the right lower lung lobe and pulmonary metastatic nodules were diminished further. His CEA was 87.84 ng/ml and CA‑125 was 22.02 U/ml. The comprehensive evaluation of effect was PR again. The patient got benefit from gefitinib once again with tolerated skin rash. DISCUSSION Skin rash has been documented as one of the most common adverse reactions in patients receiving EGFRIs. In fact, the incidence of rash in patients treated with these new agents ranges from 50% to 100%. [3,10,11] The common reported EGFRIs‑induced dermatologic AEs are acneiform‑like rash (also described as a papulopustular rash), pruritus, xerosis, fissures, desquamation, nail changes (mostly
Figure 1: Extensive erythema, local acneiform rash, pustular rash and exudate on his trunk
Figure 2: Diffuse painful erythema and edema on his upper extremity that affecting daily activities
Figure 3: Serious papulopustular eruption on the face, with edema, erythema and eschar
Figure 4: After 1 month started gefitinib again, there was a little acneform rash scattered only on the side of his nose with mild itch
Journal of Cancer Research and Therapeutics - Supplement 2 - 2013 - Volume 9
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Li, et al.: Dermatologic adverse effect of gefitinib
Figure 5: There was no rash on his hands and extremities, only remained a little skin pigmentation
paronychia, brittle nails), trichomegaly, hyperpigmentation, telangiectases, alopecia.[12,13] A papulopustular rash is the most common cutaneous toxicity of EGFRIs, affecting up to 90% of patients.[14] The severity of rash is mild to moderate. A small number of Grade 3‑4 will significantly affect the quality‑of‑life for some patients, some even effect tumor treatment. Grade 3‑4 dermatologic AEs occurred in 1.6% of gefitinib‑treated patients.[3] Some studies have reported that the emergence and extent of the rash is correlated with tumor response and the overall survival.[15] The emergence of the rash may be the performance of treatment effective. Some even suggested that the response of treatment of EGFRIs is possibly improved by increasing the doses until the acne‑like rash emerge. However, such speculation has not been confirmed yet. Some multiple studies with cetuximab[16,17] and erlotinib[18‑20] showed positive correlation of rash with response rates and survival. Data from a Phase II trial with ABX‑EGF showed a trend between the severity of rash and progression‑free survival. [21] The retrospective analysis of panitumumab confirmed an association between clinically graded skin toxicity and patient‑reported outcome, quality‑of‑life, longer progression‑free survival and overall survival. The authors suggest that skin reactions should be treated while continuing EGFR‑targeted therapy.[22] However, other studies were not drawn the conclusion of the correlation between skin rash and efficacy of anti‑EGFR therapy. [23‑27] In the large Phase II monotherapy trials, IDEAL 1 and 2, 250 mg/d and 500 mg/d gefitinib were evaluated in 200 patients with NSCLC.[25] The response rates in 250 mg/d group and 500 mg/d group were 12% and 9%, symptom control rate were 43% and 35% respectively. The occurrence and the severity of the rash in both groups were dose‑related, but the response rate was not dose‑related or any correlation between rash and tumor response rate. It might indicate that the emergence of the rash cannot guarantee a response. So there would be further studies to determine the clinical significance of these results. Though potential treatment suggestions for EGFRI‑associated dermatologic AEs have been evaluated in clinical trials, standard guidelines have not been published so far.[28,29] S112
However, a series of recent randomized controlled trials investigating the prophylactic role of oral antibiotics, such as minocycline and doxycycline, yielded encouraging results.[30] Some recommended that prophylactic treatment, such as local or systemic use of antibiotics, should be given at the beginning of targeted therapy.[31] Prophylactic treatment for skin toxicity observed in patients received panitumumab, compared with medication after skin reactions occurring the occurrence rates of the skin adverse reaction over Grade 2 were 29% and 62% respectively. It shows drug prevention impact on quality‑of‑life was significantly lower than that of the latter.[32] For this case, the treatment of gefitinib induced serious dermatologic AE, which is really rare. During the early phase the cutaneous adverse reactions only manifested as limited acne‑like rash. However, with the administration of gefitinib persistently, the severe cutaneous adverse reactions broke out in a few days. The rashes almost involved with the whole body skin, especially on the face. A variety of rash forms were coexist, accompanied by swelling, oozing, crusting and peeling and local infection. The patient’s daily life was limited, which seriously affected the quality‑of‑life. Although the anti‑tumor therapy was effective, we had to interrupt the treatment of gefitinib. After stopped the treatment of gefitinib and administrated actively, the rash was improved significantly in the short term. We analyzed that the reason is contributed to not only interruption of the treatment of gefitinib, but also the reasonable and effective medicines. It also showed that the EGFRIs‑induced cutaneous adverse reactions are reversible and can be controlled effectively. The efficacy of the anti‑allergic agents and antibiotic treatment is still pending and need to further studies. However, it is positive and necessary that using these drugs in the severe stages of the rash, which can control the systemic inflammatory response and prevent more serious skin infections. Patients took gefitinib again after the tumor progressed, but there were no serious dermatologic AE appearing. Patient got clinical benefit again from the treatment of gefitinib. That may indicate that dermatologic AE can relieve after administrating gefitinib again. On the whole, the treatment of EGFRIs is widely using in clinical and its benefit is significant. However, its dermatologic AE may eventually lead to some patient compliance reduced, interfere with normal treatment, dose reduction or even interrupt tumor treatment, in severe cases it affect quality of life significantly.[33,34] Although the incidence of severe grades is not often, we should pay enough attention to it. For reducing its adverse impact and deriving more clinical benefits, it needs more studies to confirm some results and establish the standard of EGFRIs‑related dermatologic AE as soon as possible. REFERENCES 1. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002;7 Suppl 4:2‑8. 2. Su Z. Epidermal growth factor receptor mutation‑guided treatment Journal of Cancer Research and Therapeutics - Supplement 2 - 2013 - Volume 9
Li, et al.: Dermatologic adverse effect of gefitinib
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Cite this article as: Li Y, Sun H, Xue D. A severe dermatologic adverse effect related with gefitinib: Case report and review of the literature. J Can Res Ther 2013;9:110-3. Source of Support: Nil, Conflict of Interest: No.
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