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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.86 no.4 Rio de Janeiro July/Aug. 2011
Aline DonatiI; Luiz Guilherme Martins CastroII
IDermatologist of the Check-up Service of Fleury Laboratory (Fleury Medicine and Health) - São Paulo (SP), Brazil
IIPhysician - Medical School of the University of São Paulo (FMUSP) - Responsible for the Dermatology sector of Fleury Laboratory (Fleury Medicine and Health); Clinical Director of Oncoderma Cutaneous Oncology - São Paulo (SP), Brazil
Chemotherapy with taxanes has recently become part of the treatment for many advanced neoplastic diseases, specially breast and lung cancer. Their main noncutaneous adverse reactions include neutropenia and mucositis, which eventually lead to drug discontinuation. Cutaneous adverse reactions are frequent and significantly interfere with the patient's quality of life. Treatments are poorly effective, but special recommendations may improve symptoms and prevent relapses requiring drug rechallenge.
Keywords: Drug Eruptions; Drug Therapy; Cutaneous adverse reactions; Paclitaxel; Taxoids
Taxanes (TX) are drugs used to treat severaltypes of neoplasias, such as breast and lung cancer. There are 2 types of TX in Brazil: paclitaxel (PC) (Taxol® ) and docet axel (DC) (Taxotere®). The most common side effects of these drugs are neut ropenia and mucositis. They present a similar mode of action but a distinct profile regarding cutaneous adverse reactions.1 With the purpose of making dermatologists more famitiar with this kind of reaction, which will become more frequent with greater utilization of TX, we report below 4 cases that were followed in a dert matology office.
1 - Female patient, 54 years old, after 4 years of breast cancer treatment with mastectomy and chemotherapy (CTH) with other drugs, presented bone and liver metastases; a new CTH series was started with PC and carboplatin. Two months later she presented erythema and hyperchromia on the back of hands and on the face, accompanied by dysesthesia with local burning sensation (Figure 1). She wore a moisturizer and photoprotector, and was oriented to avoid sun exposure. Two months later, in view of the intensity of cutaneous adverse reactions, PC was replaced by DC, with great improvement of symptoms. After 2 cycles of the new drug, she developed phlebitis at the place of infusion with linear hyperpigmentation following the venous pathway (Figure 2). The elementary lesions of this second episode were similar to those observed in the first. She was treat ed with creams composed of tretinoin/hydroquinone/fluocinolone on the face and glycolic acid/hydroquinone/ heparinoid on the forearm, in addition to photoprotection. Thirty days later she reported great improvement. With the new cycle of DC the facial condition was react ivated, with erythema, peeling and hyperpigmentation. She was oriented to continue the same treatment until the end of CTH. Eleven months after this last visit she mentioned that CTH with TX had been suspended. She presented melasma and mottled hyperpigmentation on the face, supposedly a residual effect of previous processes.
2 - Male patient, 84 years old, presented paronychia on both haltuces after 3 months of CTH with PC and carboplatin to treat lung cancer. Onycholysis and inflammation of nail bed and subj acent periungual tissue were observed. The plates were thickened and yellowed (Figure 3). Nail avulsion was carried out, as they were loose in most of their area. Erythema and granulation tissue were observed on the nail bed. Forty days after surgery he returned to the office mentioning that he had completed CHT. The nails and periungual tissue did not present any phlogistic signs and it was already possible to observe that the nails were growing. The patient was discharged.
3 - Female patient, 49 years old, two months after mastectomy due to breast cancer was subj ected to CHT with DC, adriamycin and cyclophosphamide. After the 4t h chemotherapy session she presented erythema and dysesthesia of the burning sensation type on the hands, that greatly improved in 2 weeks. After the next session there was recidivation of symptoms and the heels were also involved (Figures 4 and 5). She was treated with prednisone 0.2 mg/kg/day for 7 days, mometasone cream and moisturizers. There was partial improvement of symptoms. At each new CHT session she presented the same symptoms with greater intensity and less expressive improvement with the treatment.
4 - Female patient, 44 years old, presented breast cancer with liver metastasis and chemotherapy with PC was started at the same time. After 4 months she presented infiltrated maculae and hyperpigmentation on back of hands and periungual pain on hands and feet. The condition evolved with a subungual abscess on the 3r d left digit and local onycholysis; the patient was treated with prednisone 10mg/d, glycolic acid/hydroquinone bleaching cream, moisturizers and opioid analgesics. She presented discreet improvement of symptoms, but a few days later paronychia appeared on the 3r d and 4t h right digits and the erythema worsened, this time on back of hands and on the face, with local burning sensation (Figure 6). The symptom complex continued progressing with the onset of similar new lesions on toenails and on other fingers. The remission occurred only gradually, after suspension of CHT.
There are 2 types of TX in the domestic market: PC and DC. The difference between them is found in their origins: PC is extracted from the bark of the Taxus brevifolia tree, while DC is obtained from the Taxus baccata leaves. Although their mechanism of action is similar (microtubule stabilization during mitosis, blocking their ability to disaggregate and leading to cellular death), their indication and side effects are distinct.2 This may be due to the fact that DC is better absorbed by cells and is within the intracellular environment for a longer time.3
Signs of dermatological toxicity are observed in around 65% of cases and include alopecia, hypersensitivity reactions and ungual alterations.4 Most cases are treated by the oncotogist, therefore many studies on the theme do not reflect the dermatological vision of the clinical picture, briefly described as "cutaneous reaction".
