|Year : 2018 | Volume
| Issue : 1 | Page : 19-24
Study of cutaneous adverse effects of cancer chemotherapy
Ashok Menon1, Sripathi Handattu1, Jayaram Shetty2, Banavasi Shanmukha Girisha1
1 Department of Dermatology, K. S. Hegde Charitable Hospital, Mangalore, Karnataka, India
2 Department of Oncology and Radiotherapy, K. S. Hegde Charitable Hospital, Mangalore, Karnataka, India
|Date of Web Publication||5-Jan-2018|
Banavasi Shanmukha Girisha
Department of Dermatology, K. S. Hegde Charitable Hospital, Deralakatte, Mangalore - 575 018, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Cancer is a leading cause of mortality and morbidity in both developed and developing parts of the world with the disease burden projected to grow exponentially in future. Over the past several decades great advances have been made in the area of cancer chemotherapy. Objectives: To study the various cutaneous adverse events associated with cancer chemotherapy. Methodology: 100 patients diagnosed with cancer attending the departments of a tertiary hospital who underwent chemotherapy and satisfied the inclusion and exclusion criteria were included in this study. It is a hospital based observational study. All patients were counselled about the study and informed written consent was obtained. Patients were examined before start of chemotherapy treatment and after every cycle of chemotherapy. Data collected was analysed using SPSS version 16.0. Results: In this study, 100 patients including 37 females and 63 males were included in this study. Majority (56%) of the patients belonged to the age group of 41-60 years. The common indications for chemotherapy were carcinoma oropharynx (24%), carcinoma breast (18%), tongue and stomach. Among the cutaneous adverse events noted, hair changes were the most common presentation and were reported in 68 patients. Skin changes were seen in 65 cases, nail changes in 30 cases and mucosal changes in 12 patients. Xerosis (26%) and hyperpigmentation (22%) were the most commonly observed adverse event affecting skin. Cisplatin, cyclophosphamide, 5 fluorouracil, carboplatin, paclitaxel and doxorubicin were the most frequently prescribed chemotherapeutic drugs. Conclusion: Our observations necessitate a joint effort between dermatology and oncology for the early recognition and adequate treatment of the cutaneous adverse effects associated with cancer chemotherapy which may help in reducing morbidity and improving compliance.
Keywords: Adverse effects, chemotherapy, cutaneous
|How to cite this article:|
Menon A, Handattu S, Shetty J, Girisha BS. Study of cutaneous adverse effects of cancer chemotherapy. Clin Dermatol Rev 2018;2:19-24
| Introduction|| |
Cancer is a leading cause of mortality and morbidity in both developed and developing parts of the world with the disease burden projected to grow exponentially in the future. International Agency for Research on Cancer, which is the specialized cancer agency of World Health Organization (WHO), reported 14.1 million new cancer cases and 8.2 million cancer-related deaths in 2012. Indian data reported 1.14 million new cases and 0.7 million cancer-related deaths in 2012. Latest data show that the 5-year survival of all cancers has increased from 50% to 66% over the past 20 years. WHO defines an adverse drug reaction as “any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis, or therapy.” Dermatological adverse effects are often reported as causes for discontinuation of therapy though they are seldom life-threatening events. This study aims at identifying the various cutaneous adverse events associated with cancer chemotherapy.
| Materials and Methods|| |
A total of 100 patients diagnosed with cancer attending the Departments of Oncology and Dermatology of a tertiary hospital between September 2014 and April 2016 who underwent chemotherapy and satisfied the inclusion and exclusion criteria were included in this study. Patients above the age of 18 years and who gave consent for the study were included in the study. Patients on radiotherapy and those below the age of 18 years were excluded from the study. Patients who developed dermatological manifestations as a result of internal malignancy were also excluded from the study. All patients were counseled about the study and informed written consent was obtained. All patients underwent a complete dermatological examination. Information including demographic data, cancer type, chemotherapeutic agents used, any significant dermatologic history, and on-going dermatologic treatment was collected using a structured proforma. Detailed descriptions of the clinical features as well as characterization of the severity and evolution of cutaneous lesions were assessed and documented. The national cancer institute common terminology criteria for adverse events version 4.0 were used to grade the cutaneous adverse events. Patients were examined before the start of chemotherapy treatment and at each clinical visit for every cycle of chemotherapy and the lesions were photographed. Any history of hair loss or other preexisting chronic dermatoses was carefully investigated, and any changes in them during chemotherapy were documented. Data collected were analyzed using SPSS version 16 (SPSS Inc. Chicago, USA). Ethical clearance for the study was obtained from the Institutional Ethical Committee before starting the study.
