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 Table of Contents  
ORIGINAL ARTICLES
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 15-22

Dermatological adverse events of cancer chemotherapy: An observational clinicoepidemiological study from a tertiary care center


Department of Dermatology, Venereology, and Leprosy, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India

Date of Submission17-Aug-2021
Date of Decision31-Mar-2022
Date of Acceptance21-Apr-2022
Date of Web Publication11-Jun-2022

Correspondence Address:
Guneet Awal
469, East Mohan Nagar, Opp. DSP Park, Sultanwind Road, Amritsar, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_36_21

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  Abstract 

Introduction: Although newer chemotherapeutic drugs prolong patients’ survival, they cause a myriad of dermatological adverse effects leading to decreased quality of life. Aims and Objectives: The study was undertaken to assess the various cutaneous adverse effects associated with chemotherapeutic drugs. Materials and Methods: A total of 736 diagnosed cancer patients on chemotherapy attending the dermatology department of a tertiary care center were studied in this observational study between June 2019 and May 2021. Detailed dermatological examination to include skin, hair, nail, and mucosal changes was undertaken after informed consent. Results: The most common malignancy observed was breast carcinoma, which was seen in 21.33% of the cases. It was followed by carcinoma cervix in 12.09% of the cases. Most commonly implicated drugs were platinum therapy (cisplatin, carboplatin) and anthracyclines (doxorubicin and epirubicin). Alopecia was the most common adverse effect seen in 55.84% of the patients. It was followed by hand-foot syndrome in 11% of the patients. Nail changes were seen in 4.21% of the patients, and the most common nail finding was longitudinal melanonychia seen in 1.49% of the patients. Conclusion: Knowledge regarding occurrence and severity of dermatological side effects of chemotherapy aids in early recognition and treatment. It also benefits in educating patients regarding potential adverse effects, taking appropriate prophylactic measures, and therefore better compliance by the patient.

Keywords: Alopecia, chemotherapy, dermatological adverse events, hand-foot syndrome


How to cite this article:
Awal G, Singh G. Dermatological adverse events of cancer chemotherapy: An observational clinicoepidemiological study from a tertiary care center. Indian J Drugs Dermatol 2022;8:15-22

How to cite this URL:
Awal G, Singh G. Dermatological adverse events of cancer chemotherapy: An observational clinicoepidemiological study from a tertiary care center. Indian J Drugs Dermatol [serial online] 2022 [cited 2022 Jun 26];8:15-22. Available from: https://www.ijdd.in/text.asp?2022/8/1/15/347290




  Introduction Top


Cancer is a significant cause of deaths worldwide, and there is a surge in the number of cases over the past few decades. In year 2020, nearly 19.3 million new cancer cases and about 10 million deaths occurred globally.[1] The complications due to anticancer drugs are commonly experienced in dermatology practice. New chemotherapies are being developed and are utilized increasingly for treating cancer patients. Therefore, there is an increase in associated adverse effects. Cutaneous adverse effects have also increased due to the abovementioned reasons.[2] The frequent dermatological adverse effects associated with chemotherapy include alopecia, xerosis, hyperpigmentation, melanonychia, mucositis, acneiform eruptions, and pruritis. These adverse effects are non-lethal but they cause a lot of agony and discomfort to the patients.[3] Rash and pruritus due to chemotherapy have been reported to have the greatest negative impact on quality of life (QoL).[4] Although numerous studies all over the world and even in India have been done on cutaneous manifestations in internal malignancies, no such studies have been done in the northern part of India. In this article, we have studied these findings to give better understanding and thus early diagnosis.


  Materials and Methods Top


A total of 736 patients diagnosed with cancer and on chemotherapy attending the dermatology department of a tertiary care center were included in this observational study after permission from the Institutional Ethics Committee. It was conducted over a period of 2 years from June 2019 to May 2021. Diagnosed cases of internal malignancy on chemotherapy, patients above the age of 18 years, and patients who gave consent were included in the study. Patients less than the age of 18 years, suspected cases with awaited investigations, patients with primary cutaneous malignancy, patients with cutaneous manifestation due to internal malignancy (paraneoplastic syndromes), and patients on radiotherapy were excluded. Demographic details including patients’ name, age, sex, gender, and place of residence were recorded. Detailed history about the onset of malignancy, diagnosis, relevant surgical treatment, and chemotherapeutic treatment were recorded. Dermatological examination was done during the course of illness when patient was on chemotherapy, which included site, size, shape, number, morphology of lesions, and associated symptoms. A detailed examination was done to see mucosal, hair, and nail changes. Lesions were recorded photographically. Dermatoscopy and relevant investigations such as Koh examination were used to aid in diagnosis. Skin biopsy was done wherever required. Ethical clearance for the study was obtained from the Institutional Ethical Committee.


