Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer: ImmunoChemo and Radiotherapy with Erbitux) – a multicenter phase IV trial

Squamous cell carcinomas of the oropharynx, hypopharynx and larynx are the sixth leading cancer by incidence worldwide with more than 500000 new cases a year. At the time of diagnosis most patients display signs and symptoms of locally advanced disease and have lymph node metastases [1]. SCCHN is mostly caused by tobacco and alcohol consumption and/or infection with high-risk types of human papillomavirus (HPV) [2]. SCCHN often show an overexpression of epidermal growth factor receptors (EGFR) which is described to be associated with a poor prognosis [3‐6]. Standard treatment for resectable tumors is surgery including reconstruction plus post-operative radiotherapy and, for those patients found at surgery to have high risk features (extracapsular extension and/or R1 resection), post-operative chemoradiation with single agent platinum [7, 8]. At present, for non-resectable patients who can tolerate it, combined concomitant chemoradiation with platinum is the standard treatment [9, 10]. Organ-preservation protocols with combined chemoradiation therapy and surgery for salvage are increasingly being performed. These protocols are particularly effective for young patients with a good performance status presenting with moderately-advanced laryngeal or pharyngeal SCC. For patients who are not capable to receive standard platinum-based chemoradiation due to age, generally reduced condition and/or comorbidities, e.g. heart and renal disease or cirrhosis of the liver, the treatment of choice is radioimmunotherapy with cetuximab [7, 8, 11, 12]. Whereas results of a standard chemoradiation are based on thousands of patients, results of the combined radioimmunotherapy are only based on about 200 patients in the experimental arm of the pivotal trial [11, 12]. A study comparing the standard platinum-based chemoradiation with the novel radioimmunotherapy protocol with the anti-EGFR antibody cetuximab, however, is still missing. Hence, guidelines still recommend standard radiochemotherapy with cisplatin for patients able to receive chemotherapy [9, 10].

Cetuximab is a chimeric monoclonal IgG1 antibody specifically targeting the epidermal growth factor receptor (EGFR). EGFR signal cascades are involved in cell proliferation, in cell cycle regulation, in angiogenesis, cell migration and invasion and in metastases. Cetuximab binds to the EGFR in a 5 to 10 times higher affinity than endogen ligands leading to a downregulation of EGFR molecules on the cell surface. Intracellular phosphorylation of the EGFR is inhibited and consequently the down stream signalling is deficient resulting in cell cycle arrest, increased expression of pro-apoptotic enzymes and decrease in the production of matrix metalloproteinases. Effects of EGFR inhibition that have been described are a reduction of cell proliferation, an inhibition of cell division processes and tumor growth and an increase of apoptosis [13, 14]. Furthermore, cetuximab treatment leads to a decrease in the production of vascular endothelial growth factor (VEGF) blocking angiogenic processes in the tumor. Cetuximab has been found to potentiate the effects of radiotherapy in experimental systems [13‐15].

Combined radioimmunotherapy with cetuximab is a well accepted treatment option in patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) if they are not able to receive surgery or combined radiochemotherapy due to stage, reduced general condition and/or comorbidities. In the pivotal, international, randomized Phase III trial of 424 patients with locally or regionally advanced squamous cell carcinoma of the oropharynx, hypopharynx or larynx with no prior therapy, the addition of cetuximab to radiation when compared to radiation alone resulted in a higher response rate, a 9.5- month improvement in median duration of locoregional control [24.4 months versus 14.9 months], a longer disease-free survival and a 9% increase of the 5 year overall survival (OS). [11]. In retrospective comparison with chemoradiation trials, immunoradiation with cetuximab showed similar control rates in terms of overall survival (OS) and local control rate (LCR) [16]. Since the radioimmunotherapy with cetuximab is a feasible treatment option that overall shows a low incidence of systemic side effects and a favourable toxicity profile, it is especially indicated for older patients and patients with comorbidities. Recently updated EHNS-ESTRO-ESMO guidelines recommend radioimmunotherapy with cetuximab with a level of evidence of II and a recommendation grade B [8].

