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Clinical Updates

Sélim Aractingi, MD, PhD

Cutaneous Side Effects of Recently Launched Anti-Cancer Agents

Selim Aractingi

Wednesday, July 05, 2006

When most dermatologists of my generation were growing up, solid tumor neoplasia was treated with surgery and/or radiotherapy, and chemotherapy was mainly used for hematologic malignancies such as leukemias and lymphomas. Therefore, dermatologists were familiar with cutaneous reactions to the limited number of drugs given in hemopathies, such as cyclophosphamide, anthracyclines, cytarabin, nitrogen mustard, alkaloids, and bleomycin.

Later on, we became familiar with fluorouracile and platin derivatives and learned of the cutaneous localized or disseminated eruptions that these medications could induce.

However, in the last decade, medical practice has changed, particularly in treating solid tumors. Several types of drugs were developed that weren't acting only as classical cytotoxic agents. Indeed, monoclonal antibodies targeting oncogenes were launched as well as other molecules acting on signaling pathways. In addition, the majority of patients now receive ambulatory treatment, which means that delayed complications - including those involving the skin - usually develop when patients are at home. Therefore, private-practice dermatologists are often the first to diagnose these events.

In this overview, I have limited the data to taxanes, capecitabin, gemcitabine, imatinib, and epidermal growth factor receptor (EGFR) inhibitors, all of which can cause adverse skin reactions (Table 1).

Taxanes

Taxanes are mainly responsible for acral, erythema, and sclerodermatous changes. Paclitaxel (Taxol®) and docetaxel (Taxotere®) constitute a class of cytotoxic drugs largely used in tumors such as breast, non-small cell bronchial, and ovarian cancers. They are efficient and widely used.

Docetaxel is responsible for many more adverse skin reactions than paclitaxel. Indeed, cutaneous eruptions develop in 70% of patients treated with docetaxel.1 Most often, these eruptions consist of palmar-plantar erythema and, more rarely, disseminated exanthems. This acral syndrome - otherwise known as hand and foot syndrome, acral erythema, or erythrodysesthesia - can be associated with painful sensations in the affected areas. Tingling and/or even burning pain may also develop. Of note, the severity of these reactions can vary, ranging from a few red plaques to diffuse edematous erythematosus lesions that sometimes blister and then ulcerate. This cutaneous toxicity develops anywhere from 2 days after infusion to 21 days. Pathogenesis of this reaction remains unknown, as histology may display either syringometaplasia, evoking the toxic effects of secreted drugs through the eccrine coils or vasculitis, perhaps by another mechanism.2

Acral erythema may recur during later courses of treatment with similar offending drugs, and it is considered to be dose-dependent. Interestingly, a recent study showed that in a multivariate analysis, skin toxicity was the only independent factor predictive of grade 3-4 infection in docetaxel-treated patients.3 Curative treatment is poor. Treatment with topical or systemic steroids is sometimes effective, but it remains controversial. A 2005 French study showed that use of frozen gloves reduced the skin toxicity score, demonstrating that as for alopecia this could be a useful prevention tool.

Sclerodermatous-like changes in various sites, mainly hands or lower limbs, have been reported with docetaxel and more recently with paclitaxel. Clinical features usually appear within days after infusion and improve if the drug is withdrawn. There is an initial edema followed by cutaneous thickening. Skin biopsy shows only dermal fibrosis.

Nail changes are another "toxic" effect of taxanes and occur in up to 30-40% of treated patients. These changes are characterized essentially by distal onycholysis, developing with or without subungual hemorrhage and acute paronychia. The later may progress to subungual abscess of distal fingers. Patients should be instructed about these events, and nail polish should be applied.4 As with palmoplantar erythema, frozen gloves in the same study cited above were able to reduce the incidence of nail changes significantly.

Finally, patients with erythema multiforme, subacute lupus erythematosus, and even radiation recall dermatitis have all been reported. The latter is a peculiar and unexplained phenomenon characterized by the development of an inflammatory cutaneous reaction after infusion chemotherapy (such as taxanes) that develops specifically at the site of prior radiotherapy although there was no skin toxicity at the time of that treatment.