  Results Top


A total of 736 diagnosed patients of internal malignancy were included in this study, out of which 306 (41.57%) patients were males and 430 (58.43%) patients were females. The age of these cases ranged from 18 to 84 years. The mean age was 50.84 (±10.72) years. The various carcinomas encountered are enlisted in [Table 1]. The most common malignancy was breast carcinoma accounting for 157 (21.33%) cases, followed by cervix carcinoma in 89 (12.09%) cases and esophagus carcinoma in 61 (8.28%) cases.
Table 1: Frequency of various internal malignancies

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Combination of chemotherapeutic agents constituting more than one drug, according to specific chemotherapy regimens, was administered in 93.25% of the patients. Platinum chemotherapy drugs (carboplatin, cisplatin, and oxaliplatin) (39%) and anthracyclins (doxorubicin and epirubicin) (33%) were the most common chemotherapeutic groups which were administered in these patients. Other drugs which these patients received were 5-fluorouracil, cyclophosphamide, paclitaxel, docetaxel, cytarabine, capecitabine, gemcitabine, chlorambucil, imatinib, sorafenib, geftinib, actinomycin D, hydroxyurea, bleomycin, and vincristine. The duration for which chemotherapy was given in these patients ranged from 3 to6 months, with a minimum two cycles and a maximum of six cycles of chemotherapy. The mean number of cycles was 4.62 (± 0.36).

The frequency of adverse effects according to the main site involved is shown in [Table 2]. More than half of the patients (55.84%) had hair changes in some form or the other. Cutaneous changes were seen in 45.4% of the patients.
Table 2: Frequency of sites involved in cutaneous adverse effects

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A total of 792 dermatological adverse effects were noted, with 7.61% of cases showing more than one mucocutaneous findings. The details of various mucocutaneous manifestations are depicted in [Table 3]. The onset of dermatological findings ranged from 2 weeks to 18 months, with respect to initiation of chemotherapy. Alopecia was the most common finding in our study seen in 411 (55.84%) patients. About 360 (49.04%) patients had anagen effluvium and 51 (6.93%) had telogen effluvium. It was followed by hand-foot syndrome (HFS) seen in 11% of the patients, pruritis in 5.57% of the patients, xerosis in 5.3% of the patients, and nail changes in 31 patients (4.21%).
Table 3: Various cutaneous adverse effects observed

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HFS in most cases (86.4%) presented with tingling, numbness, paresthesia, and erythema over palms and soles. About 8.6% of the cases presented with hyperpigmentation along with paresthesia of palms and soles. It was accompanied by pain, desquamation, and ulceration in 4 out of 81 cases.

Around 5.57% of the patients presented with pruritis, which in many cases was intractable and associated with scratching and secondary changes. It was frequently observed in patients who had xerosis.

Among pyodermas (3.26%), furunculosis was the most common seen in 15 cases. It was followed by cellulitis, ecthyma, and wound infections.

Among the fungal infections (2.71%), Candida was the most common infection seen. Intertrigo with erythematous patch and maceration was usual presentation. Other fungal infections which were seen included pityriasis versicolor, Candida vaginitis, Pityrosporum folliculitis, and tinea.

Among the nail changes (4.21%), the most common was longitudinal melanonychia seen in 1.49% of the patients [Figure 1]. The other nail changes observed were transverse melanonychia, diffuse pigmentation, Mees’ lines, and Beau’s lines.
Figure 1: Pie chart showing nail changes observed in patients on chemotherapy

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Mucosal changes (2.17%) mainly comprised stomatitis and hyperpigmentation of the tongue and buccal mucosa.

Papulopustular rash were seen with sorefinib and vincristine in our study. Stevens–Johnson syndrome and toxic epidermal necrolysis are life-threatening mucocutaneous side effects which may occur in patients on chemotherapy. In this study, life-threatening adverse events such as toxic epidermal necrolysis and Stevens–Johnson syndrome were observed in 0.54% and 0.41% of the cases, respectively. One case of photodermatitis was seen in patient taking cyclophosphamide.


  Discussion Top


Mucocutaneous adverse events associated with cancer chemotherapy are seldom life-threatening. However, they can be a cause of discontinuation of therapy, physical, and psychological stress to the patient.[3] Having knowledge of all the cutaneous adverse effects of chemotherapy agents helps in diagnosis and management of such adverse events. Chemotherapeutic drugs are toxic to rapidly proliferating cells of hairs, skin, nails, and mucosa due to their narrow therapeutic index, thereby leading to a wide spectrum of mucocutaneous effects.[5],[6]

Alopecia (55.84%) was most common finding seen in this study. This was followed by skin (45.4%), nail (4.21%), and mucosal changes (2.17%).

