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ORIGINAL ARTICLE
Year : 2019  |  Volume : 64  |  Issue : 6  |  Page : 471-475
Cutaneous adverse drug reactions to targeted chemotherapeutic drugs: A clinico-epidemiological study


Department of Dermatology, B.J. Medical College and Civil Hospital, Ahmedabad, Gujarat, India

Date of Web Publication7-Nov-2019

Correspondence Address:
Amita Sutaria
Room No 140, Skin OPD, Wing No. 3, First Floor, OPD Building, Civil Hospital, Ahmedabad, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.IJD_491_18

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   Abstract 


Background: Targeted chemotherapeutic drugs have led to a remarkable improvement in the survival of cancer patients but also have resulted in the increased incidence of uncommon but specific muco-cutaneous adverse effects. Aims: This study aimed to highlight the spectrum of such cutaneous adverse drug reactions and to derive a causal association. Materials and Methods: A hospital-based, descriptive study was carried out in the dermatology outpatient department between August 2016 and July 2018, on patients referred from the state cancer institute, who developed muco-cutaneous lesions after the initiation of targeted chemotherapeutic drugs. Results: A total of 80 patients, 59 (74%) males and 21 (26%) females of mean age 45.83 ± 16.37 years (range 4–70 years) developed one or more uncommon albeit specific muco-cutaneous adverse effects. Among them, papulopustular and acneiform eruptions were found in 21 patients (26.25%), and PRIDE complex was seen in 3 patients. Sixteen patients (20.00%) developed palmar-plantar erythrodysesthesia, 8 patients (10%) developed lichenoid drug eruption, and 5 patients (6.25%) developed flagellate dermatitis. Twenty-two (27.5%) patients showed nail changes, the most common, being melanonychia. Conclusion: There has been a paradigm shift in the management of both hematopoietic and solid cancers with the advent of targeted chemotherapeutic drugs leading to an increase in uncommon and specific drug reactions. Early recognition of these decreases morbidity, improves quality of life, and allows continuation of the life saving chemotherapy.


Keywords: Adverse drug reactions, hand-foot syndrome, targeted chemotherapy, WHO-UMC criteria


How to cite this article:
Saini K, Sutaria A, Shah B, Brahmbhatt V, Parmar K. Cutaneous adverse drug reactions to targeted chemotherapeutic drugs: A clinico-epidemiological study. Indian J Dermatol 2019;64:471-5

How to cite this URL:
Saini K, Sutaria A, Shah B, Brahmbhatt V, Parmar K. Cutaneous adverse drug reactions to targeted chemotherapeutic drugs: A clinico-epidemiological study. Indian J Dermatol [serial online] 2019 [cited 2019 Nov 19];64:471-5. Available from: http://www.e-ijd.org/text.asp?2019/64/6/471/270577





   Introduction Top


The emergence of targeted chemotherapeutic drugs for the treatment of solid tumors has lead to a definite improvement in the survival and quality of life of cancer patients and a concomitant decrease in hematopoietic and non-specific toxicities.[1] However, the introduction of such novel agents has resulted in the emergence of new and uncommon but specific dermatologic adverse events. This clinico-epidemiological study aimed to study the spectrum of various muco-cutaneous adverse drug reactions (ADRs) to targeted chemotherapeutic drugs and to establish a causal association.


   Materials and Methods Top


This hospital-based, descriptive study was conducted in the dermatology outpatient department of a tertiary care center in west India, between August 2016 and July 2018, after obtaining ethical clearance. Patients referred from the state cancer hospital, who developed muco-cutaneous lesions, after the initiation of targeted chemotherapeutic drugs were included in this study. Patients having cutaneous manifestations because of internal malignancies and those who already had cutaneous symptoms before the initiation of chemotherapy were excluded from the study.

Demographics, detailed history, associated malignancy, chemotherapy details, and cutaneous complaints were noted. General, systemic, and muco-cutaneous examinations were carried out in all. Skin biopsy was taken in relevant cases. The evolution of skin symptoms was studied through serial photographs. The causality assessment was done through WHO-UMC criteria.


