Description and management of cutaneous side effects during erlotinib and cetuximab treatment in lung and colorectal cancer patients: A prospective and descriptive study of 19 patients

ARTICLE

Auteur(s) : Nuno Miguel Bouças Vasconcelos de Noronha e Menezes¹, Ricardo Lima², Ana Moreira¹, Paulo Varela¹, Ana Barroso², Armando Baptista¹, Bárbara Parente²

¹Serviço de Dermatologia e Venereologia do Centro Hospitalar de V. N. de Gaia/Espinho, Portugal
²Unidade de Pneumologia Oncológica, Serviço de Pneumologia do Centro Hospitalar de V. N. de Gaia/Espinho, Portugal

accepté le 1 Janvier 2009

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases is at the beginning of a complex signal transduction cascade that modulates cell proliferation, survival, adhesion, migration, and differentiation. Although growth factor-induced EGFR signaling is essential for many normal morphogenic processes and is involved in numerous additional cellular responses, the aberrant activity of members of this receptor family has been shown to play a key role in the development and growth of tumor cells. EGFR blockade represents a novel strategy for cancer treatment [1]. Erlotinib and cetuximab are members of this new class of drugs.

New targeted therapies of this type have low systemic toxicity as a result of their high specificity. Unlike conventional cytotoxic agents, they do not cause myelosuppression, neuropathy, significant nausea, vomiting, or alopecia [2]. In adults, the EGFR is expressed in the skin, primarily in proliferating, undifferentiated keratinocytes of the basal layers of the epidermis and the outer root sheath of the hair follicle [3]. For this reason, these new drugs lead to the development of cutaneous side effects, the most common being the papulopustular follicular eruption in seborrheic areas (upper aspect of the torso, face, neck, and scalp) [2, 4]. Other secondary effects are xerosis with scaly, dry itchy skin (mostly on arms and legs); painful fissures in hands and feet (nailfolds and knuckles); nail changes such as paronychia; and changes in the characteristics of the hair (elongation of eyelashes, slowing of scalp hair growth and curly hair) [5].

The aim of this study was to describe the clinical features and therapeutic management of the acneiform induced rash by the EGFR inhibitors.

Methods

Results

In addition to all the general measures referred to above, treatment included the use of topical antibiotics (nadifloxacin or clindamycin) or a combination of these with benzoyl peroxide. Grade 2 or 3 patients required oral antibiotics (doxycycline or minocycline, both 100 mg/day) or low dose isotretinoin and antihistamines whenever pruritus was present. After treatment initiation all patients were seen every other week and at week 4 response to treatment was judged (table 2). None of the patients had recurrence of the eruption or had to stop treatment. All patients (with the exception of patient number 4) showed improvement on doxycycline or minocycline treatment (42% had a complete response) (table 2). Patients 3 and 4 died due to their primary lung disease. Patient 4, who did not respond to minocycline, was started on low-dose 10 mg isotretinoin with a slight improvement, but unfortunately died, making complete response assessment impossible.

Some patients concurrently developed eczematous plaques on the face or neck which were treated with topical steroids with good response. Almost all the patients, at some point in time, had xerosis with a good response to moisturizers. Some other alterations were noticed, namely alopecia that started 3 to 4 months after the occurrence of the papulo-pustular eruption, late-occurring paronychia with a good response to topical association of corticosteroids plus antibiotics, and hirsutism (figure 3).
Table 2 Patients’ clinical details

Discussion

Anti-cancer strategies that inhibit the processes enabling tumors to grow, metastasize and evade the host’s immune system have been developed. These new drugs promise activity against various tumors at different stages of development, alone or in combination with standard therapies, while avoiding most of the nonspecific toxicities that are common in standard chemotherapy and radiotherapy. Many oncologists hope they will make cancer a manageable chronic disease for many patients in the future [6].

Initial targets included members of the human epidermal growth factor receptor family and others cytokines [6]. The EGFR inhibitors are a new class of drugs used for the treatment of head and neck cancers, lung, colorectal and pancreatic cancer [7].

However, as these drugs become routinely used, other issues are emerging such as cutaneous side-effects. A papulopustular eruption located to the upper trunk that is histologically characterized by a superficial neutrophilic suppurative folliculitis with associated rupture of epithelial lining, is the most common one. The eruption associated with this family of drugs is mostly mild to moderate, but can be more severe in some cases, leading to dose reduction, dose interruption, or treatment cessation when considered intolerable. Clinically it is similar to acne vulgaris, but it should be emphasized that the reaction is predominantly pustular, not associated with comedones [6, 8-10]. This eruption normally manifests despite prophylactic measures with a sunscreen and an oatmeal moisturizer by the second week of treatment and is reversible after drug withdrawal, but can recur or worsen when the drug is resumed [8, 11-14]. Spontaneous improvement with progressive resolution or stabilization of the rash also occurs with continued treatment [11]. To date no relationship between the eruption and treatment duration has established [15].