Alopecia was observed as the most common side effect in the studies by Chiewchanvit et al.[7] (75.6%) and Menon et al.[3] (68%), similar to that observed in our study. However, in a study by Pavey et al.,[8] nail changes were the most common adverse effect observed in 62.2% of the patients, whereas hair changes were seen in 37.7% of the patients only. Alopecia is one of the most common psychologically distressing adverse event of chemotherapy.[5],[9]

Chemotherapy agents may cause partial or complete hair loss. It is because the chemotherapy agents not only act on malignant cells but also on tissues with rapid metabolic and mitotic rates such as roots of scalp hairs. It occurs during the growth phase of hair cycle, that is, the anagen phase. Telogen effluvium also occurs because number of hairs entering into telogen phase increases, which follows hair loss months later.[10] Out of all the cases of alopecia in our study, 87.6% of the patients had anagen effluvium. Rest of the (12.4%) patients had telogen effluvium. It is in accordance with studies by Pavey et al.[8] and Menon et al.[3] Thus it would be appropriate to infer that anagen effluvium is the most commonly observed form of hair loss associated with chemotherapy. Significant hair loss was observed by patients within 4–6 weeks of initiation of therapy in 72.8% of cases, constituting the majority. Similar findings were observed in the study by Yun and Kim.[11]

In a study by Trüeb,[12] the frequency of alopecia caused by different chemotherapy drugs differed and was most common (>80% cases) with antimicrotubule agents. In our study, it was more commonly associated with combination chemotherapy when compared with monotherapy. Anagen effluvium was observed in patients receiving cisplatin, carboplatin, doxorubicin, daunorubicin, cyclophosphamide, docetaxel, paclitaxel, 5-fluorouracil, bleomycin, and vincristine. The cessation of treatment almost always leads to good regrowth of hair as alopecia is mostly reversible. Thus reassurance of patients is of utmost importance.[13]

We observed HFS [Figure 2], also known as palmoplantar erythrodysesthesia, in 11% of the cases. It is relatively higher than that in other studies which have shown relatively lower frequency.[2],[14] This might be due to more frequent use of certain chemotherapy drugs in the patients in our study such as capecitabine and 5 FU, with which HFS is more commonly reported. HFS classically presents with dysesthesia, tingling sensation, erythema over the palms and soles, eventually leading to painful vesiculation, edema, and desquamation.[15] In our study, HFS was most commonly observed with capecitabine. Other drugs with which it was seen were 5 fluorouracil, doxorubicin, docetaxel, paclitaxel, and cytarabine. HFS is more commonly seen with drugs such as 5-FU, capecitabine, pegylated liposomal doxorubicin, epirubicin, hydroxyurea, docetaxel, and cytarabine.[15],[16] Our study demonstrated that almost all patients developed HFS after a few days of first or second cycle of chemotherapy.
Figure 2: (a-c) Hand-foot syndrome in a patient of breast carcinoma on capecitabine

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Pruritis was observed in 41 (5.57%) patients. It was seen more commonly in patients receiving 5-fluorouracil, erlotinib, gefitinib, cyclophosphamide, and paclitaxel. Xerosis was seen in 5.3% of the cases in our study. It was observed mainly with epidermal growth factor receptor (EGFR) inhibitors and adriamycin. The occurrence of xerosis was significantly lower in our study when compared with a study by Fabbrocini et al.[17] and Lacouture et al.,[9] in which xerosis was seen in 41.17% of the patients. This might be due to underreporting of this side effect due to lack of consultation by the patient. Pruritus is a frequent adverse effect but rarely discussed. A survey of 379 cancer survivors reported 36% experienced pruritus during chemotherapy treatment and 44% had a negative impact on QoL.[18] A meta-analysis has demonstrated that there is significantly increased risk of developing pruritus in patients on targeted chemotherapy.[19] These agents inhibit the EGFR of basal keratinocytes, thereby disturbing the normal epidermal physiology.[20],[21] Pruritis can be due to drugs itself or it might be due to some predisposing conditions, which the patient had before or after the start of chemotherapy. The drugs implicated may be chemotherapeutic drugs or other drugs which the patient was taking for coexisting comorbidities. Xerosis is mentioned as the major cause of pruritus in oncology.[22]