Skin reactions are known to be the most frequent side effect of EGFR inhibitor therapy. About 90% of patients treated with cetuximab develop an acneiform rash, but only 15% of patients develop a grade 3 or 4 skin rash [17‐20]. Besides, patients on cetuximab treatment might develop other skin reactions like a xerosis cutis followed by a severe pruritus, hair and nail alterations, a stomatitis and eye abnormalities. All of those skin reactions can result in non-compliance as well as in an interruption or even discontinuation of an effective antitumor treatment approach. Besides, patients often feel anxious related to the cosmetic appearance of the rash and have the feeling to be stigmatized which can lead to psychosocial side effects and can negatively affect patient quality of life [21].

The most frequently seen side effect of radiotherapy in patients with head and neck cancer is radiation dermatitis that occurs in approximately 90% of patients. If cetuximab is administered simultaneously, an overlap of radiation and cetuximab induced skin reactions is seen in the radiation field which may lead to very severe skin toxicity [22, 23]. An retrospective evaluation of acute toxicity of skin and mucosa in patients with head and neck cancer receiving radiotherapy (RT) alone or in combination with radiotherapy plus chemotherapy (RCT) or with cetuximab (RIT) published by Garcia-Huttenlocher et al. showed grade 3 overall skin toxicity in 27.6% of the RIT patients compared to 0% in patients only receiving RT and compared to 7% in patients receiving RCT [22]. Cetuximab associated acneiform rash grade 3 was observed in 7% of the RIT patients. In this publication cetuximab did not lead to a higher rate of RT interruptions compared to RT and RCT. Eight weeks after RT all patients had recovered from these dermatological side effects [22]. Bonner et al. reported on 21% of patients with grade 3/4 radiation dermatitis in the RT group. In the radioimmunotherapy group, however, a significant increase to 35% of grade 3/4 radiation dermatitis was observed. Since there is a discussion about a possible correlation between the intensity of acneiform rash and the efficacy of therapy [11], Bonner et al. conducted a subgroup analysis showing an overall survival benefit in patients developing an acneiform rash grade 2–4 compared to patients with acneiform rash grade 0–1. Such patients survived for a median of 69 months, whereas patients who had no reaction or only a mild rash had a median survival of 26 months [11]. Thus, it might be possible that the acneiform rash is a predictive biomarker for immunological response and, furthermore, that it is conductive for optimal outcome. A similar pattern has already been shown for other types of cancer [24‐26]. Vermorken and colleagues,^, however, conducted a thorough analysis of cetuximab-induced skin reactions and acne-like rash with clinical markers of activity. Although development of skin reactions and acne-like rash appeared to trend toward improved response and disease control, early development of these toxicities was not associated with improved response or overall survival [27].

Budach et al. reported on two patients who had severe radiation dermatitis while receiving radioimmunotherapy with cetuximab [23]. Severe radiation dermatitis may occur after irradiation alone, but grade 4 lesions are rarely observed. Coexisting conditions like previously received chemotherapy or radiotherapy or even intensive sun exposure in the past may predispose for aggravation of radiation and cetuximab induced skin reaktions. Liver or renal dysfunction with possible alterations of pharmacodynamics of cetuximab may also predispose patients to develop more severe radiation dermatitis [28]. In a retrospective survey in EORTC institutes, the members observed that in 49% of patients treated with cetuximab and concurrent radiotherapy developed grade 3 or 4 radiation dermatitis [29]. Hence, the incidence of these severe skin reactions was twice as high compared to that reported by Bonner et al. [11, 12]. The real percentages of grade 3 and 4 radiation dermatitis during combined radioimmunotherapy with cetuximab, however, have never been evaluated. Furthermore, the differentiation between radiation dermatitis and cetuximab induced acneiform rash seems to be important for therapeutic and prognostic reasons but has never been explored in detail so far. Thus, a prospective, multicenter large-scaled study is warranted to distinguish radiation dermatitis from cetuximab induced skin reactions, to determine the real incidence of the different types of skin reactions in a large cohort of patients, and, besides, to identify and evaluate biomarkers and surrogates correlating with clinical efficacy and outcome.