Gemcitabine

Gemcitabine (Gemzar®) is a cytidin analog, chemically similar to cytarabin, acting in the cell through 2 phosphorylated metabolites. This molecule is effective in a wider spectrum of malignancies than cytarabin, being used in pancreatic cancer, non-small cell lung cancer, and, to a lesser degree, breast and ovarian tumors. Gemcitabine appears to be a "safe skin drug" but may induce erysipeloid localized inflammatory plaques.

Development of exanthema after gemcitabine infusion is possible but rare. In a series of 40 cases, treatment with this drug and cisplatin led to a unique grade 2 skin "rash".5 In another series in which 52 patients received gemcitabine and vinorelbin for non-small cell lung cancers, the authors noted a 2% incidence skin rash grade 3-4.6 This is therefore lower than what was seen with cytarabin. In my experience with similar patients, there is a low incidence. Other types of cutaneous reactions may occur. Interestingly, some patients with an intriguing erysipeloid erythema developing only in the areas of previous lymphoedema have been reported.7 Authors postulated that impaired lymphatic drainage had altered pharmacokinetics of the drug in these skin sites, allowing increased toxicity. However, a case in which the reaction developed without any previous history of such events has been published, suggesting a possible peculiar event linked to gemcitabine.8

One patient with scleroderma-like change of the lower extremities has been reported with an initial inflammatory edema, which may correspond to the same phenomenon.9

Finally, a series of patients presenting with recall radiation changes induced by gemcitabine has been described, involving mainly the skin but also deep organs.10

Capecitabine

Capecitabine (Xeloda®) is an oral prodrug that is metabolized into 5-fluorouracil - a pyrimidine analog. It is used for treating cancer of the colon after surgery but also in colorectal and breast tumors and sometimes in other malignancies.

The main problem that one should be aware of with capecitabine is a high frequency of acral erythema, also called hand and foot syndrome. In data obtained from 179 patients (4 series), hand and foot syndrome developed in 65% of treated patients, with grade 3 reactions noted in 4.5%.11 The most frequent occurrence was during cycle 2 of treatment. Analysis of these cases showed that combined use of docetaxel - already known as an inducing drug - and preceding chemotherapy-related stomatitis were significant risk factors for the development of this reaction. However, other data from 2 large phase III trials showed that the incidence of acral erythema was similar when capecitabine was administered as monotherapy or in combination.12

As stated above, treatment with corticosteroids remains controversial, relying mainly on isolated case reports. Therefore, the only proven method is dose reduction or even interruption.12

Imatinib

In chronic myeloid leukemia (Philadelphia chromosome), the BCR-ABL fusion gene, created by the Philadelphia chromosome (Ph+), displays a tyrosine kinase activity not linked to a membrane receptor. This leads to a constitutive phosphorylation of cellular proteins, with consecutive mitosis. Imatinib is the first member of an important new class of drugs, tyrosine kinase inhibitors (TKIs), part of the signal transduction inhibitors (STIs). It has been designed to link to the BCR-ABL fusion gene. It is a major oral drug in this disease, but now other indications such as gastrointestinal stromal tumors (GIST), hypereosinophilic syndromes, or even some mastocytoses may be treated with imatinib.

One of the most common side effects seen in patients receiving treatment with imatinib is skin rash, which occurs in 3-30% of treated cases.13,14 In a prospective study done in a dermatologic ward, the rash was considered severe in 5/36 eruptions and responsible for treatment withdrawal in 3/36 patients.15 This rash may be maculopapular and of variable severity. However, authors have reported that these eruptions are sometimes characterized as dark purple, pruritic papules suggestive of lichen planus. Histopathology also revealed features of lichen planus. Withdrawal of the drug has led to remissions.16

Other cutaneous reactions have been described. Some were severe, such as Stevens-Johnson syndrome, exfoliating dermatitis, acute generalized exanthematic pustulosis, and generalized erythema with chills and fever. Others have presented with features of pityriasis rosea.