A dose-related adverse reaction is generally seen, with a higher incidence and a more severe rash at higher dose levels. Another important fact is the correlation reported in some studies between rash incidence/severity and clinical outcome (response and/or survival) [16-19].

Management by dermatologists of these side-effects is mandatory for optimal cancer treatment, allowing patients to cope with treatment. Effective rash management will also be essential if, in the future, these agents are used earlier in therapy or for longer periods of time. There is no standard treatment available [18, 19].

In our department, all grade 1 eruptions are treated with a topical antibiotic or an association between an antibiotic and benzoyl peroxide. Topical retinoids are avoided because of their higher potential for irritation. All other grades are treated systemically first with doxycycline or minocycline and, if they fail, low-dose isotretinoin. Isotretinoin usage was only necessary once and a complete response assessment was impossible due to the patient’s death. A slight improvement was observed. We decided to use it when the patient failed to respond to minocycline even with double doses (200 mg/day) and we decided on a low-dose regimen to avoid worsening of the commonly observed xerosis of these patients. Despite a different physiopathology, the rash shares the location and the presence of inflammatory lesions with acne and we believe that, in a low-dose regimen, it can be a weapon for refractory disease.

It is of particular importance that in our sample almost 50% of the patients had a complete response to treatment with tetracyclines. All patients with pruritus were medicated with an oral antihistamine. If the eruption failed to respond to this protocol of treatment, smear and biopsies were taken. Less commonly, changes in the nails, hair and mucosa are found [5]. Our series of patients presents similar results to those presented in the literature regarding the occurrence of side-effects, severity, time of appearance and therapeutic responses. One patient referred hypertricosis 18 days after starting erlotinib, which is uncommon, because hair alterations with this drug occur as a late side-effect.

None of the patients had to stop treatment and despite the absence of a standard protocol for treatment of these patients, oral antibiotics (doxycycline and minocycline) normally induce a rapid improvement (faster than in acne or rosacea).

The appearance of this new class of drugs with common cutaneous toxicity makes collaboration with dermatologists necessary to manage the skin alterations so patients can cope with the oncology treatment and hopefully prolong their life.

Acknowledgements

References

2 Kimyai-Asadi A, Jih MH. Follicular toxic effects of chimeric antiepidermal growth factor receptor antibody cetuximab used to treat human solid tumors. Arch Dermatol 2002; 138: 129-31.

3 Fernandez-Galar M, Espana A, Lopez-Picazo JM. Acneiform lesions secondary to ZD1839, an inhibitor of the epidermal growth factor receptor. Clin Exp Dermatol 2004; 29: 138-40.

4 Nanney LB, Magid M, Stoscheck CM, King Jr. LE. Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. J Invest Dermatol 1984; 83: 385-93.

5 Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006; 55: 657-70.

6 Pérez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR Inhibitor-Associated Rash: Future Directions for Management and Investigation Outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist 2005; 10: 345-56.

7 Waksal HW. Role of an anti-epidermal growth factor receptor in treating cancer. Cancer Metastasis Rev 1999; 18: 427-36.

8 Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 2001; 144: 1169-76.

9 Shah NT, Kris MG, Pao W, et al. Practical management of patients with non-small-cell lung cancer treated with gefitinib. J Clin Oncol 2005; 23: 165-74.

10 Varela P, Gonçalo M, Moura C, Barroso A. Reacções Cutâneas Adversas aos Inibidores do EGFR- Receptor do Factor de Crescimento Epidérmico. Trab Soc Port Dermatol Venereol 2007; 65 (4): 451-62.

11 Saltz LB, Meropol NJ, Loehrer PJ, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22: 1201-8.

12 Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with nonesmall-cell lung cancer. J Clin Oncol 2004; 22: 3238-47.

13 Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001; 19: 3267-79.

14 Van Doorn R, Kirtschig G, Scheffer E, Stoof TJ, Giaccone G. Follicular and epidermal alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor. Br J Dermatol 2002; 147: 598-601.

15 Herbst RS, Maddox AM, Rothenberg ML, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 2002; 20: 3815-25.

16 Herbst RS, LoRusso PM, Purdom M, Ward D. Dermatologic side effects associated with gefitinib therapy: clinical experience and management. Clin Lung Cancer 2003; 4: 366-9.

17 Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004; 22: 785-94.

18 Clark G, Perez-Soler R, Siu L, et al. Rash severity is predictive of increased survival with erlotinib HCI. Proc Am Soc Clin Oncol 2003; 22: 196.

19 Saltz L, Kies M, Abbruzzese JL, et al. The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 2003; 22: 204.