The HICARE trial is a prospective, open phase IV trial exploring the prominent side effects of skin toxicities of combined radioimmun(chemo)therapy with the EGFR inhibitor cetuximab (Erbitux®) in patients with LASCCHN in great detail. The HICARE study is a national multicenter trial in Germany, 40 centers will participate.

For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients [11, 12]. However, there are no data available about a formal comparison between the combination of radiotherapy with cisplatin or cetuximab. The current guidelines still recommend using standard radiochemotherapy in patients with LASCCHN fit enough to undergo chemotherapy because there is no randomized, prospective trial comparing radiochemotherapy versus immunoradiotherapy in this patient group [8, 37]. Chemoradiation is known to be associated with significant toxicities and, furthermore, its efficacy is questioned in the elderly population. The magnitude in effect of the radioimmunotherapy with cetuximab, however, is similar or even better than that achieved by chemoradiation and it proved to be less toxic [8, 11]. The control rates were the same in retrospective comparison with radiochemotherapy trials [16].

For better patient selection, i.e. for definition of a patient cohort that benefits more from the less intense and less toxic radioimmunotherapy regimen and a patient cohort that benefits more from the more intense chemoradiation-based approach, patient characteristics including clinical and molecular prognostic markers and predictive surrogates have to be defined. Several clinical characteristics of patients with HNSCC have been linked to favourable prognosis, including non-smoker, minimum exposure to alcohol, good performance status, and absence of co-morbid disorders [38]. Several studies have shown a correlation between genetic aberrations, i.e. a p53 mutation, and lower response rates to chemotherapy and shorter overall survival times [39‐42]. The HPV-status is associated with outcome, too [2]. To date in LASCCHN specific genetic alterations, however, are not known [43]. Testing for genetic and proteomic alterations in a large patient cohort may define prognostic and predictive biomarkers that help to identify patients who are at great risk for progression or treatment resistance and patients who might benefit most from radioimmunotherapy.

Skin reactions, the most common side effect of radiotherapy and also of anti-EGFR-treatment strategies like cetuximab, have not been evaluated and characterized in detail. Interestingly, almost all studies addressing EGFR-inhibitor-induced skin rash done in patients with metastatic colorectal cancer suggest that its severity is a suitable surrogate marker for efficacy of anti-EGFR therapy [44‐47]. In patients with LASCCHN, the pivotal trial by Bonner et al. also showed that cetuximab-treated patients with prominent cetuximab-induced acneiform rash grade 2 or above had a better overall survival than patients with no or grade 1 rash [11]. A retrospective exploration of several trials done with panitumumab, another anti-EGFR monoclonal antibody, confirmed an association between clinically graded skin toxicity and patient-reported outcome, quality of life, longer progression-free survival and overall survival [26]. Other trials in patients with metastatic colorectal cancer and other solid tumors did not show any correlation between skin rash and efficacy of anti-EGFR therapy [48].

Thus, a clinical trial is warranted in patients with LASCCHN to evaluate the efficacy and toxicity of the radioimmunotherapy with cetuximab in a large patient cohort and to focus on biomarker research to better select patients who might benefit better from this treatment approach than others.

The HICARE study will be one of the largest clinical trials ever being performed in patients with LASCCHN. It will help to better understand the different clinical characteristics of skin reactions induced by radiotherapy and by cetuximab treatment, to identify molecular predictors and surrogates for treatment response and resistance and to better define a patient population where a less toxic regimen like the radioimmunotherapy with cetuximab would constitute the primary treatment option and other patient populations where a more intense chemoradiation-based approach is needed.