Periorbital edema and peripheral edema are other frequently noted adverse reactions to imatinib, noted in 21-40% of cases.13,14 The common hypothesis explaining this symptom is the effect of platelet-derived growth factor receptor (PDGFR) inhibition on interstitial-fluid homeostasis, given that blockade of PDGFR signalling in transgenic mice induces dysregulation of the tension between endothelial cells and the extracellular matrix. Highly significant relationships have been observed between the daily dose of imatinib and both rashes and edema. In a multivariate analysis, female sex and the daily dose of imatinib were independent risk factors for the development of rashes.15

Pigment modifications may occur with TKIs. Recently, patients who developed skin hypopigmentation within the first month of treatment have been reported.17 This has included the skin and hair. The hypopigmentation was reversible and potentially dose-related. C-Kit and its ligand stem cell factor have a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib in the pathogenesis of hypopigmentation. However, despite this pharmacological mechanism, development of hypopigmentation does not appear to predict leukemic cell response or clinical outcome.17 Paradoxically, hair repigmentation was noted in 9 of 133 patients given imatinib for chronic myelogenous.18

Sorafenib is another TKI. It blocks a product of RAF (serine-threonine kinases). The drug has yielded very encouraging results in renal-cell carcinoma. Sunitinib is a new oxindole agent with antiangiogenic properties that inhibits vascular endothelial growth factor receptor 2, c-Kit, FLT-3, and PDGFR. It has shown potent, broad-range anti-tumor activity in many mouse models and is being tested in renal cancer. These molecules are, like imatinib, responsible for generalized rashes, hair modifications, and edema but with differences in incidences. Hand and foot syndrome may develop 2-4 weeks after treatment. Subungual splinter hemorrhages have been reported with these 2 molecules mainly on the hands. These lesions are asymptomatic.

Epidermal Growth Factor Receptor Inhibitors

EGFR is aberrantly overexpressed in some neoplastic conditions. This overexpression was previously associated with resistance to chemotherapy and poor prognosis. But now, several investigative groups have conducted trials using various drugs acting on the signaling pathways in lung and colon carcinomas as well as colorectal, ovarian, head and neck, breast, and bladder carcinomas.

Two types of agents acting against EGFR have been developed: monoclonal antibodies to prevent EGF binding and small-molecule inhibitors of tyrosine kinase enzymatic activity and downstream intracellular signaling. The chimeric monoclonal blocking antibody is cetuximab (Erbitux®). The 2 small molecules that inhibit the tyrosine kinase of EGFR are gefitinib (Iressa®) and erlotinib (Tarceva®).

Unexpectedly, a frequent occurrence of cutaneous adverse reactions -characterized by acneiform eruptions - has been reported with all EGFR inhibitors tested. These acne or follicular eruptions are characterized by inflammatory lesions (papules and pustules) without retentional lesions. They may involve the face and upper trunk as well as sites not usually involved by classical acne (such as the extremities and lower back), and they are sometimes pruritic. Bacterial culture of pus is negative or yields only P. acnes. With cetuximab, the drug that appears to induce folliculitis most frequently, the figure reached 75-91% of patients.19 The length of time until lesions appeared was very short, with a mean delay of 10 days after initiating therapy, but it occurred as early as 2 days after cetuximab was started. With gefitinib, skin lesions occurred 5-12 days after beginning treatment. Authors have found that the intensity of the folliculitis was related to the tumor response and survival. This positive association was recorded in clinical trials with erlotinib, cetuximab, and gefitinib but is still controversial. Various treatments have been found to be efficient, mainly topical antibiotics, oral doxycyclin and even topical steroids.

Paronychia may occur after administration of any of the EGFR inhibitor. It is characterized by an erythematous painful lateral nail-fold, which may evolve to become a pyogenic granuloma-like lesion. Paronychia can affect any finger or toe, single or multiple. It occasionally recurs around the same nail or another one. It can sometimes resolve spontaneously and always disappears within a few days of discontinuing EGFR inhibitor treatment. Patients should be instructed to avoid trauma, and if lesions appear, use of antiseptics is recommended.

Conclusion

Apart from the special side effects observed with TKIs and EGFR inhibitors, the cutaneous adverse reactions to chemotherapy management remain difficult to treat. Indeed, patients are nearly always given a combination of drugs and therefore imputability to a single molecule is complicated. In addition, manuscripts reporting large series of chemotherapy patients often identify skin toxicity with few or no details since these are written by oncology teams. Much data remains controversial, such as the dose dependence of disseminated exanthema and/or the steroid responsiveness of hand and foot syndrome.

The major question that is asked is whether it is possible to continue treatment despite the cutaneous reaction. Decision making is always difficult and requires a discussion with the oncologists in order to weigh the severity of the reaction relative to the benefit from the regimen used in tumor management. Dermatologists should invest themselves fully in this essential clinical task and not leave it to other specialists.