| Results|| |
One hundred patients including 37 females (37%) and 63 males (63%) were included in this study. Majority (56, 56%) of the patients belonged to the age group of 41–60 years. Mean age of patients was 47.5 (±12.43) years with the age ranging from 18 years to 77 years.
Carcinoma affecting the oropharynx was the most common indication for chemotherapy affecting 24 patients followed by carcinoma breast (n = 18), carcinoma tongue (n = 13), carcinoma stomach (n = 10), carcinoma ovary (n = 8), and nasopharyngeal carcinomas (n = 7). Other carcinomas were those affecting rectum, esophagus, testis, lung, cervix, thyroid, ovary, pancreas, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and rhabdomyosarcoma. Among the female patients, carcinoma breast had the highest incidence (n = 18) followed by carcinoma ovary (n = 6). In males, carcinoma oropharynx affected 22 patients, followed by carcinoma tongue (n = 11) and carcinoma stomach (n = 8). Data regarding various types of carcinomas with their incidence are depicted in [Figure 1].
The patients received a minimum of three cycles and maximum of six cycles (mean: 5.37 [±0.83] cycles) of chemotherapy. The duration of therapy ranged from 4 to 20 weeks with a mean duration of 8.96 (±4.479) weeks.
Fifty-four patients received chemotherapy with a single agent and 46 patients received combination therapy. Nineteen patients (19%) received a regimen comprising three drugs, 25 patients received two drugs, and two patients received four drug regimens. The duration of therapy was <5 weeks in 44 patients and between 5 and 10 weeks in 14 patients. Thirty-three patients received therapy for 10–15 weeks.
Drugs administered to the patients include 5-fluorouracil, adriamycin, vincristine, carboplatin, cyclophosphamide, cisplatin, doxorubicin, epirubicin, etoposide, gemcitabine, oxaliplatin, paclitaxel, pemetrexed, rituximab, capecitabine, ifosfamide, and mesna. Among these, maximum number of patients received cisplatin (48, 48%), followed by cyclophosphamide (20, 20%), carboplatin (18, 18%), paclitaxel (18, 18%), and 5-fluorouracil (17, 17%).
Cutaneous adverse events noted are depicted in [Table 1]. A total of 186 dermatological manifestations were noted with 84% of patients having at least one mucocutaneous finding.
All patients (68) with hair changes had scalp involvement and 48 cases (70.6%) had involvement of other sites. Of the 68 cases, 54 (79.4%) presented with Grade 2 and 14 (20.6%) with Grade 1 alopecia. Grade 1 alopecia is defined as alopecia affecting <50% of normal for that individual and Grade 2 as alopecia affecting more than 50% of normal for that individual. Sixty-two (91.2%) patients had anagen effluvium and six (8.8%) had telogen effluvium. No other hair changes were noted. [Figure 2] and [Figure 3] show hair loss after 6 weeks of chemotherapy.
Of the seven cases of fungal infection, five were dermatophyte infections and two cases were diagnosed as pityriasis versicolor. Five cases had an onset in the 2–4th week. All viral infections were diagnosed as herpes zoster.
Among nail changes, melanonychia was the most frequently seen adverse event and occurred in 15% cases, followed by Beau's lines in 8% patients and Mee's lines [Figure 4] in 4% cases. Paronychia and loss of nail were the complaints in 2% and 1% patients, respectively.
