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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 2  |  Page : 86-89

Mucocutaneous side effects of gefitinib


1 Department of D&V, Government T D Medical College, Alappuzha, Kerala, India
2 Department of Radiotherapy, Government T D Medical College, Alappuzha, Kerala, India
3 Department of D&V, Government Medical College, Thiruvananthapuram, Kerala, India

Date of Submission20-Nov-2021
Date of Acceptance07-Jan-2022
Date of Web Publication28-Feb-2022

Correspondence Address:
Dr. Rani Mathew
Department of D&V, Government Medical College, Thiruvananthapuram, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjmsr.mjmsr_48_21

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  Abstract 


Background: Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein which is expressed in various tissues. Aberrant EGFR signaling plays an important role in carcinogenesis. Gefitinib, an EGFR inhibitor, is a promising drug in treatment of various malignancies. Awareness about the various mucocutaneous side effects of gefitinib will help in optimum management. Hence, we decided to conduct this study. Materials and Methods: We did a descriptive study and observed the various cutaneous side effects in 40 patients who were treated with gefitinib in a tertiary care center in South Kerala. Results: Dermatological adverse reactions were observed in 87.5% of our patients, the most common being dryness and pruritus in 67.5% and 65% of patients, respectively. Rashes were of Grade 1/2 severity in most of our cases. Conclusions: Cutaneous reactions, though common, were mild in majority of our patients. Studies with more sample size and follow-up are needed to improve our knowledge.

Keywords: Epidermal growth factor receptor, gefitinib, PRIDE complex


How to cite this article:
Thekkath R, Nonam C, Mathew R, Sunny B. Mucocutaneous side effects of gefitinib. Muller J Med Sci Res 2021;12:86-9

How to cite this URL:
Thekkath R, Nonam C, Mathew R, Sunny B. Mucocutaneous side effects of gefitinib. Muller J Med Sci Res [serial online] 2021 [cited 2022 May 20];12:86-9. Available from: https://www.mjmsr.net/text.asp?2021/12/2/86/338505




  Introduction Top


Epidermal growth factor receptor (EGFR) is a Type 1 receptor tyrosine kinase, normally seen at the plasma membrane of hair follicles and epithelial tissues, which control epithelial tissue development and homeostasis.[1] During angiogenesis, tumor cell proliferation, and apoptosis, it is overexpressed. Overexpression is seen in many malignancies such as head and neck, lung, breast, stomach, colon, pancreas, and glioblastoma.[1],[2] Now, EGFR-targeted therapies are used for these malignancies. Gefitinib is an oral antineoplastic reversible first-generation EGFR tyrosine kinase inhibitor. Gefitinib therapy is usually given after chemotherapy or in patients who do not tolerate chemotherapy or in advanced aged patients or palliative patients. The dosage of gefitinib is 250 mg daily till progression of disease is arrested.[3] Although well-tolerated cutaneous and gastrointestinal toxicities are well reported. Cutaneous side effects of EGFR inhibitors are collectively referred to as the PRIDE complex (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, and Dryness due to EGFR inhibitors).[4]

The aim of our study was to observe the mucocutaneous side effects in cancer patients treated with gefitinib in our area. Knowledge about these adverse events will help dermatologists to manage them effectively which will ensure better patient compliance with EGFR inhibitor therapy.


  Materials and Methods Top


Ours was a descriptive cross-sectional study in which 40 patients who were treated with gefitinib as an anticancer agent in a major tertiary care hospital of South Kerala from January 2015 were included.

Inclusion criteria

  1. Patients on treatment with gefitinib
  2. Patients should have normal hemoglobin (more than or equal to 10 g%), white blood cell count (5000–11000/mm3), platelet count (70000–300000/mm3), liver function test, and renal function test.


Exclusion criteria

  1. Any previous history of cutaneous side effects during cancer treatment
  2. Those with uncompensated congestive heart failure, renal failure, and diabetic mellitus
  3. Patients on drugs which were known to cause similar mucocutaneous side effects
  4. Poor performance status
  5. Pregnancy.