   Results Top


A total of 80 patients with various muco-cutaneous ADRs after initiation of targeted chemotherapeutic drugs were included in this study. These included 59 (74%) males and 21 (26%) females. The mean age was 45.83 ± 16.37 years (range: 4 to 70 years). The mean duration of development of cutaneous ADR was 30.31 ± 40.53 days (range: 3 to 180 days). The most common malignancy was chronic myeloid leukemia. The frequency distribution of various cancers is depicted in [Figure 1].
Figure 1: Frequency distribution of various cancers (n = 80) Ca: Carcinoma, ALL: Acute lymphocytic leukemia, NHL: Non-Hodgkin's lymphoma, HL: Hodgkin's leukemia, CML: Chronic myeloid leukemia, RCC: Renal cell carcinoma, and HCC: Hepatocellular carcinoma

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Eighteen different dermatological manifestations were seen involving skin, hair, and nails [Figure 2] among which papulopustular eruptions were the most common cutaneous manifestation, observed in 21 (26.25%) patients, out of which 3 patients showed PRIDE complex (papulo-pustular eruptions and/or paronychia, regulatory abnormalities of hair growth, itching, and dryness due to EGFR inhibitors). Other skin findings were palmar-plantar erythrodysesthesia (Hand-foot reaction or chemotherapy-associated acral erythema) in 16 patients (20.00%), lichenoid drug eruption in 8 patients (10.00%), lichen planus-like lesions in 2 patients, flagellate dermatitis in 5 patients (8.06%), and palmoplantar pigmentation, phototoxic rash, and perforating folliculitis with plantar hyperkeratosis in 1 patient each [Figure 3]. Twenty-two patients (27.5%) had nail changes out of which melanonychia was the most common, followed by Beau's, Mees', and Muehrcke's lines [Figure 4]. The causality assessment using WHO causality assessment scale showed that observed ADRs were of probable (65.67%) and possible (34.33%) categories.
Figure 2: Frequency of skin, hair, and nail involvement

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Figure 3: Distribution of various cutaneous lesions in the study. PRIDE-(papulopustular eruptions and/paronychia, regulatory abnormalities of hair growth, itching, and dryness)

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Figure 4: Distribution of various nail changes in the study

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   Discussion Top


Skin, hair, and nails are frequently affected by targeted chemotherapeutic drugs because of rapid cell turnover at these sites. Apart from the traditional anticancer drugs, the targeted chemotherapeutic drugs are also being increasingly implicated in various uncommon and specific muco-cutaneous adverse effects.

In our study, 21 (26.25%) patients developed multiple, itchy papulopustular eruptions mainly over seborrheic sites, such as face, chest, and scalp [Figure 5]. Out of these, 3 patients on epidermal growth factor receptor (EGFR) inhibitors presented all the features of PRIDE complex (papulopustular eruptions and/or paronychia, regulatory abnormalities of hair growth, itching, and dryness). The most common drugs causing papulopustular eruptions were EGFR inhibitors–cetuximab, gefitinib, and erlotinib, similar to the study by Parvey et al.[2] Four patients on taxanes monotherapy,[3] 3 patients on combination chemotherapy of EGFR inhibitors with paclitaxel,[3] and 1 patient on pazopanib[4] developed papular and acneiform eruptions. The mean duration of therapy before onset of the rash was 2 weeks (range 3 to 28 days).
Figure 5: (a and b) Papulopustular eruptions over face and chest due to cetuximab

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Palmar-plantar erythrodysesthesia or hand-foot syndrome is a well-known adverse effect with sorafenib, sunitinib,[5] and capecitabine.[6] Sixteen patients developed hand-foot syndrome while on sorafenib, capecitabine, doxorubicin, and imatinib, after a mean duration 21 days (range 7 to 35 days) [Figure 6]. Hand-foot syndrome is a proven side effect of multiple tyrosine kinase inhibitors such as sorafenib, sunitinib but not imatinib.[7] We came across 3 cases of imatinib induced hand-foot syndrome. In addition, there was correlation between dose escalation and occurrence of skin lesions. One patient of hepatocellular carcinoma developed palmoplantar hyperkeratosis and multiple perforating folliculitis after initiation of sorafenib.[8] Very few case reports exist of sorafenib induced perforating folliculitis.[9] One patient of acute lymphocytic leukemia developed diffuse palmoplantar pigmentation 2 months after starting doxorubicin and vincristine. Doxorubicin has been reported to cause palmoplantar pigmentation rarely.[10]
Figure 6: Hand-foot syndrome in a patient on sorafenib