Table 1. Major Cutaneous Reactions to Recently Launched Anti-Cancer Agents


Skin changes      
Gemcitabine Rash "erysipeloid" reaction (RARE)
Taxanes

Hand and foot syndrome
Sclerodermoid changes
Onycholysis

Capecitabine

Hand and foot syndrome

Imatinib Disseminated rash, sometimes lichenoid
EGFR inhibitors Folliculitis paronychia


References

  1. Zimmerman GC, Keeling JH, Burris HA, et al. Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent. Arch Dermatol. 1995;131(2):202-6.
  2. Karam A, Metges JP, Labat JP, et al. Squamous syringometaplasia associated with docetaxel. Br J Dermatol. 2002;146(3):524-5.
  3. Poikonen P, Sjostrom J, Klaar S, et al. Skin toxicity as a risk factor for major infections in breast cancer patients treated with docetaxel. Acta Oncol. 2004;43(2):190-5.
  4. Wasner G, Hilpert F, Schattschneider J, et al. Docetaxel-induced nail changes--a neurogenic mechanism: a case report. J Neurooncol. 2002 Jun;58(2):167-74.
  5. Shepherd FA, Cormier Y, Burkes R, et al. Phase II trial of gemcitabine and weekly cisplatin for advanced non-small cell lung cancer. Semin Oncol. 1997;24(3 Suppl 8):S8-27-S8-30.
  6. Katakami N, Sugiura T, Nogami T, et al. Combination chemotherapy of gemcitabine and vinorelbine for patients in stage IIIB-IV non-small cell lung cancer: a phase II study of the West Japan Thoracic Oncology Group (WJTOG) 9908. Lung Cancer. 2004;43(1):93-100.
  7. Brandes A, Reichmann U, Plasswilm L, et al. Time- and dose-limiting erysipeloid rash confined to areas of lymphedema following treatment with gemcitabine--a report of three cases. Anticancer Drugs. 2000;11(1):15-7.
  8. Kuku I, Kaya E, Sevinc A, et al. Gemcitabine-induced erysipeloid skin lesions in a patient with malignant mesothelioma. J Eur Acad Dermatol Venereol. 2002;16(3):271-2.
  9. Bessis D, Guillot B, Legouffe E, et al. Gemcitabine-associated scleroderma-like changes of the lower extremities. J Am Acad Dermatol. 2004;51(2 Suppl):S73-6.
  10. Jeter MD, Janne PA, Brooks S, et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys. 2002;53(2):394-400.
  11. Heo YS, Chang HM, Kim TW, et al. Hand-foot syndrome in patients treated with capecitabine-containing combination chemotherapy. J Clin Pharmacol. 2004;44(10):1166-72.
  12. Scheithauer W, Blum J. Coming to grips with hand-foot syndrome. Insights from clinical trials evaluating capecitabine. Oncology (Williston Park). 2004;18(9):1161-8, 1173; discussion 1173-6, 1181-4.
  13. Cervantes F, Hernandez-Boluda JC, Odriozola J, et al. Imatinib mesylate (STI571) treatment in patients with chronic-phase chronic myelogenous leukaemia previously submitted to autologous stem cell transplantation. Br J Haematol. 2003;120(3):500-4.
  14. van Oosterom AT, Judson IR, Verweij J, et al. Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2002 Sep;38 Suppl 5:S83-7.
  15. Valeyrie L, Bastuji-Garin S, Revuz J, et al. Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients. J Am Acad Dermatol. 2003 Feb;48(2):201-6.
  16. Roux C, Boisseau-Garsaud AM, Saint-Cyr I, et al. [Lichenoid cutaneous reaction to imatinib]. Ann Dermatol Venereol. 2004 Jun-Jul;131(6-7 Pt 1):571-3.
  17. Tsao AS, Kantarjian H, Cortes J, et al. Imatinib mesylate causes hypopigmentation in the skin. Cancer. 2003 Dec 1;98(11):2483-7.
  18. Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005 Jul;6(7):491-500.
  19. Molinari E, De Quatrebarbes J, Andre T, et al. Cetuximab-induced acne. Dermatology. 2005;211(4):330-3.
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