Management of cutaneous side effects of EGFR inhibitors: recommendations from a German expert panel for the primary treating physician

Inhibitors of the epidermal growth factor receptor (EGFR) are increasingly used in the treatment of various entities of malignant tumors. Patients treated with EGFR inhibitors very likely develop cutaneous side effects. The development of a papulopustular, follicular exanthema during the first weeks of therapy correlates with therapeutic benefit. However, this exanthema and other cutaneous side effects can impair the quality of life of the patient and might limit the therapy with the EGFR inhibitor. For an optimal therapeutic benefit and quality of life an adequate management of cutaneous side effects is necessary. A panel of German dermatologists developed on the basis of personal experience and current literature consensus recommendations for the management of cutaneous side effects of EGFR inhibitors.     

Hauttumoren bei organtransplantierten Patienten

Transplant recipients are at significantly increased risk of cancer development as a long term complication. Skin cancer is the most common cancer, representing 40-50% of post transplant malignancies. In the first 10 years post transplantation, some 15%-40% of patients develop skin cancer, primarily squamous cell carcinoma and basal cell carcinoma, but also melanoma, Merkel cell carcinoma and virally-induced Kaposi sarcoma. The management of skin cancer includes secondary prophylaxis and address attention to areas of widespread actinic damage, usually with topical agents. In high risk skin cancer or metastatic disease a substantial reduction in immunosuppression to switching to mTOR inhibitors appears to substantially improve the prognosis. The management of the individual tumor types is discussed; in general it follows the current guidelines.     

Direct effects on proliferation,antigen expression and melanin synthesis of cultured normal human melanocytes in response to UVB and UVA light

BACKGROUND/PURPOSE: Ultraviolet (UV) radiation; induces a variety of responses in the skin, including tanning and inflammation, and may also act as a carcinogen. As epidermal melanocytes are seen as the major targets of UV light, the present study was conducted to evaluate the direct effects of UVA and UVB irradiation on melanocytes in vitro. METHODS: Normal human epidermal melanocytes (NHM) were exposed on 3 consecutive days to UVA (0.072-7.2 J/cm2) and UVB (7.2-48 mJ/cm2), respectively, and changes of morphology, cell number, melanin synthesis and antigen expression (APAAP technique) were determined 5 days after the first exposure. RESULTS: UVA radiation caused only minimal effects on NHM by slightly inducing expression of the activation marker HMB-45 and decreasing expression of the proliferation marker Ki-67. No changes of morphology, cell number or melanin synthesis were detectable with any of the applied doses. On the other hand, UVB radiation significantly induced dendrite formation and decreased the number of NHM in a dose-dependent manner (74% of the controls at 7.2 mJ/cm2, 64% at 14.4 mJ/cm2 and 28% at 36 mJ/cm2). Significant induction of the activation marker HMB-45 was found in parallel to decreased expression of the differentiation marker K.1.2.58. UVB doses >or=9.6 mJ/cm2 also resulted in significant downregulation of the proliferation marker Ki-67, confirming the data of the cell counts, and melanin content was increased in NHM (20% over the controls, P<0.01) after applying 7.2 mJ/cm2 UVB. CONCLUSION: Our results may suggest that the effect of UVB radiation in skin is due to direct activation of melanocytes, whereas skin tanning caused by UVA is mediated rather in an indirect way.     

Fibroblast growth factor-2 but not Mel-CAM and/or beta3 integrin promotes progression of melanocytes to melanoma