Mucositis was reported in 12% cases, of which all cases affected the buccal mucosa. Half the cases were classified as Grade 2 and the rest were Grade 1. The various chemotherapeutic agents used and the adverse effects observed are depicted in [Table 2].
|Table 2: Cutaneous findings and their relation to chemotherapeutic agents|
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| Discussion|| |
Newer chemotherapy agents having specific targets in the pathogenesis of malignancies and older agents are associated with a variety of cutaneous adverse events. These drugs have a small therapeutic index and thus may be toxic to the rapidly proliferating cells of the skin, hair, and nails at therapeutic doses resulting in a wide array of cutaneous side effects.,
Among the 100 patients included in this study, 84 (84%) patients had at least one cutaneous finding which can be attributed to cancer chemotherapy. This was similar to the incidence of skin changes (86.4%) reported by Hackbarth et al. Chopra et al. reported an incidence of 24.6%.
Majority of the patients belonged to the fifth decade. This was comparable to the findings of other studies.,
In this study, hair changes were the most common presentation, followed by skin, nail, and mucosal changes. [Table 3] summarizes the comparison of different cutaneous findings reported by Kirthi et al., Pavey et al., Chiewchanvit et al., and our study.
Alopecia is one of the most commonly reported and psychologically distressing adverse effects of cancer chemotherapy., Fifty-eight percentage of patients rated alopecia secondary to chemotherapy as the most traumatic side effects and 8% of patients considered not undergoing chemotherapy because of fear of hair loss. The commonly observed form of hair loss associated with chemotherapy is anagen effluvium. The cessation of mitotic activity in the hair matrix results in a narrow weakened portion of the hair shaft known as Pohl-Pinkus constriction which is prone to fracture. Majority (79.4%) of the affected patients noticed significant hair loss within 3–6 weeks of initiation of therapy. This was in accordance with the studies by Yun and Kim and Hussein., Drugs which were found to cause alopecia in this study were 5-fluorouracil, adriamycin, vincristine, cyclophosphamide, doxorubicin, epirubicin, oxaliplatin, and paclitaxel. These were the same drugs implicated by other reports.,,, The severity of alopecia is directly related to the dosage, duration, and regimen of therapy. Permanent hair loss is reported with certain drugs such as cyclophosphamide and busulfan. Minoxidil was found to be ineffective in preventing chemotherapy-induced hair loss. Hair loss is almost always reversible with good regrowth seen after cessation of treatment. It is, therefore, important to reassure the patient regarding regrowth of hair after completion of treatment.
Other hair changes such as trichomegaly and hair texture changes were not observed in this study. Many studies have observed that these changes, especially trichomegaly, occur secondary to treatment with epidermal growth factor receptor inhibitors (EGFRIs).,, In this study, no patients were treated with EGFRIs, and this may explain the absence of these hair changes.
Xerosis was seen in 26% patients. Majority of them (53.9%) noticed skin lesions by 4–6th week of therapy. Abnormal keratinocyte differentiation which leads to an impaired sebaceous gland function and loss of ability to retain water may be the cause of xerosis. A similar incidence of xerosis (22.2%) was reported by Pavey et al., but the onset of lesions was noticed earlier at 2–4 weeks. Fabbrocini et al. reported an incidence of 41.7% of xerosis in his study. The drugs found to cause xerosis in this study were cyclophosphamide, carboplatin, ifosfamide, mesna, and vincristine. Liberal use of emollients and general hydrating measures should be explained to the patients to minimize this side effect.
Hyperpigmentation was the next most common adverse reaction observed in 22 (22%) patients in this study. The hyperpigmentation may be due to postinflammatory hyperpigmentation, stimulation of melanin synthesis by the increased action of adrenocorticotrophic hormone, or it may be a result of hypersensitivity reactions. The sites which were most commonly involved were dorsum of hands, feet, and periungual region. Diffuse hyperpigmentation was observed in 3% patients. Pavey et al. and Chiewchanvit et al. observed a frequency of 22.2% and 31.3% of hyperpigmentation in their respective studies., The drugs found to cause hyperpigmentation in this study were 5-fluorouracil, cyclophosphamide, cisplatin, doxorubicin, gemcitabine, and ifosfamide.