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Lichenoid drug eruption is a well-known adverse effect in patients on imatinib.[11] Seven patients on imatinib for chronic myeloid leukemia developed lichenoid drug eruption, and 2 patients developed lichen planus-like lesions and mucosal pigmentation after a mean duration of 5 months after starting imatinib [Figure 7]. One patient of Non-Hodgkin's lymphoma on bendamustine and paclitaxel combination chemotherapy developed lichenoid drug eruption after 2 months of starting bendamustine.[12] The WHO-UMC score was probable in 6 patients and possible in 4 patients. The histopathological findings showed hyperkeratosis, parakeratosis, hyperplastic squamous epithelium, with numerous eosinophils and perivascular inflammation around the mid and deep dermal plexuses, a prominent interstitial inflammatory infiltrate and pigment incontinence, and a band of mononuclear infiltrate in subepithelial tissue eroding the dermoepidermal junction [Figure 8].
Figure 7: (a and b) Imatinib induced lichen planus

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Figure 8: Drug induced lichenoid drug eruption (H and E, ×40)

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Flagellate dermatitis is a specific side effect seen in patients on bleomycin.[13] In our study, flagellate dermatitis was seen in 3 patients on ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) for Hodgkins lymphoma and in 2 patients of ovarian cancer on PEB regimen (Platinol, etoposide, and bleomycin) cisplatin, etoposide, and bleomycin [Figure 9]. The mean onset was 2 weeks (range 10–42 days). The WHO-UMC score was probable.
Figure 9: Bleomycin induced flagellate dermatitis

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Trastuzumab and paclitaxel combination chemotherapy is reported to cause phototoxic rash.[14] One patient of breast carcinoma developed photosensitive rash on the face after 15 days of starting trastuzumab and docetaxel.

Nail changes were observed in 22 (27.50%) patients. Melanonychia induced by various classes of drugs like taxanes- paclitaxel, docetaxel; platinum analogs- cisplatin carboplatin; doxorubicin and cyclophosphamide were seen in our study. A total of nine patients developed melanonychia after a mean duration of 3 months of initiation of one of these drugs. [Figure 10].[2]
Figure 10: Melanonychia in a patient on cisplatin

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Two patients of non-Hodgkins lymphoma developed Mees' lines while on CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen, similar to a study by Parvey et al.[2]

Taxanes (paclitaxel and docetaxel) are frequently implicated in a variety of nail changes such as nail pigmentation, subungual hematoma, Beau's lines, and onycholysis and subungual suppuration.[15] We found onycholysis, Beau's lines, onychomadesis, pyogenic granuloma, and paronychia in patients on taxanes [Figure 11]. Platinum based chemotherapy is commonly known to cause Muehrcke's lines,[16] seen in 3 patients on cisplatin and oxaliplatin.
Figure 11:(a and b) Paclitaxel induced onycholysis and paronychia

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Limitations

Since this was a hospital OPD based study, we missed mild reactions that did not reach the hospital. Also we missed the severe group as well who were non-ambulatory and were unable to attend the hospital OPD.


   Conclusion Top


Anticancer therapy has undergone a sea change in the last few years. Various targeted chemotherapeutic drugs such as EGFR inhibitors (cetuximab, erlotinib, and gefitinib), multikinase inhibitors (imatinib and sorafenib), taxanes (paclitaxel), vinca alkaloids (vincristine and vinblastine), and antimetabolites (capecitabine and gemcitabine) are associated with prominent, specific, and sometimes dose-limiting dermatologic adverse effects affecting skin, hair, nails, and mucosa. This study is important because majority of these are manageable with conventional therapy and do not warrant the withdrawal of the lifesaving chemotherapeutic drug in patients already suffering from grave disease. Addressing cutaneous drug side effects is very important to save the patient from any more suffering. Thus, early recognition keeping a strong clinical suspicion, timely and appropriate management, and close monitoring facilitate good symptom control, prevents treatment-related morbidity, and allows continuation of chemotherapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14:212-6.  Back to cited text no. 1
    