A variety of melanoma-associated antigens have been identified that mediate adhesion, growth, proteolysis, and modulation of immune response. However, the mechanisms by which human normal melanocytes become malignant are not clearly understood. Among the most consistent observations is the up-regulation of fibroblast growth factor-2 (FGF-2) and of the adhesion molecules beta3 integrin and Mel-CAM during melanoma progression. To evaluate the potential role of FGF-2, beta3 integrin and Mel-CAM in melanoma development we overexpressed FGF-2, beta3 integrin and Mel-CAM in normal human melanocytes using replication-deficient adenoviruses as a gene delivery vehicle. Fibroblast growth factor-2 overexpressing melanocytes in monolayer culture displayed cytological atypia. Furthermore, in human skin reconstructs where the physiological milieu is recreated in vitro, FGF-2-overexpressing melanocytes exhibited marked proliferation, upwards migration, cluster formation and type IV collagen expression within the epidermal compartment, simulating early radial growth phase melanoma. In contrast, overexpression of beta3 integrin and/or Mel-CAM in melanocytes did not affect their biological behaviour in human skin reconstructs. The described results of the current and previous studies emphasise the key role of FGF-2 in melanoma development and progression, underscoring the promise of FGF-2 as a target for therapy.     

Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study.

BACKGROUND: Temozolomide has shown some efficacy in metastatic melanoma and recently received extended approval to treat brain tumours. The purpose of this study was to test a dose-intensified regimen of temozolomide in melanoma patients with brain metastases in a prospective, open-label, multicentre phase II trial. PATIENTS AND METHODS: Forty-five patients with asymptomatic brain metastases from melanoma were stratified into arm A (no prior chemotherapy; n = 21) and arm B (previous chemotherapy; n = 24). Patients received oral temozolomide either 150 mg/m(2)/day (arm A) or 125 mg/m(2)/day (arm B), days 1-7 and 15-21, every 28 days. The primary study end point was objective response, and secondary end points were overall survival and safety. RESULTS: Two patients (4.4%) achieved a partial response (PR) in brain metastases (one in each arm), one of them (2.2%) also showing a PR in extracerebral disease. An additional five patients (11.1%; two in arm A, three in arm B) showed disease stabilisation (SD) in brain and other sites. However, 82% revealed progressive disease (PD) already evident 8 weeks after therapy initiation. Median survival time from therapy onset was 3.5 months (range 0.7-8.3; arm B) and 4.3 months (range 1.6-11.8; arm A), P = 0.43. Dose modifications and prolongations of therapy cycles due to toxicity were required in 20% of patients. Grade 3/4 toxicity was observed in one patient only (2.2%). CONCLUSIONS: Oral administration of temozolomide given bi-weekly is well-tolerated in melanoma patients with cerebral involvement. However, the efficacy is limited, with lower than 5% objective responses observed in brain and extracerebral metastases.     

Large cell neuroendocrine carcinoma of the lung: an aggressive disease potentially treatable with surgery

BACKGROUND: Assessment of clinical and pathologic features of large cell neuroendocrine carcinoma to confirm its specificity in the setting of high grade neuroendocrine pulmonary tumors. METHODS: From 1989 to 2001, 123 patients with a neuroendocrine carcinoma were surgically treated in a curative intent at a single institution. According to the 1999 World Health Organization classification, 20 patients were reviewed as having a large cell neuroendocrine carcinoma. Clinical data as well as detailed pathologic analysis and survival were collected. RESULTS: There were 18 men and 2 women. The median age was 62 years. Four patients had a preoperative diagnosis of large cell neuroendocrine carcinoma. The resections consisted of 14 lobectomies and 6 pneumonectomies. There was no operative death. Complications occurred in 7 patients (35%). Four patients had a stage I of the disease, 4 had stage II, 9 had stage III, and 3 had stage IV. At follow-up (median, 46 months), 13 patients died from general recurrence and 7 patients were still alive. Median time to progression was 9 months (range, 1 to 54 months). The 5-year survival rate was 36% (median, 49 months) and it seemed to be negatively influenced by the disease stage (54% for stage I-II vs 25% for stage III-IV; p = 0.07), the presence of metastatic lymph node (45% for N0/N1 vs 17% for N2; p = 0.12), or vessel invasion (66 vs 25%; p = 0.18). CONCLUSIONS: Large cell neuroendocrine carcinoma predominantly occurred in men. An accurate tissue diagnosis was rarely obtained preoperatively. Although overall survival after resection was substantial, large cell neuroendocrine carcinoma frequently showed pathologic features of occult metastatic disease, such as lymph node or vessel invasion, or both.