In our study, a rare distinct type of hyperpigmentation called supravenous hyperpigmentation was noted in one patient on treatment with a combination of 5-fluorouracil, cyclophosphamide, and doxorubicin [Figure 5]. Of these drugs, 5-fluorouracil and cyclophosphamide have been reported earlier to cause this rare form of hyperpigmentation.,
Acneiform eruption developed in the 6–8th week of therapy [Figure 6]. An earlier onset of lesions at 2–3rd week of therapy was reported by Lee et al. and Pavey et al., All our patients were treated with topical benzoyl peroxide and all responded well to therapy.
Four percent of patients developed thrombophlebitis secondary to treatment with 5-fluorouracil, doxorubicin, cyclophosphamide, and cisplatin therapy during the course of this study. Two patients suffered from ulceration secondary to extravasation on treatment with adriamycin, vincristine, and paclitaxel [Figure 7]. These can be classified under extravasation injuries. Vincristine has been classified as a vesicant drug and is known to cause ulceration secondary to extravasation. Severe necrosis due to paclitaxel extravasation was reported by Herrington and Figueroa. Estimated incidence from published literature varies from 0.1% to 6% which is similar to the incidence in our study.,, Adoption of better infusion techniques may help in reducing extravasation injuries.
Among infections reported in our study, fungal infections and viral infections constituted 7% and 4%, respectively. Chiewchanvit et al. reported an incidence of 8.1% for fungal infections and 4% for viral infections. Patients receiving chemotherapy may be more susceptible to acquiring infections due to myelosuppression and alteration in immune system function.
Nail matrix cells are rapidly dividing cells and are frequently affected by chemotherapy. Nail changes usually appear several weeks after initiation of therapy possibly due to the slow rate of growth of the nail plate., Pavey et al. observed that nail changes (62.2%) were the most common cutaneous adverse events and this was significantly higher compared to our study. Among the nail changes in our study, melanonychia (15%) was the most common, followed by Beau's lines (8%) and Mee's lines (4%). Chiewchanvit et al. in his study observed melanonychia in 18.9% of patients and 23% had Mee's lines. Drugs found responsible for melanonychia were adriamycin, epirubicin, etoposide, and cisplatin. Kim et al. reported nail hyperpigmentation secondary to treatment with cisplatin.
Mucositis which presents as painful erosions and aphthae was seen in 12% patients in this study. Published literature reports an incidence of 40%–70%. It is reported to be one of the main dose-limiting adverse effects. Painful oral lesions can severely impair the nutritional intake and in some cases, prevent the completion of therapy. Direct drug toxicity on the rapidly dividing oral epithelial cells results in oral ulcerations. The drugs also cause bone marrow suppression which may contribute to the symptoms. Proposed risk factors for developing mucositis include young age of patients (<20 years of age), hematologic malignancies, bolus administration of the drug, other oral disease, and poor oral hygiene. Commonly implicated drugs are 5-fluorouracil, cytarabine, paclitaxel, and vinca alkaloids. The risk of mucositis increases with subsequent cycles in patients who develop mucositis in one cycle. Spontaneous resolution of lesions usually occurs within 2–3 weeks without much scarring. Measures to manage and prevent mucositis include the use of granulocyte colony-stimulating factor, oral cryotherapy, and palifermin which is a recombinant human keratinocyte growth factor.,
No cases of palmar-plantar erythrodysthesia, erythroderma, Stevens-Johnson syndrome More Details, Toxic epidermal necrolysis, and neutrophilic eccrine hidradenitis were encountered in this study.
| Conclusion|| |
In this study, we observed that almost all patients experienced some cutaneous adverse effect which can be attributed to chemotherapeutic agents. When patients are informed about the potential side effects before initialization of therapy, it usually results in better acceptance and compliance by patients. Knowledge about the incidence and severity of various adverse events associated with cancer chemotherapy can help in early recognition and treatment. A combined effort on the part of dermatologists and oncologists in the management of these adverse events would help in preventing treatment-related morbidity.
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
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3]