Abstract
Background: There is current evidence that non-melanoma skin cancers can be successfully treated with cetuximab. Objective: To evaluate the use and efficacy of cetuximab (with or without radiotherapy) in a series of previously treated patients with metastatic squamous cell cancer of the skin (SCCS) in Switzerland. Methods: We performed a retrospective analysis of six patients from four centers. Endpoints were disease control rates (DCRs) at 4-8 weeks, 12-14 weeks and 20-36 weeks of treatment. Treatment-related toxicity was evaluated additionally. Results: A median of 14 cycles of cetuximab were applied. DCR was 67% at 4-8 weeks, 50% at 12-14 weeks and 33% at 20-36 weeks. In 4-8 weeks responders, mean relapse-free time was 12 ± 6.2 months and mean overall survival was 25 ± 16.2 months. Grade I-III acne-like rash developed around week 3 of treatment in 83%. Conclusions: Cetuximab treatment in patients with metastatic SCCS achieved an overall DCR of 67% at 4-8 weeks of treatment. This study underlines the current evidence that SCCS can be successfully treated with cetuximab. Introduction In Switzerland, squamous cell cancer of the skin (SCCS) and basal cell cancer are the most common cutaneous cancers with no less than 15,000 estimated new cases diagnosed per year [1]. The median age at diagnosis of SCCS is 70 years [2]. Most patients with primary SCCS have an excellent prognosis due to the possibility of local treatment leading to long-term disease control. High-risk groups for SCCS such as organ transplant recipients or chronic lymphatic leukemia patients are vitally threatened [3,4]. In patients with metastatic disease, long-term overall survival rates are <20% for patients with local lymph node metastases and <10% for patients with distant metastases (mainly involving the lungs, brain, liver, skin and bones) [2]. The treatment of advanced-stage SCCS is challenging as surgical excision becomes impossible. Few therapeutic options are available and the evidence supporting their use is based mainly on non-randomized trials [5,6]. Cisplatin-based chemotherapeutic regiments have short-term efficacies with an overall response rate of up to 80% in locally advanced SCCS [5,6]. However, the severe toxic side effects associated with these regimens limit their use in elderly patients, who make up the majority of cases of SCCS. Alternative treatment options are clearly needed. The epidermal growth factor receptor (EGFR) is a membrane-bound tyrosine kinase receptor that is highly expressed in normal epidermal keratinocytes, many epithelial tumors and in particular SCCS [7,8]. EGFR expression in SCCS shows no mutations or loss of expression as in other tumors [8]. EGFR is activated by ligand binding and receptor dimerization which subsequently activates multiple downstream pathways involved in cell proliferation and survival [7]. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for the treatment of squamous cell cancer of the head and neck and colorectal cancer. In a published phase II trial, single-agent cetuximab demonstrated promising clinical activity in treatment-naïve patients with unresectable, locally advanced SCCS, achieving an overall disease control rate (DCR) of 69% and a response rate of 28% [9]. Several retrospective single case reports and case series have described the effects of cetuximab in both treatment-naïve and multiply pretreated patients with metastatic SCCS [10,11,12,13,14,15]. A recently published summary of 54 cases of locally advanced and metastatic SCCS treated with cetuximab reported a 30% partial response and a 18.5% complete response in these patients [15]. Overall, pretreated patients seemed to benefit less than previously untreated patients. Since the clinical efficacy of cetuximab in colorectal tumors and squamous cell cancer of the head and neck has been correlated with early development of acne-like skin rash, the predictive role of skin rash in patients with SCCS treated with cetuximab deserves further study [9,15]. The main objective of this study was to review the use, efficacy and toxicity of cetuximab in a series of previously treated patients with metastatic SCCS in Switzerland in the context of the published literature. Methods Patient records from four participating centers in Switzerland were retrospectively reviewed to identify individuals who presented with disease progression after any previous therapy of metastatic SCCS and who were treated with cetuximab between 2010 and 2012. We collected baseline data from the patients' records using a standardized questionnaire as described below. The primary study endpoint was the DCR at 4-8 weeks, 12-14 weeks and 20-36 weeks of treatment. Moreover, relapse-free time under cetuximab treatment, i.e. the time between cetuximab treatment start and disease progression, as well as overall survival at the time of final data analysis was evaluated. We also examined treatment-related side effects and their correlation with disease control. As all data were collected as part of routine diagnosis and treatment, no ethical approval was required. Questionnaire To guide collection of baseline data from records by the physicians, a questionnaire including demographic data as well as personal and medical factors was used. Other characteristics recorded included the date of first disease presentation, pathological status, interventions, medications, control rates, dose and duration of cetuximab, adverse events that were judged to have been caused by cetuximab and overall health status (Eastern Cooperative Oncology Group [ECOG] performance status). Cetuximab-related adverse events were classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0). Tumor response (complete response, partial response) was assessed every 2-3 month until disease progression according to RECIST (version 1.1.) criteria in computed tomography or magnetic resonance imaging [16]. Statistics Statistical analysis was performed using the Excel software program (version 2010). Analyses were performed for the entire patient cohort and percentages and descriptive statistics were used to summarize the data. Results Baseline Characteristics Six patients with previously treated metastatic SCCS were identified who received cetuximab between 2010 and 2012. As listed in table 1, the median age of the patient population was 77 ± 21.8 years. There was a male predominance (67 vs. 33%). Overall, patients received a median of 14 ± 12 cycles of cetuximab (range 3-21). All six patients received a cetuximab loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2. After 2-4 weeks, treatment was changed to a two-weekly application of 500 mg/m2 in three of the six patients. The primary tumor was located in the area of the head in four (67%) patients and in the trunk and extremities on one (17%) patient each. All patients suffered from visceral metastases commonly involving the lungs, liver or brain. All patients had previously undergone surgical resection and had been previously treated either with chemotherapy (cisplatin, 5-fluorouracil) or radiotherapy. Two of the six (33%) patients received cetuximab treatment concomitant to radiotherapy. The ECOG performance status of patients at baseline was 0 in two (33%) patients and 1 in four (67%) patients.
Conen, Katrin L