History was taken and a detailed dermatological examination was done in all patients during the first visit. Patients were to report on a monthly basis to observe for any skin lesions or in between if needed. Latency of onset of symptoms and cause for which treatment was taken were noted. Symptoms were graded according to severity.

All details were entered in MS Excel spreadsheet and analyzed using SPSS software (version 12) (IBM SPSS 12 Trial version). Qualitative data were analyzed using percentage and quantitative data using mean and median.

Institutional ethical committee clearance was obtained prior to the study. The aim of the research and interview method was explained to all participants. All patients signed informed consent.


  Results Top


Out of 40 patients, 19 had non-small cell lung cancer while the rest had head-and-neck squamous cell carcinoma for which gefitinib was given. Half of the study patients were in the age group of 61–70 years, followed by 17.5% in the age group of 51–60 years, 15% in the age group of 71–80 years, and 10% in the age group of 41–50 years. The rest of the patients were above 80 years. Twenty-two patients (55%) were males and rest females.

Cutaneous side effects were observed in 35 patients (87.5%). The maximum number of patients who developed cutaneous side effects was in the age group of 61–70 years. Side effects were most commonly observed in males. Dryness and pruritus were the most common side effects reported in our study seen in 27 (67.5%) and 26 (65%) patients, respectively.

[Table 1] shows the various cutaneous lesions observed in this study.
Table 1: Types of cutaneous lesions observed in study

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Papulopustular rash was most commonly seen in the age group of 61–70 years (61.5%) and in males (69.2%). Dryness was mostly seen in the seventh decade. Grade 1 oral mucositis was observed in 3 (7.5%) patients. Dry lusterless hair, thin brittle nails, and onychomadesis were reported in one patient each. An 85-year-old female developed exfoliative dermatitis, while exanthematous rash and prurigo nodularis were reported in one patient each.

The latency of onset of various rashes is shown in [Table 2].
Table 2: Latency of onset of skin lesion

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We graded the various rashes according to Common Terminology Criteria for Adverse Events version 4.0-selected skin and subcutaneous tissue disorders,[5] as shown in [Table 3].
Table 3: Grading of rash according to Common Terminology Criteria for Adverse Events version 4.0-selected skin and subcutaneous disorders

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  Discussion Top


Of the 40 patients treated with gefitinib in our study, 35 (87.5%) developed one or more cutaneous side effects. In a study, Chanprapaph et al. reported cutaneous adverse events in 62.5% of their patients who received gefitinib.[4] Dryness and pruritus were the most common side effects observed in our study which is consistent with a study by Chanprapaph et al.[4] where the most common adverse effect was xerosis (41.7%).

Papulopustular rash was noted in 13 (32.5%) patients in the present study.

The incidence of papulopustular rash in different studies is shown in [Table 4].
Table 4: Incidence of papulopustular rash in different studies

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The lower incidence in our study is corresponding with the Indian study by Chanprapaph et al.[4] The higher incidence in other studies may be due to racial, genetic, and demographic differences. Out of 13 patients who developed papulopustular rash, 8 (61.5%) had onset within 1 month of starting gefitinib and none had onset later than 3 months, the median time of onset being 2 weeks. Wang et al. also reported a median time of onset of rash as 14 days.[2] Only one of our patients had Grade 3 rash. Chanprapaph et al. also observed Grade 1/Grade 2 severity in the majority of their patients.[4]

Paronychia with pyogenic granuloma was noted in three (7.5%) of our cases. Lee et al.[6] and Chanprapaph et al.[4] observed paronychia in 6% and 4.2% of patients, respectively, while Wang et al.[2] noted a higher incidence of paronychia (16.2%) in their patients. Two of our patients developed it in 3 months, while the other developed it 6 months after starting the drug. As per literature, gefitinib-induced paronychia may appear from 2 to 12 months after beginning treatment.[6] We noted onychomadesis and thin brittle nails in one patient each.