Among the papers published in dermatology journals one from 2008 stands out, where a list of all reactions already described as secondary to taxanes is found.5 Other texts are reports or series of cases focusing only on a facet of cutaneous adverse reactions, such as a "photo recall" phenomenon, generalized pustular dermatosis, scleroderm-like react ions, fixed pigmented erythema and erythrodysesthesia, 3,6,7,8, 9
Acral or palmar-plantar erythrodysesthesia (PPE) is a peculiar cutaneous and neurological symptom complex associated with the use of TX, mainly DC. It has already been found in patients that made use of PC or other chemotherapeutic agents (cytarabine, doxorubicin and 5-fluorouracil).10 Clinically, it varies only from erythema to edematous plaques and is especially present in acral regions. Dysesthesia sensations may or may not occur, almost always painful and of varying intensity.11 Residual hyperchromia is frequent and may be treated with bleaching creams. Histology reveals spongiotic epidermis with lichenoid alterations, such as apoptotic keratinocytes and interface activity. A discreet superficial perivascular inflammatory lymphohistiocytic infiltrate is seen on the dermis. Unspecific glandular alterations, such as neutrophilic eccrine hidradenitis, necrosis of the secret ory epithelium and syringosquamous metaplasia are also described.3,4,12
The cause of PPE is unknown, although there is a theory concerning the affinity of these drugs to eccrine sweat glands.4 The immunocytochemical characteristics of the inflammatory infiltrate and lack of a consistent response to corticosteroids and antihistamines go against an allergic origin of the reaction.3
There are no known risk factors for development of PPE, nor characteristics that predict its intensity. The reactions usually occur after the 1st treatment cycle and are dose-dependent, with relief of discomfort during relap tes when the quantity of the drug being given is decreased. There usually is spontaneous resolution of PPE after 2 weeks, with recurrence when the drug is reintroduced. The use of topical or systemic corticosteroids, elevation of legs and application of cold compresses is recommended for incapacitating pain.11 Preventive treatment with pyrit doxine was reported as beneficial in one study. It is recommended to apply local hypothermia to acral regions during medication infusion to decrease local drug perfusion.13
Another characteristic cutaneous adverse react tion is ungual infection.14 The most prevalent alteration is onychomelanosis, although onycholysis, as reported here, is the most studied finding. The hallux nail is the most affected, but there are cases of multiple infection or where all nails are infected. The use of DC, the PC/anthracycline association and protonged PC use (>12 weeks) are considered risk factors.
In some cases, in addition to onycholysis there is inflammation of the skin close to the hyponychium and it is believed that the great er sensitivity of this portion of the nail apparatus to ultraviolet rays may be part of onycholysis physiopathology.15 The exact role of UV radiation as a trigger is not totally clear, but an increase in the incidence of this cutaneous adverse reaction is observed in the summer. Moreover, nail sun protection by physical methods is able to prevent lesion recurrence in subsequent treatment cycles.
Cutaneous adverse reactions are very common with the use of TX. There are no exact numbers, as there are no epidemiological studies of such drugs used isolated, but a 65% incidence is estimated. These reactions have variable intensity and may significantly alter quality of life; the relief of symptoms and prevention of reactions are fundamental. There are few studies regarding treatment, which leaves dermatologists without much scientific evidence. Among the skin alterations that make patients seek a dermatologist are PPE and onycholysis. Preventive orientation is useful to avoid suspension of treatment, and many times it is the only way to treat the restricting symptoms of PPE triggered by TX. _
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2. Marty M, Extra JM, Giacchetti S, Cuvier C, Espie M. Taxoids: a new class of cytotoxic agents. Nouv Rev Fr Hematol. 1994;36(Suppl 1):S25-8. [ Links ]
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10. Nagore E, Insa A, Sanmartin O. Antineoplastic therapy-induced palmar plantar erythrodysesthesia ('hand-foot') syndrome. Incidence, recognition and management. Am J Clin Dermatol. 2000;1:225-34. [ Links ]
11. Katoh M, Kadota M, Nishimura Y. A Case of Docetaxel-Induced Erythrodysesthesia. J Dermatol. 2004;31:403-6. [ Links ]
12. Demirçay Z, Gürbüz O, Alpdo¤an TB, Yücelten D, Alpdo¤an O, Kurtkaya O, et al. Chemotherapy-induced acral erythema in leukemic patients: A report of 15 cases. Int J Dermatol. 1997;36:593-8. [ Links ]
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Mailing address: Received on 22.12.2009. * Study carried out at: Oncoderma Oncologia Cutanea - São Paulo (SP), Brazil.
Luiz Guilherme Martins Castro
Rua Mato Grosso, 306 - Conjunto 604, Higienópolis
05011-001 São Paulo (SP) - Brazil
Approved by the Advisory Board and accepted for publication on 11.07.2010.
Conflict of interest: None
Financial funding: None
Received on 22.12.2009.
* Study carried out at: Oncoderma Oncologia Cutanea - São Paulo (SP), Brazil.