Nail changes [Figure 3] were observed in 31 patients (4.21%), which included longitudinal melanonychia in 11, transverse melanonychia in 7, Mees’ lines in 6, diffuse pigmentation in 4, and Beau’s line in 3 patients. Similar findings were mentioned in a study by Mizaj et al.[23] However, Pavey et al.[8] observed the nail changes to be the most common cutaneous adverse effect in 62.2% of the patients. Nail pigmentary changes in our study were seen in patients receiving cyclophosphamide, 5-FU, cisplatin, and doxorubicin. It was significantly higher with cyclophosphamide when compared with other drugs (P < 0.05). Due to slow rate of growth of nail plate, these changes are usually observed after weeks to months of initiation of therapy.[24]
Figure 3: Diffuse pigmentation of the nails in a patient of carcinoma cervix on cyclophosphamide

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Thrombophlebitis [Figure 4] was observed in 29 (3.94%) cases. Patients with cancer are at increased risk of developing thrombophlebitis. It usually occurs with chemotherapy which lasts for more than 24 h, which acts as potent intravenous stimulant.[25] Several chemotherapeutic drugs such as cisplatin, L-asparaginase, cyclophosphamide, and vincristine cause thrombophlebitis.[26] In our study, it was seen with cytarabine, 5-fluorouracil, and carboplatin.
Figure 4: Thrombophlebitis in a patient of bladder carcinoma on cisplatin

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Extravasation reaction [Figure 5] was seen in 3.4% of the cases. It occurs when the drug directly infiltrates into the tissues or due to rupture of blood vessels. It precedes with pain, erythema and followed by ulceration and necrosis. It was reported with cyclophosphamide, chlorambucil, doxorubicin, cisplatin, and carboplatin in our study. Prevalence of extravasation when chemotherapy is given through peripheral venous access is 0.1–6% and when given through central venous access it is 0.26–4.7%.[27]
Figure 5: Extravasation reaction in a patient of ovarian carcinoma on carboplatin

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Patients of cancer have altered immune response which may be due to the underlying malignancy or due to chemotherapy. This leads to increased susceptibility to infections.[28] Out of all the cases of bacterial septicemia seen in cancer patients, 23% is caused by Staphylococcus aureus.[29] In our study. pyodermas were seen in 3.26% of the patients and most commonly seen was cellulitis and wound infections. Fungal infections may arise de novo at a cutaneous site or due to hematogenous spread. Neutropenic patients are at highest risk of developing cutaneous fungal infections.[30] In our study, cutaneous Candida was seen in majority of cases presenting as intertrigo, skin rash, vaginitis, and balanitis. Out of total manifestations, fungal infections comprised 2.71% of the cases. VZV has the highest risk in patients with leukemia and lymphoma. The infection rate is higher during active stage of tumor, along with dissemination.[31] Herpes simplex virus infection is also at increased risk due to reactivation, mucosal damage, and neutropenia. Viral infections were demonstrated in 2.03% of the patients in our study and the most frequent viral infection was herpes labialis.

Mucosal changes [Figure 6] were reported in 16 cases. It includes erythema, erosion, ulceration, and pigmentation. It was seen with cyclophosphamide, 5 fluorouracil, doxorubicin and daunorubicin. Oral mucosa and gastrointestinal tract are rapidly dividing tissue being targeted by chemotherapy drugs. Risk factors which have been reported to influence the frequency and severity of mucositis include type of tumor involved (hematological diseases), age (young patients), buccodental health, the nutritional condition of the patient, and the maintenance of kidney and liver function. Drugs such as antimetabolites (methotrexate, 5-fluorouracil) and purine analogs (cytarabine) are associated with incidences of oral mucositis in up to 40–60% of the patients. Almost, 40–70% of all patients receiving combination chemotherapy regimens develop mucositis.[32]
Figure 6: Tongue pigmentation in a patient of stomach carcinoma on doxorubicin chemotherapy

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Acneiform eruptions [Figure 7] manifested as erythema, papules, and pustules in seven cases treated with targeted chemotherapy agents EGFR inhibitors and actinomycin D. Acneiform rash is a common s kin toxicity in patients treated with novel targeted therapies and is the most common dermatologic side effect that occurs in patients treated with EGFRIs.[22],[33] Recent work has proposed that patients with EGFRI-induced rash might be associated with an increased number of dermal mast cells surrounding adnexal structures with increase in mediators released which may activate sensory nerves, ultimately leading to pruritis and acneiform rash.[34],[35]
Figure 7: Acneiform eruption in a patient of lung carcinoma on gefitinib