2.
Pavey RA, Kambil SM, Bhat RM. Dermatological adverse reactions to cancer chemotherapy. Indian J Dermatol Venereol Leprol 2015;81:434.  Back to cited text no. 2
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Sibaud V, Lebœuf NR, Roche H, Belum VR, Gladieff L, Deslandres M,et al. Dermatological adverse events with taxane chemotherapy. Eur J Dermatol 2016;26:427-43.  Back to cited text no. 3
    
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Eaby-Sandy B, Grande C, Viale PH. Dermatologic toxicities in epidermal growth factor receptor and multikinase inhibitors. J Adv Pract Oncol 2012;3:138-50.  Back to cited text no. 4
    
5.
Lacouture ME, Reilly LM, Gerami P, Guitart J. Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol 2008;19:1955-61.  Back to cited text no. 5
    
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Saini KS, Attili SV, Saini ML, Batra U, Lakshmaiah KC, Acharya R,et al. Capecitabine-induced hand-foot syndrome. JIACM 2007;8:144-5.  Back to cited text no. 6
    
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Alyx CR, Cristina GF, Lawrence AM, John AZ, Mario EL, Systemic anticancer agents: Dermatologic indications and adverse events, In: Stephen EW. Comprehensive Dermatologic Drug Therapy. 3rd ed. Indianapolis: Saunders Elsevier. 2013. p. 399.  Back to cited text no. 7
    
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Autier J, Escudier B, Wechsler J, Spatz A, Robert C. Prospective study of the cutaneous adverse effects of Sorafenib, a novel multikinase inhibitor. Arch Dermatol 2008;144:886-92.  Back to cited text no. 8
    
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Wolber C, Udvardi A, Tatzreiter G, Schneeberger A, Volc-Platzer B. Perforating folliculitis, angioedema, hand-foot syndrome - multiple cutaneous side effects in a patient treated with sorafenib. J Dtsch Dermatol Ges 2009;7:449-52.  Back to cited text no. 9
    
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Ramteke MN, Bhuraria DR, Khemani UN. Atypical case of hand foot syndrome due to pegylated liposomal doxorubicin presenting as hyperpigmentation. Indian J Drugs Dermatol 2015;1:30-2.  Back to cited text no. 10
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11.
Arshdeep, De D, Malhotra P, Saikia UN. IImatinib Imatinib mesylate-induced severe lichenoid rash. Indian J Dermatol Venereol Leprol 2014;80:93-5.  Back to cited text no. 11
    
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Kusano Y, Terui Y, Yokoyama M, Hatake K. Lichenoid drug eruption associated with Bendamustine. Blood Cancer J 2016;6:e438.  Back to cited text no. 12
    
13.
Ziemer M, Goetze S, Juhasz K, Elsner P. Flagellate dermatitis as a bleomycin-specific adverse effect of cytostatic therapy: A clinical-histopathologic correlation. Am J Clin Dermatol 2011;12:68-76.  Back to cited text no. 13
    
14.
Cohen AD, Mermershtain W, Geffen DB, Schoenfeld N, Mamet R, Cagnano E, et al. Cutaneous photosensitivity induced by paclitaxel and trastuzumab therapy associated with aberrations in the biosynthesis of porphyrins. J Dermatol Treat 2009;16:19-21.  Back to cited text no. 14
    
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Minisini AM, Tosti A, Sobrero AF, Mansutti M, Piraccini BM, Sacco C, et al. Taxane-induced nail changes: Incidence, clinical presentation and outcome. Ann Oncol 2003;14:333-7.  Back to cited text no. 15
    
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Reddy PK, Prasad AL, Sumathy TK, Reddy RV. Nail changes in patients undergoing cancer chemotherapy. Int J Res Dermatol 2017;3:49-54.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]



 

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