Pruritus was reported by 26 (65%) patients. The incidence of pruritus was 49.7% and 26.5% in studies by Han et al.[7] and Wang et al.,[2] respectively. As our study was conducted in a coastal area, the dryness may have contributed to a higher incidence of pruritus in our patients. The median time of onset of pruritus in our study was 12 weeks, and most of them (11.5%) had Grade 1/2 pruritus. Wang et al. noted a median time of onset of 30 days in their patients.[2]

Twenty-seven (67.5%) cases developed dryness in the present study, while another Indian study reported it in 41.7% of patients.[4] The demography may have influenced the higher incidence of dryness in our study group. Maximum of our patients (59.2%) developed dryness between 2 and 4 months with a median onset time of 12 weeks. This is in contrast with the finding of Chanprapaph et al. who reported a median time of onset of dryness as 28 days.[4] Fourteen of our patients had Grade 1 and 11 had Grade 2 dryness. Han et al. reported xerosis in 51% of cases and all had Grade 1/2 dryness.[7]

Hair change in the form of dry lusterless hair was seen in one patient in the present study. As per literature, prolonged EGFR inhibitor therapy is associated with fine, brittle, curly scalp hair and trichomegaly.[8],[9] Han et al. reported alopecia in 11.3% of patients.[7] None of our patients reported alopecia or trichomegaly.

Exanthematous rash was observed in one patient after 6 weeks of intake of gefitinib which subsided on stopping the drug. Similar presentation was reported in a study by Chanprapah et al. in 20.8% of their patients.[4] Prurigo nodularis developed in a patient following treatment for 1½ years. This may not be a direct effect of gefitinib and may have been provoked by pruritus and xerosis. Oral mucositis developed in 7.5% of patients which is in concordance with literature.[4] One patient developed exfoliative dermatitis which resolved on stopping drug and with short-course steroids. Drug was restarted with alternate-day regimen and a patient tolerated with mild itching and xerosis. This type of presentation is not seen in literature to our knowledge.


  Conclusions Top


This study gives an idea about the various possible dermatological adverse effects of gefitinib which is a relatively new form of targeted anticancer therapy. Although incidence of cutaneous drug reactions was common in our patients on gefitinib, none of them was life threatening. We observed exfoliative dermatitis and prurigo nodularis in one patient each, which is not reported earlier. Studies including more number of patients with follow-up are needed to confirm our findings. Explaining the patient about the harmless nature of most skin reactions will restore faith in treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Madke B, Gole P, Kumar P, Khopkar U. Dermatological side effects of epidermal growth factor receptor inhibitors: 'PRIDE' complex. Indian J Dermatol 2014;59:271-4.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Wang SH, Yang CH, Chiu HC, HU FC, Chan CC, Liao YH, et al. Skin manifestations of Gefitinib and the association with survival of advanced non small-cell lung cancer in Taiwan. DermatologicaSinica 2011;29:13-18.  Back to cited text no. 2
    
3.
Devita, Hellman & Rosenberg's Cancer: Principles and Practice of Oncology. 8th ed. 11th edition. Philadelphia: Wolters Kluwer;2018.  Back to cited text no. 3
    
4.
Chanprapaph K, Pongcharoen P, Vachiramon V. Cutaneous adverse events of epidermal growth factor receptor inhibitors: A retrospective review of 99 cases. Indian J Dermatol Venereol Leprol 2015;81:547.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Rosen AC, Fernandez CG, Mark LA, Zic JA, Lacouture ME. Systemic anticancer agents: Dermatologic indications and adverse events. In: Wolverton SE, editor. Comprehensive Dermatologic Drug Therapy. 3rd ed. Edinburgh: Elsevier; 2013. p. 397-402.  Back to cited text no. 5
    
6.
Lee MW, Seo CW, Kim SW, Yang HJ, Lee HW, Choi JH, et al. Cutaneous side effects in non-small cell lung cancer patients treated with Iressa (ZD1839), an inhibitor of epidermal growth factor. Acta Derm Venereol 2004;84:23-6.  Back to cited text no. 6
    
7.
Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: First-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012;30:1122-8.  Back to cited text no. 7
    
8.
Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425-33.  Back to cited text no. 8
    
9.
Pascual JC, Bañuls J, Belinchon I, Blanes M, Massuti B. Trichomegaly following treatment with Gefitinib (ZD1839). Br J Dermatol 2004;151:1111-2.  Back to cited text no. 9
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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