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The mechanism of hyperpigmentation due to anticancer drugs is largely unknown. However, it is postulated that it might be due to direct toxicity on melanocytes stimulating melanin production, accumulation of drug in the skin, elevating adrenocorticotropic hormones, and hence melanocytes stimulating hormones. The drugs commonly implicated are cyclophosphamide, 5-FU, doxorubicin, cisplatin, hydroxyurea, etoposide, busulphan, and bleomycin.[5] Although higher incidences of hyperpigmentation have been reported in various previous studies, in our study pigmentation was reported in only two patients on hydroxyurea.[7],[8]

However, our study had certain limitations. The use of various combination chemotherapy regimens made it difficult to implicate a specific drug as a causative agent of a particular adverse event. Furthermore, it may involve the possibility of sampling bias, as only patients attending the dermatology outpatient and ward were included in this observational study. Due to the aforementioned reasons, it is possible that the study over- or underestimated the incidence of various adverse events. Also, because of the larger sample size, it was arduous to evaluate the course and prognosis of these manifestations post-treatment.


  Conclusion Top


Management of malignancies with both traditional and novel targeted chemotherapeutic drugs results in numerous mucocutaneous side effects in the patients. There is a need for development of an improved system for classification of these dermatologic adverse events, with greater reflection upon their presentation and severity. Their knowledge is important in management as these side effects are the cause of morbidity and distress to patients. Prophylactic therapies and early detection and intervention with close monitoring of these untoward events are vital to ensure patient compliance and maximize clinical benefit from optimal dosing. Intervening and treating these adverse effects at the right time and also taking preventive measures can help in improving the QoL of these patients.

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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Chiewchanvit S, Noppakun K, Kanchanarattanakorn K Mucocutaneous complications of chemotherapy in 74 patients from Maharaj Nakorn Chiang Mai Hospital. J Med Assoc Thai 2004;87:508-14.  Back to cited text no. 7
    
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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. 8
    
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Lacouture ME, Boerner SA, Lorusso PM Non-rash skin toxicities associated with novel targeted therapies. Clin Lung Cancer 2006;8(Suppl. 1):S36-42.  Back to cited text no. 9
    
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Batchelor D Hair and cancer chemotherapy: Consequences and nursing care—A literature study. Eur J Cancer Care (Engl) 2001;10:147-63.  Back to cited text no. 10
    
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Yun SJ, Kim SJ Hair loss pattern due to chemotherapy-induced anagen effluvium: A cross-sectional observation. Dermatology 2007;215:36-40.  Back to cited text no. 11
    
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Trüeb RM Chemotherapy-induced alopecia. Semin Cutan Med Surg 2009;28:11-4.  Back to cited text no. 12
    
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Guillot B, Bessis D, Dereure O Mucocutaneous side effects of antineoplastic chemotherapy. Expert Opin Drug Saf 2004;3: 579-87.  Back to cited text no. 13
    
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Hueso L, Sanmartín O, Nagore E, Botella-Estrada R, Requena C, Llombart B, et al. Chemotherapy-induced acral erythema: A clinical and histopathologic study of 44 cases. Acta Dermosifiliogr 2008;99:281-90.  Back to cited text no. 14
    
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Surjushe A, Vasani R, Medhekar S, Thakre M, Saple DG Hand-foot syndrome due to capecitabine. Indian J Dermatol 2008;53:43-4.  Back to cited text no. 15
    
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Miller KK, Gorcey L, McLellan BN Chemotherapy-induced hand-foot syndrome and nail changes: A review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol 2014;71:787-94.  Back to cited text no. 16
    
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Fabbrocini G, Cameli N, Romano MC, Mariano M, Panariello L, Bianca D, et al. Chemotherapy and skin reactions. J Exp Clin Cancer Res 2012;31:50.  Back to cited text no. 17
    
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Gandhi M, Oishi K, Zubal B, Lacouture ME Unanticipated toxicities from anticancer therapies: Survivors’ perspectives. Support Care Cancer 2010;18:1461-8.  Back to cited text no. 18
    
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Ensslin CJ, Rosen AC, Wu S, Lacouture ME Pruritus in patients treated with targeted cancer therapies: Systematic review and meta-analysis. J Am Acad Dermatol 2013;69: 708-20.  Back to cited text no. 19
    
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Peuvrel L, Bachmeyer C, Reguiai Z, Bachet JB, André T, Bensadoun RJ, et al. Semiology of skin toxicity associated with epidermal growth factor receptor (EGFR) inhibitors. Support Care Cancer 2012;20:909-21.  Back to cited text no. 20
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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